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1.  Hypoxia at the heart of sudden infant death syndrome? 
Pediatric research  2013;74(4):375-379.
Sudden infant death syndrome (SIDS) remains a significant clinical problem without an accepted pathological mechanism, but with multiple conflicting models. Mutation in a growing number of genes has been found post mortem in SIDS cases, notably genes encoding ion channels. This can only account for a minority of cases, however. Our recent work on a novel mouse model of SIDS suggests a potentially more widespread role for cardiac arrhythmia in SIDS without needing to invoke inheritance of abnormal ion channel genes. We propose a model for SIDS pathogenesis whereby postnatal hypoxia leads to delayed maturation of the cardiac conduction system and an increased risk of cardiac arrhythmia. Our model may integrate several epidemiological findings related to risks factors for SIDS, and agrees with previous work suggesting a common final pathological pathway in SIDS.
doi:10.1038/pr.2013.122
PMCID: PMC3977030  PMID: 23863852
2.  Rosiglitazone preserves pulmonary vascular function in lambs with increased pulmonary blood flow 
Pediatric research  2012;73(1):54-61.
Background
Pulmonary vascular function is impaired with increased pulmonary blood flow (PBF). We hypothesized that a peroxisome proliferator-activated receptor-gamma (PPARγ) agonist would mitigate this effect.
Methods
An aorta to pulmonary artery shunt was placed in 11 fetal lambs. Lambs received the PPARγ agonist rosiglitazone (RG, 3 mg/kg/day, n=6) or vehicle (n=5) for 4-weeks. Lung tissue from 5 normal 4-week lambs was used for comparisons.
Results
At 4-weeks, pulmonary artery pressure (PAP) and vascular resistance (PVR) decreased with inhaled NO in RG and vehicle-treated shunt lambs. PAP and PVR decreased with acetylcholine in RG-treated, not vehicle-treated shunt lambs. In vehicle-treated shunt lambs, NADPH oxidase activity, rac1, superoxide, and 3-nitrotyrosine (3-NT) levels were increased and Ser1177 endothelial NO synthase (eNOS) protein was decreased compared to normal lambs. In RG-treated shunt lambs, NOX, Ser1177 eNOS protein and eNOS activity were increased, and NADPH activity, rac1, superoxide levels and 3-NT levels were decreased, compared to vehicle-treated shunt lambs. PPARγ protein expression was lower in vehicle-treated shunt lambs than normal and RG-treated shunt lambs.
Conclusions
The PPARγ agonist, RG, prevents the loss of agonist induced endothelium-dependent pulmonary vascular relaxation in lambs with increased PBF, in part, due to decreased oxidative stress and/or increased NO production.
doi:10.1038/pr.2012.149
PMCID: PMC3977665  PMID: 23128423
3.  Arginine and citrulline protect intestinal cell monolayer tight junctions from hypoxia-induced injury in piglets 
Pediatric research  2012;72(6):576-582.
Background
Arginine (Arg) is deficient in the serum of the preterm neonate and is lower in those developing intestinal ischemia. We investigated whether Arg or its precursor, citrulline (Cit), protects intestinal tight junctions (TJs) from hypoxia (HX) and determined whether inducible nitric oxide (NO) plays a role.
Methods
Neonatal piglet jejunal IPEC-J2 cell monolayers were treated with Arg or Cit, reversible and irreversible NO synthetase (NOS) inhibitors, and were exposed to HX. TJs were assessed by serial measurements of transepithelial electrical resistance (TEER), flux of inulin-fluorescein isothiocyanate, and immunofluorescent staining of TJ proteins.
Results
We found that Arg and Cit were protective against HX-related damage. At the final time point (14 h), the mean TEER ratio (TEER as compared with baseline) for Arg + HX and Cit + HX was significantly higher than that for HX alone. Both Arg and Cit were associated with decreased inulin flux across hypoxic monolayers and qualitatively preserved TJ proteins. Irreversible inhibition of NOS blocked this protective effect. Lipid peroxidation assay showed that our model did not produce oxidant injury.
Conclusion
Arg and Cit, via a mechanism dependent on NO donation, protected intestinal epithelial integrity.
doi:10.1038/pr.2012.137
PMCID: PMC3976428  PMID: 23041662
4.  Effects of nonocclusive mesenteric hypertension on intestinal function: implications for gastroschisis-related intestinal dysfunction 
Pediatric research  2012;71(6):668-674.
INTRODUCTION
Infants with gastroschisis (GS) have significant morbidity from dysmotility, feeding intolerance, and are at increased risk of developing intestinal failure. Although the molecular mechanisms regulating GS-related intestinal dysfunction (GRID) are largely unknown, we hypothesized that mechanical constriction (nonocclusive mesenteric hypertension (NMH)) from the abdominal wall defect acts as a stimulus for GRID. The purpose of this study was to determine the effect of NMH on intestinal function and inflammation.
