Iradj Sobhani

Chronic endogenous hypergastrinemia in humans: Evidence for a mitogenic effect on the colonic mucosa

BACKGROUNDnInformation concerning the influence that gastrin may exert on the colon is fragmentary and somewhat controversial. This study analyzed the effect of chronic endogenous hypergastrinemia on cell proliferation and tumor occurrence in the human colonic mucosa.nnnMETHODSnTwenty-three consecutive hypergastrinemic patients presenting with the Zollinger-Ellison syndrome and 18 normogastrinemic subjects were studied. All had fasting serum gastrin determination, colonoscopy, and cell kinetic measurement in two colonic sites using in vitro 5-bromodeoxyuridine incorporation.nnnRESULTSnMacroscopic tumors, one endocrine and five adenomas, were found in 5 of 23 hypergastrinemic patients, without apparent relationship with the level of gastrin. The labeling indices were significantly higher in hypergastrinemic than in normogastrinemic individuals in the right and left colon, (P < 0.002 to P < 0.001) without resulting in colonic cell hyperplasia. There was no correlation between labeling indices and serum gastrin concentrations or duration of hypergastrinemia. The DNA labeling distribution along the crypt was normal in the two groups, without expansion of the proliferative zone towards the surface.nnnCONCLUSIONSnThese results showed for the first time that long-lasting endogenous hypergastrinemia is accompanied by increased in vivo cell proliferation in the human colonic mucosa. However, the prevalence of adenomas (17.4%) in patients, all more than 50 years old, may not be different from that in the general population.

The H3 receptor is involved in cholecystokinin inhibition of food intake in rats.

We investigated the peripheral effects of an H3-receptor agonist and an H3-receptor antagonist (R)alpha-methylhistamine (Ralpha-MeHA) and thioperamide, respectively, on basal feeding and the CCK8-induced inhibition of food intake in rat. Intraperitoneal injection of thioperamide reduced food intake in a dose-dependent manner with maximal inhibition (35%, P<0.01 vs saline) at 3 mg/kg. (R)alpha-MeHA (0.3-3 mg/kg i.p.), an H3-receptor agonist alone had no effect on feeding but reversed the thioperamide-induced inhibition of food intake in a dose-dependent manner. The maximal feeding inhibitory dose of thioperamide (3 mg.kg i.p) increased by 40% and 22 % (P<0.01 vs saline) brain and stomach histamine contents, respectively. Histamine (0.3 - 6 mg/kg i.p.) and CCK-8 (3 - 30 microg/kg i.p) also inhibited food intake in a dose-dependent manner. Inhibition was 20% to 40% for histamine and 40% to 80% (P<0.01 vs saline) for CCK8. CCK-8 inhibition of feeding was increased by thioperamide and prevented by (R)alpha-MeHA in a dose-dependent way. In addition, CCK-8 did not reduce food intake if rats were pretreated with pyrilamine or ranitidine postsynaptic H1- and H2-receptor antagonists respectively. Our data suggest that the H3-receptor is involved in basal feeding. They also suggest that CCK satiety depends upon the release of histamine which acts on the H2- and H1-receptors, the final mediators of this effect.

Regulation of platelet-activating factor production in gastric epithelial cells

The authors have previously reported that platelet‐activating factor (PAF), a phospholipid mediator with potent proinflammatory activities, is produced in the gastric mucosa and stimulates gastric acid secretion in humans and animals. In the present study they used the human gastric tumour cells HGT1 (clone 6) to examine whether PAF production is regulated by neuromediators. PAF was extracted by ethanol and assayed by the washed platelet aggregation test. HGT1 cells produced PAF spontaneously (110u2003±u200320u2003pgu2003106 cells). The addition of vasoactive intestinal peptide (VIP; 10−9 to 10−7u2003molu2003L−1) or of histamine (10−5 to 10−3u2003molu2003L−1) increased PAF production by three‐ to fivefold, while the addition of carbachol (10−7 to 10−4u2003molu2003L−1) increased PAF production up to sevenfold. PAF production was also increased up to 10‐ to 13‐fold, in a dose‐ and time‐dependent manner, by the addition of calcium and two‐ to threefold by the addition of phorbol myristate acetate (PMA; 10−7 to 10−5u2003molu2003L−1). However, the addition of dibutyryl cyclic AMP (dBcAMP; 10−6 to 10−4u2003molu2003L−1) was without any effect. This is the first report showing PAF production by gastric epithelial cells in response to histamine, VIP and carbachol. Furthermore, the findings are consistent with a central role of calcium in this production. The results of this study, together with those of previous studies from the authors’ laboratory, support the hypothesis that PAF is a physiological mediator of gastric acid secretion.

