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Biomedical subjects

B Shneider

Publications and source records attributed to B Shneider.

12 recordsLinked to original sources
PubMed2001

The role of AP-1 in the transcriptional regulation of the rat apical sodium-dependent bile acid transporter.

Ileal reclamation of bile salts, a critical determinant of their enterohepatic circulation, is mediated primarily by the apical sodium-dependent bile acid transporter (ASBT=SLC10A2). We have defined mechanisms involved in the transcriptional regulation of ASBT. The ASBT gene extends over 17 kilobases and contains five introns. Primer extension analysis localized two transcription initiation sites 323 and 255 base pairs upstream of the initiator methionine. Strong promoter activity is imparted by both a 2.7- and 0.2-kilobase 5'-flanking region of ASBT. The promoter activity is cell line specific (Caco-2, not Hep-G2, HeLa-S3, or Madin-Darby canine kidney cells). Four distinct specific binding proteins were identified by gel shift and cross-linking studies using Caco-2 or rat ileal nuclear extracts. Two AP-1 consensus sites were identified in the proximal promoter. DNA binding and promoter activity could be abrogated by mutation of the proximal AP-1 site. Supershift analysis revealed binding of c-Jun and c-Fos to this AP-1 element. Co-expression of c-Jun enhanced promoter activity in Caco-2 cells and activated the promoter in Madin-Darby canine kidney cells. Region and developmental stage-specific expression of ASBT in the rat intestine correlated with the presence of one of these DNA-protein complexes and both c-Fos and c-Jun proteins. A specific AP-1 element regulates transcription of the rat ASBT gene.

Animals↗
PubMed2000

Abnormal hepatic sinusoidal bile acid transport in an Amish kindred is not linked to FIC1 and is improved by ursodiol.

BACKGROUND & AIMS: The mechanism for abnormal hepatic bile acid transport was investigated in an 18-month-old Amish boy who presented with pruritus, poor growth, and severe bleeding episodes. Serum bilirubin, gamma-glutamyltranspeptidase, and cholesterol levels were normal, but prothrombin time and partial thromboplastin time were prolonged and bone alkaline phosphatase level was elevated. METHODS AND RESULTS: Cholic acid plus chenodeoxycholic acid levels measured by capillary gas-chromatography were 32 times higher than control in serum (34.7 vs. 1.1+/-0.4 microg/dL) but were not detected in liver and were reduced in gallbladder bile. Treatment with ursodiol, a more hydrophilic bile acid, improved pruritus, produced 37% weight gain, and after 2 years reduced serum primary bile acid concentrations about 85%, while accounting for 71% of serum and 24% of biliary bile acid conjugates. On ursodiol therapy, hepatic bile acid synthesis was enhanced 2-fold compared with controls, and microscopy revealed chronic hepatitis without cholestasis. Three younger sisters with elevated serum bile acids responded positively to ursodiol. Microsatellite markers for the FIC1 (gene for Byler's disease) region in these 4 children were inconsistent with linkage to FIC1. CONCLUSIONS: Conjugated cholic acid and chenodeoxycholic acid were synthesized in the liver and secreted into bile but could not reenter the liver from portal blood and accumulated in serum. In contrast, unconjugated ursodiol entered the liver and was conjugated and secreted into bile. Thus, the enterohepatic circulation of all conjugated bile acids was interrupted at the hepatic sinusoidal basolateral membrane. Unconjugated ursodiol bypassed the hepatic uptake block to enlarge the biliary and intestinal bile acid pools. A mutation in FIC1 recognized among the Amish and linkage of the disorder to FIC1 were excluded.

Adenosine Triphosphatases↗
PubMed1999

Living related liver transplantation for acute liver failure in children.

