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https://www.readbyqxmd.com/read/28539871/protein-quality-control-and-the-amyotrophic-lateral-sclerosis-frontotemporal-dementia-continuum
#1
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
#2
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
#3
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...
May 19, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28480639/pyrimethamine-significantly-lowers-csf-sod1-in-als-patients-with-sod1-mutations
#4
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
BACKGROUND: 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 leucocytes 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 ALS (fALS/SOD1). METHODS AND STUDY DESIGN: Multicenter (5 sites), open-label, 9-month duration, dose-ranging, to determine safety and efficacy of pyrimethamine to lower SOD1 levels in the CSF of 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
#5
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
#6
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
#7
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
#8
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...
May 8, 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
#9
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
#10
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
#11
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
#12
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
https://www.readbyqxmd.com/read/28382000/als-clinical-trials-review-20-years-of-failure-are-we-any-closer-to-registering-a-new-treatment
#13
REVIEW
Dmitry Petrov, Colin Mansfield, Alain Moussy, Olivier Hermine
Amyotrophic lateral sclerosis (ALS) is a devastating condition with an estimated mortality of 30,000 patients a year worldwide. The median reported survival time since onset ranges from 24 to 48 months. Riluzole is the only currently approved mildly efficacious treatment. Riluzole received marketing authorization in 1995 in the USA and in 1996 in Europe. In the years that followed, over 60 molecules have been investigated as a possible treatment for ALS. Despite significant research efforts, the overwhelming majority of human clinical trials (CTs) have failed to demonstrate clinical efficacy...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28374969/randomized-cross-over-trial-of-ventilator-modes-during-non-invasive-ventilation-titration-in-amyotrophic-lateral-sclerosis
#14
Bart Vrijsen, Bertien Buyse, Catharina Belge, Goele Vanpee, Philip Van Damme, Dries Testelmans
BACKGROUND AND OBJECTIVE: Non-invasive ventilation (NIV) improves survival, quality of life and sleep in patients with amyotrophic lateral sclerosis (ALS). Nevertheless, NIV titration is conducted in different ways. We aim to provide more insight into NIV titration by comparing the effects of a spontaneous (S) and spontaneous-timed (ST) modes on gas exchange, sleep architecture and patient-ventilator asynchronies (PVAs). METHODS: After an initial night of NIV titration, patients were randomized to S or ST mode in a cross-over design...
April 4, 2017: Respirology: Official Journal of the Asian Pacific Society of Respirology
https://www.readbyqxmd.com/read/28367604/ultra-high-field-proton-mr-spectroscopy-in-early-stage-amyotrophic-lateral-sclerosis
#15
Ian Cheong, Małgorzata Marjańska, Dinesh K Deelchand, Lynn E Eberly, David Walk, Gülin Öz
A major hurdle in the development of effective treatments for amyotrophic lateral sclerosis (ALS) has been the lack of robust biomarkers for use as clinical trial endpoints. Neurochemical profiles obtained in vivo by high field proton magnetic resonance spectroscopy ((1)H-MRS) can potentially provide biomarkers of cerebral pathology in ALS. However, previous (1)H-MRS studies in ALS have produced conflicting findings regarding alterations in the levels of neurochemical markers such as glutamate (Glu) and myo-inositol (mIns)...
