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We recently showed that the developing gut is a significant site of methionine transmethylation to homocysteine and transsulfuration to cysteine. We hypothesized that sulfur amino acid (SAA) deficiency would preferentially reduce mucosal growth and antioxidant function in neonatal pigs. Neonatal pigs were enterally fed a control or an SAA-free diet for 7 days, and then whole body methionine and cysteine kinetics were measured using an intravenous infusion of [1-[sup.13]C;methyl-[sup.2][H.sub.3]]methionine and [[sup.15]N]cysteine. Body weight gain and plasma methionine, cysteine, homocysteine, and tanrine and total erythrocyte glutathione concentrations were markedly decreased (-46% to -85%) in SAA-free compared with control pigs. Whole body methionine and cysteine fluxes were reduced, yet methionine utilization for protein synthesis and methionine remethylation were relatively preserved at the expense of methionine transsulfuration, in response to SAA deficiency. Intestinal tissue concentrations of methionine and cysteine were markedly reduced and hepatic levels were maintained in SAA-free compared with control pigs. SAA deficiency increased the activity of methionine metabolic enzymes, i.e., methionine adenosyltransferase, methionine synthase, and cystathionine [beta]-synthase, and S-adenosylmethionine concentration in the jejunum, whereas methionine synthase activity increased and S-adenosylmethionine level decreased in the liver. Small intestine weight and protein and DNA mass were lower, whereas liver weight and DNA mass were unchanged, in SAA-free compared with control pigs. Dietary SAA deficiency induced small intestinal villus atrophy, lower goblet cell numbers, and Ki-67-positive proliferative crypt cells in association with lower tissue glutathione, especially in the jejunum. We conclude that SAA deficiency upregulates intestinal methionine cycle activity and suppresses epithelial growth in neonatal pigs. transmethylation; transsulfuration; remethylation; homocysteine

The study aims to compare the efficacy of aggressive phototherapy as compared to conservative phototherapy in preventing neurotoxic effects in infants with extremely low birth weight. Results indicate that aggressive phototherapy was not effective in reducing the rate of mortality.

Glutamate (Glu) is a major intestinal oxidative fuel, key neurotransmitter, and may be a useful dietary supplement to augment health of the infant gut. We quantified the metabolic fate of various supplemental dietary Glu intakes in young pigs surgically implanted with vascular, intraduodenal (ID), or intragastric (IG) catheters and a portal blood flow probe. Piglets were acutely fed a range of dietary Glu intakes using a basal milk formula (100%) supplemented with varying amounts of monosodium Glu (up to 400%) via ID or IG routes. We quantified the gastrointestinal metabolic fate of dietary Glu using [U-[sup.13]C] Glu tracer. The Glu net absorption in the basal 100% group was low in both ID and IG groups, ranging from 13 to 17% of intake. Enteral Glu supplementation significantly increased the absolute absorption rate and arterial concentration of Glu. In both the ID and IG groups, enteral [[sup.13]C]Glu absorption was limited (

We previously demonstrated the dose-dependent glucagon-like peptide (GLP)-2 activation of intracellular signals associated with increased epithelial cell survival and proliferation in the neonatal intestine. Our current aim was to quantify the acute, temporal GLP-2 activation of these key intracellular signals and relate this to changes in epithelial cell survival and proliferation in the neonatal intestine. We studied 29 total parenteral nutrition-fed neonatal piglets infused intravenously with either saline (control) or human GLP-2 (420 [micro]mol * [kg.sup.-1] * [h.sup.-1]) for 1, 4, or 48 h. GLP-2 infusion increased small intestinal weight, DNA and protein content, and villus height at 48 h, but not at 1 or 4 h. Intestinal crypt and villus apoptosis decreased and crypt cell proliferation and protein synthesis increased linearly with duration of GLP-2 infusion, but were statistically different from controls only after 48 h. Before the morphological and cellular kinetic changes, GLP-2 rapidly activated putative GLP-2 receptor downstream signals within 1-4 h, including phosphorylation of protein kinase A, protein kinase B, extracellular signal-regulated kinase 1/2, and the transcription factors cAMP response element-binding protein and c-Fos. GLP-2 rapidly suppressed caspase-3 activation and upregulated Bcl-2 abundance within 1 h, whereas there was an increase in apoptosis inhibitors X-linked inhibitor of apoptosis at 1 h and cellular inhibitor of apoptosis-2 at 4 and 48 h. We also show that the increased c-Fos and reduced active caspase-3 immunostaining after GLP-2 infusion was localized in epithelial cells. We conclude that GLP-2-induced activation of intracellular signals involved in both cell survival and proliferation occurs rapidly and precedes the trophic cellular kinetic effects that occur later in intestinal epithelial cells. glucagon-like peptide-2; total parenteral nutrition

