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      Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis

      research-article
      1 , 2 , 3 , 4 , 5 , 1 , 1 , 1 , 1 , 6 , 7 , 8 , 9 , 10 , 9 , 9 , 9 , 9 , 11 , 12 , 9 , 13 , 14 , 15 , 14 , 14 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , ITALSGEN, 24 , 25 , 24 , 10 , 7 , 4 , 26 , 27 , 3 , 21 , 1 , 22
      Nature neuroscience

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          Abstract

          MATR3 is an RNA/DNA binding protein that interacts with TDP-43, a major disease protein linked to amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia. Using exome sequencing, we identified mutations in MATR3 in ALS kindreds. We also observed MATR3 pathology in the spinal cords of ALS cases with and without MATR3 mutations. Our data provide additional evidence supporting the role of aberrant RNA processing in motor neuron degeneration.

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          Long Term Outcomes Following Hospital Admission for Sepsis Using Relative Survival Analysis: A Prospective Cohort Study of 1,092 Patients with 5 Year Follow Up

          Background Sepsis is a leading cause of death in intensive care units and is increasing in incidence. Current trials of novel therapeutic approaches for sepsis focus on 28-day mortality as the primary outcome measure, but excess mortality may extend well beyond this time period. Methods We used relative survival analysis to examine excess mortality in a cohort of 1,028 patients admitted to a tertiary referral hospital with sepsis during 2007–2008, over the first 5 years of follow up. Expected survival was estimated using the Ederer II method, using Australian life tables as the reference population. Cumulative and interval specific relative survival were estimated by age group, sex, sepsis severity and Indigenous status. Results Patients were followed for a median of 4.5 years (range 0–5.2). Of the 1028 patients, the mean age was 46.9 years, 52% were male, 228 (22.2%) had severe sepsis and 218 (21%) died during the follow up period. Mortality based on cumulative relative survival exceeded that of the reference population for the first 2 years post admission in the whole cohort and for the first 3 years in the subgroup with severe sepsis. Independent predictors of mortality over the whole follow up period were male sex, Indigenous Australian ethnicity, older age, higher Charlson Comorbidity Index, and sepsis-related organ dysfunction at presentation. Conclusions The mortality rate of patients hospitalised with sepsis exceeds that of the general population until 2 years post admission. Efforts to improve outcomes from sepsis should examine longer term outcomes than the traditional primary endpoints of 28-day and 90-day mortality.
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            Preparation of Artificial Plasma Membrane Mimicking Vesicles with Lipid Asymmetry

            Lipid asymmetry, the difference in lipid distribution across the lipid bilayer, is one of the most important features of eukaryotic cellular membranes. However, commonly used model membrane vesicles cannot provide control of lipid distribution between inner and outer leaflets. We recently developed methods to prepare asymmetric model membrane vesicles, but facile incorporation of a highly controlled level of cholesterol was not possible. In this study, using hydroxypropyl-α-cyclodextrin based lipid exchange, a simple method was devised to prepare large unilamellar model membrane vesicles that closely resemble mammalian plasma membranes in terms of their lipid composition and asymmetry (sphingomyelin (SM) and/or phosphatidylcholine (PC) outside/phosphatidylethanolamine (PE) and phosphatidylserine (PS) inside), and in which cholesterol content can be readily varied between 0 and 50 mol%. We call these model membranes “artificial plasma membrane mimicking” (“PMm”) vesicles. Asymmetry was confirmed by both chemical labeling and measurement of the amount of externally-exposed anionic lipid. These vesicles should be superior and more realistic model membranes for studies of lipid-lipid and lipid-protein interaction in a lipid environment that resembles that of mammalian plasma membranes.
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              Efficacy and Safety of Endovascular Treatment versus Intravenous Thrombolysis for Acute Ischemic Stroke: A Meta-Analysis of Randomized Controlled Trials

