Adenomas with potential for malignancy occur frequently in the upper gastrointestinal tract of patients with familial adenomatous polyposis. However, an assessment of relative risk of upper gastrointestinal cancer in patients with adenomatous polyposis has never been performed. Therefore, the incidence rate of upper gastrointestinal cancer in patients with familial adenomatous polyposis in The Johns Hopkins Registry was compared with the rate of the general population through person-year analysis with adjustment for demographics. There was an increased relative risk of duodenal adenocarcinoma (relative risk, 330.82; 95% confidence limits, 132.66 and 681.49; P less than 0.001) and ampullary adenocarcinoma (relative risk, 123.72; 95% confidence limits, 33.65 and 316.72; P less than 0.001). No significant increased risk was found for gastric or nonduodenal small intestinal cancer. These results indicate that periodic surveillance of the upper gastrointestinal tract for duodenal and periampullary cancer is needed in patients with familial adenomatous polyposis. Prophylactic duodenectomy is a consideration when large adenoma(s) with high-grade dysplasia are identified but awaits risk benefit analysis.

Indian childhood cirrhosis is a fatal liver disease characterized by a striking accumulation of copper-containing granules within hepatocytes. A two-year-old American boy, the product of a third-cousin marriage, with clinical, biochemical, and histological signs of Indian childhood cirrhosis was studied. Liver biopsies at 22 and 30 months of age revealed a rapid progression from fibrosis to micronodular cirrhosis, with many of the remaining hepatocytes staining strongly for copper and copper-binding proteins. Electron microscopy showed characteristic dense granules containing copper and sulfur by electron probe analysis. Hepatic copper content was 1500 micrograms/g dry weight (normal, 20-50). Urinary copper was 3.6 mumol/d (229 micrograms/24 hours; normal, 15-20), and serum ceruloplasmin was 352 mg/L (normal, 150-320). The case suggests that both genetic and environmental components contribute to the manifestations of Indian childhood cirrhosis, and that the diagnosis of Indian childhood cirrhosis should be considered even in non-Indian infants with progressive liver disease.

Crohn's disease (CD) is characterized by granulomatous inflammation of the intestinal mucosa, but the etiology and pathogenesis of the inflammatory lesions are unknown. The aim of this study was to determine whether T-cell activation and lymphokine production occurs in the mucosal lesions of this disease. Total cellular RNA was isolated from peripheral blood lymphocytes and from colonoscopic mucosal biopsies of normal individuals and patients with CD of the colon or ulcerative colitis (UC). Levels of interleukin-2 (IL-2) messenger RNA (mRNA) transcripts in samples were determined using a quantitative reverse transcriptase polymerase chain reaction method. IL-2 mRNA transcripts were detected in histologically normal intestinal mucosal biopsies obtained from control subjects. In CD, higher levels of IL-2 mRNA transcripts were detected in the mucosa from areas of active inflammation, but in areas that were histologically normal, levels were similar to control subjects. The levels of IL-2 mRNA transcripts in biopsies from active and inactive UC were similar to control subjects. Levels of IL-2 mRNA in peripheral blood lymphocytes were low and not significantly different in all groups of subjects. In conclusion, the normal intestinal mucosa contains IL-2 mRNA transcripts and may be an important source of IL-2. Furthermore, the inflammatory lesions of CD, but not UC, have higher levels of IL-2 mRNA transcripts, suggesting that T-cell activation and lymphokine secretion in the intestine may be important in the pathogenesis of CD. These data provide further evidence that the pathogenesis of CD and UC are different.

