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1.  Corrigendum: The Human Neonatal Gut Microbiome: A Brief Review 
PMCID: PMC4485073  PMID: 26176006
newborn; microbiome; gut; probiotics; necrotizing enterocolitis
2.  The Human Neonatal Gut Microbiome: A Brief Review 
The field of genomics has expanded into subspecialties such as metagenomics over the course of the last decade and a half. The development of massively parallel sequencing capabilities has allowed for increasingly detailed study of the genome of the human microbiome, the microbial super organ that resides symbiotically within the mucosal tissues and integumentary system of the human host. The gut microbiome, and particularly the study of its origins in neonates, has become subtopics of great interest within the field of genomics. This brief review seeks to summarize recent literature regarding the origins and establishment of the neonatal gut microbiome, beginning in utero, and how it is affected by neonatal nutritional status (breastfed versus formula fed) and gestational age (term versus preterm). We also explore the role of dysbiosis, a perturbation within the fragile ecosystem of the microbiome, and its role in the origin of select pathologic states, specifically, obesity and necrotizing enterocolitis (NEC) in preterm infants. We discuss the evidence supporting enteral pre- and pro-biotic supplementation of commensal organisms such as Bifidobacterium and Lactobacillus in the neonatal period, and their role in the prevention and amelioration of NEC in premature infants. Finally, we review directions to consider for further research to promote human health within this field.
PMCID: PMC4350424  PMID: 25798435
newborn; preterm; microbiota; probiotics; dysbiosis
Exposure to hyperoxia, invasive mechanical ventilation and systemic/local sepsis are important antecedents of postnatal inflammation in the pathogenesis of bronchopulmonary dysplasia (BPD). This review will summarize information obtained from animal (baboon, lamb/sheep, rat and mouse) models that pertain to the specific inflammatory agents and signaling molecules that predispose a premature infant to BPD.
PMCID: PMC4023567  PMID: 24578018
invasive ventilation; infection; hyperoxia; lung; newborn
4.  Conditional overexpression of TGFβ1 promotes pulmonary inflammation, apoptosis and mortality via TGFβR2 in the developing mouse lung 
Respiratory Research  2015;16(1):4.
Earlier studies have reported that transforming growth factor beta 1(TGFβ1) is a critical mediator of hyperoxia-induced acute lung injury (HALI) in developing lungs, leading to impaired alveolarization and a pulmonary phenotype of bronchopulmonary dysplasia (BPD). However, the mechanisms responsible for the TGFβ1-induced inflammatory signals that lead to cell death and abnormal alveolarization are poorly understood. We hypothesized that TGFβ1 signaling via TGFβR2 is necessary for the pathogenesis of the BPD pulmonary phenotype resulting from HALI.
We utilized lung epithelial cell-specific TGFβ1 overexpressing transgenic and TGFβR2 null mutant mice to evaluate the effects on neonatal mortality as well as pulmonary inflammation and apoptosis in developing lungs. Lung morphometry was performed to determine the impaired alveolarization and multicolor flow cytometry studies were performed to detect inflammatory macrophages and monocytes in lungs. Apoptotic cell death was measured with TUNEL assay, immunohistochemistry and western blotting and protein expression of angiogenic mediators were also analyzed.
Our data reveals that increased TGFβ1 expression in newborn mice lungs leads to increased mortality, macrophage and immature monocyte infiltration, apoptotic cell death specifically in Type II alveolar epithelial cells (AECs), impaired alveolarization, and dysregulated angiogenic molecular markers.
Our study has demonstrated the potential role of inhibition of TGFβ1 signaling via TGFβR2 for improved survival, reduced inflammation and apoptosis that may provide insights for the development of potential therapeutic strategies targeted against HALI and BPD.
PMCID: PMC4307226  PMID: 25591994
Transforming growth factor; Oxygen; Inflammation; Cell death; Angiopoietin; Newborn; Pulmonary; Bronchopulmonary dysplasia
5.  The Temporal Kinetics of Circulating Angiopoietin Levels in Children with Sepsis 
Capillary integrity continues to challenge critical care physicians worldwide when treating children with sepsis. Vascular growth factors, specifically angiopoietin (angpt)-1 and angpt-2, play opposing roles in capillary stabilization in septic patients, respectively. We aim to determine whether pediatric patients with severe sepsis/shock have persistently high angpt-2/1 ratios when compared to non-septic pediatric intensive care unit (PICU) patients over a 7-day period.
Prospective, observational study. Patients were classified within 24h of admission into: non-systemic inflammatory response syndrome (non-SIRS), SIRS/sepsis, or severe sepsis/shock. Plasma levels of angpt-1 and angpt-2 were measured via ELISA. The angpt-2/1 ratio was graphically plotted and determined whether patients fell into ‘constant’ or ‘variable’ patterns.
