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Biomedical subjects

J Calam

Publications and source records attributed to J Calam.

At least 73 records · Page 4Linked to original sources
PubMed1994

Reciprocal changes in antral gastrin and somatostatin mRNA in pernicious anemia.

Somatostatin is involved in the regulation of gastrin by intragastric pH in animal models. To investigate whether this is so in man, we measured gastrin and somatostatin mRNA in endoscopic biopsies from six patients with hypergastrinemia and achlorhydria due to pernicious anemia and 12 age- and sex-matched controls. The pernicious anemia patients had significantly higher fasting plasma gastrin concentrations with a median (range) of 640 (420-3500) pmol/liter compared with 5 (2-58) pmol/liter, P < 0.001. The median gastrin mRNA/rRNA ratio was 10.4 (3.7-38.0) in the pernicious anemia patients compared with 1.7 (0.7-8.3) in the controls (P < 0.02), and it correlated strongly with the plasma gastrin concentration, r = 0.93, P < 0.0001. In contrast, the median somatostatin mRNA/rRNA ratio was lower in the pernicious anemia patients 0.84 (0.58-2.32) versus 2.04 (0.05-6.47) in the controls, P < 0.05. These findings suggest that in pernicious anemia gastric neutralization leads to hypergastrinemia through the modulation of antral gastrin synthesis by somatostatin.

Aged↗
PubMed1994

Influence of inflammation and atrophy on pancreatic secretory trypsin inhibitor levels within the gastric mucosa.

BACKGROUND/AIMS: Gastrointestinal epithelia contain a powerful protease inhibitor called pancreatic secretory trypsin inhibitor (PSTI). Gastric mucus obtained from patients with atrophic gastritis or gastric ulceration shows changes suggestive of excessive proteolytic digestion. Therefore, the aim of this study was to examine whether mucosal PSTI levels are affected by gastritis and/or ulceration. METHODS: Mucosal PSTI levels were measured in 12 patients with normal gastric histology and 26 patients with gastritis and/or gastric ulceration. RESULTS: In control subjects, mean gastric PSTI concentrations were 990 ng/mg protein (95% confidence interval, 819-1195) in the antrum and 445 ng/mg protein (95% confidence interval, 395-502) in the body. Immunostaining for PSTI was strongly positive in the pyloric glands of the antrum and in the foveolar/surface and mucus neck cells of the gastric body. Tissue levels of PSTI were reduced by 40% in biopsy specimens showing superficial gastritis (P = 0.035) and by 75% in biopsy specimens showing atrophic gastritis and/or gastric ulceration (P < 0.001). Immunostaining was also reduced in specimens showing atrophic gastritis. CONCLUSIONS: The decrease in tissue PSTI levels associated with gastric atrophy probably represents a permanent reduction in one of the mucosal defense mechanisms. This may lead to the maintenance and even expansion of the gastritic process with time.

Aged↗
PubMed1994

Mesalazine induced interstitial nephritis.

5-Aminosalicylic acid (5-ASA) has structural similarities to both phenacetin and aspirin, which are known to cause 'analgesic nephropathy'. Because of the increasing use of 5-ASA, this paper draws attention to two cases of severe interstitial nephritis resulting from 5-ASA and emphasises the importance of monitoring renal functions of patients with inflammatory bowel diseases who are receiving 5-ASA preparations.

Adult↗
PubMed1994

Cytokine gene expression in Helicobacter pylori associated antral gastritis.