Our results in a previous study indicated that the portal absorption of intragastrically fed [alpha]-ketoglutarate (AKG) was limited in young pigs. Our aim was to quantify the net portal absorption, first-pass metabolism, and whole-body flux of enterally infused AKG. In study 1, we quantified the net portal nutrient absorption in young pigs (n = 9) given an intraduodenal infusion of milk replacer [10 mL/(kg * h)] and either saline (control) or 930 [micro]mol/(kg. h) AKG for 4 h. In study 2, we quantified the luminal disappearance of a duodenal AKG bolus in young pigs (n = 7). In study 3, we quantified the whole-body kinetics of [sup.13]C-AKG metabolism when infused either enterally (n = 9) or intravenously (n = 9) in young pigs. In study 1, when compared with the control group, enteral AKG infusion increased (P< 0.01) the arterial (13.8 [+ or -] 1.7 vs. 27.4 [+ or -] 3.6 [micro]mol/L) and portal (22.0 [+ or -] 1.4 vs. 64.6 [+ or -] 5.9 [micro]mol/L) AKG concentrations and the net portal absorption of AKG [19.7 [+ or -] 2.8 vs. 95.2 [+ or -] 12.0 [micro]mol/(kg * h)]. The mean fractional portal appearance of enterally infused AKG was 10.23 [+ or -] 1.3%. In study 2, the luminal disappearance of AKG was 663 [micro]mol/(kg * h), representing 63% of the intraduodenal dose. In study 3, the wholebody [sup.13]C-AKG flux [4685 [+ or -] 666 vs. 801 [+ or -] 67 [micro]mol/(kg * h)] was higher (P < 0.05) when given enterally than intravenously, but [sup.13]C[O.sub.2] recovery was not different (37.3 [+ or -] 1.0 vs. 36.2 [+ or -] 0.7%dose). The first-pass splanchnic [sup.13]C-AKG utilization was ~80%, of which 30% was oxidized to [sup.13]C[O.sub.2]. We conclude that the intestinal absorption of AKG is limited in young pigs largely due to substantial first-pass gastrointestinal metabolism.

Total parenteral nutrition (TPN) induces a high rate of liver disease in infants, yet the pathogenesis remains elusive. We used neonatal piglets as an animal model to assess early events leading to TPN-mediated liver injury. Newborn piglets (n = 7) were nourished for 7 d on TPN or enteral nutrition (EN) and the liver tissue and isolated hepatocytes were subjected to morphologic and molecular analysis. Histological analysis revealed prominent steatosis (grade > 2) in 6 of 7 TPN pigs, whereas minimal steatosis (grade [less than or equal to] 1) was observed in only 2 EN pigs. Abundant cytosolic cytochrome C and DNA fragmentation were observed in hepatocytes from TPN compared with EN piglets. Markers of mitochondrial and Fas-mediated apoptosis were altered in TPN liver tissue, as indicated by a lower ATP concentration (P < 0.05), accumulation of ubiquitin, 9.9-fold activation of caspase-3 activity (P < 0.01), and increased cleavage of poly-(ADP-ribose) polymerase, caspase-8, -9, and -7 when compared with EN livers. Bcl-2 and proliferating cell nuclear antigen expression was downregulated, whereas Fas and Bax were upregulated in TPN livers. However, levels of caspase-12 and Bip/GRP78, both markers of endoplasmic reticulum-mediated apoptosis, did not differ between the groups. Short-term TPN induces steatosis and oxidative stress, which results in apoptosis mediated by the mitochondrial and Fas pathways. Thus, TPN-induced steatosis in newborn piglets may serve as a novel animal model to assess the pathogenesis of fatty liver and apoptosis-mediated liver injury in infants.

