Pitfalls in the determination of protein requirements in premature infants.
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Biomedical subjects
Publications and source records attributed to D K Rassin.
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Fasting duodenal bile acid concentrations and conjugation patterns were studied during the first 5 weeks of life in 65 low-birth-weight infants, 31 to 36 weeks of gestational age. One group was fed human milk. Approximately 55% of this milk was pooled, expressed, and pasteurized (62 degrees C for 30 minutes), 35% was similarly treated milk from the infant's own mother, and the remainder (10%) was provided by breast-feeding. The other infants, from 3 days of age, were fed one of three formulas: an adapted formula (F1), F1 supplemented with taurine (F2), or F1 supplemented with taurine and cholesterol (F3). The fasting intraluminal concentration of conjugated bile acids was higher in the infants fed human milk than in the infants fed formulas (F = 30.03, p less than .001) reflecting the higher concentrations of all individual bile acids. No significant increase over time was found in the concentration of total bile acids in any feeding group. Chenodeoxycholic acid concentrations, however, increased significantly over time in the infants fed human milk (r = .286, P less than .05). Thus, in the infants fed human milk, the ratio of cholates to chenodeoxycholates changed from 2.03 to 1.29 (P less than .001), whereas it remained stable (2.61) in the groups fed formula. Tauroconjugated bile acids predominated until at least 5 weeks of life in all the infants fed human milk, F2, or F3. In the infants fed F1, the concentration of glycoconjugates increased and that of tauroconjugates remained stable.(ABSTRACT TRUNCATED AT 250 WORDS)
Taurine and cholesterol are constituents of human milk that are present in smaller amounts in infant formulas. Infants fed such formulas have lower plasma and urine concentrations of taurine and of serum total cholesterol. In the present investigation, in infants of 31 to 36 weeks gestational age, the effects of supplementing a 1.5 g/100 mL whey-predominant formula with taurine alone or with taurine plus cholesterol were examined. Infants fed the supplemented formula were compared with infants fed the unsupplemented formula and with infants fed pooled, expressed human milk (185 mL/kg/d). Approximately 45% of the human milk provided to each infant was that of the infant's mother (35% pasteurized and 10% fresh). From the time of reaching a weight of 2,400 g to 4 months of age the last group of infants was fed ad libitum. No consistent statistically significant differences in growth, as measured by rate of gain in crown-rump length, crown-heel length, or head circumference, were observed. There was a tendency, however, for the formula-fed infants to gain weight more slowly before reaching 2,400 g and to gain weight more quickly after a weight of 2,400 g was attained to 4 months of age. No differences in concentrations of BUN, total serum proteins, or acid-base status were observed among the formula-fed groups. The concentration of BUN increased in the formula-fed groups compared with the group fed human milk during the last half of the study. The formula-fed infants tended to have higher total serum proteins and to be slightly more acidotic than the infants fed human milk prior to discharge at a weight of 2,400 g but not thereafter. Thus, infants fed 185 mL/kg/d gained weight at rates comparable to those for fetuses of the same gestational age. Supplementation of formulas with taurine or taurine plus cholesterol did not produce changes in growth or general metabolism discernible under the present experimental conditions.
Plasma and urine concentrations of taurine were consistently lower in preterm infants fed unsupplemented formula than those observed in the infants fed human milk or formulas supplemented with taurine alone or with taurine plus cholesterol. Such supplementation of formula restored plasma and urine concentrations of taurine to those observed in the infants fed human milk. Taurine was the only amino acid that was present at lower concentrations in the infants fed unsupplemented formula than in those fed human milk. The other acidic and neutral amino acids were present in higher concentrations in the formula-fed infants than in the group fed human milk either during the early weeks of the study (serine, glutamine, glycine, alanine, tyrosine, and methionine) or consistently higher during the entire study (threonine, glutamate, citrulline, valine, isoleucine, leucine, and phenylalanine). Supplementation of formula with taurine plus cholesterol did not appear to have any effect on the amino acid concentrations in the plasma and urine, other than that on taurine itself. Plasma total cholesterol concentration decreased during the fifth to the 12th postnatal weeks of life in all feeding groups. It then returned to the concentrations found during the first and third postnatal weeks in all feeding groups except in the infants fed formulas supplemented with taurine plus cholesterol which had a greater decrease.
