Safety of long-term large doses of aspartame.

Safety of long-term administration of 75 mg/kg of aspartame per day was evaluated with the use of a randomized, double-blind, placebo-controlled, parallel-group design in 108 male and female volunteers aged 18 to 62 years. Subjects received either aspartame or placebo in capsule form three times daily for 24 weeks. No persistent changes over time were noted in either group in vital signs; body weight; results of standard laboratory tests; fasting blood levels of aspartame's constituent amino acids (aspartic acid and phenylalanine), other amino acids, and methanol; or blood formate levels and 24-hour urinary excretion of formate. There also were no statistically significant differences between groups in the number of subjects experiencing symptoms or in the number of symptoms per subject. These results further document the safety of the long-term consumption of aspartame at doses equivalent to the amount of aspartame in approximately 10 L of beverage per day.

Induction of apoptosis in the CNS during development by the combination of hyperoxia and inhibition of glutathione synthesis.

Apoptosis in the central nervous system (in contrast to necrosis) is an endogenous cell suicide mechanism triggered in response to biological factors and genotoxic stimuli often resulting from oxidative stress. Excessive neural apoptosis may result in longterm brain dysfunction. A significant proportion of prematurely born infants are exposed to high oxygen and nutritional regimens deficient in antioxidant precursors. Such infants frequently display cognitive deficits when studied in later childhood. Studies in cell culture have characterized a close relationship between oxidative stress, glutathione availability and cell death. Here, we assessed this relationship in rat brain, as a model approximation of the situation that occurs in human infants. Two day old rats were exposed to an atmosphere of 95% oxygen and treated with buthionine sulfoximine (BSO), a glutathione synthesis inhibitor. Control groups consisted of rat-pups kept in air, air plus BSO, or oxygen alone. At the end of 5 days of treatment, brains were harvested, dissected and nerve growth factor protein (NGF), glutathione, and extent of apoptosis were measured. Hyperoxia induced a decrease in NGF protein while BSO induced a decrease in glutathione concentrations. Animals treated with both hyperoxia and BSO had a dramatic increase in the extent of brain apoptosis detected. We conclude from these studies that the brains of animals exposed to both oxidative stress and limited antioxidant protection are liable to pro-apoptotic changes. Increased cell death via apoptosis reflecting changes in neurotrophin and glutathione homeostasis may represent the mechanism responsible for the induction of the longterm cognitive deficits observed in some preterm infants.

Cyst(e)ine measurements during total parenteral nutrition.

Using a method that measures plasma protein-bound 1/2 cystine, plasma free cyst(e)ine, and urine free cyst(e)ine, we have observed that infants receiving total parenteral nutrition supplemented with cysteine-HCl have significantly higher plasma and urine free cyst(e)ine concentrations (11.3 +/- 3.4 microns/dl and 47.2 +/- 24.0 microns/dl, means +/- SD) than when 1/2 cystine concentrations are measured by automated amino acid analysis (7.4 +/- 2.0 microns/dl, plasma and 25.0 +/- 7.0 microns/dl, urine). These data suggest that both the sulfhydryl and disulfide form of cyst(e)ine must be measured to assess the effect of cysteine-HCl supplemented total parenteral nutrition.

Plasma cyst(e)ine in homocyst(e)inemia.

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.

Milk protein quantity and quality in low-birth-weight infants: II. Effects on selected aliphatic amino acids in plasma and urine.

The optimal quantity and quality of protein for low-birth-weight infants is undefined. In this study, 106 well, appropriate-for-gestational-age, low-birth-weight infants weighing 2,100 gm or less were divided into three gestational age groups and assigned randomly within each age group to one of five feeding regimens: pooled human milk; formula 1 (protein content, 1.5 gm/100 ml- 60 parts bovine whey proteins to 40 parts bovine caseins); formula 2 (3.0 gm/100 ml, 60:40); formula 3 (1.5 gm/100 ml, 18:82); and formula 4 (3.0 gm/100 ml, 18:82). The concentrations of the free amino aicds in the plasma and urine of these infants were determined. The plasma concentrations of free amino acids were generally far greater in the infants fed the 3.0-gm/100 ml protein diets than they were in the infants fed pooled human milk. The plasma concentrations of free amino acids of the infants fed the 1.5-gm/100 ml protein diets were intermediate. In general, the concentrations of the free amino acids in the plasma of the infants fed the 3.0-gm/100 ml casein-predominant formula (F4) were furthest from those fed pooled human milk. Glutamate showed the highest plasma amino acid concentrations in infants fed the 3.0-gm/100 ml casein-predominant formula (F4) were furthest from those fed pooled human milk. Glutamate showed the highest plasma amino acid concentrations in infants fed both the high- and low-protein casein-predominant formulas. This was true despite the fact that the intake of glutamate on the high-protein, whey-predominant formula was twice that on the low-protein, casein-predominant formula. The differences between groups in the essential amino acids in plasma were generally greater than those of the nonessential amino acids. The concentrations of amino acids in the urine tended to parallel those of the plasma.

