Saul Teichberg

The effects of phenobarbital and diphenylhydantoin on liver function and morphology

Sixty-three children with seizure disorders receiving phenobarbital and/or diphenylhydantoin for more than 12 months had liver function tests evaluated. All 56 whose serum anticonvulsant concentrations were in the therapeutic range had elevations of their serum gamma glutamyl transpeptidase activity. Of the 11 who had elevated SGOT and SGPT concentrations initially, six had persistent transaminase abnormalities for more than 20 weeks. Liver tissue from these six patients revealed by light microscopy uniform swelling of the hepatocytes without cell necrosis, inflammation, fibrosis, or disturbance of hepatic architecture. Electron microscopy demonstrated proliferation of the smooth endoplasmic reticulum without other ultrastructural alterations. All six patients were maintained on the same dosages of PB and/or DPH, and their transaminase activities returned to normal within eight to 14 months. The clinical well being of these patients, the transient nature of their SGOT and SGPT elevations, and the absence of specific histopathology suggest that chronic treatment with PB and/or DPH does not result in hepatotoxicity but rather in enzyme induction. The data indicate that liver biopsies are not warranted in such children and that PB and DPH may be continued despite mild elevations of SGOT and SGPT, without concern for hepatic damage.

Development of the neonatal rat small intestinal barrier to nonspecific macromolecular absorption: effect of early weaning to artificial diets.

ABSTRACT: We studied the effect of early weaning from maternal breast milk to artificial diets on rat jejunal absorption of an exogenous 40-kD glycoprotein, horseradish peroxidase (HRP). Rat pups, fed maternal milk (MM) from birth, received one of three diets for the last 4 d before weaning (d 17-21): MM, protein hydrolysate formula (PH), or soy formula (S). Some rats were pretreated on d 14 with intraperitoneal hydrocortisone (5 mg/rat). In MM-fed rat pups, jejunal HRP absorption was markedly higher on d 17 than on d 21. [Geometric means (95% confidence interval) were: d 17, 626.4 (461.3, 850.6) versus d 21, 90.6 (48.2, 170.5) IU HRP/mL x cm x min, p<0.01.] By contrast, 21-d-old PH- and S-fed pups maintained elevated absorption of the tracer [PH, 292.3 (177.5,480.6), p <0.05 versus MM pups, S, 340.8 (164.4, 704.8), p<0.01 versus MM pups]. wt-matched control studies indicate that the difference in HRP absorption was not due to the smaller body wt of formula-fed pups. The increased absorption in formula-fed animals was suppressed by hydrocortisone. In S-fed pups, the increased macromolecular absorption appeared, in part, to be the result of diffusion across altered villus absorptive cells. In PH-fed pups, there was no evidence of damage and HRP absorption appeared to occur by vesicle-mediated transport. Delay in the normal maturation of small intestinal “closure” appears to be associated with early weaning to artificial diets. This may lead to increased nonspecific macromolecular permeability that could result in immune-mediated sensitization and food intolerance.

Selective Fetal Malnutrition: the Effect of in Vivo Ethanol Exposure upon in Vitro Placental Uptake of Amino Acids in the Non-Human Primate

Summary: In vitro uptake (45 and 90 minutes) of amino acids, alpha-amino isobutyric (AIB) and valine (VAL), was measured in six placentae from the nonhuman primate, Macacca fascicularis. Three of the pregnant primates were chronically treated with ethanol before and throughout pregnancy (CHR); one during the last trimester only (LT); and two were controls (C). Compared to the C placentae, the LT placenta had significantly decreased uptake only for AIB at 45 min: 33.4 ± 6.8% reduction (mean ± S.E.) (P < 0.05). In contrast, the CHR placentae demonstrated significantly reduced uptake (P < 0.01) for both amino acids at both time points. Percent reduction at 45 and 90 min: AIB, 35.2 ± 6.5% and 32.6 ± 5.6% and VAL, 38.7 ± 2.9% and 22.1 ± 4.1%. The results indicate that chronic in vivo ethanol exposure impairs the in vitro placental uptake of two actively transported amino acids, using an animal with a placenta almost identical to the human.

