Mesophase formation during cholesterol gallstone dissolution in human bile: effect of bile acid composition.

Duodenal bile obtained from patients with gallstones who were acutely infused with chenodeoxycholic acid, ursodeoxycholic acid, or cholic acid were examined for the propensity toward the formation of a liquid crystalline mesomorphic phase when cholesterol gallstones were incubated in these bile acids. Bile taken from patients infused with ursodeoxycholic acid was found to be enriched in ursodeoxycholic acid; mesophase formation was detected in these samples but not in bile from patients infused with chenodeoxycholic acid or cholic acid.

Dissolution rates of model gallstones in human and animal biles and importance of interfacial resistance.

Cholesterol monohydrate dissolution kinetics in human gallbladder bile were studied to determine the magnitudes of the in vitro dissolution rates, the rate resistances in human gallbladder bile, and the extent that the interfacial resistance is the rate-determining factor. Dissolution rate studies also were conducted using human duodenal bile and animal bile for comparison. The dissolution rate resistance, R, ranged from 10(4) sec/cm for chicken bile to 10(4)-10(6) sec/cm for human bile. Interfacial resistance was the rate-determining factor for essentially all results. Where chemical composition data were obtained, the R values for the human bile samples were consistent with predictions made from the simulated bile studies. In two human gallbladder specimens having low bile acid-lecithin molar ratios (i.e., 2.9 and 2.3), very high R values of 1.9 X 10(5) and 4.1 X 10(5) sec/cm were found. These values were in good agreement with the findings in the simulated bile studies and suggest that stone dissolution in patients with low bile acid-lecithin ratios may proceed very slowly, even when the bile is highly undersaturated with respect to cholesterol.

Economic impact and clinical benefits of pharmacist involvement on surgical wards.

A one-year pilot project was performed to assess the economic and clinical benefit of pharmacist involvement on the surgical wards of a 600-bed tertiary care, teaching hospital. A total of 405 recommendations were collected with a physician acceptance rate of 90%. From these recommendations, 1416 patient follow-ups were performed to document outcome. The total documented cost avoidance of the pharmacists' activities was $33,265.58. The total annual drug expenditure for the department of surgery declined by $59,662 representing a 9% decrease over the previous year with the greatest decline involving antimicrobials which decreased by $52,587 compared with the previous year. Most of the cost-avoidance in this area was attributable to antimicrobial selection and dosing adjustment in renal impairment. Pharmacist-directed pharmacokinetic monitoring of aminoglycosides resulted in a clinical success rate of 93.8% for treatment regimens and a 6.2% incidence of nephrotoxicity. Housestaff education aimed at improving prescribing practices were identified and provided for select agents including midazolam, ketorolac, vancomycin and aminoglycosides. As well, select recommendations were documented which illustrated the benefit to patient care of pharmacist involvement. Pharmacist involvement on the surgery services produced both financial and clinical benefits.

The role of the department of surgery in undergraduate education. Development of the undergraduate teacher.

Three components are necessary for effective undergraduate teaching in a department of surgery: (a) departmental organization and membership priority focused on teaching; (b) a clear understanding and appropriate utilization of all teaching methods, for example, lectures, large seminars or demonstrations, small seminars and bedside teaching; (c) the acquisition and maintenance of teaching and evaluation skills by all department members. The author discusses the advantages and disadvantages of the four principal teaching methods and the means of acquiring teaching and evaluation skills that includes the use of professional educators.

Perioperative blood transfusion and albumin administration are independent risk factors for the development of postoperative infections after colorectal surgery.