OBJECTIVES. Previous studies have shown that incidence of invasive candidiasis varies substantially among centers, and previous use of broad-spectrum antibiotics is a risk factor for candidiasis in extremely low birth-weight infants. Differences in center practices, such as antibiotic strategies and the effects of these strategies on center incidence of candidiasis, are not reflected in assessments of an individual&apos;s risk of candidiasis. We evaluated the relationship between empirical antibiotic practices for extremely low birth-weight infants and center incidence of candidiasis. METHODS. We studied a cohort of extremely low birth-weight infants who survived [greater than or equal to] 72 hours and were admitted to 1 of 12 tertiary centers between 1998 and 2001. Multivariable logistic regression was used to validate previous broad-spectrum antibiotics use as a risk factor for subsequent candidiasis in individual infants. We calculated correlation coefficients to assess the relationship between center incidence of candidiasis with antibiotic practice patterns. RESULTS. There were 3702 infants from 12 centers included, and 284 (7.7%) developed invasive candidiasis. Broad-spectrum antibiotics use was associated with candidiasis for individual infants. Center candidiasis incidence ranged from 2.4% to 20.4%. Center incidence of candidiasis was correlated with average broad-spectrum antibiotics use per infant and average use of broad-spectrum antibiotics with negative cultures per infant. CONCLUSIONS. Center incidences of invasive candidiasis differ substantially, and antibiotic practice differences are possible contributors to center variation in candidiasis risk. Key Words antibiotic use, bloodstream infection, candida, candidemia, LBW, extremely low birth weight Abbreviations ELBW--extremely low birth weight BSA-- broad-spectrum antibiotic NEC--necrotizing enterocolitis CC--correlation coefficient, NEONATAL CANDIDIASIS IS associated with high mortality and increased risk of neurodevelopmental impairment among survivors. (1-3) Investigators have identified multiple risk factors for individual infants to develop candidiasis (1,4-6) and [...]

OBJECTIVE. Antenatal dexamethasone and betamethasone may not be equally efficacious in the prevention of adverse neonatal outcomes. We compared the risks of periventricular leukomalacia (PVL), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), and neonatal death among very low birth weight infants who were exposed to dexamethasone, betamethasone, or neither steroid. METHODS. Infants (401-1500 g) in the National Institute of Child Health and Human Development Neonatal Research Network were studied. Multivariate logistic regression analyses compared the 3 groups with regard to PVL, IVH, ROP, and neonatal death, adjusting for network center and selected covariates. RESULTS. A total of 3600 infants met entry criteria. Compared with no antenatal steroids, there were trends for a reduced risk for PVL associated with dexamethasone and betamethasone but no difference in risk between dexamethasone and betamethasone. Dexamethasone reduced the risk for IVH and severe IVH, compared with no antenatal steroid exposure. Betamethasone reduced the risk for IVH, severe IVH, and neonatal death, compared with no antenatal steroids. Compared with betamethasone, dexamethasone had a statistically significant increased risk for neonatal death. There were trends for greater risks associated with dexamethasone compared with betamethasone for IVH and severe ROP. CONCLUSIONS. Betamethasone was associated with a reduced risk for neonatal death, with trends of decreased risk for other adverse neonatal outcomes, compared with dexamethasone. It may be in the best interest of neonates to receive betamethasone rather than dexamethasone when available. Key Words antenatal glucocorticoids, dexamethasone, betamethasone, neonatal morbidity, neonatal mortality, Abbreviations IVH--intraventricular hemorrhage PVL--periventricular leukomalacia ROP--retinopathy of prematurity NICHD--National Institute of Child Health and Human Development VLBW--very low birth weight GA--gestational age OR--odds ratio O--confidence interval PROM--prolonged rupture of membranes [...]

Glucagon-like peptide-2 (GLP-2) is a gut hormone that is secreted in response to enteral feeding and stimulates small intestinal mucosal growth. We have previously shown that GLP-2 infusion acutely increases portal venous blood flow in TPN-fed piglets. The aim of this study was to localize the vasoactive effect of GLP-2 within the gastrointestinal tissues and other visceral organs in TPN-fed piglets. Tissue blood flow rates were quantified using fluorescent microsphere deposition in anesthetized TPN-fed piglets given intravenous infusion of GLP-2 at either 500 pmol*[kg.sup.-1]*[h.sup.-1] (low GLP-2, n = 7 pigs) or 2,000 pmol*[kg.sup.-1*[h.sup.-1] (high GLP-2, n = 8 pigs) for 2 h. Compared with baseline, the low and the high GLP-2 treatment significantly increased the blood flow rate in the duodenum (+77%) and jejunum (+40% and 80%), respectively, but blood flow to the distal small intestine and colon (-15%) was unchanged or slightly decreased. Baseline mucosal blood flow was five-fold higher than serosal blood flow; however, high GLP-2 treatment increased serosal (+ 140%) to a larger degree than mucosal blood flow (+73%). The high GLP-2 dose increased pancreatic flow (+34%) but decreased blood flow in the kidneys (-14%) and stomach (-12%), whereas the spleen and brain were unaffected. These findings suggest that the acute GLP-2-mediated stimulation of portal blood flow in TPN-fed piglets occurs principally via increased blood flow through the superior mesenteric artery to the proximal small intestine, a tissue region where the GLP-2R mRNA abundance and trophic GLP-2 effects are greatest. glucagon-like peptide-2 receptor; mucosal growth; premature infants; enteral feeding; intestinal ischemia

