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Biomedical subjects

S R Bloom

Publications and source records attributed to S R Bloom.

At least 541 records · Page 30Linked to original sources

Elevated plasma enteroglucagon alone fails to alter distal colonic carcinogenesis in rats.

The effect of physiologic increases of plasma enteroglucagon, induced by massive bypass or resection of small bowel, on large bowel cell turnover and carcinogenesis was studied in rats in which the distal colon was isolated as a mucous fistula. After injections of azoxymethane, either 85% end-to-side jejunoileal bypass, 85% jejunoileal resection, or sham bypass was performed. Controls underwent colonic transection and resuture, azoxymethane treatment, and then sham bypass. Thirty weeks later the plasma enteroglucagon level had almost trebled after jejunoileal bypass (p less than 0.001) and almost doubled after jejunoileal resection (p less than 0.002) when compared with sham bypass; sham values did not differ from controls. The median number of tumors per rat in the distal (defunctioned) colon fell from 2 to 0 (p less than 0.05). Segmental weight fell by 45% (p less than 0.001) and crypt cell production rate by 75% (p less than 0.001). Neither tumor yield nor adaptation was affected by jejunoileal bypass or jejunoileal resection. Plasma enteroglucagon has no effect on colonic cell turnover or carcinogenesis in the absence of luminal content.

Animals↗

Escape of the response to a long-acting somatostatin analogue (SMS 201-995) in patients with VIPoma.

Two patients with severe secretory diarrhea due to metastatic vasoactive intestinal peptidoma were treated with a synthetic somatostatin analogue in an attempt to control the patients' vasoactive intestinal peptide-related symptoms. In both patients, a good initial response to this treatment could be demonstrated; not only did diarrhea subside but there was also a dramatic fall in vasoactive intestinal peptide plasma levels. However, after 11 and 4 days respectively, diarrhea recurred accompanied by a rise in vasoactive intestinal peptide plasma levels. In fact, under treatment with the somatostatin analogue and with natural somatostatin, a significant rebound state was observed regarding diarrhea as well as vasoactive intestinal peptide levels, which caused considerable difficulty in the clinical management in 1 patient. This patient had to undergo surgery. In the second patient, the responsiveness to somatostatin analogue returned a few days after discontinuation of the treatment, lasting, however, for a short period only. The possible mechanism of this escape and rebound with somatostatin treatment is discussed.

Adenoma, Islet Cell↗

Renal function during bovine neurotensin infusion in man.

The peptide hormone neurotensin (NT) is found mainly in gut endocrine cells of the ileum, but has also been identified as a putative neurotransmitter in the central and peripheral nervous systems. It may have a dual role as a circulating gastrointestinal hormone and peripheral neurotransmitter. Its predominant effects are to reduce oesophageal sphincter tone, inhibit gastric secretion and emptying and inhibit intestinal motility, but stimulate intestinal and pancreatic exocrine secretion; NT-like immunoreactivity has been found in kidney and therefore NT may influence renal function. When infused i.v. in rabbits it causes antinatriuresis. We have studied its renal effects in 11 healthy males by i.v. infusion under conditions of altered dietary sodium. Postprandial circulating neurotensin levels were reproduced by infusion. There were no consistent systemic or renal haemodynamic effects. Plasma electrolytes and renin did not change. Only renal chloride excretion changed significantly, falling by ca. 30%, and recovering after infusion. There is no evidence for a specific renal tubular chloride transport mechanism, but coupled cotransport, Na+:K+:2CI-, may be hormonally regulated. NT might stimulate this process and contribute to the renal response to changes in dietary composition, especially sodium intake.

Adult↗

Expression of the C-terminal flanking peptide of human progastrin in human gastroduodenal mucosa, G-cell hyperplasia and islet cell tumours producing gastrin.

