A PEX10 defect in a patient with no detectable defect in peroxisome assembly or metabolism in cultured fibroblasts.

Zellweger spectrum disorders (ZSD) are diagnosed by biochemical assay in blood, urine and cultured fibroblasts and PEX gene mutation identification. In most cases studies in fibroblasts corroborate results obtained in body fluids. In 1996 Clayton and colleagues described a 10-year old girl with evidence of a peroxisome disorder, based on elevated bile acid metabolites and phytanate. At the time it was not possible to distinguish whether she had a ZSD or a single peroxisomal protein defect. Studies in our laboratory showed that she also had elevated plasma pipecolate, supporting the former diagnosis. Despite the abnormal metabolites detected in blood (phytanate, bile acid intermediates and pipecolate), analysis of multiple peroxisomal pathways in fibroblasts yielded normal results. In addition, she had a milder clinical phenotype than usually associated with ZSD. Since complementation analysis to determine the gene defect was not possible, we screened this patient following the PEX Gene Screen algorithm (PGS). The PGS provides a template for sequencing PEX gene exons independent of complementation analysis. Two mutations in PEX10 were identified, a frameshift mutation inherited from her father and a de novo missense mutation in a conserved functional domain on the other allele. This case highlights that molecular analysis may be essential to the diagnosis of patients at the milder end of the ZSD spectrum. Furthermore, it supports the concept that some tissues are less affected by certain PEX gene defects than brain and liver.

Primary bile acid malabsorption caused by mutations in the ileal sodium-dependent bile acid transporter gene (SLC10A2).

Primary bile acid malabsorption (PBAM) is an idiopathic intestinal disorder associated with congenital diarrhea, steatorrhea, interruption of the enterohepatic circulation of bile acids, and reduced plasma cholesterol levels. The molecular basis of PBAM is unknown, and several conflicting mechanisms have been postulated. In this study, we cloned the human ileal Na+/bile acid cotransporter gene (SLC10A2) and employed single-stranded conformation polymorphism analysis to screen for PBAM-associated mutations. Four polymorphisms were identified and sequenced in a family with congenital PBAM. One allele encoded an A171S missense mutation and a mutated donor splice site for exon 3. The other allele encoded two missense mutations at conserved amino acid positions, L243P and T262M. In transfected COS cells, the L243P, T262M, and double mutant (L243P/T262M) did not affect transporter protein expression or trafficking to the plasma membrane; however, transport of taurocholate and other bile acids was abolished. In contrast, the A171S mutation had no effect on taurocholate uptake. The dysfunctional mutations were not detected in 104 unaffected control subjects, whereas the A171S was present in 28% of that population. These findings establish that SLC10A2 mutations can cause PBAM and underscore the ileal Na+/bile acid cotransporter's role in intestinal reclamation of bile acids.

Health Status and Lifestyle Habits of US Medical Students: A Longitudinal Study.

BACKGROUND: Evidence shows that physicians and medical students who engage in healthy lifestyle habits are more likely to counsel patients about such behaviors. Yet medical school is a challenging time that may bring about undesired changes to health and lifestyle habits. AIMS: This study assessed changes in students' health and lifestyle behaviors during medical school. SUBJECTS AND METHODS: In a longitudinal study, students were assessed at both the beginning and end of medical school. Anthropometric, metabolic, and lifestyle variables were measured at a clinical research center. Data were collected from 2006 to 2011, and analyzed in 2013-2014 with SAS version 9.3. Pearson's correlations were used to assess associations between variables and a generalized linear model was used to measure change over time. RESULTS: Seventy-eight percent (97/125) of participants completed both visits. At baseline, mean anthropometric and clinical measures were at or near healthy values and did not change over time, with the exception of increased diastolic blood pressure (P = 0.01), high-density lipoprotein-cholesterol (P < 0.001), and insulin (P < 0.001). Self-reported diet and physical activity habits were congruent with national goals, except for Vitamin D and sodium. Dietary intake did not change over time, with the exceptions of decreased carbohydrate (percent of total energy) (P < 0.001) and sodium (P = 0.04) and increased fat (percent of total energy) and Vitamin D (both P < 0.01). Cardiovascular fitness showed a trend toward declining, while self-reported physical activity increased (P < 0.001). CONCLUSIONS: Students' clinical measures and lifestyle behaviors remain generally healthy throughout medical school; yet some students exhibit cardiometabolic risk and diet and activity habits not aligned with national recommendations. Curricula that include personal health and lifestyle assessment may motivate students to adopt healthier practices and serve as role models for patients.