Tertiary care center PICU.
Critically ill pediatric patients with varying sepsis severity.
Measurements and Main Results
Forty five patients were enrolled (n=9 non-SIRS, n=19 SIRS/sepsis, and n=17 severe sepsis/shock). Gender, age, weight, comorbidities and PICU length of stay were not significantly different between the groups. Admission pediatric risk stratification scores and net fluid ins/outs were significantly elevated in the severe sepsis/shock group when compared (all p<0.05). Admission angpt-2 levels and angpt-2/1 ratios were significantly different in the severe sepsis/shock group when all groups were compared (both p<0.05). Additionally, the latter were significantly elevated in the severe sepsis/shock group at multiple time points (all p≤0.05) with the peak occurring on day 2 of illness. In a separate analysis, 32% of SIRS/sepsis and 82% of severe sepsis/shock had ‘variable’ angpt-2/1 ratio patterns compared to none in the control group (p<0.001).
Pediatric patients with severe sepsis and septic shock possess significantly elevated angpt-2/1 ratios during their first 3 days of illness which peak at day 2 of illness. A subset of these patients demonstrated ‘variable’ angpt-2/1 ratio patterns.
PMCID: PMC3947338  PMID: 24141659
Pediatric; capillary leak; shock; intensive care
6.  Angiopoietin-1, Angiopoietin-2 and Bicarbonate as Diagnostic Biomarkers in Children with Severe Sepsis 
PLoS ONE  2014;9(9):e108461.
Severe pediatric sepsis continues to be associated with high mortality rates in children. Thus, an important area of biomedical research is to identify biomarkers that can classify sepsis severity and outcomes. The complex and heterogeneous nature of sepsis makes the prospect of the classification of sepsis severity using a single biomarker less likely. Instead, we employ machine learning techniques to validate the use of a multiple biomarkers scoring system to determine the severity of sepsis in critically ill children. The study was based on clinical data and plasma samples provided by a tertiary care center's Pediatric Intensive Care Unit (PICU) from a group of 45 patients with varying sepsis severity at the time of admission. Canonical Correlation Analysis with the Forward Selection and Random Forests methods identified a particular set of biomarkers that included Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), and Bicarbonate (HCO) as having the strongest correlations with sepsis severity. The robustness and effectiveness of these biomarkers for classifying sepsis severity were validated by constructing a linear Support Vector Machine diagnostic classifier. We also show that the concentrations of Ang-1, Ang-2, and HCO enable predictions of the time dependence of sepsis severity in children.
PMCID: PMC4178003  PMID: 25255212
7.  Drug Therapy Trials for the Prevention of Bronchopulmonary Dysplasia: Current and Future Targets 
PMCID: PMC4110623  PMID: 25121076
newborn; clinical trials; drug therapy; lung; chronic lung disease
8.  Hyperoxia and Interferon-γ–Induced Injury in Developing Lungs Occur via Cyclooxygenase-2 and the Endoplasmic Reticulum Stress–Dependent Pathway 
We noted a marked increase in cyclooxygenase-2 (Cox2) and the activation of the endoplasmic reticulum (ER) stress pathway in newborn murine lung on exposure to hyperoxia and IFN-γ. We sought to evaluate Cox2-mediated ER stress pathway activation in hyperoxia-induced and IFN-γ–mediated injury in developing lungs. We applied in vivo genetic gain-of-function and genetic/chemical inhibition, as well as in vitro loss-of-function genetic strategies. Hyperoxia-induced and IFN-γ–mediated impaired alveolarization was rescued by Cox2 inhibition, using celecoxib. The use of small interfering RNA against the ER stress pathway mediator, the C/EBP homologous protein (CHOP; also known as growth arrest and DNA damage–inducible gene 153/GADD153), alleviated cell death in alveolar epithelial cells as well as in hyperoxia-induced and IFN-γ–mediated murine models of bronchopulmonary dysplasia (BPD). In addition, CHOP siRNA also restored alveolarization in the in vivo models. Furthermore, as evidence of clinical relevance, we show increased concentrations of Cox2 and ER stress pathway mediators in human lungs with BPD. Cox2, via CHOP, may significantly contribute to the final common pathway of hyperoxia-induced and IFN-γ–mediated injury in developing lungs and human BPD.
