Urinary F2-isoprostanes are poor prognostic indicators for the development of bronchopulmonary dysplasia.

OBJECTIVE: Oxygen toxicity is thought to contribute to the development of bronchopulmonary dysplasia (BPD). Oxidant injury leads to formation of F(2)-isoprostanes (F(2)-IsoP). We hypothesized that urinary excretion of the stable metabolite of F(2)-IsoP, 8-iso-PGF(2alpha), would be higher in infants who develop BPD than those who did not. METHODS: Forty infants <30-weeks gestational age (GA) were enrolled, 24 infants with BPD and 16 without BPD. Urine specimens were collected weekly and stored at -80 degrees C until analyzed. Urinary 8-iso-PGF(2alpha) was measured by gas chromatography/mass spectrometry (GC-MS) and normalized to creatinine excretion. RESULTS: GA and birth weight (BW) were lower in infants who developed BPD than those who did not. Urinary 8-iso-PGF(2alpha) levels in the first or third weeks of age were not significantly different between the two groups. CONCLUSION: Urinary excretion of 8-iso-PGF(2alpha) in early postnatal life in preterm infants is not correlated with the development of BPD.

Dietary fat has minimal effects on fatty acid metabolism transcript concentrations in pigs.

Young, crossbred pigs were fed either a low-fat, corn-based diet; a high-fat, tallow-based diet with a considerable saturated fatty acid (FA) content; or a high-fat, fish oil-based diet with a considerable polyunsaturated FA content, for 14 d. There were six pigs per dietary group (approximately 4-wk-old with a body weight of 6.16 kg). The plasma and adipose tissue FA composition reflected the composition of the diet to a large extent, but also reflected de novo FA synthesis coupled with chain elongation and desaturation. The liver and skeletal muscle FA composition reflected the diet and endogenous synthesis, but the indications for preferential incorporation or exclusion of specific FA were greater in these tissues than in plasma or adipose tissue. An important transcription factor for adipocyte differentiation and other aspects of lipid metabolism is adipocyte determination and differentiation-dependent factor 1 (ADD1). Liver ADD1 messenger RNA (mRNA) tended to be decreased (P = 0.06) in the fish oil-fed group, as well as in the combined high-fat-fed groups (tallow + fish oil) compared to the low-fat-fed group (P = 0.06). The muscle acyl-CoA oxidase mRNA tended to be increased in the tallow-fed group and decreased in fish oil-fed groups (P = 0.06). The muscle carnitine palmitoyltransferase mRNA tended to be elevated in both fat-fed groups (P = 0.07). None of the adipose tissue mRNA were changed by the diet (P > 0.20). The observations suggest there are major differences between rodents and pigs in modulation of transcripts associated with lipid metabolism by the dietary FA composition or concentration. Also, in porcine adipose tissue, as well as in liver and skeletal muscle, these transcripts are rather refractory to modification by dietary FA.

Relationship between omega3 long-chain polyunsaturated fatty acid status during early infancy and neurodevelopmental status at 1 year of age.

OBJECTIVE: To determine the influence of alpha-linolenic acid (ALA; 18 : 3omega3) intake and, hence, the influence of plasma and/or erythrocyte phospholipid content of docosahexaenoic acid (DHA; 22 : 6omega3) during early infancy on neurodevelopmental outcome of term infants. METHODS: The Bayley Scales of Infant Development (second edition), the Clinical Adaptive Test/Clinical Linguistic and Auditory Milestone Scale (CAT/CLAMS) and the Gross Motor Scale of the Revised Gesell Developmental Inventory were administered at a mean age of 12.26 +/- 0.94 months to 44 normal term infants enrolled in a study evaluating the effects of infant formulas differing only in ALA content (0.4, 1.0, 1.7 and 3.2% of total fatty acids). RESULTS: As reported previously [Jensen et al., Lipids 13 (1996) 107; J. Pediatr. 131 (1997) 200], the group fed the formula with the lowest ALA content had the lowest mean plasma and erythrocyte phospholipid DHA contents at 4 months of age. This group also had the lowest mean score on every neurodevelopmental measure. The difference in mean gross motor developmental quotient of this group versus the group fed the formula with 1.0% ALA but not of the other groups was statistically significant (P < 0.05). Across the groups, motor indices correlated positively with each other and with the plasma phospholipid DHA content at 4 months of age (P=0.02-0.03). The CLAMS developmental quotient correlated with the erythrocyte phospholipid content of 20 : 5omega3 (P < 0.01) but not with DHA. CONCLUSIONS: These statistically significant correlations suggest that the omega3 fatty acid status during early infancy may be important with respect to neurodevelopmental status at 1 year of age and highlight the need for further studies of this possibility.

A randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: To determine whether docosahexaenoic acid (DHA) supplementation for 4 months decreases the symptoms of attention-deficit/hyperactivity disorder (ADHD). STUDY DESIGN: Sixty-three 6- to-12-year-old children with ADHD, all receiving effective maintenance therapy with stimulant medication, were assigned randomly, in a double-blind fashion, to receive DHA supplementation (345 mg/d) or placebo for 4 months. Outcome variables included plasma phospholipid fatty acid patterns, scores on laboratory measures of inattention and impulsivity (Test of Variables of Attention, Children's Color Trails test) while not taking stimulant medication, and scores on parental behavioral rating scales (Child Behavior Checklist, Conners' Rating Scale). Differences between groups after 4 months of DHA supplementation or placebo administration were determined by analysis of variance, controlling for age, baseline value of each outcome variable, ethnicity, and ADHD subtype. RESULTS: Plasma phospholipid DHA content of the DHA-supplemented group was 2.6-fold higher at the end of the study than that of the placebo group (4.85 +/- 1.35 vs 1.86 +/- 0.87 mol % of total fatty acids; P <.001). Despite this, there was no statistically significant improvement in any objective or subjective measure of ADHD symptoms. CONCLUSION: A 4-month period of DHA supplementation (345 mg/d) does not decrease symptoms of ADHD.

Impaired synthesis of DHA in patients with X-linked retinitis pigmentosa.

Many patients with X-linked retinitis pigmentosa (XLRP) have lower than normal blood levels of the long-chain polyunsaturated omega3 fatty acid docosahexaenoic acid (DHA; 22:6omega3). This clinical trial was designed to test whether down-regulation of DHA biosynthesis might be responsible for these reduced DHA levels. DHA biosynthesis was assessed in five severely affected patients with XLRP and in five age-matched controls by quantifying conversion of [U-(13)C]alpha-linolenic acid (alpha-LNA) to [(13)C]DHA. Following oral administration of [U-(13)C]alpha-LNA, blood samples were collected at designated intervals for 21 days and isotopic enrichment of all omega3 fatty acids was determined by gas chromatography/mass spectroscopy. Activity of each metabolic step in the conversion of alpha-LNA to DHA was determined by comparison of the ratios of the integrated concentration of (13)C-product to (13)C-precursor in plasma total lipid fractions. The ratio of [(13)C]DHA to [(13)C]18:3omega3 (the entire pathway) and that of [(13)C]20:5omega3 to [(13)C]20:4omega3 (Delta(5)-desaturase) were significantly lower in patients versus controls (P = 0.03 and 0.05, respectively). The estimated biosynthetic rates of [(13)C]20:5omega3, [(13)C]22:5omega3, [(13)C]24:5omega3, [(13)C]24:6omega3, and [(13)C]22:6omega3 were significantly lower in XLRP patients (42%, 43%, 31%, 18%, and 32% of control values, respectively; P < 0.04), supporting down-regulation of Delta(5)-desaturase in XLRP. The disappearance of (13)C-labeled fatty acids from plasma was not greater in XLRP patients compared with controls, suggesting that XLRP was not associated with increased rates of fatty acid oxidation or other routes of catabolism.Thus, despite individual variation among both patients and controls, the data are consistent with a lower rate of Delta(5)-desaturation, suggesting that decreased biosynthesis of DHA may contribute to lower blood levels of DHA in patients with XLRP.

The role of polyunsaturated fatty acids in term and preterm infants and breastfeeding mothers.