The role of human growth hormone in the regulation of cholesterol and bile acid metabolism.

Cholesterol and bile acid metabolism was studied in 16 children with human GH (hGH) deficiency (11 with isolated hGH deficiency and 5 with multiple trophic hormone deficiency) before and after 6 months of hGH therapy. We measured plasma lipid concentrations, biliary lipid composition, and cholesterol saturation indices; calculated the bile acid pool size measured by the isotopic dilution technique using the stable isotope chenodeoxycholic-[11,12-d2] acid; and measured cholesterol and bile acid synthetic rates by sterol balance techniques. In all 16 patients, plasmas lipid concentrations were unchanged after hGH therapy; total plasma cholesterol was 182 +/- 10 (+/-SEM) mg/dl before and 179 +/- 9 mg/dl after treatment, high density lipoprotein-cholesterol was 47 +/- 2 mg/dl before and 49 +/- 3 mg/dl after treatment, low density lipoprotein-cholesterol was 112 +/- 10 mg/dl before and 111 +/- 8 mg/dl after therapy, and triglyceride was 113 +/- 13 mg/dl before and 107 +/- 10 mg/dl after hGH therapy. Biliary lipid composition and cholesterol saturation in 10 patients were similar to those in controls and unchanged with hGH therapy. Cholesterol synthesis (n = 14) was unchanged (7.6 +/- 1.4 vs. 9.6 +/- 1.2 mg/kg X day); however, bile acid synthesis (n = 15) increased from 3.1 +/- 0.4 to 4.3 +/- 0.6 mg/kg X day (P less than 0.025) after therapy. The chenodeoxycholate pool size (n = 8) was significantly reduced (P less than 0.025) before hGH treatment (416 +/- 64 mg/m2) compared to that in controls (617 +/- 45 mg/m2) and increased to 620 +/- 72 mg/m2 after hGH therapy (P less than 0.05). Chenodeoxycholate pool size expansion during hGH therapy was, at least in part, caused by an increase in hepatic bile acid synthesis. These findings suggest that hGH may indirectly modulate cholesterol metabolism through regulation of hepatic cholesterol 7 alpha-hydroxylase activity, the rate-limiting enzyme of bile acid synthesis.

Isoflavone content of infant formulas and the metabolic fate of these phytoestrogens in early life.

Soy-based infant formulas have been in use for >30 y. These formulas are manufactured from soy protein isolates and contain significant amounts of phytoestrogens of the isoflavone class. As determined by HPLC, the isoflavone compositions of commercially available formulas are similar qualitatively and quantitatively and are consistent with the isoflavone composition of soy protein isolates. Genistein, found predominantly in the form of glycosidic conjugates, accounts for >65% of the isoflavones in soy-based formulas. Total isoflavone concentrations of soy-based formulas prepared for infant feeding range from 32 to 47 mg/L, whereas isoflavone concentrations in human breast milk are only 5.6 +/- 4.4 microg/L (mean +/- SD, n = 9). Infants fed soy-based formulas are therefore exposed to 22-45 mg isoflavones/d (6-11 mg x kg body wt(-1) x d(-1)), whereas the intake of these phytoestrogens from human milk is negligible (<0.01 mg/d). The metabolic fate of isoflavones from soy-based infant formula is described. Plasma isoflavone concentrations reported previously for 4-mo-old infants fed soy-based formula were 654-1775 microg/L (mean: 979.7 microg/L: Lancet 1997:350;23-7), significantly higher than plasma concentrations of infants fed either cow-milk formula (mean +/- SD: 9.4 +/- 1.2 microg/L) or human breast milk (4.7 +/- 1.3 microg/L). The high steady state plasma concentration of isoflavones in infants fed soy-based formula is explained by reduced intestinal biotransformation, as evidenced by low or undetectable concentrations of equol and other metabolites, and is maintained by constant daily exposure from frequent feeding. Isoflavones circulate at concentrations that are 13,000-22,000-fold higher than plasma estradiol concentrations in early life. Exposure to these phytoestrogens early in life may have long-term health benefits for hormone-dependent diseases.

