We studied the macromolecular permeability of segments of jejunum from 2-wk-old piglets after the animals had been experimentally infected with an invasive enteric virus, transmissible gastroenteritis virus. Jejunal segments were mounted in Ussing chambers at stages of the infection, and permeability was measured using three probe molecules of differing molecular weights. In control tissue, permeability to horseradish peroxidase was 2.6 times higher across segments with Peyer's patches than across segments without Peyer's patches, whereas polyethylene glycol 4000 and mannitol permeabilities were the same in patch and nonpatch segments. Twelve hours after infection, when virus had invaded the mucosa causing a structural lesion, and before diarrhea had begun, horseradish peroxidase permeability increased in non-patch-containing segments to equal that across patch-containing tissue. At this early 12-h stage, polyethylene glycol 4000 and mannitol permeation were unchanged in patch-containing segments compared with controls. Ninety-six hours after transmissible gastroenteritis infection, when diarrhea was severe, horseradish peroxidase permeability in patch-free segments had returned to normal and patch-containing tissue permeability was diminished below control levels. Increased macromolecular permeability appears to occur only in the very early invasive stage of this viral enteritis and only in patch-free segments. Any consideration of the immunologic relevance of these complex phenomena must take into account the specialized function of the Peyer's patch regions of the small intestine.

Four silver-silver chloride electrodes were surgically implanted at 5-cm intervals on the jejunal serosa of 7 neonatal pigs. Daily recordings, 7 h in duration, were made from each piglet beginning 3 days after surgery. Characteristic migrating motility complexes and short, distinct (2.5-5.0 s), rapidly aboral migrating bursts of intense spike activity ("migrating action potential complexes") were seen in all preinfection recordings. Piglets were inoculated with a 1-ml oral dose of a 0.1% gut suspension from coronavirus (transmissible gastroenteritis) infected pigs. This resulted in inappetence, vomiting, and diarrhea, most marked on the second day postinfection, but which had abated by the third day. When compared to recordings from both fed and fasted noninfected (control) animals, infection significantly altered jejunal myoelectrical activity by (a) shortening the duration of the migrating motility complex on day 1 postinfection and prolonging it on day 2, (b) increasing the number of abnormal activity fronts, and (c) decreasing the number of migrating action potential complexes. Slow wave frequency and the duration of phase 3 of the migrating motility complex were unaffected. When compared to fed control animals, infected piglets also showed a slight shortening of phase 1 of the migrating motility complex on day 1 postinfection and a prolongation on days 2 and 3, as well as a shortening of phase 2 on the second and third days postinfection. Changes in myoelectrical activity were not solely due to decreases in food intake, as abnormalities persisted when food intake returned to normal on postinfection day 3, and disruption of the activity front and migrating motility complex duration were purely transmissible-gastroenteritis-virus-induced phenomena. These findings suggest that infection with transmissible gastroenteritis virus disrupts organized propulsive activity in the jejunum of the neonatal pig.

Absorption of water and electrolytes by the small and large intestine was examined using a nonabsorbable marker technique in 3-day-old and 3-wk-old pigs. One-half of the pigs in each group were orally infected with transmissible gastroenteritis virus; the remaining pigs served as controls. Three-day-old control pigs concentrated the nonabsorbable fluid marker twelve fold along the small and large intestine, indicating an efficiency of about 95% in absorption of the exogenous daily fluid load presented to the intestine. In contrast, the marker concentration in infected pigs showed no change whatsoever along either the small or large intestine, indicating a complete absence of net fluid absorption or secretion in these animals. Three-week-old control pigs concentrated the marker similarly to the 3-day-old group, with the bulk of the fluid absorption occurring in the small intestine. Infected pigs in the 3-wk-old group had marked net fluid secretion in the proximal small intestine, so that about twice the fluid load was presented to the large intestine of the 3-wk-old infected pigs as compared to the 3-day-old infected group. However, in contrast to the 3-day-old infected group, the large intestine of the 3-wk-old infected pigs increased fluid absorption some six times over the control, and this compensatory response prevented diarrhea in these older animals. Analysis of luminal contents indicated that in the older pigs, unabsorbed carbohydrate was almost completely fermented to short-chain fatty acids in the colon, whereas in the younger pigs the carbohydrate passed through the colon unchanged. These results demonstrate that development of microbial digestion, together with rapid short-chain fatty acid absorption, is a primary feature responsible for the colonic compensation in the older pigs with transmissible gastroenteritis.