Effect of gum arabic in an oral rehydration solution on recovery from diarrhea in rats

BACKGROUNDnIt has been shown that gum arabic, a soluble fiber, enhances water, electrolyte, and glucose absorption from oral rehydration solutions in jejunal perfusion of healthy rats and in animals with theophylline-induced secretion or chronic osmotic-secretory diarrhea. This report concerns a study of the effectiveness of an oral rehydration solution supplemented with gum arabic, during recovery from chronic osmotic secretory diarrhea in free-living rats.nnnMETHODSnChronic diarrhea was induced in 60- to 80-g juvenile rats by providing a magnesium citrate-phenolphthalein solution as the sole fluid source for 7 days. This led to diarrhea characterized by dehydration, soft stools, increased cecal volume, decreased food and fluid intake and failure to gain weight. After 7 days of diarrhea, rats recovered for 24 hours with either tap water or an oral rehydration solution (90 mM Na, 111 mM glucose, 20 mM K, 80 mM chloride, 20 mM citrate) with or without 2.5 g/l gum arabic.nnnRESULTSnAlthough all three solutions improved the diarrhea, optimal recovery from diarrhea was achieved with the gum arabic-supplemented oral rehydration solution. After 4 hours and 24 hours, rats drinking the gum arabic-supplemented solution gained more weight and had lower fecal output than rats receiving water or the rehydration solution without gum arabic. All three solutions normalized plasma osmolality after 24 hours.nnnCONCLUSIONSnThe positive effects of the gum arabic-supplemented rehydration solution on fluid and electrolyte absorption seen during jejunal perfusion also occurred during recovery from chronic osmotic secretory diarrhea, when free-living animals drank the solution ad libitum.

Development of the Neonatal Rat Small Intestinal Barrier to Nonspecific Macromolecular Absorption. II. Role of Dietary Corticosterone

ABSTRACT: The role of oral corticosterone (C) in the maturation of the neonatal rat jejunal barrier to the absorption of nonspecific macromolecules was evaluated. This was done by adding C to the diet of rat pups weaned at an early age, 17 d, from maternal milk (MM) to either a protein hydrolysate (PH) or soy (S) artificial formula. Both PH and S are known to cause a delay in small intestinal closure to the absorption of a 40-kD glycoprotein tracer, horseradish peroxidase (HRP), on d 21 of age. C was added to PH and S formulas from d 17 to 21 at 0.26 μmol/L (10 μg/dL), a level found in the MM of lactating rat dams, or at 10.29 μmol/L (400 Mg/dL) (PH + 10C, PH + 400C) (S + 10C, S + 400C). Controls consisted of rat pups fed PH or S without C and animals remaining with the dam on MM. The delay in jejunal closure to HRP on d 21 in both PH- and S-fed pups was prevented by C supplementation at both the higher and lower concentrations. Geometric mean (95% confidence intervals) jejunal HRP absorption in PH + 10C pups was 74 (32,167) IU HRP/mL ± cm ± min, less than in pups fed PH without C [353 (200,615); p <0.05] and indistinguishable from HRP absorption in MM-fed animals [111 (79,154)]. HRP absorption in PH + 400C pups [52 (23, 115)] was also less than that in animals fed PH without C (p < 0.01) and indistinguishable from those fed MM. In S-fed pups, closure delay was accompanied by a lamina propria eosinophilia not seen with PH or MM feedings; this did not occur in S + 400C pups. Our results lend support to the view that C, a glucocorticoid known to be present in rat MM, may play a role in the normal ontogenetic closure of the small intestine to macromolecular absorption in the neonatal rat.

Carcinosarcoma of the pancreas: a case report and review of the literature.

We report the case of a 74-year-old white man with a mass in the head of the pancreas, which was found incidentally on computerized tomographic scan during a workup for deep vein thrombosis. Endoscopy with pancreatic duct brushings yielded a diagnosis of adenocarcinoma. A pancreaticoduodenectomy followed, with complete resection of the tumor. Pathologic examination showed 2 distinct components. One component was a conventional infiltrating pancreatic ductal adenocarcinoma, and the other component was high-grade sarcoma with features of malignant fibrous histiocytoma. To our knowledge, this carcinosarcoma is the seventh reported case of a primary pancreatic neoplasm with mixed carcinomatous and sarcomatous elements.

Oral rehydration solutions: increased water and sodium absorption by addition of a viscosity-enhancing agent in a rat model of chronic osmotic diarrhea.

Viscosity-enhancing agents such as carboxymethylcellulose (CMC) can alter absorption of solutes and fluid exchange in the small intestine. We investigated whether the standard World Health Organization oral rehydration solution (WHO-ORS) with the addition of CMC would improve net water and sodium absorption in rats using an in vivo intestinal perfusion technique. Four WHO-ORS, containing either 0, 2.5,5.0, or 10.0 g/L of CMC, were perfused in rats with a well-tested model of cathartic-induced chronic osmotic diarrhea (D) and in normal controls (C). In D rats, the ORSs with CMC improved sodium absorption at the three concentrations used (p < 0.01). The same effect was shown in C rats. Net water absorption was also enhanced in D rats given ORSs with CMC, although the changes in C animals were less marked. The improvement in sodium and water absorption in both C and D rats positively correlated with the log of relative ORS viscosity. Ultrastructural examination of tissues perfused with 10 g/L of CMC showed an extended brush border glycocalyx. This study indicates that CMC added to WHO-ORS in the perfused rat jejunum improves the effectiveness of the solution by increasing sodium and water absorption.

