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https://www.readbyqxmd.com/read/28628244/phosphorylated-neurofilament-heavy-chain-a-biomarker-of-survival-for-c9orf72-associated-amyotrophic-lateral-sclerosis
#1
Tania F Gendron, Lillian M Daughrity, Michael G Heckman, Nancy N Diehl, Joanne Wuu, Timothy M Miller, Pau Pastor, John Q Trojanowski, Murray Grossman, James D Berry, William T Hu, Antonia Ratti, Michael Benatar, Vincenzo Silani, Jonathan D Glass, Mary Kay Floeter, Andreas Jeromin, Kevin B Boylan, Leonard Petrucelli
As potential treatments for C9ORF72-associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions...
June 19, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28619000/astrocytes-pathology-in-als-a-potential-therapeutic-target
#2
Sonja Johann
The mechanisms underlying neurodegeneration in amyotrophic lateral sclerosis (ALS) are multifactorial and include genetic and environmental factors. Nowadays, it is well accepted that neuronal loss is driven by non-cell autonomous toxicity. Non-neuronal cells, such as astrocytes, have been described to significantly contribute to motoneuron cell death and disease progression in cell culture experiments and animal models of ALS. Astrocytes are essential for neuronal survival and function by regulating neurotransmitter and ion homeostasis, immune response, blood flow and glucose uptake, antioxidant defence and growth factor release...
June 15, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28608303/assessment-of-the-factorial-validity-and-reliability-of-the-alsfrs-r-a-revision-of-its-measurement-model
#3
Leonhard A Bakker, Carin D Schröder, Michael A van Es, Paul Westers, Johanna M A Visser-Meily, Leonard H van den Berg
The amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) is a widely used primary outcome measure in amyotrophic lateral sclerosis (ALS) clinical practice and clinical trials. ALSFRS-R items cannot, however, validly be summed to obtain a total score, but constitute domain scores reflecting a profile of disease severity. Currently, there are different measurement models for estimating domain scores. The objective of the present study is, therefore, to derive the measurement model that best fits the data for a valid and uniform estimation of ALSFRS-R domain scores...
June 12, 2017: Journal of Neurology
https://www.readbyqxmd.com/read/28600459/patients-with-als-show-highly-correlated-progression-rates-in-left-and-right-limb-muscles
#4
David J Rushton, Patricia L Andres, Peggy Allred, Robert H Baloh, Clive N Svendsen
OBJECTIVE: Amyotrophic lateral sclerosis (ALS) progresses at different rates between patients, making clinical trial design difficult and dependent on large cohorts of patients. Currently, there are few data showing whether the left and right limbs progress at the same or different rates. This study addresses rates of decline in specific muscle groups of patients with ALS and assesses whether there is a relationship between left and right muscles in the same patient, regardless of overall progression...
June 9, 2017: Neurology
https://www.readbyqxmd.com/read/28599400/the-use-of-mesenchymal-stem-cells-mscs-for-amyotrophic-lateral-sclerosis-als-therapy-a-perspective-on-cell-biological-mechanisms
#5
Bor Luen Tang
Recent clinical trials of mesenchymal stem cells (MSCs) transplantation have demonstrated procedural safety and clinical proof of principle with a modest indication of benefit in patients with amyotrophic lateral sclerosis (ALS). While replacement therapy remained unrealistic, the clinical efficacy of this therapeutic option could be potentially enhanced if we could better decipher the mechanisms underlying some of the beneficial effects of transplanted cells, and work toward augmenting or combining these in a strategic manner...
May 25, 2017: Reviews in the Neurosciences
https://www.readbyqxmd.com/read/28569393/multidimensional-latent-trait-linear-mixed-model-an-application-in-clinical-studies-with-multivariate-longitudinal-outcomes
#6
Jue Wang, Sheng Luo
Multilevel item response theory (MLIRT) models have been widely used to analyze the multivariate longitudinal data of mixed types (e.g., categorical and continuous) in clinical studies. The MLIRT models often have unidimensional assumption, that is, the multiple outcomes are clinical manifestations of a univariate latent variable. However, the unidimensional assumption may be unrealistic because some diseases may be heterogeneous and characterized by multiple impaired domains with variable clinical symptoms and disease progressions...
