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Biomedical subjects

R H Dowling

Publications and source records attributed to R H Dowling.

At least 73 records · Page 4Linked to original sources
PubMed1989

Induction of pancreatic tumours by longterm duodenogastric reflux.

The incidence of pancreatic cancer is increased in patients who have undergone gastric surgery. An animal model is described in which pancreatic hyperplasia and adenoma formation developed within 56 weeks. The effects of a simple gastrojejunostomy were compared with those after a split gastrojejunostomy, in which the jejunum was transected and the two limbs implanted separately into the greater curvature of the glandular stomach 1 cm apart. After 56 weeks no animals in the simple gastrojejunostomy group had pancreatic hyperplasia whereas all 10 animals in the split gastrojejunostomy group had generalised pancreatic hyperplasia with macroscopic nodules. Microscopy of the nodules showed that in nine animals hyperplastic nodules had developed, and four of these also had adenomatous nodules. The remaining animal had enlarged lymph nodes. Pancreatic hyperplasia was associated with jejunal hyperplasia. Jejunal morphometry showed that the villus height was doubled and the villus height:crypt depth ratio was higher in the split gastrojejunostomy group compared with those animals with a simple gastrojejunostomy. This finding represents a new model for the investigation of pancreatic neoplastic change.

Adenoma↗
PubMed1988

Is the ex vivo rat gastric chamber model suitable for studying the gastrotoxicity of refluxed duodenal contents? Initial results using deoxycholic acid.

Duodenogastric reflux has been implicated in the pathogenesis of gastric mucosal disease but the relative toxicities of its constituents are not known. The suitability of the ex vivo rat gastric chamber model for systematic studies of bile acid gastrotoxicity was assessed using deoxycholic acid (DCA 0.2-5.0 mmol/l). Acute challenge with 5.0 mmol/l DCA produced significant loss of gastric transmucosal potential difference (delta PD = 25.9 +/- 3.3 mV: mean +/- SEM; p less than 0.01) compared with saline challenge (1.5 +/- 0.5 mV). Significant delta PD values were produced by DCA concentrations down to 0.5 mmol/l (16.0 +/- 2.8 mV). Challenge with 5.0 mmol/l DCA also caused significant increases in chamber fluid concentrations of nucleic acid (2.8 +/- 0.3 micrograms/ml; p less than 0.05) and acid phosphatase (130 +/- 23.4 microU/ml; p less than 0.01). This study demonstrates DCA gastrotoxicity at concentrations comparable to human intragastric total bile acid concentrations and the suitability of this model for studying the toxic components of refluxed duodenal contents.

Animals↗
PubMed1988

Prevention of gallstone recurrence by non-steroidal anti-inflammatory drugs.

In laboratory animals, non-steroidal anti-inflammatory drugs (NSAIDs) are reported to inhibit diet-induced gallstone formation. To see if these drugs had a similar effect in man, 82 patients who had taken part in a comparison of ursodeoxycholic acid, placebo, and diet for prevention of gallstone recurrence were sent questionnaires about their use of NSAIDs during the period of the trial. 75 replied. After a mean follow-up of 33 (SEM 4) months none of the 12 regular users of NSAIDs had had gallstone recurrences, compared with 20 of the 63 who never or rarely used these drugs (p less than 0.02).

Adult↗
PubMed1988

Piezo-ceramic lithotripsy of gallbladder stones: initial experience in 38 patients.

The efficacy, safety, and side-effects of a piezo-ceramic system for extracorporeal shock-wave lithotripsy of gallbladder stones were assessed in the first 38 patients treated. Gallstone fragmentation was achieved in 34 patients; 25 required more than 1 treatment session (range 1-5). Extracorporeal shock-wave lithotripsy, conducted without sedation, analgesia, or anaesthesia, was well tolerated by all patients; no patient reported pain or discomfort either during or after the procedure. Side-effects were negligible: transient microscopic haematuria in 2 patients, transiently abnormal liver function tests in 1, and short-lived cutaneous petechiae in 4. Initial experience shows that lithotripsy with this system is effective, safe, and well tolerated.

