Autoantibodies to gastrin in patients with pernicious anaemia--a novel antibody.
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Autoantibodies arise when there is a breakdown in immunological tolerance. Autoantibodies to parietal cells and intrinsic factor are found in autoimmune atrophic gastritis (AAG) and are associated with elevated plasma gastrin. Endogenous gastrin autoantibodies have not been described to date. The aim of this study was to investigate the occurrence of autoantibodies to gastrin. Plasma from 50,000 patients, including more than 2000 with AAG, was tested. Gastrin was measured by radioimmunoassay (RIA) in whole plasma and the presence of autoantibody determined by using a control which omitted assay antibody. The quantity and affinity of gastrin autoantibodies was assessed. Three patients had autoantibodies to gastrin. All three had AAG and pernicious anaemia (PA). The antibodies were of low titre and relatively high affinity. Free circulating plasma gastrin levels were within the normal range, but total gastrin levels were elevated. This is the first description of autoantibodies to endogenous gastrin. The incidence of antibodies to gastrin is low, they are found in association with PA, and they may lead to falsely low measurements of plasma gastrin. (+info)
Proliferative effects of cholecystokinin in GH3 pituitary cells mediated by CCK2 receptors and potentiated by insulin.
(2/1487)
1. Proliferative effects of CCK peptides have been examined in rat anterior pituitary GH3 cells, which express CCK2 receptors. 2. CCK-8s, gastrin(1-17) and its glycine-extended precursor G(1-17)-Gly, previously reported to cause proliferation via putative novel sites on AR4-2J and Swiss 3T3 cells, elicited significant dose dependent increases of similar magnitude in [3H]thymidine incorporation over 3 days in serum-free medium of 39 +/- 10% (P < 0.01, n = 20), 37 +/- 8% (P < 0.01, n = 27) and 41 +/- 6% (P < 0.01, n = 36) respectively. 3. CCK-8s and gastrin potentially stimulated mitogenesis (EC50 values 0.12 nM and 3.0 nM respectively), whilst G-Gly displayed similar efficacy but markedly lower potency. L-365,260 consistently blocked each peptide. The CCK2 receptor affinity of G-Gly in GH3 cells was 1.09 microM (1.01;1.17, n = 6) and 5.53 microM (3.71;5.99, n = 4) in guinea-pig cortex. 4. 1 microM G-Gly weakly stimulated Ca2+ increase, eliciting a 104 +/- 21% increase over basal Ca2+ levels, and was blocked by 1 microM L-365,260 whilst CCK-8s (100 nM) produced a much larger Ca2+ response (331 +/- 14%). 5. Insulin dose dependently enhanced proliferative effects of CCK-8s with a maximal leftwards shift of the CCK-8s curve at 100 ng ml(-1) (17 nM) (EC50 decreased 500 fold, from 0.1 nM to 0.2 pM; P < 0.0001). 10 microg ml(-1) insulin was supramaximal reducing the EC50 to 5 pM (P = 0.027) whilst 1 ng ml(-1) insulin was ineffective. Insulin weakly displaced [125I]BHCCK binding to GH3 CCK2 receptors (IC50 3.6 microM). 6. Results are consistent with mediation of G-Gly effects via CCK2 receptors in GH3 cells and reinforce the role of CCK2 receptors in control of cell growth. Effects of insulin in enhancing CCK proliferative potency may suggest that CCK2 and insulin receptors converge on common intracellular targets and indicates that mitogenic stimuli are influenced by the combination of extracellular factors present. (+info)
RIN ZF, a novel zinc finger gene, encodes proteins that bind to the CACC element of the gastrin promoter.
(3/1487)
Expression of gastrin, a gut hormone and growth factor, has tissue-specific transcriptional regulation and can be induced in some tumors. Previous studies have shown that a CACC cis-regulatory element is important for transcriptional activation in pancreatic insulinoma cells. To identify CACC-binding proteins, a lambda phage cDNA library derived from a rat insulinoma cell line, RIN 38A, was screened by a Southwestern method. A novel member of the Cys2-His2 zinc finger gene family was cloned and designated RIN ZF, having a cDNA sequence of 3.8 kilobases. One full-length and a shorter splice variant were sequenced and had predicted protein masses of 91.6 and 88.7 kDa. Expression of both splice forms were ubiquitous in fetal and adult rat tissues. Recombinant RIN ZF protein exhibited sequence-specific binding to the gastrin CACC element in a gel mobility shift assay. In transient transfections, both splice variants appeared to have only weak activating effects on gastrin-luciferase reporter gene transcription. Furthermore, RIN ZF coexpression with Sp1 appeared to block the strongly activating effects of Sp1 mediated through the CACC element. These findings suggest that a novel set of zinc finger proteins may help regulate gastrin gene expression by interfering with Sp1 transactivation. (+info)
Helicobacter pylori infection potentiates the inhibition of gastric acid secretion by omeprazole.