Although much is known about the neuropsychological functioning of cirrhotic individuals with Laennec's (alcohol associated) cirrhosis, little is known about the neuropsychological functioning of individuals with nonalcoholic cirrhosis. In the present investigation, we have determined that individuals suffering from chronic nonalcoholic cirrhosis, despite the absence of clinical signs of hepatic encephalopathy, are impaired on neuropsychological tests that measure visuopractic capacity, visual scanning, and perceptual-motor speed. In contrast, intellectual, language, memory, attentional, motor, and learning abilities are intact. In comparison with a chronically ill control group of patients suffering from Crohn's disease, individuals with advanced nonalcoholic cirrhosis exhibit less emotional disturbance, but are more impaired in their daily activities. These findings indicate that individuals with nonalcoholic cirrhosis, even in the absence of overt clinical signs of encephalopathy, manifest neuropsychological impairments and experience significant disruption in the routines of everyday living.

Estrogen binding protein activities were determined in the cytosol from adult male Buffalo rat liver and Morris hepatoma 7777. Estrogen receptors were prepared using the protamine sulfate precipitation technique of Chamness. The ability of various unlabeled steroids competing with [3H]estradiol was examined to establish the binding specificity. Estradiol binding in Morris hepatoma 7777 cytosol was greatly decreased compared with that present in hepatic cytosol prepared from normal rat liver. The receptor concentration expressed as femtomoles per milligram of cytoplasmic protein was 31.1 +/- 2.9 SD for normal rat liver and 0.41 +/- 0.88 SD for the hepatoma. Gel filtration chromatography revealed the presence of an estrogen binder in hepatoma cytosol which was not present in either normal liver or in the protamine sulfate precipitates of hepatoma cytosol. The molecular weight, binding specificity, and precipitation of this protein by specific antiserum suggests that it is alpha-fetoprotein.

Estrogen receptor activity was quantitated in the cytosol and nucleus of normal rat liver and in regenerating rat liver at several time intervals after 75% hepatectomy. Cytosolic estradiol binding in regenerating liver decreases at 12, 24, and 48 h after hepatectomy and at 48 h is 30% of that in normal rat liver. Nuclear estrogen binding 48 h after surgery is elevated fivefold over normal values. No alterations in affinity of the receptor for estrogen have been observed. Specificity studies indicate that the estrogen receptors from both normal and regenerating liver were similar and are highly specific for estrogens. These changes in cellular distribution of receptors parallel increases in nuclear deoxyribonucleic acid synthesis and mitotic indices in the liver.

A patient with Budd-Chiari syndrome who underwent orthotopic liver transplantation and developed recurrent disease is described. The immediate postoperative period was complicated by multiple thrombotic episodes, followed by a period of apparent remission associated with the initiation of coumadin and persantine therapy. After discontinuation of such antithrombotic therapy in order to biopsy the liver, the patient experienced another series of clinically overt vascular thromboses and ultimately died of sepsis 15 mo posttransplantation after a prolonged and complicated terminal hospital course. At autopsy, recurrent Budd-Chiari syndrome as well as thromboses in numerous other organs was demonstrated.

Lactase and sucrase are two disaccharidases that differ not only in their substrate specificity and developmental patterns, but also in their resistance to mucosal insult. In this experiment, we tested the hypothesis that there might be a dichotomy in expression of enzyme activity along the jejunal villuscrypt unit. Sectioning of the villus-crypt unit in a cryostat enabled direct comparison of the distribution of lactase and sucrase enzyme activities in the adult rat. There is a stepwise increase in mean lactase/sucrase ratio going from crypt to villus. The data indicate that unlike sucrase activity, which is expressed maximally in enterocytes along the entire villus, maximal lactase activity is not attained until midvillus. The delay in expression of maximal lactase activity might help to explain the vulnerability of this enzyme to acute mucosal insult such as occurs in viral gastroenteritis.

Liver transplantation in humans was first attempted more than 15 yr ago. The 1-yr survival has slowly improved until it has now reached about 50%. In our experience, 46 patients have lived for at least 1 yr, with the longest survival being 9 yr. The high acute mortality in early trials was due in many cases to technical and management errors and to the use of damaged organs. With elimination of such factors, survival increased. Further improvements will depend upon better immunosuppression. Orthotopic liver transplantation (liver replacement) is the preferred operation in most cases, but placement of an extra liver (auxiliary transplantation) may have a role under special circumstances.

