Hydrophobic bile acids have been shown to be hepatotoxic, whereas treatment with ursodeoxycholic acid, a hydrophilic bile acid, has improved liver function indices in patients with chronic liver disease. Taurine administration has also been suggested to be useful for chronic hepatitis, taurine-conjugated bile acids being more hydrophilic than glycine-conjugated bile acids. To determine if taurine and ursodeoxycholic acid are beneficial and if their effects are additive, a double-blind, randomized trial was designed comparing the effects of ursodeoxycholic acid, taurine, and a combination of the two on indices of liver injury in 24 patients with chronic hepatitis. They were assigned at random to two of the four following treatments: ursodeoxycholic acid (600 mg/day), taurine (1.5 g/day), ursodeoxycholic acid plus taurine (600 mg + 1.5 g/day) or placebo, given in two successive cycles of 2 mo each, according to a balanced incomplete-block design. Ursodeoxycholic acid became the predominant biliary bile acid when administered alone or in combination with taurine, and taurine conjugate levels increased during taurine administration. Ursodeoxycholic acid reduced aspartate aminotransferase (35%), alanine aminotransferase (33%), and gamma-glutamyl transpeptidase (41%), whereas taurine alone did not. The addition of taurine to ursodeoxycholic acid produced only minor changes in the effects of ursodeoxycholic acid alone. Results were confirmed by the administration of ursodeoxycholic acid, in a successive open phase of the study, to the entire patient population, which was large enough for different subsets of patients to be compared. Serum bile acids were measured at entry and during the open phase: primary bile acids did not change, whereas ursodeoxycholic acid levels increased from trace amounts to very high levels, especially in patients with more severe histological disease. It is concluded that ursodeoxycholic acid, but not taurine, improves enzymatic indices of liver injury in chronic hepatitis.

Gastric mucosal prostaglandin E2 and F2 alpha content was evaluated in healthy human subjects who received either fish oil or olive oil (control) daily for 3 wk before exposure to aspirin or no aspirin. Two hours after aspirin administration, when mean serum salicylate concentration was approximately 12 mg/dl, gastric mucosal prostaglandin E2 and F2 alpha content was reduced by greater than 95% in the fundus and antrum (p less than 0.001) and there was endoscopic evidence of gastric mucosal damage (erosions, submucosal hemorrhages). Fish oil feeding had no significant effect on mucosal prostaglandin E2 or F2 alpha content or on the damaging effect of aspirin on the stomach, despite the fact that fish oil reduced serum triglyceride concentrations significantly. These studies indicate that the damaging effects of aspirin on the gastric mucosa are not influenced by dietary fish oil.

Thirty-five severely malnourished cirrhotic patients were randomized to receive either enteral-tube feeding as the sole nutritional support (n = 16) or an isocaloric, isonitrogenous, low-sodium standard oral diet (n = 19). Both groups were homogeneous regarding age, sex distribution, etiology of liver cirrhosis, history of previous complications, clinical status, liver and renal function, modified Child's score, and nutritional status at admission. The enteral formula diet was energy dense, containing 40 mmol Na/day, whole protein plus branched-chain amino acids, medium- and long-chain triglycerides, and maltodextrin. It supplied 2115 kcal/day. The amount of vitamins and trace elements was at the upper limit of the recommended dietary allowances. The orally fed patients were encouraged to eat all meals served. Total enteral nutrition was well tolerated without major complications. Serum albumin and Child's score improved in the enterally fed patients but not in controls. Mortality rate while in the hospital was lower in patients on enteral feeding than in controls (12% vs 47%). These results show that total enteral nutrition is safe and effective in improving the short-term clinical outcome in severely malnourished cirrhotics.

