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1.  Urinary prostasin excretion is associated with adiposity in non-hypertensive African American adolescents 
Pediatric research  2013;74(2):206-210.
BACKGROUND
Metabolic abnormalities in obesity can overstimulate the renal epithelial sodium channel (ENaC) and subsequently lead to blood pressure (BP) elevation. Prostasin, a membrane-bound/secretive serine protease, is thought to activate ENaC via the proteolytic cleavage of the channel. Our specific aim was to explore whether there is a relationship between adiposity and urinary prostasin excretion at the population level.
METHODS
In 271 African-American adolescents, urinary prostasin concentrations were determined by enzyme-linked immunosorbent assay and normalized by urinary creatinine.
RESULTS
Urinary prostasin excretion increased in the over- weight/obese group (n = 110, 38.2 ± 4.0 ng/mg) vs. the normal-weight group (n = 161, 20.7 ± 1.2 ng/mg, P = 0.03). Urinary prostasin excretion was significantly correlated with BMI percentiles (r = 0.14, P = 0.02), waist circumference (r = 0.13, P = 0.05), total body fat mass (r = 0.20, P < 0.01), and percentage body fat (r = 0.23, P < 0.01). Urinary prostasin excretion was also correlated with plasma aldosterone (r = 0.11, P = 0.05) and systolic BP (SBP; r = 0.15, P = 0.02), but the significances disappeared after adjustment of any of the adiposity variables.
CONCLUSION
Our data for the first time suggest that adiposity plays a role in urinary prostasin excretion, and its associations with aldosterone and BP appear to be modulated by adiposity. Whether urinary prostasin excretion is a biomarker/mechanism underlying obesity-related hypertension deserves further investigations.
doi:10.1038/pr.2013.81
PMCID: PMC4332551  PMID: 23863785
2.  Epithelial calcium-sensing receptor activation by eosinophil granule protein analog stimulates collagen matrix contraction 
Pediatric research  2012;73(4 0 1):414-419.
Background
Eosinophils reside in normal gastrointestinal tracts and increase in disease. Receptors for eosinophil derived granule proteins (EDGPs) have not been identified but highly cationic molecules, similar to eosinophil proteins, bind extracellular calcium-sensing receptors (CaSR). We hypothesized that stimulation of CaSR by eosinophil proteins activates epithelial cells.
Methods
Caco2 intestinal epithelial cells, AML14.3D10 eosinophils, wild type human embryonic kidney 293 (HEK293) cells not expressing CaSR (HEK-WT) or CaSR transfected HEK293 cells (HEK-CaSR) were stimulated with an eosinophil protein analog poly-L-arginine (PA) and phosphorylated extracellular signal-regulated kinases 1/2 (pERK) was measured. Functional activation was measured with collagen lattice contraction assays.
Results
Co-culture of Caco2 cells with AML14.3D10 eosinophils augmented lattice contraction compared to lattices containing Caco2 cells alone. PA stimulation of Caco2 lattices augmented contraction. HEK-CaSR stimulation with PA or Ca2+ resulted in greater pERK activation than stimulated HEK-WT cells. PA stimulated greater HEK-CaSR lattice contraction than unstimulated lattices. Contraction of PA stimulated and unstimulated HEK-WT lattices did not differ.
Conclusion
Exposure of intestinal epithelia to the EDGP analog, PA, stimulates CaSR dependent ERK phosphorylation and epithelial mediated collagen lattice contraction. We speculate that EDGP release within the epithelial layers activates the CaSR receptor leading to matrix contraction and tissue fibrosis.
doi:10.1038/pr.2012.198
PMCID: PMC4321999  PMID: 23269116
3.  [No title available] 
PMCID: PMC4104134  PMID: 24858141
4.  [No title available] 
PMCID: PMC4104136  PMID: 24819378
5.  Maternal Pre-Gravid Obesity Changes Gene Expression Profiles Towards Greater Inflammation and Reduced Insulin Sensitivity in Umbilical Cord 
Pediatric research  2014;76(2):202-210.
Background
Maternal obesity is associated with unfavorable outcomes, which may be reflected in the as yet undiscovered gene expression profiles of the umbilical cord (UC).