Ceramics↗
PubMed1987

Comparison of effects of ingested medium- and long-chain triglyceride on gallbladder volume and release of cholecystokinin and other gut peptides.

In a double-blind, crossover study of the effect of ingested medium-chain triglyceride (MCT) and long-chain triglyceride (LCT) in six normal subjects, the gallbladder did not contract after ingestion of MCT but instead had significantly increased in volume at 2 hr after the meal. Plasma cholecystokinin (CCK) increased after the MCT meal, but gastrin, motilin, pancreatic polypeptide (PP), and GIP were unaffected. The long-chain triglyceride meal evoked a brisk and sustained gallbladder contraction, higher levels of CCK, and a significant increase in plasma PP and GIP levels.

Adult↗
PubMed1987

Role of polyamines in intestinal adaptation in the rat.

The cellular mechanisms controlling adaptive intestinal mucosal hypo- and hyperplasia are poorly understood but changes in tissue polyamine levels and in the activity of the key enzymes controlling their synthesis (ornithine decarboxylase: ODC) and degradation (diamine oxidase: DAO) have been implicated. Therefore, in two models of adaptive mucosal hyperplasia (pancreatico-biliary diversion, PBD, achieved by surgically transposing the jejunum to lie between pylorus and ampulla of Vater, and 90% small bowel resection, SBR-both studied 8 weeks after surgery) and in one model of hypoplasia (8 days total parenteral nutrition) we measured indices of mucosal mass (wet weight, protein and DNA per 10-cm intestine), the growth-associated polyamines (putrescine, spermidine and spermine per 10-cm intestine and per mg DNA) and DAO activity in the duodenum, five 10-cm segments of jejunum, five 10-cm segments of ileum and in the colon, and compared the results with those found in transected or unoperated controls. The results for the indices of mucosal mass confirmed that TPN led to a modest degree of small bowel mucosal hypoplasia whilst PBD, and particularly 90% SBR, stimulated marked adaptive hyperplasia. There were corresponding changes in the amounts of putrescine and spermidine (but not of spermine)-not only when the results were expressed per unit length but also when calculated per mg mucosal DNA and in the ratio of spermidine:spermine. There was an increasing proximal-to-distal gradient in mucosal DAO per unit length intestine in all experimental groups but when the results were expressed per mg DNA, the ileal DAO levels were significantly reduced in the PBD and resection groups, when compared with the controls. These data support the hypothesis that polyamines play a major, and perhaps a controlling, role in regulating adaptive intestinal mucosal growth.

Amine Oxidase (Copper-Containing)↗
PubMed1987

Mucosal polyamine profile in normal and adapting (hypo and hyperplastic) intestine: effects of DFMO treatment.

The polyamines, putrescine, spermidine, and spermine, are believed to play an important role in modulating normal and adaptive intestinal mucosal growth. Polyamine synthesis is rate limited by ornithine decarboxylase (ODC) and ODC activity is specifically inhibited by -difluoromethyl ornithine (DFMO). To assess the importance of polyamines in adaptive growth we first measured mucosal polyamine profiles at different sites in the normal rat intestine and compared the results with those obtained in adaptive hypoplasia (seven days parental nutrition, TPN), in the adaptive hyperplasia of two weeks after 90% small bowel resection (SBR) or pancreatico biliary diversion (PBD). We then examined the effects of DFMO (2% in drinking water, daily from two days before surgery) on the polyamine concentrations and the adaptive response to PBD. The hyperplasia of SBR and PBD was associated with increases in all the polyamine concentrations particularly putrescine. TPN induced a modest degree of hypoplasia and little change in polyamine synthesis resulting in subnormal polyamine concentrations and significantly inhibited the mucosal adaptive response. Changes in polyamine metabolism are important in intestinal mucosal adaptation and by controlling these changes adaptive growth can be controlled.

Adaptation, Physiological↗
PubMed1987

Longterm pancreaticobiliary diversion stimulates hyperplastic and adenomatous nodules in the rat pancreas: a new model for spontaneous tumour formation.