The National Polyp Study (NPS), a randomized clinical trial to evaluate effective surveillance of patients discovered to have one or more colorectal adenomas, was the framework for this statistical analysis which used a multiple logistic model to assess the independent risk factors of patient and polyp characteristics associated with high-grade dysplasia in adenomas. The database included 3371 adenomas from 1867 patients. Adenoma size and the extent of the villous component were found to be the major independent polyp risk factors associated with high-grade dysplasia (p less than 0.0001). The adjusted odds ratios were 3.3 for medium-sized adenomas and 7.7 for large adenomas relative to small adenomas and 2.7 for villous A adenomas, 3.4 for villous B adenomas, and 8.1 for villous C and D adenomas relative to tubular adenomas. Increased frequency of high-grade dysplasia in adenomas located distal to the splenic flexure was attributable mainly to increased size and villous component rather than to location per se. The adjusted odds ratio was 1.4 (p less than 0.11) for left-sided location. Multiplicity of adenomas affected the risk for high-grade dysplasia in patients but was dependent on adenoma size and villous component and was not an independent factor. The adjusted odds ratio was 1.3 (p less than 0.17) for multiplicity. Increasing age was associated with risk for high-grade dysplasia in patients, and this effect was independent of the effect of adenoma size and histological type. The adjusted odds ratio was 1.8 (p less than 0.0016) for age greater than or equal to 60 yr. Gender was not associated with high-grade dysplasia. The adjusted odds ratio was 1.0 (p less than 0.95) for men. The size of the patient series, the prospective nature of the data collection, the completeness of information on all patients, the requirements of complete examination of the entire colon and pathological examination of all lesions encountered, and the exclusion of patients with previously diagnosed adenomas are, collectively, features unique to this study. The detailed model provided by the analysis integrates multiple patient and adenoma factors associated with high-grade dysplasia in colorectal adenomas.

In a double-blind, parallel-group clinical trial in 248 patients with symptomatic duodenal ulcers [97% greater than 5 mm diameter], 126 were randomized to receive omeprazole 20 mg once daily in the morning and 122 were randomized to receive ranitidine 300 mg once daily at night for 2 wk and if the ulcers were unhealed for a total of 4 wk. When ulcer healing was assessed on an intention-to-treat basis, 79% of those receiving omeprazole had healed ulcers after 2 wk compared with 62% of those receiving ranitidine (p less than 0.005; therapeutic gain for omeprazole, 18%; 95% confidence intervals, +6% to +29%). At 4 wk the figures were 91% (omeprazole) and 80% (ranitidine) (p less than 0.05). After 2 wk, 77% of omeprazole-treated and 59% of ranitidine-treated patients were free of ulcer pain (p = 0.005). Assessed by diary cards (successfully completed by 92% of patients), daytime pain resolved more quickly in omeprazole-treated patients than in those receiving ranitidine (p less than 0.01). Omeprazole-treated patients took fewer antacids (p less than 0.05) over the first 2 wk. Omeprazole, 20 mg each morning, provides more rapid relief of the symptoms of duodenal ulcer and heals a greater proportion of duodenal ulcers within 2 and 4 wk than ranitidine, 300 mg each night.

A double-blind controlled study of long-acting propranolol in the secondary prevention of variceal hemorrhage was conducted in 81 cirrhotic patients. After the index hemorrhage, all patients were treated with injection sclerotherapy on one occasion to secure hemostasis and then randomized within 72 h to propranolol or placebo therapy which was continued for 2 yr. Study endpoints were severe recurrence of variceal hemorrhage or death. Forty-two patients did not fulfill the entry criteria for the study. Thirty-eight patients received propranolol of whom 18 (47%) had further hemorrhage, 14 died, eight had side-effects (2 withdrawals), and 3 did not complete follow-up. Forty-three patients received placebo of whom 33 (77%) had further hemorrhage, 19 died, 5 had side-effects (2 withdrawals), and 5 failed to complete follow-up. The median time from onset of hemorrhage to starting drug therapy was 6 days for both groups. Life table analysis showed an equivalent incidence of further hemorrhage in both groups over the first 60 days, following which the propranolol group did consistently better than the placebo group. There was a significantly lower incidence of rebleeding in modified Child's C patients receiving propranolol (39%) than those on placebo (90%). No statistically significant effect on mortality was seen. In this study, propranolol reduced the incidence of late recurrence of variceal hemorrhage in patients with cirrhosis.

