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Biomedical subjects

C N Ou

Publications and source records attributed to C N Ou.

At least 37 records · Page 2Linked to original sources
PubMed1999

Simulated airplane flight increases plasma lactate in fetal rabbits.

We studied the effect of 9 h of simulated airplane cabin conditions at cruising altitude (8,000 feet; inspired oxygen equivalent to 15% O2 at sea level) on fetal plasma lactate in near-term pregnant rabbits. Controls (n = 19) spent 9 h at sea level (21% O2). Study group I (n = 21) experienced airplane cabin conditions. Study group II (n = 17) was studied at 8,000 feet with the inspired O2 concentration normalized to sea level. Study group III (n = 19) remained at sea level breathing 15% O2. Before ending each exposure, fetal blood sampling for lactate was performed under ultrasound guidance. Maternal lactates were obtained before and after sampling fetuses. Wilcoxon signed rank test, analysis of variance, and Bonferroni's method were used as appropriate. P < 0.05 denoted statistical significance. Study group I (altitude/hypoxia) had higher fetal lactates than controls (sea level/normoxia) and study group II (altitude/normoxia). Fetal lactates in study group I (altitude/hypoxia) were higher than in study group III (sea level/hypoxia). Maternal lactates were lower after fetal sampling. Fetal lactic acidemia was observed after 9 h of airplane cabin conditions. This was attributed to the combined effect of the lowered oxygen concentration and the decrease in atmospheric pressure.

Acidosis, Lactic↗
PubMed1998

Retrovirus-mediated in vivo gene transfer in the replicating liver using recombinant hepatocyte growth factor without liver injury or partial hepatectomy.

Retrovirus-mediated gene delivery into hepatocytes in vivo provides long-term gene expression, which is of great importance for treating most genetic and metabolic disorders. However, clinical application has not been realized because of the requirement for prior 70% partial hepatectomy or chemical (toxic) liver injury to initiate hepatocyte replication at the time of retroviral gene transduction. In this paper, we describe a novel gene delivery system that uses recombinant hepatocyte growth factor (rHGF) prior to retrovirus-mediated in vivo gene transfer in the liver without partial hepatectomy or liver injury. A single retroviral infusion through the portal vein following five systemic injections (via the tail vein) of 100 microg/kg rHGF resulted in a 10.4% 5-bromo-2'-deoxyuridine (BrdU) labeling index (BLI) and 0.14% retroviral gene transduction efficiency (RGTE) in hepatocytes, which were 6.3- and 12.9-fold higher than those of controls, respectively. Modest additional increases in BLI and RGTE (13.4% and 0.22%, respectively) were seen after five systemic injections of 500 microg/kg rHGF. The correlation between BLI and RGTE was statistically confirmed regardless of treatment. When rats received multiple retroviral infusions through a cannulated portal vein following five portal injections of 100 microg/kg rHGF, RGTE was dramatically increased (1.3%) and in some areas of the liver exceeded more than 10%. There was no evidence of liver injury in any animal. This approach has great potential for clinical application in terms of avoiding invasive procedures or liver injury.

Animals↗
PubMed1998

Ex vivo hepatic gene therapy of a mouse model of Hereditary Tyrosinemia Type I.

Previously, this lab has reported the use of hepatocyte transplantation and in vivo gene therapy for the correction of a mouse model of Hereditary Tyrosinemia Type I (HT1). Here, we demonstrate repopulation of fumarylacetoacetate hydrolase (FAH)-deficient livers with cultured hepatocytes. Correction of the disease phenotype was achieved by retrovirally transducing cultured FAH- hepatocytes ex vivo, followed by transplantation and selective repopulation. Treated mice were phenotypically normal and had corrected plasma amino acid levels and liver function tests. Our results demonstrate that efficient hepatic repopulation using ex vivo genetically manipulated hepatocytes is feasible.

Amino Acid Metabolism, Inborn Errors↗
PubMed1998

Early feeding, feeding tolerance, and lactase activity in preterm infants.