METHODS
Neonatal rats had placement of a silastic disk to the base of the mesentery (NMH) or no disk placement (sham). At 24 and 72 h, mesenteric venous pressures (MVPs), intestinal transit, electric impedance, permeability, length, and tissue water content were measured.
RESULTS
After placement of the silastic disk, there was a significant increase in MVP at both time points. There was also decreased intestinal transit. As compared to Sham animals, NMH animals had significant changes in bowel impedance without an increase in tissue water, suggesting significant intestinal remodeling. NMH rats had significantly increased smooth-muscle thickness and loss of intestinal length as compared with Sham rats.
DISCUSSION
NMH may be an initiating factor for GRID. Measurement of MVP and/or bowel impedance may be a way to assess severity and monitor progression and/or resolution of GRID.
doi:10.1038/pr.2012.20
PMCID: PMC3974566  PMID: 22476046
5.  Kinetics of procalcitonin and C-reactive protein and the relationship to postoperative infection in young infants undergoing cardiovascular surgery 
Pediatric research  2013;74(4):413-419.
Background
The utility of procalcitonin and C-reactive protein (CRP) as infectious biomarkers following infant cardiothoracic surgery is not well defined.
Methods
We designed a prospective cohort study to evaluate procalcitonin and CRP after infant cardiothoracic surgery. Procalcitonin and CRP were drawn pre-operatively and 24/72 hours post-operation or daily in delayed sternal closure patients. Presence of infection within 10 days of surgery, vasoactive-inotropic scores at 24 and 72 hours, and length of intubation, intensive care unit stay, and hospital stay were documented.
Results
Procalcitonin and CRP were elevated at 24 hours. Procalcitonin then decreased while CRP increased in patients undergoing delayed sternal closure or cardiopulmonary bypass. In the delayed sternal closure group, procalcitonin was significantly higher on post-operative days 2–5 in patients who ultimately developed infection. Higher procalcitonin was independently associated with increased vasoactive-inotropic score at 72 hours. CRP did not correlate with infection or post-operative support.
Conclusions
Procalcitonin rises after cardiothoracic surgery in infants but decreases by 72 hours while CRP remains elevated. Sternal closure may affect CRP but not procalcitonin. Procalcitonin is independently associated with circulatory support requirements at 72 hours post-operation and development of infection. Procalcitonin may have greater utility as a biomarker in this population.
doi:10.1038/pr.2013.124
PMCID: PMC3955993  PMID: 23863853
6.  Necrotizing Enterocolitis is associated with Ureaplasma Colonization in Preterm Infants 
Pediatric research  2011;69(5 0 1):442-447.
The study objective was to determine whether Ureaplasma respiratory tract colonization of preterm infants <33 weeks gestation is associated with an increased risk for necrotizing enterocolitis (NEC). One or more tracheal or nasopharyngeal aspirates for Ureaplasma culture and PCR were obtained during the first week of life from 368 infants <33 weeks gestation enrolled from 1999-2003 or from 2007-2009. NEC Bell stage ≥2 was confirmed by radiological criteria, and pathology, if available. Cord serum samples were analyzed for IL-6 and IL-1β concentrations and placentas were reviewed for histological chorioamnionitis in the first cohort. NEC was confirmed in 29/368 (7.9%) of the combined cohorts. The incidence of NEC was 2.2-fold higher in Ureaplasma-positive (12.3%) than Ureaplasma-negative infants (5.5%) <33 wk (OR 2.43, 95%CI 1.13-5.22, P=0.023) and 3.3-fold higher in Ureaplasma-positive (14.6%) than Ureaplasma-negative (4.4%) infants ≤28 wks (OR 3.67, 95%CI 1.36-9.93, P=0.01). Age of onset, hematologic parameters at onset, and NEC severity were similar between Ureaplasma-positive and negative infants. Cord serum IL-6 and IL-1β concentrations were significantly higher in Ureaplasma-positive than in Ureaplasma-negative NEC-affected infants. Ureaplasma may be a factor in NEC pathogenesis in preterm infants by contributing to intestinal mucosal injury and/or altering systemic or local immune responses.
doi:10.1203/PDR.0b013e3182111827
PMCID: PMC3968774  PMID: 21258263
7.  Postnatal infection is associated with widespread abnormalities of brain development in premature newborns 
Pediatric research  2012;71(3):274-279.