A diffuse T lymphocytic gastrointestinal mucosal infiltration associated with Sjögren's syndrome resulting in a watery diarrhea syndrome and responsive to immunosuppressive therapy

We report the case of a 45-yr-old white man, investigated for chronic diarrea, malabsorption and weight loss associated with sicca syndrome. Endoscopic and x-ray examinations showed normal macroscopic mucosa in gastrointestinal tract (GIT). Immunohistochemistry showed diffuse polyclonal T cell lymphocytes infiltrating either epithelium and lamina propria in GIT. There was no villous atrophy in the jejunum and ileum. Corticosteroids, azathioprine, and cyclosporine failed to improve symptoms. Monthly intravenous ciclophosphamide administered over 1 yr, stopped the diarrhea and weight loss. The patient is free of symptoms up to a 5-yr follow-up.

Regression of rectal stenosis secondary to neoplasm in an HIV1-Positive patient with gancyclovir antiviral therapy

PURPOSE: The case of a human immunodeficiency viruspositive patient with rectal stenosis caused by a tumor that completely regressed in response to gancyclovir is presented. METHODS: Several biopsies from the tumoral mass failed to show any stigmata of non-Hodgkins lymphoma, adenocarcinoma, or Kaposi sarcoma. No parasites could be detected in rectal biopsies. Viral inclusions showing both Epstein-Barr virus and cytomegalovirus on immunostained sections suggested an unusual form of viral infection. RESULTS: Antiviral therapy (gancyclovir 10 mg/kg/day) had a dramatic effect on pain and discharge of blood, and suppressed rectal difficulties within three days of therapy. The antiviral treatment was stopped at Day 10 because of leukopenia. Endoscopic and histologic examinations revealed normal rectal mucosa after 3, 6, 9, 12, and 18 months of follow-up. CONCLUSION: This is the first case of complete and long-term regression of a rectal stenosis secondary to a tumoral mass in response to antiviral therapy in patients with human immunodeficiency virus.

Stimulation by Bombesin of Gastrin Release from Human Gastrinoma Cells in Long‐Term Cultures

Tumor tissue was derived from a pancreatic tumor (tumor I) and an hepatic metastasis (tumor 11) of a different tumor. After mincing, the fragments were exposed to a solution containing 0.25% collagenase (type V, Sigma Chemical Co., St. Louis, MO), 15 mM HEPES and 0.2% bovine serum albumin for one hour. Cells were counted, tested for viability, and then plated onto collagen-coated dishes at a density of 2-4 x lo6 cells per dish. Culture medium was composed of Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal calf serum, antibiotics, and hormones. Two separate culture groups were initiated for each tumor. Culture medium was changed once a week during the first month of culture and biweekly thereafter. Specimens of the tumors and of the cultures in situ were fixed (a ) in Bouin’s solution for light microscopy and (6) in 2.5% glutaraldehyde with post-fixation in 1% osmium tetroxide for ultrastructural studies. Immunohistochemistry was performed by the peroxidase-anti-peroxidase technique according to Sternberger’s method: using a human anti-gastrin-1 7 carboxyl terminus antiserum at 1 : 1000 dilution. Each day of the secretory studies, the medium was changed, either to Hanks’ balanced salt solution alone (HBSS-CMF, calciumand magnesium-free) or with Ca2+ (HBSS-Ca2+) or to DMEM. Following 2-hr exposure to these control solutions for determination of basal gastrin release, the cultures were incubated with the secretagogue (BBS) for 2 hr. Gastrin (G-17) released into the medium was determined by radioimmunoassay, and data was expressed as percentage of basal release (n = 3). The non-parametric Mann and Whitney Utest was used for significance (p < 0.05).