Prabhu S. Parimi

Methionine metabolism in human pregnancy

BACKGROUND Hyperhomocysteinemia during pregnancy, which is a consequence of perturbations in methionine and/or folate metabolism, has been implicated in adverse outcomes such as neural tube defects, preeclampsia, spontaneous abortion, and premature delivery. The adaptive changes in methionine metabolism during pregnancy in humans have not been determined. OBJECTIVE Our objective was to examine the kinetics of methionine and its rate of transsulfuration and transmethylation in healthy women with advancing gestation. DESIGN The whole-body rate of appearance (Ra) of methionine and phenylalanine was measured in healthy pregnant women during the first (n = 10), second (n = 5), and third (n = 10) trimesters of pregnancy. These data were compared with those for nonpregnant women (n = 8). Tracers [1-(13)C]methionine, [C(2)H(3)]methionine, and [(2)H(5)]phenylalanine were administered as prime-constant rate infusions. The effect of enteral high-protein, mixed-nutrient load on tracer-determined variables was also examined. RESULTS In pregnant women, the Ra of phenylalanine was significantly (P < 0.05) lower in the first trimester than in the second and third trimesters and was significantly lower than that in nonpregnant women. A linear positive correlation was evident between gestational age and phenylalanine Ra. The fractional rate and total rate of transsulfuration of methionine was significantly (P < 0.05) higher during the first trimester, whereas the rate of transmethylation was higher during the third trimester. Plasma concentrations of total cysteine and homocysteine were lower during pregnancy. CONCLUSIONS Uncomplicated pregnancy in humans is associated with a higher rate of transsulfuration early in gestation and a higher rate of transmethylation of methionine in late gestation. These data may have implications for understanding the role of methionine and homocysteine in complications of pregnancy and for the nutritional care of pregnant women.

Dexamethasone Therapy and Candida Sepsis in Neonates Less Than 1250 Grams

OBJECTIVE: To determine whether dexamethasone use increases the risk for Candida sepsis (CS) in very low birth weight premature infants (<1250 g).DESIGN: Retrospective chart review of all infants with a birth weight <1250 g, admitted to the neonatal intensive care unit of the MetroHealth Medical Center, Cleveland, Ohio between January 1, 1996 and December 31, 1999. Infant groups with (n=65) and without (n=229) CS were compared.RESULTS: Two hundred and ninety four infants with a birth weight <1250 g were identified. CS was diagnosed at a median age of 18 days, and 6 of 65 (10%) infants died directly from Candida-related complications. Candida albicans (n=30, 60%) and Candida parapsilosis (n=14, 25%) were the predominant isolates. Use of dexamethasone in infants at risk for chronic lung disease before 14 days of age (p=0.001), duration of antibiotics (p=0.001), and total duration of parenteral nutrition and intralipid (p=0.0001) were all significantly greater in infants who developed CS. Regression analysis showed that duration of antibiotics before the diagnosis of Candida infection (r2=0.69, p=0.0002) and duration of dexamethasone (r2=0.93, p=0.0002) correlated with Candida infection. Early dexamethasone use was also related to the age at diagnosis of Candida infection (r2=0.51, p=0.01).CONCLUSIONS: Dexamethasone therapy and prolonged duration of antibiotics are associated with Candida infection in premature infants.

Parenteral Amino Acid and Metabolic Acidosis in Premature Infants

BACKGROUND Aggressive parenteral nutrition (PN) including amino acids is recommended for low-birth-weight infants to prevent energy and protein deficit. Their impact on acid-base homeostasis has not been examined. METHODS We investigated the impact of dose and duration of parenteral amino acids, with cysteine, on acid-base parameters in 122 low-birth-weight infants. Premature infants <or=32 weeks, <or=1850 g, and receiving parenteral amino acids at 1.5 g/kg/d for an extended period (>24 hours), or 3 g/kg/d for a short (5 hour), extended (24 hour), or prolonged (3-5 days) duration were included in the study. Data were obtained at age 0-3 days (n = 43) or, when clinically stable, age 3-5 days (n = 49). Data from 30 infants, matched for birth weight and gestational age, receiving PN during the first 5 days after birth were also obtained. Acidosis was defined as pH <7.25. RESULTS Acidosis was evident in all infants between 2 and 5 days after birth. Infants with large patent ductus arteriosus (PDA) exhibited significantly (p < .05) lower pH early, had higher blood urea nitrogen levels (26 +/- 9 vs 18 + 8 mg/dL; p < .05), and had greater weight loss ( approximately 17% of birth weight) when compared with infants without PDA. Gestational age, weight loss, and patent ductus arteriosus accounted for 65% of variance in acidosis. CONCLUSIONS Low-birth-weight infants develop metabolic acidosis between 2 and 5 days after birth, irrespective of dose and duration of parenteral amino acid administration. Careful management of parenteral fluids and comorbidities may lower the incidence of acidosis and promote protein accretion.