Hepatitis in children with acquired immune deficiency syndrome

Hepatic morphology and immunocytology were evaluated in 4 children with clinical and immunologic characteristics of the acquired immune deficiency syndrome or acquired immune deficiency syndrome related complex. All 4 children had hepatomegaly and increased serum alanine and aspartate aminotransferase activity. Both lobular and portal changes were noted. Lymphocytic infiltration, piecemeal necrosis, hepatocellular and bile duct damage, sinusoidal cell hyperplasia, and endothelialitis were prominent. Vesicular rosettes in sinusoidal lymphocytes and tubuloreticular structures in sinusoidal endothelial cells were demonstrated by electron microscopy. The lymphocytic infiltrate in both the lobular and portal spaces was characterized by a relative increase of cytotoxic/suppressor (T8) cells. Hepatitis may be a common feature of pediatric acquired immune deficiency syndrome and acquired immune deficiency syndrome-related complex. Although the histopathologic changes are consistent with chronic active hepatitis, the specific pathogenesis remains to be determined.

Response of Rat Intestine to a Hyperosmotic Feeding

Summary: After a single force-feeding of hypertonic (1300 mOsm) mannitol to rats there is rapid osmotic equilibration of the jejunal fluid, a sharp drop in luminal mannitol concentration and large influxes of water and sodium. During osmotic equilibration there was a significant loss of cells from the jejunal mucosa. In hypertoaically fed rats there was an accumulation of protein, DNA, [3H] thymidine-labeled DNA, and disaccharidases in intestinal washings. Brush border disaccharidase specific activities on the jejunal mucosa were unaltered. Under the light microscope jejunal villi from hypertonic mannitol rats were comparable to controls. Some epithelial cells from rats force-fed hypertonic mannitol showed transient ultrastructural damage. Microvilli of some cells were shortened and fused at their bases 20 and 40 min after the force-feeding. By 120 min epithelial cell microvilli were all normal in appearance. In hypertonically fed rats the lateral interdigitating plasma membranes became disorganized. Large fragments budded off into one cell and fused to form larger structures. By 120 min many lysosomal autophagic vacuoles and residual bodies were seen. A single hypertonic force feeding produced jejunal cell loss associated with loss of brush border disaccharidases and focal ultrastructural damage.Speculation: The damage induced in the jejunal mucosa of rats by a hypertonic feeding may provide clues concerning the pathophysiology of certain clinical conditions. Damage to the lateral interdigitating plasma membranes of adjacent epithelial cells could reflect alterations in permeability allowing the passage of bacterial toxins or allergens into the circulation, or permitting massive bacterial gas leakage leading to pneumatosis intestinalis. The loss of jejunal cells and parallel loss of disaccharidases into the intestinal lumen could, in part, account for the disaccharidase deficiences seen in diarrheal disease where osmotic pressure can become significant because of unabsorbed carbohydrate. This malabsorption may be further enhanced by microvillar alterations such as shortening and fusion, which significantly decrease the effective absorptive area.

Cancer family syndrome: marker studies.

Individuals from kindreds with the cancer family syndrome (CFS) have an increased hereditary risk for the development of adenocarcinoma of the colon in childhood and early adulthood. Previous studies have suggested that this high occurrence of adenocarcinoma may be due to a genetic defect in the control of colonic epithelial proliferation. Others have suggested that these families may have an underlying abnormality in immunologic tumor surveillance. We have investigated these possibilities in 15 cancer-free, at-risk individuals (10 children, ages 3-15 yr, and 5 adults) from two unrelated CFS kindreds. Colonic mucosal proliferative activity was studied by in vitro autoradiography after tritiated thymidine labeling in 7 subjects. The mean labeling index (12.7 +/- 0.9%) was comparable to that in controls, as was the distribution of thymidine labeling. Immunologic evaluation revealed depressed lymphocyte culture responses to stimulation by microbial antigens, but not to that by mitogens. Mixed lymphocyte culture responses were depressed in 4 of 8 subjects, but became normal in 2 of these after filtration through a Sephadex G10 column. Natural killer cell cytotoxicity was significantly depressed in 5 of 13 subjects, and borderline normal in another 3 subjects. These data suggest that many cancer-free members of CFS kindreds have a spectrum of in vitro cell-mediated immunologic defects that might interfere in vivo with the recognition or killing of incipient tumor cells.