June 1, 2017: Statistics in Medicine
https://www.readbyqxmd.com/read/28561886/improving-symptom-management-for-people-with-amyotrophic-lateral-sclerosis
#7
Katharine Nicholson, Alyssa Murphy, Erin McDonnell, Jordan Shapiro, Ericka Simpson, Jonathan Glass, Hiroshi Mitsumoto, Dallas Forshew, Robert Miller, Nazem Atassi
INTRODUCTION: Symptomatic management is the main focus of ALS clinical care. We aim to report the prevalence of ALS-related symptoms and characterize self-reported symptomatic management. METHODS: A symptom management survey developed by the MDA Clinical Research Network was completed by ALS registrants. Logistic regression identified potential predictors of symptom prevalence, severity, and treatment. RESULTS: 567 ALS participants reported fatigue (90%), muscle stiffness (84%), and muscle cramps (74%) as most prevalent symptoms...
May 31, 2017: Muscle & Nerve
https://www.readbyqxmd.com/read/28552237/ex-vivo-gene-therapy-for-the-treatment-of-neurological-disorders
#8
Genevieve Gowing, Soshana Svendsen, Clive N Svendsen
Ex vivo gene therapy involves the genetic modification of cells outside of the body to produce therapeutic factors and their subsequent transplantation back into patients. Various cell types can be genetically engineered. However, with the explosion in stem cell technologies, neural stem/progenitor cells and mesenchymal stem cells are most often used. The synergy between the effect of the new cell and the additional engineered properties can often provide significant benefits to neurodegenerative changes in the brain...
2017: Progress in Brain Research
https://www.readbyqxmd.com/read/28539871/protein-quality-control-and-the-amyotrophic-lateral-sclerosis-frontotemporal-dementia-continuum
#9
Hamideh Shahheydari, Audrey Ragagnin, Adam K Walker, Reka P Toth, Marta Vidal, Cyril J Jagaraj, Emma R Perri, Anna Konopka, Jessica M Sultana, Julie D Atkin
Protein homeostasis, or proteostasis, has an important regulatory role in cellular function. Protein quality control mechanisms, including protein folding and protein degradation processes, have a crucial function in post-mitotic neurons. Cellular protein quality control relies on multiple strategies, including molecular chaperones, autophagy, the ubiquitin proteasome system, endoplasmic reticulum (ER)-associated degradation (ERAD) and the formation of stress granules (SGs), to regulate proteostasis. Neurodegenerative diseases are characterized by the presence of misfolded protein aggregates, implying that protein quality control mechanisms are dysfunctional in these conditions...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28527102/studies-of-environmental-risk-factors-in-amyotrophic-lateral-sclerosis-als-and-a-phase-i-clinical-trial-of-l-serine
#10
Walter G Bradley, R X Miller, T D Levine, E W Stommel, P A Cox
β-N-Methylamino-L-alanine (BMAA) has been linked to Guam ALS/PDC and shown to produce neurodegeneration in vitro and in vivo (Drosophila, mice, rats, primates). BMAA misincorporation into neuroproteins produces protein misfolding and is inhibited by L-serine. Case-control studies in Northern New England indicate that living near to water-bodies with cyanobacterial blooms increases the risk of developing amyotrophic lateral sclerosis (ALS). The distribution of addresses of ALS cases in New Hampshire, Vermont, and Florida was compared to that of controls...