DHA and AA, which are components of breast milk but not infant formulas marketed in the United States and some other countries, are important components of the brain, and DHA is a major component of the retina. Also, many studies have demonstrated advantages of breastfeeding versus formula-feeding on subsequent cognitive and visual function; however, available data are insufficient to justify the conclusion that the presence of DHA and AA in breast milk is partially or soley responsible for the apparent advantages of breastfeeding. On the other hand, many studies of DHA (and AA)-supplemented versus unsupplemented formulas have shown clear advantages of the supplemented formulas on visual acuity at 2 and 4 months of age or neurodevelopmental status at 12 to 18 months of age. Although one logically may assume that these early effects may have long-term effects, this assumption is not warranted by the available data. One of the major problems is the difficulty of assessing visual and cognitive function of infants. Scores on standard neurodevelopmental tests at 1 year of age, for example, are only weakly correlated with performance at school age (when more definitive assessments are possible), and little is known about the predictability of later visual function from behavioral or electrophysiologic assessments of visual function early in life. Even prematurely born infants can synthesize DHA and AA and other omega-3 and omega-6 LC-PUFAs from the dietary EFAs, LA and ALA. Nonetheless, plasma, erythrocyte and brain lipid levels of DHA are lower in infants whose diets do not contain DHA. Whether more optimal intakes of ALA result in higher plasma and tissue levels of this FA is unclear. The breast-milk content of LC-PUFAs is not regulated by the mammary gland but, rather, reflects the concentrations of LC-PUFAs in maternal plasma lipids that, in turn, are dependent on maternal diet and, probably, maternal activities of the desaturases and elongases involved in converting dietary LA and ALA to LC-PUFAs. This occurrence suggests that some infants receive sufficient LC-PUFA to support normal rates of deposition, whereas others may not. Also, some infants probably can synthesize additional LC-PUFAs from the LA and ALA contents of human milk. Thus, depending on maternal diet and maternal and infant desaturase and elongase activities, some breastfed infants may receive less than adequate LC-PUFAs to support normal rates of deposition. Clearly, the role of LC-PUFAs in infant development is not a simple issue. Also, no foolproof method exists to ensure an adequate but not excessive intake. Thus, because some evidence shows that dietary LC-PUFA (DHA, AA, or both) as components of breast milk or formula confers at least transient developmental benefits, supplementation of infant formulas with LC-PUFAs is supportable provided that the supplements used are safe. The safety of all available supplements is unknown; however, some trials reveal few reasons for major concerns about the safety of single-cell oils, low-EPA fish oil, or egg-yolk phospholipid or triglyceride fractions.

Determination of nutritional requirements in preterm infants, with special reference to 'catch-up' growth.

The usual recommendation for feeding preterm infants is to provide sufficient nutrients to support rates of growth and nutrient accretion equal to intrauterine rates. However, most preterm infants don't tolerate feedings immediately and, therefore, incur significant deficits prior to achieving sufficient intake to support growth. Furthermore, unless they receive nutrient intakes in excess of those usually recommended, they will be smaller than a fetus of the same postmenstrual age at discharge and remain smaller for some time thereafter. The consequences of these early deficits are not known with certainty but there is some evidence that they should be repleted as soon as possible. This requires a redefinition of requirements to include those for both normal growth and catch-up growth. Strategies for doing so include: more aggressive early parenteral nutrition to reduce the magnitude of early losses; greater enteral intakes of protein, and, perhaps, other nutrients once enteral feedings are tolerated; and more attention to nutrition post-discharge. Of these, the latter is somewhat problematic. This is because there seems to be a finite period - perhaps as brief as a few weeks - during which response to increased nutrient intake occurs. Firm data are limited, but those available suggest that current nutritional management of preterm infants can be improved. Whether this will have long-term benefits remains to be determined.

Internal consistency, temporal stability, and reproducibility of individual index scores of the Test of Variables of Attention in children with attention-deficit/hyperactivity disorder.