Infection is a risk factor for adverse neurodevelopmental outcome in preterm newborns. Our objective was to characterize the association of postnatal infection with adverse microstructural and metabolic brain development in premature newborns. One hundred seventeen preterm newborns (24–32 weeks gestation) were studied prospectively at a median of 32.0 and 40.3 weeks postmenstrual age: MRI (white matter injury, hemorrhage), MR (magnetic resonance) spectroscopy (metabolism) and diffusion tensor imaging (microstructure). Newborns were categorized as having “no infection”, “clinical infection”, or “positive-culture infection.” We compared brain injuries, as well as metabolic and microstructural development across these infection groups. In 34 newborns, clinical signs were accompanied by positive cultures while 17 had clinical signs of sepsis alone. White matter injury was identified in 34 newborns. In multivariate regression models infected newborns had brain imaging measures indicative of delayed brain development: lower N-acetylaspartate/choline, elevated average diffusivity (DAV) and decreased white matter fractional anisotropy. These widespread brain abnormalities were found in both newborns with positive-culture infection and in those with clinical infection. These findings suggest that postnatal infection, even without a positive culture, is an important risk factor for widespread abnormalities in brain. These abnormalities extend beyond brain injuries apparent with conventional MRI.
doi:10.1038/pr.2011.40
PMCID: PMC3940469  PMID: 22278180 CAMSID: cams4005
8.  POSTWEANING EXPOSURE TO A HIGH FAT DIET IS ASSOCIATED WITH ALTERATIONS TO THE HEPATIC HISTONE CODE IN JAPANESE MACAQUES 
Pediatric research  2013;74(3):252-258.
Background
Expression of the circadian gene, Npas2, is altered in fetal life with maternal high fat diet exposure by virtue of alterations in the fetal histone code. We postulated that these disruptions would persist postnatally.
Methods
Pregnant macaques were fed a control (CTR) or high fat (HF) diet and delivered at term. When offspring were weaned, they were placed on either CTR or HF diet for a period of 5 months to yield four exposure models (in utero diet/postweaning diet: CTR/CTR n = 5; CTR/HF n = 4; HF/CTR n = 4; HF/HF n = 5). Liver specimens were obtained at necropsy at one year of age.
Results
Hepatic trimethylation of lysine 4 of histone H3 is decreased, (CTR/HF 0.87-fold, P = 0.038; HF/CTR 0.84-fold, P = 0.038) while hepatic methyltransferase activity increased by virtue of diet exposure (HF/HF 1.3-fold, P = 0.019). Using chromatin immunoprecipitation to determine Npas2 promoter occupancy, we found alterations of both repressive and permissive histone modifications specifically with postweaning high fat diet exposure.
Conclusion
We find altered Npas2 expression corresponds with a change in the histone code within the Npas2 promoter.
doi:10.1038/pr.2013.106
PMCID: PMC3766448  PMID: 23788059
9.  Math1, Retinoic Acid, and TNFα Synergistically Promote the Differentiation Of Mucous Cells in Mouse Middle Ear Epithelial Cells In Vitro 
Pediatric research  2013;74(3):259-265.
Background
A key issue in otitis media (OM) is mucous cell metaplasia in the middle ear mucosa, a condition for hyperproduction of mucus in the middle ear mucosa and development of chronic OM. However, little is known about the driving force for the differentiation of mucous cells in OM.
Methods
Mouse middle ear epithelial cells (mMEEC) were used in this study to test whether Math1, a critical transcription factor for the development of mucous cells in the intestine, synergize with inflammatory cytokines (tumor necrotic factor alpha, TNFα) and other epithelial differentiation factors (retinoid acid, RA) to induce the differentiation of mMEEC into mucus-like cells in vitro. Simultaneously, Math1 was transduced into the middle ear mucosa and see whether it induces mucous cell hyperplasia in vivo.
Results
Math1 significantly increased the mucus cell numbers in the middle ear mucosa of mice. Math1, in the presence of TNFα and epithelial differentiation factor retinoic acid (RA), synergistically promoted the differentiation of mMEEC into mucus-like cells via upregulation of mucins and their chaperones:trefoil factors (TFFs) in vitro. RA treatment for 12 hours activated Math1 although RA alone had very limited effects on mucus-like cell differentiation.
Conclusion
Math1 plays a critical role in the pathogenesis of OM by induction of mucous cell differentiation, in the presence of TNFα and RA.
doi:10.1038/pr.2013.103
PMCID: PMC3766487  PMID: 23783432
10.  Placental miRNA Expression Profiles Associated with Measures of Infant Neurobehavioral Outcomes 
Pediatric research  2013;74(3):272-278.
Background
A growing body of research suggests that the intrauterine environment influences fetal neurodevelopment by altering the functional placental epigenome. A number of miRNAs are expressed in the placenta, may be sensitive to dysregulation by environmental exposures, and are associated with adverse pregnancy outcomes. Our study aimed to identify relationships between placental miRNA expression and newborn neurobehavior.
Methods
We examined the association between the expression of miR-16, miR-21, miR-93, miR-135b, miR-146a, and miR-182 in total RNA from the placentas of 86 term infants as measured by quantitative real-time PCR and newborn neurobehavioral outcomes as assessed using the NICU Network Neurobehavioral Scales (NNNS).
