64 research outputs found

    X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis.

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    BACKGROUND & AIMS: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. METHODS: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). RESULTS: Single-marker association analyses found approximately 100 loci displaying P < 5 √ó 10(-4), with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 √ó 10(-6); odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 √ó 10(-8)), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 √ó 10(-9); OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). CONCLUSIONS: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.The article is available via Open Access. Click on the 'Additional link' above to access the full-text.Published version, accepted versio

    Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

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    BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

    Differential human brain activation by vertical and horizontal global visual textures

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    Mid-level visual processes which integrate local orientation information for the detection of global structure can be investigated using global form stimuli of varying complexity. Several lines of evidence suggest that the identification of concentric and parallel organisations relies on different underlying neural substrates. The current study measured brain activation by concentric, horizontal parallel, and vertical parallel arrays of short line segments, compared to arrays of randomly oriented segments. Six subjects were scanned in a blocked design functional magnetic resonance imaging experiment. We compared percentage BOLD signal change during the concentric, horizontal and vertical blocks within early retinotopic areas, the fusiform face area and the lateral occipital complex. Unexpectedly, we found that vertical and horizontal parallel forms differentially activated visual cortical areas beyond V1, but in general, activations to concentric and parallel forms did not differ. Vertical patterns produced the highest percentage signal change overall and only area V3A showed a significant difference between concentric and parallel (horizontal) stimuli, with the former better activating this area. These data suggest that the difference in brain activation to vertical and horizontal forms arises at intermediate or global levels of visual representation since the differential activity was found in mid-level retinotopic areas V2 and V3 but not in V1. This may explain why earlier studies‚ÄĒusing methods that emphasised responses to local orientation‚ÄĒdid not discover this vertical-horizontal anisotrop

    Individual differences in children's global motion sensitivity correlate with TBSS-based measures of the superior longitudinal fasciculus.

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    Reduced global motion sensitivity, relative to global static form sensitivity, has been found in children with many neurodevelopmental disorders, leading to the "dorsal stream vulnerability" hypothesis (Braddick et al., 2003). Individual differences in typically developing children's global motion thresholds have been shown to be associated with variations in specific parietal cortical areas (Braddick et al., 2016). Here, in 125 children aged 5-12years, we relate individual differences in global motion and form coherence thresholds to fractional anisotropy (FA) in the superior longitudinal fasciculus (SLF), a major fibre tract communicating between parietal lobe and anterior cortical areas. We find a positive correlation between FA of the right SLF and individual children's sensitivity to global motion coherence, while FA of the left SLF shows a negative correlation. Further analysis of parietal cortical area data shows that this is also asymmetrical, showing a stronger association with global motion sensitivity in the left hemisphere. None of these associations hold for an analogous measure of global form sensitivity. We conclude that a complex pattern of structural asymmetry, including the parietal lobe and the superior longitudinal fasciculus, is specifically linked to the development of sensitivity to global visual motion. This pattern suggests that individual differences in motion sensitivity are primarily linked to parietal brain areas interacting with frontal systems in making decisions on integrated motion signals, rather than in the extra-striate visual areas that perform the initial integration. The basis of motion processing deficits in neurodevelopmental disorders may depend on these same structures

    Different trajectories of decline for global form and global motion processing in ageing, Mild Cognitive Impairment and Alzheimer’s disease

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    The visual processing of complex motion is impaired in Alzheimer's disease (AD). However, it is unclear whether these impairments are biased toward the motion stream or part of a general disruption of global visual processing, given some reports of impaired static form processing in AD. Here, for the first time, we directly compared the relative preservation of motion and form systems in AD, mild cognitive impairment, and healthy aging, by measuring coherence thresholds for well-established global rotational motion and static form stimuli known to be of equivalent complexity. Our data confirm a marked motion-processing deficit specific to some AD patients, and greater than any form-processing deficit for this group. In parallel, we identified a more gradual decline in static form recognition, with thresholds raised in mild cognitive impairment patients and slightly further in the AD group compared with controls. We conclude that complex motion processing is more vulnerable to decline in dementia than complex form processing, perhaps owing to greater reliance on long-range neural connections heavily targeted by AD pathology

    Global Visual Motion Sensitivity: Associations with Parietal Area and Children's Mathematical Cognition.

