Two French families were investigated. In the first a husband, wife, and 4 children had Crohn's disease; in the second 7 of 11 children had the disease. There was no history of Crohn's disease in antecedent generations and no linkage to HLA haplotypes.

Developmental changes in passive bile salt absorption may alter the enterohepatic circulation.

Ménétrier's disease is an uncommon disorder of unknown etiology characterized by enlarged gastric folds with foveolar hyperplasia and cystic dilatation of gastric glands. Biochemical features that are seen frequently include hypoproteinemia, hypochlorhydria, and increased gastric mucus. Because transforming growth factor alpha (TGF alpha) is an epithelial cell mitogen that inhibits gastric acid secretion and increases gastric mucin content, we hypothesized that its altered expression might be involved in the pathogenesis of this disease. Therefore, we characterized TGF alpha immunoreactivity in the gastric mucosa of 4 patients with Ménétrier's disease. In contrast to the normal pattern of TGF alpha immunostaining in which TGF alpha appears most concentrated in parietal cells, there was intense staining in the majority of mucous cells in the gastric mucosa of patients with Ménétrier's disease. In one patient from whom sufficient fresh tissue was obtained to isolate RNA, expression of TGF alpha and the epidermal growth factor receptor was higher in the gastric mucosa relative to a normal control. In addition, metallothionein-TGF alpha transgenic mice, which overexpress TGF alpha in gastric mucosa, show a number of features characteristic of Ménétrier's disease. These include foveolar hyperplasia and glandular cystic dilatation, increased gastric neutral mucin staining, and reduced basal and histamine-stimulated rates of acid production. Taken together, observations derived from the human material and correlation with data from a transgenic mouse model support an important role for TGF alpha in the pathogenesis of Ménétrier's disease.

The effects of sex differences and of fasting on gastric alcohol dehydrogenase activity were determined in Sprague-Dawley rats. Gastric alcohol dehydrogenase activity and enzyme protein levels were higher in female than in male rats. Ovariectomy and orchiectomy had no effect on alcohol dehydrogenase and did not alter the sex difference in enzyme activity. Fasting decreased the enzyme activity more in female than in male rats, abolishing the sex difference. Serum gastrin levels measured in female rats decreased on fasting and returned to normal levels within 24 hours of refeeding. Short- and long-term administration of pentagastrin to fasted and fed female rats did not affect the enzyme activity or enzyme protein level, except for a transient increase in enzyme activity but not in enzyme protein level 12 hours after administration to fasted fats. Omeprazole, which increased serum gastrin levels and decreased enzyme activity but not enzyme protein levels, was found to be a competitive inhibitor of the enzyme with a Ki of 0.40 mmol/L. The mechanisms for the sex differences and changes with fasting in rat gastric alcohol dehydrogenase activity remain unknown.

Enzymatic and immunohistological analyses of lactase were performed at different stages of development and within different regions of the small intestine of the rabbit and rat. As previously reported, there seems to be a sharp decline of lactase activity on weaning but variable and higher levels of activity are seen in adult animals. Two monoclonal antibodies to rat lactase were available to study the protein in rats. Four monoclonal antibodies to human lactase were shown to cross-react with rabbit lactase and used for the rabbit studies. Immunohistological analysis of small intestine of adult rabbits and rats showed residual lactase protein within the enterocytes throughout the small intestine. In the middle of the small intestine (lower jejunum, upper ileum), uniform staining of the brush border was observed. In the proximal and distal regions, a patchy pattern of staining was observed. This pattern, which resembles that observed in adult hypolactasic humans, indicates an underlying heterogeneity of enterocyte differentiation.

Intracellular microelectrodes were used to evaluate electrical properties of the cell membranes in Necturus antral mucosa during exposure to luminal acid alone (pH 4) or to 5 mmol/L aspirin [acetylsalicylic acid (ASA)] in the presence of luminal acid. When nutrient solutions were buffered by HCO3- (pH 7.3), ASA moderately depolarized and increased the resistances of both cell membranes. When nutrient solutions were buffered by HEPES (pH 7.3), ASA induced even greater depolarizations of the cell membranes. In addition, resistance of the apical membrane did not increase and resistance of the basolateral membrane decreased. The changes in basolateral membrane resistance were observed when tissues were exposed to 5 mmol/L salicylate but not during exposure to luminal acid alone or to acidified luminal solutions containing 5 mmol/L acetate, a small and permeable organic acid. Electron microscopy confirmed that these initial electrophysiological changes precede alterations in cell morphology. The findings suggest that nutrient HCO3- attenuates changes in membrane potentials caused by ASA. Loss of nutrient HCO3- seems to accelerate alterations in basolateral membrane resistance caused by ASA and its salicylate moiety.

