Isolated rat hepatocyte couplets in short-term culture (6 h) were labeled for 3 min with horseradish peroxidase (HRP) to characterize the transcytotic vesicle transport pathway in this cell culture system that retained an "apical" canalicular membrane polarity. Microtubules were identified with monoclonal antibodies to beta-tubulin and fluorescein iso-thiocyanate-labeled goat-antimouse antibody and were concentrated in the apical domain, a structural polarity that was eliminated by pretreatment with colchicine. In control cells, HRP immediately labeled vesicles and tubules in the submembrane regions of the periphery of the cell. Within 10 min tubules and vesicles were prominently labeled in pericanalicular regions, a process blocked by colchicine but not by lumicolchine or taurocholate administration. A quantitative morphometric analysis utilizing a Zeiss Videoplan-2 image analyzer established that (a) HRP-containing structures increased in density, area, length, and diameter in the pericanalicular region by 10 min; (b) colchicine, but not lumicolchicine, pretreatment diminished their density, area, and length; and (c) taurocholate (50 microM), a choleretic and biliary lipid-stimulating bile acid, had no effect on HRP density or percentage of area in the pericanalicular region, but decreased the diameter of the pericanalicular HRP-containing structures and increased the percentage of tubules containing HRP from 29% to 40%. Tubules were particularly prominent in thick sections (400 nm) in both peripheral and pericanalicular regions and were viewed as continuous anastomosing linear arrays in stereo-paired micrographs. These studies established that isolated rat hepatocyte couplets maintain a highly polarized tubulovesicular transcytotic pathway in short-term culture that is micro-tubule-dependent. Taurocholate stimulates the transformation of tubules from vesicles in this isolated rat hepatocyte couplet system.

Women with symptoms indicative of irritable bowel syndrome who had not consulted a physician were compared with female patients at a gastroenterology clinic to investigate whether self-selection for treatment accounts for psychologic abnormalities in clinic patients' with irritable bowel syndrome. Two sets of diagnostic criteria were compared: restrictive criteria based on the work of Manning and conventional criteria (abdominal pain plus altered bowel habits). Lactose malabsorbers were included as a control group because they have medically explained bowel symptoms similar to those that define irritable bowel syndrome. Thus they control for the causative effects of chronic bowel symptoms on psychologic distress. Women who met restrictive criteria for irritable bowel syndrome but had not consulted a physician had no more symptoms of psychologic distress on the Hopkins Symptom Checklist than asymptomatic controls. However, medical clinic patients with both irritable bowel syndrome and lactose malabsorption had significantly more psychologic symptoms than asymptomatic controls or nonconsulters with the same diagnoses. Individuals who met only the conventional criteria for irritable bowel syndrome reported more psychologic distress than controls, whether or not they consulted a physician. These results suggest that (a) symptoms of psychologic distress are unrelated to irritable bowel syndrome but influence which patients consult a doctor and (b) conventional diagnostic criteria identify more psychologically distressed individuals than do restrictive criteria.

Since its approval by the Food and Drug Administration in September 1985, the Garren-Edwards gastric bubble has been extensively used as an adjunct to diet and behavioral modification in the treatment of exogenous obesity. In an attempt to evaluate the efficacy of the Garren-Edwards gastric bubble, a double-blind crossover study was undertaken. Ninety patients were randomized into three groups: bubble-sham, sham-bubble, and bubble-bubble in two successive 12-wk periods. Sixty-one patients completed the entire 24-wk study. All groups participated in ongoing diet and behavioral modification therapy in a free-standing obesity program, the members of which were blinded to randomization arms. All patient groups lost weight during this study. The mean cumulative weight loss in pounds at 12 wk was as follows: bubble-sham = 19, sham-bubble = 12, and bubble-bubble = 8; and at 24 wk: bubble-sham = 23, sham-bubble = 16, and bubble-bubble = 18. The mean cumulative change in body mass index (kg/m2) at 12 wk was as follows: bubble-sham = -3.1, sham-bubble = -2.3, and bubble-bubble = -2.9; and at 24 wk: bubble-sham = -3.1, sham-bubble = -3.0, and bubble-bubble = -3.3. Although weight loss occurred more consistently in patients with a Garren-Edwards gastric bubble, there were no significant differences between any of the three groups at 12 or 24 wk with respect to weight loss or change in body mass index. The major part of the weight loss noted during this study occurred during the first 12-wk period, irrespective of therapy (bubble or sham). Side effects observed during this study included gastric erosions (26%), gastric ulcers (14%), small bowel obstruction (2%), Mallory-Weiss tears (11%), and esophageal laceration (1%). We conclude that, in this study, the use of a Garren-Edwards gastric bubble did not result in significantly more weight loss than diet and behavioral modification alone in the management of exogenous obesity, and it may result in significant morbidity.