Altered total nuclear DNA content is frequent in colorectal carcinomas, but the mechanisms producing aneuploidy are unknown. Therefore, DNA ploidy by flow cytometry was correlated with molecular genetic alterations and tumor characteristics in 50 colorectal carcinomas. The prognostic value of these alterations was also evaluated because aneuploidy has been associated with poor prognosis. Thirty-nine of the carcinomas (78%) were DNA aneuploid. When compared with diploid carcinomas, aneuploid tumors had greater mean fractional allelic loss, defined as the fraction of evaluable nonacrocentric autosomal arms with deletion (0.25 +/- 0.15, range 0-0.667, vs. 0.12 +/- 0.10, range 0-0.345; P = 0.006). DNA index by flow cytometry correlated with fractional allelic loss (r = 0.38, P = 0.006). Aneuploid tumors also had more frequent allelic loss on chromosome 17p (87% vs. 55%; P = 0.017), but less frequent ras gene mutation (44% vs. 82%; P = 0.025). Among the 25 right-sided and 25 left-sided tumors, DNA diploid tumors were more frequent on the right side (P = 0.002), whereas deletion of 17p was found predominantly on the left side. Aneuploidy was associated with moderate and poor differentiation of the carcinomas but not with distant metastasis. By contrast, high fractional allelic loss, deletion of 17p, and deletion of 18q were associated with distant metastasis. In survival analysis of patients with Dukes' B or C carcinoma, DNA aneuploidy was not a significant discriminator, but patients whose tumor had deletion of 17p or deletion of both 17p and 18q had poorer survival (P = 0.045 and 0.022, respectively). The results suggest that DNA aneuploidy is associated with some of the molecular genetic alterations and phenotypic characteristics of colorectal carcinomas but is not a reliable indicator of metastatic potential.

Sodium retention and peripheral vasodilatation are common consequences of portal hypertension secondary to cirrhosis. Although peripheral vasodilatation has been extensively documented in prehepatic portal hypertension, it is not known whether sodium retention is also a feature of this entity. The aim of this study in portal vein-constricted rats was to evaluate (a) whether sodium retention is a feature of prehepatic portal hypertension and (b) if sodium retention is present in this model, what its temporal relationship with peripheral vasodilatation might be. It was proposed that an understanding of the temporal interplay between peripheral vasodilatation and sodium retention could shed light on the current theories of sodium retention in portal hypertension. Rats were studied 1, 2, 3, and 4 days after partial portal vein ligation (n = 80) or sham operation (n = 63). Sodium retention was evaluated by changes in the size of the sodium space measured by the volume of distribution of 22Na. Systemic vascular resistance was calculated from mean arterial pressure (measured by arterial catheterization) and cardiac index (measured by thermodilution). A decrease in systemic vascular resistance was already observed on day 1 after constriction of the portal vein (4.2 +/- 0.2 vs. 5.2 +/- 6.1 mm Hg.min.mL-1.100 g; P less than 0.01). However, an expansion of the sodium space, which indicates sodium retention, was not observed until day 2 after induction of portal hypertension (37.1 +/- 0.8 vs. 32.6 +/- 0.7 mL.100 g-1; P less than 0.01). Therefore, sodium retention should be considered along with peripheral vasodilatation among the characteristic features of prehepatic portal hypertension. Because the reduction in systemic vascular resistance preceded the expansion of the sodium space by at least 24 hours, the finding of this study indicates that sodium retention follows peripheral vasodilatation.

A 33-year-old white homosexual man, infected with the human immunodeficiency virus, presented with acute anemia and thrombocytopenia not responsive to transfusions or to treatment with steroids and intravenous gamma-globulin. Hematologic workup was compatible with peripheral sequestration or loss of blood cells; however, there was no evidence of gastrointestinal or other sources of hemorrhage, and the only significant finding was a progressive liver enlargement. An abdominal computerized tomographic scan showed a massive homogeneous liver without focal lesions, a very small amount of ascites, and no retroperitoneal fluid collections. A transjugular liver biopsy specimen showed the cystic, blood-filled cavities characteristic of peliosis hepatis. Cavities varied in size, all contained pooled erythrocytes, and some had areas suggestive of thrombi in various stages of organization. Bacteria similar in morphology to those described in bacillary peliosis hepatis were seen in the peliotic spaces. The clinical picture began resolving shortly after treatment with zidovudine and ampicillin/sulbactam was started and had totally resolved 6 months after presentation. This case shows that bacillary peliosis hepatis is a reversible entity that may produce acute sequestration of blood in the liver.