Infection of the gastric antrum by Helicobacter pylori is characterised by a cellular inflammatory infiltrate. Whether cytokines are involved in the pathogenesis of this gastritis has been investigated by studying the effect of eradicating H pylori on the expression of genes encoding the cytokines interleukin 8 (IL-8) and tumour necrosis factor alpha (TNF-alpha) in the antral mucosa. Gastric antral biopsy specimens were taken from nine patients with duodenal ulcers and cytokine transcripts were identified and quantified by northern blotting. After H pylori had been eradicated the chronic inflammatory infiltrate decreased in all the patients and the polymorphonuclear infiltrate virtually disappeared. Expression of genes also decreased. After eradication, the median TNF-alpha mRNA/rRNA fell to 48% (p = 0.02) and the median IL-8 mRNA/rRNA fell to 5% (p = 0.004) of initial values. These results support the role of increased synthesis of these cytokines in the pathogenesis of the gastritis.

Adult↗
PubMed1993

Effect of luminal growth factor preservation on intestinal growth.

Intestinal atrophy contributes to the clinical difficulties of patients who cannot eat normally. Atrophy is prevented by luminal food proteins but not by the equivalent aminoacids. This observation is not explained by current theories of intestinal physiology. Epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) are secreted into the gut lumen. We speculated that these are digested by pancreatic enzymes in fasting juice, but preserved when food proteins block the active sites of these enzymes. Studies based on molecular size and bioactivity confirmed that fasting human jejunal juice destroys EGF and TGF alpha. EGF, but not TGF alpha, was preserved when the milk protein casein or an enzyme inhibitor were present; elemental diets were ineffective. Diversion of pancreatic juice to the mid point of the small intestine in rats significantly increased luminal EGF-like bioactivity and all variables of growth in the proximal enzyme-free segment. Our findings support a novel mechanism of control of intestinal growth, which has important clinical implications. The addition of enzyme-inhibiting proteins such as casein to elemental diets may preserve intestinal integrity and function.

Animals↗
PubMed1993

Use of endoscopic biopsies and microelectrodes to study human gastric acid secretion in vitro.

We have investigated the possibility of measuring acid secretion from human gastric mucosa in vitro as a potential pharmacological preparation. We used open-ended 10 microns-tip, lix-based glass microelectrodes to measure the pH of the mucus layer of gastric biopsies superfused with a HEPES buffered solution in an organ bath. With no drugs added the pH of the mucus layer of biopsies from the body of the stomach stayed constant but the pH of antral biopsies fell slightly by a median of 0.12 pH units over 80 min (P < 0.05). Stimulation of the biopsies with 1-100 microM histamine produced a dose-dependent decrease in pH which was significantly greater in biopsies from the gastric body than from the antrum. 500 pM pentagastrin produced a median fall in pH of 1.20 (P < 0.01) which was prevented by the prior addition of 100 microM omeprazole or 10 microM ranitidine. Omeprazole or ranitidine alone produced slight rises in the median pH of 0.47 (P < 0.05) and 0.26 (P < 0.05) units respectively. Those biopsies which were infected with Helicobacter pylori had a slightly elevated initial pH of about 0.2 of a pH unit (P < 0.05). This novel system provides a means to study human gastric acid secretion in vitro and may be valuable in the testing of new drugs on the stomach.

Adolescent↗
PubMed1993

Inhibitory effect of a cholecystokinin antagonist on pancreatic carcinogenesis after pancreatobiliary diversion.

The role of cholecystokinin (CCK) has been explored in pancreatic carcinogenesis following pancreatobiliary diversion (PBD), using the specific CCK receptor antagonist CR-1409. Male Wistar rats (n = 80) weighing 70-100 g were given weekly i.p. injections of azaserine (30 mg kg-1 week-1) for 3 consecutive weeks. One week later animals were randomised to receive either PBD or sham PBD and thereafter to receive s.c. injections of either saline or CR-1409 (10 mg kg-1 day-1, 5 days a week). Six months after operation surviving rats were killed as follows: sham + saline 20, PBD + saline 19, sham + CR-1409 14, PBD + CR-1409 11. Cardiac blood was taken for CCK assay and the pancreas was excised for wet weight measurement and quantitative estimation of atypical acinar cell foci (AACF), the precursor of carcinoma. PBD reduced median body weight (3-20% less than shams) but trebled the absolute and relative pancreatic weights (P < 0.001). CR-1409 blunted this adaptive response to PBD, reducing absolute pancreatic weight by 35% (P < 0.005). PBD quadrupled circulating CCK concentrations, regardless of the antagonist treatment. Acidophilic AACF occurred only in rats with PBD. CR-1409 markedly reduced the number of observed acidophilic AACF by 90% (P < 0.001) and the number of foci per pancreas by 93% (P < 0.001). Moreover, CR-1409 reduced the mean focal diameter of each lesion by 18% (P < 0.005), the mean focal volume by 58% (P < 0.05) and the percentage of pancreas occupied by acidophilic foci by 95% (P < 0.001). PBD enhances pancreatic carcinogenesis by causing hypercholecystokininaemia, and CR-1409 largely inhibits this enhancement.