After massive small bowel resection, total parenteral nutrition (TPN) is prescribed to maintain nutritional status. However, TPN reduces the mass of the remaining intestinal mucosa, whereas adaptation to small bowel resection is associated with increased mucosal mass. Short-chain fatty acids (SCFAs) have been shown to stimulate mucosal cell mitotic activity. This study determined whether the addition of SCFAs to TPN following small bowel resection would prevent intestinal mucosal atrophy produced by TPN. Adult rats underwent an 80% small bowel resection and then received either standard TPN or TPN supplemented with SCFAs (sodium acetate, propionate, and butyrate). After 1 wk, jejunal and ileal mucosal weights, deoxyribonucleic acid, ribonucleic acid, and protein contents were measured and compared with the parameters obtained at the time of resection. Animals receiving TPN showed significant loss of jejunal mucosal weight, deoxyribonucleic acid, ribonucleic acid, and protein and ileal mucosal weight and deoxyribonucleic acid after small bowel resection, whereas animals receiving SCFA-supplemented TPN showed no significant change in the jejunal mucosal parameters and a significant increase in ileal mucosal protein. These data demonstrate that SCFA-supplemented TPN reduces the mucosal atrophy associated with TPN after massive bowel resection and thys may facilitate adaptation to small bowel resection.

In vivo observations have suggested that acid secretion may potentiate pepsinogen release. We measured pepsinogen and acid secretion by guinea pig fundic mucosal sheets stimulated by 10(-4) M histamine, 10(-8) and 10(-9) M cholecystokinin, and 3 x 10(-7) M carbamylcholine and then investigated the effects of 10(-4) M omeprazole on basal, carbachol-stimulated, and cholecystokinin-stimulated secretion. Histamine increased basal acid secretion fivefold (p less than 0.01) without altering pepsinogen secretion. Cholecystokinin did not stimulate acid secretion but increased pepsinogen secretion by factors of 23.1 at 10(-8) M and 9.1 at 10(-9) M (both p less than 0.01). The combination of 10(-4) M histamine and 10(-9) M cholecystokinin increased acid secretion 3.5-fold and pepsinogen secretion 6.4-fold, statistically equivalent to the sum of the effects of histamine and cholecystokinin alone. Carbachol increased acid secretion and pepsinogen secretion by factors of 4.0 and 10.9, respectively (both p less than 0.01). Pretreatment with 10(-4) M omeprazole abolished basal and carbachol-stimulated acid secretion. However, pepsinogen secretion was unaffected (p greater than 0.05). Furthermore, omeprazole-treated tissues increased pepsinogen secretion by factors of 10.0 with 3 x 10(-7) M carbachol and 9.1 with 10(-9) M cholecystokinin (both p less than 0.01). Thus, basal and secretagogue-stimulated pepsinogen secretion appear independent of acid secretion in intact guinea pig mucosa.

