Effect of intravenous amino acids on glutamine and protein kinetics in low-birth-weight preterm infants during the immediate neonatal period

Glutamine may be a conditionally essential amino acid in low-birth-weight (LBW) preterm neonates. Exogenously administered amino acids, by providing anaplerotic carbon into the tricarboxylic acid cycle, could result in greater cataplerotic efflux and glutamine de novo synthesis. The effect of dose and duration of amino acid infusion on glutamine and nitrogen (N) kinetics was examined in LBW infants in the period immediately after birth. Preterm neonates (<32 weeks gestation, birth weights 809-1,755 g) were randomized to initially receive either 480 or 960 micromol x kg(-1) x h(-1) of an intravenous amino acid solution for 19-24 hours, followed by a higher or lower amino acid load for either 5 h or 24 h. Glutamine de novo synthesis, leucine N, phenylalanine, and urea kinetics were determined using stable isotopic tracers. An increase in amino acid infusion from 480 to 960 micromol x kg(-1) x h(-1) for 5 h resulted in decreased glutamine de novo synthesis in every neonate (384.4 +/- 38.0 to 368.9 +/- 38.2 micromol x kg(-1) x h(-1), P < 0.01) and a lower whole body rate of proteolysis (P < 0.001) and urea synthesis (P < 0.001). However, when the increased amino acid infusion was extended for 24 h, glutamine de novo synthesis increased (369.7 +/- 92.6 to 483.4 +/- 97.5 micromol x kg(-1) x h(-1), P < 0.001), whole body rate of proteolysis did not change, and urea production increased. Decreasing the amino acid load resulted in a decrease in glutamine rate of appearance (R(a)) and leucine N R(a), but had no effect on phenylalanine R(a). Acutely stressed LBW infants responded to an increase in amino acid load by transiently suppressing whole body rate of glutamine synthesis, proteolysis, and oxidation of protein. The mechanisms of this transient effect on whole body protein/nitrogen metabolism remain unknown.     

Identification of bile acids in the serum and urine in cholestasis. Evidence for 6alpha-hydroxylation of bile acids in man.

In this qualitative study of the pattern of bile acid excretion in cholestasis, methods are described for the isolation of bile acids from large volumes of urine and plasma. The bile acids were subjected to a group separation and identified by combined gas chromatography-mass spectrometry. The techniques were developed to allow identification of the minor components of the bile acid mixture. Four bile acids that have not previously been described in human urine and plasma were detected, namely 3beta, 7alpha-dihydroxy-5beta-cholan-24-oic acid, 3alpha, 6alpha-dihydroxy-5beta-cholan-24-oic acid (hyodeoxycholic acid), 3alpha, 6alpha, 7alpha-trihydroxy-5beta-cholan-24-oic acid (hyocholic acid) and 3alpha, 7beta, 12alpha-trihydroxy-5beta-cholan-24-oic acid. In addition three C27 steroids were found; 26-hydroxycholesterol and a trihydroxy cholestane, probably 5 beta-cholestane-3alpha, 7alpha, 26-triol were found in the sulphate fraction of plasma and urine. In the plasma sample, a sulphate conjugate of 24-hydroxycholesterol was found. The presence of these compounds probably reflects the existence of further pathways for bile acid metabolism. It is not yet known whether this is a consequence of the cholestasis or whether they are also present in normal man, at much lower concentrations.     

A further study of the bile acids in infants with coprostanic acidemia

The structure of the bile acids in serum of infants with coprostanic acidemia was further investigated. The identity of 3α-hydroxy-5β-cholestan-26-oic acid and 3β-hydroxy-5-cholesten-26-oic acid was confirmed. The biosynthesis of the 3α,7α,12α-trihydroxy-5β-C₂₉ dicarboxylic bile acid does not start from β-sitosterol.     

A diagnostic survey of infants referred for chromosome analysis in the neonatal period.

Examination and assessment of 140 liveborn and stillborn infants referred within two weeks of birth for chromosome analysis showed that 48 had Down''s syndrome, 12 other chromosome abnormalities, 17 single gene disorders, 18 recognisable anomalads, 8 recognisable syndromes of unknown aetiology, and the remainder were undiagnosed. Of the non-Down''s cases that were diagnosed, 21% had a chromosomal abnormality. These results suggest that a request for chromosome analysis in the newborn period should be viewed as one step in syndrome identification.     

