The purposes of this study were to determine the association, in 10 pedigrees, between adenomatous polyposis coli, hereditary nonpolyposis colorectal cancer, and occult radiopaque jaw lesions, and to assess whether these radiodensities are predictors for adenomatous polyposis. In seven kindreds with adenomatous polyposis, all patients with polyps had jaw lesions; in one kindred, no jaw lesions were found. In one of two kindreds with hereditary nonpolyposis colorectal cancer, no affected individuals had jaw lesions. In the other, the 1 affected patient with dental radiographs had generalized jaw lesions. Twelve children less than 16 yr old at risk for adenomatous polyposis were observed. Seven children with jaw lesions developed polyps after a mean interval of 4 yr. Five children without jaw lesions were polyp-free during a 5-10-yr follow-up. Thus, occult jaw lesions are consistently found only in some families with adenomatous polyposis coli, providing support for heterogeneity in polyposis syndromes. Jaw lesions are good predictors for polyp development in kindreds with adenomatous polyposis coli and jaw lesions. Their role as markers in hereditary nonpolyposis colorectal cancer needs exploration.

We previously have shown that aging alters the expression of several intestinal enzymes during cell migration from the crypt base to the villus tip. The activities of many mucosal enzymes are dramatically altered by starvation and refeeding. We compared the effects of starvation and refeeding on the activities of selected intestinal enzymes in young and aging Fischer 344 rats. Gut mass fell during starvation and rose during refeeding to a similar extent in both groups. Sucrase and maltase specific activities in control aging rats were lower than in young controls and, during starvation, enzyme activities declined at approximately similar rates in both groups. Total duodenal enzyme activities fell by about two-thirds in young animals and by greater than 80% in aged animals. Alkaline phosphatase and adenosine deaminase activities also were lower in aging than young animals. During refeeding, enzyme activities rose more in aging rats than in the young. In fact, the specific activities of sucrase and maltase in aging rats refed for 1 day exceeded the values found in fed aging controls. The adaptive responses of duodenal enzymes exceeded those in the jejunum. In conclusion, the aging intestine responds appropriately to starvation and refeeding. However, the fluctuations in brush-border enzyme activities are much greater in aging than in young rats. Such alterations may be an important influence of aging on gut differentiation and might have an adverse impact upon nutritional maintenance in aging animals.

The pathogenesis of Clostridium difficile enterocolitis appears to involve colonization of the bowel followed by release of toxin A, an enterotoxin, and toxin B, a cytotoxin. The purpose of this study was to determine the effect of purified toxins A and B on intestinal secretion, epithelial permeability, and morphology in perfused rabbit ileal loops. Intestinal permeability after toxin exposure was assessed by blood-to-lumen clearance of [3H]mannitol. Toxin A at doses of 5-100 micrograms/10 cm ileal loop caused a threefold to fivefold increase in [3H]mannitol permeability (p less than 0.001) vs. equal concentrations of toxin B or buffer control. In addition, perfusate from toxin A-exposed loops contained significantly more neutrophils (p less than 0.001) than toxin B or control loops. Toxin A caused severe epithelial cell necrosis with destruction of villi and polymorphonuclear infiltration. Electron microscopy of mucosa subjected to a low dose of toxin revealed widespread nonspecific dilatation of endoplasmic reticulum and mitochondrial swelling. In contrast to these effects of toxin A in ileal loops, in vitro experiments with ileal explants in short-term organ culture revealed that toxin A had no effect on epithelial cell permeability, protein synthesis, release of alkaline phosphatase, or morphology. Our results show that purified toxin A but not toxin B causes severe inflammatory enteritis in rabbit ileal loops, but has no discernable effect on rabbit ileum in vitro. We speculate that toxin A may contribute significantly to intestinal damage in C. difficile-associated colitis and diarrhea.

