Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

Subsequent to binding to the zona pellucida, mammalian sperm undergo a regulated sequence of events that ultimately lead to acrosomal exocytosis. Like most regulated exocytotic processes, a rise in intracellular calcium is sufficient to trigger this event although the precise mechanism of how this is achieved is still unclear. Numerous studies on mouse sperm have indicated that a voltage-operated Ca2+ channel plays some immediate role following sperm binding to the zona pellucida glycoprotein ZP3. However, there is also evidence that the mammalian sperm acrosome contains a high density of IP3 receptors, suggesting that the exocytotic event involves the release of Ca2+ from the acrosome. The release of Ca2+ from the acrosome may directly trigger exocytosis or may activate store-operated Ca2+ channels in the plasma membrane. To test the hypothesis that the acrosome is an intracellular store we loaded mammalian sperm with the membrane permeant forms of three Ca2+-sensitive fluorescent indicator dyes: fura-2, indo-1, and Calcium Green-5N. Fluorescence microscopy revealed that the sperm were labeled in all intracellular compartments. When fura-2 labeled sperm were treated with 150 microM MnCl2 to quench all fluorescence in the cytosol, or when the sperm were labeled with the low affinity dye Calcium Green-5N, there was a large Ca2+ signal in the acrosome. Consistent with the acrosome serving as an intracellular Ca2+ reservoir, the addition of 20 microM thapsigargin, a potent inhibitor of the smooth endoplasmic reticular Ca2+-ATPase (SERCA), to populations of capacitated sperm resulted in nearly 100% acrosomal exocytosis within 60 min (tau1/2 approximately 10 min), in the absence of extracellular Ca2+. Additionally, treatment of sperm with 100 microM thimerosal, an IP3 receptor agonist, also resulted in acrosomal exocytosis. Taken together, these data suggest that the mouse sperm acrosome is a Ca2+ store that regulates its own exocytosis through an IP3 Ca2+ mobilization pathway.

SummaryBackgroundInfliximab and adalimumab have established roles in inflammatory bowel disease (IBD) therapy. UK regulators mandate reassessment after 12 months' anti‐TNF therapy for IBD, with consideration of treatment withdrawal. There is a need for more data to establish the relapse rates following treatment cessation.AimTo establish outcomes following anti‐TNF withdrawal for sustained remission using new data from a large UK cohort, and assimilation of all available literature for systematic review and meta‐analysis.MethodsA retrospective observational study was performed on 166 patients with IBD (146 with Crohn's disease (CD) and 20 with ulcerative colitis [UC) and IBD unclassified (IBDU)] withdrawn from anti‐TNF for sustained remission. Meta‐analysis was undertaken of all published studies incorporating 11 further cohorts totalling 746 patients (624 CD, 122 UC).ResultsRelapse rates in the UK cohort were 36% by 1 year and 56% by 2 years for CD, and 42% by 1 year and 47% by 2 years for UC/IBDU. Increased relapse risk in CD was associated with age at diagnosis [hazard ratio (HR) 2.78 for age <22 years], white cell count (HR 3.22 for >5.25 × 109/L) and faecal calprotectin (HR 2.95 for >50 μg/g) at drug withdrawal. Neither continued immunomodulators nor endoscopic remission were predictors. In the meta‐analysis, estimated 1‐year relapse rates were 39% and 35% for CD and UC/IBDU respectively. Retreatment with anti‐TNF was successful in 88% for CD and 76% UC/IBDU.ConclusionsAssimilation of all available data reveals remarkable homogeneity. Approximately one‐third of patients with IBD flare within 12 months of withdrawal of anti‐TNF therapy for sustained remission.

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Reduction in mortality in single- and double-organ failure was as high as 28% in septic patients with combined extracorporeal detoxification. A prospective randomized trial in sepsis and double-organ failure should be projected.