The purpose of our study was to determine the site of origin of vagal neurons that innervate specific parts of the stomach (the fundus, corpus, and antrum/pylorus). This was done by injecting the retrograde fluorescent tracer Fast Blue into these parts of the cat stomach and examining the hindbrain for cells labeled with retrograde tracer. We found that vagal preganglionic innervation to the stomach originates from two medullary nuclei, namely, the dorsal motor nucleus of the vagus (bilateral) and the nucleus retroambiguus (left). All parts of the stomach receive innervation from the dorsal motor nucleus of the vagus (primarily from the area ranging from 0.5 to 1.8 mm rostral to the obex), but only the fundus and corpus receive innervation from the nucleus retroambiguus. Injection of tracer into the fundus labeled cells within the lateral half of the dorsal motor nucleus of the vagus and injection of tracer into the antrum/pylorus labeled cells within the medial portion. Finally, injection of tracer into the corpus labeled cells throughout the mediolateral axis of the dorsal motor nucleus of the vagus. The finding of a columnar organization of the dorsal motor nucleus of the vagus implies some type of functional organization of gastrointestinal control. The fact that vagal inputs to the stomach arise from the dorsal motor nucleus of the vagus and nucleus retroambiguus suggests a separation of vagal pathways controlling different gastric functions (e.g., pacemaker activity, motility, and secretion).

The use of sigmoidoscopy as a screening method for colorectal cancer is controversial. Evidence regarding its efficacy is reviewed critically, with special attention given to potential biases in screening studies. The vast majority of studies are uncontrolled and without follow-up information and thus shed little light on the actual benefits of sigmoidoscopy. Two uncontrolled studies with follow-up and one randomized trial suggest a colorectal cancer mortality reduction because of the use of sigmoidoscopy, but all three studies have major shortcomings. The authors conclude that the currently available data are insufficient to establish a national recommendation for screening with sigmoidoscopy. To establish such a recommendation, a properly conducted randomized trial with colorectal cancer mortality as an outcome is needed.

Campylobacter pylori organisms were found with similar frequency in the stomachs of patients with Barrett's esophagus and in age- and sex-matched controls (10 of 26 vs. 11 of 26). Campylobacter pylori was also observed in esophageal Barrett's mucosa in some patients with gastric C. pylori, but not when gastric infection was absent (4 of 10 vs. 0 of 16). Campylobacter pylori was not detected in esophageal squamous mucosa from patients with Barrett's esophagus or in 25 non-Barrett's patients with gastric C. pylori and histologic changes of esophageal reflux. Overall frequency of ulceration in Barrett's esophagus was 35% (9 of 26), and frequency of ulceration was similar whether or not C. pylori was noted in gastric or Barrett's mucosa.

Intragastric balloons have been suggested as a treatment for severe obesity, a degree of obesity associated with a relatively greater eating disorder or lack of control of energy balance. The premises that 250-500-ml balloons are able to simulate "satiety" in a 1700-ml stomach sufficiently to cause weight loss, that the stomach will not stretch to accommodate such a besoar (with or without ulcerating), and that behavioral modification is cost-effective in weight control in this population have not been corroborated. Experience from gastric restrictive surgery has demonstrated the conceptual failure of gastric satiety as a means of achieving and sustaining weight loss in a substantial percentage of morbidly obese patients. Other methods are needed to reduce the increased morbidity and mortality of severe obesity.

Digoxin is metabolized to cardioinactive reduced metabolites (digoxin reduction products) in some patients by anaerobic bacteria present in the gut flora. We compared the tendencies of Americans and Bangladeshis to reduce digoxin by this pathway. Of 97 normal Americans in New York City, 34 (35.1%) were metabolizers in contrast to 14 of 100 Bangladeshis in Dhaka (p less than 0.002). Forty-three (35.8%) of 120 American patients in New York City receiving digoxin reduced the drug compared with 4 (13.8%) of 29 Bangladeshi patients in Dhaka (p less than 0.05). In Americans who emigrated to Dhaka or Bengali immigrants to New York City, the frequency of digoxin reduction product excretion was that of their country of origin. Fourteen Bengali immigrants who were nonmetabolizers when first studied in New York did not metabolize digoxin when restudied 4 yr later. In the Bangladeshis studied in Dhaka, income, education, and most strongly, urban residence during childhood correlated positively with digoxin inactivation. The findings are consistent with the hypothesis that the metabolic functions of the anaerobic gut flora may be determined by environmental factors operative early in life and tend to remain stable in adulthood. Interethnic variations in drug metabolism may be the consequence of differences in the intestinal microflora.