The effect of continuous enteral feeding on cholic acid kinetics in a child.

Continuous enteral feeding is utilized for nutritional support and specific therapy for several pediatric diseases, including protracted infantile diarrhea. Its effects on the enterohepatic circulation of bile acids were studied in a boy during continuous intragastric feeding of a high fat diet at age 42 months and after recovery while on bolus feedings at age 51 months. Cholic acid kinetics measured by the isotopic dilution technique using cholic-COOH-14C acid and meal stimulated intraluminal bile acid concentrations were measured. Cholic acid pool size was unaltered (1294 mg/m(2)) during continuous feeding compared to 999 mg/m(2) during bolus feeds and 1072 plus or minus 243 mg/m(2) (mean plus or minus SE) in nine control children. However, the cholic acid fractional turnover rate was increased 3-fold (0.912 days(-1)) during continuous feeds compared to 0.309 days(-1) during bolus feeding and 0.365 plus or minus 0.163 in controls. Similarly, synthesis rate was increased 3-4 fold during continuous feeds (1180 mg/m(2)/day) compared to controls (363 plus or minus 193 mg/m(2)/day) and the patient during bolus feeding (309 mg/m(2)/day). The intraluminal bile salt concentration was apparently reduced both during treatment (3.86 mM) and when bolus fed (3.85 mM) but were significantly different from controls (7.12 plus or minus 1.74 mM). During continuous enteral feeding with a high fat diet, effective homeostatic mechanisms in the enterohepatic circulation of bile salts ensured intraluminal bile salt concentrations adequate for normal fat solubilization and, consequently, normal fat absorption.

Intestinal calcium absorption of women during lactation and after weaning.

We investigated whether intestinal calcium absorption and serum 1,25-dihydroxycholecalciferol (calcitriol) concentrations are higher in women during lactation and after weaning to compensate for calcium lost in breast milk. Measurements were obtained at 4.6 mo postpartum in 24 lactating women and 24 nonlactating women, at 9.6 mo postpartum in 24 lactating women (2.6 mo after complete weaning) and 24 nonlactating women. One-half of the women in each group were randomly assigned to receive 1 g supplemental Ca/d as calcium carbonate. Fractional calcium absorption was measured by using stable isotopic tracers 42Ca and 44Ca. Fractional absorption was 0.32+/-0.02 (+/-SEM) in both lactating and nonlactating women, but was higher in lactating women after weaning (0.37+/-0.02) compared with nonlactating postpartum control subjects (0.31+/-0.02). These effects were independent of calcium intake. Changes in serum calcitriol paralleled changes in fractional absorption. There were no differences in calcitriol concentrations between lactating and nonlactating women, but calcitriol was greater in women after weaning compared with postpartum control subjects. Lactating women who had resumed menses had higher fractional absorption and serum calcitriol than did lactating women who had not. Serum calcium and phosphorus concentrations were greater in lactating compared with nonlactating women; there were no differences between groups after weaning. We conclude that lactation stimulates increases in fractional calcium absorption and serum calcitriol, but the responses are only apparent after weaning or the resumption of menses.

Calcium kinetics in lactating women with low and high calcium intakes.