PMCID: PMC3727872  PMID: 23470621
newborn; oxygen; BPD; CHOP; cell death
9.  Basic Science: Obstetrics Nucleated Red Blood Cells are a Direct Response to Mediators of Inflammation in Newborns with Early Onset Neonatal Sepsis 
To test the hypothesis that inflammation modulates fetal erythroblastosis and/or the release of NRBCs independent of hypoxia or fetal stress. We sought to determine if fetal inflammation is associated with an elevation in neonatal NRBC count in the setting of inflammation-associated preterm birth.
Study Design
The relationships between peripheral NRBC count, histological chorioamnionitis, umbilical cord interleukin-6 (IL-6), erythropoietin (EPO), cortisol and acid-base status were analyzed in 68 preterm singletons, born to mothers who had an amniocentesis to rule out infection. Proteomic profiling of amniotic fluid identified presence of intra-amniotic inflammation according to established parameters. NRBC counts were assessed within 1-hour of birth. Early-onset neonatal sepsis (EONS) was established based on hematological and microbiological indices. IL-6, EPO and cortisol levels were measured by immunoassays. Fetal acid-base status was determined within 10 minutes of delivery. Parametric or nonparametric statistics was employed.
Fetuses with EONS (n=19) were delivered at earlier gestational ages (mean±SD: 27.1±2.8 weeks, P=0.001) and more often by mothers with intra-amniotic inflammation (P=0.022) and histological chorioamnionitis (P<0.001). Neonates with EONS had higher absolute NRBCs counts (P=0.011). NRBC counts were directly correlated with cord blood IL-6 levels (P<0.001) but not with EPO, cortisol or parameters of acid-base status levels regardless of EONS status. These relationships remained following correction for gestational age, diabetes, intrauterine growth restriction (IUGR) and steroid exposure.
In the setting of inflammation-associated preterm birth and in the absence of hypoxia, elevations in NRBCs in the early neonatal period may be a direct response to exposure to inflammatory mediators in utero.
PMCID: PMC4023236  PMID: 18395034
infection; inflammation; NRBC preterm birth; chorioamnionitis
10.  Need for Supplemental Oxygen at Discharge in Infants with Bronchopulmonary Dysplasia Is Not Associated with Worse Neurodevelopmental Outcomes at 3 Years Corrected Age 
PLoS ONE  2014;9(3):e90843.
To determine if chronic oxygen dependency (discharge home on supplemental oxygen) in children with bronchopulmonary dysplasia (BPD; defined as requirement for supplemental O2 at 36 weeks postmenstrual age) predicts neurodevelopmental disability rates and growth outcomes at 36 months corrected age (CA).
Study Design
Longitudinal cohort study.
Southern Alberta regional center located at high altitude.
Preterm infants weighing ≤1250 grams with no BPD, BPD, and BPD with chronic oxygen dependency.
Main outcome measures
Neurodevelopmental and growth outcomes.
Of 1563 preterm infants admitted from 1995–2007, 1212 survived. Complete follow-up data were available for 1030 (85%) children. Children in BPD and BPD with chronic oxygen dependency groups had significantly lower birth weights, gestational ages, prolonged mechanical ventilation and oxygen supplementation and received more postnatal steroids, compared to those without BPD. Children with BPD and BPD with chronic oxygen dependency were more likely to be below the 5th centile in weight and height compared to those without BPD but there was little difference between the BPD and BPD with chronic oxygen dependency groups. After controlling for confounding variables, children who had BPD and BPD with chronic oxygen dependency had higher odds of neurodevelopmental disability compared to those without BPD [OR (odds ratio) 1.9 (95%CI 1.1 to 3.5) and OR 1.8 (1.1 to 2.9), respectively], with no significant difference between BPD and BPD with chronic oxygen dependency [OR 0.9 (95% CI 0.6 to 1.5)].
BPD and BPD with chronic oxygen dependency in children predicts abnormal neurodevelopmental outcomes at 36 months CA. However, the neurodevelopmental disability rates were not significantly higher in BPD with chronic oxygen dependency children compared to children with BPD only. Compared to those without BPD, growth is impaired in children with BPD and BPD with chronic oxygen dependency, but no difference between the latter two groups.
PMCID: PMC3960119  PMID: 24646665
11.  Targeting mitochondrial dysfunction in lung diseases: emphasis on mitophagy 
During mild stressful conditions, cells activate a multitude of mechanisms in an attempt to repair or re-establish homeostasis. One such mechanism is autophagic degradation of mitochondria or mitophagy to dispose damaged mitochondria. However, if stress persists beyond recovery then dysfunctional mitochondria can ignite cell death. This review article summarizes recent studies highlighting the molecular pathways that facilitate mitochondria to alter its morphological dynamics, coordinate stress responses, initiate mitophagy and activate cell death in relevance to pulmonary pathologies. Thorough understanding of how these signaling mechanisms get disrupted may aid in designing new mitochondria-based therapies to combat lung diseases.