Propranolol, a nonselective beta-adrenergic blocker, has been shown to reduce portal pressure and the risk fo variceal bleeding. The portal pressure-reducing effect of propranolol is mediated by splanchnic arterial constriction, which decreases portal flow. A double-blind randomized control study (crossover on 2 consecutive days) was designed to compare the effects of propranolol vs. placebo on portal flow in cirrhotic patients during fasting and after a standardized meal. Portal flow was measured with an ATL Ultramark 8 echo-Doppler system (Advanced Technological Laboratories, Bothel, WA) in 23 cirrhotic patients. Fasting portal flow and heart rate were obtained at baseline and 2 hours after the administration of propranolol or placebo. A standard test meal was then given, and measurements were repeated 30 minutes later. Thirteen patients (group 1) received placebo on day 1 and propranolol on day 2, whereas 10 patients (group 2) received propranolol on day 1 and placebo on day 2. In group 1 patients, heart rate declined by 20% (P less than 0.0001) and portal flow decreased by 12% (P less than 0.05) after propranolol administration. Similar reductions were found in heart rate (-21%, P less than 0.0001) and portal flow (-17%, P less than 0.001) for group 2 patients. For all 23 patients, 2 hours after propranolol administration, heart rate declined by 21% (P less than 0.0001) and portal blood flow was reduced by 14% (P less than 0.0001). The 10 patients who received propranolol on day 1 (group 2) showed a carryover effect of propranolol on day 2. On day 2, baseline portal flow and heart rate values were significantly lower than baseline values on day 1. This long-lasting effect of a single dose of propranolol may be caused by the longer half-life of propranolol in cirrhotic patients. The postprandial portal blood flow percentage increase after the meal was similar for both placebo and propranolol. Propranolol did not blunt postprandial hyperemia. However, whereas the absolute value of blood flow after the meal increased significantly in comparison with baseline in placebo-treated patients (P less than 0.001), this did not occur with propranolol. Furthermore, in propranolol-treated patients the absolute value of blood flow after the meal was lower than in placebo-treated patients. This may constitute a protective effect of propranolol in portal hypertension.

The basolateral membrane of the enterocyte was previously shown to contain an adenosine triphosphate-dependent calcium pump. Using immunological procedures, the localization of the Ca2+ pump in chick intestine, and the effect of dietary variables on the concentration of the pump, were studied. A monoclonal antibody produced against the human erythrocyte calcium pump was shown to cross-react with a chick intestinal Ca2+ pump epitope. The most intense staining of intestinal tissue, as determined immunohistochemically, occurred at the basolateral membrane of the duodenum, jejunum, ileum, and colon, with minor staining elsewhere. By the Western blotting procedure, vitamin D repletion of vitamin D-deficient chicks was shown to significantly increase the concentration of the Ca2+ pump epitope of duodenal, jejunal, and ileal mucosa by a factor of 2-3. Chicks were also fed diets deficient in calcium or phosphorus, a situation known to result in the stimulation of the synthesis of calbindin-D28k and an enhancement of the efficiency of Ca2+ absorption. Adaptation of the chicks to these deficient diets was verified by an increase in intestinal levels of calbindin-D28k, and is now shown to increase the Ca2+ pump epitope. From these immunological studies, it seems apparent that dietary variables that enhance intestinal Ca2+ absorption also increase the amount of the intestinal basolateral Ca2+ pump.

Four human colon adenocarcinoma cell lines, SNU-C1, SNU-C4, SNU-C5, and NCI-H716, that are capable of proliferating autonomously in serum-free medium containing no added peptide growth factors were identified. All four cell lines show epidermal growth factor (EGF) receptors (EGFRs), express transforming growth factor alpha (TGF-alpha) messenger RNA, and release anti-TGF-alpha-immunoreactive molecules. The blocking anti-EGFR monoclonal antibody (mAb) 225 blocks autonomous proliferation of SNU-C1 and SNU-C4 cells. In both of these cell lines, the inhibitory effect of mAb 225 is reversible by the addition of EGF, TGF-alpha, or conditioned medium from any of the four cell lines. In contrast, autonomous proliferation of SNU-C5 and NCI-H716 cells is not inhibited by mAb 225 and is not affected by exogenous EGF, TGF-alpha, or conditioned medium. Together, these data confirm the previous finding that anti-EGFR antibodies can inhibit the proliferation of some carcinoma cell lines that coexpress TGF-alpha and EGFR. However, here it is shown that the mechanisms of autonomous proliferation of colon carcinoma cell lines are heterogeneous and not always sensitive to antibody disruption of TGF-alpha/EGFR autocrine interactions.

We investigated a hormonal mechanism in a trypsin inhibitor-induced pancreatic hypersecretion in rats. Intraduodenal administration of a synthetic trypsin inhibitor, camostat, resulted in significant increases in plasma concentration of both secretin and cholecystokinin in a dose-related manner that paralleled a significant increase in exocrine pancreatic secretion. To eliminate the effect of circulating secretin in rats, a rabbit antisecretin serum was given IV that resulted in a 77% reduction in bicarbonate secretion stimulated by intraduodenal camostat. A cholecystokinin receptor antagonist, MK-329, also inhibited significantly the camostat-induced increase in pancreatic secretion; volume and bicarbonate output were reduced by 35% each and amylase output by 73%. The combined administration of antisecretin serum and MK-329 completely abolished the pancreatic exocrine secretion stimulated by camostat. These observations indicate that the camostat-stimulated pancreatic exocrine secretion is mediated by the increased release of both secretin and cholecystokinin in rats.