April 3, 2017: Neurochemical Research
https://www.readbyqxmd.com/read/28356511/poly-gp-proteins-are-a-useful-pharmacodynamic-marker-for-c9orf72-associated-amyotrophic-lateral-sclerosis
#16
Tania F Gendron, Jeannie Chew, Jeannette N Stankowski, Lindsey R Hayes, Yong-Jie Zhang, Mercedes Prudencio, Yari Carlomagno, Lillian M Daughrity, Karen Jansen-West, Emilie A Perkerson, Aliesha O'Raw, Casey Cook, Luc Pregent, Veronique Belzil, Marka van Blitterswijk, Lilia J Tabassian, Chris W Lee, Mei Yue, Jimei Tong, Yuping Song, Monica Castanedes-Casey, Linda Rousseau, Virginia Phillips, Dennis W Dickson, Rosa Rademakers, John D Fryer, Beth K Rush, Otto Pedraza, Ana M Caputo, Pamela Desaro, Carla Palmucci, Amelia Robertson, Michael G Heckman, Nancy N Diehl, Edythe Wiggs, Michael Tierney, Laura Braun, Jennifer Farren, David Lacomis, Shafeeq Ladha, Christina N Fournier, Leo F McCluskey, Lauren B Elman, Jon B Toledo, Jennifer D McBride, Cinzia Tiloca, Claudia Morelli, Barbara Poletti, Federica Solca, Alessandro Prelle, Joanne Wuu, Jennifer Jockel-Balsarotti, Frank Rigo, Christine Ambrose, Abhishek Datta, Weixing Yang, Denitza Raitcheva, Giovanna Antognetti, Alexander McCampbell, John C Van Swieten, Bruce L Miller, Adam L Boxer, Robert H Brown, Robert Bowser, Timothy M Miller, John Q Trojanowski, Murray Grossman, James D Berry, William T Hu, Antonia Ratti, Bryan J Traynor, Matthew D Disney, Michael Benatar, Vincenzo Silani, Jonathan D Glass, Mary Kay Floeter, Jeffrey D Rothstein, Kevin B Boylan, Leonard Petrucelli
There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated...
March 29, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28331770/traditional-food-items-in-ogimi-okinawa-l-serine-content-and-the-potential-for-neuroprotection
#17
REVIEW
Paul Alan Cox, James S Metcalf
PURPOSE OF REVIEW: Ogimi village is renowned for its aging population. We sought to determine if the l-serine content of their diet could account for their neurological health. RECENT FINDINGS: The most frequently consumed food items, including tofu and seaweeds, are rich in the dietary amino acid l-serine. l-serine content of the Ogimi diet >8 grams/day for Ogimi women significantly exceeds the average American dietary intake of 2.5 grams/day for women >70 years old...
2017: Current Nutrition Reports
https://www.readbyqxmd.com/read/28302022/glial-cell-a-potential-target-for-cellular-and-drug-based-therapy-in-various-cns-diseases
#18
Shakeeb Ahmed, Azka Gull, Tahir Khuroo, Mohd Aqil, Yasmin Sultana
Glial cells are integrated part of neurovascular unit of blood brain barrier (BBB). They undergo mitosis and mainly classified as astrocytes, oligodendrocytes, microglia, ependymal cells and nerve glial antigen 2 cells. Being a most versatile glial cell, astrocytes provide structural support to neurons, maintain brain homeostasis, take part in neuronal communication, and perform some housekeeping functions. Oligodendrocytes myelinate the neuronal axons for proper transmission of nerve impulse and microglia are brain immune cells...
March 16, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28293476/evaluating-the-levels-of-csf-and-serum-factors-in-als
#19
Jie Guo, Xuan Yang, Lina Gao, Dawei Zang
OBJECTIVES: The aim of this study was to identify CSF and serum factors as biomarkers that may aid in distinguishing ALS patients from control subjects and predicting ALS progression as well as prognosis. METHODS: Serum and CSF samples from 105 patients with ALS and 56 control subjects were analyzed for 13 factors using ELISA. The revised ALS functional rating scale (ALSFRS-r) was used to evaluate the overall functional status of ALS patients, and we also followed up with ALS patients either by phone or with clinic visits for five years after enrollment in this study...
March 2017: Brain and Behavior
https://www.readbyqxmd.com/read/28277881/drugs-in-clinical-development-for-the-treatment-of-amyotrophic-lateral-sclerosis
#20
REVIEW
Ana Martinez, Maria Del Valle Palomo Ruiz, Daniel I Perez, Carmen Gil
Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron progressive disorder for which no treatment exists to date. However, there are other investigational drugs and therapies currently under clinical development may offer hope in the near future. Areas covered: We have reviewed all the ALS ongoing clinical trials (until November 2016) and collected in Clinicaltrials.gov or EudraCT. We have described them in a comprehensive way and have grouped them in the following sections: biomarkers, biological therapies, cell therapy, drug repurposing and new drugs...
April 2017: Expert Opinion on Investigational Drugs
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