PMCID: PMC3872744  PMID: 24421769
mitochondria; reactive oxygen species; mitophagy; apoptosis; pulmonary disease
12.  Which Biomarkers Reveal Neonatal Sepsis? 
PLoS ONE  2013;8(12):e82700.
We address the identification of optimal biomarkers for the rapid diagnosis of neonatal sepsis. We employ both canonical correlation analysis (CCA) and sparse support vector machine (SSVM) classifiers to select the best subset of biomarkers from a large hematological data set collected from infants with suspected sepsis from Yale-New Haven Hospital's Neonatal Intensive Care Unit (NICU). CCA is used to select sets of biomarkers of increasing size that are most highly correlated with infection. The effectiveness of these biomarkers is then validated by constructing a sparse support vector machine diagnostic classifier. We find that the following set of five biomarkers capture the essential diagnostic information (in order of importance): Bands, Platelets, neutrophil CD64, White Blood Cells, and Segs. Further, the diagnostic performance of the optimal set of biomarkers is significantly higher than that of isolated individual biomarkers. These results suggest an enhanced sepsis scoring system for neonatal sepsis that includes these five biomarkers. We demonstrate the robustness of our analysis by comparing CCA with the Forward Selection method and SSVM with LASSO Logistic Regression.
PMCID: PMC3867385  PMID: 24367543
13.  Hyperoxia Exacerbates Postnatal Inflammation-Induced Lung Injury in Neonatal BRP-39 Null Mutant Mice Promoting the M1 Macrophage Phenotype 
Mediators of Inflammation  2013;2013:457189.
Rationale. Hyperoxia exposure to developing lungs—critical in the pathogenesis of bronchopulmonary dysplasia—may augment lung inflammation by inhibiting anti-inflammatory mediators in alveolar macrophages. Objective. We sought to determine the O2-induced effects on the polarization of macrophages and the role of anti-inflammatory BRP-39 in macrophage phenotype and neonatal lung injury. Methods. We used RAW264.7, peritoneal, and bone marrow derived macrophages for polarization (M1/M2) studies. For in vivo studies, wild-type (WT) and BRP-39−/− mice received continuous exposure to 21% O2 (control mice) or 100% O2 from postnatal (PN) 1 to PN7 days, along with intranasal lipopolysaccharide (LPS) administered on alternate days (PN2, -4, and -6). Lung histology, bronchoalveolar lavage (BAL) cell counts, BAL protein, and cytokines measurements were performed. Measurements and Main Results. Hyperoxia differentially contributed to macrophage polarization by enhancing LPS induced M1 and inhibiting interleukin-4 induced M2 phenotype. BRP-39 absence led to further enhancement of the hyperoxia and LPS induced M1 phenotype. In addition, BRP-39−/− mice were significantly more sensitive to LPS plus hyperoxia induced lung injury and mortality compared to WT mice. Conclusions. These findings collectively indicate that BRP-39 is involved in repressing the M1 proinflammatory phenotype in hyperoxia, thereby deactivating inflammatory responses in macrophages and preventing neonatal lung injury.
PMCID: PMC3855965  PMID: 24347826
To evaluate the fetal renal artery impedance in the context of inflammation-associated preterm birth (PTB).
We conducted a prospective Doppler assessment of the fetal renal artery impedance in 70 singleton fetuses. The study group consisted of 56 premature fetuses (28.1 [25.3–30.6] weeks at enrollment). Gestational age (GA) reference ranges were generated based on fetuses with uncomplicated pregnancies (n=14). Doppler studies included renal artery pulsatility index (PI), resistance index (RI), systolic/diastolic (S/D) ratio and presence-or-absence of end-diastolic blood flow. We assessed amniotic fluid (AF) inflammation by proteomic profiling (SELDI-TOF). Data were interpreted in relationship to amniotic fluid index (AFI), cord blood interleukin-6 (IL-6) and erythropoietin (EPO) levels. The cardiovascular and metabolic profiles of the neonates were investigated in the first 24 hours of life.
Fetuses delivered by mothers with intra-amniotic inflammation had higher cord blood IL-6 but not EPO levels. Fetal inflammation did not affect either renal artery PI,RI,S/D ratio or end-diastolic blood flow. Neonates delivered in the context of intraamniotic inflammation had higher serum blood urea nitrogen levels, which correlated significantly with AF IL-6 levels. The renal artery RI and SD ratio were inversely correlated with the AFI independent of GA, cord blood IL-6 and status of the membranes.
The fetus is capable of sustaining normal renal artery impedance despite inflammation. Resistance in the renal vascular bed affects urine output independent of inflammation.
