The roles of proteinase-activated receptors (PARs) in platelet functions other than aggregation are not well understood. Among these is the release of factors that regulate the process of angiogenesis, such as endostatin and VEGF, which, respectively, inhibit and promote angiogenesis. PAR1 and PAR4 are expressed on the surface of human platelets and can be activated by thrombin. In the present study, we have attempted to determine the roles of PAR1 and PAR4 in regulating release of endostatin and VEGF from human platelets. Aggregation and endostatin release could be elicited by a specific PAR4 agonist (AYPGKF-NH2). The PAR4 agonist concentration dependently suppressed VEGF release. A selective PAR1 agonist (TFLLR-NH2) induced platelet aggregation and VEGF release but suppressed endostatin release. Thrombin did not affect endostatin or VEGF release. However, in the presence of a selective PAR1 antagonist (SCH79797), thrombin stimulated endostatin release and suppressed VEGF release. Conversely, in the presence of a selective PAR4 antagonist (transcinnamoyl-YPGKF-NH2), thrombin stimulated VEGF release. In vivo, treatment of rats with established gastric ulcers with a PAR1 antagonist each day for 1 wk resulted in a significant retardation of healing. We conclude that PAR1 and PAR4 counter-regulate the release of endostatin and VEGF from platelets. These protease-activated receptors could therefore play a crucial role in regulating angiogenesis and in turn could regulate the processes of wound healing and tumor growth.angiogenesis ͉ aggregation ͉ thrombin ͉ protease I n addition to its central roles in blood coagulation and hemostasis, thrombin participates in a variety of biological processes, including inflammation and wound healing (1). Activation of platelets by thrombin is mediated at least in part through cleavage of proteinase-activated receptors (PARs). Four distinct PARs have been identified, with PAR1, PAR3, and PAR4 acting as receptors for thrombin. Human platelets express PAR1 and PAR4, and activation of either is sufficient to trigger platelet aggregation and secretion (2-5). A variety of bioactive substances, including growth factors and chemokines (6-8), are stored in platelets and released during activation. We have reported (9) that endostatin, a potent inhibitor of angiogenesis, is contained within rat platelets and released in response to thrombin via PAR4 in an aggregation-independent manner (10). In studies in rats, we demonstrated that pharmacological manipulation of platelet and͞or serum levels of proangiogenic (VEGF) and antiangiogenic (endostatin) factors resulted in profound effects on healing of gastric ulcers (11,12).Whether human platelets contain endostatin is unknown. Moreover, the relative importance of PAR1 vs. PAR4 in regulating platelet endostatin release has not been reported. In the present study, we have demonstrated that human platelets contain endostatin, and that its release can be triggered by activation of PAR4 but not PAR1. Indeed, PAR1 activation leads to suppression of e...

Background: The purpose was to assess in Italy the clinical features at diagnosis of inflammatory bowel disease (IBD) in children. Methods: In 1996 an IBD register of disease onset was established on a national scale. Results: Up to the end of 2003, 1576 cases of pediatric IBD were recorded: 810 (52%) ulcerative colitis (UC), 635 (40%) Crohn's disease (CD), and 131 (8%) indeterminate colitis (IC). In the period 1996–2003 an increase of IBD incidence from 0.89 to 1.39/105 inhabitants aged <18 years was observed. IBD was more frequent among children aged between 6 and 12 years (57%) but 20% of patients had onset of the disease under 6 years of age; 28 patients were <1 year of age. Overall, 11% had 1 or more family members with IBD. The mean interval between onset of symptoms and diagnosis was higher in CD (10.1 months) and IC (9 months) versus UC (5.8 months). Extended colitis was the most frequent form in UC and ileocolic involvement the most frequent in CD. Upper intestinal tract involvement was present in 11% of CD patients. IC locations were similar to those of UC. Bloody diarrhea and abdominal pain were the most frequent symptoms in UC and IC, and abdominal pain and diarrhea in CD. Extraintestinal symptoms were more frequent in CD than in UC. Conclusions The IBD incidence in children and adolescents in Italy shows an increasing trend for all 3 pathologies. UC diagnoses exceeded CD. (Inflamm Bowel Dis 2008)

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Our findings suggest that, despite the fact that bacterial infections are more common in cirrhotic alcoholics, its seems that the mortality rate is associated more with the severity than with the etiology of the hepatic disease.

Population-based GI NHL incidence rates in Calgary are higher than those described elsewhere in North America or in Britain. The incidence of GI NHL within the HIV population has virtually disappeared, presumably due to the advent of highly active retroviral therapy.

Successful management of IRSHDI after LC requires adequate identification of the lesion, and multidisciplinary treatment is necessary. Half of the patients can be treated successfully by nonsurgical procedures.

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause damage in the upper gastrointestinal (GI) tract by impairing the ability of the mucosa to resist and respond to injury. Many of these effects of NSAIDs can be attributed to their ability to suppress mucosal prostaglandin synthesis. Selective inhibitors of cyclooxygenase (COX)-2 are less likely to disrupt mucosal defence and do not interfere with platelet aggregation. Thus, their use is associated with a reduced incidence of serious GI adverse events; however, a significant risk of such events still persists. At least in animal models, selective COX-2 inhibitors interfere with ulcer healing to the same extent as conventional NSAIDs. In contrast, COX-inhibiting nitric oxide donors (CINODs) produce anti-inflammatory and analgesic effects comparable or superior to those of NSAIDs, but with greatly reduced GI toxicity. Unlike NSAIDs and selective COX-2 inhibitors, CINODs do not interfere with ulcer healing. Moreover, because CINODs suppress the activity of both COX-1 and COX-2, they do not share with selective COX-2 inhibitors the lack of cardioprotection afforded by significant suppression of platelet aggregation. Because of their safety profile, CINODs may be particularly useful for long term prevention applications, such as for colon cancer, cardiovascular disease and Alzheimer's disease.

Portal hypertensive gastropathy (PHG) is often seen in patients with portal hypertension, and can lead to transfusion-dependent anemia as well as acute, life-threatening bleeding episodes. This Review focuses on the mechanisms that underlie the pathogenesis of PHG that provide reasonable grounds for the treatment of this condition, and ultimately enable translation of basic research into clinical practice. Increased portal pressure associated with cirrhosis and liver dysfunction is critical for the development of clinically significant PHG, and leads to impaired gastric mucosal defense mechanisms that render the stomach susceptible to mucosal injury. The use of pharmacological agents such as beta-blockers reduces the frequency of bleeding episodes in PHG. As a last resort, surgical decompression of the portal system, transjugular intrahepatic stent placement and liver transplantation can resolve this condition. Elimination of known risk factors for gastric injury such as alcohol, aspirin and traditional NSAIDs is critical. The role of Helicobacter pylori colonization of the gastric mucosa in PHG is not clear. Careful and critical interpretation of human and experimental data can be helpful to establish a rationale for the medical management of this important condition.