1,631 research outputs found
Spatial dependency between task positive and task negative networks
Functional neuroimaging reveals both relative increases (task-positive) and
decreases (task-negative) in neural activation with many tasks. There are
strong spatial similarities between many frequently reported task-negative
brain networks, which are often termed the default mode network. The default
mode network is typically assumed to be a spatially-fixed network; however,
when defined by task-induced deactivation, its spatial distribution it varies
depending on what specific task is being performed. Many studies have revealed
a strong temporal relationship between task-positive and task-negative networks
that are important for efficient cognitive functioning and here. Here, using
data from four different cognitive tasks taken from two independent datasets,
we test the hypothesis that there is also a fundamental spatial relationship
between them. Specifically, it is hypothesized that the distance between task
positive and negative-voxels is preserved despite different spatial patterns of
activation and deactivation being evoked by different cognitive tasks. Here, we
show that there is lower variability in the distance between task-positive and
task-negative voxels across four different sensory, motor and cognitive tasks
than would be expected by chance - implying that deactivation patterns are
spatially dependent on activation patterns (and vice versa) and that both are
modulated by specific task demands. We propose that this spatial relationship
may be the macroscopic analogue of microscopic neuronal organization reported
in sensory cortical systems, and we speculate why this spatial organization may
be important for efficient sensorimotor and cognitive functioning.Comment: 16 pages, 4 figure
Hepatic encephalopathy : novel insights into classification, pathophysiology and therapy
Hepatic encephalopathy (HE) is a frequent and serious complication of both chronic liver disease and acute liver failure. HE manifests as a wide spectrum of neuropsychiatric abnormalities, from subclinical changes (mild cognitive impairment) to marked disorientation, confusion and coma. The clinical and economic burden of HE is considerable, and it contributes greatly to impaired quality of life, morbidity and mortality. This review will critically discuss the latest classification of HE, as well as the pathogenesis and pathophysiological pathways underlying the neurological decline in patients with end-stage liver disease. In addition, management strategies, diagnostic approaches, currently available therapeutic options and novel treatment strategies are discussed
Autotaxin, bile acid profile and effect of ileal bile acid transporter inhibition in primary biliary cholangitis patients with pruritus
Background and Aims
Pruritus is a common symptom in patients with primary biliary cholangitis (PBC) for which ileal bile acid transporter (IBAT) inhibition is emerging as a potential therapy. We explored the serum metabonome and gut microbiota profile in PBC patients with pruritus and investigated the effect of GSK2330672, an IBAT inhibitor.
Methods
We studied fasting serum bile acids (BAs), autotaxin and faecal microbiota in 22 PBC patients with pruritus at baseline and after 2 weeks of GSK2330672 treatment. Control group included 31 asymptomatic PBC patients and 18 healthy volunteers. BA profiling was done by ultra performance liquid chromatography coupled to a mass spectrometry (UPLCâMS). Faecal microbiomes were analysed by 16S ribosomal RNA gene sequencing.
Results
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In PBC patients with pruritus, serum levels of total and glycoâconjugated primary BAs and autotaxin were significantly elevated. Autotaxin activity correlated significantly with tauroâ and glycoâconjugated cholic acid (CA) and chenodeoxycholic acid (CDCA), both at baseline and after GSK2330672. GSK2330672 significantly reduced autotaxin and all tauroâ and glycoâ conjugated BAs and increased faecal levels of CA (P = 0.048) and CDCA (P = 0.027). Gut microbiota of PBC patients with pruritus was similar to control groups. GSK2330672 increased the relative abundance of Firmicutes (P = 0.033) and Clostridia (P = 0.04) and decreased Bacteroidetes (P = 0.033) and Bacteroidia (P = 0.04).