This study was designed to evaluate the hemodynamic response to vasopressin infusion during hemorrhage and blood transfusion in a rat model of portal hypertension. Portal pressure, arterial pressure, and regional and systemic blood flows were measured in a rat model of portal hypertension receiving placebo or vasopressin infusion. Effects of the drugs were compared in control rats and rats subjected to hemorrhage and blood transfusion. In a stable portal hypertensive rat group (no hemorrhage or transfusion) a standard vasopressin dose, 2.5 mU X kg-1 X min-1, resulted in a significantly lower portal pressure (11.5 +/- 0.7 vs. 14.4 +/- 0.6 mmHg) with a concomitantly lower portal venous inflow (8.5 +/- 0.3 vs. 11.1 +/- 0.6 ml X min-1 X 100 g body wt-1) when compared with rats receiving placebo. These findings are in contrast to the effects obtained with the same dose of vasopressin given during blood transfusion to hemorrhaged portal hypertensive rats. The standard dose of vasopressin had no effect on any of the splanchnic or systemic circulatory parameters. Only when a dose of vasopressin 10 times larger was used in the hemorrhaged-transfused animals were hemodynamic effects noted. A significant decrease in portal flow and pressure was noted. These findings suggest that vasopressin given during hemorrhage may be less effective than when given during a stable state. Larger doses of vasopressin may be needed during hemorrhage to produce the same effect as seen during a controlled stable state. Caution should be used in extrapolating the results of pharmacologic studies in stable portal-hypertensive models to hypovolemic states in humans.

The clinicopathologic features and natural history of primary sclerosing cholangitis were reviewed in 53 patients followed at the Yale Liver Center during the past 30 yr. At presentation, the mean age of patients was 46 yr, and the male to female ratio was 1.4:1. Biliary sclerosis was limited to the intrahepatic ductal system in 21% of the patients. Fifty-three percent of the patients had mild disease without portal hypertension at presentation, and 25% had no symptoms attributable to their liver disease. Long-term follow-up was available for 42 patients and averaged 56 mo. Over this period, 16 patients remained mildly symptomatic, and 11 were asymptomatic. Survival was calculated by a Kaplan-Meier life-table analysis and demonstrated that 75% of the patients were alive 9 yr after the diagnosis of primary sclerosing cholangitis. A multivariate analysis of clinical features revealed that hepatomegaly and a serum bilirubin level greater than 1.5 mg/dl at the onset of disease were independent discriminators of a poor prognosis. Patients referred to this university medical center displayed different clinical characteristics than previously reported in primary sclerosing cholangitis. A higher percentage were older, female, and asymptomatic, and more had disease limited to the intrahepatic ductal system. Survival was also considerably improved in this group of patients and suggests that the long-term prognosis for patients with primary sclerosing cholangitis may be considerably better than previously believed.

We prospectively followed up 821 adults with acute viral hepatitis hospitalized at the Athens Hospital for Infectious Diseases between May 1981 and May 1983. Radioimmunoassays for the detection of serologic markers of hepatitis A virus, hepatitis B virus, and hepatitis delta virus, and molecular hybridization techniques for the detection of serum hepatitis B virus deoxyribonucleic acid and hepatitis delta virus ribonucleic acid were used. Based on the results of an enzyme immunoassay for the detection of immunoglobulin M antibody to hepatitis B core antigen (Corzyme-M), 563 cases were diagnosed as acute hepatitis B and 45 as acute hepatitis superimposed on hepatitis B surface antigen carriage. Development of the hepatitis B surface antigen carrier state was observed in only 1 (0.2%) of the 507 cases with acute hepatitis B that were followed. In contrast, hepatitis B surface antigen persisted in all the latter cases. Acute hepatitis superimposed on hepatitis B surface antigen carriage was attributed to hepatitis A virus superinfection in 2 (4.4%), hepatitis delta virus superinfection in 22 (48.9%), reactivation of chronic type B hepatitis in 12 (26.7%), seroconversion from hepatitis B e antigen-positive to anti-hepatitis B e antibody-positive in 2 (4.4%), presumed superinfection by non-A, non-B agent(s) in 6 (13.4%), and the first clinical manifestation of chronic active hepatitis in 1 (2.2%) case. These data show that acute clinical hepatitis B in adults seems to be a self-limited disease and rarely leads to the development of the carrier state in this epidemiologic setting and hepatitis delta virus superinfection and spontaneous reactivation of chronic hepatitis B are the principal causes of acute hepatitis superimposed in hepatitis B surface antigen carriers in an area with a moderately high prevalence of hepatitis B virus infections.