Three antisera to the C-terminally extended form of gastrin or the C-terminal flanking peptide of progastrin were used in an attempt to investigate the post-translational processing of progastrin at the cellular level by light and electron microscopical immunocytochemistry. In the normal human gastric antrum, the G-cell secretory granules were found to contain both gastrin and the C-terminal progastrin determinants (progastrin 87-93, 87-95 and 93-101). Immunostaining of serial sections at the light microscopical level revealed that duodenal gastrin-containing cells also express the C-terminal progastrin determinants, as well as gastrin-34. In foetal tissue, cells containing C-terminal gastrin and the C-flanking peptide of progastrin were first seen at 8 weeks of gestation, in the duodenum. They were not found in the stomach until the 11th week. In hyperplastic G-cells and in gastrin-producing tumour cells, the level of C-terminal peptide immunoreactivity was variable and often lower than that seen in normal antrum and only minimal immunoreactivity could be detected using electron immunocytochemistry. This was interpreted as representing altered post-translational processing of progastrin in modified G-cells.

Adenoma, Islet Cell↗

Vasoactive intestinal polypeptide in relation to penile erection in the cat evoked by pelvic and hypogastric nerve stimulation.

The hemodynamics of penile erection were elucidated in the anesthetized cat by studying volumetrically determined erectile responses of the penis and penile blood flow during frequency-graded bilateral stimulation of the pelvic and the hypogastric nerves, selectively or in combination. The study also provided information on possible neurotransmitter mechanisms. The results indicated that the erectile response is mediated by both the pelvic and hypogastric nerves, operating synergistically to evoke a seemingly maximum erection. Optimum erectile responses for either nerve system were obtained at 16 Hz and threshold responses at 0.5 to one Hz. In the presence of atropine, the erectile response to selective stimulation of the pelvic and the hypogastric nerves, respectively, were clearly curtailed, suggesting a cholinergic mechanism to be partly responsible for the diversion of blood from the penile "resistance vessels" to the cavernous bodies, possibly accomplished via the opening of vessels with a shunt-like function. However, the magnitude of the erectile response to combined pelvic and hypogastric nerve stimulation seemed to be surprisingly little affected by muscarinic blockade. Selective stimulations of the pelvic and the hypogastric nerves, respectively, were both found to cause about a five-fold increase in VIP output from the penis, coordinated in time with the local blood flow increase during erection. These data suggest a VIP-ergic neurotransmitter mechanism to be involved in penile erection in the cat, possibly controlling the dilation of the penile arterial "resistance vessels."

Animals↗

Bladder vasodilatation and release of vasoactive intestinal polypeptide from the urinary bladder of the cat in response to pelvic nerve stimulation.

In the feline urinary bladder blood flow was determined by means of a direct blood flow measurement technique before and during pelvic nerve stimulation. Simultaneous sampling of venous blood from the bladder was performed, and the output of vasoactive intestinal polypeptide (VIP) was determined by means of radioimmunoassay. Maximal stimulation of the pelvic nerves led to a clearcut increase in intravesical pressure and a small but sustained increase of blood flow in the bladder wall. These changes were associated with a drastic increase in VIP output from the bladder, increasing from a control level of 0.2 fmol./min. to 15 fmol./min. during stimulation. The results suggest that VIP might be the neurotransmitter responsible for the vasodilatation in the feline urinary bladder in response to pelvic nerve stimulation. The discrepancy between the moderate blood flow increase and the pronounced increase in VIP-release might, however, indicate that VIP exerts its main effects elsewhere in the bladder than in the vascular bed, for instance the detrusor smooth muscle.

Animals↗

Delayed postprandial plasma bile acid response in coeliac patients with slow mouth-caecum transit.