Results
Bivariate analysis revealed that placental miR-16 expression is negatively associated with attention score (p=0.006), while expression of miR-146a and miR-182 are both positively associated with quality of movement score (p=0.016 and p=0.016, respectively). Controlling for potential confounders, high miR-16 expression is significantly associated with reduced attention score (p=0.04), and high miR-146a expression and high miR-182 expression are significantly associated with increased quality of movement score (p=0.04 and p=0.01, respectively).
Conclusions
These results suggest that placental miRNA expression is associated with early neurobehavioral outcomes and miRNAs in the placenta may contribute to the developmental origins of infant neurobehavior.
doi:10.1038/pr.2013.102
PMCID: PMC3766495  PMID: 23783433
11.  The Longitudinal Trajectory of Vitamin D Status from Birth to Early Childhood on the Development of Food Sensitization 
Pediatric research  2013;74(3):321-326.
Background
Increasing evidence supports the immunomodulatory effect of vitamin D on allergic diseases. The combined role of prenatal and postnatal vitamin D status in the development of food sensitization (FS) and food allergy remains under-studied.
Methods
460 children in the Boston Birth Cohort had plasma 25(OH)D measured at birth and early childhood, and were genotyped for rs2243250 (C-590T) in the IL4 gene. We defined FS as specific IgE ≥0.35kUA/L to any of eight common food allergens; and persistently low vitamin D status as cord blood 25(OH)D <11ng/ml and postnatal 25(OH)D <30ng/ml.
Results
We observed a moderate correlation between cord blood 25(OH)D at birth and venous blood 25(OH)D measured at 2–3 years (r=0.63), but a weak correlation at <1 year (r=0.28). There was no association between low vitamin D status and FS at any single time point alone. However, in combination, persistence of low vitamin D status at birth and early childhood increased the risk of FS (OR=2.03, 95%CI:1.02–4.04), particularly among children carrying the C allele of rs2243250 (OR=3.23, 95%CI:1.37–7.60).
Conclusions
Prenatal and early postnatal vitamin D levels, along with individual genetic susceptibility, should be considered in assessing the role of vitamin D in the development of FS and food allergy.
doi:10.1038/pr.2013.110
PMCID: PMC3773018  PMID: 23797532
12.  Pancreatic lipase-related protein 2 digests fats in human milk and formula in concert with gastric lipase and carboxyl ester lipase 
Pediatric research  2013;74(2):127-132.
INTRODUCTION
Dietary fats must be digested into fatty acids and monoacylglycerols prior to absorption. In adults, colipase-dependent pancreatic triglyceride lipase (PTL) contributes significantly to fat digestion. In newborn rodents and humans, the pancreas expresses low levels of PTL. In rodents, a homologue of PTL, pancreatic lipase related protein 2 (PLRP2) and carboxyl ester lipase (CEL) compensate for the lack of PTL. In human newborns, the role for PLRP2 in dietary fat digestion is unclear. To clarify the potential of human PLRP2 to influence dietary fat digestion in newborns, we determined PLRP2 activity against human milk and infant formula.
METHODS
The activity of purified recombinant PLRP2, gastric lipase and CEL against fats in human milk and formula was measured with each lipase alone and in combination with a standard pH-stat assay.
RESULTS
Colipase added to human milk stimulated fat digestion. PLRP2 and CEL had activity against human milk and formula. Pre-digestion with gastric lipase increased PLRP2 activity against both substrates. Together, CEL and PLRP2 activity was additive with formula and synergistic with human milk.
CONCLUSIONS
PLRP2 can digest fats in human milk and formula. PLRP2 acts in concert with CEL and gastric lipase to digest fats in human milk in vitro.
doi:10.1038/pr.2013.90
PMCID: PMC3737390  PMID: 23732775
13.  Growth Inhibition and Compensation in Response to Neonatal Hypoxia in Rats 
Pediatric research  2013;74(2):111-120.
Background
Hypoxia is an important disease mechanism in prematurity, childhood asthma and obesity. In children, hypoxia results in chronic inflammation.
Methods
We investigated the effects of hypoxia (Hx) (12% O2) during postnatal day 2 to 20 in rats. Control groups were normoxic (Nc), and normoxic growth restricted (14 pup liters) (Gr).
Results
Hypoxia decreased growth similar Gr. Hx increased plasma TNFα and IL-6 and decreased IGF-I and VEGF. Hypoxia resulted in right ventricular (RV) hypertrophy but disproportionate decrements in limb skeletal muscle (SM) growth. miR206 was depressed in the hypertrophied RV of Hx rats while increased in growth retarded SM. Hx resulted in a decreased RV mRNA for myostatin but had no effect on SM myostatin. The mRNA for hypoxia sensitive factors such as HIFα was depressed in the RV of Hx rats suggesting negative feedback.
