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Biomedical subjects

R H Dowling

Publications and source records attributed to R H Dowling.

At least 109 records · Page 6Linked to original sources
PubMed1980

Lack of response to chenodeoxycholic acid in obese and non-obese patients. Role of cholesterol synthesis and possible response to ursodeoxycholic acid.

This paper describes seven patients with radiolucent gallstones in functioning gallbladders who did not respond to chenodeoxycholic acid (CDCA). Despite large doses (greater than or equal to 19 mg CDCA/kg/day), CDCA-rich bile (CDCA conjugates 70-97% of total biliary bile acids) and greater than or equal to one year's treatment, their fasting duodenal bile remained supersaturated with cholesterol and their gallstones did not dissolve. Five patients came to cholecystectomy, gallstone analysis and liver biopsy for measurement of hepatic cholesterogenesis (HMGCoAR activity). In three who stopped CDCA before surgery, the mean HMGCoAR (pmol/mg microsomal protein/min) of 50.2 was higher than in our untreated gallstone controls (32.2 +/- SEM 2.0; P less than 0.05). Two patients who took CDCA until surgery had a mean HMGCoAR of 33.5--more than twice that in CDCA-treated gallstone controls. These findings suggest that non-response to CDCA may be related to high or unsuppressed hepatic cholesterogenesis. In one patient who did not respond to CDCA, treatment with 19 mg ursodeoxycholic acid/kg/day did desaturate his bile.

Adult↗
PubMed1979

Pituitary hormones and the small bowel: effect of hypophysectomy on intestinal adaptation to small bowel resection in the rat.

The influence of pituitary hormones on intestinal adaptation to small bowel resection was studied by examining jejunal and ileal structure and function in control and in sham-operated rats, and in animals with 50% proximal or distal resection which were divided into three main groups: normally-fed, hypophysectomized. and pair-fed. The pituitary was removed 2 weeks before intestinal surgery and gut structure and function were studied 4 weeks later. The effectiveness of hypophysectomy was confirmed by histological examination of the aspirated pituitary, and by showing a significant subsequent reduction in weight of the testes and adrenals. Food intake and body weight fell significantly after removing the pituitary; intestinal surgery caused a transient further decrease in food intake. Measurements of intestinal villus height and crypt depth, indices of mucosal mass (mucosal wet weight, protein and DNA content/cm intestine), measurements of mucosal alpha-glucosidase activity, and in vivo galactose absorption/unit length of intestine all showed comparable results. In rats with an intact intestine, resection resulted in mucosal hyperplasia and increased segmental absorption. Following hypophysectomy, there was marked mucosal hypoplasia and hypofunction which seemed to be due largely to associated hypophagia since comparable changes were found in the pair-fed, sham-operated rats. However following pituitary removal, both distal jejunum and proximal ileum retained their capacity to regenerate though the magnitude of this adaptive change was much greater in the resected, pair-fed rats suggesting that hypophagia alone cannot explain the diminished adaptation to resection after hypophysectomy. By inference, pituitary hormones do influence the adaptive response to resection.

Adaptation, Physiological↗
PubMed1978

Resistance to chenodeoxycholic acid (CDCA) treatment in obese patients with gall stones.

In most patients with radiolucent gall stones who were given chenodeoxycholic acid (CDCA) in doses of 13-15 mg/kg body weight/day the bile became unsaturated in cholesterol, and their gall stones dissolved. The patients whose stones did not dissolve were significantly heavier and fatter than the responders, which suggested that obese patients might be "resistant" to the effects of CDCA. To test this hypothesis, 32 consecutive patients presenting for medical treatment of gall stones had their ideal body weight (IBW) and estimated body fat mass calculated. The eight most obese and the eight least obese patients were then selected, and their fasting bile lipid responses to CDCA 13-15 mg/kg/day were measured. The very obese patients were also given larger doses, and any changes in bile lipid composition were studied in relation to subsequent gall-stone dissolution.Before treatment the obese patients had a higher mean biliary cholesterol saturation index than the non-obese patients, and this difference was maintained during treatment with the normal dose of CDCA: the bile in the obese patients remained supersaturated while that in the non-obese became unsaturated with cholesterol. When the obese patients were given larger doses of CDCA their bile ultimately became unsaturated in cholesterol. Gall stones dissolved partially or completely in five of the eight non-obese patients after 6-18 months of 13-15 mg CDCA/kg/day, but none of the obese patients showed any response after comparable periods of treatment with this standard dose. With increased doses and unsaturated bile, however, three of the obese patients showed partial gall-stone dissolution after 3-12 months' treatment and one showed complete gall-stone dissolution after three years' treatment.These results suggest that when giving CDCA to patients with gall stones, larger than normal doses (some 18-20 mg/kg/day) should be prescribed. Alternatively the lipid composition of the patients' bile should be monitored by duodenal intubation and the CDCA dose increased until the bile becomes unsaturated in cholesterol.