Rectal mucosal biopsy specimens from 75 human immunodeficiency virus (HIV)-seropositive and 16 HIV-seronegative subjects were examined. The histopathologic changes were correlated with immunoperoxidase staining for UCHL-1 and HIV core protein p24, quantitative p24 enzyme-linked immunosorbent assay (ELISA) assay in homogenized rectal tissue and serum, and a modified Walter Reed clinical stage. Four phases were seen in the HIV-infected subjects: (1) early phase, in Walter Reed stage 1-2 subjects, with nearly normal histology and low p24; (2) inflammatory phase, typically in Walter Reed stage 3-4 subjects, with a superficial lamina propria infiltrate of lymphocytes, plasma cells, and eosinophils with degranulation, abundant UCHL-1 staining, and maximal p24 by both immunoperoxidase staining and ELISA; (3) transitional phase, in many Walter Reed 5 and some Walter Reed 6 subjects, with normal lymphocyte population density but with subtle inflammatory changes; and (4) lymphoid depletion phase, mainly in Walter Reed stage 6 subjects, with decreased lymphocytes but often with endothelial cell activation and apoptosis. These phases presumably result from effective HIV suppression by a relatively intact immune system, followed by maximal HIV infection and lymphocyte activation, then progressive lymphocyte depletion. The inflammation correlated with the presence and amount of HIV in rectal tissue determined by immunohistochemistry and ELISA and was maximal before overt immunodeficiency developed. Intestinal mucosa could be a preferred site of HIV proliferation and T-cell destruction.

Hepatitis C virus (HCV) is the agent responsible for posttransfusion hepatitis. The incidence, timing, and clinical course of HCV positive hepatitis in liver transplant recipients are unknown. Three hundred and seventeen donor-recipient liver transplant pairs were grouped on the basis of their pretransplant HCV antibody status. The biopsy findings were examined. Four distinct groups were identified on the basis of HCV serology: group I, both were negative; group II, donor was negative and recipient was positive; group III, donor was positive and recipient was negative; group IV, both were positive. The prevalence of anti-HCV positivity in recipients was 13.6%. The rate of seroconversion was 9.2%. Histologic hepatitis not ascribable to any specific cause other than non-A, non-B (NANB) hepatitis occurred in 13.8%. The incidence of histologic chronic active hepatitis was 1.6%, and none progressed to cirrhosis. The concordance rate for a positive anti-HCV serology and NANB hepatitis was 2.8%. Of the 35 patients (group II and IV) with positive anti-HCV serology pretransplant, only 17 were positive posttransplantation. Based on these data it can be concluded that posttransplant NANB hepatitis occurred in 13.8% of liver recipients. Twenty percent of these were anti-HCV positive. Progression to histologic chronic active hepatitis occurs over a period of 1-5 years in 1.6% of cases.

Increased levels of circulating vasodilators have been claimed to be the causative factor in the hyporesponsiveness to endogenous vasopressors in portal hypertension. To investigate whether this hyporeactivity to vasopressors is also present in an in vitro system perfused with a synthetic medium, the responsiveness to graded concentrations of norepinephrine, arginine-vasopressin, and potassium chloride was tested in perfused superior mesenteric arterial beds of normal rats and rats with portal hypertension induced by partial portal vein ligation (PVL). The same vasopressors were tested after incubation of vessel preparations with the stereo-specific nitric oxide formation inhibitor N omega-nitro-L-arginine (NNA, 10(-4) mol/L). Vessel preparations of PVL compared with normal rats (n = 8 per group and vasopressor) expressed a significant (P less than 0.05) hyporeactivity to norepinephrine, arginine-vasopressin, and potassium chloride over a wide range of concentrations. This hyporesponsiveness was overcome by preincubating vessel preparations with NNA. In summary, portal hypertension is accompanied by a significant in vitro hyporeactivity of splanchnic vessels to norepinephrine, arginine-vasopressin, and potassium chloride, and secretion of nitric oxide in this preparation seems responsible for this blunted response.

