Chronic progressive hepatocerebral degeneration with spastic paraparesis, dementia, dysarthria, ataxia, tremor, and neuropsychiatric symptoms follows long-standing portal-systemic shunting, is associated with structural changes in the central nervous system, and does not respond to conventional therapy for hepatic encephalopathy. A case of advanced chronic liver disease with severe, progressive hepatocerebral degeneration after 23 yr of portal-systemic shunting is reported in whom there was significant objective improvement in intellectual function and in the chronic neurological signs 3 mo after orthotopic liver transplantation and further improvement 12 mo after transplantation.

Adenocarcinomas of the proximal and distal stomach have significant clinical and biological differences. A study was undertaken to determine if a difference in the incidence of mutated ras oncogenes exists between proximal (gastroesophageal junction or cardia) and distal (body or antrum) gastric tumors, and to assess the overall incidence in gastric cancers from non-Asian patients. Deoxyribonucleic acid from 28 primary gastric adenocarcinomas were analyzed for point mutations in codons 12, 13, and 61 of the Ha-ras, Ki-ras, and N-ras protooncogenes using polymerase-catalyzed chain reaction methodology. Twelve tumors were located at the gastroesophageal junction or cardia, and 16 in the body or antrum. Mutated ras genes were detected in 2 of 28 tumors for an overall incidence of 7%. The mutations occurred in codon 61 of the N-ras gene in a proximal gastric cancer and in codon 12 of the Ki-ras gene in a distal gastric cancer. These data indicate that mutations in ras genes are an uncommon event in primary gastric cancers and that there is no meaningful difference in the incidence of ras mutations in proximal and distal stomach cancers.

We have previously shown that Entamoeba histolytica lysates contain the neurohormones serotonin, neurotensin, immunoreactive substance P, and probably acetylcholine, and that amebic lysates inhibit sodium and chloride absorption and stimulate chloride secretion in the rat descending colon as measured by the Ussing chamber-voltage clamp technique. We now demonstrate that these transport effects have both calcium-dependent and calcium-independent components. In addition, arachidonic acid metabolites of the cyclooxygenase pathway are probably involved in the Entamoeba histolytica-induced changes in colonic transport that are not dependent on Ca++ entry. Prostaglandin E2 (10(-5) M), indomethacin (10(-6) M), piroxicam (5 x 10(-5) M), and mepacrine (10(-4) M) partially inhibited the amebic lysate effect on active transport in the rat descending colon. In addition, verapamil (10(-4) M) partially inhibited the effect of amebic lysates. The effect of verapamil was additive with that of indomethacin, totally blocking the effect of amebic lysate on short-circuit current. However, amebic lysates do not contain prostaglandin E2 as measured by sensitive radioimmunoassay. Amebic lysates stimulated prostaglandin E2 release from rat colonic mucosal strips. Amebic lysate significantly increased colonic cyclic adenosine monophosphate content. Piroxicam inhibited the lysate-induced increase in colonic cyclic adenosine monophosphate content. These results indicate that although amebic lysate does not contain prostaglandin E2, it caused arachidonic acid metabolites to be produced by the cyclooxygenase pathway, and these are probably involved in the Entamoeba histolytica-induced changes in colonic transport. Neurohormones in Entamoeba histolytica may act directly on colonic tissue to stimulate intestinal secretion, probably via a Ca+(+)-dependent mechanism that is blockable by verapamil, or indirectly via stimulation of prostaglandin E2 generation and release from the rat colon via a cyclic adenosine monophosphate-dependent mechanism. These effects appear separate. The cyclic adenosine monophosphate-dependent secretion is the predominant mechanism in this model of colonic amebic diarrhea.

We prospectively evaluated gastric acid output (mEq/h), gastric volume output (ml/h), ambulatory 24-h esophageal pH monitoring, and the endoscopic appearance of the esophagus in 23 patients undergoing treatment of chronic long-standing pyrosis. Twelve of these 23 individuals (52%) remained symptomatic after 3 mo of standard antisecretory treatment with ranitidine, 150 mg twice daily. When compared with initial responders, those patients who did not experience complete symptomatic relief on therapy had significantly higher basal acid output (p less than 0.001), basal volume output (p less than 0.02), and basal upright (but not supine) reflux time (p less than 0.05). Nine of the 12 patients who did not respond to initial treatment had gastric acid hypersecretion (basal acid output greater than 10 mEq/h), and 10 of the 12 had Barrett's epithelium compared with only 1 patient in the initial-responder group (p less than 0.001). All 12 nonresponders were treated for an additional 3 mo with increased doses of ranitidine (mean, 1280 mg/day; range, 600-1800 mg/day), and complete disappearance of pyrosis occurred in 10 of the 12, although no significant endoscopic regression was observed in the extent of the underlying columnar mucosa in those with Barrett's esophagus over the 6-mo duration of the study. A significant correlation was shown between the daily ranitidine dose required to eliminate symptoms and the pretreatment basal acid output (r = 0.81, p less than 0.001); gastric acid output had to be almost totally suppressed (i.e., less than 1 mEq/h) for pyrosis to disappear completely. No side effects occurred with any of these high doses of ranitidine. We conclude that a subgroup of patients with long-standing symptomatic gastroesophageal reflux disease who do not respond to standard ulcer-healing doses of histamine2-receptor antagonists are hypersecretors of basal gastric acid and require increased acid-suppressive therapy. Many of these individuals also have underlying Barrett's epithelium.