Conclusion
The results indicate that Hx induces a proinflammatory state that depresses growth regulating mechanisms and that tissues critical for survival, such as the heart, can escape from this general regulatory program to sustain life. This study identifies accessible biomarkers for evaluating the impact of interventions designed to mitigate the long-term deleterious consequences of hypoxia that all too often occur in babies born prematurely.
doi:10.1038/pr.2013.80
PMCID: PMC3737398  PMID: 23842077
14.  Bone mineral content and density in Rett syndrome and their contributing factors 
Pediatric research  2011;69(4):293-298.
This study used densitometry to investigate the areal bone mineral density (aBMD) and bone mineral content (BMC) in an Australian Rett syndrome cohort and assess how factors such as genotype, epilepsy, BMI and mobility affect these parameters. The influence of lean tissue mass (LTM) and bone area (BA) on total body BMC (TBBMC) was also investigated. Participants, recruited from the Australian Rett Syndrome Database (ARSD), had TBBMC and lumbar spine (LS) and femoral neck (FN) aBMD measured using Dual energy X-ray absorptiometry. Mean height standardised z-scores and confidence intervals for the bone outcomes were obtained from multiple regression models. The mean height z-score for the FN aBMD was low at −2.20, while the LS aBMD was −0.72. The TBBMC mean height z-score was −0.62, although once adjusted for BA and LTM the mean was above zero, suggesting that low BMC can be explained by narrow bones and decreased muscle mass, likely secondary to decreased mobility. Multiple linear regression identified the p.R168X and p.T158M mutations as the strongest predictors of low aBMC and BMD for all bone outcomes. The strong relation between genotype, BMC and aBMD, is likely underpinned by the strong relation between LTM, mobility and bone outcome measures.
doi:10.1203/PDR.0b013e31820b937d
PMCID: PMC3906210  PMID: 21178825
15.  Lucinactant attenuates pulmonary inflammatory response, preserves lung structure, and improves physiologic outcomes in a preterm lamb model of RDS 
Pediatric research  2012;72(4):375-383.
Background
Acute inflammatory responses to supplemental oxygen and mechanical ventilation have been implicated in the pathophysiological sequelae of respiratory distress syndrome (RDS). Although surfactant replacement therapy (SRT) has contributed to lung stability, the effect on lung inflammation is inconclusive. Lucinactant contains sinapultide (KL4), a novel synthetic peptide that functionally mimics surfactant protein B, a protein with anti-inflammatory properties. We tested the hypothesis that lucinactant may modulate lung inflammatory response to mechanical ventilation in the management of RDS and may confer greater protection than animal-derived surfactants.
Methods
Preterm lambs (126.8 ± 0.2 SD d gestation) were randomized to receive lucinactant, poractant alfa, beractant, or no surfactant and studied for 4 h. Gas exchange and pulmonary function were assessed serially. Lung inflammation biomarkers and lung histology were assessed at termination.
Results
SRT improved lung compliance relative to no SRT without significant difference between SRT groups. Lucinactant attenuated lung and systemic inflammatory response, supported oxygenation at lower ventilatory requirements, and preserved lung structural integrity to a greater degree than either no SRT or SRT with poractant alfa or beractant.
Conclusion
These data suggest that early intervention with lucinactant may more effectively mitigate pulmonary pathophysiological sequelae of RDS than the animal-derived surfactants poractant alfa or beractant.
doi:10.1038/pr.2012.96
PMCID: PMC3888789  PMID: 22821059
16.  High and Low Dose OPG-Fc Cause Osteopetrosis-Like Changes in Infant Mice 
Pediatric research  2012;72(5):495-501.
Background
Receptor Activator of Nuclear Factor-κB ligand (RANKL) inhibitors are being considered for use in children with osteogenesis imperfecta (OI). We sought to assess efficacy of two doses of a RANKL inhibitor, OPG-Fc, in a growing animal model of OI, the col1α2-deficient mouse (oim/oim) and its wildtype controls (+/+).
Methods
Treated mice showed runting and radiographic evidence of osteopetrosis with either high (20 mg/kg twice weekly) or low dose (1 mg/kg/week) OPG-Fc. Because of this adverse event, OPG-Fc treatment was halted and the mice were euthanized or monitored for recovery with monthly radiographs and assessment of serum osteoclast activity (TRACP-5b) until 25 weeks of age.
Results
Twelve weeks of OPG-Fc treatment resulted in radiographic and histologic osteopetrosis with no evidence of bone modeling and negative Tartrate-resistant acid phosphatase (TRAP) staining, root dentin abnormalities, and TRACP-5b activity suppression. Signs of recovery appeared four to eight weeks post-treatment cessation.
Conclusion
Both high and low dose OPG-Fc treatment resulted in osteopetrotic changes in infant mice, an outcome not seen in studies with the RANKL inhibitor RANK – Immunoglobulin Fc segment complex (RANK-Fc), or in studies with older animals. Further investigations of RANKL inhibitors prior to their consideration for use in children are necessary.
doi:10.1038/pr.2012.118
PMCID: PMC3888234  PMID: 22926546
17.  The Iron Supplementation Dose for Perinatal Iron Deficiency Differentially Alters the Neurochemistry of Frontal Cortex and Hippocampus in Adult Rats 
Pediatric research  2012;73(1):31-37.
