Toxic effects of oxygen-derived free radicals on rat pancreatic acini; an in vitro study.

Isolated pancreatic acini were incubated with either a combination of xanthine and xanthine oxidase which generates superoxide (O2), or hydrogen peroxide (H2O2), and the direct cytotoxic effect of active oxygen species on the pancreatic acini was examined in vitro in the isolated pancreatic acini system of the rat. Both amylase secretion and lactic dehydrogenase discharge were increased dose-dependently by the addition of xanthine and xanthine oxidase, and suppressed by the addition of a superoxide scavenger, superoxide dismutase. In addition, amylase and lectate dehydrogenase discharge was increased dose-dependently by hydrogen peroxide and decreased by catalase. These results suggest that superoxide and hydrogen peroxide directly injure pancreatic acinar cells and that active oxygen species are involved in the pathogenesis of acute pancreatitis.     

Acute cytotoxic effect of cyclosporin A on pancreatic acinar cells in rats. Protective effect of the synthetic protease inhibitor E3123.

This study was designed to evaluate the acute toxic effects of cyclosporin A on the exocrine pancreas and the protective effects of a new potent protease inhibitor, 4-(2-succinimidoethylthio) phenyl 4-guanidinobenzoate methanesulfonate, E3123. Cyclosporin A in a dose of 5 mg/kg.h caused a significant increase in serum amylase levels, pancreatic amylase content, and interstitial edema, suggesting that it induces exocrine pancreatic injury. Cyclosporin A also caused redistribution of cathepsin B from the lysosomal fraction to the zymogen fraction, indicating colocalization of lysosomal enzymes with pancreatic digestive enzymes. E3123 in a dose of 2 mg/kg.h prevented almost completely these changes caused by cyclosporin A. These results indicate that exocrine pancreatic injury is induced by cyclosporin A and that lysosomal enzymes play important roles in the pathogenesis of this injury and also suggest that E3123 might protect the exocrine pancreas of patients receiving cyclosporin A after organ transplantation.     

Gastrin Release from Antral G Cells Stimulated with Secretin

Recently, gastrinoma cells were demonstrated to release gastrin when directly stimulated by secretin both in vivo and in vitro. In this study, the reaction of antral G cells was investigated. Secretin was injected into the right gastroepiploic artery in canines, and into the common hepatic artery during a selective arteriography in patients without gastrinomas. G cells obtained from the antrum of rats were attached to 0.45-microns filters and irrigated with medium containing secretin. The serum gastrin concentration increased rapidly in significant amounts and very quickly after an intraarterial injection of secretin, both in humans and in dogs. The rate of gastrin release from the rat antral G cells in vitro increased significantly when the medium contained secretin. In conclusion, secretin stimulated gastrin release from antral G cells both in vivo and in vitro.     

Effect of synthetic porcine neuropeptide Y (NPY) on splanchnic blood flows and Exocrine pancreatic secretion in dogs

This study examined the effect of synthetic porcine neuropeptide Y on the splanchnic blood flows and the exocrine pancreatic secretion in dogs. Graded doses of neuropeptide Y (0.1–5 g/kg, intravenous) caused dose-dependent reduction of the secretin-stimulated exocrine pancreatic secretion and of the blood flows in the superior mesenteric artery, the portal vein, and the pancreatic tissue. Neuropeptide Y at 5 g/kg reduced the blood flows to 45.9±13.3% (superior mesenteric artery), 63.0±10.5% (portal vein), and 77.9±4.8% (pancreatic tissue), respectively. This dose also reduced secretin-stimulated pancreatic juice volume and CCK-8 plus secretin-stimulated protein output to 65.2±9.3 and 63.3±14.0%, respectively. This study shows a potent vasoconstrictor effect of neuropeptide Y on splanchnic vessels. Neuropeptide Y also inhibited exocrine pancreatic secretion in a significant correlation with the reduction in pancreatic tissue blood flow, which suggests that reduction in the blood flow may be one of the possible mechanisms of the inhibitory action of neuropeptide Y on exocrine secretion.This work was supported by a grant from the Ministry of Education, Japan (A-61440060).     

A framework for discussion on how to improve prevention, management, and control of hypertension in Canada

Increased blood pressure is a leading risk for premature death and disability. The causes of increased blood pressure are intuitive and well known. However, the fundamental basis and means for improving blood pressure control are highly integrated into our complex societal structure both inside and outside our health system and hence require a comprehensive discussion of the pathway forward. A group of Canadian experts was appointed by Hypertension Canada with funding from Public Health Agency of Canada and the Heart and Stroke Foundation of Canada, Canadian Institute for Health Research (HSFC-CIHR) Chair in Hypertension Prevention and Control to draft a discussion Framework for prevention and control of hypertension. The report includes an environmental scan of past and current activities, proposals for key indicators, and targets to be achieved by 2020, and what changes are likely to be required in Canada to achieve the proposed targets. The key targets are to reduce the prevalence of hypertension to 13% of adults and improve control to 78% of those with hypertension. Broad changes in government policy, research, and health services delivery are required for these changes to occur. The Hypertension Framework process is designed to have 3 phases. The first includes the experts' report which is summarized in this report. The second phase is to gather input and priorities for action from individuals and organizations for revision of the Framework. It is hoped the Framework will stimulate discussion and input for its full intended lifespan 2011-2020. The third phase is to work with individuals and organizations on the priorities set in phase 2.     