The effects of liquid versus solid diet on human colonic transit were investigated, and transit following cecal instillation of tracer was compared with transit following instillation in the proximal jejunum. In a randomized cross-over, single-blind fashion, 6 normal volunteers ingesting either normal solid foods or a liquid diet were studied using colonic transit scintigraphy. 111In-DTPA was instilled either into the cecum via a long intestinal tube or into the proximal jejunum via a feeding tube. Compared with the liquid diet, the solid diet slowed transit in the cecum and ascending colon (p less than 0.025) and delayed progression of the geometric center (p less than 0.05) during the first 4 h of the study. Transit from 18 to 48 h was similar on the 2 diets. On the solid diet, transit was similar whether 111In-DTPA was instilled into the proximal jejunum or into the cecum. Transit from the terminal ileum to the cecum was assessed in an additional 5 volunteers following jejunal instillation of 99mTc-DTPA. Cecal filling was rapid (T1/2 = 0.49 h) and complete in all subjects before the onset of cecal emptying. These results suggest that colonic transit is slower on a solid than a liquid diet and that jejunal instillation of radiopharmaceuticals should be suitable for colonic transit studies in most subjects.

The aims of this study were to determine (a) whether dietary fiber supplements modify symptoms in patients with irritable bowel syndrome, (b) the effect of fiber on rectosigmoid pressures, and (c) the relationship, if any, between rectosigmoid pressure and symptoms. Fourteen patients entered and 9 completed a double-blind, controlled, cross-over study of 7 mo duration. The mean age was 26 yr (range, 18-37). Patients received 4 cookies daily containing 20 mg corn fiber or placebo. Symptoms and compliance were evaluated monthly. Rectosigmoid pressures and dietary intake were evaluated at the outset and completion of each study arm. Symptoms improved during both fiber and placebo treatments. Those symptoms demonstrating significant improvement with time were pain severity, stool frequency, stool consistency (p = 0.001), number of additional gastrointestinal symptoms present (p = 0.02), and total symptom score (p less than 0.001). Rectosigmoid pressures were not significantly altered by fiber or placebo. Fasting pressures at the distal recording site tended to correlate with pain severity (r = 0.6; p = 0.06). It was concluded that (a) corn fiber and placebo were both effective in alleviating symptoms, (b) there was a correlation between symptom severity and fasting rectosigmoid pressure, and (c) there was a trend toward reduction in fasting and postprandial rectosigmoid pressures after fiber therapy.

This study evaluates the effects of the specific cholecystokinin receptor antagonist loxiglumide on gall-bladder emptying after a meal or after intravenous infusion of caerulein in humans. Ten healthy male volunteers were studied five times on separate days. The following five studies were performed in randomized order: (a) caerulein was intravenously infused at doses increasing from 7.5 to 120 ng/kg.h without the antagonist; (b) in addition to increasing doses of caerulein, loxiglumide was given intravenously at doses of 0.2, 1.0, or 5.0 mg/kg.h; (c) a solid-liquid 800-kcal meal was given without loxiglumide; (d) the 800-kcal meal was given with simultaneous infusion of 1 or 5 mg/kg.h loxiglumide; and (e) loxiglumide (5 mg/kg.h) was given. without caerulein or the test meal. Gallbladder volume was measured by ultrasound. Loxiglumide dose-dependently inhibited gallbladder emptying induced by caerulein or the meal. High doses of the antagonist did not only abolish meal-induced gallbladder emptying but increased gallbladder volume after administration of caerulein or the meal when compared with prior fasting values. The antagonist given alone markedly increased gallbladder volumes compared with prior fasting values. In conclusion, given alone markedly increased gallbladder volumes compared with prior fasting values. In conclusion, cholecystokinin is the hormone primarily and mainly responsible for mediation of gallbladder emptying after a regular meal. Cholecystokinin might also play a physiologic role in the regulation of the fasting tone of the gallbladder.