Background
Long-term prefrontal cortex and hippocampus-based cognitive deficits are the sequelae of perinatal iron deficiency, despite iron supplementation starting in the newborn period. Whether high dose iron supplementation prevents these deficits is not known.
Methods
Perinatal iron deficiency was induced in rat pups using low-iron (3 mg/kg diet) diet during gestation until postnatal day (P) 8. Iron was supplemented using standard (40 mg/kg diet) or 10-fold higher (400 mg/kg diet) iron-containing diet until P21. Prefrontal cortex and hippocampal neurochemistry was determined using in vivo 1H nuclear magnetic resonance spectroscopy at 9.4 tesla on P90.
Results
Both iron supplementation doses corrected anemia and brain iron deficiency by P21. The neurochemical profile of the prefrontal cortex in both supplementation groups was comparable to the control group. In the hippocampus, standard-dose iron supplementation resulted in lower N-acetylaspartate and phosphoethanolamine, and higher N-acetylaspartylglutamate and glycerophosphocholine + phosphocholine concentrations. High-dose iron supplementation resulted in lower phosphoethanolamine and higher glycerophosphocholine + phosphocholine concentrations.
Conclusions
The iron supplementation dose for perinatal iron deficiency differentially alters the neurochemical profile of the prefrontal cortex and hippocampus in adulthood. The neurochemical changes suggest altered glutamatergic neurotransmission, hypomyelination and abnormal phospholipid metabolism in the formerly iron-deficient hippocampus.
doi:10.1038/pr.2012.143
PMCID: PMC3563322  PMID: 23095980
18.  L-Carnitine Preserves Endothelial Function in a Lamb Model of Increased Pulmonary Blood Flow 
Pediatric research  2013;74(1):39-47.
Background
In our model of congenital heart disease (CHD) with increased pulmonary blood flow (Shunt), we have recently shown a disruption in carnitine homeostasis, associated with mitochondrial dysfunction and decreased eNOS/Hsp90 interactions that contribute to eNOS uncoupling, increased superoxide levels, and decreased bioavailable NO. Thus, we undertook this study to test the hypothesis that L-carnitine therapy would maintain mitochondrial function, and NO signaling.
Methods
Thirteen fetal lambs underwent in utero placement of an aortopulmonary graft. Immediately following delivery, lambs received daily treatment with oral L-carnitine or its vehicle.
Results
L-carnitine-treated lambs had decreased levels of acyl carnitine, and a reduced acyl carnitine: free carnitine ratio compared to vehicle treated Shunt lambs. These changes correlated with increased carnitine acetyl transferase (CrAT) protein and enzyme activity and decreased levels of nitrated CrAT. The lactate: pyruvate ratio was also decreased in L-carnitine-treated lambs. Hsp70 protein levels were significantly decreased and this correlated with increases in eNOS/Hsp90 interactions, NOS activity, NOx levels, and a significant decrease in eNOS-derived superoxide. Further, acetylcholine significantly decreased left pulmonary vascular resistance (PVR) only in L-carnitine-treated lambs.
Conclusion
L-carnitine therapy may improve the endothelial dysfunction noted in children with CHD, and has important clinical implications that warrant further investigation.
doi:10.1038/pr.2013.71
PMCID: PMC3709010  PMID: 23628882
19.  Fetal and infant growth predict hip geometry at six years old: Findings from the Southampton Women’s Survey 
Pediatric research  2013;74(4):450-456.
Background
We investigated relationships between early growth and proximal femoral geometry at age six years in a prospective population-based cohort, the Southampton Women’s Survey.
Methods
In 493 mother-offspring pairs we assessed linear size (individual measure dependent on developmental stage) using high-resolution ultrasound at 11, 19 and 34 weeks gestation (femur length) and at birth, 1, 2, 3, 4 and 6 years (crown-heel length/height). Standard deviation (SD)-scores were created and conditional regression modelling generated mutually independent growth variables. Children underwent hip DXA (Dual X-ray absorptiometry) at 6 years (Hologic Discovery, Hologic Inc., MA); hip structure analysis software yielded measures of geometry and strength.
Results
There were strong associations between early linear growth and femoral neck section modulus (Z) at 6 years, with the strongest relationships observed for femur growth from 19-34 weeks gestation (β=0.26 cm3/SD, p<0.0001), and for height growth from birth to 1 year (β=0.25 cm3/SD, p<0.0001) and 1-2 years (β=0.33 cm3/SD, p<0.0001), with progressively weaker relationships over years 3 (β=0.23 cm3/SD, p=0.0002) and 4 (β=0.10 cm3/SD, p=0.18).