May 19, 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/28527045/amyotrophic-lateral-sclerosis-like-superoxide-dismutase-1-proteinopathy-is-associated-with-neuronal-loss-in-parkinson-s-disease-brain
#11
Benjamin G Trist, Katherine M Davies, Veronica Cottam, Sian Genoud, Richard Ortega, Stéphane Roudeau, Asuncion Carmona, Kasun De Silva, Valerie Wasinger, Simon J G Lewis, Perminder Sachdev, Bradley Smith, Claire Troakes, Caroline Vance, Christopher Shaw, Safa Al-Sarraj, Helen J Ball, Glenda M Halliday, Dominic J Hare, Kay L Double
Neuronal loss in numerous neurodegenerative disorders has been linked to protein aggregation and oxidative stress. Emerging data regarding overlapping proteinopathy in traditionally distinct neurodegenerative diseases suggest that disease-modifying treatments targeting these pathological features may exhibit efficacy across multiple disorders. Here, we describe proteinopathy distinct from classic synucleinopathy, predominantly comprised of the anti-oxidant enzyme superoxide dismutase-1 (SOD1), in the Parkinson's disease brain...
July 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28480639/pyrimethamine-significantly-lowers-cerebrospinal-fluid-cu-zn-superoxide-dismutase-in-amyotrophic-lateral-sclerosis-patients-with-sod1-mutations
#12
Dale J Lange, Mona Shahbazi, Vincenzo Silani, Albert C Ludolph, Jochen H Weishaupt, Senda Ajroud-Driss, Kara G Fields, Rahul Remanan, Stanley H Appel, Claudia Morelli, Alberto Doretti, Luca Maderna, Stefano Messina, Ulrike Weiland, Stefan L Marklund, Peter M Andersen
OBJECTIVE: Cu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1-transgenic animal models. Pyrimethamine produces dose-dependent SOD1 reduction in cell culture systems. A previous phase 1 trial showed pyrimethamine lowers SOD1 levels in leukocytes in patients with SOD1 mutations. This study investigated whether pyrimethamine lowered SOD1 levels in the cerebrospinal fluid (CSF) in patients carrying SOD1 mutations linked to familial amyotrophic lateral sclerosis (fALS/SOD1)...
May 8, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28465220/the-six-minute-walk-6mwt-as-a-measure-walking-capacity-wc-in-ambulatory-individual-with-amyotrophic-lateral-sclerosis-ambals
#13
Mohammed Sanjak, Velma Langford, Scott Holsten, Nigel Rozario, Charity G Moore Patterson, Elena Bravver, William L Bockenek, Benjamin R Brooks
OBJECTIVE: To determine the validity of the 6MWT as an outcome measure to evaluate WC in ambALS. DESIGN: Observational study. Participants performed 6MWT, 25FWT, TUG, lower extremity maximum voluntary isometric contraction (MVIC), ALSFRS-R, and forced vital capacity (FVC). SETTING: Multidisciplinary ALS clinic at an academic medical center. PARTICIPANTS: AmbALS (N=186) who ambulate without (stage I) or with (stage II) assistive device...
April 29, 2017: Archives of Physical Medicine and Rehabilitation
https://www.readbyqxmd.com/read/28456383/adult-onset-spinal-muscular-atrophy-an-update
#14
REVIEW
R Juntas Morales, N Pageot, G Taieb, W Camu
Spinal muscular atrophy (SMA) refers to a group of disorders affecting lower motor neurons. The age of onset of these disorders is variable, ranging from the neonatal period to adulthood. Over the last few years, there has been enormous progress in the description of new genes and phenotypes that throw new light on the molecular pathways involved in motor neuron degeneration. Advances in our understanding of the pathophysiology of the most frequent forms, SMA linked to SMN1 gene mutations and Kennedy disease, has led to the development of therapeutic strategies currently being tested in clinical trials...
April 26, 2017: Revue Neurologique
https://www.readbyqxmd.com/read/28455693/therapeutic-strategies-under-development-targeting-inflammatory-mechanisms-in-amyotrophic-lateral-sclerosis
#15
REVIEW
Sebastiano Giuseppe Crisafulli, Simona Brajkovic, Maria Sara Cipolat Mis, Valeria Parente, Stefania Corti
Amyotrophic lateral sclerosis (ALS) is a neurological disease characterized by the progressive loss of cortical, bulbar, and spinal motor neurons (MNs). The cardinal manifestation of ALS is a progressive paralysis which leads to death within a time span of 3 to 5 years after disease onset. Despite similar final output of neuronal death, the underlying pathogenic causes are various and no common cause of neuronal damage has been identified to date. Inflammation-mediated neuronal injury is increasingly recognized as a major factor that promotes disease progression and amplifies the MN death-inducing processes...