Mice were immunized with human intrinsic factor, and their lymph node cells were fused with a myeloma cell line by standard hybridoma techniques. Eleven of the resulting 227 hybridomas secreted immunoglobulin G capable of binding to intrinsic factor-cobalamin complex. Cloning by limiting dilution gave 6 clones secreting anti-intrinsic factor antibodies that bound human intrinsic factor-cobalamin complex with affinities of 13-116 nM; 3 antibodies also bound rabbit intrinsic factor-cobalamin complex. Five antibodies inhibited to some degree the binding of cobalamin by intrinsic factor, and 2 also prevented attachment of intrinsic factor-cobalamin complex to guinea pig ileal receptors. Anti-rabbit intrinsic factor antibodies specifically precipitated a peptide of molecular weight 53,000, corresponding to the molecular weight of rabbit intrinsic factor from homogenates of rabbit gastric mucosal explants biosynthetically labeled with [35S]methionine and from culture medium in which the explants were incubated. Indirect fluorescence immunocytochemistry with the antibodies in human and rabbit gastric mucosal sections showed intense selective staining of parietal cells. These results (a) document species differences between human and rabbit intrinsic factors not previously demonstrable with polyclonal anti-intrinsic factor sera; (b) confirm earlier evidence that cobalamin binding and receptor functions occur at separate sites in intrinsic factor; and (c) provide a useful approach to studying structure-function relations of the intrinsic function molecule.

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.

The organic matrix of cholesterol gallstones contains a macromolecular complex of mucin and bilirubin that may inhibit stone dissolution by limiting contact of desaturated bile with crystalline cholesterol. The goal of this study was to determine if the mucolytic agent N-acetylcysteine could accelerate gallstone dissolution in vitro. Paired gallstones were dissolved in either pure taurocholate (140 mM) or ursodeoxycholate (100 mM), or in bovine bile supplemented with either taurocholate or ursodeoxycholate to achieve the same respective bile-salt concentrations. N-acetylcysteine was added to 1 stone from each pair at a concentration of 500 mM in pure bile salts and 100 mM in supplemented bile. Gallstones dissolved significantly faster in bovine bile supplemented with taurocholate or ursodeoxycholate than in pure solutions of the respective bile salts (n = 30, p less than 0.001). N-acetylcysteine significantly accelerated gallstone dissolution in pure solutions of bile acids (n = 30, p less than 0.001 for each) and in supplemented bovine biles (n = 30, p less than 0.001). N-acetylcysteine also significantly increased the frequency of complete gallstone dissolution in taurocholate-supplemented (66.6% vs. 40.0%) and ursodeoxycholate-supplemented (76.6% vs. 50.0%) bile. These results indicate that the mucolytic agent N-acetylcysteine significantly accelerates in vitro gallstone dissolution. We speculate that adjuvant therapy with an appropriate mucolytic agent may potentially increase the efficacy of clinical gallstone dissolution.

Previous studies have reported that small and large intestinal crypt hyperplasia and hyperproliferation occur in senescent rats about 27 mo of age. We have studied duodenal and ileal architecture in ad libitum chow-fed rats and have demonstrated that the increase in duodenal crypt depth and crypt hyperplasia do not develop throughout the life span, but become apparent at 21 and 27 mo of age. These crypt hyperplastic features occur without a change in duodenal villus cell number. Ileal villus cellularity increased throughout the life span, suggesting exposure to a gradually increasing luminal nutrient load. Diet restriction to 60% of the ad libitum feeding rate prolonged the life span of animals from 27 to greater than 33 mo and prevented both the duodenal hyperplasia and the increase in ileal villus cell numbers to the age of 27 mo. Thirty-three-month diet-restricted rats did show evidence of duodenal crypt hyperplasia. We conclude that proximal intestinal hyperplasia is a phenomenon that develops in advanced age, but that ileal villus cellularity increases throughout the ad libitum-fed rodent life span. Diet restriction dramatically retards these intestinal changes that are seen with ad libitum feeding and provides an experimental model for the study of age-related cellular changes of the rodent gastrointestinal tract.