Conclusions
Pruritus in PBC does not show a distinct gut bacterial profile but is associated with elevated serum bile acid and autotaxin levels which decrease after IBAT inhibition. In cholestatic pruritus, a complex interplay between BAs and autotaxin is likely and may be modified by IBAT inhibition
Regulation of immune responses in primary biliary cholangitis: a transcriptomic analysis of peripheral immune cells
BACKGROUND AIMS: In patients with primary biliary cholangitis (PBC), the serum liver biochemistry measured during treatment with ursodeoxycholic acid-the UDCA response-accurately predicts long-term outcome. Molecular characterization of patients stratified by UDCA response can improve biological understanding of the high-risk disease, thereby helping to identify alternative approaches to disease-modifying therapy. In this study, we sought to characterize the immunobiology of the UDCA response using transcriptional profiling of peripheral blood mononuclear cell subsets. METHODS: We performed bulk RNA-sequencing of monocytes and TH1, TH17, TREG, and B cells isolated from the peripheral blood of 15 PBC patients with adequate UDCA response ("responders"), 16 PBC patients with inadequate UDCA response ("nonresponders"), and 15 matched controls. We used the Weighted Gene Co-expression Network Analysis to identify networks of co-expressed genes ("modules") associated with response status and the most highly connected genes ("hub genes") within them. Finally, we performed a Multi-Omics Factor Analysis of the Weighted Gene Co-expression Network Analysis modules to identify the principal axes of biological variation ("latent factors") across all peripheral blood mononuclear cell subsets. RESULTS: Using the Weighted Gene Co-expression Network Analysis, we identified modules associated with response and/or disease status (q<0.05) in each peripheral blood mononuclear cell subset. Hub genes and functional annotations suggested that monocytes are proinflammatory in nonresponders, but antiinflammatory in responders; TH1 and TH17 cells are activated in all PBC cases but better regulated in responders; and TREG cells are activated-but also kept in check-in responders. Using the Multi-Omics Factor Analysis, we found that antiinflammatory activity in monocytes, regulation of TH1 cells, and activation of TREG cells are interrelated and more prominent in responders. CONCLUSIONS: We provide evidence that adaptive immune responses are better regulated in patients with PBC with adequate UDCA response
A deformation of AdS_5 x S^5
We analyse a one parameter family of supersymmetric solutions of type IIB
supergravity that includes AdS_5 x S^5. For small values of the parameter the
solutions are causally well-behaved, but beyond a critical value closed
timelike curves (CTC's) appear. The solutions are holographically dual to N=4
supersymmetric Yang-Mills theory on a non-conformally flat background with
non-vanishing R-currents. We compute the holographic energy-momentum tensor for
the spacetime and show that it remains finite even when the CTC's appear. The
solutions, as well as the uplift of some recently discovered AdS_5 black hole
solutions, are shown to preserve precisely two supersymmetries.Comment: 16 pages, v2: typos corrected and references adde
Bacterial and metabolic phenotypes associated with inadequate response to ursodeoxycholic acid treatment in primary biliary cholangitis
Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with ursodeoxycholic acid (UDCA) as first-line treatment. Poor response to UDCA is associated with a higher risk of progressing to cirrhosis, but the underlying mechanisms are unclear. UDCA modulates the composition of primary and bacterial-derived bile acids (BAs). We characterized the phenotypic response to UDCA based on BA and bacterial profiles of PBC patients treated with UDCA. Patients from the UK-PBC cohort (n = 419) treated with UDCA for a minimum of 12-months were assessed using the Barcelona dynamic response criteria. BAs from serum, urine, and feces were analyzed using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry and fecal bacterial composition measured using 16S rRNA gene sequencing. We identified 191 non-responders, 212 responders, and a subgroup of responders with persistently elevated liver biomarkers (n = 16). Responders had higher fecal secondary and tertiary BAs than non-responders and lower urinary bile acid abundances, with the exception of 12-dehydrocholic acid, which was higher in responders. The sub-group of responders with poor liver function showed lower alpha-diversity evenness, lower abundance of fecal secondary and tertiary BAs than the other groups and lower levels of phyla with BA-deconjugation capacity (Actinobacteriota/Actinomycetota, Desulfobacterota, Verrucomicrobiota) compared to responders. UDCA dynamic response was associated with an increased capacity to generate oxo-/epimerized secondary BAs. 12-dehydrocholic acid is a potential biomarker of treatment response. Lower alpha-diversity and lower abundance of bacteria with BA deconjugation capacity might be associated with an incomplete response to treatment in some patients
Planning ahead in public health? A qualitative study of the time horizons used in public health decision-making
<p>Abstract</p> <p>Background</p> <p>In order to better understand factors that influence decisions for public health, we undertook a qualitative study to explore issues relating to the time horizons used in decision-making.</p> <p>Methods</p> <p>Qualitative study using semi-structured interviews. 33 individuals involved in the decision making process around coronary heart disease were purposively sampled from the UK National Health Service (national, regional and local levels), academia and voluntary organizations. Analysis was based on the framework method using N-VIVO software. Interviews were transcribed, coded and emergent themes identified.</p> <p>Results</p> <p>Many participants suggested that the timescales for public health decision-making are too short. Commissioners and some practitioners working at the national level particularly felt constrained in terms of planning for the long-term. Furthermore respondents felt that longer term planning was needed to address the wider determinants of health and to achieve societal level changes. Three prominent 'systems' issues were identified as important drivers of short term thinking: the need to demonstrate impact within the 4 year political cycle; the requirement to 'balance the books' within the annual commissioning cycle and the disruption caused by frequent re-organisations within the health service. In addition respondents suggested that the tools and evidence base for longer term planning were not well established.</p> <p>Conclusion</p> <p>Many public health decision and policy makers feel that the timescales for decision-making are too short. Substantial systemic barriers to longer-term planning exist. Policy makers need to look beyond short-term targets and budget cycles to secure investment for long-term improvement in public health.</p
Prevention of Liver Fibrosis and Cancer in Africa: The PROLIFICA project â a collaborative study of hepatitis B-related liver disease in West Africa
Hepatitis B virus (HBV) infection causes a spectrum of acute and chronic liver disease ranging from inactive chronic carrier status to progressive chronic hepatitis, culminating in end-stage cirrhosis and liver cancer. In sub-Saharan Africa, HBV infection is endemic and the HBV-related disease burden is high, making HBV a signficant threat to health in the African continent. The European Union-funded Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) project was established in 2011, with the central directive to reduce the incidence of HBV-related liver cancer in West Africa. In this editorial, we outline some of the achievements and challenges of the PROLIFICA platform in West Africa, highlighting the the importance of collaborative studies in Africa
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