Adult↗
PubMed1978

Physiological factors influencing serum bile acid levels.

This study defines the effects of fasting (prolongation of an overnight fast for a further four hours), feeding (the response to eating the three main ;solid' meals of the day), and cholecystokinin-induced gallbladder contraction (75-100 units of CCK given as a bolus intravenous injection) on serum individual bile acids in five to eight healthy control subjects. The serum conjugates of the two primary bile acids, cholic and chenodeoxycholic, were measured using sensitive specific radio-immunoassays. During fasting, there was no significant change in the levels of the serum individual bile acids (conjugates of cholate, 1.28 +/- 0.19; conjugates of chenodeoxycholate, 1.17 +/- 0.17 mumol/l). After breakfast, the serum conjugates of cholate and chenodeoxycholate increased significantly but thereafter the mean values remained high with less consistent responses to lunch and dinner, some subjects showing a peak and trough response to all three meals, while others showed a plateau response throughout the day. After breakfast, the serum chenodeoxycholate conjugates increased more rapidly (peak at 60 minutes when the concentration reached 2.07 +/- 0.30 mumol/l) and to a greater extent than the conjugates of cholate (peak at 90 minutes; 1.50 +/- 0.24 mumol/l). A similar pattern of results was seen after intravenous CCK, suggesting either preferential jejunal absorption of chenodeoxycholate conjugates and/or preferential hepatic clearance of cholate conjugates. These results provide essential background data for future studies of serum individual bile acids in intestinal and hepatic disease.

Adult↗
PubMed1978

Effect of ioglycamide (Biligram) on bile flow and biliary lipid secretion in man.

Twenty-one anicteric patients with a t-tube in situ were studied between the ninth and 11th postoperative days. Eleven patients were given an intravenous infusion of the biliary contrast agent ioglycamide (Biligram), while the other 10 acted as controls. Bile flow was recorded and the biliary concentrations of ioglycamide, bile salt, phospholipid, and cholesterol estimated in the two groups. The biliary excretion of ioglycamide was associated with a significant choleresis which was probably due to the obligatory coupling of the osmotically active contrast agent molecules with water. Biliary ioglycamide excretion did not significantly alter bile salt secretion rates. In contrast, the biliary secretion of both phospholipid and cholesterol was significantly lowered (P less than 0.001). Unlike chenodeoxycholic acid, ioglycamide significantly reduced bile acid independent cholesterol secretion (P less than 0.01), although secretion rate in terms of mumol of bile acid was essentially unchanged.

Bile↗
PubMed1978

Cholecystokinin and secretin prevent the intestinal mucosal hypoplasia of total parenteral nutrition in the dog.

Because the pancreas undergoes involutional changes during total parenteral nutrition (TPN) and because pancreatico-biliary secretions are trophic to the intestine, we studied jejunal and ileal structure and function and exocrine pancreatic function before and after 6 weeks of TPN in two groups of beagle dogs, one of which had TPN alone, the other having TPN plus daily stimulation of pancreatico-biliary secretions with intravenous infusions of cholecystokinin (CCK) and secretin. The injections of 1 U each per kg of body weight per day of CCK and secretin completely prevented the proximal and distal small bowel mucosal hypoplasia which developed in the TPN alone group. They also resulted in significant increases in in vivo galactose absorption (64 mM) per unit length of jejunum and ileum. However, there was no significant change in mucosal alpha-glucosidase and catalase activity or in in vitro mucosal uptake of 1 mM [14C]leucine when expressed per unit weight of intestinal mucosa. The capacity of the pancreas to respond to CCK and secretin was unaffected by excluding food from the intestine with 6 weeks of TPN in terms of pH, volume, and peak secretion rates of bicarbonate and protein, but maximum amylase output (units per 15 min per kg of body weight) fell significantly (P less than 0.05) from a mean of 1022 +/- 155 to 874 +/- 426 in TPN alone group and to 472 +/- 79 in the TPN dogs given CCK and secretin. These results show that daily CCK and secretin is trophic to the intestine of dogs nourished by TPN but do not indicate whether this trophic effect is attributable to CCK alone, secretin alone, the combination of the two hormones, or to the resultant stimulation of pancreatico-biliary secretions.