To determine whether bowel symptoms covary in a pattern consistent with the existence of irritable bowel as a distinct syndrome, bowel symptom questionnaires from 2 independent samples were factor analyzed. Samples consisted of 351 18-40-yr-old women who visited Planned Parenthood clinics for contraception and 149 18-89-yr-old women recruited through church women's societies. Factor analysis of 23 bowel symptoms identified 4 factors (clusters of symptoms that were correlated with each other) in both samples. The factor accounting for the most variance in both samples included relief of pain with defecation, looser stools with pain onset, more frequent stools with pain, and gastrointestinal reactions to eating. This irritable bowel factor was not correlated with an objective measure of lactose intolerance. An independent constipation factor was found in both samples to include self-reported constipation, straining with bowel movements, feeling of incomplete evacuation, and rectal bleeding. Thus factor analysis of bowel symptoms supports the existence of a specific irritable bowel syndrome and suggests symptoms that may be used to diagnose this syndrome.

Vitamin E uptake by Caco-2 cells, a human intestinal cell line, was studied by incubating the cells with alpha-tocopherol/triglyceride emulsions with or without bile activated lipase or lipoprotein lipase. During a 1-h incubation, vitamin E was transferred to Caco-2 cells only in the presence of triglyceride hydrolysis by bile activated lipase and not by lipoprotein lipase. Incubation with either lipase resulted in hydrolysis of approximately 20% of the medium [3H]-triolein to free fatty acids and a 3-5-fold increase in cellular radioactivity. In the absence of lipases but the presence of taurocholate, addition of oleic acid in an amount equal to the molar concentration of triglyceride (5.7 mM) to triglyceride emulsions containing either alpha-tocopherol or cholesteryl ester resulted in an increase in cellular [3H]-triglyceride and alpha-tocopherol or cholesteryl ester. We suggest that the absorption of hydrophobic molecules such as vitamin E may occur in the presence of bile and amphipathic lipids via the uptake of micellar neutral lipids by the intestine.

The epidemiological understanding of inflammatory bowel disease has been limited by the referral bases of most inflammatory bowel disease studies. The Colitis-Ileitis Study Group of Rochester, N.Y., developed a community-wide, computerized cumulative registry of all inflammatory bowel disease patients hospitalized at the 8 community hospitals for 1973-86. Clinical data were abstracted from each of the 1651 identified hospital charts. All of these patients resided in Monroe County (city and suburbs) and the 5 contiguous counties (Genesee/Finger Lakes Region, population 1,030,640). Of the 1651 hospital patients identified in the study, 1358 resided in Monroe County (Rochester and its immediate suburbs, population 702,238). Incidence, defined as time of onset of symptoms of inflammatory bowel disease, rose from baseline rates in the 1930s to peak in 1980 (Crohn's disease = 50.29/10(5) per decade, ulcerative colitis = 35.12/10(5) per decade) and declined through 1986. For Crohn's disease, the age-specific incidence rates peaked in the 20-29-yr-old group in each of the 5 decades studied. Ulcerative colitis seems to occur at all ages and may have a bimodal distribution. There was a period effect, with the 1970s having the highest incidence of Crohn's disease and ulcerative colitis for each age group. However, the age-specific incidence rate for Crohn's disease showed a 40% decrease in the 1980s compared with the 1970s in the 10-39-yr-old group (p less than 0.001). The age-specific incidence rate for ulcerative colitis showed a 50% decrease in the 1980s compared with the 1970s in the 10-49-yr-old group (p less than 0.001).

The manometric responses to graded intraesophageal balloon distention were studied in 30 patients with symptoms of intermittent dysphagia but without evidence of structural narrowing on barium swallow or endoscopy, or both. These studies were compared with those performed in 10 normal volunteers. Using a manometric catheter with a balloon of reproducible dimension, balloon distention produced a sustained pressure proximal to the distended esophageal balloon in 28 of 30 (93%) patients and 9 of 10 (90%) normal volunteers. Patients with dysphagia had the reproduction of their characteristic symptom during balloon distention in 23 of 30 (76%) cases. Atypical symptoms not characteristic of the patients' usual dysphagia developed in the other 4 patients with dysphagia and in all controls. There were no electrocardiographic changes during balloon distention and symptoms were immediately reversible with balloon deflation. Repeated simultaneous contractions consistent with spasm distal to the distending esophageal balloon occurred in 21 of 30 (70%) patients with dysphagia but in no normal volunteers (p less than 0.05). Dysphagia reproduction was associated with the finding of repeated simultaneous contractions distal to the intraesophageal balloon being found in 20 of 30 (66%) patients (p less than 0.05). Distal activity during balloon distention of the esophagus is associated with dysphagia reproduction in a significant number of patients without any other explanation for their symptom. The development of distal spasm in patients with intermittent dysphagia suggests an abnormality of neural control that may be important in the pathophysiology of dysphagia in these patients.