Absorption of calcium and its mobilization from bone during lactation are important for delivery of calcium to breast-feeding infants; whether calcium intake offsets bone resorption is not known. We hypothesized that calcium absorption is increased in lactation and greater in women on low calcium diets, resulting in similar rates of bone resorption and accretion. Calcium absorption and kinetic indexes were calculated by using two stable isotopic tracers in 8 women; 6 were studied both during lactation and nonlactation. Women consumed low calcium diets, with half receiving supplemental calcium. Intestinal absorption was related to serum 1,25-dihydroxyvitamin D and did not increase during lactation. Despite decreased urinary calcium excretion during lactation, especially in women with low calcium intake, net balance tended to be lower during lactation. Mean residence time decreased and bone resorption exceeded accretion in almost all lactating women. Calcium need for milk production appears to be met by decreased urinary excretion and increased bone resorption, and not by increased intestinal absorption.

Bone mineral content in infants and children with chronic cholestatic liver disease.

OBJECTIVE: To assess bone mineral content (BMC) status and serum vitamin D metabolite levels of infants and children with chronic cholestatic liver disease. To determine if severity of bone disease in these patients correlates with serum vitamin D metabolite levels. METHODOLOGY: We measured radial BMC with the use of a single-beam photon absorptiometer and serum vitamin D metabolite levels in 56 patients with chronic cholestasis seen at our institution from 1985 through 1991. Patients were divided into two groups according to age. RESULTS: In group 1 (n = 37; age 2 to 22 months), decreased levels of BMC were seen as early as the first few months of life, with sharp decline observed with increasing age (approaching 3 to 5 standard deviations [SD] below the mean, P < .0003). Older patients (group 2, n = 19; age 2 to 20 years) had BMC values which clustered between 2 and 4 SD below the mean throughout the age range. Although a downward trend also was noted with increasing age, this was not statistically significant. Despite correction for weight-age or height-age, BMC was decreased in most of these patients. No correlation between severity of osteopenia and serum levels of 25(OH)-vitamin D and 1,25(OH)2-vitamin D was observed in either infants or older children. CONCLUSIONS: Decreased bone mineralization, as a complication of chronic cholestatic conditions, is a disease process that begins early in infancy, rapidly worsens with increasing age and hepatic dysfunction, and remains relatively stable in children with more stable liver disease.

Pharmacokinetics, tolerability, and clinical effectiveness of quetiapine fumarate: an open-label trial in adolescents with psychotic disorders.

BACKGROUND: This is the first investigation of the pharmacokinetics, tolerability, and efficacy of quetiapine fumarate in adolescents with chronic or intermittent psychotic disorders. METHOD: Ten patients with DSM-IV chronic or intermittent psychotic disorders (ages 12.3 through 15.9 years) participated in an open-label, rising-dose trial and received oral doses of quetiapine twice daily (b.i.d.), starting at 25 mg b.i.d. and reaching 400 mg b.i.d. by day 20. The trial ended on day 23. Key assessments were pharmacokinetic analysis of plasma quetiapine concentrations and neurologic, safety, and efficacy evaluations. RESULTS: No statistically significant differences were observed between 100-mg b.i.d. and 400-mg b.i.d. quetiapine regimens for total body clearance, dose-normalized area under the plasma concentration-time curve, or dose-normalized premorning- or postmorning-dose trough plasma values obtained under steady-state conditions after multiple-dose regimens. No unexpected side effects occurred with quetiapine therapy, and no statistically significant changes from baseline were observed for the UKU Side Effect Rating Scale items that were rated. No serious adverse events or clinically important changes in hematology or clinical chemistry variables were reported. The most common adverse events were postural tachycardia and insomnia. Extrapyramidal side effects improved, as evidenced by significant (p < .05) decreases from baseline to endpoint in the mean Simpson-Angus Scale total scores and Barnes Akathisia Scale scores. Quetiapine improved positive and negative symptoms, as shown by significant (p < .05) decreases from baseline to endpoint in the mean Brief Psychiatric Rating Scale total score, the Clinical Global Impressions-Severity of Illness scale, and the Modified Scale for the Assessment of Negative Symptoms summary score. CONCLUSION: Quetiapine pharmacokinetics were dose proportional in adolescents and were similar to those previously reported for adults. Quetiapine was well tolerated and effective in the small number of adolescents studied.