In transmissible gastroenteritis (TGE) of piglets, an infection closely resembling human rotavirus enteritis, we studied the timing and extent of epithelial viral invasion along the small intestine after a single oral inoculum of virus; we related these findings to measured alterations in mucosal structure, kinetics, and differentiation, and to previously documented abnormalities of ion transport that occurred at the height of diarrhea. Six and twelve hours after inoculation, before diarrhea, extensive specific viral immunofluorescence and viral particles on electron microscopy were seen in villus but not crypt enterocytes in jejunum, mid-intestine, and ileum. At 24 and 40 hr, when diarrhea was most severe, immunofluorescence was patchy; villus blunting (P < 0.001) and increased crypt depth (P < 0.001) were observed by light microscopy in all segments; radioautographically labeled enterocytes showed accelerated migration and shortened life span; and cells on villi were deficient in sucrose activity (P < 0.001) and rich in thymidine kinase activity (P < 0.005), suggesting relative immaturity. Villus structure recovered by 72 and 144 hr, although deeper crypts (P < 0.001) and accelerated migration still persisted. We conclude that extensive, almost simultaneous direct viral invasion of villus enterocytes can occur along the entire length of the small intestine after a single exposure to virus, and thus can cause shedding of mature villus cells and proliferation and accelerated migration of cells from the crypts. At the height of diarrhea, when enterocyte turnover is maximal, the epithelium consists predominantly of immature virus-free cells which have migrated to the villi in a relatively undifferentiated state.

To understand mechanisms of viral diarrhea further, we studied ileal ion transport in vitro in relation to mucosal changes and epithelial differentiation in transmissible gastroenteritis in piglets, an invasive viral enteritis thought to involve mainly proximal intestine. In infected pigs, at the height of diarrhea, short-circuited ileal epithelium failed actively to transport Na+ and Cl-, and there was a defect of glucose-mediated Na+ transport. The Cl- secretory response to theophylline remained intact. Conductance measurements indicate that paracellular permeability may be reduced and transcellular transport may be altered. A mucosal lesion was observed at the time of the transport changes, characterized by villus blunting, crypt hyperplasia, and immature crypt-type enterocytes on the villus epithelium, deficient in disaccharidase and (Na+, K+)ATPase activity but rich in thymidine kinase. Consideration of the major determinants of diarrhea in this invasive enteritis must take into account not only altered mucosal function and differentiation but also the extent of intestinal involvement, including the ileum, a major site of fluid absorption in the intestine.

Glucagon was tested for its effect on plasma adenosine 3',5'-cyclic monophosphate (cyclic AMP), insulin, and glucose in healthy subjects and in patients with advanced cirrhosis of the liver. In the normal subjects, intravenous infusion of glucagon caused a significant increase in plasma cyclic AMP, glucose, and insulin. In advanced cirrhotics, plasma cyclic AMP, glucose, and insulin did not increase. Adenylate cyclase concentration was measured in liver tissue from end stage cirrhotic patients and from brain-dead organ donors whose cardiovascular function was maintained in a stable state. Basal and total adenylate cyclase concentration were not different in the two groups. Adenylate cyclase from the livers of advanced cirrhotics was, however, significantly less responsive to glucagon stimulation than was that from donor livers. Hepatocytes in advanced cirrhosis have abnormal metabolic behavior characterized by abnormal adenylate cyclase-cyclic AMP response to hormonal stimulation.

Ion transport in the jejunal mucosa of 14-to 16-day-old piglets with severe diarrhea 40 hr after infection with transmissible gastroenteritis (TGE) virus was studied. In infected pigs Na+ transport failed to respond normally to glucose when studied either in Ussing short-circuited chambers or in suspensions of enterocytes isolated selectively from jejunal villi. Theophylline, 10mM, added to the chambers produced the same brisk electrical responses and increments in net Cl- secretion in tissue from both infected and control groups. A defect in glucose-stimulated Na+ absorption in the acute stage of a viral enteritis has been identified which probably contributes to the impaired lumen-to-extracellular fluid flux of Na+ found previously in the jejunum of intact TGE-infected pigs. The mechanisms causing diarrhea in this invasive viral enteritis differ from those causing toxigenic diarrhea.