Milk protein quantity and quality in low-birthweight infants: I. Metabolic responses and effects on growth.

The optimal quantity and quality of protein for low-birthweight infants is undefined. In this study, 106 well, appropriate-for-gestational age, low-birthweight infants weighing 2,100 gm or less were grouped in three gestational age categories: T1 = 28 to 30 weeks; T2 = 31 to 33 weeks; T3 = 34 to 36 weeks. Each group was assigned randomly to either banked human milk (BM) or to one of four isocaloric formulas varying in quantity and quality of protein but not in mineral content or in fat content: formula 1 = 1.5 gm of protein per 100 ml, 60 parts bovine whey proteins to 40 parts bovine caseins; formula 2 = 3.0 gm of protein per 100 ml, 60:40; formula 3 = 1.5 gm of protein per 100 ml, 18:82; formula 4 = 3.0 gm of protein per 100 ml, 18:82. Caloric intake was 117 kcal/150 ml/kg/day for the formulas. Human milk was fed at 170 ml/kg/day in order to attain a caloric intake approximately equal to that of the formulas. No significant differences were found in the rate of growth in crown-rump length, in femoral length, in head circumference, or in rate of gain in weight from time of regaining birthweight to time of discharge at 2,400 gm. Blood urea nitrogen, urine osmolarity, total serum protein, serum albumin, and serum globulin varied directly with the quantity of protein in the diet: F2, F4 greater than F1, F3 greater than BM. Blood ammonia concentration varied with both quantity and quality of protein in the diet: F2, F3, F4 greater than F1, BM. Metabolic acidosis was more frequent, more severe, and more prolonged in the infants fed the casein-predominant formulas (F3,F4) than in those fed the whey protein-predominant formulas (F1, F2).

Feeding the low-birth-weight infant. III. Diet influences bile acid metabolism.

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)

Feeding the low-birth-weight infant: I. Taurine and cholesterol supplementation of formula does not affect growth and metabolism.

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.

Feeding the low-birth-weight infant: II. Effects of taurine and cholesterol supplementation on amino acids and cholesterol.

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.

Milk protein quantity and quality in the term infant. I. Metabolic responses and effects on growth.

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).

Milk protein quantity and quality in the term infant. II. Effects on acidic and neutral amino acids.

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.

Use of C-reactive protein in differentiation between acute bacterial and viral otitis media.

OBJECTIVES: The objectives of this investigation were: (1) to determine degree of elevation of serum C-reactive protein (CRP) in uncomplicated acute otitis media (AOM); (2) to compare serum CRP levels in bacterial and viral otitis media; and (3) to determine whether a single serum CRP level, obtained early in the course of AOM, could be used to differentiate between viral and bacterial otitis media. DESIGN AND METHODS: Sera were obtained from otherwise healthy infants and children with AOM who were 3 months to 7 years of age between 1989 and 1991. Tympanocentesis, bacterial and viral studies of the middle ear fluids, virologic studies of nasal wash specimens, measurements of serum antibody titers to respiratory viruses, blood counts, and quantitation of serum CRP concentrations were performed. After the initial tympanocentesis, an oral antibiotic was given for the next 10 days. The patients were clinically reevaluated over next 4 weeks. OUTCOME MEASURES: Serum CRP concentrations were compared among subjects with AOM who were divided into four groups based on the results of bacteriologic and virologic studies: group I, Bacterial infection (n = 82); group II, bacterial and viral infections (n = 69); group III, viral infection (n = 12); and group IV, no identifiable pathogen (n = 22). RESULTS: There was no statistical difference in serum CRP values among the four groups. The ranges of CRP were less than 0.6 to 22.8, less than 0.6 to 17.8, less than 0.6 to 2.0, and less than 0.6 to 6.8 mg/dL in groups I through IV, respectively. However, when CRP values in bacteria-positive cases were compared with CRP concentrations in bacteria-negative cases (1.58 +/- 3.16 vs 0.64 +/- 1.24 mg/dL), the difference was statistically significant. Furthermore, a significantly higher proportion of bacteria-positive cases had serum CRP concentrations greater than 2 mg/dL, compared with those in bacteria-negative cases. There was no correlation between initial CRP values and clinical findings and/or the clearance of bacteria from the middle ear. After 10 days of antibiotic treatment, CRP values returned to normal (< 0.6 mg/dL) in all cases. CONCLUSION: In AOM, the range of serum CRP varied from less than 0.6 to 22.8 mg/dL. High CRP values (> 2.0 mg/dL) were associated with 22% of cases of bacterial AOM but only with 6% of nonbacterial AOM. High levels of serum CRP were found to be very specific in detecting bacterial AOM, and no cases of viral AOM without a concurrent bacterial infection were found to exhibit high serum levels of CRP.