Enteral metronidazole for the prevention of graft versus host disease in pediatric marrow transplant recipients: results of a pilot study.

The use of enteral antibiotics to prevent acute graft versus host disease (GvHD) has not been studied prospectively in children. We hypothesized the risk of GvHD in pediatric bone marrow transplant (BMT) recipients would be decreased with enteral metronidazole. Eligible subjects included pediatric patients referred to one center for first allogeneic BMT. Enteral metronidazole 20 mg/kg/day divided thrice daily (maximum 750 mg/day) was administered from day -14 to day +35. The risk of GvHD grade II or more severe among subjects treated with metronidazole was compared to historical controls. There were no significant differences between treated (n=19) and historical controls (n=83) with respect to age, gender, prophylaxis, or conditioning regimens, proportion receiving unrelated donor marrow, proportion receiving umbilical cord blood, or transplantation indication. The probability of remaining free of GvHD at day +100 was lower in the treated group (P=0.047). The adjusted relative risk of developing GvHD among subjects treated with metronidazole was 0.36 (95% CI: 0.13-0.997; P=0.05). Five patients were unable to complete the study; two were likely related to study medication. We conclude that enteral metronidazole appears effective in the prevention of GvHD. These results suggest that a randomized trial is justifiable in children, especially recipients of alternative donor BMT.

The spectrum of bile duct complications in pediatric liver transplantation.

It has been noted that reduced-size liver transplants are associated with increased rates of biliary complications, and it has been suggested that some of these complications can be handled nonoperatively. In a 6-year period, 91 orthotopic liver transplants were performed in 77 children. The medical records were reviewed to analyze the effect of reduced-size grafts on the incidence of bile duct complications and to investigate the utility of interventional radiology techniques for treatment. Forty-two children received 47 whole-organ transplants, and 35 children received 44 reduced-size transplants. The median age and weight were greater for children receiving whole-organ transplants (age, 4.25 years; weight, 16 kg) than for those receiving reduced-size grafts (age, 1.0 year; weight, 8 kg). The overall incidence of bile duct complications was 19.5% (n = 15). The incidence was not different between the whole organ group (17%) and the reduced-size group (16%). Four of the children with bile duct complications had associated hepatic artery thrombosis, two of whom had another transplant. Complications included anastomotic stricture (n = 6), anastomotic leak (n = 5), intraparenchymal biloma (n = 3), and multiple strictures (n = 1). Twelve of 15 children presented within 3 months of transplantation. Six children had initial percutaneous drainage or placement of transanastomotic stents (external). Operative repair was eventually required for all 15 children, three of whom received a second transplant. There was a 40% incidence of cytomegalovirus infection involving the liver or extrahepatic bile ducts near the time of presentation.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation of serum cholylglycine level with hepatic dysfunction in children with sickle cell anemia.

Hepatic dysfunction occurs commonly in children with sickle cell disease (SCD). Although the etiology is multifactorial, cholestasis is a prominent feature. Serum cholylglycine (CG) has been found to be a very sensitive indicator of cholestasis. Our objective was to determine whether CG levels are elevated in children with SCD and whether they are predictive of hepatic dysfunction. Blood samples were obtained from 97 children with SCD. Liver function tests were done and serum CG concentrations were measured. Patients were followed up for 2 years. Thirty-eight percent of the patients had an elevated CG level. During the 2 years of follow-up, 16% of the children with a previously elevated CG level developed abnormal liver function test results or required a cholecystectomy as compared with 13% with a previously normal CG level (p = 0.92). We conclude that although CG level was elevated in 38% of the patients with SCD, it did not appear to predict liver dysfunction during the ensuring 2 years.

Micellar solubilisation of cholesterol is essential for absorption in humans.