A model for spontaneous tumour formation in the rat pancreas is described that requires neither cocarcinogens nor dietary manipulation. Short term hypercholecystokininaemia, when induced by raw soya flour feeding, induces benign and malignant tumours of the rat pancreas. Pancreaticobiliary diversion (PBD) results in hypercholecystokininaemia and in the short term, pancreatic hyperplasia. Longterm PBD was done to establish whether hypercholecystokininaemia thus produced would also lead to pancreatic neoplasia. After a period of 16-21 months hyperplastic and adenomatous nodules, one of the latter showing carcinoma in situ, were found in PBD rats but not in sham operated control rats.

Adenoma↗
PubMed1986

Polyamine distribution in the rat intestinal mucosa.

As the first step in a study of mucosal polyamine metabolism during intestinal adaptation, we have measured mucosal polyamine concentrations at different sites along the normal rat intestine. Putrescine, spermidine, spermine and cadaverine were measured by spectrofluorometric analysis after thin-layer chromatography of their dansylated derivatives. Spermidine was present in the largest amounts at each of the sampling sites. The ratio of the concentration of spermidine to that of spermine paralleled the established pattern of cellular proliferation in the normal intestine as did the putrescine concentration (nmol per 10 cm) which decreased from duodenum to colon. These results provide the essential background to an assessment of the role of polyamines in the intestinal adaptive response.

Animals↗
PubMed1986

Effect of obesity and weight reduction on biliary cholesterol saturation and the response to chenodeoxycholic acid.

Biliary cholesterol saturation indices (SI's) were measured in fasting duodenal bile from (i) obese and non-obese individuals with and without cholesterol gallstones, (ii) obese individuals undergoing weight reduction and (iii) obese gallstone patients receiving chenodeoxycholic acid (CDCA) therapy. Biliary lipid secretion rates were also measured in three obese subjects before and during 11 days starvation. The mean SI in fifteen non-obese controls (0.89 +/- SEM 0.06) was significantly lower than that in the twenty-four obese without (1.14 +/- 0.07; P less than 0.01), and in the twenty-nine non-obese with gallstones (1.30 +/- 0.05; P less than 0.001) while in sixteen obese gallstone patients, the mean SI of 1.55 +/- 0.06 was significantly higher than that seen in the other three groups (P less than 0.01-0.001). Although fifteen obese subjects lost 15% of their initial body weight during dieting, this did not change their SI's consistently. However in three obese individuals, total starvation did reduce the SI's and significantly lowered the biliary cholesterol secretion rate. Ten obese gallstone patients responded to 15.8 +/- 0.3 mg CDCA kg-1 day-1 by developing unsaturated fasting duodenal bile (SI 0.89 +/- 0.04). A further increase in CDCA dose to 19.0 +/- 0.7 mg kg-1 day-1, as a result of reducing body weight, was more effective in lowering SI's (0.75 +/- 0.06, range 0.51-1.0) than that achieved by increasing the dose to 18.9 +/- 0.46 mg kg-1 day-1 through more capsules per day (SI 0.89 +/- 0.03, range 0.67-1.25). These studies show that (i) biliary cholesterol SI's are greater when obesity and gallstones occur together than in either obesity or gallstones alone, and (ii) although weight loss in obese individuals does not consistently alter biliary cholesterol SI's, it may be beneficial in obese patients receiving CDCA therapy for gallstone dissolution.

Adolescent↗
PubMed1986

Gall stone disease without gall stones--bile acid and bile lipid metabolism after complete gall stone dissolution.