OBJECTIVE: We sought to ascertain whether the timing of feeding initiation affected the development of intestinal lactase activity and whether there are clinical ramifications of lower lactase activity. STUDY DESIGN: Preterm infants (26 to 30 weeks' gestation; n = 135) were randomly assigned to begin enteral feedings at either 4 (early group) or 15 days of age (standard group). At 10, 28, and 50 days of age lactase activity was determined by measuring the urinary ratio of lactulose/lactose after the 2 sugars were administered. RESULTS: Lactase activity increased significantly over time. Infants in the early group had greater lactase activity at 10 days of age (by 100%) and 28 days of age (by 60%) than the standard group. At 10 days of age lactase activity was greater in milk- versus formula-fed infants. The time required to achieve full enteral feedings, the number of abnormal abdominal x-ray examinations, and the total number of abdominal x-ray examinations were inversely related to lactase activity. CONCLUSIONS: Early feeding increases intestinal lactase activity in preterm infants. Lactase activity is a marker of intestinal maturity and may influence clinical outcomes. Whether the effects of milk on lactase activity were due to the greater concentration of lactose in human milk compared with that in formula must be determined.

Age Factors↗
PubMed1998

Assessment of intestinal permeability with a two-hour urine collection.

The differential urinary excretion of orally administered lactulose and mannitol is used to evaluate intestinal permeability. This test usually involves a 5- to 6-hr urine collection. We hypothesized that a shorter collection time would give an equivalent result. Forty-three patients with a variety of gastrointestinal symptoms and diagnoses (group 1) and 42 patients with Crohn's disease (group 2) had a standard lactulose/mannitol permeability test. The lactulose and mannitol urinary excretion was calculated using the first urine (group 1) or the 1-hr and 2-hr urine (group 2) and was compared to the values calculated from the routine 5- or 6-hr collection. Lactulose excretion kinetics, expressed as the percent of the total urinary excretion within a given time period, were as follows: 21% in first hour (group 2), 29% in second hour (group 2), and 46% in first 2.5 hr (group 1). Mannitol urinary excretion kinetics were 16%, 31%, and 44%, respectively. The lactulose/mannitol ratio based on a standard urine collection correlated well with the ratio based on just the first urine produced by the patient (R2 = 0.94; P < 0.001; group 1) and the 2-hr urine (R2 = 0.464; P < 0.001; group 2). Future use of the lactulose/mannitol ratio to assess intestinal permeability may be able to be simplified by shortening the urine collection time.

Administration, Oral↗
PubMed1998

The effect of a marathon run on plasma and urine mineral and metal concentrations.

BACKGROUND: Little data exist on the requirements of trace metals and minerals for endurance athletes. Changes in body status of these elements must be examined before specific nutritional recommendations can be made. This study was designed to determine whether a marathon run was associated with changes in serum and urine metal and mineral concentrations. METHODS: Forty subjects who planned to complete the 1996 Houston-Tennaco marathon were recruited. Subjects had blood and urine samples collected 2 weeks prior to the race and immediately following the race. Blood and urine specimens were analyzed for copper, iron, magnesium and zinc concentrations. Blood was also analyzed for calcium concentration and ceruloplasmin activity. RESULTS: Twenty-six subjects (24 male, 2 female) completed the marathon. Finish times varied between 2 hours 43 minutes and 5 hours 28 minutes. There was no significant change in serum calcium, copper or zinc concentrations or ceruloplasmin activity. Serum and urine magnesium concentration decreased significantly (19.55+/-1.73 to 16.55+/-1.53 ppm, p=0.00001; 34.02+/-8.64 to 21.80+/-12.24 ppm, p=0.003, respectively). Serum iron concentration increased significantly (1.06+/-0.48 to 1.35+/-0.42 ppm, p=0.006), while urine copper and iron concentrations were below the limits of detection, zinc concentration did not change. CONCLUSIONS: Serum and urinary magnesium concentrations decrease during endurance running, consistent with the possibility of magnesium deficiency. This may be related to increased demand in skeletal muscle. Serum iron concentration increases, possibly related to tissue injury. The exact etiology for these observations, as well as their clinical significance, requires further investigation.

Calcium↗
PubMed1998

Early feeding, antenatal glucocorticoids, and human milk decrease intestinal permeability in preterm infants.