Penetration of the pericardium and heart by benign peptic ulcers is rare. Before 1965 it was almost invariably fatal, but about 20% of recently reported cases have survived. We report 4 representative cases and review 91 additional cases from the literature. The ulcers arose in esophagus, hiatus hernias, abdominal stomach, and near anastomoses, and the predominant predisposing factor was previous surgery to the esophagogastric region. Whereas penetrating esophageal ulcers had a slightly better prognosis than gastric lesions, the principal determinant of clinical presentation, findings, and prognosis was the site of cardiac involvement. The clinicopathological features of pericardial, atrial, and ventricular involvement are distinct. We evaluate the different implications of these features for diagnosis, management, and prognosis and make some tentative recommendations regarding diagnostic procedures and treatment. Early diagnosis and prompt surgical intervention are critical to successful treatment of this entity, which may present with predominantly cardiac or gastrointestinal symptomatology.

To assess the effect of malnutrition on gastric acidity and gastric bacterial colonization, we studied 35 severely malnourished Bangladeshi children before (0 wk) and after (3 wk) they received nutritional rehabilitation for 3 wk. These results were compared with those obtained from a similarly examined group of 20 better-nourished Bangladeshi children. Gastric acid output, both basal and after betazole stimulation, was significantly lower in the malnourished group at 0 wk compared with the better-nourished children (p less than 0.01): basal 0.22 vs. 0.52 mEq HCl/h and stimulated 0.90 vs. 2.5 mEq HCl/h. Both the concentration of acid and the rate at which gastric juice was secreted were decreased in the malnourished group but serum gastrin levels were not significantly different. After 3 wk, the malnourished children had improved from 61% (+/- 9.0%; SD) to 81% (+/- 8.1%) of expected weight-for-height and were not significantly different than the better-nourished group (86% +/- 11%). Nevertheless, gastric acid concentration remained depressed in the 3-wk group, although the rate of gastric juice secretion equaled levels observed in the better-nourished group. None of the better-nourished children had detectable gram-negative bacterial colonization of their gastric juice. In contrast, 26 of 32 (81%) malnourished children at 0 wk were colonized--even after betazole stimulation, 11 of 33 (33%) gastric juice samples yielded viable organisms--suggesting that the decrease in gastric acid output greatly reduced the gastric acid barrier. Interestingly, only 9 of 20 (45%) better-nourished children had gastric juice with basal pH values below 4.0, suggesting that the gastric acid barrier may be an intermittent defense factor in Bangladeshi children.

Ten consecutive patients with metastatic gastrinoma that increased in size over time were studied prospectively during treatment with monthly cycles of streptozotocin (3 g/m2), 5-fluorouracil (1.2 g/m2), and adriamycin (40 mg/m2) to determine the response rate and time-courses of changes during chemotherapy and to assess various methods of evaluating the effect of chemotherapy. Forty percent of patients demonstrated an initial objective response (greater than or equal to 25% decrease in tumor size with no new lesions) and 60% failed chemotherapy (greater than or equal to 25% increase in tumor size or appearance of new lesions). The mean dose of streptozotocin was 27 g/m2 with objective responses occurring at 3.7 +/- 0.7 mo and failures at 4.5 +/- 0.7 mo. Responses lasted 9.7 +/- 2.8 cycles and no complete responses occurred. Survival was not significantly different in responders versus nonresponders (26 +/- 11 vs. 15 +/- 4.8 mo, p greater than 0.1). Changes in serum gastrin concentration, basal acid output, or sensitivity to a given dose of histamine H2-receptor antagonist did not reflect changes in tumor size. Computed tomography and angiography were the best methods to assess changes in tumor size during chemotherapy, whereas liver-spleen scan and ultrasound were relatively insensitive. All patients developed side effects with chemotherapy: 100% had vomiting, 80% alopecia, 40% transient proteinuria, and 20% leukopenia. The present results indicate that chemotherapy with streptozotocin, 5-fluorouracil, and adriamycin is much less effective in patients with extensive metastatic gastrinoma than previously reported. Computed tomography scanning is the method of choice to assess changes in tumor size. Changes in serum gastrin concentration, acid secretion, or tumor size assessed by liver-spleen scan or ultrasound are not sensitive indicators of the tumor response during chemotherapy.