PMCID: PMC3791328  PMID: 19185102
15.  Fetal Inflammatory Response in Women with Proteomic Biomarkers Characteristic of Intra-Amniotic Inflammation and Preterm Birth 
To determine the relationship between presence of amniotic fluid (AF) biomarkers characteristic of inflammation (defensins 2 and 1, calgranulins C and A) and fetal inflammatory status at birth.
Prospective observational cohort.
Tertiary referral University hospital
132 consecutive mothers (gestational age, median [interquartile range]: 29.6 [24.1-33.6] weeks), who had a clinically indicated amniocentesis to rule-out infection and their newborns.
Intra-amniotic inflammation was diagnosed by mass spectrometry SELDI-TOF. The AF proteomic fingerprint [Mass Restricted (MR) score] ranges from 0-4 (none to all biomarkers present). The intensity of intra-amniotic inflammation was graded based on the number of proteomic biomarkers: MR score 0: “no” inflammation; MR score 1-2: “minimal” inflammation; MR score 3-4: “severe” inflammation. At birth, cord blood was obtained for all cases. Severity of histological chorioamnionitis (HCA) and early onset neonatal sepsis (EONS) was based on established histological and hematological criteria. Interleukin-6 (IL-6) levels were measured by sensitive immunoassays. The cord blood-to-AF IL-6 ratio was used as an indicator of the differential inflammatory response in the fetal versus the AF compartment.
Main Outcome Measures
to relate proteomic biomarkers of intra-amniotic infection to cord blood IL-6 and to use the latter as the primary marker of fetal inflammatory response.
Women with intra-amniotic inflammation delivered at an earlier gestational age (ANOVA, P<0.001) and had higher AF IL-6 levels (P<0.001). At birth, neonates of women with “severe” intra-amniotic inflammation had higher cord blood IL-6 levels (P=0.002) and a higher frequency of EONS (P=0.002). EONS was characterized by significantly elevated cord blood IL-6 levels (P<0.001). Out of the 39 neonates delivered by mothers with “minimal” intra-amniotic inflammation, 15 (39%) had umbilical cord blood IL-6 levels above the mean for the group, and 2 neonates had confirmed sepsis. The severity of the neutrophilic infiltrate in the chorionic plate (P<0.001), choriodecidua (P=0.002), umbilical cord (P<0.001), but not amnion (P>0.05) was an independent predictor of the cord blood-to-AF IL-6 ratio. Relationships were maintained following correction for gestational age, birthweight, amniocentesis-to delivery interval, cesarean delivery, status of the membranes, race, MR score, antibiotics and steroid exposure.
We provide evidence that presence in the AF of proteomic biomarkers characteristic of inflammation is associated with an increased inflammatory status of the fetus at birth. Neonates mount an increased inflammatory status and have positive blood cultures even in the context of “minimal” intra-amniotic inflammation.
PMCID: PMC3791329  PMID: 18947340
Proteomics; biomarkers; amniotic fluid; inflammation; defensin; calgranulin; umbilical cord blood; interleukin-6
Biochemistry  2012;51(28):5642-5654.
MIP-2/CXCL2 is a murine chemokine related to human chemokines that possess the Glu-Leu-Arg (ELR) activation motif and activates CXCR2 for neutrophil chemotaxis. We determined the structure of MIP-2 to 1.9Å resolution and created a model with its receptor murine CXCR2 based on the coordinates of human CXCR4. Chemokine-induced migration of cells through specific G protein-coupled receptors is regulated by glycosaminoglycans (GAGs) that oligomerize chemokines. MIP-2 GAG-binding residues were identified that interact with heparin disaccharide I-S by NMR spectroscopy. A model a GAG:MIP-2:CXCR2 complex that supports a 2:2 complex between chemokine and receptor was created. Mutants of these disaccharide-binding residues were made and tested for heparin binding, in vitro neutrophil chemotaxis, and in vivo neutrophil recruitment to the mouse peritoneum and lung. The mutants have a 10-fold decrease in neutrophil chemotaxis in vitro. There is no difference in neutrophil recruitment between wild-type MIP-2 and mutants in the peritoneum but all activity of the mutants is lost in the lung supporting the concept that GAG regulation of chemokines is tissue-dependent.
PMCID: PMC3511906  PMID: 22686371
17.  VEGF levels in humans and animal models with RDS and BPD: Temporal relationships 
Experimental lung research  2012;38(4):192-203.
Respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) contribute significantly to neonatal morbidity and mortality. Pulmonary function depends on the interaction between alveolar microvasculature and airspace development. While it has been shown in various animal models that vascular endothelial growth factor (VEGF) and its receptors increase in normal animal lung development, its pathophysiological role in neonatal respiratory failure is not yet entirely clear. Current animal and human studies exhibit controversial results. Though animal models are invaluable tools in the study of human lung disease, inherent differences in physiology mandate clarification of the timing of these studies to ensure that they appropriately correlate with the human stages of lung development. The purpose of this review article is to highlight the importance of considering the temporal relationship of VEGF and lung development in human neonates and developmentally-appropriate animal models with RDS and BPD.
PMCID: PMC3705912  PMID: 22394267
VEGF; bronchopulmonary dysplasia; neonatal lung disease; respiratory distress syndrome
18.  Neutrophil Cd64 as a Diagnostic Marker in Neonatal Sepsis 
We assessed neutrophil CD64 as a diagnostic marker for neonatal sepsis. For early-onset sepsis, the CD64 index with a cut-point value of 2.38 had sensitivity, specificity and a negative predictive values of 100%, 68%, and 100%, respectively. For late-onset sepsis, the respective values were 3.62, 75%, 77%, and 96%. Neutrophil CD64 index can be incorporated as a valuable marker for excluding neonatal sepsis.
PMCID: PMC3375383  PMID: 22481422
Sensitivity; specificity; infection; newborn; CD64; diagnosis of sepsis
19.  Cord blood erythropoietin and interleukin-6 for prediction of intraventricular hemorrhage in the preterm neonate 
To evaluate cord blood erythropoietin (EPO) and interleukin-6 (IL-6) levels to predict preterm infants at risk of developing intraventricular hemorrhage (IVH).
Levels of umbilical cord EPO, acid–base status and IL-6 were analyzed in 116 consecutive, preterm newborns (GA at delivery: 29 [23–34] weeks) born to mothers who had a clinically indicated amniocentesis to rule out infection. Early-onset neonatal sepsis (EONS) was diagnosed using symptoms, hematological criteria and blood cultures.
IVH was diagnosed by cranial ultrasounds. The prevalence of IVH in our population was 25% (29/116). There was a direct relationship between cord blood EPO and cord blood IL-6 concentration (r = 0.225, p = 0.014), independent of GA at birth. Elevated cord blood EPO levels (r = 0.182, p = 0.016) and GA birth at birth (r = –0.236, p = 0.004) remained significant independent factors associated with the risk of IVH, when evaluated with stepwise logistic regression analyses. Cord blood IL-6, pH, and EONS were not associated with IVH. These relationships remained following correction for GA at birth (p = 0.027).
Our results suggest that elevation in cord blood EPO may predict newborns at risk for IVH, independent of fetal inflammatory status. Further studies are warranted to confirm this association.
PMCID: PMC3683649  PMID: 20937006
Erythropoietin; IL-6; premature; newborn; IVH
20.  Increased Hyperoxia-Induced Lung Injury in Nitric Oxide Synthase 2 Null Mice Is Mediated via Angiopoietin 2 
Supplemental oxygen is frequently prescribed. However, prolonged exposure to high concentrations of oxygen causes hyperoxic acute lung injury (HALI), which manifests as acute respiratory distress syndrome in adults and leads to bronchopulmonary dysplasia in newborns (NBs). Nitric oxide (NO), NO synthases (NOSs), and angiopoietin (Ang) 2 have been implicated in the pathogenesis of HALI. However, the mechanisms of the contributions of NOS/NO and the relationship(s) between NOS/NO and Ang2 have not been addressed. In addition, the relevance of these moieties in adults and NBs has not been evaluated. To address these issues, we compared the responses in hyperoxia of wild-type (NOS [+/+]) and NOS null (−/−) young adult and NB mice. When compared with NOS2+/+ adult controls, NOS2−/− animals manifest exaggerated alveolar–capillary protein leak and premature death. These responses were associated with enhanced levels of structural cell death, enhanced expression of proapoptotic regulatory proteins, and Ang2. Importantly, silencing RNA knockdown of Ang2 decreased the levels of cell death and the expression of proapoptotic mediators. These effects were at least partially NOS2 specific, and were development dependent, because survival was similar in adult NOS3+/+ and NOS3−/− mice and NB NOS2+/+ and NOS2−/− mice, respectively. These studies demonstrate that NOS2 plays an important protective role in HALI in adult animals. They also demonstrate that this response is mediated, at least in part, by the ability of NOS2 to inhibit hyperoxia-induced Ang2 production and thereby decrease Ang2-induced tissue injury.
PMCID: PMC3359903  PMID: 22227562
cytokines; hyperoxia; lung
21.  Risk Factors Associated with Biliary Pancreatitis in Children 
Little is known about risk factors for biliary pancreatitis in children.