Incidence of breast-feeding in a low socioeconomic group of mothers in the United States: ethnic patterns.

Breast-feeding has been shown to have increased in incidence during recent years in the United States. However, this increase is not particularly evident in lower socioeconomic groups. Factors associated with the decision to breast-feed or not were investigated in a population of 379 mothers. Self-completed questionnaires were obtained from 94.5% of these mothers. Data with respect to demographics, reproductive history, prenatal care, and education were collected. Only 27.2% of the study population indicated that they intended to breast-feed. Using the chi2 test for equality of proportions, marital status, head of household, maternal and paternal ethnicity, maternal education, income, and number of pregnancy were found to be the most important variables associated with breast-feeding. The effect of ethnicity predominated over that of the other demographic variables when they were examined jointly within ethnic groups. The effect of ethnicity was apparent when the number of each ethnic group in the study population was compared with the percent of that group that intended to breast-feed: 145 Anglo-Americans, 43.5% breast-feeding; 131 black Americans, 9.2%; 62 Mexican Americans, 22.6%; 19 others, 42.1%. The importance of ethnicity in the decision to breast-feed has probably been underestimated. Efforts to increase breast-feeding in the United States ought to be designed with full consideration of this factor.

Acculturation and the initiation of breastfeeding.

Despite the fact that breastfeeding is the most appropriate form of nutrition for the healthy term infant, the rate of initiation in the U.S. is declining. One demographic factor associated with this low rate is ethnicity and so in this study we measured acculturation (one aspect of ethnicity) into the U.S. and its relationship to the successful initiation of breastfeeding in a sample of women recruited approximately 2 months prenatally in a U.S.-Mexico border city. Interviews were administered in English or Spanish by bilingual interviewers prenatally (n = 906), natally (n = 788), and postnatally (n = 715). Acculturation (measured with a 20 item instrument) was strongly related to the intent to (p < 0.001) or the successful initiation of breastfeeding (p < 0.001). Marital status (p = 0.014) and education (p = 0.002) were related to breastfeeding prenatally and natally. Initiation of breastfeeding was highest among those women least acculturated (52.9%) and lowest in those most acculturated (36.1%) indicating an inhibiting effect of acculturation. To improve the rate of initiation of breastfeeding in the U.S. (a national health goal) intervention programs must consider cultural factors.

Height, infant-feeding practices and cardiovascular functioning among 3 or 4 year old children in three ethnic groups.

Barker recently hypothesized that factors affecting prenatal and infant growth are related to adult blood pressure and CVD mortality. Predictions from Barker's hypothesis in regard to infant feeding were tested among a sample of 3 or 4 year old children. The relationship of infant-feeding characteristics (duration of breast-feeding, times of introduction of high fat, high carbohydrate, high potassium foods and table salt) to indicators of cardiovascular functioning (resting blood pressures and heart rates, and heart rate response to graded activity) while controlling for anthropometric (height, sum of seven skinfolds, BMI) and demographic (ethnicity, gender, social status) characteristics revealed that infant-feeding practices were not related to CV functioning in the predicted directions among this sample of 3 or 4 year old children. Furthermore, the positive relationship between height and systolic blood pressure was inconsistent with the Barker hypothesis.

Brain large neutral amino acids and catecholamines in parenterally nourished preterm rabbits.

