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.

From 1979 to 1985 2435 patients having had transient ischaemic attacks (TIAs) or minor ischaemic strokes, were enrolled in the UK TIA trial and were randomised to receive either aspirin 300 mg, daily or aspirin 1200 mg or placebo. Analysis of reported upper gastrointestinal bleeding events (defined as haematemesis or melaena, or both) showed a risk of bleeding in a dose dependent manner, odds ratios (95% CI) for 300 mg of aspirin=3.3 (1.2 to 9.0) and for 1200 mg=6.4 (2.5 to 16.5) and, as would be expected, an increased risk of hospitalisation because of bleeding also in a dose dependent manner, odds ratio=3.6 (0.7 to 17.2) for 300 mg and 8.7 (2.0 to 37.6) for 1200 mg. Further analysis suggested greater risks of bleeding from duodenal ulcers than gastric ulcers and that bleeding is more likely early in the course of treatment with aspirin used as secondary prevention.There was also an increased risk of lower gastrointestinal bleeding, defined as fresh blood per rectum for both doses of aspirin, odds ratio 1-8 (0.5 to 6.1) for 300 mg of aspirin, and 1.5 (0.4 to 5.3) for 1200 mg of aspirin. (Gut 1995; 37: 509-511)

The effect of 28 days' continuous administration of oral indomethacin on gastroduodenal morphology, gastric mucosal blood flow, and gastric mucosal prostaglandin E2 (PGE2) metabolism in man was studied to define further the mechanisms of mucosal injury induced by indomethacin. Indomethacin caused acute gastroduodenal damage in ali cases, which was maximal at 24 hours of administration. With continued intake, mucosal adaptation occurs resulting in resolution of endoscopic mucosal damage. At the time of maximal mucosal damage, gastric mucosal blood flow was significantly reduced compared with values before treatment (p<0001 in fundus and p<0002 in antrum), with good correlation between the severity of damage and the magnitude of the reduction in blood flow (r=076). Mucosal recovery was associated with a return of the blood flow to normal. PGE2 in mucosal homogenate was significantly reduced by indomethacin in both the hfndus (p<0O01) and antrum (p<001) after 24 hours but there was no correlation between the magnitude of this reduction and the severity of mucosal damage (r=-034). Despite mucosal recovery by 28 days, PGE2 values remained significantly below those before treatment in both the fundus (p<0.01) and antrum (p<0.01). The PGE2 degredation capacity was not influenced by indomethacin. In conclusion, mucosal adaptation to acute damage by indomethacin occurs in man and seems independent of local PGE2 metabolism.

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