Animals↗
PubMed1993

Amino acid infusion blocks renal tubular uptake of an indium-labelled somatostatin analogue.

The Indium-labelled somatostatin analogue pentetreotide has been successfully developed for imaging of somatostatin receptor positive tumours. However there is significant renal tubular uptake of the radiolabelled peptide, which can obscure upper abdominal tumours and would preclude its use for targeted radiotherapy. The aim of this study was to determine whether amino acid infusion, which has been shown to block renal tubular peptide reabsorption, diminishes renal parenchymal uptake of this radiolabelled analogue. Eight patients being scanned with the 111In-labelled somatostatin analogue, pentetreotide, for localisation of gastroenteropancreatic tumours received an infusion of synthetic amino acids. The ratio of isotope uptake in kidney to that in spleen was assessed, and compared to the ratio for matched control patients, to determine if amino acid infusion reduced renal parenchymal uptake of the radiopharmaceutical. The amount of isotope in the urine was determined to ensure that any effect of the amino acid infusion was unrelated to changes in clearance. Infusion of amino acids significantly reduced renal parenchymal uptake of isotope at 4 h. There was a non-significant increase in urinary clearance of isotope over the 4 h, consistent with reduced reuptake and a lack of effect on glomerular filtration rate. This technique, by preventing renal damage, may allow the use of this somatostatin analogue for local radiotherapy, and could be of wider value in blocking tubular re-uptake of potentially nephrotoxic agents, such as radiolabelled Fab fragments.

Adult↗
PubMed1993

Effects of diet and the cholecystokinin antagonist; devazepide (L364,718) on CCK mRNA, and tissue and plasma CCK concentrations.

The mechanisms by which raw soya diets and CCK-receptor antagonists increase postprandial plasma CCK concentrations are not fully understood. Therefore we examined the effects of different diets including raw soya, and the effect of the potent CCK antagonist devazepide in the fed and fasted state on CCK concentrations in plasma and in the duodenal mucosa and on the duodenal CCK:beta-tubulin mRNA ratio in rats. Diets which stimulated high plasma CCK levels, such as raw soya, also gave the highest CCK tissue and mRNA concentrations with a close correlation between plasma and tissue CCK concentrations within each group (r = 0.94, P = 0.018) and between tissue CCK concentrations and CCK:beta-tubulin mRNA ratios (r = 0.91, P = 0.030). Animals fed ad libitum and treated with devazepide (1 mg kg-1) had higher CCK:beta-tubulin mRNA ratios, tissue CCK concentrations and plasma CCK concentrations than animals injected with vehicle. Fasted animals treated with devazepide for 28 h also had higher CCK mRNA:beta-tubulin mRNA ratios (1.86 +/- 0.43 vs. 0.85 +/- 0.15, P < 0.05), and higher tissue CCK concentrations (0.99 +/- 0.09 vs. 0.69 +/- 0.04, P < 0.01). However, despite these intracellular changes devazepide did not elevate plasma CCK concentrations in the fasted state. Therefore, devazepide increases tissue concentrations of CCK but requires an additional dietary stimulus to raise plasma concentrations. These findings indicate that devazepide produces a dissociation between synthesis and release of CCK in fasted animals.