Total parenteral nutrition (TPN) has been adapted as a standard for providing nutrition to ill term and preterm infants. The availability of tyrosine in amino acid preparations utilized for TPN is limited and may potentiate a tyrosine-deficient state. Phenlyalanine hydroxylase activity, responsible for catalyzing tyrosine synthesis, has been suggested to be decreased in fetal and neonatal animals. Parenterally nourished premature rabbits (n = 16) and suckled rabbits (n = 19) were studied in order to compare growth parameters and amino acids in the plasma and brain, as well as whole brain catecholamine concentrations. Influx velocities into the brain of amino acids were also determined in these two groups. The preterm rabbit's average birth weight (42.6 +/- 6.0) was less than that of term rabbits (56.7 +/- 8.7, P < 0.005). Significantly lower concentrations of the catecholamine precursor tyrosine were found in both the plasma and brain of the parenterally nourished animals compared to the suckled animals. Tyrosine is reduced in the brain in TPN-supported animals reflecting both low tyrosine intake and increased plasma concentrations of large neutral amino acids that compete for uptake at the blood-brain barrier. However, no difference was observed between the two groups in their brain catecholamine concentrations. The seven-day parenterally nourished rabbit appears to be tyrosine-deficient but no evident effects on brain catecholamine concentrations were seen. The effects and impact of a tyrosine-deficient state might better be evaluated by regional evaluation of catecholaminergic areas of the brain or over a longer period of parenteral nutrition.

Homocysteine and cysteine loads in patients with homocystinuria due to cystathionine synthase deficiency: effects of vitamin B-6.

The metabolic response of patients with homocystinuria due to cystabhionine synthase deficiency to oral loads of homocysteine indicates: that even severely affected patients with homocystinuria have pools of cystine in their tissues; that control of sulfur amino acid metabolism favors increased concentrations of methionine rather than homocystine in the plasma; and that even patients who apparently are not B-6-responsive respond differently to the loads of homocysteine when challenged during B-6-treatment compared with their response before B-6 treatment. Loading tests with homocysteine indicate that B-6 treatment be of some benefit even in individuals who do not have an obvious biochemical response to such therapy.

Fetal tissue amino acid concentrations in argininosuccinic aciduria and in "maternal homocystinuria".

Free amino acid concentrations have been measured in the tissues of a fetus at risk for argininosuccinic aciduria and of an obligate heterozygous fetus in a mother homozygous for homocystinuria. Argininosuccinic acid was detected in all tissues studied of the homozygous affected fetus from the heterozygous mother. Abnormal concentrations of methionine and cystathionine were observed in the tissues of the fetus who was an obligate heterozygote for homocystinuria. These abnormal free amino acid concentrations occur early in fetal development and may be related to later brain dysfunction.

Facilitating faculty development and research through critical review of grant proposals and articles.

BACKGROUND: In 1983 the Department of Pediatrics at the University of Texas Medical Branch at Galveston established a faculty development program to address faculty needs for continuing education and improved resources for research. At first a part-time coordinator was hired; then, in 1985, a full-time, faculty-level science communicator provided help with strategic planning of projects and intensive review of grant proposals and journal articles. Faculty participation in the program was voluntary. METHOD: Pre- and post-intervention data for 1983-1992 included numbers of faculty using the program, faculty evaluations of the program, grant dollars awarded, counts of grant submissions and awards, and numbers of published articles. RESULTS: The review services were used heavily for grant proposals (75% of the department's proposals), but were used lightly for research articles (18% of publications). Grant funding quadrupled from 1983 to 1988; although funding peaked in 1988, it thereafter remained at three to four times the 1983 level. In contrast, the mean number of publications per faculty per year dropped between 1983 and 1990. CONCLUSION: The program provided valuable assistance to the faculty in writing grant proposals, and it helped to generate critically needed resources. However, the program's failure to increase the publication productivity of the faculty suggests that despite financial pressures, similar programs should use their influence and resources to promote a balance between scholarly publication and grant acquisition.

Hexosaminidase: a biochemical marker for necrotizing enterocolitis in the preterm infant.

To evaluate hexosaminidase as a biochemical marker for the early detection of necrotizing enterocolitis in preterm infants, 33 preterm infants without necrotizing enterocolitis and 18 preterm infants with necrotizing enterocolitis had hexosaminidase activity measured during the course of their hospitalization. Although hexosaminidase activity could not identify those preterm infants with necrotizing enterocolitis who had impending perforation, the data strongly suggest that measurements of serum hexosaminidase activity may provide an early biochemical indication of the presence of necrotizing enterocolitis in the preterm infant. Hopefully, early detection of necrotizing enterocolitis in these infants will reduce the morbidity and mortality of this disease.