To determine the effects of age, feeding regimen, and antenatal glucocorticoids on intestinal permeability, preterm infants (n = 132) were stratified by gestational age and by diet (mothers' own milk versus preterm formula), and assigned randomly to one of four feeding regimens: early-continuous, early-bolus, standard-continuous, and standard-bolus. At 10, 28, and 50 d of age permeability was determined by measuring the ratio of lactulose/ mannitol in the urine after the two sugars were administered enterally for 30 h. The mean (+/-SE) birth weight and gestational age of the infants were 1044 +/- 13 g and 27 +/- 0.1 wk, respectively. Permeability changed as a function of age (p = 0.003). Early feeding was associated with a reduction in permeability at 10 d of age (p = 0.01). Antenatal steroid administration was associated with decreased permeability at 28 d of age (p = 0.017). The feeding of human milk (versus formula) was associated with decreased permeability at 28 d of age (p = 0.02). Continuous versus bolus feeding did not affect permeability.

Aging↗
PubMed1997

Metabolism of leukotriene C4 in gamma-glutamyl transpeptidase-deficient mice.

We have investigated the metabolism of leukotriene C4 (LTC4) in gamma-glutamyl transpeptidase (GGT)-deficient mice (Lieberman, M. W., Wiseman, A. L., Shi, Z-Z., Carter, B. Z., Barrios, R., Ou, C-N., Chevez-Barrios, P., Wang, Y., Habib, G. M., Goodman, J. C., Huang, S. L., Lebovitz, R. M., and Matzuk, M. M. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 7923-7926) and have found substantial conversion of LTC4 to leukotriene D4 by high performance liquid chromatography and continuous flow fast atom bombardment-tandem mass spectrometric analyses. LTC4-converting activity has a tissue distribution different from GGT with highest activity in spleen followed by small intestine, kidney, and pancreas and lower activity in liver and lung. The activity is membrane-bound and is inhibited by acivicin, a known inhibitor of GGT. The enzyme was partially purified from the small intestine of GGT-deficient mice by papain treatment and gel filtration chromatography. The partially purified fragment released by papain has an apparent molecular mass of 65-70 kDa and the same substrate specificity as the tissue homogenate. In addition to LTC4, S-decyl-GSH is also cleaved. GSH itself, oxidized GSH, and the synthetic substrates used to analyze GGT activity (gamma-glutamyl-p-nitroanilide and gamma-glutamyl-4-methoxy-2-naphthylamide) are not substrates for this newly discovered enzyme. These data demonstrate that in addition to GGT at least one other enzyme cleaves LTC4 in mice. To reflect this enzyme's preferred substrate, we suggest that it be named gamma-glutamyl leukotrienase.

Animals↗
PubMed1997

Adenovirus-mediated gene therapy in a mouse model of hereditary tyrosinemia type I.

Mice lacking the enzyme fumarylacetoacetate hydrolase (FAH) have symptoms similar to humans with the disease hereditary tyrosinemia type I (HT1). FAH-deficient mice were injected with a first-generation adenoviral vector expressing the human FAH gene and followed for up to 9 months. Nontreated FAH mutant control mice died within 6 weeks from fulminant liver failure, whereas FAH adenovirus-infected animals survived until sacrifice at 2-9 months. Nine of 13 virus-treated animals developed hepatocellular cancer. Immunohistochemical analysis revealed a mosaic of FAH-deficient and FAH-positive cells in all animals and liver function tests were improved compared to controls. Even mice harvested 9 months after viral infection had > 50% FAH-positive cells. These results demonstrate the strong selective advantage of FAH-expressing cells in an FAH-deficient liver but also illustrate the danger of carcinomas arising from FAH-deficient hepatocytes in HT1.

Adenoviridae↗
PubMed1997

X-linked glycerol kinase deficiency in the mouse leads to growth retardation, altered fat metabolism, autonomous glucocorticoid secretion and neonatal death.