Knowledge of the stimulatory effects of enteral and parenteral (intravenous) feeding on the synthesis and turnover of trypsin would help in the management of acute pancreatitis, because the disease is caused by the premature activation of trypsin. To investigate this, we labeled intravenous infusions with [1-[sup.13]C]leucine and enterals with [[sup.2]H]leucine and measured isotope enrichment of plasma, secreted trypsin, and duodenal mucosal proteins over 6 h by duodenal perfusion/aspiration and endoscopic biopsy. Thirty healthy volunteers were studied during fasting (n = 7), intravenous feeding (n = 6), or postpyloric enteral feeding [duodenal polymeric (n = 6), elemental duodenal (n = 6), and jejunal elemental (n = 5)]. All diets provided 1.5 g*[kg.sup.-1]*[day.sup.-1] protein and 40 kcal*[kg.sup.-1]*[day.sup.-1] energy. Results demonstrated that compared with fasting, enteral feeding increased the rate of appearance (71 [+ or -] 4 vs. 91 [+ or -] 5 min, P = 0.01) and secretion (546 [+ or -] 80 vs. 219 [+ or -] 37 U/h, P = 0.01) of newly labeled trypsin and expanded zymogen stores (1,660 [+ or -] 237 vs. 749 [+ or -] 133 units, P = 0.03). These differences persisted whether the feedings were polymeric or elemental, duodenal, or jejunal. In contrast, intravenous feeding had no effect on basal rates. Differential labeling of the plasma amino acid pool by enteral and intravenous isotope infusions suggested that 35% of absorbed amino acids were retained within the splanchnic bed during enteral feeding and that mucosal protein turnover increased from a fasting rate of 34 [+ or -] 6 to 108 [+ or -] 8%/day (P < 0.05) compared with no change after intravenous feeding. In conclusion, all common forms of enteral feeding stimulate the synthesis and secretion of pancreatic trypsin, and only parenteral nutrition avoids it. pancreatic enzymes; humans; trypsin synthesis; enteral parenteral nutrition

BACKGROUND. Neonatal candidiasis is associated with substantial morbidity and mortality rates. Neurodevelopmental follow-up data for a large multicenter cohort have not been reported. METHODS. Data were collected prospectively for neonates born at RESULTS. The cohort consisted of 4579 infants; 320 of 4579 (7%) developed candidiasis; 307 of 320 had Candida isolated from blood, 27 of 320 had Candida isolated from cerebrospinal fluid, and 13 (48%) of 27 of those with meningitis had negative blood cultures. In multivariate analysis of risk factors on day of life 3, birth weight, cephalosporins, gender, and lack of enteral feeding were associated with development of candidiasis. After diagnosis, most neonates had multiple positive cultures despite antifungal therapy, and 10% of neonates had candidemia for [greater than or equal to] 14 days. Death or neurodevelopmental impairment (NDI) was observed for 73% of extremely low birth weight infants who developed candidiasis. Death and NDI rates were greater for infants who had delayed removal or replacement of central catheters (>1 day after initiation of antifungal therapy), compared with infants whose catheters were removed or replaced promptly. CONCLUSIONS. Blood cultures were negative for approximately one half of the infants with Candida meningitis. Persistent candidiasis was common. Delayed catheter removal was associated with increased death and NDI rates. www.pediatrics.org/cgi/doi/10.1542/ peds.2004-2292 doi:10.1542/peds.2004-2292 The authors had full access to all of the data. The listed authors contributed to generation of the hypotheses (all authors), data collection (B.J.S., A.A.F., W.O., S.D., and R.G.), data analysis (D.K.B., S.A.M., and K.P.), data interpretation (all authors), and writing of the report (all authors). The members of the National institute of Child Health and Human Development Neonatal Research Network contributed to the collection data. Key Words candidiasis, meningitis, sensitivity, specificity, culture, premature infant Abbreviations CSF--cerebrospinal fluid CI--confidence interval DOL--day of life EGA--estimated gestational age ELBW--extremely low birth weight IVH--intraventricular hemorrhage NDI--neurodevelopmental impairment MDI--Mental Developmental Index OR--odds ratio PDA--patent ductus arteriosus PDI--Psychomotor Developmental Index, NEONATAL CANDIDIASIS IS often fatal among premature infants. (1-4) Most reports of neonatal candidiasis are single-center investigations. (2,5-9) Because of the gravity of the condition, newer diagnostic and treatment strategies [...]