Methods
UCs from 12 lean (pre-gravid BMI < 24.9) and 10 overweight/obese (OW/OB, pre-gravid BMI ≥25) women without gestational diabetes were collected for gene expression analysis using Human Primeview microarrays (Affymetrix). Metabolic parameters were assayed in mother’s plasma and cord blood.
Results
Although offspring birth weight and adiposity (at 2-wk) did not differ between groups, expression of 232 transcripts was affected in UC from OW/OB compared to those of lean mothers. GSEA analysis revealed an up-regulation of genes related to metabolism, stimulus and defense response and inhibitory to insulin signaling in the OW/OB group. We confirmed that EGR1, periostin, and FOSB mRNA expression was induced in UCs from OW/OB moms, while endothelin receptor B, KFL10, PEG3 and EGLN3 expression was decreased. Messenger RNA expression of EGR1, FOSB, MEST and SOCS1 were positively correlated (p<0.05) with mother’s first trimester body fat mass (%).
Conclusions
Our data suggest a positive association between maternal obesity and changes in UC gene expression profiles favoring inflammation and insulin resistance, potentially predisposing infants to develop metabolic dysfunction later on in life.
doi:10.1038/pr.2014.72
PMCID: PMC4135718  PMID: 24819376
6.  Interleukin-10 Versus Dexamethasone: Effects on Polymorphonuclear Leukocyte Functions of the Newborn 
Pediatric research  2009;65(4):425-429.
Interleukin-10 (IL-10), an anti-inflammatory cytokine, may have therapeutic potential in the fetal inflammatory response syndrome and its sequelae such as bronchopulmonary dysplasia (BPD). Our aim was to compare the effects of IL-10 versus dexamethasone (DEX) on important PMN functions of the newborn. PMNs were isolated into culture medium from cord blood after elective cesarean section deliveries. IL-10 and DEX were compared on an equimolar basis corresponding to previously measured plasma levels of DEX from infants treated for BPD. The endotoxin (LPS)-stimulated release of the pro-inflammatory cytokines, tumor necrosis factor (TNFα) and IL-1β, were markedly inhibited equally by IL-10 and DEX; the anti-inflammatory cytokine IL-4 was not released and IL-1 receptor antagonist (IL-1ra) was released less with DEX compared to IL-10. PMNs exposed to LPS, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP), or S. aureus did not show a significant difference between control, DEX and IL-10 for apoptosis, respiratory burst, phagocytosis or killing respectively. Chemotaxis to fMLP or IL-8 was unaffected by DEX or IL-10. The principal effects of both IL-10 and DEX, on the PMN functions studied, are related to the control of pro- and anti-inflammatory cytokine release.
doi:10.1203/PDR.0b013e318199384d
PMCID: PMC4288846  PMID: 19127214
7.  Pediatric Sarcomas: Translating Molecular Pathogenesis of Disease to Novel Therapeutic Possibilities 
Pediatric research  2012;72(2):112-121.
Pediatric sarcomas represent a diverse group of rare bone and soft tissue malignancies. Though the molecular mechanisms that propel the development of these cancers are not well understood, identification of tumor-specific translocations in many sarcomas has provided significant insight into their tumorigenesis. Each fusion protein resulting from these chromosomal translocations is thought to act as a driving force in the tumor, either as an aberrant transcription factor, constitutively active growth factor, or ligand-independent receptor tyrosine kinase. Identification of transcriptional targets or signaling pathways modulated by these oncogenic fusions has led to the discovery of potential therapeutic targets. Some of these targets have shown considerable promise in pre-clinical models and are currently being tested in clinical trials. This review summarizes the molecular pathology of a subset of pediatric sarcomas with tumor-associated translocations and how increased understanding at the molecular level is being translated to novel therapeutic advances.
doi:10.1038/pr.2012.54
PMCID: PMC4283808  PMID: 22546864
8.  CHLORHEXIDINE INHIBITS L1 CELL ADHESION MOLECULE MEDIATED NEURITE OUTGROWTH IN VITRO 
Pediatric research  2013;75(0):8-13.