To explore the involvement of NO in normal peristalsis, the effects of inhibitors of NO synthase, including N omega-nitro-L-arginine (L-NNA) and N omega-nitro-L-arginine methyl ester (L-NAME), on esophageal peristaltic contractions induced by diverse stimuli that may involve different neuronal circuits were studied. Studies were performed in opossums. Experimental conditions in vivo included primary peristalsis (P) induced by pharyngeal stroking, short-train (1 second) electrical stimulation of the vagus nerve which caused peristaltic (S) contractions, and long-train (10 second) electrical stimulation of the vagus nerves which caused contractions at the onset of (A contractions) and after (B contractions) the stimulation period. In vitro experiments were performed on strips of esophageal circular muscle using electrical field stimulation which caused contractions at the onset of (on contractions) and after (off contractions) the stimulation period. The administration of L-NAME significantly decreased the latency period and reduced the latency gradient for P contractions, thereby increasing the velocity of peristalsis. Concomitant administration of atropine prolonged the latency period but did not restore the latency gradient. L-NAME abolished B contractions in a dose-dependent fashion. In vitro, L-NAME caused dose-dependent inhibition of off contractions and augmentation of on contractions. These studies support the hypothesis that NO may be involved in (a) both the latency period and the latency gradient, as well as in the contraction amplitude of esophageal peristalsis; and (b) esophageal B and off contractions.

Extracellular HCO3- stimulates colonic net Cl- absorption in part by inhibiting basal Cl- secretion. This inhibition was investigated by measuring serosal-to-mucosal Cl- flux across short-circuited colonic segments from Sprague-Dawley rats. Mucosal intracellular pH and bicarbonate were estimated using the pH-sensitive dye BCECF. When extracellular [HCO3-] ([HCO3-]e) was increased from 0 to 39 mmol/L at PCO2 33 mm Hg, mucosal intracellular [HCO3-] ([HCO3-]i) increased to 25.3 mmol/L and serosal-to-mucosal Cl- flux decreased from 13.0 to 7.1 microEq.cm-2.h-1. When PCO2 was increased to 72 mm Hg at [HCO3-]e 39 mmol/L, [HCO3-]i increased to 29.8 mmol/L and serosal-to-mucosal Cl- flux decreased to 5.9 microEq.cm-2.h-1. In Ringer's solution containing 21 mmol/L HCO3- and 20 mmol/L Cl- (but not 100 mmol/L Cl-), increasing PCO2 from 21 to 70 mm Hg increased [HCO3-]i to 22.6 mmol/L and decreased serosal-to-mucosal Cl- flux from 3.0 to 1.7 microEq.cm-2.h-1. Overall, serosal-to-mucosal Cl- flux was inversely related to [HCO3-]i on either side of an [HCO3-]i plateau of 9-18 mmol/L at which flux was stable. These data suggest that [HCO3-]i is an important modulator of basal Cl- secretion in rat distal colon.

To examine the postliver transplant recurrence of hepatitis C virus (HCV) infection in patients with pretransplant infection, as well as its acquisition in patients without prior infection, we used the polymerase chain reaction to amplify HCV RNA in serum and/or liver samples of 89 patients with alcoholic and cryptogenic cirrhosis undergoing liver transplantation. Results were correlated with histologic findings from posttransplant liver biopsies. Ninety-five percent of patients with pretransplant infection had posttransplant viremia. In contrast, 35% of patients without pretransplant infection acquired the virus (P less than 0.0001). Pretransplant HCV infection predisposed patients to hepatitis in the new graft. HCV RNA was present in serum of 96% of patients with posttransplant hepatitis. Fifty-six percent of patients with posttransplant HCV infection had no evidence of liver damage at least 1 year posttransplant. However, of those patients with histologic hepatitis, chronic active hepatitis was common. It is concluded that although HCV infection recurs posttransplant in almost all infected patients, acquisition of the HCV infection with transplant is common. Pretransplant HCV infection is an independent risk factor for the development of posttransplant hepatitis. HCV infection accounts for the majority of posttransplant hepatitis not due to cytomegalovirus, and although many patients with posttransplant viremia have little evidence of histologic hepatitis, significant hepatic damage may occur.