Objective. To compare multiple logistic regression and neural network models in predicting death for extremely low birth weight neonates at 5 time points with cumulative data sets, as follows: scenario A, limited prenatal data; scenario B, scenario A plus additional prenatal data; scenario C, scenario B plus data from the first 5 minutes after birth; scenario D, scenario C plus data from the first 24 hours after birth; scenario E, scenario D plus data from the first 1 week after birth. Methods. Data for all infants with birth weights of 401 to 1000 g who were born between January 1998 and April 2003 in 19 National Institute of Child Health and Human Development Neonatal Research Network centers were used (n = 8608). Twenty-eight variables were selected for analysis (3 for scenario A, 15 for scenario B, 20 for scenario C, 25 for scenario D, and 28 for scenario E) from those collected routinely. Data sets censored for prior death or missing data were created for each scenario and divided randomly into training (70%) and test (30%) data sets. Logistic regression and neural network models for predicting subsequent death were created with training data sets and evaluated with test data sets. The predictive abilities of the models were evaluated with the area under the curve of the receiver operating characteristic curves. Results. The data sets for scenarios A, B, and C were similar, and prediction was best with scenario C (area under the curve: 0.85 for regression; 0.84 for neural networks), compared with scenarios A and B. The logistic regression and neural network models performed similarly well for scenarios A, B, D, and E, but the regression model was superior for scenario C. Conclusions. Prediction of death is limited even with sophisticated statistical methods such as logistic regression and nonlinear modeling techniques such as neural networks. The difficulty of predicting death should be acknowledged in discussions with families and caregivers about decisions regarding initiation or continuation of care. logistic models, neural networks (computer), predictive value, receiver operating characteristic curve. ABBREVIATIONS. ELBW, extremely low birth weight; ROC, receiver operating characteristic; AUC, area under the curve; SNAP, Score for Neonatal Acute Physiology; PPV, positive predictive value; NPV, negative predictive value., Extremely low birth weight (ELBW) infants continue to have a disproportionately high mortality rate, compared with larger, more mature infants, despite advances in perinatal and neonatal care. (1-3) Decisions regarding [...]

A randomized trial of hypothermia in infants is conducted with a gestational age of at least 36 weeks who were admitted to the hospital at or before six hours of age with either severe acidosis or perinatal complications and resuscitation at birth and who had moderate or severe encephalopathy. Observations suggest that whole-body hypothermia reduces the risk of death or disability in infants with moderate or severe hypoxic-ischemic encephalopathy.

A multicenter, randomized, blinded, controlled trial is conducted to determine whether inhaled nitric oxide reduced the rate of death or bronchopulmonary dysplasia in premature infants with severe respiratory failure. The results reveal that the use of inhaled nitric oxide in critically ill premature infants weighing less than 1500 g does not decrease the rates of death or bronchopulmonary dysplasia.