The mortality rate among children with acute liver failure (ALF) on the waiting list for liver transplantation is high. We present our experience with living related donor liver transplantation (LRD-LT) in children who required urgent transplantation for ALF. Between December 1995 and July 1997, 6 children underwent LRD-LT for ALF. Cause of liver failure, recipient and donor demographics, clinical and laboratory data, surgical details, complications, and 6-month and 2-year graft and patient survival were recorded. Five boys and 1 girl received left lateral segment grafts from their parents. The mean age was 4 +/- 2.8 years (range, 1 to 9 years). ALF was caused by Wilson's disease in 1 patient and sickle cell intrahepatic cholestasis syndrome in 1 patient; in 4 patients, the cause was unknown. All patients had mental status changes; 2 were on life support. Mean pretransplantation liver function test values were: alanine aminotransferase, 972 +/- 565 U/L (normal, 1 to 53 U/L), total bilirubin, 31.3 +/- 12.4 mg/dL (normal, 0.1 to 1.2 mg/dL), prothrombin time, 34.3 +/- 12.4 seconds (normal, 10.8 to 13.3 seconds), international normalized ratio, 8.46 +/- 5.4 (normal < 2), and fibrinogen, 109 +/- 23.9 mg/dL (normal, 175 to 400 mg/dL). The donors were 5 mothers and 1 father. The mean donor age was 32.5 +/- 7.6 years (range, 19 to 40 years). No donor required blood transfusion, and no donor had any early or late postoperative complications. The donors' mean hospital length of stay was 5 days. In five cases, grafts were blood group-compatible; 1 child received a blood group-incompatible graft. All grafts functioned immediately. No patient had hepatic artery or portal vein thrombosis or biliary complications. The child who received a mismatched graft died of infection of the brain caused by Aspergillus spp at 22 days posttransplantation with a functioning graft. The child with ALF caused by sickle cell intrahepatic cholestasis syndrome developed outflow obstruction 3 months posttransplantation and required retransplantation; he eventually died of vascular complications related to his primary disease. Four children are alive at a mean follow-up of 27 months (range, 14 to 36 months). LRD-LT for children with ALF facilitates timely transplantation without drawing on cadaveric donor resources. The established safety record of LRD-LT made this option appealing to both physicians and parental donors.

Adult↗
PubMed1991

A prospective analysis of cholestasis in infants supported with extracorporeal membrane oxygenation.

Cholestasis develops in many infants supported with extracorporeal membrane oxygenation. We prospectively investigated the role of hemolysis and di-(2-ethylhexyl) phthalate exposure in the development of this cholestasis. Both di-(2-ethylhexyl) phthalate levels and hemolysis, as measured by maximum free hemoglobin, were significantly (p less than 0.025) associated with the degree of cholestasis. Other clinical and laboratory factors that may contribute to cholestasis were also investigated and not found to be related to the degree of cholestasis. We speculate that hemolysis during extracorporeal membrane oxygenation support produces a large bilirubin load whose excretion is inhibited by mechanisms similar to the inspissated bile syndrome and/or by di-(2-ethylhexyl) phthalate. This would result in a predominantly direct hyperbilirubinemia with little evidence of hepatocellular or canalicular injury.

Analysis of Variance↗
PubMed1989

The effect of biliary enteroenterostomy on the pharmacokinetics of enterally administered cyclosporine in rats.

A major factor in poor bioavailability of cyclosporine in children undergoing orthotopic liver transplantation appears to be poor absorption of the drug. Our hypothesis is that the Roux-en-Y choledochojejunostomy used for biliary drainage in these children causes cyclosporine malabsorption by reducing the length of bowel available for absorption and by distally displacing the entry of bile into the intestine. In these experiments, we determined the effect of biliary enteroenterostomy on the pharmacokinetics of enterally administered cyclosporine in Sprague-Dawley rats. Experimental rats (n = 24) were prepared for study by constructing self-emptying jejunal blind loops. Sham rats (n = 9) had jejunal transection and reanastomosis. Control rats (n = 26) had no operation. Two to 4 weeks later, chronic biliary-enteric fistulae were formed in all animals. In experiments, [3H]cyclosporine was delivered into the duodenum while the site of bile delivery varied. Hourly and cumulative [3H]cyclosporine excretion into bile was quantitated, which our preliminary data show to be a valid estimate of absorption. In control rats, bile was delivered into the duodenum or was replaced with saline and sucrose solution. In experimental rats, bile was infused either into the duodenum, which tested bowel shortening only, or into the proximal end of the blind loop, which tested the combined effects of bowel shortening and distal displacement of bile entry. In sham rats, bile was infused into the duodenum, which controlled for previous abdominal surgery, or into the midjejunum, which tested for distal bile entry only. Two effects of biliary enteroenterostomy on cyclosporine absorption were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Anastomosis, Surgical↗