BACKGROUND AND AIMS: Intralumenal bile acid (BA) concentrations have a profound effect on cholesterol absorption. We performed studies to assess the effects of markedly reduced lumenal BA on cholesterol absorption in children with inborn errors in BA synthesis and the role of micellar solubilisation of cholesterol on its absorption in an animal model using human intestinal contents. METHODS: We studied five subjects: two with 3beta hydroxy-C27 steroid dehydrogenase isomerase deficiency (3-HSD), two with Delta(4)-3-oxosteroid 5beta reductase deficiency (5beta reductase), and one with 2-methylacyl CoA racemase deficiency (racemase). Subjects were studied on supplemental BA therapy and three weeks after withdrawal of supplements. During each treatment period a liquid meal was consumed. Duodenal samples were collected and analysed, and cholesterol absorption and cholesterol fractional synthetic rates were measured. Human intralumenal contents were infused in a bile diverted rat lymph fistula model to assess micellar versus vesicular absorption of cholesterol. RESULTS: Without BA supplementation, intralumenal BA concentrations were below the critical micellar concentration (CMC) whereas intralumenal BAs increased to above the CMC in all subjects on BA supplementation. Lumenal cholesterol was carried primarily as vesicles in untreated subjects whereas it was carried as both micelles and vesicles in treated subjects. Cholesterol absorption increased approximately 55% in treated compared with untreated subjects (p=0.041), with a simultaneous 70% decrease in synthesis rates (p=0.029). In the rat lymph fistula model, minimal vesicular cholesterol was absorbed whereas vesicular and micellar fatty acid and phospholipid were comparably absorbed. CONCLUSIONS: Increasing micellar cholesterol solubilisation by supplemental BA in subjects with inborn errors of BA synthesis leads to an improvement in cholesterol absorption and reduction in cholesterol synthesis due to improved micellar solubilisation of cholesterol.

Hepatocyte glycogen accumulation in patients undergoing dietary management of urea cycle defects mimics storage disease.

OBJECTIVES: Anecdotal reports have described excess hepatocyte glycogen in patients with urea cycle enzyme defects. Retrospectively, the authors evaluated the prevalence and possible cause of liver glycogen accumulation in such patients. METHODS: The authors searched the files of the Division of Pathology at Cincinnati Children's Hospital from 1975 and 2004 for cases of urea cycle enzyme defects and identified 11 patients who had had liver biopsy performed and/or liver transplantation. All patients were on diets containing essential amino acids as the protein source before liver biopsy and/or transplantation. RESULTS: All but one patient had focal or diffuse glycogen accumulation in hepatocytes in at least one specimen by light microscopic examination. Two young infants also had cholestasis. Electron microscopy performed on six patients showed diffuse or focal glycogen excess in the cytoplasm of individual hepatocytes. Biochemical studies of three patients revealed two with hepatic glycogen content in the upper normal range and one that was abnormally high. Glycolytic enzyme activities were normal in two patients, and one patient had low phosphorylase activity. CONCLUSIONS: Hepatocyte glycogen accumulation in urea cycle enzyme defects resembles that seen in glycogen storage disease but can be distinguished in most cases by non-uniformity of distribution and/or the absence of sinusoidal compression by expanded hepatocytes. We speculate that therapeutic modification of dietary protein content by restriction to essential amino acids, including leucine, may promote glycogen accumulation by increasing insulin secretion.

Role of thyroxine on postnatal development of ileal active bile salt transport.

The role of thyroid hormone on the postnatal development of ileal active taurocholate transport uptake was measured by an in vitro incubation technique in Sprague-Dawley rats. In 16-day-old rats treated with pharmacological doses of L-thyroxine (50 micrograms X 100 g body wt-1 X day-1 on days 10-13), ileal active transport appeared precociously whose Km was 1.60 +/- 0.48 mM and Vapp (apparent maximal velocity) was 8.09 +/- 1.14 nmol X min-1 X mg dry wt-1, while age-matched shams had only passive diffusion of taurocholate. To determine whether enhanced endogenous secretion of thyroxine was capable of stimulating development of ileal active taurocholate transport, thyrotrophic stimulating hormone (TSH) (0.5 U/100 g body wt twice daily) was given on days 10-13, with uptake measured on day 16. Following TSH treatment, only passive transport for taurocholate was observed in the ileum; uptake rates were consistently higher than those for untreated controls at each study concentration. Thyroidectomy performed at age 14 days with uptake measured at age 21 days did not ablate development of ileal active transport but resulted in a significant reduction (P less than 0.001) in the Vapp (7.39 +/- 1.10 nmol X min-1 X mg dry wt-1) and a significant increase (P less than 0.014) in Km (1.72 +/- 0.53 mM) compared with age-matched controls. Thyroid hormone does not appear to be obligatory for the postnatal development of ileal active taurocholate transport.