              Background and Purpose Although endovascular therapy (ET) is increasingly used in patients with moderate to severe acute ischemic stroke, its efficacy and safety remains controversial. We performed a meta-analysis aiming to compare the benefits and safety of endovascular treatment and intravenous thrombolysis in the treatment of acute ischemic stroke. Methods We systematically searched PubMed, Embase, Science direct and Springer unitil July, 2013. The primary outcomes included good outcome (mRS ≤ 2) and excellent outcome (mRS ≤ 1) at 90 days or at trial end point. Secondary outcomes were occurrence of symptomatic hemorrhage and all-cause mortality. Results Using a prespecified search strategy, 5 RCTs with 1106 patients comparing ET and intravenous thrombolysis (IVT) were included in the meta-analysis. ET and IVT were associated with similar good (43.06% vs 41.78%; OR=1.14; 95% CI, 0.77 to 1.69; P=0.52;) and excellent (30.43% vs 30.42%; OR=1.05; 95% CI, 0.80 to 1.38; P=0.72;) outcome. For additional end points, ET was not associated with increased occurrence of symptomatic hemorrhage (6.25% vs. 6.22%; OR=1.03; 95% CI, 0.62 to 1.69; P=0.91;), or all-cause mortality (18.45% vs. 17.35%; OR=1.00; 95% CI, 0.73 to 1.39; P=0.99;). Conclusions Formal meta-analysis indicates that there are similar safety outcomes and functional independence with endovascular therapy and intravenous thrombolysis for acute ischemic stroke.
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                Author and article information

                Journal
                9809671
                21092
                Nat Neurosci
                Nat. Neurosci.
                Nature neuroscience
                1097-6256
                1546-1726
                16 April 2014
                30 March 2014
                May 2014
                01 November 2014
                : 17
                : 5
                : 664-666
                Affiliations
                [1 ]Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892, USA
                [2 ]Department of Neurology, Neurological Institute, Neuromuscular Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
                [3 ]Division of Neurology, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ 85013, USA
                [4 ]Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
                [5 ]Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA
                [6 ]Institute of Medical Genetics, Catholic University of Sacred Heart, 10100 Rome, Italy
                [7 ]Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
                [8 ]Computational Biology Core, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
                [9 ]Department of Molecular Neuroscience and Reta Lila Weston Laboratories, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK
                [10 ]Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
                [11 ]Department of Clinical Neuroscience, Institute of Neurology, University College London, London NW3 2PG, UK
                [12 ]Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, North-East London and Essex Regional MND Care Centre, E1 2AT, UK
                [13 ]Department of Neurodegenerative Disease, University College London, Queen Square, London WC1N 3BG, UK
                [14 ]Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA
                [15 ]Department of Neurology, Cedars-Sinai Medical Center, 8730 Alden Drive, Los Angeles, CA 90048, USA
                [16 ]Tanz Centre for Research of Neurodegenerative Diseases, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, M5S 3H2, Canada
                [17 ]Division of Neurology, Department of Internal Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, M4N 3M5, Canada
                [18 ]Department of Neurology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
                [19 ]Department of Neurology, Azienda Universitaria-Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy
                [20 ]ALS Center, Salvatore Maugeri Foundation, Milan, Italy
                [21 ]‘Rita Levi Montalcini’ Department of Neuroscience, University of Turin, 10126 Turin, Italy
                [22 ]Brain Science Institute and Department of Neurology, Johns Hopkins Hospital, 855 N. Wolfe Street, Baltimore, MD 21205, USA
                [24 ]Institute for Clinical Neurobiology, University of Würzburg, D-97078 Würzburg, Germany
                [25 ]Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, D-97080 Würzburg, Germany
                [26 ]Molecular Genetics Unit, Department of Clinical Pathology, A.S.O. O.I.R.M.-S. Anna, 10126 Turin, Italy
                [27 ]Neurological Institute, Catholic University and I.C.O.M.M. Association for ALS Research, 10100 Rome, Italy
                Author notes
                Corresponding Author: Bryan J. Traynor, MD, PhD, Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Room 1A-1000, Bethesda, MD 20892. Phone: (301) 451 7606. Fax: (301) 451 7295. traynorb@ 123456mail.nih.gov
                [23]

                For a list of consortium members, please see the Supplementary Information online

                Article
                NIHMS573157
                10.1038/nn.3688
                4000579
                24686783
                43b29492-a437-4f47-b1b7-7e5732feb78b
                Categories
                Article

                Neurosciences
                Neurosciences

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