Glycerol kinase is an X chromosome-encoded enzyme involved in the metabolism of endogenous and dietary glycerolipids. The physiological significance of its activity in mammals is not well understood. Glycerol kinase deficiency in humans occurs as an isolated enzyme deficiency or as part of a contiguous gene deletion syndrome in variable association with Duchenne muscular dystrophy and adrenal hypoplasia congenita. Isolated glycerol kinase deficiency has an inconstant phenotype, ranging from asymptomatic hyperglycerolemia to a severe metabolic disorder with growth and psychomotor retardation. Although intragenic mutations were reported recently, the pathophysiological basis for the phenotypic variability remains unknown. To understand better the physiological significance of glycerol kinase and the pathophysiology of its deficiency, we generated glycerol kinase-deficient mice by gene targeting. Mutant male mice appear normal at birth, but exhibit postnatal growth retardation, altered fat metabolism with profound hyperglycerolemia and elevated free fatty acids, autonomous glucocorticoid synthesis and death by 3-4 days of age. Heterozygous females are healthy and biochemically normal. The biochemical features observed in glycerol kinase-deficient mice provide the basis for further investigations into the pathogenesis of the human disorder.

Animals↗
PubMed1997

Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes.

Previous work has shown that adult mouse hepatocytes can divide at least 18 times in vivo. To test whether this represents the upper limit of their regenerative capacity, we performed serial transplantation of hepatocytes in the fumarylacetoacetate hydrolase deficiency murine model of liver repopulation. Hepatocytes from adult donors were serially transplanted in limiting numbers six times and resulted in complete repopulation during each cycle. This corresponds to a minimal number of 69 cell doublings or a 7.3 x 10(20)-fold expansion. No evidence for abnormal liver function or altered hepatic architecture was found in repopulated animals. We conclude that a fraction of adult mouse hepatocytes have growth potential similar to that of hematopoietic stem cells.

Animals↗
PubMed1996

Pharmacokinetics of kanamycin in the developing rat.

The developing rat is hypersensitive to aminoglycoside ototoxicity during the period of anatomical and functional development of the cochlea. Toxicity is expressed only after a few days of treatment when kanamycin is given during the most sensitive period for production of ototoxicity (postnatal days 11-20). In contrast, when the drug is administered after the 20th postnatal day, the same dose and duration of treatment do not produce an ototoxic effect. Only after prolonged treatment (e.g., > or = 20 days) is there an observed effect. We characterized the pharmacokinetics of kanamycin in the serum of 12- and 25-day-old rats and observed a greater than 2.5-fold increase in elimination half-life in the 12- versus 25-day-old rat. The longer duration half-life of kanamycin in younger rats may explain the hypersensitivity of immature mammals to aminoglycoside ototoxicity.

Analysis of Variance↗
PubMed1996

Growth retardation and cysteine deficiency in gamma-glutamyl transpeptidase-deficient mice.

gamma-Glutamyl transpeptidase (GGT) is an ectoenzyme that catalyzes the first step in the cleavage of glutathione (GSH) and plays an essential role in the metabolism of GSH and GSH conjugates of carcinogens, toxins, and eicosanoids. To learn more about the role of GGT in metabolism in vivo, we used embryonic stem cell technology to generate GGT-deficient (GGTm1/GGTm1) mice. GGT-deficient mice appear normal at birth but grow slowly and by 6 weeks are about half the weight of wild-type mice. They are sexually immature, develop cataracts, and have coats with a gray cast. Most die between 10 and 18 weeks. Plasma and urine GSH levels in the GGTm1/GGTm1 mice are elevated 6-fold and 2500-fold, respectively, compared with wild-type mice. Tissue GSH levels are markedly reduced in eye, liver, and pancreas. Plasma cyst(e)ine levels in GGTm1/GGTm1 mice are reduced to approximately 20% of wild-type mice. Oral administration of N-acetylcysteine to GGTm1/GGTm1 mice results in normal growth rates and partially restores the normal agouti coat color. These findings demonstrate the importance of GGT and the gamma-glutamyl cycle in cysteine and GSH homeostasis.

Animals↗
PubMed1996

Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I.

Current strategies for hepatic gene therapy are either quantitatively inefficient or suffer from lack of permanent gene expression. We have utilized an animal model of hereditary tyrosinaemia type I (HT1), a recessive liver disease caused by deficiency of fumarylacetoacetate hydrolase (FAH), to determine whether in vivo selection of corrected hepatocytes could improve the efficiency of liver gene transfer. As few as 1,000 transplanted wild-type hepatocytes were able to repopulate mutant liver, demonstrating their strong competitive growth advantage. Mutant hepatocytes corrected in situ by retroviral gene transfer were also positively selected. In mutant animals treated by multiple retrovirus injections >90% of hepatocytes became FAH positive and liver function was restored to normal. Our results demonstrate that in vivo selection is a useful strategy for hepatic gene therapy and may lead to effective treatment of human HT1 by retroviral gene transfer.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

Effects of aspirin and Helicobacter pylori on the gastroduodenal mucosal permeability to sucrose.