Background
Chlorhexidine is a skin disinfectant that reduces skin and mucous membrane bacterial colonization and inhibits organism growth. Despite numerous studies assessing chlorhexidine safety in term infants, residual concerns have limited its use in hospitalized neonates, especially low birth weight preterm infants. The aim of this study was to assess the potential neurotoxicity of chlorhexidine on the developing central nervous system using a well-established in vitro model of neurite outgrowth that includes laminin and L1 cell adhesion molecule (L1) as neurite outgrowth promoting substrates.
Methods
Cerebellar granule neurons are plated on either poly L-lysine, L1 or laminin. Chlorhexidine, hexachlorophene or their excipients are added to the media. Neurons are grown for 24 h, then fixed and neurite length measured.
Results
Chlorhexidine significantly reduced the length of neurites grown on L1 but not laminin. Chlorhexidine concentrations as low as 125 ng/ml statistically significantly reduced neurite length on L1. Hexachlorophene did not affect neurite length.
Conclusion
Chlorhexidine at concentrations detected in the blood following topical applications in preterm infants specifically inhibited L1 mediated neurite outgrowth of cerebellar granule neurons. It is now vital to determine whether the blood brain barrier is permeable to chlorhexidine in preterm infants.
doi:10.1038/pr.2013.175
PMCID: PMC3946665  PMID: 24126818
9.  Diffusion Tractography and Neuromotor Outcome in Very Preterm Children with White Matter Abnormalities 
Pediatric research  2014;76(1):86-92.
Background
Moderate-severe white matter abnormality (WMA) in the newborn has been shown to produce persistent disruptions in cerebral connectivity, but does not universally result in neurodevelopmental disability in very preterm (VPT) children. The aims of this hypothesis driven study were to apply diffusion imaging to: 1) examine whether bilateral WMA detected in VPT children in the newborn period can predict microstructural organization at age 7; 2) compare corticospinal tract (CST) and corpus callosum (CC) measures in VPT children at age 7 with neonatal WMA with normal versus impaired motor functioning.
Methods
Diffusion parameters of the CST and CC were compared between VPT 7-year-olds with (n=20) and without (n=42) bilateral WMA detected in the newborn period. For those with WMA, diffusion parameters were further examined.
Results
Microstructural organization of CST and CC tracts at age 7 years were altered in VPT children with moderate-severe WMA detected at term equivalent age compared to those without injury. Furthermore, diffusion parameters differed in the CC for children with WMA categorized by motor outcome (N=8).
Conclusions
WMA on conventional MRI at term equivalent age is associated with altered microstructural organization of the CST and CC at 7 years of age.
doi:10.1038/pr.2014.45
PMCID: PMC4062577  PMID: 24713814
10.  Maternal or neonatal infection: association with neonatal encephalopathy outcomes 
Pediatric research  2014;76(1):93-99.
Background
Perinatal infection may potentiate brain injury among children born preterm. The objective of this study was to examine whether maternal and/or neonatal infection are associated with adverse outcomes among term neonates with encephalopathy.
Methods
Cohort study of 258 term newborns with encephalopathy whose clinical records were examined for signs of maternal infection (chorioamnionitis) and infant infection (sepsis). Multivariate regression was used to assess associations between infection, pattern and severity of injury on neonatal MRI, as well as neurodevelopment at 30 months (neuromotor exam, or Bayley Scales of Infant Development II MDI <70 or Bayley III cognitive score <85).
Results
Chorioamnionitis was associated with lower risk of moderate-severe brain injury (adjusted OR 0.3; 95% CI 0.1–0.7, P=0.004), and adverse cognitive outcome in children when compared to no chorioamnionitis. Children with signs of neonatal sepsis were more likely to exhibit watershed predominant injury than those without (P=0.007).
Conclusions
Among neonates with encephalopathy, chorioamnionitis was associated with a lower risk of brain injury and adverse outcomes, whereas signs of neonatal sepsis carried an elevated risk. The etiology of encephalopathy and timing of infection and its associated inflammatory response may influence whether infection potentiates or mitigates injury in term newborns.
doi:10.1038/pr.2014.47
PMCID: PMC4062582  PMID: 24713817
11.  Cytokines Associated with Necrotizing Enterocolitis in Extremely Low Birth Weight Infants 
Pediatric research  2014;76(1):100-108.