Psychometric properties of the Test of Variables of Attention (TOVA) were examined in a cohort of children (n=63) strictly diagnosed with attention-deficit/hyperactivity disorder (AD/HD). Internal consistency was assessed via correlational analyses to determine the degree of agreement among various test portions. The temporal stability of errors of omission, errors of commission, response time, and response time variability was evaluated using test-retest reliability. Reproducibility of individual scores for the same indices was assessed using the Bland-Altman procedure. Select TOVA index scores exhibited high internal consistency in this cohort. Although the temporal stability of group scores (test-retest reliability) was satisfactory, individual test scores were less reproducible. Temporal stability and individual test-retest score agreement were greater for response time and response time variability than for errors of omission and errors of commission.

In vivo rates of erythrocyte glutathione synthesis in children with severe protein-energy malnutrition.

Although the compromised GSH status of children with edematous protein-energy malnutrition (PEM) has been documented, the in vivo kinetic mechanism(s) responsible for this is not known. To determine if decreased synthesis contributes to the alteration of GSH homeostasis, the fractional and absolute rates of synthesis of erythrocyte GSH were determined shortly after admission (study 1), approximately 9 days postadmission (study 2), and at recovery (study 3) in seven children with edematous PEM and seven children with nonedematous PEM. Children with edematous PEM had significantly lower erythrocyte GSH and slower absolute rates of GSH synthesis than children with nonedematous PEM both shortly after admission, when they were both malnourished and infected, and approximately 9 days later, when the infection had resolved but they were still malnourished. At these times, the edematous group also had significantly lower erythrocyte GSH concentrations and absolute rates of synthesis than at recovery. Plasma and erythrocyte-free cysteine concentrations of the edematous group were significantly lower at studies 1 and 2 than at recovery. In contrast, erythrocyte GSH concentrations, rates of GSH synthesis, and plasma and erythrocyte free cysteine concentrations of the nonedematous group were similar at all three time points and greater at studies 1 and 2 than in the edematous group. These results confirm that GSH deficiency is characteristic of edematous PEM and suggest that this is due to a reduced rate of synthesis secondary to a shortage in cysteine.

Effect of docosahexaenoic acid supplementation of lactating women on the fatty acid composition of breast milk lipids and maternal and infant plasma phospholipids.

To determine whether docosahexaenoic acid (DHA) supplementation of breast-feeding mothers increases the DHA contents of breast milk and infant plasma phospholipids (PPs), breast-feeding women were randomly assigned to 3 DHA-supplementation groups (170-260 mg/d) or a control group. Group 1 (n = 6) consumed an algae-produced high-DHA triacylglycerol; group 2 (n = 6) consumed high-DHA eggs; group 3 (n = 6) consumed a high-DHA, low-eicosapentaenoic acid marine oil; and group 4 (n = 6) received no supplementation. From before to after supplementation (2 and 8 wk postpartum), mean (+/-SD) maternal PP DHA increased in groups 1, 2, and 3 by 1.20 +/- 0.53, 0.63 +/- 0.82, and 0.76 +/- 0.35 mol% of fatty acids, respectively (23-41%), but decreased in group 4 by 0.44 +/- 0.34 mol% (15%). Breast-milk DHA of groups 1, 2, and 3 increased by 0.21 +/- 0.16, 0.07 +/- 0.11, and 0. 12 +/- 0.07 mol%, respectively (32-91%) but decreased in group 4 by 0.03 +/- 0.04 mol% (17%). Mean infant PP DHA in groups 1, 2, and 3 increased by 1.63 +/- 0.79, 0.40 +/- 1.0, and 0.98 +/- 0.61 mol%, respectively (11-42%), but only by 0.18 +/- 0.74 mol% (5%) in group 4. Correlations between the DHA contents of maternal plasma and breast milk and of milk and infant PPs were significant. Breast-milk and maternal and infant PP 22:5n-6 concentrations were lowest in group 2. DHA supplementation increases the plasma and breast-milk DHA concentrations of lactating women, resulting in higher PP DHA concentrations in infants.

Evaluation of methods for assessing visual function of infants.