Animals↗
PubMed1993

Acid secretion and sensitivity to gastrin in patients with duodenal ulcer: effect of eradication of Helicobacter pylori.

The effect of ulcer healing with eradication of Helicobacter pylori (H pylori) on gastric function was investigated in nine patients with duodenal ulcer disease. One month after eradication there were significant reductions in both basal plasma gastrin concentration, from a median (range) of 19 (1-22) to 6 (2-15) pmol/l (p < 0.05), and of basal acid secretion from 8.3 (2.4-24) to 2.6 (1.4-8.1) mM H+/h, (p < 0.01). The peak acid secretion rate was unchanged from 37 (16-59) to 37 (21-59) mM H+/h. After treatment there was no change in the parietal cell sensitivity to stepped infusions of gastrin heptadecapeptide: the median concentration of gastrin required for 50% of maximal acid secretion (EC50) was 41 (14.8-126) before and 33 (23-125) pmol/l after eradication of H pylori. The metabolic clearance rate of gastrin was also unaffected by the eradication of H pylori. Thus eradication of H pylori infection from patients with active duodenal ulcers is accompanied by falls in both basal gastrin release and basal acid secretion without a change in the parietal cell sensitivity to gastrin. Cyclical changes in H pylori infection may cause the variations in basal acid secretion that are seen in duodenal ulcer disease.

Acute Disease↗
PubMed1992

Effect of Helicobacter pylori on gastric somatostatin in duodenal ulcer disease.

Infection of the gastric antrum by Helicobacter pylori is associated with recurrent duodenal ulcer disease but the mechanism of ulcerogenesis is unclear. Since pathways inhibiting gastric secretion are defective in patients with duodenal ulcers, we investigated whether H pylori interferes with the normal gastric inhibition that is mediated by somatostatin. We studied 28 patients with active duodenal ulcers in whom H pylori was eradicated successfully. In 18 patients, we measured the density of antral somatostatin-immunoreactive cells and in a further 10 subjects, the amount of somatostatin mRNA before and after eradication of H pylori was determined. After eradication, the median density of somatostatin-immunoreactive cells increased significantly from 9 (range 3-47) to 19 (6-57) cells per mm muscularis mucosa (p = 0.025). The median somatostatin mRNA/rRNA ratio increased from 50 (25-160) to 95 (40-180) (p = 0.01). The number of gastrin cells and quantity of gastrin mRNA did not change significantly. Our results suggest that in duodenal ulcer disease, gastric secretory function is disinhibited through the suppression of mucosal somatostatin.

Adult↗
PubMed1992

Effect of chymotrypsin on human cholecystokinin release: use of clostripain in the validation of a new radioimmunoassay.

We have developed and validated a new radioimmunoassay for cholecystokinin. In order to establish that the antiserum binds large and small forms of CCK to an equal extent, we used the microbial enzyme clostripain, which cleaves large forms of CCK yielding CCK 8. Cleavage by clostripain of synthetic and purified forms of CCK, and CCK extracted at from human jejunum and CCK in human plasma was found not to affect immunoactivity, indicating that the antiserum reacts similarly with all forms of CCK. There is controversy over whether intraduodenal trypsin inhibits release of CCK in man. We used our radioimmunoassay to investigate whether chymotrypsin, rather than trypsin, could be the major mediator of negative feedback control of CCK release. Six normal subjects received an intraduodenal infusion of L-phenylalanine and L-tryptophan on two occasions, with the addition of either 1 g/l bovine chymotrypsin or 1 g/l albumin. Plasma CCK concentrations rose in response to the amino acid infusion, but were not affected by the addition of chymotrypsin, indicating that this enzyme is not a mediator of CCK feedback regulation in man.