The metabolism of sulfur amino acids, methionine and cysteine, has been linked to several key aspects of human health and cellular function. In addition, the metabolism of dietary amino acids by the gastrointestinal tract is nutritionally important for normal function. In the case of sulfur amino acids (SAAs), in vivo, stable isotope studies in adults suggest that the splanchnic tissues utilize as much as 30-44% of the dietary methionine and cysteine. Similarly, the dietary methionine requirement is 30% lower in total parenteral nutrition (TPN)-fed piglets, a condition in which dietary nutrients largely bypass intestinal metabolism. These data suggest that intestinal metabolism of methionine is substantial, yet the intestinal metabolic fate of dietary methionine is largely unknown. Dietary cysteine likely plays a key role in intestinal epithelial antioxidant function as a precursor for glutathione. Moreover, cysteine and glutathione may also regulate epithelial cell proliferation via modulation of redox status. Recent evidence indicates that transformed colonic epithelial cells are capable of methionine transmethylation and transsulfuration. This review discusses the evidence of intestinal SAA metabolism and how this affects nutrient requirements and epithelial function. J. Nutr. 135: 1609-1612, 2005. KEY WORDS: * methionine * cysteine * homocysteine * transmethylation * transsulfuration * neonate

The whole-body threonine requirement in parenterally fed piglets is substantially lower than that in enterally fed piglets, indicating that enteral nutrition induces intestinal processes in demand of threonine. We hypothesized that the percentage of threonine utilization for oxidation and intestinal protein synthesis by the portal-drained viscera (PDV) increases when dietary protein intake is reduced. Piglets (n = 18) received isocaloric normal or protein-restricted diets. After 7 h of enteral feeding, total threonine utilization, incorporation into intestinal tissue, and oxidation by the PDV, were determined with stable isotope methodology [[U.sup.-13]C threonine infusion]. Although the absolute amount of systemic and dietary threonine utilized by the PDV was reduced in proteinrestricted piglets, the percentage of dietary threonine intake utilized by the PDV did not differ between groups (normal protein 91% vs. low protein 85%). The incorporation of dietary threonine into the proximal jejunum was significantly different compared with the other intestinal segments. Dietary, rather than systemic threonine was preferentially utilized for protein synthesis in the small intestinal mucosa in piglets that consumed the normal protein diet (P < 0.05). Threonine oxidation by the PDV was limited during normal protein feeding, in protein-restricted pigs, half of the total whole-body oxidation occurred in the PDV. We conclude that, in vivo, the PDV have a high obligatory visceral requirement for threonine. The high rate of intestinal threonine utilization is due mainly to incorporation into mucosal proteins. KEY WORDS: * amino acid * intestine * nutrition * piglets * threonine

Objectives. Necrotizing enterocolitis (NEC) is a significant complication for the premature infant. However, subsequent neurodevelopmental and growth outcomes of extremely low birth weight (ELBW) infants with NEC have not been well described. We hypothesized that ELBW infants with surgically managed (SurgNEC) are at greater risk for poor neurodevelopmental and growth outcomes than infants with medically managed NEC (MedNEC) compared with infants without a history of NEC (NoNEC). The objective of this study was to compare growth, neurologic, and cognitive outcomes among ELBW survivors of SurgNEC and MedNEC with NoNEC at 18 to 22 months" corrected age. Methods. Multicenter, retrospective analysis was conducted of infants who were born between January 1, 1995, and December 31, 1998, and had a birth weight Results. A total of 2948 infants were evaluated at 18 to 22 months, 124 of whom were SurgNEC and 121 of whom were MedNEC. Compared with NoNEC, both SurgNEC and MedNEC infants were of lower birth weight and had a greater incidence of late sepsis; SurgNEC but not MedNEC infants were more likely to have received a diagnosis of cystic periventricular leukomalacia and bronchopulmonary dysplasia and been treated with postnatal steroids. Weight, length, and head circumference Conclusions. Among ELBW infants, SurgNEC is associated with significant growth delay and adverse neurodevelopmental outcomes at 18 to 22 months&apos; corrected age compared with NoNEC. MedNEC does not seem to confer additional risk. SurgNEC is likely to be associated with greater severity of disease. Pediatrics 2005;115:696-703; necrotizing enterocolitis, extremely low birth weight, neurodevelopmental outcome, cerebral palsy, Bayley Scales of Infant Development, growth., ABBREVIATIONS. NEC, necrotizing enterocolitis; ELBW, extremely low birth weight; VLBW, very low birth weight; SurgNEC, surgically managed necrotizing enterocolitis; MedNEC, medically managed necrotizing enterocolitis; NICHD, National Institute of Child Health [...]