Changes in gastric microvasculature and blood flow at different phases of portal hypertension were studied in rats 1, 2, 3, 4, and 15 days after induction of portal hypertension or sham operation. Vessel lumen and vessel wall thickness were expressed as a ratio referred to the vessel size. On day 2 after constriction of the portal vein, gastric blood flow was decreased (0.57 +/- 0.06 vs. 0.99 +/- 0.20 mL.min-1.100 g-1; P less than 0.05), and gastric vessels had a distended lumen (0.42 +/- 0.02 vs. 0.28 +/- 0.03; P less than 0.01) and a thin wall (2.11 +/- 0.2 vs. 3.82 +/- 0.4; P less than 0.01). On day 4, the gastric blood flow of portal hypertensive animals was increased (1.15 +/- 0.14 vs. 0.71 +/- 0.07 mL.min-1.100 g-1; P less than 0.05), whereas gastric vessels had a reduced lumen (0.27 +/- 0.02 vs. 0.33 +/- 0.02; P less than 0.01) and a thick wall (4.19 +/- 0.52 vs. 3.16 +/- 0.30; P less than 0.05). By day 15, vessels with the largest lumens (0.45 +/- 0.01 vs. 0.29 +/- 0.01; P less than 0.01) and the thinnest walls (1.78 +/- 0.26 vs. 3.58 +/- 0.62; P less than 0.01) were observed in portal hypertensive animals. In conclusion, the gastric vessels of the 15-day portal vein-ligated rat resemble the structural abnormalities described in human portal hypertensive gastropathy.

The quantitative impact of mesenteric vasoconstriction on the systemic hemodynamic response to cardiogenic shock induced by pericardial tamponade was evaluated. Graded increases in pericardial pressure produced corresponding decreases in cardiac output to 44% +/- 2% and arterial pressure to 64% +/- 3% of baseline and increases in total peripheral vascular resistance to 131% +/- 4% of baseline. Total mesenteric blood flow decreased disproportionately, to 28% +/- 3% of baseline, because of a disproportionate increase in mesenteric vascular resistance to 223% +/- 6% of baseline. Nonmesenteric vascular resistance increased only to 119% +/- 4% of baseline. Thus mesenteric vasoconstriction accounted for 42% of the increase in total peripheral resistance. Prior blockade of the renin-angiotensin axis ablated this response and eliminated the mesenteric contribution to systemic vascular resistance, while confirmed blockade of the alpha-adrenergic system or vasopressin system had no effect. Without shock, central intravenous infusions of angiotensin II (but not norepinephrine or vasopressin) closely mimicked this selective vasoconstriction. Angiotensin-mediated selective mesenteric vasoconstriction accounts for more than 40% of the overall increase in systemic vascular resistance in cardiogenic shock.

To determine the effect of mucosal sodium and mucosal ouabain on active Rb+(K+) absorption, unidirectional and net 86Rb+ fluxes were measured under voltage-clamp conditions in the distal colon of normal and sodium-depleted rats. The role of mucosal sodium (independent of serosal sodium) was evaluated in a model of Rb+(K+) absorption in which serosal ouabain markedly enhanced active Rb+(K+) absorption. In normal rats, mucosal sodium was a competitive inhibitor of Rb+(K+) absorption, and Rb+(K+) absorption consisted of a mucosal sodium-sensitive component and a mucosal sodium-insensitive component. Further, mucosal ouabain almost completely inhibited the mucosal sodium-insensitive component but did not affect the mucosal sodium-sensitive component. In sodium-depleted rats, both mucosal sodium-sensitive and mucosal sodium-insensitive fractions of Rb+(K+) absorption were also identified. Aldosterone markedly stimulated the mucosal sodium-sensitive component (1.68 +/- 0.15 vs. 0.60 +/- 0.10 muEq.h-1.cm-2) but not the sodium-insensitive component (0.88 +/- 0.09 vs. 0.64 +/- 0.06 muEq.h-1.cm-2) component of Rb+(K+) absorption; however, in contrast to normal animals, mucosal sodium in sodium-depleted animals was a noncompetitive inhibitor of Rb+(K+) absorption. The mucosal sodium-insensitive component of Rb+(K+) absorption in sodium-depleted animals was substantially inhibited by mucosal ouabain, but the mucosal sodium-sensitive component, unlike that in normal animals, was partially inhibited by mucosal ouabain. These studies indicate that the characteristics of the Rb+(K+) absorptive process in sodium-depleted animals differ significantly from those present in normal animals, suggesting that aldosterone induces an Rb+(K+) absorptive mechanism not present in normal animals.