This study was conducted to compare the influence of diet on the physiologic changes in bile acid kinetics, intraluminal bile acid concentrations, conjugation patterns, and nutrient lipid absorption, which occur postnatally. Preterm infants, 31-35 wk gestation, were fed one of four diets: (a) human milk pasteurized at 62 degrees C for 30 min, 55% from a pooled source, 35% from the infant's own mother, with the remainder (approximately 10%) being fresh human milk; (b) an adapted infant formula (F1); (c) F1 supplemented with taurine, 30 mumol/dl, (F2); and (d) F1 with both taurine, 30 mumol/dl, and cholesterol, 9.6 mg/dl, to a total of 12.7 mg/dl, the levels found in human milk (F3). In all infants, the bile acid pool size increased nearly twofold between 11 and 35 days, irrespective of dietary regimens. Taurine conjugation of bile acids predominated in all infants at 11 days of age and at 35 days in those infants fed human milk or the taurine-supplemented formulas. In taurine-supplemented formulas, the conjugation pattern did not influence bile acid kinetics. However, the bile acid pool and intraluminal bile acid concentrations were significantly greater in infants fed human milk at all ages, suggesting that human milk feeding, per se, uniquely influences intestinal and possibly hepatic function independent of developmental factors.
The relationship of taurine to glutamate, and to other amino acids, has been examined in the occipital lobe of the developing rhesus monkey. During development taurine decreases in concentration (4.96 mumol/g in fetus to 1.52 mumol/g in adult) while glutamate increases (7.92 mumol/g in fetus to 11.26 mumol/g in adult). When the concentration of taurine is plotted against that of glutamate in fetal, neonatal and adult animals there is a significant correlation in the fetal (p less than 0.01) and adult (p less than 0.01) but not in the neonatal occipital lobe samples. This correlation in both fetal and adult brain is specific for these amino acids. Subcellular fractionation studies further indicate that this relationship may be of special importance in nerve endings.
In an effort to further understand the pathogenesis of Lesch-Nyhan syndrome, an X-linked recessive disease of purine metabolism associated with a deficiency of hypoxanthine-guanine phosphoribosyltransferase, we have analyzed the amino acids in autopsy brain material obtained from five patients and six controls. The amino acids glycine and glutamine serve as substrates for the synthesis of purines in man. Amino acids were measured in the occipital cortex, limbic cortical area, cerebellar cortex, hippocampus and putamen. In general the amino acids were usually lower in concentration in brain material from affected individuals. Most dramatically decreased were threonine, serine, valine, isoleucine, lysine and arginine. Only glutamine and urea were higher than controls. Glutamate, gamma-aminobutyrate and cystathionine were essentially unaffected. The data reported here do not support a role for increased glycine in the pathogenesis of this disease as implied by findings previously reported in cultured cell lines (Skaper and Seegmiller 1976, 1977). The current findings suggest that individuals with Lesch-Nyhan syndrome have a generally lower concentration of free amino acids in brain. This decrease may be involved in the etiology of the disease or the decrease may be a result of the generally malnourished state of these individuals. These results imply that affected patients have a limited supply of amino acid precursors available for the synthesis of either proteins or neurotransmitters that the brain requires for normal function. Thus, the low amino acid pools could be an important factor in the brain dysfunction observed in patients with Lesch-Nyhan syndrome.
The growth and metabolic response of healthy, term infants during the first 12 weeks of life to feeding one of two formulas or human milk have been measured. Two groups of infants were fed ad libitum a 1.5 gm/100 ml bovine protein formula made up of either 60% whey and 40% casein proteins or 18% whey and 82% casein proteins. A third group of infants was breast-fed ad libitum. No consistent significant differences were observed among the groups with respect to rate of gain in weight, crown-rump length, crown-heel length, or head circumference. Blood urea concentration was significantly higher, and there was evidence suggesting compensation for an increased acid load from the second to the fourth weeks in both of the formula-fed groups compared with the breast-fed group. Blood cholesterol was significantly lower in both the formula-fed groups compared with the breast-fed group (P less than .001) and lower in the group fed the casein-predominant formula than it was in those fed the whey-predominant formula (P less than .05).
The response of the plasma and urine concentrations of acidic and neutral amino acids to two bovine protein formulas (1.5 gm/100 ml) containing, respectively, 60% whey proteins and 40% caseins or 18% whey proteins an 82% caseins was measured in term infants. These two groups of infants were compared with a group of infants that were breast-fed; all infants were fed ad libitum. Concentrations of citrulline, threonine, phenylalanine, and tyrosine in the plasma and urine were higher in the formula-fed infants than in the breast-fed infants and were a reflection of the amount of protein provided. Concentrations of tyrosine and phenylalanine were higher in the plasma and urine of infants fed the casein-predominant formulas than they were in those fed whey-predominant formulas. The opposite was true for threonine, which was present in higher concentrations in plasma and urine of infants fed whey-predominant formulas than it was in infants fed casein-predominant formulas. Concentrations of taurine were lower in the plasma and urine of formula-fed infants than they were in breast-fed infants. These differences give further evidence that formulas now in common use may provide a protein intake in excess of protein requirements and that there is a dietary requirement for taurine in man which is not satisfied by such formulas. Although these differences have not been established as nutritionally deleterious, neither can they be assumed to be entirely acceptable.