Our aim was to characterize the postprandial total and dietary N fluxes in the portal drained viscera (PDV) and whole body after administration of a single meal in young pigs. Seven 4-wk-old piglets, implanted with a portal flow probe and portal, arterial and venous catheters, received a primed constant [[sup.18]O]urea intravenous infusion and were studied for 8 h after a bolus mixed meal ingestion (46 mmol N/kg body wt) intrinsically labeled with [sup.15]N to trace dietary N fluxes. The real cecal digestibility of the formula was 94.3% (SD 1.8). PDV output of dietary N was found principally in the pool of circulating protein (51% of the measured dietary N PDV output), in the free [alpha]-amino N pool (44%), and to a lesser extent in ammonia (5%). Dietary N release in [alpha]-amino N and ammonia mainly occurred during the first 3 h. Total and exogenous postprandial urea productions were 5.8 and 2.0 mmol N/kg body wt, respectively. At the end of the postprandial period, losses of dietary N amounted to 10.3% of the dose: 5.7% through ileal losses and 4.6% by deamination and transfer to urea. Net postprandial retention of dietary N was 90.4% (SD 1.3), of which 20% was found in splanchnic zone (small intestine 10%, liver 5%, and plasma protein 3%) and 42% in peripheral zone (muscle 31%, skin 6%). In conclusion, our results show a high efficiency of dietary N utilization for muscular uptake and anabolic utilization. However, the results obtained point out the necessity to further explore the form of dietary N released into the portal blood. dietary nitrogen; postprandial metabolism; portal drained viscera; nonsteady state; pigs

Neonatal infections are frequent complications of extremely low-birth-weight (ELBW) infants receiving intensive care. The objective of the study is to determine if neonatal infections in ELBW infants are associated with risks of adverse neurodevelopment and growth sequelae in early childhood.

Enteral L-glutamate is extensively utilized as an oxidative fuel by the gut mucosa in the neonate. To identify major uptake pathways and to understand uptake regulation, we examined transport kinetics and molecular identities of apical membrane L-glutamate transporters in epithelial cells sequentially isolated along the small intestinal crypt-villus axis from milk protein-fed, 16-day-old pigs. The distended intestinal sac method was used to isolate t2 sequential cell fractions from the tip villus to the bottom crypt. Initial rates and kinetics of L-glutamate uptake were measured with L-[G-[sup.3]H]glutamate by fast filtration in apical membrane vesicles prepared by [Mg.sup.2+] precipitation and differential centrifugation, with membrane potential clamped by SC[N.sup.-]. Initial L-glutamate uptake results suggested the presence of [B.sup.o] and [X.sup.-.sub.AG]. transport systems, but the [X.sup.-.sub.AG] system was predominant for uptake across the apical membrane. Kinetic data suggested that L-glutamate uptake through the [X.sup.-.sub.AG] system was associated with higher maximal transport activity but lower transporter affinity in crypt than in villus cells. Molecular identity of the [X.sup.-.sub.AG] glutamate transporter, based on immunoblot and RT-PCR analysis, was primarily the defined excitatory amino acid carrier (EAAC)-1. EAAC-1 expression was increased with cell differentiation and regulated at transcription and translation levels from crypt to upper villus cells. In conclusion, efficiency and capacity of luminal L-glutamate uptake across the apical membrane are regulated by changing expression of the [X.sup.-.sub.AG] system transporter gene EAAC-1 at transcription and translation levels as well as maximal uptake activity and transporter affinity along the intestinal crypt-villus axis in the neonate. excitatory amino acids; gut mucosa; transporter affinity; gene expression; neonates

Our aim was to determine the speed of onset of total parenteral nutrition (TPN)-induced mucosal atrophy, and whether this is associated with changes in intestinal blood flow and tissue metabolism in neonatal piglets. Piglets were implanted with jugular venous and duodenal catheters and either a portal venous or superior mesenteric artery (SMA) blood flow probe. At 3 wk of age, piglets were randomly assigned to receive continuous enteral formula feeding (n = 8) or TPN (n = 17) for 24 or 48 h. Blood flow was recorded continuously and piglets were given an i.v. bolus of bromodeoxyuridine and [sup.13]C-phenylalanine to measure crypt cell proliferation and protein synthesis, respectively. After 8 h of TPN, portal and SMA blood flow decreased 30% compared with enteral feeding (P < 0.01), and remained near levels of food-deprived piglets for the remaining 48 h of TPN. After 24 h, TPN reduced jejunal inducible nitric oxide synthase (iNOS) activity and protein abundance (P < 0.05), small intestinal weight, and villous height (P < 0.01) compared with enterally fed piglets. Cell proliferation and DNA mass were decreased (P < 0.05) and apoptosis increased (P < 0.05) after 48 h of TPN. Protein synthesis was lower (P < 0.05) after 24 h of TPN, and protein mass was lower (P < 0.05) after 48 h of TPN, compared with enteral feeding. These data indicate that the transition from enteral to parenteral nutrition induced a rapid ( KEY WORDS: * enteral nutrition * intestinal adaptation * nitric oxide synthase * cell proliferation * protein synthesis