OBJECTIVES: To determine whether transfused colorectal surgery patients were at increased risk for postoperative infections in a tertiary care teaching hospital and whether transfusion alone was the only significant risk factor. DESIGN: A retrospective study. SETTING: A single tertiary care teaching hospital. PATIENTS: All patients admitted to St. Boniface General Hospital, Winnipeg, for colorectal surgery during the period Apr. 1, 1995, through Mar. 31, 1996, were studied (N = 154). RESULTS: The overall infection rate was 17%: nontransfused patients, 13%, and transfused patients, 28% (p < 0.038). Patients who received albumin perioperatively had a significantly higher infection rate (38%) than those who did not (13%) (p < 0.001). Stepwise logistic regression analysis identified transfusion and albumin administration as the only independent risk factors for postoperative infection. CONCLUSION: Perioperative transfusion or albumin administration significantly increases the risk of postoperative infection in colorectal surgery patients.

Massive intestinal infarction in young women: complication of use of oral contraceptives?

Massive intestinal infarction due to occlusion of the celiac, superior mesenteric and inferior mesenteric arteries occurred in two young women, one of who subsequently died. Both were smokers. They had ingested oral contraceptives for 5 and 8 years, respectively, but this therapy could not be proven to be a causative factor in their ischemic bowel disease; although such an association is uncommon, it should be considered in young women with abdominal pain.

Low-dose chenodeoxycholic acid for gallstone dissolution: a randomized trial in poor operative risk patients.

Thirty-five patients, with minimally symptomatic radiolucent gallstones in well opacifying gallbladders who had an unusually high risk of operative mortality, were randomized, double blind, into three groups: group 1, placebo; group 2,250 mg chenodeoycholic acid (CDC)/day; group 3,375 mg CDC/day. Every six months, oral cholecystograms and duodenal bile were obtained. Serum was collected at 0, 1, 2, 3, and 6 months, then at 6-month intervals. After 6 months, all placebo patients were assigned to 375 mg CDC/day (group 3b). No changes occurred in group 1 (N = 15). Gallstones dissolution: group 2, 2/10; 1 complete (C), 1 partial (P); group 3, 4/10, 1C, 3P; group 3b, 2/12, 2C. Lowest dose with complete dissolution was 3 mg/k/day (actual body wt). Lithogenic index of bile only improved with 375 mg/day (1.27 +/- 0.13 vs 0.88 +/- 0.05; mean +/- SDM), P < 0.01. No diarrhea or serum biochemical changes occurred; however, three patients died of their other medical illness. Low fixed doses of CDC, although not optimal, dissolved stones without toxicity in very ill patients.

Differing effects of hydroxy-7-oxotaurine-conjugated bile acids on bile flow and biliary lipid secretion in dogs.

The effects on bile flow and biliary lipid secretion of two taurine-conjugated 7-oxo bile acids, 3 alpha-hydroxy-7-oxocholanoyltaurine (I) and 3 alpha,12 alpha-dihydroxy-7-oxocholanoyltaurine (II), were measured in the unanesthetized, chronic bile fistula dog. Each synthetically prepared compound, or cholyltaurine as control, was infused intravenously at a physiological rate of 1 mumol X kg-1 X min-1 for randomized 90-min periods. Bile samples were collected and analyzed for biliary lipids (bile acids, phospholipid, and cholesterol) and bile acid composition. Both compounds were secreted efficiently in bile, recovery averaging 90%. The trisubstituted compound (II) induced a greater choleresis and less phospholipid and cholesterol secretion than the disubstituted compound (I) or cholyltaurine. Each oxo compound was partially reduced during hepatic passage: about 47% of I (to mostly chenodeoxycholyltaurine) and about 30% of II (to mostly cholyltaurine). The effect of the individual bile acids on biliary lipid secretion was then calculated by assuming that a) the infused bile acid induced biliary lipid secretion after its hepatic biotransformation and b) each bile acid or its biotransformation product exerted an independent effect on biliary lipid secretion (expressed as a linkage coefficient, e.g., phospholipid secretion/bile acid secretion). For phospholipid, the calculated linkage coefficient for I was 0.31; for II, 0.07. For cholesterol, the calculated linkage coefficient for I was 0.014; for II, 0.003. In vitro studies indicated that the critical micellar concentration (CMC) in 0.15 M Na+ was 22 mM for I and 40 mM for II (compared with 6 mM for cholyltaurine.(ABSTRACT TRUNCATED AT 250 WORDS)

Biliary secretion and hepatic metabolism of taurine-conjugated 7 alpha-hydroxy and 7 beta-hydroxy bile acids in the dog. Defective hepatic transport and bile hyposecretion.