We characterized cases of pediatric biliary pancreatitis, compared biliary with non-biliary cases, examined differences in presentation between younger and older children, and studied features distinguishing gallstone- from sludge-induced pancreatitis.
We evaluated 76 episodes of biliary pancreatitis from 271 cases of acute pancreatitis in children admitted to a tertiary care hospital from 1994 to 2007.
Of the 76 cases, 55% had gallstones, 21% had sludge, and 24% had structural defects. Hispanic children had a 2.85 (p=0.01) and 5.59 (p=0.003) higher probability for biliary pancreatitis than white and black children, respectively. Median serum amylase and lipase in children with biliary pancreatitis were 64% and 49% higher, respectively, compared to other etiologies (p<0.05). In multiple logistic regression, aspartate aminotransferase (AST) was an independent predictor of biliary pancreatitis (OR=6.69, p=0.001). When comparing gallstone- with sludge-induced etiologies, obesity was an independent predictor (38% more prevalent, p<0.01) of gallstone cases.
Hispanic ethnicity is a risk factor and AST is a biomarker for biliary pancreatitis over other etiologies. Furthermore, obesity can distinguish gallstone- from sludge-induced pancreatitis. These findings may spur prospective studies to determine the optimal evaluation and management of children with biliary pancreatitis.
PMCID: PMC3626418  PMID: 22002481
Acute pancreatitis; children; pediatric; biliary; gallstone; sludge; Hispanic ethnicity; obesity
22.  Novel Characterization of Drug-associated Pancreatitis in Children 
Background and Objectives
Medications are a major cause of acute pancreatitis; however, little is known about their influence in children. Our primary aims were to identify common comorbidities and concomitant pancreatitis etiologies in children with drug-associated pancreatitis. Our secondary aims were to identify the most commonly associated drugs in the different age groups, evaluate management practices, and compare drug-associated cases with non–drug-associated cases.
Patients and Methods
In the present study, we examined children (ages 0–20 years) admitted to Yale-New Haven Children’s Hospital with pancreatitis between 1994 and 2007.
Of a total of 271 pediatric cases, drugs were associated with pancreatitis in 25.6% (55). The 3 most common comorbidities in children with drug-associated pancreatitis were seizure disorders, acute lymphocytic leukemia, and Crohn disease. One third of drug-associated cases had an additional pancreatitis etiology. The most commonly associated drugs were valproic acid and corticosteroids. Compared with non–drug-associated cases, children with drug-associated cases were more likely to undergo CT scanning (54.5% vs 28.4%; P < 0.001), stay in the hospital longer (10 vs 4 days; P < 0.001), and transition to parenteral nutrition from a nil per os status (37.5% vs 21.2%; P < 0.05). There was a higher frequency of valproic acid–associated cases in children younger than 11 years (29.4% vs 9.5% in the 11- to 20-year-old age group).
Our study underscores the importance of considering drugs as a cause and a contributor to pancreatitis in children, particularly valproic acid in young children.
PMCID: PMC3626448  PMID: 21681111
acute pancreatitis; children; drug; medications; pediatric; valproic acid
23.  Small molecular modulation of macrophage migration inhibitory factor in the hyperoxia-induced mouse model of bronchopulmonary dysplasia 
Respiratory Research  2013;14(1):27.
The role and mechanism of action of MIF in bronchopulmonary dysplasia (BPD) are not known. We hypothesized that increased MIF signaling would ameliorate the pulmonary phenotype of BPD in the mouse lung.
We studied newborn wild type (WT), MIF knockout (MIFKO), and lung MIF transgenic (MIFTG) mice in room air and a BPD model, and examined the effects of administering a small molecule MIF agonist and antagonist. Lung morphometry was performed and mRNA and protein expression of vascular mediators were analyzed.
The pulmonary phenotype of MIFKO and MIFTG mice lungs in room air (RA) and BPD model were comparable to the WT-BPD mice at postnatal (PN) day 14. Vascular endothelial growth factor (VEGF)-A, -R1 and Angiopoietin (Ang)1 mRNA were decreased, and Ang2 increased in the WT-BPD, MIFKO-RA, MIFKO-BPD, MIFTG-RA and MIFTG-BPD mice lungs, compared to appropriate controls. The protein expression of Ang1 in the MIFKO-RA was similar to WT-RA, but decreased in MIFTG-RA, and decreased in all the BPD groups. Ang2 was increased in MIFKO-RA, MIFTG-RA and in all 3 BPD groups. Tie2 was increased in WT-BPD compared to WT-RA, but decreased in MIFKO- and MIFTG- RA and BPD groups. VEGFR1 was uniformly decreased in MIFKO-RA, MIFTG-RA and in all 3 BPD groups. VEGF-A had a similar expression across all RA and BPD groups. There was partial recovery of the pulmonary phenotype in the WT-BPD model treated with the MIF agonist, and in the MIFTG mice treated with the MIF antagonist.