PURPOSE: Commonly used behavioral and electrical testing methods for estimation of visual acuity and visual function in infants yield different estimates and may not accurately predict visual acuity and visual function in later life. Moreover, neither test-retest variability nor side-by-side comparisons of the various methods have been thoroughly evaluated in the same infant population. The purpose of this study was to provide such an evaluation. METHOD: The test-retest variability of visual acuity and visual function was evaluated for the Teller Acuity Card (TAC) procedure, sweep visual evoked potential (VEP), as well as latency and amplitude measured by transient pattern VEP. Groups of approximately 20 infants contributed test-retest data. Visual function estimated by the various methods in a larger group of infants (n = 118) was compared. Correlations between methods and the validity of the various methods to detect maturational changes between 4 and 8 months of age were also assessed. Administration of these tests was according to standard and usual procedures. RESULTS: The average percent difference between test and retest estimates of acuity as well as the SD was lowest for transient VEP latency (3%, 7% SD). The other methods were markedly more variable: sweep VEP (2%, 22% SD), TAC procedure (8%, 20% SD), and transient VEP amplitude (7.5%, 39% SD). Average coefficients of variation showed a similar trend: transient VEP latency, 8%; sweep VEP, 15%; TACs, 30%; and transient amplitude, 53%. Correlations among estimates by the methods were poor, but expected changes in visual maturation from 4 to 8 months of age were detected with all methods. CONCLUSIONS: All methods evaluated provide valid and reliable test-retest data for a group, but are less valid for estimating visual acuity and visual function of an individual subject. The poor correlations between any 2 of the testing methods suggest that each test assesses a different aspect of vision. Nonetheless, expected maturational changes between 4 and 8 months of age were readily detectable by all methods evaluated.

Stimulant medications decrease energy expenditure and physical activity in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: To determine the effect of stimulant medications used to treat children with attention-deficit/hyperactivity disorder (AD/HD) on energy expenditure, fuel utilization, and physical activity. STUDY DESIGN: Energy expenditure and physical activity were measured, respectively, by room respiration calorimetry and microwave motion detectors in 31 children with AD/HD (26 boys and 5 girls; ages 6 to 12 years) both while they were receiving their prescribed stimulant medication and after the medication had been discontinued for at least 24 hours. Fuel utilization was calculated from calorimetry data. RESULTS: Total and awake energy expenditure including energy expended while doing schoolwork, riding a stationary bicycle, resting, and watching a movie were from 4% to 8% lower when the children were receiving their prescribed stimulant medication. Total and awake activity were also lower while they were receiving medication (16% to 22%) and accounted for the lower rates of energy expenditure. Sleeping metabolic rate, basal metabolic rate, and fuel utilization were unaffected by medication. CONCLUSIONS: Stimulant medications decrease physical activity, and hence, decrease the activity component of total daily energy expenditure in children with AD/HD.

Biological effects and safety issues related to long-chain polyunsaturated fatty acids in infants.

The purpose of this workshop at the American Oil Chemists' Society Symposium, "PUFA in Infant Nutrition: Consensus and Controversies," was to enumerate the safety issues raised by the prospect of supplementing infant formulas with long-chain polyunsaturated fatty acids (LC-PUFA), to evaluate the evidence that these concerns are problematical, or theoretically problematical, and to identify the safety issues most in need of resolution. This was approached by reviewing briefly the known biological effects of LC-PUFA and how these effects might give rise to concerns about safety of LC-PUFA as components of infant formulas. Some of these issues were then discussed in more detail by invited participants, all of whom had submitted abstracts concerning the issue discussed. The pertinent aspects of all issues discussed during the workshop are summarized. In addition, since the symposium was held over 2 yr ago, an addendum summarizing additional data reported since the symposium that either support or refute issues discussed during the workshop also is included.

Cholesterol-lowering effect of soy protein in normocholesterolemic and hypercholesterolemic men.