The areas under the curve (AUCs) of blood ethanol concentrations are much smaller after oral than after intravenous administration of a small dose of ethanol. To study whether this difference is due to ethanol oxidation in the stomach, in the small intestine, or during first pass through the liver, we compared the AUCs after random administration of the same ethanol dose by the intravenous, oral, and intraduodenal routes to 5 abstaining alcoholics and via the two former routes to 10 subjects with Billroth II subtotal gastrectomy. In the nonoperated subjects, the AUCs after an ethanol dose (0.15 g/kg) given orally were 17% (p less than 0.01) of those achieved intravenously, in spite of the fact that greater than 99% of the dose had disappeared from the stomach at the completion of the AUC. By contrast, the AUCs after intraduodenal administration did not differ from those produced intravenously, indicating that neither the intestine nor the liver make a detectable contribution to this first-pass metabolism. Moreover, gastrectomy completely abolished the first-pass metabolism of ethanol. Gastric metabolism decreases the bioavailability of the ingested alcohol and thus attenuates its systemic toxicity. The abolition of this "protective barrier" in gastrectomized patients may increase their vulnerability to ethanol.

We studied the effect of ursodeoxycholic acid on 18 women and 2 men with primary biliary cirrhosis, mainly stages I and II. After a 3-mo observation period, patients were randomized to a 9-mo treatment period with ursodeoxycholic acid, 10 mg/kg.day, or placebo. Two patients on placebo left the study. In all patients on ursodeoxycholic acid, mean values of serum glutamate dehydrogenase, aspartate and alanine aminotransferases, alkaline phosphatase, and gamma-glutamyl transpeptidase fell significantly by 48%-79% after 18-24 wk; 7 of 10 showed a mean decrease of 35% in immunoglobulin M after 24 wk. Prothrombin time, serum bilirubin, albumin, the antipyrin breath test, and plasma disappearance of indocyanine green were normal initially and did not change. Total serum bile acid concentrations increased; ursodeoxycholic acid became the predominant bile acid. No significant improvement occurred in the placebo group. Hepatic histology improved in 6 patients of the ursodeoxycholic acid group but deteriorated in 4 patients receiving placebo. In studies with erythrocyte membranes, changes in electron spin resonance revealed that ursodeoxycholic acid was less toxic than chenodeoxycholic or deoxycholic acid, and coaddition of ursodeoxycholic acid prevented their toxic effect.

We have developed an ultrathin endoscope for repeated endoscopy in unsedated subjects and used it with assessment of bleeding rates to investigate aspirin-induced gastric mucosal injury and its prevention by famotidine. Compared with placebo, 900 mg of aspirin b.i.d. taken for 48 h caused significant endoscopic injury (median grade 3.5, interquartile range 2-4, modified Lanza scale, p less than 0.01), with an increase in mucosal bleeding from 2.0 (geometric mean; 95% confidence limits, 1.1-3.9) microliters/12 min, to 8.3 (2.4-28.8) microliters/12 min (p less than 0.05). Famotidine (20 mg b.i.d.) raised intragastric pH and reduced endoscopic antral injury (median 1.5, interquartile range 0.5-2, p less than 0.05) and bleeding [3.1 (1.2-8.3) microliters/12 min, p less than 0.01] to levels not significantly different from placebo [1 (0-1) and 2.0 (1.1-3.9) microliters/12 min, respectively]. By contrast, 2 mg of famotidine b.i.d. had no significant effect on intragastric pH endoscopic injury or bleeding rates. The two assessments of gastric mucosal injury correlated strongly (r = 0.71, p less than 0.01). The reduction in bleeding with famotidine tended to be higher, the greater the intragastric pH (r = 0.66, p = 0.057). Ultrathin endoscopy is a simple technique that validates gastric mucosal bleeding as a measure of acute gastric mucosal injury in humans. Acid suppression is an effective method of ameliorating this injury.