Experiments were carried out using chronic bile fistula dogs to define the physiologic properties and metabolism of two unnatural epimeric monohydroxy conjugated bile acids, 7 alpha-hydroxy cholanoyltaurine and 7 beta-hydroxy cholanoyltaurine. The compounds, labeled with 14C, were infused intravenously at a rate of 1 mumol/kg X min; effects on bile flow and biliary lipid secretion as well as hepatic biotransformation were defined. The 7-monohydroxy bile acids were secreted quite slowly in bile: recovery during the 90-min infusion interval averaged 16% for the 7 alpha compound and 23% for the 7 beta compound, and after 6 h was only about 60% for the 7 alpha compound and 80% for the 7 beta compound. Uptake by tissues, presumably the liver, appeared to be efficient, as the level of radioactivity in peripheral blood remained quite low. Both bile acids failed to induce the anticipated increase in bile flow; canalicular bile flow, which was assessed using erythritol clearance, was about half the value observed when cholyltaurine was infused at a similar rate. The "hyposecretion" of bile, which was thought likely to be caused by impaired canalicular transport of the monohydroxy conjugates, was fully reversible, as a subsequent cholyltaurine infusion at a rate of 1 mumol/min X kg immediately restored bile flow and the infused cholyltaurine was secreted normally. Each compound was partly 3-hydroxylated during hepatic passage: the 7 alpha compound, about 36% (to form chenodeoxycholyltaurine); the 7 beta compound, about 23% (to form ursodeoxycholyltaurine). No other biotransformation occurred. Each compound induced phospholipid and cholesterol secretion, but compared to the effects of cholyltaurine, the amount of phospholipid secretion induced (per micromole of secreted bile acid) was less, and that of cholesterol, greater. Thus, the two 7-monohydroxy taurine-conjugated bile acids caused a striking dissociation of induced phospholipid and cholesterol secretion. The results indicate that taurine-conjugated 7-monohydroxy bile acids are poorly secreted by the liver and that their impaired transport is associated with bile hyposecretion, possibly reflecting decreased bile acid-dependent flow; the configuration of their 7-hydroxy group influences their rate of secretion into bile. The results also establish a novel type of bile acid biotransformation (3-hydroxylation) in the dog.

Effect of replacement therapy with cholylsarcosine on fat malabsorption associated with severe bile acid malabsorption. Studies in dogs with ileal resection.

The efficacy of cholylsarcosine, a synthetic deconjugation-resistant and nonsecretory conjugated bile acid analog for the treatment of fat malabsorption caused by severe bile acid malabsorption, was assessed in an animal model. In two dogs, the ileum and ileocecal valve were resected, causing severe diarrhea, steatorrhea, bile acid malabsorption, and progressive weight loss. Cholylsarcosine was administered as the water-soluble sodium salt by mixing with the dog food. Various doses were explored as well as varying intakes of dog food. Fat absorption was assessed by gravimetric measurement of fecal fat; a nonabsorbable recovery marker (polyethylene glycol mol wt 4000) was used to correct for incomplete fecal collections. Cholylsarcosine caused a 5- to 30-fold increase in fat absorption but had no significant effect on weight loss or fecal weight. Duodenal content was collected during digestion of a meal via a surgically placed Thomas cannula; the aspirates were dilute, acidic, and had a low bile acid concentration. The bile acid concentration increased modestly when cholylsarcosine was administered, but remained below the critical micellization concentration. The results indicate that oral administration of cholylsarcosine improved dietary fat absorption in a canine model of severe bile acid malabsorption with associated steatorrhea and bile acid deficiency in the proximal small intestine. Studies with this compound in patients with nutritional problems because of steatorrhea and severe bile acid malabsorption appear warranted.