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Biomedical subjects

J Calam

Publications and source records attributed to J Calam.

At least 55 records · Page 3Linked to original sources
PubMed1995

Epidermal growth factor is digested to smaller, less active forms in acidic gastric juice.

BACKGROUND/AIMS: Epidermal growth factor (EGF) is present in gastric juice and has potent mitogenic properties. The stability of EGF in gastric juice under various physiological and pathophysiological conditions was examined. METHODS: Recombinant human EGF1-53 was incubated with HCl containing pepsin. We also determined the forms of EGF present in the gastric juice of patients under basal conditions, patients taking the acid suppressant omeprazole, patients with achlorhydria, and volunteers undergoing intragastric neutralization with NaHCO3 (n = 6 per group). Samples were analyzed using mass spectroscopy and/or high-pressure liquid chromatography followed by radioimmunoassay. The effect of acid and pepsin digestion on EGF bioactivity was determined using an in vitro hepatocyte bioassay and an in vivo cytoprotection assay in the rat stomach. RESULTS: EGF1-53 was digested to the EGF1-49 and EGF1-46 forms in all samples containing pepsin when the pH was < 4. In gastric juice samples with pH > 4, the proportion of intact EGF increased to about 60%. For both methods of bioassay, intact EGF1-53 was about 3-4 times as potent as acid and pepsin-treated EGF. CONCLUSIONS: EGF is produced in the 1-53 form but is rapidly cleaved to smaller, less active forms in acidic gastric juice. In contrast, only a small proportion of the EGF is cleaved if the pH is maintained above 4. This mechanism may be relevant to the healing process of acid suppressants.

Achlorhydria↗
PubMed1995

Pathogenic mechanisms.

Research is asking how H. pylori causes diseases, and also why the same bacteria produces different conditions in different persons. The process involves bacterial factors and the host's response. Some bacterial factors such as urease are produced by all strains of H. pylori. This enzyme may damage the gastric epithelium by practically releasing ammonia. Other bacterial factors such as vacuolating toxin are only produced by some strains, and these strains are more likely to cause ulcers or cancer. The host's response has been studied by physiologists, immunologists, and histologists, but the separation of systems is artificial. For example, physiologists find that H. pylori stops gastric D-cells from expressing somatostatin normally, which impairs reflex inhibition of acid secretion, but the D-cell malfunction is probably due to inflammatory factors. In H. pylori gastritis, the gastric epithelial cells behave like immunocytes and express class II molecules and cytokines such as interleukin-8. The patient's histological response to H. pylori is quite closely related to the disease outcome. Patients who respond by developing gastric atrophy are more likely to get gastric ulcers or stomach cancer, but patients whose gastric corpus remains healthy tend to secrete more acid and develop duodenal ulcers, particularly if they have gastric metaplasia in their duodenum. Studies of disease mechanisms provide a valuable insight into the development of these common diseases, and may enable us to identify at-risk groups who particularly merit eradication therapy.

Animals↗
PubMed1995

Diets causing taurine depletion in cats substantially elevate postprandial plasma cholecystokinin concentration.

Excessive secretion of the intestinal hormone cholecystokinin (CCK) was postulated to cause diet-related taurine depletion in cats. To test this hypothesis, plasma CCK-like immunoreactivity (CCK-LI) was measured in cats given four diets, two purified and two canned, that contained similar concentrations of protein, fat, moisture and taurine but produced variable rates of taurine depletion. Plasma CCK-LI was measured by RIA with a tyrosine-sulfate specific, C-terminal anti-serum, validated for use in cat plasma. As indicated by measurements of taurine in whole blood and urine, a purified diet containing casein maintained body taurine, whereas the same diet containing soybean protein and a commercial canned diet preserved either by freezing or cooking depleted body taurine. Preprandial and peak postprandial plasma CCK-LI in cats given the casein-containing diet were 10.6 +/- 1.4 and 27.6 +/- 4.8 pmol/L, respectively, approximately two- to tenfold greater than those reported in humans. Integrated postprandial plasma CCK-LI was less for cats given the casein diet than cats given both forms of the canned diet; it tended to be lower in cats given the casein diet than in cats given the soy protein diet. A negative linear correlation was observed between apparent nitrogen digestibilities of the diets and integrated plasma CCK-LI. The results indicated that diets that cause taurine depletion have lower protein digestibilities and cause greater endocrine secretion of CCK than diets that maintain body taurine status.