Background
The goal was to identify cytokines associated with necrotizing enterocolitis (NEC). Based on our earlier reports of decreased tissue expression of transforming growth factor (TGF)-β, we hypothesized that infants with NEC also have low blood TGF-β levels. We further hypothesized that because fetal inflammation increases the risk of NEC, infants who develop NEC have elevated blood cytokine levels in early neonatal period.
Methods
Data on 104 extremely low birth weight (ELBW) infants with NEC and 893 without NEC from 17 centers were analyzed. Clinical information was correlated with blood cytokine levels on postnatal day 1 (D1), D3, D7, D14, and D21.
Results
Male gender, non-Caucasian/non-African-American ethnicity, sepsis, lower blood TGF-β and interleukin (IL)-2, and higher IL-8 levels were associated with NEC. The NEC group had lower TGF-β levels than controls since D1. The diagnosis of NEC was associated with elevated IL-1β, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1/CC-motif ligand (CCL)-2, macrophage inflammatory protein-1β/CCL3, and C-reactive protein.
Conclusions
Clinical characteristics, such as gender and ethnicity, and low blood TGF-β levels are associated with higher risk of NEC. Infants who developed NEC did not start with high blood levels of inflammatory cytokines, but these rose mainly after the onset of NEC.
doi:10.1038/pr.2014.48
PMCID: PMC4062583  PMID: 24732104
12.  ADMINISTRATION OF ANTENATAL GLUCOCORTICOIDS AND POSTNATAL SURFACTANT AMELIORATES RESPIRATORY DISTRESS SYNDROME-ASSOCIATED NEONATAL LETHALITY IN ERK3−/− PUPS 
Pediatric research  2014;76(1):24-32.
BACKGROUND
Respiratory distress syndrome (RDS) persists as a prevalent cause of infant morbidity and mortality. We have previously demonstrated that deletion of Erk3 results in pulmonary immaturity and neonatal lethality. Using RNA-Seq, we identified corticotrophin releasing hormone (CRH) and surfactant protein B (SFTPB) as potential molecular mediators of Erk3-dependent lung maturation. In this study, we characterized the impact of antenatal glucocorticoids and postnatal surfactant on neonatal survival of Erk3 null mice.
METHODS
In a double crossover design, we administered dexamethasone (dex) or saline to pregnant dams during the saccular stage of lung development, followed by postnatal surfactant or saline via inhalation intubation. Survival was recorded, detailed lung histological analysis and staining for CRH and SFTPB protein expression was performed.
RESULTS
Without treatment, Erk3 null pups die within 6 hours of birth with reduced aerated space, impaired thinning of the alveolar septa, and abundant PAS-positive glycogen stores; as described in human RDS. The administration of dex and surfactant improved RDS-associated lethality of Erk3−/− pups, and partially restored functional fetal lung maturation by accelerating the down-regulation of pulmonary CRH and partially rescuing production of SFTPB.
CONCLUSION
These findings emphasize that Erk3 is integral to terminal differentiation of type II cells, SFTPB production, and fetal pulmonary maturity.
doi:10.1038/pr.2014.54
PMCID: PMC4062596  PMID: 24732107
13.  High Dose IgG Therapy Mitigates Bile Duct Targeted Inflammation and Obstruction in a Mouse Model of Biliary Atresia 
Pediatric research  2014;76(1):72-80.
Background
A proposed etiology of biliary atresia (BA) entails a virus-induced, progressive immune-mediated injury of the biliary system. Intravenous immunoglobulin (IVIg) has demonstrated clinical benefit in several inflammatory diseases. The aim of this study was to determine the therapeutic effects of high dose immunoglobulin (IgG) treatment in the rhesus rotavirus (RRV)-induced mouse model of BA.
Methods
Newborn mice were infected with RRV and jaundiced mice were given high dose IgG or albumin control. Survival, histology, direct bilirubin, liver immune cell subsets and cytokine production were analyzed.