Coeliac patients are known to have an expanded bile salt pool which recirculates slowly due, at least in part, to impaired gall bladder contractility. We have investigated the possibility that delayed small bowel transit of chyme and bile may also contribute to this sluggish recycling. Plasma cholylglycine, total bile acids and cholecystokinin concentrations were measured after a lactulose-labelled test meal whose mouth-caecum transit time (M-C TT) was assessed by the breath hydrogen technique. Overall there were no significant differences in plasma bile acid profiles between seven healthy controls and a group of 25 coeliac patients. However, when subjects were divided according to their M-C TT, the 10 with the slowest transit were found to have significant elevation of fasting levels when compared with the 10 with the fastest transit, fasting total bile acids being 3.4 +/- 1.3 versus 0.7 +/- 0.6 mumol/l (P less than 0.02) and fasting cholylglycine being 0.43 +/- 0.17 versus 0.06 +/- 0.04 mumol/l (P less than 0.05) respectively. Peak bile acid levels did not differ significantly between subjects with fast or slow transit. However, subjects with slow transit were found to have a delay in the return of plasma bile acid levels to fasting levels so that the 4 h postprandial levels were significantly elevated when compared with those observed in the subjects with fast transit (total bile acids 3.6 +/- 1.2 versus 0.19 +/- 0.1 mumol/l and cholylglycine 0.70 +/- 0.13 versus 0.24 +/- 0.07 mumol/l respectively, both P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Oral absorption of the somatostatin analogue SMS 201-995: theoretical and practical implications.

Oral administration of SMS 201-995 (SMS), a subcutaneously injectable somatostatin analogue, was investigated in five healthy volunteers, who drank 2 mg of SMS with 75 g of glucose. Mean maximal plasma SMS concentrations after the 2 mg oral dose were comparable with those after subcutaneous injection of 50 micrograms, although the peak was delayed (90 vs 15 min). Biological activity of absorbed SMS was shown by significant and lasting suppression of plasma insulin concentrations, resulting in significant hyperglycaemia at 90 and 120 min compared with the control study. The feasibility of oral administration of SMS may extend its use in the treatment of acromegaly and gut endocrine tumours. Other peptide hormone analogues, structurally 'protected' against enzymatic degradation, may also be active orally and thus be useful therapeutically.

Absorption↗

Atrial natriuretic peptide: evidence of action as a natriuretic hormone at physiological plasma concentrations in man.

The administration of exogenous atrial natriuretic peptide (ANP) causes a natriuresis and diuresis in man, but this has, to date, only been demonstrated at plasma ANP concentrations within the high pathological or pharmacological ranges. Evidence that ANP acts physiologically requires the demonstration of a natriuretic effect when it is infused to recreate plasma concentrations similar to those observed after physiological stimuli. We infused human alpha-ANP (1-28) at a calculated rate of 1.2 pmol min-1 kg-1 for 3 h into seven water-loaded normal subjects, achieving plasma ANP concentrations within the upper part of the physiological range. The subjects' resting plasma ANP concentration increased from 3.8 +/- 1.5 to 20.9 +/- 1.9 pmol/l. The infusion of ANP caused a 60% increase of mean urinary sodium excretion from 111 +/- 18 to 182 +/- 30 mumol/min (P less than 0.001) and a 28% increase of mean water excretion from 10.8 +/- 0.8 to 13.8 +/- 1.6 ml/min (P less than 0.01). The infusion suppressed mean plasma renin activity from 1.55 +/- 0.10 to 1.17 +/- 0.06 pmol of ANG I h-1 ml-1 (P less than 0.001). Mean plasma aldosterone concentration (242 +/- 16 basally and 215 +/- 15 pmol/l at the end of ANP infusion) did not change significantly. Pulse rate and blood pressure were unchanged throughout the study. No significant change in any of the variables mentioned above occurred during the infusion of the vehicle alone on a separate study day.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

The effect of insulin-induced hypoglycaemia on gastrointestinal motility in man.