Animals↗
PubMed1977

Speed of change in biliary lipids and bile acids with chenodeoxycholic acid--is intermittent therapy feasible?

To see whehter intermittent chenodeoxycholic acid (CDCA) therapy is a potential alternative to continous treatment for gallstone dissolution, the speed of change in bile lipid composition was studied after starting and stopping CDCA therapy. In addition, the relationship between bile lipid composition and the proportions of the bile acids was examined. Bile-rich duodenal fluid was collected twice in the first week and then at approximately weekly intervals for four to six weeks, from six gallstone patients starting 13-15 mg CDCA.kg BW-1 day-1 and from another group of six patients whose treatment was stopped after gallstone dissolution. After starting treatment, the mean biliary cholesterol saturation index (based on criteria of Hegardt and Dam, 1971) decreased from 1-49 +/- SEM 0-17 to 0-92 +/- 0-13 at three weeks and 0-88 +/- 0-10 at four weeks, by which time bile lipid composition had become relatively constant. In patients whose treatment was stopped, bile reverted to its supersaturated state within one week, changing from an on-treatment mean saturation index of 0-74 +/- 0-10 to 1-15 +/- 0-15 in six to eight days after withdrawing CDCA. The proportion of conjugated CDCA in the biliary bile acids increased from 27-9 +/- 2-5% to 60-5 +/- 4-2% within four days and to 80-7 +/- 6-2% by four weeks after starting CDCA. When treatment was stopped, the proportion of CDCA reverted to pretreatment levels by two to three weeks. The saturation index was significantly related (P less than 0-001) to the percent of conjugated CDCA present, such that when the proportion of CDCA exceeded 70%, bile was almost invariably unsaturated. Since the mean time taken for bile to become unsaturated was not shorter than the time taken for bile to revert to its supersaturated state, it seems that intermittent treatment would not be adequate to maintain an unsaturated bile and is, therefore, unlikely to be as effective as continuous treatment in dissolving gallstones.

Adult↗
PubMed1976

The mechanism for small-bowel adaptation in lactating rats.

1. To study the relative contributions of luminal nutrition, bile and pancreatic secretions and hormonal factors in intestinal adaptation, lactation hyperphagia was chosen as a model for increased luminal nutrition, either alone (intestinal transection control group) or in combination with (i) exclusion of bile and pancreatic secretions from the jejunum (by transposition of the jejunum above the Ampulla of Vater) or (ii) exclusion of bile, pancreatic secretions and exogenous luminal nutrition from the jejunum (proximal Thiry-Vella by-pass group). 2. The results confirm that in lactation there is mucosal hyperplasia with increases in villus height and crypt depth, and in small-bowel wet and defatted dry-tissue weights per unit length of intestine. 3. There are corresponding changes in absorptive function with increased glucose and water absorption per unit length of intestine. 4. These structural and functional adaptive changes are proportionately greater in ileum than in jejunum. 5. The exclusion of exogenous luminal nutrition, bile and pancreatic secretions from the jejunum did not diminish the degree of intestinal mucosal hyperplasia and functional adaptation seen in lactation. 6. Diversion to the ileum of greater than normal amounts of bile, pancreatic secretions and luminal nutrition did not further increase the degree of mucosal hyperplasia and enhanced absorption seen in the lactating intestinal transection control group. 7. Unlike other models of intestinal adaptation, the changes in small-bowel mucosal structure and function seen in lactation are probably due to hormonal factors.

Adaptation, Physiological↗
PubMed1976

Effects of oral versus intravenous nutrition on intestinal adaptation after small bowel resection in the dog.