Results
There was no difference in overall survival between RRV-infected groups, however high dose IgG resulted in decreased bilirubin, bile duct inflammation, and increased extrahepatic bile duct patency. High dose IgG decreased vascular cell adhesion molecule-1, resulting in limited migration of immune cells to portal tracts. High dose IgG significantly decreased CD4+ T cell production of IL-2, IFN-γ and TNF-α and CD8+ T cell production of IFN-γ, as well as increased levels of regulatory T cells.
Conclusions
High dose IgG therapy in murine BA dramatically decreased Th1 cell-mediated inflammation and biliary obstruction. This study lends support for consideration of IVIg clinical trials in infants with BA, to diminish the progressive intrahepatic bile duct injury.
doi:10.1038/pr.2014.46
PMCID: PMC4062601  PMID: 24727948
14.  Hypoxic preconditioning protection is eliminated in HIF-1α knockout mice subjected to neonatal hypoxia-ischemia 
Pediatric research  2014;76(1):46-53.
BACKGROUND
Hypoxic preconditioning (HPc) protects the neonatal brain in the setting of hypoxia-ischemia (HI). The mechanisms of protection may depend on activation of hypoxia inducible factor (HIF-1α). The present study sought to clarify the role of HIF-1α after HPc and HI.
METHODS
To induce HPc, HIF-1α knockout and wildtype mice were exposed to hypoxia at postnatal day 6. At day 7, the mice underwent HI. Brain injury was determined by histology. HIF-1α, downstream targets, and markers of cell death were measured by Western blot.
RESULTS
HPc protected the wildtype brain compared to wildtype without HPc, but did not protect the HIF-1α knockout brain. In wildtype, HIF-1α increased after hypoxia and after HI, but not with HPc. The HIF-1α knockout showed no change in HIF-1α after hypoxia, HI, or HPc/HI. After HI, spectrin 145/150 was higher in HIF-1α knockout, but after HPc/HI, it was higher in wildtype. LAMP2 was higher in wildtype early after HI, but not later. After HPc/HI, LAMP2 was higher in HIF-1α knockout.
CONCLUSION
These results indicate that HIF-1α is necessary for HPc protection in the neonatal brain, and may affect cell death after HI. Different death and repair mechanisms depend on the timing of HPc.
doi:10.1038/pr.2014.53
PMCID: PMC4167022  PMID: 24713818
15.  ANGIOTENSIN II INDUCED CARDIOVASCULAR LOAD REGULATES CARDIAC REMODELING AND RELATED GENE EXPRESSION IN LATE GESTATION FETAL SHEEP 
Pediatric research  2014;75(6):689-696.
Background
Angiotensin II (ANG II) stimulates fetal heart growth, though little is known regarding changes in cardiomyocyte endowment or the molecular pathways mediating the response. We measured cardiomyocyte proliferation and morphology in ANG II treated fetal sheep and assessed transcriptional pathway responses in ANG II and losartan (an ANG II type 1 receptor antagonist) treated fetuses.
Methods
In twin gestation pregnant sheep, one fetus received ANG II (50 μg/kg/min iv) or losartan (20 mg/kg/d iv) for 7 days; non-instrumented twins served as controls.
Results
ANG II produced increases in heart mass, cardiomyocyte area (left ventricle (LV) and right ventricle mononucleated and LV binucleated cells) and the percentage of Ki-67-positive mononucleated cells in the LV (all p< 0.05). ANG II and losartan produced generally opposing changes in gene expression, affecting an estimated 55% of the represented transcriptome. The most prominent significantly effected biological pathways included those involved in cytoskeletal remodeling and cell cycle activity.
Conclusion
ANG II produces an increase in fetal cardiac mass via cardiomyocyte hypertrophy and likely hyperplasia, involving transcriptional responses in cytoskeletal remodeling and cell cycle pathways.
doi:10.1038/pr.2014.37
PMCID: PMC4251591  PMID: 24614802
16.  Correction 
Pediatric research  2014;75(6):803-.
PMCID: PMC4243298
17.  Increased rat neonatal activity influences adult cytokine levels and relative muscle mass 
Pediatric research  2010;68(5):399-404.