Respiratory involvement in IgG4-related Mikulicz’s disease

'Immunoglobulin G4 (IgG4)-related disease' is a new clinical concept of multi-organ diseases, with Mikulicz's disease (MD) being a clinical phenotype of IgG4-related disease. To clarify the clinical characteristics of respiratory involvement associated with IgG4-related MD, we retrospectively assessed 25 patients with MD, 11 (44%) of whom had allergic symptoms, and 7 (28%) of whom complained of respiratory problems. Thirteen patients (52%) presented with pulmonary and/or mediastinal lesions (P-MD) on chest computed tomography (CT), and 11 (44%) had lesions limited to the lacrimal and/or salivary glands (L-MD). Mean serum total protein, IgG, and IgG4 concentrations were significantly higher and CH50 was significantly lower in the P-MD than in the L-MD group. Immune complex was present only in the P-MD group. Chest CT images showed bronchial wall thickening, consolidation, nodule(s), interlobular thickening, ground glass opacity, pleural thickening/effusion, and mediastinal lymphadenopathy. Five of seven patients who underwent histological examination of the lungs had abundant IgG4-positive plasma cell infiltrates (IgG4/IgG-positive plasma cells >40%), but the other two did not. These findings suggest that respiratory lesions are not rare in patients with IgG4-related MD, and that they present with various manifestations. IgG4-related MD should be differentiated from similar diseases, such as sarcoidosis, bronchial asthma, Sj?gren's syndrome, and malignant lymphoma.     

Cockroach diuretic hormones: characterization of a calcitonin-like peptide in insects

Insect diuretic hormones are crucial for control of water balance. We isolated from the cockroach Diploptera punctata two diuretic hormones (DH), Dippu-DH(31) and Dippu-DH(46), which increase cAMP production and fluid secretion in Malpighian tubules of several insect species. Dippu-DH(31) and -DH(46) contain 31 and 46 amino acids, respectively. Dippu-DH(46) belongs to the corticotropin-releasing factor (CRF)-like insect DH family, whereas Dippu-DH(31) has little sequence similarity to the CRF-like DH, but is similar to the calcitonin family. Dippu-DH(46) and -DH(31) have synergistic effects in D. punctata but have only additive effects in Locusta migratoria. Dippu-DH(31) represents a distinct type of insect DH with actions that differ from those of previously identified insect peptides with diuretic activity.     

Sequence of an intestinal cDNA encoding human gastric inhibitory polypeptide precursor.

Gastric inhibitory polypeptide (GIP) is a 42-amino acid hormone that stimulates insulin secretion in the presence of glucose. Complementary DNA clones encoding human GIP were isolated from a library prepared with RNA from duodenum. The predicted amino acid sequence indicates that GIP is derived by proteolytic processing of a 153-residue precursor, preproGIP. The GIP moiety is flanked by polypeptide segments of 51 and 60 amino acids at its NH2 and COOH termini, respectively. The former includes a signal peptide of about 21 residues and an NH2-terminal propeptide of 30 amino acids. GIP is released from the precursor by processing at single arginine residues. There is a region of nine amino acids in the COOH-terminal propeptide of the GIP precursor that has partial homology with a portion of chromogranin A as well as pancreastatin.     

Effects of sera from patients with obstructive jaundice on the generation of oxygen intermediates by normal polymorphonuclear leukocytes

Recently it has been suggested that oxygen intermediates play an important role in the pathogenesis of tissue damage. The effect of sera from patients with obstructive jaundice on the generation of oxygen intermediates by normal polymorphonuclear leukocytes (PMNs) was investigated. Sera from patients with obstructive jaundice increased superoxide anion (O2-), hydrogen peroxide (H2O2) and hydroxol radical (OH.) generation compared with sera from healthy individuals or patients with biliary tract stones and/or tumors of the biliary tract or pancreas (without obstructive jaundice). In particular, the hydroxyl radical, which is one of the most potent oxidants capable of causing tissue damage, was produced in large quantities. Sera from patients with obstructive jaundice have a strong capacity to induce production of oxygen intermediates from PMNs, and oxygen intermediates may play a role in the pathogenesis of hepatic and other organ injury in obstructive jaundice.