Although bile acid and bile lipid metabolism have been studied in established cholelithiasis, little is known about them in patients destined to develop gall stones, but in whom the stones have not yet appeared (prestone gall stone disease). After confirmed complete gall stone dissolution and withdrawal of treatment, gall stones recur frequently. Before the stones reappear, these patients have 'poststone gall stone disease'. In 13 such patients we confirmed complete gall stone dissolution with two normal cholecystograms and in 11 of the 13 by normal ultrasonography, measured bile acid and bile lipid composition in fasting duodenal bile, bile acid synthesis from marker corrected three day faecal bile acid excretion, bile acid pool size using an abbreviated isotope dilution technique, 'steady-state' bile lipid secretion using a duodenal amino acid perfusion system and then calculated the enterohepatic cycling frequency of the bile acid pool and the relationship between pool size and body weight. The results confirm that after withdrawal of treatment the biliary cholesterol saturation index reverts to levels (1.6 +/- SEM 0.4) comparable with those before dissolution therapy first began (1.6 +/- 0.2; NS). The mean bile acid pool size in the 13 patients of 4.4 +/- 0.5 mmol was comparable with that in untreated gall stone patients. Pool size was significantly smaller in the nine non-obese patients (3.5 +/- 0.3), than in the four obese (6.0 +/- 0.8; p less than 0.05). It also correlated significantly with body weight (r = 0.72) and with %IBW (r = 0.79). The coefficients of variation for biliary bile acid, phospholipid and cholesterol secretion were high, but the mean hourly secretion rates were of the same order as those seen in untreated gall stone patients studied with the amino acid duodenal perfusion stimulus. These results provide a baseline for assessing the response to postdissolution treatment and may indicate metabolic events leading to gall stone formation.

Adult↗
PubMed1985

[Potential adaptation of the gastrointestinal system. Existence of an enteropancreatic trophic axis, the role of hormones and polyamines].

The evidence for an enteropancreatic trophic axis is reviewed. Luminal nutrition is essential for the maintenance of normal intestinal mucosal, as well as exocrine pancreatic structure and function. Exclusion of luminal nutrition leads to mucosal hypoplasia and hypofunction with similar changes in the pancreas. The trophic effect of luminal nutrition may be mediated through the release of regulatory peptides with endocrine or paracrine effects. Enteroglucagon is the strongest candidate for the role of "enterotrophin" while cholecystokinin (CCK) markedly influences pancreatic growth. Thus, CCK not only stimulates exocrine pancreatic secretion but makes acinar cells divide and the pancreas grow. The cellular mechanisms whereby trophic peptides influence normal and adaptive growth are also discussed with emphasis on polyamines (putrescine, spermidine and spermine) and the key enzymes controlling their synthesis (ornithine decarboxylase [ODC]) and degradation (diamine oxidase [DAO]). When polyamine synthesis is blocked with the ODC inhibitor difluoromethyl ornithine (DFMO), the adaptive intestinal hyperplasia of pancreaticobiliary diversion is either inhibited or completely prevented. A proposed sequence of events might be: luminal nutrients, particularly long chain fat, reach the ileum and colon and stimulate increased enteroglucagon release. Enteroglucagon binds to cell receptors and triggers an intracellular cascade involving ODC and the polyamines which, in turn, stimulate RNA polymerase, DNA, RNA and protein synthesis, cell division and adaptive tissue growth.

Adaptation, Physiological↗
PubMed1985

Bile lipid secretion in obese and non-obese individuals with and without gallstones.

Biliary lipid secretion rates were measured in non-obese and obese individuals with and without cholesterol gallstones, using a steady-state, amino acid duodenal perfusion method. In addition, biliary lipid secretion rates were measured in five obese gallstone patients receiving high-dose chenodeoxycholic acid therapy (16-22 mg day-1 kg-1). Bile acid secretion rates in the non-obese patients with cholesterol gallstones (563 +/- SEM 70 mumol/h, n = 6) were significantly lower than in the non-obese controls (1078 +/- 210 mumol/h, n = 10, P less than 0.05), whereas cholesterol secretion rates were similar in the non-obese individuals with and without gallstones (51 +/- 7 and 42 +/- 4 mumol/h respectively). In the obese, both with and without gallstones, the major abnormality was hypersecretion of cholesterol (107 +/- 7 mumol/h, n = 7, and 81 +/- 15 mumol/h, n = 7, respectively). Both these values were significantly greater than those in the non-obese controls (P less than 0.01-0.02). Biliary cholesterol secretion rates correlated significantly with bile acid secretion rates but, for every mole of bile acid secreted, the obese secreted more cholesterol than the non-obese. Chenodeoxycholic acid treatment lowered biliary cholesterol saturation in obese gallstone patients by reducing biliary cholesterol secretion. These results suggest that there are two major types of defect in biliary lipid secretion in gallstone patients: reduced biliary bile acid secretion in non-obese gallstone patients and excessive biliary cholesterol secretion in the obese.