Little is known about the effect of physical activity in early life on subsequent growth and regulation of inflammation. We previously reported that exposure of muscles in growing rats to IL-6 results in decreased muscle growth apparently due to a state of resistance to growth factors such IGF-I and that running exercise could ameliorate this growth defect. Herein we hypothesized that increased activity, for a brief period during neonatal life, would pattern the adult rat towards a less inflammatory phenotype. Neonatal rats were induced to move about their cage for brief periods from day 5 to day 15 postpartum. Additional groups were undisturbed controls (CON) and handled (HAND). Sub-groups of rats were sampled at 30 and 65 days of age. Relative to CON and HAND, neonatal exercise (EX) results in decreased circulating levels of TNFα, IL-6 and IL-1β in adulthood, primarily in male rats. In addition, adult male EX rats had lower body mass and increased skeletal muscle mass suggesting a leaner phenotype. The results of this study suggest that moderate increases in activity early in life can influence the adult toward a more healthy phenotype with regard to inflammatory mediators and relative muscle mass.
doi:10.1203/PDR.0b013e3181f2e836
PMCID: PMC4242013  PMID: 20657345
18.  Systemic effects of whole-body cooling to 35°C, 33.5°C and 30°C in a piglet perinatal asphyxia model: implications for therapeutic hypothermia 
Pediatric research  2012;71(5):573-582.
The precise temperature for optimal neuroprotection in infants with neonatal encephalopathy is unclear. Our aim was to assess systemic effects of whole-body cooling to 35°C, 33.5°C and 30°C in a piglet perinatal asphyxia model. Twenty-eight anesthetised male piglets aged <24h underwent hypoxia-ischemia and randomized to normothermia; or cooling to rectal temperature (Trec) 35°C, 33.5°C, or 30°C during 2-26 h post insult (groups n=7). Heart rate (HR), mean arterial blood pressure (MABP) and Trec were recorded continuously. Five 30°C animals had fatal cardiac arrests. During 30°C cooling HR was lower vs normothermia (p<0.001). Although MABP did not vary between groups, more fluid boluses were needed at 30°C than normothermia (p<0.02); dopamine use was higher at 30°C than normothermia and 35°C (p=0.005, p=0.02). Base deficit was increased at 30°C at 12,24 and 36h vs all other groups (p<0.05), pH was acidotic at 36h vs normothermia (p=0.04) and blood glucose higher for 30°C at 12h vs normothermia and 35°C (p<0.05). Potassium was lower at 12h in the 30°C group vs 33.5°C and 35°C groups. Cortisol was no different between groups. Cooling to 30°C led to metabolic derangement, more cardiac arrests and deaths than cooling to 33.5°C or 35°C. Inadvertent overcooling should be avoided.
doi:10.1038/pr.2012.8
PMCID: PMC4241373  PMID: 22314664
19.  Nebulized PPARγ Agonists: A Novel Approach to Augment Neonatal Lung Maturation and Injury Repair 
Pediatric research  2014;75(5):631-640.
BACKGROUND
By stimulating lipofibroblast maturation, parenterally administered PPARγ agonists promote lung homeostasis and injury repair in the neonatal lung. In this study, we determined whether PPARγ agonists could be delivered effectively via nebulization to neonates, and whether this approach would also protect against hyperoxia-induced lung injury.
METHODS
One-day old Sprague-Dawley rat pups were administered PPARγ agonists rosiglitazone (RGZ, 3 mg/kg), pioglitazone (PGZ, 3 mg/kg), or the diluent, via nebulization every 24h; animals were exposed to 21% or 95% O2 for up to 72h. Twenty-four and 72h following initial nebulization, the pups were sacrificed for lung tissue and blood collection to determine markers of lung maturation, injury repair, and RGZ and PGZ plasma levels.
RESULTS
Nebulized RGZ and PGZ enhanced lung maturation in both males and females, as evidenced by the increased expression of markers of alveolar epithelial and mesenchymal maturation. This approach also protected against hyperoxia-induced lung injury, since hyperoxia-induced changes in bronchoalveolar lavage cell and protein contents and lung injury markers were all blocked by nebulized PGZ.