Postnatal development of intestinal bile salt transport. Relationship to membrane physico-chemical changes.

The postnatal development of intestinal bile salt transport in the rat was examined using the villus technique. Jejunal uptake of taurocholate was linear with respect to incubation concentration at all study ages. Ileal uptake was linear with taurocholate concentration during the first 2 postnatal weeks; a curvilinear relationship indicating the presence of saturable transport appeared during the third week. With the appearance of ileal active transport at age 3 weeks, the Km (app) was constant at 0.49 mM, 0.59 mM, and 0.50 mM in 3-week, 4-week, and adult animals, respectively. The V(app) was 14.65 nmol X mg-1 (dry wt) X min-1 at 3 weeks and declined with age to 11.40 and 10.51 nmol X mg-1 (dry wt) X min-1 in 4-week and adult animals, respectively. The role of physico-chemical changes in the microvillus membrane in the development of ileal active transport was examined. With increasing postnatal age, microvillus membrane cholesterol content rose while the phospholipid content remained unchanged in both ileum and jejunum. Corresponding rises in the cholesterol/phospholipid ratio were observed in both sites. Simultaneously, the microvillus membrane fatty acid composition was changing from predominantly saturated to unsaturated species in both ileum and jejunum. The microvillus membrane fluorescence anisotropy (r) increased with postnatal age in jejunum when measured at 25 degrees C and 37 degrees C and ileum when measured at 25 degrees C; however, no change was noted in ileum when measured at 37 degrees C. Ileal active bile salt transport develops during the third postnatal week, and is associated with concurrent changes in membrane lipid composition and fluidity when measured at 25 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of glucocorticoids in the postnatal development of ileal active bile salt transport.

The role of glucocorticoids in the regulation of the postnatal development of ileal active bile salt transport was examined in the rat using the villus technique. Ileal taurocholate uptake was initially by passive transport alone on day 14 and 16 which changed to an active and passive transport mechanism at 18 days which persisted thereafter. The Michaelis-Menten constant (Km, mM) was unchanged between days 18 (0.67 +/- 0.12 mM), 20 (0.84 +/- 0.25 mM), 21 (0.49 +/- 0.05 mM), 28 (0.59 +/- 0.06 mM), and 49 (0.50 +/- 0.05 mM) whereas the apparent maximal velocity nmol/mg(dry wt)/min declined after a peak at 18 days (18.17 +/- 1.92 on day 18, 16.14 +/- 1.89 on day 20, 14.65 +/- 0.52 on day 21, 11.40 +/- 0.35 on day 28, and 10.51 +/- 0.32 on day 49). Adrenalectomy performed in sucklings on day 14 with taurocholate transport studies on day 21 and in adults on day 42 studied on day 49 resulted in reductions in uptake at most study concentrations but no change in the Km (1.33 +/- 0.54 in sucklings and 0.75 +/- 0.14 mM in adults) or apparent maximal velocity [11.78 +/- 2.06 in sucklings and 9.24 +/- 0.65 nmol/mg (dry wt)/min in adults]. Treatment of sucklings with corticosterone (5 mg/100 g body weight) on days 10-13 with study on day 14 and 16 did not produce precocious development of ileal active taurocholate transport; however, corticosterone treatment led to apparent increases in ileal permeability to taurocholate in both sucklings and adults. Glucocorticoids appear to play a minor, if any, role in the physiologic postnatal development of ileal active bile salt transport.