Animals↗
PubMed1995

Effect of peptide YY on human renal function.

Peptide YY (PYY) is released from the intestine into the circulation in response to ingestion of food. As PYY/neuropeptide Y (NPY) receptors have recently been identified in the human kidney, we examined the effect of PYY on human renal function. Male subjects (6 per group) received control infusate or PYY at 0.4 or 1.2 pmol.kg-1.min-1 intravenously for 90 min with control periods before and after. Infusion of PYY at the lower dose reproduced normal postprandial plasma concentrations and caused significant decreases in glomerular filtration rate (10% reduction), plasma renin activity (30% reduction), and aldosterone levels while increasing sodium excretion by approximately 30% (all P < 0.01). Infusion of PYY at the higher dose, which reproduced plasma levels seen during a diarrheal illness, resulted in similar changes in renal function and also reduced renal plasma flow by approximately 10% (P < 0.05). Therefore, PYY may be an important mediator of the normal postprandial natriuretic response, and PYY agonists could provide a novel approach to the treatment of patients with sodium overload.

Adult↗
PubMed1995

The somatostatin-gastrin link of Helicobacter pylori infection.

Helicobacter pylori is the new-found cause of duodenal ulcers (DU), but acid secretion remains necessary and is elevated in DU patients. My group and others have asked whether H. pylori itself alters gastric physiology. This infection has been found to decrease local expression of the inhibitory peptide somatostatin, and to increase release of the acid-stimulating hormone gastrin. H. pylori infection can alter acid secretion in both directions. Acid disappears temporarily on first infection, and may dwindle later if H. pylori causes gastric atrophy. DU patients have approximately twice the normal parietal cell mass, which increases their maximal secretory capacity, but it is not clear whether or not this is due to H. pylori. However, the infection certainly does change physiological control of acid secretion, as expected from the endocrine changes. Acid secretion is elevated during fasting, during stimulation with an acidic meal and during infusions of gastrin-releasing peptide. The balance between these opposing effects of H. pylori on acid may be crucial in determining the clinical outcome of H. pylori infection. High-acid secretion leads to DUs whilst low acid secretion is found in patients with gastric ulcers and gastric cancer. Inflammatory cytokines released in H. pylori gastritis may cause some of these changes in gastric physiology.

Animals↗
PubMed1995

Helicobacter pylori, acid and gastrin.

Before the discovery of Helicobacter pylori, duodenal ulcers were thought to be caused by excessive acid secretion. Duodenal ulcer patients have more parietal cells than controls. In addition, they cannot suppress their acid secretion when the gastric lumen is empty or acidic. These changes, plus an increase in the release of gastrin were attributed to a paucity of the inhibitory peptide somatostatin in the gastric mucosa. It has now been established that the paucity of somatostatin and the failure to suppress acid secretion are actually the result of H. pylori infection. In patients without duodenal ulcers H. pylori infection is often associated with decreased acid secretion. This occurs on first infection and also later because H. pylori gastritis predisposes to gastric atrophy.

Duodenal Ulcer↗
PubMed1995

Influence of inflammatory bowel disease on the distribution and concentration of pancreatic secretory trypsin inhibitor within the colon.

Gastrointestinal epithelia contain a powerful protease inhibitor called pancreatic secretory trypsin inhibitor (PSTI). Patients with inflammatory bowel disease have changes in mucus structure suggestive of increased proteolysis. We therefore examined the distribution and concentration of PSTI in the colon of normal subjects and patients with inflammatory bowel disease. In normal subjects (N = 12), mucosal levels of PSTI were approximately 200 ng/mg protein in all regions of the colon and was localized to goblet and endocrine cells. Mucosal PSTI levels in the (affected) left side of the colon of patients with active (N = 12) or quiescent (N = 10) ulcerative colitis were reduced (approximately 80% of control in descending colon, 55% of control in sigmoid colon, and 50% of control in rectum, all P < 0.01), whereas levels in the (unaffected) right side of the colon were normal. PSTI levels were also reduced to approximately 65% of control in colonic tissue affected by Crohn's disease (N = 6, P = 0.01) and immunostaining showed PSTI positivity within the ulcer-associated cell lineage. As the mucous layer is important in preserving mucosal integrity, our finding of prolonged reduction in mucosal PSTI levels after an episode of ulcerative colitis probably represents a long-term reduction in a mucosal defense mechanisms that could lead to increased susceptibility to episodes of inflammation.

Colitis, Ulcerative↗
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↗