CONCLUSIONS
Nebulized PPARγ agonist administration promotes lung maturation and prevents neonatal hyperoxia-induced lung injury in both males and females.
doi:10.1038/pr.2014.8
PMCID: PMC4016987  PMID: 24488089
20.  Effects of Preoperative Hypoxia on White Matter Injury Associated with Cardiopulmonary Bypass in a Rodent Hypoxic and Brain Slice Model 
Pediatric research  2014;75(5):618-625.
Background
White matter (WM) injury is common after cardiopulmonary bypass or deep hypothermic circulatory arrest (DHCA) in neonates who have cerebral immaturity secondary to in utero hypoxia. The mechanism remains unknown. We investigated effects of preoperative-hypoxia on DHCA-induced WM-injury using a combined experimental paradigm in rodents.
Methods
Mice were exposed to hypoxia (Pre-Hypoxia). Oxygen-glucose deprivation (OGD) was performed under three temperatures to simulate brain conditions of DHCA including ischemia-reperfusion/reoxygenation under hypothermia.
Results
WM-injury in Pre-Normoxia was identified after 35°C-OGD. In Pre-Hypoxia, injury was displayed in all groups. Among oligodendrocyte stages, the pre-oligodendrocyte was the most susceptible while the oligodendrocyte progenitor was resistant to insult. When effects of Pre-Hypoxia were assessed, injury of mature oligodendrocytes and oligodendrocyte progenitors in Pre-Hypoxia significantly increased compared with Pre-Normoxia, indicating that mature oligodendrocytes and progenitors which had developed under hypoxia had greater vulnerability. Conversely, damage of oligodendrocyte progenitors in Pre-Hypoxia were not identified after 15°C-OGD, suggesting that susceptible oligodendrocytes exposed to hypoxia are protected by deep hypothermia.
Discussion
Developmental alterations due to hypoxia result in an increased WM susceptibility to injury. Promoting WM regeneration by oligodendrocyte progenitors after earlier surgery using deep hypothermia is the most promising approach for successful WM development in CHD patients.
doi:10.1038/pr.2014.9
PMCID: PMC3992169  PMID: 24488087
21.  Effect of Temperature on Thromboelastography (TEG) and Implications for Clinical Use in Neonates Undergoing Therapeutic Hypothermia 
Pediatric research  2014;75(5):663-669.
Background
Encephalopathic neonates undergoing therapeutic hypothermia have increased risk for coagulopathy secondary to perinatal asphyxia and effects of cooling on the coagulation enzyme cascade. Thromboelastography (TEG) allows for a comprehensive assessment of coagulation that can be regulated for temperature. TEG has not been previously evaluated in newborns undergoing hypothermia treatment.
Methods
Encephalopathic neonates treated with systemic hypothermia were enrolled in this prospective observational study. Daily blood specimens were collected for standard coagulation tests and platelet counts during hypothermia and after rewarming. Concurrent TEG assays were performed at 33.5°C and 37.0°C for comparison.
Results
A total of 48 paired TEGs from 24 subjects were performed. Mean (± SD) birthweight was 3.2±0.7 Kg, gestational age 38.4±1.4 weeks, and 40% were male. TEG results differed significantly between assays performed at 37.0°C versus 33.5°C, indicating more impaired coagulation at 33.5°C. TEG parameters K, α, MA and CI were significantly associated with clinical bleeding (p<0.05). These remained significant (except for MA) after controlling for transfusion therapy.
Conclusions
TEG results are affected by temperature, consistent with the known association of hypothermia with coagulopathy. Several TEG parameters are predictive of clinical bleeding in newborns undergoing hypothermia. Selected cutpoints to predict bleeding risk are temperature dependent.
doi:10.1038/pr.2014.19
PMCID: PMC3992188  PMID: 24522100
22.  Impact of repeated procedural pain-related stress in infants born very preterm 
Pediatric research  2014;75(5):584-587.
