BACKGROUND In several animal species the pancreas has the capacity to partially regenerate in a self regulating process. A complex network of growth factors modulates this process. There is evidence that bombesin stimulates pancreatic regeneration in rodents. Whether bombesin stimulates pancreas regrowth in large mammals is unknown. Shc proteins, the target of tyrosine kinase-coupled receptors, activate p42 and p44 mitogen-activated protein (MAP) kinase and induce the transcriptional upregulation of genes involved in cell proliferation. The aims of our study were to determine whether bombesin stimulates pancreatic growth in large mammals and whether this event requires Shc-MAP kinase pathway upregulation. METHODS Three groups of pigs were submitted to sham operation (group 1); to subtotal (70%) distal pancreatectomy (group 2), and to subtotal pancreatectomy followed by bombesin (5 mg three times daily) for 4 weeks (group 3). After a 4-week follow-up a second laparotomy was performed, and the residual pancreas removed. p46Shc, p52Shc and p66Shc, Grb2, and p42/p44 MAP kinase expression and phosphorylation were measured either in freshly isolated pancreatic acinar cells or whole pancreatic extracts. RESULTS In vivo bombesin administration resulted in: 1) approximately 100% growth of pancreatic duodenal lobe; 2) rapid recovery from exocrine pancreatic failure; and 3) a threefold increase in the rate of pancreatic acinar cell proliferation. Incubating freshly isolated pancreatic acinar cells with bombesin resulted in time- and concentration-dependent stimulation of p46Shc/p52Shc phosphorylation, Shc-Grb2 complex formation, and p42/p44 MAP kinase activation. In vivo bombesin administration significantly upregulated p46Shc/p52Shc and MAP kinase expression and/or activity in whole pancreatic extracts. CONCLUSIONS In vivo chronic bombesin administration stimulates pancreatic regeneration after pancreatectomy in large mammals. Bombesin-stimulated pancreatic growth is associated with upregulation of the Shc-Grb2-SOS-Ras-MAP kinase pathway.

OBJECTIVES:Laparoscopic cholecystectomy (LC) has become the treatment of choice for patients with symptomatic cholelithiasis. About 10% of patients with symptomatic gallstones may bear associated common bile duct (CBD) stones. The preferred approach to these patients is the removal of CBD stones by endoscopic retrograde cholangiography (ERCP) before LC. However, ERCP before LC should be performed only in patients with suspected choledocholithiasis. The aims of this study were to: 1) generate an efficacious predictive model for selecting patients with suspected choledocholithiasis to submit to preoperative ERCP, and 2) test the safety of the endoscopic/laparoscopic procedure.METHODS:Historical, biochemical, and ultrasonographic data were collected prospectively. Receiver operating characteristics curve analysis was adopted for determining optimal biochemical and ultrasonographic cut-off values. Multivariate analysis using logistic regression with generation of the best model identifying independent predictors of CBD stones was also employed.RESULTS:The optimal model predicted a 95% probability of CBD stones in a patient who presented with elevated ALP (over 300 IU/L) and ALT (over 40 IU/L) levels and CBD dilation > 8 mm at ultrasonography. Endoscopic removal of CBD stones was achieved in 95% of patients, with minimal morbidity and no mortality.CONCLUSIONS:The identified independent predictors of CBD stones are highly efficient selectors of patients with choledocholithiasis. Moreover, endoscopic removal of CBD stones before LC is a safe and efficacious procedure.

There is recent evidence that nitric oxide, a soluble gas produced from L-arginine, is released by the smooth muscle cells and neurons of the gastrointestinal tract where it exerts a myorelaxive action. However, little is known about the effects nitric oxide has on gastric and gallbladder motility during the inter- and postprandial phases in man. We therefore investigated the effects 200 mg/kg/hr L-arginine exerts on the gastric and gallbladder motility induced by 2 mg/kg erythromycin or a liquid meal in 21 subjects in a double-blind, placebo-controlled study. Gastric and gallbladder emptying were evaluated by sonography. Fasting antral motility was expressed as antral motility index (MI). In fasting subjects, L-arginine administration determined a threefold increase in plasma nitrite concentrations. Administration of erythromycin caused a significant rise in the antral MI, which was inhibited by L-arginine (P < 0.05). Ingestion of a liquid meal also significantly increased antral MI, but it returned to basal values 90 min after the end of the meal. Although L-arginine administration caused a significant reduction in the antral MI (P < 0.05), it did not inhibit gastric emptying. L-Arginine provoked an approximately 40% increase in basal gallbladder volume, completely blocked erythromycin-induced emptying, and partially, but significantly, prevented the emptying induced by a liquid meal (P < 0.01). Our study suggests that nitric oxide may be implicated in the physiological modulation of gastric and gallbladder motility during the inter- and postprandial phases in man.