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BACKGROUND: Omeprazole has a greater intragastric pH elevating effect in Helicobacter pylori positive than negative subjects. Ammonia production by H pylori has been suggested as a probable mechanism. AIMS: To assess the effect of H pylori status on gastric acid secretion during omeprazole treatment, and to examine the possible role of ammonia neutralisation of intragastric acid in increased omeprazole efficacy in infected subjects. METHODS: Twenty H pylori positive and 12 H pylori negative healthy volunteers were examined before and six to eight weeks after commencing omeprazole 40 mg/day. On both occasions plasma gastrin and acid output were measured basally and in response to increasing doses of gastrin 17 (G-17). Gastric juice ammonium concentrations were also measured. RESULTS: Prior to omeprazole, measurements were similar in the H pylori positive and negative subjects. During omeprazole, median basal intragastric pH was higher in the H pylori positive (7.95) versus negative (3.75) subjects (p<0.002). During omeprazole basal, submaximal (180 pmol/kg/h G-17), and maximal acid outputs (800 pmol/kg/h G-17) were lower in H pylori positive subjects (0.0, 3.6, 6.0 mmol/h respectively) versus negative subjects (0.3, 14.2, 18.6 mmol/h) (p<0.03 for each). This effect was not explained by neutralisation by ammonia. CONCLUSION: The presence of H pylori infection leads to a more profound suppression of acid secretion during omeprazole treatment. The effect cannot be explained by neutralisation of intragastric acid by bacterial ammonia production and its precise mechanism has to be explained. (+info)
Gastrin stimulates the formation of a p60Src/p125FAK complex upstream of the phosphatidylinositol 3-kinase signaling pathway.
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The molecular events whereby gastrin occupancy of G/CCK(B) receptors leads to phosphatidylinositol (PI) 3-kinase activation have been examined. We report here that this peptide promotes the association between two non-receptor tyrosine kinases, p60Src and p125FAK, and elicits a parallel increase in tyrosine phosphorylation and activity of both kinases. Gastrin-induced PI 3-kinase activity was coprecipitated with p60Src and p125FAK and was inhibited by herbimycin A, the selective Src inhibitor PP-2 or cytochalasin D, which disrupts the actin cytoskeleton and prevents p125FAK activity. These results indicate, for the first time, that a p60Src/p125FAK complex acts upstream of the gastrin-stimulated PI 3-kinase pathway. (+info)
Serum gastrin and chromogranin A during medium- and long-term acid suppressive therapy: a case-control study.
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BACKGROUND: Serum chromogranin A (CgA) is regarded as a reliable marker of neuroendocrine proliferation. We previously described increased serum CgA levels during short-term profound gastric acid inhibition. AIM: To investigate serum gastrin and CgA levels in dyspeptic patients during continuous medium- (6 weeks to 1 year), or long-term (1-8 years) gastric acid suppressive therapy. PATIENTS AND METHODS: 114 consecutive dyspeptic patients referred for upper gastrointestinal endoscopy were enrolled in a cross-sectional, case-control study [62 patients on continuous antisecretory therapy, either with proton pump inhibitors (n = 47) or H2-receptor antagonists (H2RA) (n = 15) for gastro-oesophageal reflux disease with or without Barrett's oesophagus or functional dyspepsia, and 52 age- and sex-matched patients without medical acid inhibition and with normal endoscopic findings (control group)]. Omeprazole doses ranged from 20 mg to 80 mg daily and ranitidine from 150 mg to 450 mg daily. Fasting serum CgA and serum gastrin levels were measured by radioimmunoassay (reference values: serum CgA < 4.0 nmol/L; serum gastrin < 85 ng/L). RESULTS: Fasting serum CgA levels positively correlated with serum gastrin in the entire study population (r = 0. 55, P = 0.0001). Median serum CgA values were higher in patients treated with a proton pump inhibitor than H2RA [2.8 (2.0-5.9) nmol/L vs. 2 (1.9-2.3) nmol/L, P < 0.002] and controls [2.8 (2.0-5.9) nmol/L vs. 1.8 (1.5-2.2) nmol/L, P < 0.0001) and did not differ between patients treated with H2RA or controls. Serum gastrin and CgA levels in patients on proton pump inhibitor therapy positively correlated with the degree and duration of acid inhibition. Patients on long-term proton pump inhibitor therapy had significantly higher fasting serum gastrin and CgA than those on medium-term proton pump inhibitor therapy [127 (73-217) ng/L vs. 49 (29-78) ng/L, P < 0.0001 and 4.8 (2.8-8) ng/L vs. 2.1 (1.9-2.6) ng/L, P < 0.001]. No such relation was found in patients on medium- vs. long-term H2RA. Overall, patients with positive Helicobacter pylori serology had higher serum gastrin and CgA levels than those with negative H. pylori serology [51 (27-119) ng/L vs. 27 (14-79) ng/L, P = 0.01, 2.4 (1.9-3.4) nmol/L vs. 2.0 (1.7-2.5) nmol/L, P = 0.05]. CONCLUSIONS: During long-term continuous proton pump inhibitor treatment, serum gastrin and CgA levels are significantly elevated compared to H2RA treatment and nontreated dyspeptic controls. H. pylori infection seems to affect gastric ECL cell secretory function. Increased serum CgA values during long-term profound gastric acid inhibition could reflect either gastric enterochromaffin-like cell hyperfunction or proliferative changes. (+info)
Comparison of rabeprazole 20 mg versus omeprazole 20 mg in the treatment of active duodenal ulcer: a European multicentre study.