The purpose of this study was to determine the intrinsic functions of the feline pylorus in vitro. The myoelectric and pressure characteristics of the intact pylorus, antrum, and duodenum, free of extrinsic hormonal or neural influences, were studied in an in vitro bath that allowed separation of the bathing medium surrounding the different bowel segments. Basal recordings revealed a zone of tonic high pressure of 28.4 +/- 3.5 mmHg (mean +/- SEM) at the pylorus. The basal slow wave frequencies in the pylorus and duodenum were 2.8 +/- 1.4 and 12.6 +/- 0.6 cycles/min, respectively. Spontaneous action potential-associated phasic contractions of the pylorus were noted in 38% of preparations. Enteric nerve stimulation with direct electric current (10 Hz, 1 ms, 10-50 V) applied proximal to the pylorus gave relaxation of the pylorus at the lower voltages and rebound excitation at higher voltages. Electrical stimulation distal to the pylorus yielded phasic contractile pyloric response during the entire stimulus. The duodenal instillation of 0.5 N HCl produced action potential-associated phasic contractions of the pylorus and duodenum but not the antrum. Pyloric responses to electrical stimulation or acidification were abolished by tetrodotoxin (10(-5) M). Bethanechol (10(-6) M) or substance P (10(-7) M) produced a contractile response at the site of stimulation but this response was not transmitted to include adjacent bowel segments. These studies suggest that the pyloric sphincter with its intrinsic reflex properties can be studied in vitro.

Hepatitis delta-virus (the delta-agent) is now recognized as a cause of acute hepatitis, fulminant hepatitis, chronic hepatitis, and cirrhosis in hepatitis B surface antigen-positive hosts. This report describes the clinical course and liver biopsy histopathology of acute delta-hepatitis in a young American woman with presumed chronic hepatitis B infection. The liver biopsy specimen features included severe cytotoxic and cytopathic hepatocellular damage, small droplet vacuolar liver cell degeneration, and few parenchymal inflammatory cells, lesions resembling epidemic delta-hepatitis in Venezuelan Indians and experimental chimpanzee delta-superinfection. This case suggests that this form of cytopathic liver injury is an important morphologic expression of delta-virus hepatitis that deserves wider diagnostic recognition.

The management alternatives of segmental colonic resection versus follow-up alone for colonic adenomas containing early invasive carcinoma (i.e., polypectomy resection margin free of tumor) were evaluated by decision tree analysis. Using data from the literature, the major variables influencing the decision were as follows: probability of residual disease after polypectomy, operative efficacy (defined as the chance of curing a tumor that would otherwise recur without surgery), and operative mortality. For a hypothetical patient with low operative risk (operative mortality of 0.2%), resection would yield the best outcome in terms of life expectancy as long as the probability of residual disease was greater than 0.5%. Extensive analysis of the impact of changes in assumptions about the parameters characterizing the problem showed this conclusion to be unchanging over wide ranges of operative efficacy and probability of residual disease. However, the decision to do a secondary resection in this situation was still close because surgery was only marginally justifiable on economic grounds. Observation would be preferred in patients with higher operative risk (operative mortality greater than 2%).

The accuracy and reliability of a noninvasive pressure-sensitive capsule for the endoscopic measurement of esophageal varix pressure was evaluated. Capsule pressure was correlated with direct intraluminal pressure measurements. The influence of vessel wall tension on capsule pressure was also assessed. In vitro studies demonstrated an excellent correlation (r greater than or equal to 0.94; p less than 0.001) between the pressure obtained with the capsule and intraluminal pressure over a range of vessel diameters and wall thicknesses. In vivo correlation of pressures obtained with the capsule with direct venous pressure measurements was excellent (r = 0.85). However, this correlation decreased with a decrease in vessel diameter (group 1 diameter greater than or equal to 10 mm, r = 0.95; group 2 diameter greater than or equal to 5 mm but less than 10 mm, r = 0.75; group 3 diameter greater than or equal to 3 mm but less than 5 mm, r = 0.81). This decrease in accuracy was significant (p less than 0.001) between group 1 and groups 2 and 3. In vitro and in vivo, capsule pressure variability was significantly greater (p less than 0.001) in vessels of smaller diameter. Wall tension significantly influenced capsule pressure (p less than 0.05), although this effect was only seen in large "vessels" with a diameter beyond a clinically relevant range. Therefore, despite obtaining technically acceptable capsule pressure measurements in ideal experimental conditions, the accuracy and variability of these measurements are limited by vessel size.