To study the influence of luminal nutrition on the structural and functional adaptive changes which are seen in the residual intestine after partial small bowel resection, quantitative histology, in vitro uptake of 14C l-leucine, mucosal enzyme activities, and in vivo absorption of glucose were studied before and 6 weeks after 50% proximal small bowel resection in 10 greyhound dogs, 5 of which were nourished exclusively by the intravenous route while 5 were pair-fed by mouth. In the orally fed jejunectomized dogs, the ileum became dialed with mucosal hyperplasia, the villus height increased from 796 +/- SEM 26 mum to 1102 +/- 28 mum (P less than 0.001), and there was a corresponding increase in glucose absorption in vivo (milligrams -centimeter of intestine -1min-1) from 5.3 +/- 1.2 to 10.1 +/-1.6. The increased absorption seems mainly caused by the dilation and villus hyperplasia, since there was no significant change in in vitro absorption and mucosal enzyme activity when expressed per unit weight of intestine. In the absence of exogenous luminal nutrition, the well nourished intravenously fed dogs showed no evidence of functional adaptation and a significant fall in mean ileal villus height from 823 +/-48 mum at the initial operation to 732 +/-57 mum 6 weeks after jejunectomy. These results provide the most direct evidence to date that luminal nutrition is essential for the development of intestinal adaptation after resection. They also suggest that luminal contents are necessary to maintain the structural and functional integrity of the normal small bowel.

Adaptation, Physiological↗
PubMed1975

Adaptive changes in vitamin B12 absorption in celiac disease and after proximal small-bowel resection in man.

Resection of the proximal small bowel is known to cause mucosal hyperplasia and enhanced absorption in the ileum of experimental animals, but similar adaptive changes had not previously been studied in man. Since intrinsic-factor-bound vitamin B12 (IF-B12) absorption is confined to the ileum, as an index of ileal adaptation, we measured whole-body IF-58 Co B12 absorption in 24 control subjects, in 4 patients after proximal small-bowel resection, and in 9 patients with adult celiac disease (where mucosal damage is often limited to the proximal intestine and spares the ileum). Control subjects absorbed 20.4% (+/- 1 SD 6.2%) of the administered 5-mug dose of vitamin B12, while the corresponding 7-day retention values in patients with proximal resection (mean 42.3%; range 32-61%) and in 2 of the 9 celiac patients (44.1% and 54%, respectively), were above the normal range. The increased vitamin B12 absorption in these patients suggest that functional adaptation also occurs in the ileum in man. The results also illustrate the application of a newly developed whole-body counting technique to study vitamin B12 absorption in man.

Adolescent↗
PubMed1975

The value of radiology in predicting gallstone type when selecting patients for medical treatment.

Since medical treatment of gallstones is confined to cholesterol-rich stones, the ability of clinical radiographs to predict gallstone type was tested prospectively by comparing the preoperative radiological appearance of gallstones from 57 unselected patients with cholelithiasis coming to cholecystectomy with the subsequent analysis of the stones both by X-ray diffraction and by chemical techniques. Fifty-two per cent of the patients had 'non-functioning' gallbladders which failed to opacify after at least two contrast examinations and 25 out of 50 had radioopaque stones. Of the 25 patients with radiolucent stones, the stones in 20 ((80%) were predominantly cholesterol in type but radiology was misleading in five; three contained 40-55% calcium salts but were still radiolucent while two were amorphous and contained less than 10% cholesterol by weight on chemical analysis. While radiology was sometimes misleading when the stones were small and irregular, large radiolucent stones with a smooth profile were invariably cholesterol-rich stones. The results also show that in men calcified stones were commoner than in women and that in older women the gallstones contained more calcium salts and less cholesterol than in younger women less than 50 yr). This paper analyses critically the value and limitations of clinical radiology in predicting gallstone type.

Adult↗
PubMed1975

Effect of pentagastrin on small bowel structure and function in the rat.

Since chronic pentagastrin stimulates pancreatic and proximal duodenal growth (15), we studied jejunal structure and function following subcutaneous pentagastrin (2 mg-100 g-1 day-1). After 15 days, macroscopic enlargement was confined to the proximal duodenum with a significant increase in wet weight (from 231 +/- SEM 6 to 308 +/- 13 mg) but there was no significant difference in wet and defatted dry intestinal weights, histological measurements of villous height and mucosal thickness or in glucose absorption per unit length of distal duodenum and proximal jejunum. Since chronic pentagastrin causes parietal cell hyperplasia and hypersecretion of gastric acid, the results suggest that the adaptive changes seen in the jejunum after ileectomy are neither mediated by gastrin nor by factors present in gastric secretions.

Animals↗