The estrogenic effects of clomiphene during the neonatal period in the rat

The ability of clomiphene and its isomers to cause estrogenic responses during the neonatal period in the rat was examined. Rats were injected s.c. with clomiphene (CL), zuclomiphene (ZUC) or enclomiphene (ENC) on days 1,3, and 5 of life and the stimulation of the reproductive tract and estrogen receptor binding was observed. Uterine weight and DNA content were increased significantly by day 7 in animals treated with clomiphene or zuclomiphene. Uterine epithelial hypertrophy was present in all groups by day 10 and hyperplasia was present in the animals treated with ZUC and CL. The time of vaginal opening was greatly accelerated in all drug treated groups with the earliest day of opening occurring on day 7. Ovarian hemorrhage and blood in the periovarian sac occurred between days 12-14 and continued to be present through day 25. Drug treatment caused the estrogen receptor to accumulate in the nuclear fraction of the uterus and to be depleted from the cytosol fraction. We conclude that clomiphene administered to neonatal rats causes estrogenic stimulation of the reproductive tract in a fashion similar to other estrogens. This stimulation may account for the reproductive tract abnormalities which develop in rats treated with those drugs during the neonatal period.     

Chemical synthesis of 24-beta-D-galactopyranosides of bile acids: a new type of bile acid conjugates in human urine

A method is reported for the preparation of the C-24 carboxyl-linked beta-D-galactopyranosides of lithocholic, deoxycholic, chenodeoxycholic, ursodeoxycholic, and cholic acids, two of which were recently identified as a novel type of the metabolites of bile acids excreted in human urine. Direct esterification (galactosidation) of the unprotected bile acids with 2,3,4,6-tetra-O-benzyl-D-galactopyranose in the presence of 2-chloro-1,3,5-trinitrobenzene as a coupling agent and subsequent hydrogenolysis of the resulting benzyloxy-protected bile acid 24-beta-D-galactopyranosides over 10% palladium on charcoal under atmospheric pressure afforded the title compounds. The structures of the bile acid acyl galactosides were confirmed by measuring several (1)H-(1)H and (1)H-(13)C shift correlated 2D NMR.     

Identification of short side chain bile acids in urine of patients with cerebrotendinous xanthomatosis

Urine from patients with cerebrotendinous xanthomatosis (CTX) was found to contain a number of minor bile acids along with three major bile acids, 7-epicholic acid, norcholic acid, and cholic acid. The following minor bile acids were identified by combined gas-liquid chromatography-mass spectrometry: 7-ketobisnordeoxycholic acid; 12-ketobisnorchenodeoxycholic acid; 7-ketonordeoxycholic acid; 12-ketochenodeoxycholic acid; 7-ketodeoxycholic acid; 12-ketochendeoxycholic acid; bisnorcholic acid; allonorcholic acid; allocholic acid; 1 beta-hydroxybisnorcholic acid; 1 beta-hydroxynorcholic acid; 1 beta-hydroxycholic acid; 2 beta-hydroxybisnorcholic acid; 2 beta-hydroxy-norcholic acid; 2 beta-hydroxycholic acid. The presence of C22 and C23 bile acids in urine of the CTX patients suggests that bile alcohols having a hydroxyl group at C22 or C23 in the side chain may be further degraded to these bile acids.     

Chromosome constitution of 500 infants dying during the perinatal period

Summary 500 chromosome results were obtained from 726 necropsied hospital perinatal deaths in London. There were 28 chromosome abnormalities (5.6% of the results). 9% of ante-partum deaths, 4% of intra-partum deaths and 6% of early neonatal deaths were chromosomally abnormal. 13% of lethally malformed infants had a chromosomal anomaly. Trisomy 18 was the most common abnormality and appears to be considerably more frequent at birth than is generally thought. Genetic disorders were found in a further 1% of perinatal deaths. The importance of the perinatal necropsy as a screening procedure for genetic disease is stressed.

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Zusammenfassung 500 Chromosomenbefunde wurden bei 726 sezierten perinatalen Todesfällen in London erhoben. Es fanden sich 28 Chromosomenanomalien (5,6%). 9% der vor der Geburt Verstorbenen, 4% der Verstorbenen unter der Geburt sowie 6% der Todesfälle lurz danach zeigten eine Chromosomenanomalie. 13% der letal mißgebildeten Kinder wiesen einen Chromosomenbefund auf. Trisomie 18 was am häufigsten; sie scheint zum Zeitpunkt der Geburt wesentlich häufiger zu sein, als bisher angenommen. Bei einem weiteren Prozent der verstorbenen Neugeborenen wurden genetisch bedingte Erkrankungen entdeckt. Es wird die Bedeutung der Sektion perinataler Todesfälle als Screeningverfahren für genetisch bedingte Erkrankungen betont.