The absorption of water and electrolytes from the proximal jejunal lumen increases immediately after a meal. This meal-induced jejunal absorption occurs in jejunal segments out of normal gastrointestinal continuity. This study was designed to characterize the jejunal absorptive response to a series of isovolumetric gavage-delivered stimuli. Twenty-five-centimeter canine proximal jejunal Thiry-Vella fistulas were constructed, and jejunal absorption studies (n = 66) were performed by luminal perfusion of the jejunal segments with an isotonic buffer containing 14C-labeled polyethylene glycol. Each study consisted of a 1-hour basal period, followed by a 3-hour experimental period. Nine groups were studied, each receiving one of the following isovolumetric stimuli delivered via the gavage route: water, 0.9% saline, mixed meal, protein, lipid, carbohydrate, and mannitol (150 mmol/L, 300 mmol/L, and 600 mmol/L). The water and 0.9% saline gavage groups showed no significant changes in integrated postprandial water and electrolyte absorption above basal. The isocaloric mixed meal, protein, lipid, carbohydrate, and mannitol groups all had significantly increased integrated postprandial jejunal water and electrolyte absorption above basal (P less than 0.05). These results indicate that a proabsorptive signal for meal-induced jejunal absorption originates from or distal to the stomach. Meal-induced jejunal absorption occurs in response to nutrients of diverse composition and is also responsive to nonnutritive solutes such as mannitol. These findings support a new role for gastric or intestinal chemo- or osmo-receptors in stimulating the neurohumoral mechanisms that mediate meal-induced jejunal absorption.

The contribution of toxin B to Clostridium difficile-associated infection is undefined. Toxin B induces dramatic phenotypic alterations (cytotoxic effects) in cultured mesenchymal and nonintestinal epithelial cells, yet its effects on intestinal epithelial cells are not clearly understood. The alterations induced by toxin B in nonintestinal cells appear to be secondary to toxin-induced redistribution of filamentous actin. It has not been determined whether toxin B exerts similar effects on cultured intestinal epithelial cells or whether such phenotypic alterations are of any physiological consequence. To address these questions, we examined the effect of C. difficile toxin B on the phenotype and barrier function of T84 cell monolayers. Our studies show that the cytotoxic effects of toxin B, i.e., cell rounding, do extend to cultured intestinal epithelial cells (T84). In addition, toxin B dramatically reduces the barrier function of T84 monolayers grown on collagen-coated filters. Toxin B-induced redistribution of filamentous actin appears to be responsible for the alterations in both intestinal epithelial cell phenotype and barrier function. Specifically, filamentous actin comprising the perijunctional actomyosin ring, known to be important in regulating tight junction permeability, is condensed into discrete plaques. Flux studies confirm that the permeability defect is at the level of the tight junction. We conclude that toxin-induced changes in actin distribution perturb intercellular junctional contacts and thereby ablate epithelial barrier function. There was no evidence of cell death as determined by lactate dehydrogenase release assays.

An increase in ambient CO2 tension from 3% to 11% augments colonic Na absorption in the rat. The membrane site of action of CO2 was examined by measuring colonic Na absorption in the Ussing chamber when nystatin was used to permeabilize the luminal (apical) membrane. The equal rates of ouabain-sensitive Na absorption at 3% and 11% CO2 in the presence of nystatin and at 11% CO2 in its absence suggested that CO2 acted at the luminal membrane. This finding was also observed at a submaximal rate of Na absorption (produced by lowering bathing solution Na from 140 to 27 mmol/L) and in a Cl-free solution (to prevent cell swelling). The basolateral membrane was indeed rate limiting for Na absorption in the presence of nystatin, because methylprednisolone (3 mg/kg SC for 3 days to increase sodium-potassium--stimulated adenosine triphosphatase activity) increased Na absorption measured in the presence of nystatin and because CO2 increased absorption in steroid-treated rats in the absence of nystatin. These results validate the protocol and confirm the luminal site of action of CO2 and nystatin on colonic Na absorption.