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- Thompson, Paul M., et al.
(author)
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The ENIGMA Consortium : large-scale collaborative analyses of neuroimaging and genetic data
- 2014
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In: BRAIN IMAGING BEHAV. - : Springer Science and Business Media LLC. - 1931-7557 .- 1931-7565. ; 8:2, s. 153-182
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Journal article (peer-reviewed)abstract
- The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
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- Raposo, B., et al.
(author)
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Epitope-specific antibody response is controlled by immunoglobulin V(H) polymorphisms
- 2014
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In: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 211:3, s. 405-411
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Journal article (peer-reviewed)abstract
- Autoantibody formation is essential for the development of certain autoimmune diseases like rheumatoid arthritis (RA). Anti-type II collagen (CII) antibodies are found in RA patients; they interact with cartilage in vivo and are often highly pathogenic in the mouse. Autoreactivity to CII is directed to multiple epitopes and conserved between mice and humans. We have previously mapped the antibody response to CII in a heterogeneous stock cohort of mice, with a strong association with the IgH locus. We positioned the genetic polymorphisms and determined the structural requirements controlling antibody recognition of one of the major CII epitopes. Polymorphisms at positions S31R and W33T of the associated variable heavy chain (VH) allele were identified and confirmed by gene sequencing. The Fab fragment binding the J1 epitope was crystallized, and site-directed mutagenesis confirmed the importance of those two variants for antigen recognition. Back mutation to germline sequence provided evidence for a preexisting recognition of the J1 epitope. These data demonstrate a genetic association of epitope-specific antibody responses with specific VH alleles, and it highlights the importance of germline-encoded antibodies in the pathogenesis of antibody-mediated autoimmune diseases.
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- Ekman, Inger, 1952, et al.
(author)
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Impact of device-guided slow breathing on symptoms of chronic heart failure: a randomized, controlled feasibility study
- 2011
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In: European journal of heart failure. - : Wiley. - 1879-0844 .- 1388-9842. ; 13:9, s. 1000-5
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Journal article (peer-reviewed)abstract
- AIMS: In many patients with chronic heart failure (CHF) even normal daily life activities cause dyspnoea and fatigue, well-being might be considerably improved by even a modest decrease in such symptoms. The aim of this study was to investigate if lowering breathing rate with the help of a respiratory modulation (RM) device could improve symptoms in patients with CHF. METHODS AND RESULTS: Stable CHF patients with symptoms of dyspnoea were randomized to twice-daily 20 min sessions using an RM device or to music listening (ML) using a CD player, for a 4-week study period. Respiratory modulation guides the user to achieve a slow breathing rate (<10 breaths/min) while increasing exhalation time (Tex) relative to inhalation time (Tin). Lower breathing rate was accomplished by synchronizing respiratory movements with musical tones generated in response to breathing movements monitored with a belt-type sensor. Endpoints were reduced breathlessness and New York Heart Association (NYHA) class. Seventy-two patients (52 male, age 73 +/- 11 years, NYHA 3.1 +/- 0.9) were randomized and 65 completed the study (30 RM and 35 ML, respectively). There was no in-between group improvement in breathlessness and NYHA class. Patients in the RM group who displayed an average increase in Tex/Tin of >0.2 and a reduction in the average respiration rate during 30 sessions were considered responders. Responders reported reduced breathlessness (-0.86 +/- 0.23 units, P < 0.005) and improved NYHA class (-0.64 +/- 0.20, P < 0.01) compared with non-responders. CONCLUSION: Device-guided RM might have the potential to relieve symptoms of heart failure in outpatients by changing their breathing pattern.
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- Forster, M., et al.
(author)
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Genetic control of antibody production during collagen-induced arthritis development in heterogeneous stock mice
- 2012
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In: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 71
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To identify genetic factors driving pathogenic autoantibody formation in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA), in order to better understand the etiology of RA and identify possible new avenues for therapeutic intervention. METHODS: We performed a genome-wide analysis of quantitative trait loci controlling autoantibody to type II collagen (anti-CII), anti-citrullinated protein antibody (ACPA), and rheumatoid factor (RF). To identify loci controlling autoantibody production, we induced CIA in a heterogeneous stock-derived mouse cohort, with contribution of 8 inbred mouse strains backcrossed to C57BL/10.Q. Serum samples were collected from 1,640 mice before arthritis onset and at the peak of the disease. Antibody concentrations were measured by standard enzyme-linked immunosorbent assay, and linkage analysis was performed using a linear regression-based method. RESULTS: We identified loci controlling formation of anti-CII of different IgG isotypes (IgG1, IgG3), antibodies to major CII epitopes (C1, J1, U1), antibodies to a citrullinated CII peptide (citC1), and RF. The anti-CII, ACPA, and RF responses were all found to be controlled by distinct genes, one of the most important loci being the immunoglobulin heavy chain locus. CONCLUSION: This comprehensive genetic analysis of autoantibody formation in CIA demonstrates an association not only of anti-CII, but interestingly also of ACPA and RF, with arthritis development in mice. These results underscore the importance of non-major histocompatibility complex genes in controlling the formation of clinically relevant autoantibodies.
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