Conclusions
These results demonstrate that growth before age 3 years predicts proximal femoral geometry at six years old. The data suggest critical periods in which there is capacity for long term influence on the later skeletal growth trajectory.
doi:10.1038/pr.2013.119
PMCID: PMC3797011  PMID: 23857297
20.  Erythropoietin Signaling Promotes Oligodendrocyte Development Following Prenatal Systemic Hypoxic-Ischemic Brain Injury 
Pediatric research  2013;74(6):10.1038/pr.2013.155.
Background
Brain injury from preterm birth causes white matter injury (WMI), and leads to chronic neurological deficits including cerebral palsy, epilepsy, cognitive and behavioral delay. Immature O4+ oligodendrocytes are particularly vulnerable to WMI. Understanding how the developing brain recovers after injury is essential to finding more effective therapeutic strategies. Erythropoietin (EPO) promotes neuronal recovery after injury however its role in enhancing oligodendroglial lineage recovery is unclear. Previously we found recombinant EPO (rEPO)-treatment enhances MBP expression and functional recovery in adult rats after prenatal transient systemic hypoxia-ischemia (TSHI). We hypothesized that after injury rEPO would enhance oligodendroglial lineage cell genesis, survival, maturation and myelination.
Methods
In vitro assays were used to define how rEPO contributes to specific stages of oligodendrocyte development and recovery after TSHI.
Results
After prenatal TSHI injury, rEPO promotes genesis of oligodendrocyte progenitors from oligodendrospheres, survival of oligodendrocyte precursor cells (OPCs) and O4+ immature oligodendrocytes, O4+ cell process extension and MBP expression. rEPO did not alter OPC proliferation.
Conclusion
Together, these studies demonstrate that EPO signaling promotes critical stages of oligodendroglial lineage development and recovery after prenatal TSHI injury. Erythropoietin treatment may be beneficial to preterm and other infant patient populations with developmental brain injury hallmarked by WMI.
doi:10.1038/pr.2013.155
PMCID: PMC3865073  PMID: 24108187
21.  A Pilot Study of Novel Biomarkers in Neonates With Hypoxic-Ischemic Encephalopathy 
Pediatric research  2010;68(6):10.1203/PDR.0b013e3181f85a03.
Severe hypoxic-ischemic encephalopathy (HIE) is a devastating condition that can lead to mortality and long-term disabilities in term newborns. No rapid and reliable laboratory test exists to assess the degree of neuronal injury in these patients. We propose two possible biomarkers: 1) phosphorylated axonal neurofilament heavy chain (pNF-H) protein, one of the major subunits of neurofilaments, found only in axonal cytoskeleton of neurons and 2) Ubiquitin C-terminal hydrolase 1 (UCHL1 protein) that is heavily and specifically concentrated in neuronal perikarya and dendrites. High-serum pNF-H and UCHL1 levels are reported in subarachnoid hemorrhage and traumatic brain injury, suggesting that they are released into blood following neuronal injury. We hypothesized that serum pNF-H and UCHL1 were higher in neonates with moderate-to-severe HIE than in healthy neonates. A time-limited enrollment of 14 consecutive patients with HIE and 14 healthy controls was performed. UCHL1 and pNF-H were correlated with clinical data and brain MRI. UCHL1 and pNF-H serum levels were higher in HIE versus controls. UCHL1 showed correlation with the 10-min Apgar score, and pNF-H showed correlation with abnormal brain MRI. Our findings suggest that serum UCHL1 and pNF-H could be explored as diagnostic and prognostic tools in neonatal HIE.
doi:10.1203/PDR.0b013e3181f85a03
PMCID: PMC3851011  PMID: 20736881
22.  Association of Amino Acids with Common Complications of Prematurity 
Pediatric research  2013;73(6):700-705.
Background
Tandem mass spectrometry has been proposed as a method of diagnosing or predicting the development of common complex neonatal diseases. Our objective was to identify metabolites associated with common complications of prematurity.
Methods
We performed a retrospective analysis of medical data and metabolite measurements from routine neonatal screening on 689 preterm (<37 weeks of gestational age) neonates.
Results
We observed higher levels of phenylalanine in infants with respiratory distress syndrome (RDS; P=1.7×10−5), the only association that was significant after correction for multiple testing. We found suggestive significance (P<0.001) of higher essential amino acids in infants with patent ductus arteriosus (PDA). Functionality of these findings was explored in the ductus arteriosus (DA) isolated from term and preterm mouse pups. None of the amino acids had a direct vasodilatory effect on the isolated DA.
Conclusion
We found newborns with RDS had higher levels of phenylalanine that may be due to impaired phenylalanine hydroxylase activity. We also detected marginally higher levels of all measured essential amino acids in infants with PDA. We did not find dilation of the mouse ductus for these metabolites indicating that instead of potentially causing PDA they are likely serving as markers of catabolism.
doi:10.1038/pr.2013.43
PMCID: PMC3660469  PMID: 23481552
23.  Digested formula but not digested fresh human milk causes death of intestinal cells in vitro: implications for necrotizing enterocolitis 
Pediatric research  2012;72(6):560-567.