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    Sensitivity to global visual motion has been proposed as a signature of brain development, related to the dorsal rather than ventral cortical stream. Thresholds for global motion have been found to be elevated more than for global static form in many developmental disorders, leading to the idea of "dorsal stream vulnerability." Here we explore the association of global motion thresholds with individual differences in children's brain development, in a group of typically developing 5- to 12-year-olds. Good performance was associated with a relative increase in parietal lobe surface area, most strongly around the intraparietal sulcus and decrease in occipital area. In line with the involvement of intraparietal sulcus, areas in visuospatial and numerical cognition, we also found that global motion performance was correlated with tests of visuomotor integration and numerical skills. Individual differences in global form detection showed none of these anatomical or cognitive correlations. This suggests that the correlations with motion sensitivity are unlikely to reflect general perceptual or attentional abilities required for both form and motion. We conclude that individual developmental variations in global motion processing are not linked to greater area in the extrastriate visual areas, which initially process such motion, but in the parietal systems that make decisions based on this information. The overlap with visuospatial and numerical abilities may indicate the anatomical substrate of the "dorsal stream vulnerability" proposed as characterizing neurodevelopmental disorders

    Brain responses to global perceptual coherence

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    Coherence thresholds for concentric patterns of contour segments or dot trajectories have revealed differential development and vulnerability of extrastriate form and motion pathways respectively (Braddick et al, Neuropsychologia, 2003). Here we explore the properties of visual evoked potentials (VEPs) specific to form and motion coherence. Coherent contour or motion arrays alternate with incoherent arrays at 0.5-4 Hz. A 2nd harmonic VEP signal (F2) may arise from local changes occuring at each transition, but a first harmonic (F1) must reflect differential responses to coherence and incoherence, indicating global processing. F1 amplitude is approximately linear with coherence for both form and motion, confirming that F1 measures global processing. F2 is independent of coherence for form, and nearly so for motion, implying that it reflects local changes. Occipital F1 amplitudes for motion: form coherence are approximately 2:1. However, this does not reflect underlying sensitivity: psychophysical form and motion coherence thresholds are similar, and extrapolation of the linear region of F1 amplitude vs coherence reaches zero close to threshold coherence in each case. F1 amplitude for both displays increases gradually from 0.5-4 Hz. However, this is opposite to psychophysical coherence sensitivity, which falls over the same range. We conclude: (a) coherence-dependent VEPs provide measures of global form and motion processing, practical for infants and non-verbal (e.g. autistic) children; (b) this response is elicited efficiently at relatively high presentation rates; (c) the level tapped by the VEP does not provide the limiting factor on temporal integration in global perceptual processing

    Automatic Detection of Attention Shifts in Infancy: Eye Tracking in the Fixation Shift Paradigm

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    <div><p>This study measured changes in switches of attention between 1 and 9 months of age in 67 typically developing infants. Remote eye-tracking (Tobii X120) was used to measure saccadic latencies, related to switches of fixation, as a measure of shifts of attention, from a central stimulus to a peripheral visual target, measured in the Fixation Shift Paradigm. Fixation shifts occur later if the central fixation stimulus stays visible when the peripheral target appears (competition condition), than if the central stimulus disappears as the peripheral target appears (non-competition condition). This difference decreases with age. Our results show significantly faster disengagement in infants over 4 months than in the younger group, and provide more precise measures of fixation shifts, than behavioural observation with the same paradigm. Reduced saccadic latencies in the course of a test session indicate a novel learning effect. The Fixation Shift Paradigm combined with remote eye-tracking measures showed improved temporal and spatial accuracy compared to direct observation by a trained observer, and allowed an increased number of trials in a short testing time. This makes it an infant-friendly non-invasive procedure, involving minimal observational training, suitable for use in future studies of clinical populations to detect early attentional abnormalities in the first few months of life.</p></div
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