These data point to the careful regulatory balance exerted by MIF in the developing lung and response to hyperoxia and support the potential therapeutic value of small molecule MIF modulation in BPD.
PMCID: PMC3637059  PMID: 23448134
Newborn; Oxygen; Bronchopulmonary dysplasia
24.  Comparative Microbial Analysis of Paired Amniotic Fluid and Cord Blood from Pregnancies Complicated by Preterm Birth and Early-Onset Neonatal Sepsis 
PLoS ONE  2013;8(2):e56131.
16S rRNA-based genomic analyses have revolutionized our understanding of infectious diseases. Many cases which were recognized as “idiopathic” are now known to have an infectious etiology. Here, we present a proof-of-concept study to examine the microbial link between intra-amniotic infection (IAI) and early-onset neonatal sepsis (EONS).
Using culture independent methods, we analyzed paired amniotic fluid (AF) and cord blood (CB) samples from 36 singleton pregnancies complicated by preterm birth (PTB), IAI, and/or EONS. PTB cases were grouped as 1) Group 1– neonatal blood culture-positive EONS (n = 6). 2) Group 2– neonatal blood culture-negative presumed EONS with positive IAI (n = 16). 3) Group 3– neonatal blood culture-negative presumed EONS with no IAI (n = 7); 4) Group 4– no EONS or IAI (n = 7). In addition, samples from term healthy deliveries (n = 8) served as technical controls. A total of 31 species (15 non-redundant) were identified in AF, of which only 1/3 were cultivated. Significantly fewer microorganisms were detected in CB, with a total of 18 species (7 non-redundant) identified, of which only 2 (Escherichia coli, Streptococcus agalactiae) were cultivated. Of those, Bergeyella, Fusobacterium nucleatum, and Sneathia sanguinegens had not been detected in EONS before. The novel species identified in AF by PCR include Peptoniphilus harei and Lachnospiraceae sp. The majority (72%) of CB species were also detected in the matching AF, with E. coli and F. nucleatum as the most prevalent. The 16S rRNA sequences of paired AF and CB were 99.9–100% identical, while no identical sequences were found between different pregnancies.
Previously unrecognized, uncultivated or difficult-to-cultivate species are implicated in EONS. Microbial species in paired AF and CB likely share the same infectious origin. Given its prevalence in EONS, F. nucleatum should be placed on the same importance scale as E. coli.
PMCID: PMC3577789  PMID: 23437088
Use of nasal intermittent positive pressure ventilation (NIPPV) in the neonatal intensive care unit (NICU) has shown promise with better clinical outcomes in premature neonates. It is not known if synchronization makes a significant clinical impact when using this technique.
To compare clinical outcomes of premature infants on synchronized NIPPV (SNIPPV) vs. NIPPV in the NICU.
Retrospective data were obtained (1/04 to 12/09) of infants who received NIPPV anytime in the NICU. SNIPPV (Infant Star with StarSync) was utilized from 2004–06, while NIPPV (Bear Cub) was used from 2007–09. BPD was defined using the NIH consensus definition. Unadjusted associations between potential risk factors and BPD/death were assessed using the chi-square or Wilcoxon Rank Sum test. Adjusted analyses were performed using generalized linear mixed models, taking into account correlation among infants of multiple gestation.
There was no significant difference in the mean gestational age and birth weight in the 2 groups: SNIPPV (n=172; 27.0w; 1016g), NIPPV (n=238; 27.7w; 1117g). There were no significant differences in maternal demographics, use of antenatal steroids, gender, multiple births, SGA, or Apgar scores in the 2 groups. More infants in the NIPPV group were given resuscitation in the delivery room (SNIPPV vs. NIPPV: 44.2% vs. 63%, p<0.001). Surfactant use (84.4% vs. 70.2%; p<0.001) was significantly higher in the SNIPPV group. There were no differences in the rate of PDA, IVH, PVL, ROP, and NEC in the 2 groups. After adjusting for the significant variables, use of NIPPV vs. SNIPPV (OR 0.74; 95%CI: 0.42, 1.30) was not associated with BPD/death.
These data suggest that use of SNIPPV vs. NIPPV is not significantly associated with a differential impact on clinical outcomes.
PMCID: PMC3534723  PMID: 22116527
Premature newborn; non invasive ventilation; BPD

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