We have investigated the in vitro properties of SMS 201-995, a long-acting somatostatin analogue, on electrolyte transport in rabbit ileum. Similar to native somatostatin, serosal addition of this compound inhibits electrogenic anion secretion and stimulates neutral sodium and chloride absorption. Both compounds have similar maximal effects on ion transport; however, the ED50 of SMS 201-995 (2.4 X 10(-10) M) was 60 times less than that for somatostatin. In addition, unlike somatostatin, no inherent tachyphylaxis was observed in response to SMS 201-995. The antisecretory profile of SMS 201-995 was also compared with that of epinephrine. Unlike treatment with epinephrine, pretreatment of tissues with SMS 201-995 did not directly inhibit electrogenic anion secretion stimulated by vasoactive intestinal polypeptide, calcium ionophore A23187, and bethanechol. In contrast, this agent blocked vasoactive intestinal polypeptide and bethanechol inhibition of net sodium absorption. We conclude that SMS 201-995 has several unique in vitro properties that may explain its greater biologic activity compared with that of somatostatin. Its effects on secretagogue-stimulated electrogenic anion secretion and electroneutral NaCl absorption appear to differ.

The aim of this study was to determine the composition of gallstones from the common bile duct of patients from the United States and the relationship of stone type to the time interval after cholecystectomy. We analyzed 56 sets of common bile duct gallstones collected over a 10-yr period using infrared and atomic absorption spectroscopy and chemical methods. Twenty-four sets (43%) of stones were cholesterol stones containing 85.3% cholesterol, 3.2% pigment, 0.6% phosphate, and 1.3% total calcium. Ten sets (18%) were black pigment stones containing 36.5% pigment, 11.4% cholesterol, 7.6% carbonate, 3.0% phosphate, and 6.2% total calcium. Twenty-two sets (39%) were brown pigment stones containing 52.7% pigment, 16.5% calcium palmitate, 10.1% cholesterol, 0.4% phosphate, and 3.4% total calcium. Most of the 26 stones found at the same time as or within several months after cholecystectomy were either cholesterol (69%) or black pigment (19%). In contrast, the majority (59%) of the 22 common duct stones that were diagnosed greater than or equal to 21 mo after cholecystectomy were brown pigment stones. In conclusion, brown pigment stones are a distinct type of pigment stone characterized by their content of substantial amounts of calcium palmitate. They comprise a significant proportion of common duct stones in this series of United States patients, particularly of those found greater than or equal to 21 mo after cholecystectomy.

Primary biliary cirrhosis is a frequent indication for liver transplantation. The purpose of this report is to present our experience with liver transplantation for primary biliary cirrhosis. Attention is given to the causes of hepatic dysfunction seen in allografts. In addition, we review the postoperative problems encountered and the quality of life at time of last follow-up in patients with transplants for primary biliary cirrhosis. A total of 97 orthotopic liver transplant procedures were performed in 76 patients with advanced primary biliary cirrhosis at the University of Pittsburgh from March 1980 through September 1985. The transplant operation was relatively easy to perform. The most common technical complications experienced were fragmentation and intramural dissection of the recipient hepatic artery, which required an arterial graft in 20% of the cases. Most of the postoperative mortality occurred in the first 6 mo after transplantation, with an essentially flat actuarial life survival curve from that time point to a projected 5-yr survival of 66%. Common causes of death included rejection and primary graft nonfunction. Thirteen of the 76 patients had some hepatic dysfunction at the time of the last follow-up, although none were jaundiced. Recurrence of primary biliary cirrhosis could not be demonstrated in any of the patients. Antimitochondrial antibody was detected in the serum of almost all of the patients studied postoperatively for it. Most important, almost all of the 52 surviving patients have been rehabilitated socially and vocationally.