It has been suggested that regional differences in membrane properties of circular esophageal smooth muscle play an important role in the mechanism of esophageal peristalsis. The purpose of this study was to examine both the passive and active membrane properties of circular smooth muscle at proximal and distal esophageal sites so as to delineate the role of myogenic properties in the intramural mechanism of peristalsis. Intracellular recordings were made in circular muscle strips taken from proximal (8 cm above the gastroesophageal junction) and distal (2 cm above the gastroesophageal junction) sites in 10 opossums using the partition method of Abe and Tomita. At both esophageal sites, determinations were made of resting membrane potentials, time constants, space constants, thresholds for action potentials, action potential amplitudes, rates of rise of action potentials, and action potential durations at half-amplitude. The values for these parameters at the proximal and distal sites, respectively, were as follows: mean resting membrane potential, 49.7 +/- 0.24 and 49.5 +/- 0.3 mV; length constant, 4.0 +/- 0.4 and 3.8 +/- 0.4 mm; time constant, 513 +/- 49 and 456 +/- 53 ms; threshold for action potentials, 9.3 +/- 0.4 and 8.8 +/- 0.3 mV; amplitude of action potentials, 36.0 +/- 5.2 and 35.3 +/- 1.7 mV; rate of rise of action potentials, 2.3 +/- 0.3 and 2.6 +/- 0.4 mV/ms; duration of action potentials at half-amplitude, 5.0 +/- 1.2 and 4.1 +/- 0.4 ms; and the conduction velocity for evoked potentials, 3.9 +/- 0.3 and 3.8 +/- 0.4 cm/s. Our studies show that there are no differences between proximal and distal esophageal sites in any of these determinations. These studies also show that regional differences in the electrical membrane properties of circular smooth muscle do not account for esophageal peristalsis.

Diarrhoeal diseases are among the most important health problems in the world today. While they are generally mild, nuisance illnesses in the developed world, where clean water and sanitation are adequate, these diseases are the most common cause of death in young children in the developing world, where clean water is not available and sanitation is inadequate. In these areas, up to 25% of children may never reach their fifth birthday. In addition, although the impact on growth and nutritional status is difficult to quantify, the cumulative toll on overall child health is enormous. A wide variety of infectious agents are implicated in the aetiology of acute diarrhoeal illness, many of which were unknown 20 years ago. The epidemiology, pathogenic mechanisms and clinical presentation of the common bacterial and viral pathogens, as they are currently understood, will be discussed in this chapter.

Eight infants presented with a malabsorption syndrome, normal fasting triglycerides, hypocholesterolemia (64.3 +/- 10.0 mg/dl), and deficiency of vitamins A and E. Plasma low-density lipoprotein, apolipoprotein B, and apolipoprotein A-I were decreased. After a fatty meal, plasma triglycerides did not increase and chylomicrons could not be identified. Lipoprotein composition was characterized by normal apoproteins, high phospholipids, and low cholesterol. Increased triglycerides were present in low-density lipoproteins. Immunoperoxidase localization of apolipoprotein B on fasting biopsy specimens showed increased staining of the lipid-laden intestinal epithelial cells compared to normals. On electron microscopy after a fat load, the enterocytes contained large numbers of fat particles vesiculating the endoplasmic reticulum. These particles, morphologically similar to chylomicrons, were also present as aggregates of well-individualized lipid droplets within dilated vesicles in the Golgi zone, but were not seen in the intercellular spaces and lacteals. This recessively transmitted condition differs from abetalipoproteinemia and from the homozygous form of hypobetalipoproteinemia and may be caused by a defect in the final assembly of chylomicrons or in the mechanism of their exocytosis.

To determine if bile acids reflux into the esophagus in patients with gastroesophageal reflux disease and in normal subjects during physiological gastroesophageal reflux episodes, esophageal aspiration and pH monitoring were performed simultaneously in 16 patients with gastroesophageal reflux disease and 8 normal subjects. Esophageal samples were collected for 30 min in the fasting state and for 3 h (as hourly samples) after the ingestion of a test meal (egg salad sandwich, peaches, and milk). Bile acids were assayed by a standard enzymatic assay and also by a sensitive and specific assay, liquid secondary ion mass spectrometry. Bile acids were not detected by enzymatic assay in any of the fasting samples. In 6 of the 8 normal subjects and 15 of the 16 patients with gastroesophageal reflux disease, bile acid-like reactivity was detected by the enzymatic assay in postprandial samples. However, bile acid-like reactivity was also found by enzymatic assay in aliquots of the homogenized test meal in concentration similar to the highest concentrations detected in esophageal aspirates. Bile acids were not detected by the liquid secondary ion mass spectrometry method in any of the fasting or postprandial esophageal aspirates (limit of detection greater than 2 microM). However, this assay accurately identified samples to which exogenous bile acids were added as controls. Our results suggest that bile acids did not reflux into the esophagus of patients with gastroesophageal reflux disease whom we studied and caution must be exercised in the use of enzymatic assay for bile acids in postprandial gastrointestinal fluids, as the commonly used hydroxysteroid dehydrogenase assay is not specific for bile acids alone.