Cardiovascular heart disease is a major health problem in the United States. Elevated blood cholesterol has been shown to significantly increase the risk of cardiovascular heart disease. The National Cholesterol Educational Program (NCEP) Step I diet, which restricts fat and cholesterol intakes, is usually recommended as the initial treatment to lower blood cholesterol. Soy protein has been shown to be hypocholesterolemic, particularly in hypercholesterolemic subjects. However, the hypocholesterolemic effect of soy protein in subjects with a blood total cholesterol concentration <5.17 mmol/L is not clear. To determine whether soy protein could enhance the hypocholesterolemic effect of the NCEP Step I diet, 13 normocholesterolemic and 13 hypercholesterolemic men aged 20-50 y were enrolled in a randomized, 2-part, crossover study. Subjects were fed either an NCEP Step I soy-protein diet or an NCEP Step I animal protein diet for 5 wk. After a washout period of 10-15 wk, the subjects were fed the alternate diet for 5 wk. The hypocholesterolemic effect of soy protein was found to be independent of age, body weight, pretreatment plasma lipid concentrations, and sequence of dietary treatment. Regardless of plasma lipid status, the soy-protein diet was associated with a statistically significant decrease in the plasma concentrations of LDL cholesterol (P = 0.029) as well as the in the ratio of plasma LDL cholesterol to HDL cholesterol (P = 0.005). Our results indicate that soy protein enhances the hypocholesterolemic effect of the NCEP Step I diet in both normocholesterolemic and hypercholesterolemic men.

Parenteral nutrition selectively decreases protein synthesis in the small intestine.

We investigated the effects of an elemental diet fed parenterally or enterally on total mucosal protein and lactase phlorizin hydrolase (LPH) synthesis. Catheters were placed in the stomach, jugular vein, and carotid artery of 12 3-day-old pigs. Half of the animals were given an elemental regimen enterally and the other half parenterally. Six days later, animals were infused intravenously with [2H3]leucine for 6 h and killed, and the midjejunum of each animal was collected for analysis. The weight of the midjejunum was 8 +/- 1.5 and 17 +/- 1.6 g in parenterally fed and enterally fed piglets, respectively. LPH activities (mumol.min-1.g protein-1) were significantly higher in parenterally vs. enterally fed piglets. Total small intestinal LPH activities were lower in parenterally vs. enterally fed animals. The abundance of LPH mRNA relative to elongation factor-1 alpha mRNA was not different between groups. The fractional synthesis rate of total mucosal protein and LPH was significantly lower in parenterally fed animals (67 +/- 7 and 66 +/- 7%/day, respectively) than in enterally fed animals (96 +/- 7 and 90 +/- 6%/day, respectively). The absolute synthesis rate (the amount of protein synthesized per gram of mucosa) of total mucosal protein was significantly lower in parenterally fed than in enterally fed piglets. However, the absolute synthesis rate of LPH was unaffected by the route of nutrient administration. These results suggest that the small intestine partially compensates for the effects of parenteral feeding by maintaining the absolute synthesis rate of LPH at the same levels as in enterally fed animals.

Amino acids in pediatric and neonatal nutrition.

Modern infant formulas contain sufficient indispensable as well as dispensable amino acids to support normal growth of both term and preterm infants. However, current parenteral and specialized enteral amino acid preparations do not appear to be optimal. Many of the problems with parenteral preparations reflect the fact that ingested amino acids (protein) undergo more extensive enteric and hepatic metabolism than parenterally administered amino acids, including conversion to other amino acids (e.g. arginine) that reach the plasma for support of ongoing protein synthesis. Because this important source of amino acids is bypassed when nutrients are delivered parenterally, parenteral requirements of these amino acids are increased. In addition, while ingested phenylalanine and methionine appear to be converted to tyrosine and cysteine, respectively, it seems that parenterally administered phenylalanine and methionine are not. While glutamine, the branched-chain amino acids and arginine appear to be important in stressed infants and infants with compromised gastrointestinal function, specific roles have not been defined. Finally, because some amino acids are insoluble (e.g. tyrosine) and others are unstable in aqueous solution (e.g. glutamine and cysteine), suitable ways to provide these amino acids are needed. Soluble dipeptides of all types are available and have been shown to be both efficacious and safe in adults. This is also likely to be true for pediatric patients but data concerning their efficacy and safety in this population are lacking. Although recent research has been helpful, further research is necessary to define the optimal amino acid requirements of infants who are dependent on specialized nutrition regimens and to investigate whether these needs may differ depending upon the reasons why parenteral nutrition is required (e.g. growth versus response to stress).