Although nocturnal acid secretion has been emphasized in the pathophysiology and treatment of duodenal ulcer, its importance in gastric ulcer disease has been questioned. To explore this area, this multicenter U.S. trial compared the effect of a once-daily nighttime dose of H2-receptor antagonist with placebo on the healing of gastric ulcer and relief of associated symptoms. One hundred fifty-seven patients with endoscopically verified benign gastric ulcers were randomized in a double-blind fashion to either famotidine (40 mg at bedtime) or placebo. Antacid tablets were allowed as needed. The healing rates for famotidine were 45%, 66%, and 78% at weeks 4, 6, and 8, respectively. In comparison, placebo healing rates were 39%, 44%, and 64%. These differences were statistically significant in favor of famotidine at weeks 6 (p less than or equal to 0.01) and 8 (p less than or equal to 0.05), as well as in a life-table analysis (p less than or equal to 0.05). Nocturnal famotidine was also significantly better than placebo with respect to time to complete relief of pain and to the percentage of patients with complete relief of pain. No concomitant factor (including ulcer size, ulcer location, smoking history, or regular alcohol use) affected healing rates in this study. Famotidine was well-tolerated and no serious clinical or laboratory adverse effects were judged to be related to this dosing regimen of famotidine. In conclusion, suppression of nocturnal acid secretion with famotidine (40 mg at bedtime) was more effective than placebo in promoting the healing of acute benign gastric ulcer and its associated symptoms. The results of this study suggest that suppression of nocturnal acid secretion alone is as effective as "around the clock" acid suppression in the healing of benign gastric ulcer.

Meta-analytic methods were applied to review clinical trials published in English that have assessed the efficacy of parenteral nutrition for cirrhotic patients with acute hepatic encephalopathy. Modified amino acid solutions containing increased amounts of branched-chain amino acids were used as part of the treatment regimen in all studies. Pooled analysis of five randomized controlled studies showed a highly significant improvement in mental recovery (p less than 0.001) from high-grade encephalopathy over follow-up times varying from 5 to 14 days. The significance level of the treatment effect did not change when the analysis was repeated using alternative methods of counting and attributing events in these trials. Sharp differences in direction of treatment effect precluded pooling case fatality data. Two studies reported an increased risk of death in the treatment group. Two others showed a clear benefit from administration of parenteral nutrition: the aggregate relative risk reduction was 0.59 (95% confidence interval: 0.23-0.80, p = 0.002). Addition of unpublished data from a third positive study increased the relative risk reduction to 0.82 (p less than 0.0001), and the most conservative interpretation of the published data still yielded a significant reduction in mortality (p = 0.023). However, given the uncertainty about effects on mortality and short follow-up times in all studies, a confirmatory randomized controlled trial with longer follow-up periods is warranted.

The diagnostic accuracy and practical impact of high-resolution sonography were prospectively studied in 523 consecutive patients admitted to the hospital with suspected appendicitis. The criteria for ultrasound diagnosis of acute appendicitis included visualization of a noncompressible aperistaltic appendix, with a targetlike appearance in transverse view and a diameter greater than or equal to 7 mm. In 115 of 130 patients with proven appendicitis the inflamed appendix or appendiceal abscess could be visualized, giving a sensitivity of 88.5%. The mean diameter of ultrasonically visible appendices was 11.4 +/- 3.2 mm. The overall accuracy and specificity of sonography in the diagnosis of acute appendicitis were 95.7% and 98%, respectively. The predictive value of a positive test was 94.5% and that of a negative result 96.3%. In a separate analysis of the results in 121 women of childbearing age, who have a high risk of preoperative misdiagnosis, the overall accuracy was found to be 96.7%, with 82.6% sensitivity and 100% specificity. Twenty-four (89%) of the 27 patients with appendiceal rupture (incidence 20.8%) were correctly diagnosed with ultrasound. The other 3 cases (11%) were missed. Routine use of ultrasonography has significantly improved the diagnostic accuracy in patients with suspected appendicitis and has reduced the negative laparotomy rate from 22.9% to 13.2%.

Data are presented on the sensitivity, specificity, and positive predictivity of the Hemoccult test based on the experience of the Minnesota Colon Cancer Control Study, a randomized clinical trial to determine whether the use of the Hemoccult test can reduce mortality from colorectal cancer. Rehydrating the slides with a drop of water before processing resulted in an increase in positivity (2.4% to 9.8%), and sensitivity (80.8% to 92.2%) but a decrease in specificity (97.7% to 90.4%) and positive predictivity (5.6% to 2.2%). The effects of age and sex were also evaluated. The test was less specific for men than women (p = 0.03). Specificity was highest for those less than 60 yr of age and decreased with increasing age (p = 0.05). The positive predictivity increased with age from 1.6% for those under 60 yr to 3.6% for those over 70 yr (p = 0.0004).