Background
Premature infants fed formula are more likely to develop necrotizing enterocolitis (NEC) than if fed breast milk, but the mechanisms of intestinal necrosis in NEC and protection by breast milk are unknown. We hypothesized that after lipase digestion, formula, but not fresh breast milk, contains levels of unbound free fatty acids (FFAs) that are cytotoxic to intestinal cells.
Methods
We digested multiple term and preterm infant formulas or human milk with pancreatic lipase, proteases (trypsin and chymotrypsin), lipase + proteases, or luminal fluid from a rat small intestine and tested FFA levels and cytotoxicity in vitro on intestinal epithelial cells, endothelial cells, and neutrophils.
Results
Lipase digestion of formula, but not milk, caused significant death of neutrophils (ranging from 47–99% with formulas vs. 6% with milk) with similar results in endothelial and epithelial cells. FFAs were significantly elevated in digested formula versus milk and death from formula was significantly decreased with lipase inhibitor pretreatment, or treatments to bind FFAs. Protease digestion significantly increased FFA binding capacity of formula and milk but only enough to decrease cytotoxicity from milk.
Conclusion
FFA-induced cytotoxicity may contribute to the pathogenesis of NEC.
doi:10.1038/pr.2012.125
PMCID: PMC3526678  PMID: 23007028
free fatty acids; shock; lipase; cytotoxicity
24.  Esophageal human beta-defensin expression in eosinophilic esophagitis 
Pediatric research  2013;73(5):10.1038/pr.2013.23.
Background
Defensins are antimicrobial peptides expressed on mucosal surfaces that contribute to maintaining intestinal homeostasis by providing innate defense mechanisms for the epithelia. Defensin expression is altered in a number of diseases that affect mucosal surfaces, such as atopic dermatitis, allergic rhinitis, and inflammatory bowel disease. Similar to atopic dermatitis, eosinophilic esophagitis (EoE) is a chronic disease in which the squamous epithelial surface is affected by a similar TH2 microenvironment and eosinophil predominant inflammation. Therefore, we hypothesized defensin expression would be decreased in EoE.
Methods
To address this, we measured defensin expression in vitro in cell lines derived from patients with EoE (EoE1-T) or gastroesophageal reflux disease (GERD) (NES-G4T cells), and ex vivo in esophageal mucosal biopsy samples from children with EoE, GERD, and control children without esophageal disease.
Results
IL-5 induced a decrease in human beta-defensin 1 (hBD1) and human beta-defensin 3 (hBD3) expression in EoE1-T but not in NES-G4T cells. Compared to esophageal biopsy specimens from GERD and control children, specimens from EoE pediatric patients revealed significant decrease in mRNA and protein expression for hBD1 and hBD3.
Conclusion
Diminished expression of hBD1 and hBD3 may make the esophageal epithelium more susceptible to the development and/or perpetuation of EoE.
doi:10.1038/pr.2013.23
PMCID: PMC3844519  PMID: 23385963
25.  URINARY PROSTASIN: A POSSIBLE BIOMARKER FOR RENAL PRESSURE NATRIURESIS IN BLACK ADOLESCENTS 
Pediatric research  2009;65(4):10.1203/PDR.0b013e3181994b85.
Prostasin is a membrane-bound/secretive serine protease interacting with aldosterone and the epithelial sodium channel in the kidney. We and others have previously proposed the concept of stress-induced pressure natriuresis (SIPN) where increased urinary sodium excretion (UNaV) is coupled with elevated blood pressure (BP) in response to behavioral stress in normotensive adolescents. This study thus aimed to test the relationship between prostasin and pressure natriuresis using the SIPN model. A cohort of 102 normotensive black adolescents (mean age: 17.0±1.2 years; 56% females) were placed on a controlled sodium (4000±200 mg/day) and potassium (2600±200 mg/day) diet for three days before testing. The SIPN protocol consisted of a one-hour baseline period, a one-hour stress period (competitive video games), and a one-hour recovery period. During the stress period, BP elevation was coupled with an increase in UNaV. Urinary prostasin concentration had more than a two-fold reduction from baseline (38.4±32.7 ng/ml) to stress (17.2±16.0 ng/ml), and further declined during recovery (12.1±16.2 ng/ml) (p<0.001). Urinary prostasin was inversely correlated with UNaV during stress (r=−0.43, p=0.0001), even after being normalized by urinary creatinine. Our data suggest that urinary prostasin could be a novel biomarker and/or mechanism for renal pressure natriuresis in normotensive black adolescents.
doi:10.1203/PDR.0b013e3181994b85
PMCID: PMC3826778  PMID: 19127211
prostasin; adolescents; pressure natriuresis; blood pressure; urinary sodium excretion

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