Metabolic Responses to Protein Restriction During Pregnancy in Rat and Translation Initiation Factors in the Mother and Fetus

A low-protein diet during pregnancy in the rat results in intrauterine growth restricted (IUGR) fetuses. The adaptive responses of the mother to low-protein diet and the mechanisms of IUGR in this model are not understood. In the present study, we report the maternal metabolic responses to protein restriction and their impact on growth, carcass composition, and translation initiation in the fetus. Pregnant Sprague-Dawley rats were pair-fed either a 6% protein (LP, n = 7) or a 24% protein (NP, n = 7) diet from conception until delivery. Plasma amino acids and urea levels and rate of oxygen consumption were measured sequentially through pregnancy. Translation initiation factors eIF2α, Ser51 phosphorylated eIF2α, eIF4E, phosphorylated eIF4E, and 4E-BP1 were quantified in the maternal and fetal muscle and liver. Protein restriction resulted in higher rate of oxygen consumption (p < 0.01), lower plasma branched chain amino acid (p < 0.05) in the mother, and lower plasma histidine levels (p < 0.05) in the fetus. Plasma urea nitrogen was lower in the LP group throughout gestation. The phosphorylated 4E-BP1 (γ form) in the maternal liver was 4-fold higher in the LP group. The phosphorylated eIF2α was higher in the livers of IUGR fetuses. We speculate that the lower plasma branched chain amino acids in the mother during early pregnancy may be due to a lower rate of protein turnover in the LP group. The mechanism of increased energy consumption due to protein restriction remains unclear. The data on translation initiation factors suggest a higher rate of protein synthesis in the maternal liver and a lower rate in the fetal liver in response to protein restriction.

Effect of Reduced Maternal Inspired Oxygen on Hepatic Glucose Metabolism in the Rat Fetus

Perturbations in glucose metabolism in the fetus and in the neonate are a consistent finding in several different animal models of intrauterine growth retardation (IUGR) as well as in humans. Studies in rats who have undergone IUGR have shown decreased hepatic glycogen stores in the fetus and delayed induction of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) at birth. Hepatic transcription factors CCAAT enhancer binding protein (C/EBP)α and C/EBPβ and the increase in cyclic AMP at birth have been implicated in the initial appearance of PEPCK-C. We have examined the effect of IUGR induced by reduced maternal inspired oxygen (fractional inspired oxygen concentration 0.14) on a) the expression of genes for hepatic C/EBPα, C/EBPβ, PEPCK-C and glycogen synthase; and b) transcription of the genes for C/EBPβ and PEPCK-C by dibutyryl cyclic AMP in the fetus. Three days (d 18-21) of decrease in maternal inspired oxygen resulted in lower maternal arterial PO2 and a lower birth weight of the pups (p < 0.01). Fetuses that underwent IUGR had significantly lower concentrations of plasma glucose, hepatic glycogen, and glycogen synthase mRNA and a higher hepatic lactate:pyruvate ratio. They also had lower levels of hepatic PEPCK-C mRNA at birth. The concentration of hepatic mRNA for C/EBPα and C/EBPβ as well as the transcription factors themselves were not affected by the decreased maternal inspired oxygen. Fetal injection of dibutyryl cyclic AMP after 24 h of decreased maternal inspired oxygen (d 18-19) had no effect on the expression of C/EBPβ. However, it resulted in an attenuated induction of PEPCK-C in the fetuses with IUGR. We speculate that a decrease in maternal inspired oxygen induced certain mediators, either in the mother or in the placenta, that caused lower fetal glucose concentration and affected the transcription of genes involved in fetal hepatic glucose metabolism. IUGR, as a result of decreased fractional inspired oxygen concentration may also be the consequence of pH-mediated changes in uterine blood flow. However, these remain to be examined in this experimental model.

Increased parenteral amino acid infusion has only a transient effect on whole body rate of proteolysis and de novo glutamine synthesis in lbw infants: 190

Early administration of parenteral nutrition to LBW infants has been advocated in order to (a) meet the nutrient needs and (b) achieve intrauterine growth velocity. We have examined the impact of high parenteral amino acids on whole body protein/nitrogen turnover in low birth weight infants (<1500g, <32 weeks gestation) at <48 h and at 3–5 d after birth.