Adult↗
PubMed1985

Hormones and polyamines in intestinal and pancreatic adaptation.

The evidence for and against an enteropancreatic trophic axis is reviewed. Luminal nutrition is essential for the maintenance of normal intestinal mucosal, and exocrine pancreatic, structure and function. Exclusion of luminal nutrition leads to mucosal hypoplasia and hypofunction with similar changes in the pancreas. The trophic effect of luminal nutrition may be mediated through the release of regulatory peptides with endocrine or paracrine effects. Enteroglucagon is the strongest candidate for the role of 'enterotrophin' while cholecystokinin (CCK) markedly influences pancreatic growth. Thus, CCK not only stimulates exocrine pancreatic secretion but makes acinar cells divide and the pancreas grow. The cellular mechanisms whereby trophic peptides influence normal and adaptive growth are also discussed with emphasis on polyamines (putrescine, spermidine and spermine) and the key enzymes controlling their synthesis (ornithine decarboxylase; ODC) and degradation (diamine oxidase; DAO). When polyamine synthesis is blocked with the ODC inhibitor, difluoromethyl ornithine (DFMO), the adaptive intestinal hyperplasia of pancreatico-biliary diversion is either inhibited or completely prevented. A proposed sequence of events might be as follows: luminal nutrients, particularly long-chain fats, reach the ileum and colon and stimulate increased enteroglucagon release. Enteroglucagon binds to cell receptors and triggers an intracellular cascade involving ODC and the polyamines, which, in turn, stimulate RNA polymerase, DNA, RNA and protein synthesis, cell division, and adaptive tissue growth.

Adaptation, Physiological↗
PubMed1984

Clinical testing of gliadin fractions in coeliac patients.

Since the toxic fraction of cereal flour which damages the small bowel mucosa of patients with coeliac disease has not been fully defined in vivo, we studied the effect of intraduodenal infusions of different doses of unfractionated gliadin and of alpha-, beta-, gamma- and omega-gliadin subfractions on the morphology of multiple jejunal biopsies taken from two patients with treated coeliac disease. A dose-response study with increasing quantities of unfractionated gliadin in one coeliac patient showed that 1000 mg produced marked damaged in serial jejunal biopsies taken 2-3 h after commencing the infusion and that the changes had almost completely disappeared 72 h later. alpha-, beta-, gamma- and omega-gliadin were prepared, checked for purity and investigated for toxicity in two coeliac patients. After an intraduodenal challenge with 1000 mg of the four gliadin subfractions these were shown to have induced damage in the mucosa of jejunal biopsies taken 6 h later. These observations confirm the results of studies in vitro, which suggest that not only alpha-but beta-, gamma- and omega-gliadin are enterotoxic in coeliac disease.

Adult↗
PubMed1984

Influence of gallstones and ursodeoxycholic acid therapy on gallbladder emptying.

Altered gallbladder motility could predispose to, or result from, gallstone formation and could also explain the alleged relief of biliary colic seen during bile acid therapy. Therefore, in 14 controls, 25 patients with radiolucent gallstones, and 14 patients with radiopaque gallstones, we used two techniques to measure gallbladder contraction--radionuclide imaging and real-time ultrasound--in response to one of two stimuli--a Lundh meal or intravenous cholecystokinin-octapeptide. Using the radionuclide technique, postprandial gallbladder emptying (t1/2) was prolonged (p less than 0.01) both in patients with radiopaque (26.7 +/- 3.1 min, mean +/- SEM) and radiolucent (21.7 +/- 3.1) gallstones when compared with controls (10.2 +/- 1.5). In patients with radiolucent stones, the t1/2 of gallbladder emptying became further prolonged (p less than 0.05) after 1 mo of therapy with 8-10 mg/kg body wt X day of ursodeoxycholic acid, to 32.1 +/- 4.4 min. A similar pattern of results was seen after cholecystokinin-octapeptide and also with real-time ultrasound. Thus, after both stimuli and using two independent techniques, gallbladder contraction was reduced in patients with gallstones. The slower and less complete gallbladder emptying with ursotherapy might explain the reduction in biliary colic noted during treatment.

Adult↗