Background. Glutamine is one of the most abundant amino acids in both plasma and human milk, yet it is not included in standard intravenous amino acid solutions. Previous studies have suggested that parenteral nutrition (PN) supplemented with glutamine may reduce sepsis and mortality in critically ill adults. Whether glutamine supplementation would provide a similar benefit to extremely low birth weight (ELBW) infants is not known. Methods. We performed a multicenter, randomized, double-masked, clinical trial to assess the safety and efficacy of early PN supplemented with glutamine in decreasing the risk of death or late-onset sepsis in ELBW infants. Infants 401 to 1000 g were randomized within 72 hours of birth to receive either TrophAmine (control) or an isonitrogenous study amino acid solution with 20% glutamine whenever they received PN up to 120 days of age, death, or discharge from the hospital. The primary outcome was death or late-onset sepsis. Results. Of the 721 infants who were assigned to glutamine supplementation, 370 (51%) died or developed late-onset sepsis, as compared with 343 of the 712 infants (48%) assigned to control (relative risk: 1.07; 95% confidence interval: 0.97-1.17). Glutamine had no effect on tolerance of enteral feeds, necrotizing enterocolitis, or growth. No significant adverse events were observed with glutamine supplementation. Conclusions. Parenteral glutamine supplementation as studied did not decrease mortality or the incidence of late-onset sepsis in ELBW infants. Consequently, although no harm was demonstrated, routine use of parenteral glutamine supplementation cannot be recommended in this population. ABBREVIATIONS. PN, parenteral nutrition; ELBW, extremely low birth weight; RIK relative risk; CI, confidence interval., Although glutamine is the most abundant amino acid in both plasma and human milk, (1) it is not included in standard intravenous amino acid solutions because of its limited stability [...]

Context. Neonatal meningitis is associated with significant morbidity and mortality. We speculated that meningitis may be underdiagnosed among very low birth weight (VLBW) infants because of the failure to perform lumbar punctures (LPs) in infants with suspected sepsis. Objective. This study was undertaken to review the epidemiology of late-onset meningitis in VLBW (401-1500 g) infants and to evaluate the concordance of cerebrospinal fluid (CSF) and blood culture (BC) results. Methods. VLBW infants (excluding those with intraventricular shunts) born at centers of the National Institute of Child Health and Human Development Neonatal Research Network from September 1, 1998, through December 31, 2001, were studied. Late-onset meningitis was defined by culture-based criteria and classified as meningitis with or without associated sepsis. Unadjusted comparisons were made using [chi square] tests and adjusted comparisons using regression models. Results. Of 9641 VLBW infants who survived >3 days, 2877 (30%) had [greater than or equal to] 1 LPs, and 6056 (63%) had [greater than or equal to] 1 BC performed after day 3. One hundred thirty-four infants had late-onset meningitis (1.4% of all patients; 5% of those with an LP). Pathogens associated with meningitis were similar to those associated with sepsis. One third (45 of 134) of the infants with meningitis had negative BCs. Lower gestational age and prior sepsis increased risk for meningitis. Compared with uninfected infants, those with meningitis had a longer time on mechanical ventilation (28 vs 18 days), had longer hospitalizations (91 vs 79 days), were more likely to have seizures (25% vs 2%), and were more likely to the (23% vs 2%). Conclusions. Meningitis is a serious complication among VLBW infants, associated with increased severity of illness and risk of death. Of note, one third of the infants with meningitis had meningitis in the absence of sepsis. Because CSF cultures were performed only half as often as BCs, this discordance in blood and CSF culture results suggests that meningitis may be under-diagnosed among VLBW infants. Pediatrics 2004;113: 1181-1186; meningitis, sepsis, lumbar puncture, very low birth weight infants., ABBREVIATIONS. LP, lumbar puncture; VLBW, very low birth weight; LOM, late-onset meningitis; NICHD, National Institute of Child Health and Human Development; BC, blood culture; CSF, cerebrospinal fluid; CONS, coagulase-negative staphylococcus; [...]