BACKGROUND: A non-invasive marker is needed to identify patients with significant gastrointestinal injury due to non-steroidal anti-inflammatory drugs. Gastrointestinal permeability to sucrose has been suggested as such a test. AIMS: To assess the utility of sucrose permeability as a marker of gastroduodenal mucosal injury after single and multiple doses of aspirin, to identify the site of increased sucrose permeability, to explore the relation between sucrose permeability and endoscopic findings, and to evaluate whether Helicobacter pylori infection influenced gastroduodenal sucrose permeability. METHODS: After a fasting urine was obtained, 500 ml of a solution containing 100 g of sucrose was ingested. Urine was collected for five hours and assayed for sucrose by high performance liquid chromatography. Sucrose permeability was also assessed 20 minutes after ingestion of 650 mg of aspirin and eight to 12 hours after a 72 hour course of 650 mg aspirin four times a day. The site of increased permeability was identified after pyloric occlusion with a double balloon tube. RESULTS: Thirty seven healthy volunteers participated. Sucrose permeability (mean (SEM)) increased after both single (195.2 (27) mg and multiple (196.4 (31) mg) doses of aspirin compared with baseline (53.7 (10) mg; p < 0.0005). Balloon pyloric occlusion confirmed that the site of increased sucrose permeability was the stomach. The effect of aspirin on sucrose permeability was similar in those with and without H pylori infection. CONCLUSION: These results confirm the use of sucrose permeability as a marker of aspirin induced gastroduodenal mucosal injury and identify the stomach as the major site of increased permeability. H pylori infection does not seem to change gastric mucosal sucrose permeability either at baseline or after ingestion of aspirin.

Adult↗
PubMed1995

Impaired energy homeostasis in C/EBP alpha knockout mice.

Mice homozygous for the targeted deletion of the c/ebp alpha gene, which expresses the CCAAT/enhancer-binding protein alpha (C/EBP alpha), did not store hepatic glycogen and died from hypoglycemia within 8 hours after birth. In these mutant mice, the amounts of glycogen synthase messenger RNA were 50 to 70 percent of normal and the transcriptional induction of the genes for two gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, was delayed. The hepatocytes and adipocytes of the mutant mice failed to accumulate lipid and the expression of the gene for uncoupling protein, the defining marker of brown adipose tissue, was reduced. This study demonstrates that C/EBP alpha is critical for the establishment and maintenance of energy homeostasis in neonates.

Adipose Tissue↗
PubMed1995

Placental transfer of sulindac and its active sulfide metabolite in humans.

OBJECTIVE: Our aim was to investigate whether the human placenta is permeable to sulindac or its active sulfide metabolite. STUDY DESIGN: Nine pregnant patients (median gestational age [range]: 31.8 [24.3 to 36.4] weeks) were given a 200 mg oral dose of sulindac 5.5 (4.4 to 6.7) hours before 18 intravascular transfusions for rhesus or Kell alloimmunization. At each procedure maternal and fetal serum levels of sulindac and the active sulfide metabolite were measured by high-performance liquid chromatography. RESULTS: The maternal sulfide level was significantly higher than the fetal sulfide levels, but no significant difference was noted between maternal and fetal sulindac levels. The sulfide fetal/maternal ratio was significantly lower than the sulindac fetal/maternal ratio. The sulfide/sulindac ratio was significantly higher in maternal serum versus fetal serum. The sulfide/sulindac ratio correlated with time from drug ingestion to sampling on the maternal side only. In patients studied on more than one occasion no consistent relationship between fetal sulindac, fetal sulfide, or fetal sulfide/sulindac ratio, and gestational age could be demonstrated. CONCLUSION: The placenta is permeable to sulindac but less so to its active sulfide metabolite. The reduction of sulindac to its active sulfide metabolite is decreased in the human fetus.

Female↗