The majority of infants born very preterm (24–32 weeks gestational age) now survive, however, long-term neurodevelopmental and behavioral problems remain a concern. As part of their neonatal care very preterm infants undergo repeated painful procedures during a period of rapid brain development and programming of stress systems. Infants born this early have the nociceptive circuitry required to perceive pain, however, their sensory systems are functionally immature. An imbalance of excitatory versus inhibitory processes leads to increased nociceptive signaling in the central nervous system. Specific cell populations in the central nervous system of preterm neonates are particularly vulnerable to excitoxicity, oxidative stress, and inflammation. Neonatal rat models have demonstrated that persistent or repeated pain increases apoptosis of neurons, and neonatal pain and stress lead to anxiety-like behaviors during adulthood. In humans, greater exposure to neonatal pain-related stress has been associated with altered brain microstructure and stress hormone levels, as well as with poorer cognitive, motor and behavioral neurodevelopment in infants and children born very preterm. Therefore, it is important that pain-related stress in preterm neonates is accurately identified, appropriately managed, and that pain management strategies are evaluated for protective or adverse effects in the long term.
doi:10.1038/pr.2014.16
PMCID: PMC3992189  PMID: 24500615
23.  Impact of repeated procedural pain-related stress in infants born very preterm 
Pediatric research  2014;75(5):584-587.
The majority of infants born very preterm (24–32 weeks gestational age) now survive, however, long-term neurodevelopmental and behavioral problems remain a concern. As part of their neonatal care very preterm infants undergo repeated painful procedures during a period of rapid brain development and programming of stress systems. Infants born this early have the nociceptive circuitry required to perceive pain, however, their sensory systems are functionally immature. An imbalance of excitatory versus inhibitory processes leads to increased nociceptive signaling in the central nervous system. Specific cell populations in the central nervous system of preterm neonates are particularly vulnerable to excitoxicity, oxidative stress, and inflammation. Neonatal rat models have demonstrated that persistent or repeated pain increases apoptosis of neurons, and neonatal pain and stress lead to anxiety-like behaviors during adulthood. In humans, greater exposure to neonatal pain-related stress has been associated with altered brain microstructure and stress hormone levels, as well as with poorer cognitive, motor and behavioral neurodevelopment in infants and children born very preterm. Therefore, it is important that pain-related stress in preterm neonates is accurately identified, appropriately managed, and that pain management strategies are evaluated for protective or adverse effects in the long term.
doi:10.1038/pr.2014.16
PMCID: PMC3992189  PMID: 24500615 CAMSID: cams4023
24.  Recent advances in human milk glycobiology 
Pediatric research  2014;75(5):675-679.
doi:10.1038/pr.2014.24
PMCID: PMC4125201  PMID: 24522101
25.  Murine Model for Cystic Fibrosis Bone Disease Demonstrates Osteopenia and Sex-Related Differences in Bone Formation 
Pediatric research  2009;65(3):311-316.
As the incidence of cystic fibrosis (CF) bone disease is increasing, we analyzed cystic fibrosis transmembrane conductance regulator (CFTR) deficient mice (CF mice) to gain pathogenic insights. In these studies comparing adult (14 wk) CF and C57BL/6J mice, both bone length and total area were decreased in CF mice. Metaphyseal trabecular & cortical density were also decreased, as well as diaphyseal cortical & total density. Trabecular bone volume was diminished in CF mice. Female CF mice revealed decreased trabecular width and number compared to C57BL/6J, whereas males demonstrated no difference in trabecular number. Female CF mice had reduced mineralizing surface and bone formation rates. Conversely, male CF mice had increased mineralizing surface, mineral apposition and bone formation rates compared to C57BL/6J males. Bone formation rate was greater in males compared to female CF mice. Smaller bones with decreased density in CF, despite absent differences in osteoblast and osteoclast surfaces, suggest CFTR influences bone cell activity rather than number. Differences in bone formation rate in CF mice are suggestive of inadequate bone formation in females, but increased bone formation in males. This pro-anabolic observation in male CF mice is consistent with other clinical sex differences in CF.
doi:10.1203/PDR.0b013e3181961e80
PMCID: PMC4201032  PMID: 19047917
cystic fibrosis; CFTR; osteopenia; sex-related; bone formation

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