The purpose of this study was to compare the effects of Clostridium difficile toxin A and cholera toxin on fluid secretion, intestinal permeability, and arachidonate metabolites in rabbit ileum. Injection of 25 micrograms of either purified toxin into 10-cm ileal loops caused significant increases in fluid secretion and intestinal permeability to mannitol as well as release of prostaglandin E2 into the lumen. Toxin A, but not cholera toxin, caused a severe inflammatory reaction of the lamina propria and necrosis of enterocytes as well as increased release of leukotriene B4. The toxin A-mediated increases in prostaglandin E2 and leukotriene B4 could be blocked by prior instillation of 10 mg of 5-aminosalicylic acid into ileal loops. 5-Aminosalicylic acid also significantly diminished the expected increase in mannitol permeability after both toxins, but had no significant inhibitory effect on fluid secretion or, in the case of toxin A, intestinal inflammation. Our results indicate that C. difficile and cholera enterotoxins differ substantially in their effects on the rabbit intestine. Clostridium difficile toxin A, an inflammatory toxin, produces a striking infiltration of the lamina propria with neutrophils that is associated with increased release of leukotriene B4. In contrast, cholera toxin does not cause inflammation or leukotriene B4 release. Increased release of prostaglandin E2 occurs after exposure to both toxins and appears to be correlated with increased intestinal permeability.

Humans with cholesterol gallstones have been reported to have alterations in the molecular species of phospholipids in bile. Both decreases in phospholipids with linoleic acid and increases in those with arachidonic acid have been found. The purpose of this study was to investigate the effect of a lithogenic diet (0.34% cholesterol) on the relative abundance of individual molecular species of phospholipids in the biliary tract of the prairie dog. In hepatic bile, cholesterol feeding resulted in increases in phospholipid species containing arachidonate and decreases in the major species containing its precursor, linoleate. In gallbladder bile of both control and cholesterol-fed animals, phospholipid species containing linoleate were significantly less abundant than in hepatic bile, suggesting that linoleoyl species were selectively absorbed by the gallbladder epithelium. This apparent uptake was significantly increased by cholesterol feeding. Phosphatidylcholines and phosphatidylethanolamines containing arachidonate were also significantly increased in the gallbladder mucosa of the cholesterol-fed animals. These increases in arachidonate-containing phospholipids in the gallbladder mucosa may contribute to the increase in gallbladder prostaglandin synthesis that precedes gallstone formation in this animal model.

Diarrhea due to enteric pathogens is an important complication of advanced human immunodeficiency virus infection. Whereas numerous bacterial and parasitic agents have been implicated, the role of pathogenic enteric viruses is less clear. Stools from 153 human immunodeficiency virus seropositive men were tested by electrophoresis, enzyme-linked immunosorbent assay, and immune electron microscopy for the presence of rotaviruses (group A and non-group A), adenoviruses, and Norwalk agent. Virus was detected in 9% of the patients with acquired immunodeficiency syndrome, 3% of the patients with acquired immunodeficiency syndrome-related complex, and none of the seropositive men without these diagnoses. Virus detection was not more likely in stool from patients with diarrhea.

We hypothesized that supplemental nutritional support delivered at home by nocturnal nasogastric feedings would result in accelerated growth in growth-retarded adolescents with Crohn's disease. Eight Tanner stage I adolescents with Crohn's disease, mean age 14 yr 5 mo, had a mean weight gain of 0.38 kg and height gain of 1.4 cm for the year before initiation of nasogastric feedings. All had been either asymptomatic or had only minimal symptoms in the year before the study, but were ingesting only 55%-80% of their daily required caloric intake. The subjects were taught to pass by themselves a nasogastric feeding tube, through which 1000-1500 ml of commercial, nonelemental isocaloric formula was infused during sleep to supplement their usual dietary intake. After 12 mo of nocturnal feedings, the subjects had a mean weight gain of 11.75 kg and a mean height gain of 6.98 cm. Six control subjects, matched for age and degree of growth and sexual retardation at the beginning of the study period, but who had refused the nasogastric feedings, had no change in weight and height during the same period of observation. We conclude that home nocturnal nasogastric feedings can achieve dramatic improvement in weight gain and linear growth in motivated adolescents with Crohn's disease and growth retardation.