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Using a method developed to measure plasma protein-bound 1/2-cystine, we have observed that the metabolic state can affect the distribution of plasma cyst(e)ine between the bound and the free form. In five patients with homocyst(e)inemia, 1/2-homocystine was found to have replaced virtually all the cysteine normally present on sulfhydryl-binding sites of plasma proteins. The majority of the cyst(e)ine measured in the plasma of these patients (6.9 +/- 2.4 mumol/dl, mean +/- SD) was present in the form of a mixed disulfide with 1/2-homocystine (5.4 +/- 0.9 mumol/dl) rather than being free in the plasma or bound to plasma proteins.
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The subcellular distributions of the enzymes associated with the methylation and cystathionine-synthesizing portion of the sulfur amino acid metabolic pathway have been determined in the occipital lobe of the rhesus monkey. 5-Methyltetrahydrofolate-homocysteine methyltransferase and 5, 10-methylenetetrahydrofolate reductase activities are located mainly in the soluble compartment. Serine hydroxymethyltransferase activity is located primarily in mitochondria. Cystathionine beta-synthase is a soluble enzyme with a significant component occluded within the nerve endings. Glycine, serine, and cystathionine increase per gram of tissue during development. Glycine and serine are approximately 30% occluded within the nerve endings. These data are consistent with a localization of sulfur amino acid metabolism that supports a differential compartmentation of potential neurotransmitter function and methylation function in the primate.
Taurine, cysteinesulfinic acid decarboxylase (CSAD), glutamate, gamma-aminobutyric acid (GABA), and glutamic acid decarboxylase (GAD) were measured in subcellular fractions prepared from occipital lobe of fetal and neonatal rhesus monkeys. In addition, the distribution of [35S]taurine in subcellular fractions was determined after administration to the fetus via the mother, to the neonate via administration to the mother prior to birth, and directly to the neonate at various times after birth. CSAD, glutamate, GABA, and GAD all were found to be low or unmeasurable in early fetal life and to increase during late fetal and early neonatal life to reach values found in the mother. Taurine was present in large amounts in early fetal life and decreased slowly during neonatal life, arriving at amounts found in the mother not until after 150 days of age. Significant amounts of taurine, CSAD, GABA, and GAD were associated with nerve ending components with some indication that the proportion of brain taurine found in these organelles increases during development. All subcellular pools of taurine were rapidly labeled by exogenously administered [35S]taurine. The subcellular distribution of all the components measured was compatible with the neurotransmitter or putative neurotransmitter functions of glutamate, GABA, and taurine. The large amount of these three amino acids exceeds that required for such function. The excess of glutamate and GABA may be used as a source of energy. The function of the excess of taurine is still not clear, although circumstantial evidence favors an important role in the development and maturation of the CNS.
In beagle pups (from 5 to 84 days of age), plasma taurine concentration decreased between 5 and 21 days of age with no change thereafer; cerebral taurine concentration decreased throughout the period of study but cerebral taurine content increased between 5 and 21 days of age; hepatic taurine content (but not concentration) increased throughout. Both hepatic cysteinesulfinic acid decarboxylase (CSAD) activity and the concentration of taurine-conjugated bile acid of gallbladder bile increased during the period of study. Plasma and cerebral taurine pools were not affected by taurine-free total parenteral nutrition (TPN). Hepatic taurine content was also not affected, but taurine concentration decreased; however, this change resulted from an increase in hepatic size. Hepatic CSAD activity of animals that received TPN was greater than that of 35-day control animals while the concentration of taurine-conjugated bile acids in the gallbladder bile was less. Although plasma taurine concentration was not affected by intravenous glucose therapy, both the hepatic taurine concentration and content of these animals were less than those of 35-day control animals. Cerebral taurine concentration of these animals, on the other hand, were greater. Hepatic CSAD activity of the animals that received only intravenous glucose was similar to that of controls, but the taurine-conjugated bile acid concentration in the gallbladder bile, like that of animals that received TPN, was less than that observed in 35-day control animals.
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The concentrations of taurine in all regions of fetal and neonatal rhesus monkey brain are greater than in the same regions of adult monkey brain. [35S]Taurine injected into pregnant rhesus monkeys is accumulated by the fetus. This process occurs rapidly in most tissues, but occurs slowly in fetal brain. Neonatal rhesus monkey brain also accumulates [35S]taurine slowly compared with other tissues after i.v. injection, and continues to accumulate [35S]taurine for a long period of time. These results suggest that the accumulation and exchange of taurine in developing rhesus monkey brain is slow, as found in neonatal rats, and that if there is a period of development at which rapid exchange of brain taurine occurs in the rhesus monkey, it is before the rapid brain growth spurt.