Antibody Specificity↗
PubMed1992

Duodenogastric reflux enhances growth and carcinogenesis in the rat pancreas.

Surgery for peptic ulcer disease may increase the risk of pancreatic cancer. The effect of duodenogastric reflux on pancreatic carcinogenesis was tested, and changes in the circulating levels of cholecystokinin (CCK) and gastrin were measured. Male Wistar rats (n = 40) weighing 250-300 g were randomized to undergo gastrotomy (control) or split gastrojejunostomy (to produce complete duodenogastric reflux) and then to receive azaserine (30 mg/kg/week intraperitoneally) or saline injections for 3 weeks. At 6 months, blood CCK was assayed and the pancreas was excised for quantitative estimation of atypical acinar cell foci (AACF), the precursor lesions of carcinoma. Rats that had undergone split gastrojejunostomy weighed 15-19 per cent less than controls (P < 0.05), but their relative pancreatic weight (mg pancreas per 100 g body-weight) was 52-60 per cent greater (P < 0.001). Acidophilic AACF occurred only in azaserine-treated rats with duodenogastric reflux. Although plasma CCK concentrations were unchanged, split gastrojejunostomy increased basal and postprandial gastrin levels by 98-175 per cent (P < 0.05). Duodenogastric reflux produces sustained hypergastrinaemia and promotes experimental pancreatic carcinogenesis.

Anastomosis, Surgical↗
PubMed1992

Enhancing effect of partial gastrectomy on pancreatic carcinogenesis.

The controversial issue of enhanced pancreatic carcinogenesis following partial gastrectomy has been explored in male Wistar rats (n = 40) weighing 250-300 g. Animals were randomised to receive either 60% distal gastrectomy with Roux-en-Y reconstruction or gastrotomy and resuture (control). Immediately after operation each group was further divided into two subgroups, receiving i.p. injections of either saline or azaserine (30 mg kg-1 wk-1 for 3 weeks). At 15 months blood was obtained at 0, 5, 15 and 30 min after a fatty meal for cholecystokinin (CCK) assay; rats were then killed. Pancreatic wet weight was measured, and histological sections were examined for atypical acinar cell foci (AACF), the putative precursor lesion of carcinoma. There were no significant differences in body weight or pancreatic weight between controls and rats with gastrectomy. Only azaserine-treated rats had acidophilic AACF. Partial gastrectomy substantially increased the number of acidophilic AACF per pancreas (median 26.05 vs 2.09; P less than 0.005), with a 9-fold increase in their volume (P less than 0.005). Basal and postprandial plasma CCK concentrations were higher after gastrectomy than in controls (P less than 0.05). Partial gastrectomy has an enhancing effect on azaserine-induced pancreatic carcinogenesis, probably by means of increased CCK release.

Anastomosis, Roux-en-Y↗
PubMed1992

Sucralfate diminishes basal acid output without affecting gastrin, H. pylori or gastritis in duodenal ulcer patients.

Twelve patients with active duodenal ulcer disease and Helicobacter pylori infection were treated with 1 g sucralfate q.d.s. for 1 month. Ulcers healed in 8 of the 12 patients without an alteration in the H. pylori-associated antral gastritis. Sucralfate produced a significant fall in basal acid output in all the patients, from a median of 4.8 (range 2.1-12.1) to 1.6 (0.4-8) mmol/h, P less than 0.01, whereas peak acid output was unchanged from 41 (21-59) before to 38 (24-55) mmol/h after treatment. Basal plasma gastrin concentrations and the meal-stimulated integrated gastrin response were not altered significantly by sucralfate: 8 (2-17) pmol/L and 732 (188-1045) pmol. min/L pre-treatment and 6 (2-17) pmol/L and 600 (140-1302) pmol. min/L post-treatment, respectively. The fall in basal acid output observed may contribute to prolonged duodenal ulcer remission after treatment with sucralfate.

Adult↗