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BACKGROUND: Rabeprazole sodium is the newest member of a class of substituted benzimidazole molecules known as proton pump inhibitors. Other proton pump inhibitors have been shown to be effective in healing active duodenal ulcer. METHOD: This randomized, double-blind, multicentre study, conducted at 25 European sites, compared the efficacy and tolerability of rabeprazole and omeprazole in patients with active duodenal ulcers. One hundred and two patients with active duodenal ulcer received rabeprazole 20 mg and 103 patients omeprazole 20 mg once daily for 2 or 4 weeks, with ulcer healing monitored by endoscopy. RESULTS: After 2 weeks, complete ulcer healing was documented in 69% of patients given rabeprazole 20 mg and in 62% of patients given omeprazole 20 mg (N.S.). After 4 weeks, healing rates were 98% in the rabeprazole group and 93% in the omeprazole group (P = 0.083). Rabeprazole-treated patients had significantly greater improvement in daytime pain symptom relief than those treated with omeprazole at the conclusion of the study (P = 0.038). Both drugs were well tolerated over the 4-week treatment period. Mean changes from baseline to end-point in fasting serum gastrin were significantly greater in the rabeprazole group, but at end-point mean values were well within normal limits for both groups. No clinically meaningful changes or other between-group differences were observed in laboratory parameters. CONCLUSION: In this study, rabeprazole produced healing rates equivalent to omeprazole at weeks 2 and 4, and provided significantly greater improvement in daytime pain. Both treatments were well tolerated. (+info)
Mouse model of Helicobacter pylori infection: studies of gastric function and ulcer healing.
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BACKGROUND: Helicobacter pylori infection in humans is a major risk factor for peptic ulcer, but studies on the relation between H. pylori infection and gastric pathology are limited due to a deficiency of convenient animal models resembling this infection in humans. METHODS: We studied the effects of inoculation of conventional BALB/c mice with CagA and VacA positive (type I) H. pylori or CagA and VacA negative H. pylori (type II) strains on gastric secretion and healing of chronic acetic acid-induced ulcers in mouse stomachs. The ulcer area, gastric blood flow, plasma interleukin (IL)-1beta and IL-12, as well as plasma gastrin and gastric luminal somatostatin were determined. Gastric mucosal biopsy samples were also taken for assessment of the presence of viable H. pylori using a rapid urease test, H. pylori-culture and the RT-PCR analysis of the signal for H. pylori CagA. RESULTS: Gastric acid and pepsin secretion was reduced by over 50% immediately after H. pylori inoculation and accompanied by a significant increment in plasma gastrin and fall in gastric luminal somatostatin content observed over all test days, particularly in mice infected with type I H. pylori. The area of ulcers in vehicle-treated controls decreased significantly starting from day 2 after ulcer induction and then continued to decline for a further 14 days to heal almost completely after 28 days. In contrast, the ulcers were present until day 28 in all mice infected with type I or type II H. pylori strains, being significantly larger, especially with type I H. pylori infection. The gastric blood flow at the ulcer margin and ulcer crater in vehicle-treated mice gradually increased with decreasing ulcer size, after 14 and 28 days reaching a value which was not significantly different from that in vehicle-administered mice. In contrast, the gastric blood flow in type I H. pylori and, to a lesser extent, in type II H. pylori infected mice was significantly lower than in vehicle controls, both at the margin and at the crater of ulcers at all tested days. Histological changes such as oedema or congestion of surface epithelium were found after 7 days whereas mucosal inflammatory infiltration appeared after 14 days with a further increase after 28 days, especially in type I H. pylori and to a lesser extent in type II H. pylori infected mice. Plasma IL-1beta and IL-12 were significantly elevated at all tested days of ulcer healing and their increments were significantly higher in type I than in type II H. pylori infection. CONCLUSIONS: Conventional mice with gastric ulcers can be successfully infected by both toxigenic and nontoxigenic H. pylori strains, and this infection causes an immediate suppression of gastric secretion and markedly delays the healing of ulcers due to the fall in mucosal microcirculation in the ulcer region, cytokine release and an impairment in the gastrin-somatostatin link that appears to be independent of gastritis and more pronounced with infection of toxigenic than nontoxigenic strains. (+info)