Administration of a chemically defined, elemental diet to rats given 20 mg/kg of methotrexate intraperitoneally has consistently resulted in a 100% mortality from severe enteritis within 156 h. This study examined the importance of specific dietary components in the etiology of this enhanced toxicity. Rats were given their respective diets for 7 days, whereupon methotrexate (20 mg/kg) was given intraperitoneally, and percent of survivors was recorded. Varying the concentration of carbohydrate as polysaccharide (0%, 50%, 100%) (n = 30) had no effect on survival. An increase in the percent of protein as polypeptide (0%, 25%, 50%, 75%, 100%) (n = 50) in the elemental diet resulted in a progressively significant increase in percent survival. Addition of either fat or bulk to this elemental diet had no effect on survivorship. Serum and bile methotrexate levels of rats fed an elemental liquid diet (whether or not all of the protein was provided as polypeptide) were significantly increased from 12 to 72 h (p less than 0.03) compared with rats fed a regular Chow diet. When the protein content of the elemental liquid diet was provided as 100% polypeptide, serum and bile methotrexate levels were significantly lower at 48 h compared with the elemental diet group given 100% of protein as amino acid. Administration of methotrexate to rats fed an elemental liquid diet in which all of the protein is provided as amino acids is extremely toxic to the gastrointestinal tract, probably as a result of delayed clearance of the drug from the systemic circulation and from bile. This toxicity is alleviated by the provision of protein as polypeptide in the elemental diet. No toxicity to the drug is seen at this dose in rats fed a regular Chow diet. If these results are applicable to humans, the use of elemental liquid diets as the only source of enteral nutrition would appear contraindicated in patients receiving methotrexate.

To determine if hiatus hernia (HH) contributes to the delayed clearance of acid from the esophagus in patients with gastroesophageal reflux (GER), we performed simultaneous esophageal pH recordings and radionuclide studies in three study populations: 12 GER patients with HH, 5 GER patients with no HH, and 8 subjects with HH but no GER symptoms. Acid clearance was measured at 5 cm. above the manometrically located lower esophageal sphincter (LES) after injecting a 15-ml. bolus of 0.1 N HCl at 15 cm. above the LES. The acid was labeled with 200 mu Ci of 99mTc-sulfur colloid. Acid clearance was also measured at 10 cm. above the LES after injection of a 15-ml. bolus of 0.1 N HCl at 20 cm. above the LES. Acid clearance at 5 cm. above the LES was faster in GER patients with no HH compared to GER patients with HH and asymptomatic HH subjects. Acid clearance was faster at 10 cm. than 5 cm. above the LES in all HH and non-HH subjects studied. In non-HH subjects, each swallow resulted in an increase in pH (a monophasic pH response) at 5 and 10 cm. above the LES. In symptomatic as well as asymptomatic HH subjects, swallows resulted in an initial fall followed by a rise in pH at 5 cm. above the LES (a biphasic pH response). Radionuclide studies showed reflux of the isotope-labeled acid into the esophagus followed by clearance (a biphasic response) accompanying swallows in 15 of the 20 HH subjects. Swallow-induced reflux was not detected by radionuclide scanning in non-HH subjects. Based on these observations, we conclude that during acid clearance a small amount of acid is trapped in the HH sac and refluxes into the esophagus during subsequent swallows when there is relaxation of the LES, and these repeated episodes of acid reflux from the HH account for the delayed acid clearance observed in GER patients with HH.

Patients with exocrine pancreatic insufficiency may absorb greater than 50% of dietary fat despite the absence of measurable pancreatic lipase activity. Nonpancreatic lipolytic activity was measured in gastric and duodenal aspirates from 5 patients with exocrine pancreatic insufficiency secondary to alcoholism and in aspirates from 5 alcoholics without evidence of exocrine pancreatic dysfunction (controls). Samples were collected under fasting and postprandial conditions. All patients with exocrine pancreatic insufficiency had nonpancreatic lipolytic activity in gastric and duodenal aspirates. Lipolytic activity in gastric aspirates was not significantly different between the patients with exocrine pancreatic insufficiency and the controls during the fasting and postprandial periods. Pancreatic insufficiency was associated with significantly (p less than 0.05) higher nonpancreatic lipolytic activity in the duodenum under fasting conditions. No significant difference between the groups was found in postprandial nonpancreatic lipolytic activity. Nonpancreatic lipolytic activity accounted for approximately 90% of total lipolytic activity at the ligament of Treitz in patients with exocrine pancreatic insufficiency as opposed to 7% in the control subjects. These observations suggest a significant role for nonpancreatic lipolytic activity (lingual lipase and gastric lipase) in fat digestion in patients with pancreatic insufficiency secondary to chronic alcohol abuse.