The effect of insulin-induced hypoglycaemia on gastro-jejunal motility was studied in five, healthy, male subjects using tethered, pressure sensitive, radiotelemetry capsules. Thirty minutes after the intravenous injection of soluble insulin (0.15 unit/kg body weight), a significant reduction in blood glucose concentration (control: 5.26 +/- 0.19 SEM mmol/l; insulin: 1.48 +/- 0.44 mmol/l; P less than 0.001) was associated with a rise in heart rate (mean peak rise 29 +/- 8 beats/min, P less than 0.05), systolic arterial blood pressure (mean peak rise 28 +/- 4 mmHg, P less than 0.01) and plasma pancreatic polypeptide concentration (control: 20 +/- 7 pmol/l; insulin: 287 +/- 66 pmol/l; P less than 0.01). These events coincided with a short period of jejunal motor activity, which was not associated with gastric motor activity nor with raised plasma motilin concentrations. During the control study, there were no changes in blood glucose concentration, heart rate, arterial blood pressure or plasma pancreatic polypeptide concentrations, and there was no jejunal motor activity. The interval between successive gastric migrating motor complexes (MMC) was not significantly different in the insulin and control studies (control: median interval 110 min, range 108-148 min; insulin: median interval 124 min, range 115-125 min), suggesting that the fasting gastrojejunal MMC and jejunal motor activity arose independently. Insulin-induced hypoglycaemia is accompanied by jejunal motor activity, which may underlie the abdominal symptoms associated with hypoglycaemia.

Adult↗

Fentanyl and the beta-endorphin, ACTH and glucoregulatory hormonal response to surgery.

The effect of the supplementation of nitrous oxide-oxygen anaesthesia with either fentanyl 15 micrograms kg-1 or 0.5% halothane on the beta-endorphin, ACTH, glucoregulatory hormonal and metabolic response to pelvic surgery was investigated. Fentanyl inhibited the increases in circulating beta-endorphin, ACTH, growth hormone, cortisol and glucose concentrations found in the patients receiving halothane. Changes in circulating beta-endorphin concentrations during surgery probably reflect alterations in pituitary secretion and appear to have no major metabolic effects. The suppression of pituitary secretion persisted for at least 4 h after the start of surgery.

Adult↗

Effect of a long-acting analogue of somatostatin, SMS 201-995, on the development of intestinal tumours in azoxymethane-treated rats.

The effect of daily parenteral administration of a long-acting analogue of somatostatin (SMS 201-995) on the development of intestinal tumours and the rate of crypt cell proliferation in azoxymethane-treated rats has been studied. SMS 201-995 had no significant effect on the number of colonic tumours induced. In the duodenum, SMS 201-995 administration was associated with a change in the number of tumours from 1.4/rat in saline-treated animals to 2.4/rat in animals treated for the last third of the study and 2.8/rat in animals treated with SMS for the entire duration of the study (P less than 0.02). SMS had no significant effect on the rate of cell proliferation in the duodenum, ileum or colon. The inhibition of release of gastrointestinal trophic hormones by this analogue of somatostatin thus does not appear to reduce the number of tumours in the intestine of azoxymethane-treated rats.

Animals↗

Chronic administration of the somatostatin analogue SMS 201-995 does not lead to endogenous antibody formation.

Plasma samples of seven patients with gut and pancreatic endocrine tumours who have been on long-term treatment with a long-acting somatostatin analogue (SMS 201-995) were investigated for endogenous antibodies to the peptide by incubation with radiolabelled SMS 201-995. The duration of treatment with the somatostatin analogue was between 9 and 26 months and the dose from 100 to 300 micrograms day-1. In none of the patients could antibodies to SMS be detected. The effect of this somatostatin analogue is unlikely to be impaired by formation of endogenous antibodies, even after long-term treatment.

Adult↗

SMS 201-995 treatment and advanced intestinal cancer: a pilot study.

The hypothesis that somatostatin, a compound with antitrophic effects on the gastrointestinal tract, may affect beneficially the progression of advanced intestinal cancer has been tested in a small pilot study. Ten patients, four with advanced pancreatic cancer, four with advanced colorectal cancer and two with gastric cancer, were treated with a long-acting analogue of somatostatin, SMS 201-995, 50, 100 micrograms subcutaneously twice daily. There were no clinical, radiological or biochemical indicators of a response to this treatment. There are no indications from this study that hormonal manipulation alters the rate of growth of advanced gastrointestinal cancer.

Adult↗

The effect of a long-acting somatostatin analogue (SMS 201-995) on intermediary metabolism and gut hormones after a test meal in normal subjects.