April 28, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28443372/cord-blood-as-a-potential-therapeutic-for-amyotrophic-lateral-sclerosis
#16
Svitlana Garbuzova-Davis, Jared Ehrhart, Paul R Sanberg
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord. Treatment options are limited due to the complexity of underlying disease factors. Cell therapy, using human umbilical cord blood (hUCB) cells may be a promising new treatment for ALS, mainly by providing a protective microenvironment for motor neuron survival. Areas covered: Composition, in vitro and in vivo differentiation of hUCB cells, and the advantages of cord blood as a source of transplant cells are discussed...
July 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/28443187/treatment-with-penicillin-g-and-hydrocortisone-reduces-als-associated-symptoms-a-case-series-of-three-patients
#17
Bert Tuk, Harmen Jousma, Pieter J Gaillard
Three male Caucasian patients with ALS were admitted to the hospital due to progressive dysphagia and dysarthria. During two 21-day courses of penicillin G and hydrocortisone, these patients' dysphagia and dysarthria resolved. The patient's other ALS-associated symptoms also improved, including respiratory function, coordination, walking, and muscle strength. This is the first report of a treatment with a protocol for treating dysphagia, dysarthria, respiratory depression and other ALS-related symptoms. Furthermore, the observations are consistent with the recent hypothesis that the successful treatment of ALS symptoms with this treatment course in six patients with syphilitic ALS was not directly due to the treatment of syphilis; but that the administered penicillin G and/or hydrocortisone treated these patients' ALS symptoms due the off-target pharmacological activity of penicillin G and/or hydrocortisone...
2017: F1000Research
https://www.readbyqxmd.com/read/28412941/survival-prediction-in-amyotrophic-lateral-sclerosis-based-on-mri-measures-and-clinical-characteristics
#18
Christina Schuster, Orla Hardiman, Peter Bede
BACKGROUND: Amyotrophic lateral sclerosis (ALS) a highly heterogeneous neurodegenerative condition. Accurate diagnostic, monitoring and prognostic biomarkers are urgently needed both for individualised patient care and clinical trials. A multimodal magnetic resonance imaging study is presented, where MRI measures of ALS-associated brain regions are utilised to predict 18-month survival. METHODS: A total of 60 ALS patients and 69 healthy controls were included in this study...
April 17, 2017: BMC Neurology
https://www.readbyqxmd.com/read/28406915/predicting-functional-decline-and-survival-in-amyotrophic-lateral-sclerosis
#19
Mei-Lyn Ong, Pei Fang Tan, Joanna D Holbrook
BACKGROUND: Better predictors of amyotrophic lateral sclerosis disease course could enable smaller and more targeted clinical trials. Partially to address this aim, the Prize for Life foundation collected de-identified records from amyotrophic lateral sclerosis sufferers who participated in clinical trials of investigational drugs and made them available to researchers in the PRO-ACT database. METHODS: In this study, time series data from PRO-ACT subjects were fitted to exponential models...
2017: PloS One
https://www.readbyqxmd.com/read/28406335/clinical-efficacy-of-edaravone-for-the-treatment-of-amyotrophic-lateral-sclerosis
#20
Hideyuki Sawada
Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disease. Although the pathogenesis remains unresolved, oxidative stress is known to play a pivotal role. Edaravone works in the central nervous system as a potent scavenger of oxygen radicals. In ALS mouse models, edaravone suppresses motor functional decline and nitration of tyrosine residues in the cerebrospinal fluid. Areas covered: Three clinical trials, one phase II open-label trial, and two phase III placebo-control randomized trials were reviewed...
May 2017: Expert Opinion on Pharmacotherapy
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