SMS 201-995 is an octapeptide analogue of somatostatin. The effect of a single subcutaneous (s.c.) injection of 50 micrograms SMS 201-995 on post-prandial intermediary metabolism was investigated in normal subjects. In spite of a long-lasting post-prandial suppression of insulin secretion, there were no significant changes in the plasma concentration of alanine, glycerol, 3-OH-butyrate or lactate. However, SMS 201-995 impairs carbohydrate tolerance, probably due to inhibition of insulin secretion. Basal and post-prandial plasma concentrations of the gut regulatory peptides pancreatic glucagon, motilin, pancreatic polypeptide, gastric inhibitory polypeptide, enteroglucagon, gastrin and peptide YY were suppressed up to 5 hours after subcutaneous administration of a single dose of SMS 201-995.

3-Hydroxybutyric Acid↗

Effective long-term treatment of acromegaly with a long-acting somatostatin analogue (SMS 201-995).

Nine acromegalic patients, six previously untreated, were studied before and after 3-15 months of treatment with a long-acting somatostatin analogue (SMS 201-995; 100 micrograms injected s.c. three times daily). During treatment, the mean (+/- SEM) 24-h GH concentration fell from 82 +/- 22 mIU/l to 33 +/- 7 mIU/l (P less than 0.001), and eight of the 9 patients showed a reduction of at least 50% in GH levels in the fasting state and/or during a glucose tolerance test. There was a significant 30% fall in serum concentrations of insulin-like growth factor (IGF-1) with SMS. All patients showed rapid clinical improvement, with diminished sweating and headaches, and reduction in skinfold thickness, hand volumes and finger size. Computer tomographic scanning of the pituitary in eight patients showed no change in the size of the pituitary tumour during treatment. The only side-effects of SMS noted were transient abdominal discomfort and loose stools in two patients on initiating therapy. Although fasting plasma glucose concentration did not change during treatment (5.4 +/- 0.3 vs 5.5 +/- 0.3 mmol/l), mean 24-h plasma glucose concentration was higher with SMS (6.6 +/- 0.5 mmol/l vs 6.0 +/- 0.4 mmol/l; P less than 0.02). Mean 24-h plasma insulin concentration fell from 87 +/- 11 mIU/l before treatment to 39 +/- 6 mIU/l during treatment (P less than 0.005). No change in other anterior pituitary hormones was observed. SMS appears to be a safe, rapidly effective, long-term treatment for certain patients with acromegaly.

Acromegaly↗

Effect of naloxone on the antral motor response to solid food in man.

Antroduodenal motor activity was recorded in eight healthy subjects using perfused tubes connected to external strain gauge transducers. Each subject was studied over a 2.5-h period following ingestion of a solid meal, on 2 separate days. Intravenous saline was administered on one day and saline plus naloxone (40 micrograms kg-1 h-1) on the other, in randomized order. Naloxone markedly inhibited the antral motor response to food and this effect was due to decreased amplitude and contractile frequency. The duodenal motor response to solid food and the postprandial rise in serum gastrin and plasma pancreatic polypeptide were not altered by naloxone. These observations suggest that peripheral or central opiate receptors play a role in regulating the antral motor response to food.

Adult↗

Resolution of acromegaly after removal of a bronchial carcinoid shown to secrete growth hormone releasing factor.

A 29 year old woman with an enlarged pituitary fossa and classical acromegaly, possibly present for ten years, had biochemical and partial somatic resolution of the disorder after removal of a bronchial carcinoid tumour. In addition, galactorrhea stopped, menstruation returned after two years, and amenorrhea and elevated prolactin levels fell towards normal. Immunocytochemistry showed numerous growth hormone releasing factor (GRF) staining cells in the tumour. The tumour cells, when cultured, produced a supernatant selectivity stimulating human pituitary somatotrophic cell cultures to produce growth hormone (GH). The bronchial carcinoid did not secrete detectable GH, but extracts of it, and preoperative serum contained GRF immunoreactivity which coeluted with synthetic human pancreatic GRF.

Acromegaly↗