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1.  Fetal hyperglycemia and a high fat diet contribute to aberrant glucose tolerance and hematopoiesis in adulthood 
Pediatric research  2014;77(2):316-325.
Background
Children exposed to gestational diabetes mellitus (GDM) during pregnancy are at increased risk of obesity, diabetes, and hypertension. Our goal was to identify metabolic and hematopoietic alterations after intrauterine exposure to maternal hyperglycemia that may contribute to the pathogenesis of chronic morbidities.
Methods
Streptozotocin treatment induced maternal hyperglycemia during the last third of gestation in rat dams. Offspring of control mothers (OCM) and diabetic mothers (ODM) were evaluated for weight, glucose tolerance, insulin tolerance, and hematopoiesis defects. The effects of aging were examined in normal and high fat diet (HFD)-fed young (8-week-old) and aged (11-month-old) OCM and ODM rats.
Results
Young adult ODM males on a normal diet, but not females, displayed improved glucose tolerance due to increased insulin levels. Aged ODM males and females gained more weight than OCM on a HFD and had worse glucose tolerance. Aged ODM males fed a HFD were also neutrophilic. Increases in bone marrow cellularity and myeloid progenitors preceded neutrophilia in ODM males fed a HFD.
Conclusion
When combined with other risk factors like HFD and aging, changes in glucose metabolism and hematopoiesis may contribute to the increased risk of obesity, type 2 diabetes, and hypertension observed in children of GDM mothers.
doi:10.1038/pr.2014.185
PMCID: PMC4297501  PMID: 25412163
2.  Tracheal Suctioning Improves Gas Exchange but not Hemodynamics in Asphyxiated Lambs with Meconium Aspiration 
Pediatric research  2014;77(2):347-355.
Background
Current neonatal resuscitation guidelines recommend tracheal suctioning of non-vigorous neonates born through meconium stained amniotic fluid.
Methods
We evaluated the effect of tracheal suctioning at birth in 29 lambs with asphyxia induced by cord occlusion and meconium aspiration during gasping.
Results
Tracheal suctioning at birth (n=15) decreased amount of meconium in distal airways (53±29 particles/mm2 lung area) compared to no-suction (499±109 particles/mm2, n=14, p<0.001). Three lambs in the suction group had cardiac arrest during suctioning requiring chest compressions and epinephrine. Onset of ventilation was delayed in the suction group (146±11 vs. 47±3 sec in no-suction group, p=0.005). There was no difference in pulmonary blood flow, carotid blood flow, pulmonary or systemic blood pressure between the two groups. Left atrial pressure was significantly higher in the suction group. Tracheal suctioning resulted in higher PaO2/FiO2 levels (122±21 vs. 78±10 mmHg) and ventilator efficiency index (0.3±0.05 vs.0.16±0.03). Two lambs in the no-suction group required inhaled NO. Lung 3-nitrotyrosine levels were higher in the suction group (0.65±0.03 ng/μg protein) compared to the no-suction group (0.47 ± 0.06).
Conclusion
Tracheal suctioning improves oxygenation and ventilation. Suctioning does not improve pulmonary/systemic hemodynamics or oxidative stress in an ovine model of acute meconium aspiration with asphyxia.
doi:10.1038/pr.2014.186
PMCID: PMC4297526  PMID: 25406897
3.  Kidney disease among children in sub-Saharan Africa: a systematic review 
Pediatric research  2014;77(2):272-281.
The global burden of kidney disease is increasing, and several etiologies first begin in childhood. Risk factors for pediatric kidney disease are common in Africa, but data regarding its prevalence are lacking. We completed a systematic review of community-based studies describing the prevalence of proteinuria, hematuria, abnormal imaging, or kidney dysfunction among children in sub-Saharan Africa. Medline and Embase were searched. Five hundred twenty-three references were reviewed. Thirty-two references from 9 countries in sub-Saharan Africa were included in the qualitative synthesis. The degree of kidney damage and abnormal imaging varied widely: proteinuria 32.5% (2.2%-56.0%); hematuria 31.1% (0.6%-67.0%); hydronephrosis 11.3% (0.0%-38.0%), hydroureter 7.5% (0.0%-26.4%), major kidney abnormalities 0.1% (0.0%-0.8%). Serum creatinine was reported in four studies with insufficient detail to identify the prevalence renal dysfunction. A majority of the studies were performed in Schistosoma haematobium endemic areas. A lower prevalence of kidney disease was observed in the few studies from non-endemic areas. Published data on pediatric kidney disease in sub-Saharan Africa is highly variable and dependent on S. haematobium prevalence. More community-based studies are needed to describe the burden of pediatric kidney disease, particularly in regions where S. haematobium infection is non-endemic.
doi:10.1038/pr.2014.189
PMCID: PMC4426498  PMID: 25420180
5.  Brain development of the preterm neonate after neonatal hydrocortisone treatment for chronic lung disease 
Pediatric research  2009;66(5):555-559.
Previous studies reported impaired cerebral cortical gray matter development and neurodevelopmental impairment following neonatal dexamethasone treatment for chronic lung disease in preterm newborns. No long-term effects on neurocognitive outcome have yet been shown for hydrocortisone treatment. A prospective study was performed to evaluate brain growth at term in preterm infants who did receive neonatal hydrocortisone for chronic lung disease. Thirty-eight preterm infants (n=19 hydrocortisone, n=19 controls) were matched for gestational age at birth. Gestational age and birth weight were 27.0±1.4 vs. 27.6±1.1 weeks (p=ns), and 826±173 vs. 1017±202 gram respectively (p<0.05). Infants were studied at term equivalent age. Hydrocortisone was started with a dose of 5 mg/kg/day for 1 week, followed by a tapering course over 3 weeks. A 3D-MRI technique was used to quantify cerebral tissue volumes: cortical grey matter, basal ganglia/thalami, unmyelinated white matter, myelinated white matter, cerebellum, and cerebrospinal fluid. Infants who were treated with hydrocortisone had more severe respiratory distress. There were no differences in cerebral tissue volumes between the 2 groups at term equivalent age. In conclusion, no effect on brain growth, measured at term equivalent age, was shown following treatment with hydrocortisone for chronic lung disease.
doi:10.1203/PDR.0b013e3181b3aec5
PMCID: PMC4495650  PMID: 19851225
6.  Upper and Lower Esophageal Sphincter Kinetics are Modified During Maturation: Effect of Pharyngeal Stimulus in Premature Infants 
Pediatric research  2014;77(0):99-106.
Background
We hypothesized that changes in proximal and distal esophageal sphincter kinetics evoked upon pharyngeal provocation undergo longitudinal maturation.
Methods
Pharyngeal stimulation-induced reflexes were characterized using novel pharyngoesophageal motility methods in 19 healthy premature neonates, studied at 34.7 ± 0.8 wks (time-1), and 39.3 ± 1.1 wks postmenstrual age (time-2). Graded volumes of air (290 infusions) and sterile water (172 infusions) were infused to define sensory-motor characteristics of upstream (pharyngeal reflexive swallow, PRS) and downstream (pharyngo-lower esophageal sphincter relaxation reflex, PLESRR) esophageal reflexes. Data displayed as mean ± SE.
Results
Threshold volumes were similar with air and water for PRS and PLESRR at time-1 and time-2. Multiple PRS responses were noted with water stimulus, and were different between the media (time-1 vs. air, P< 0.0001; time-2 vs. air, P =0.0003). Dose response relationships for water were significant (P<0.01 for PRS and PLESRR time-1 and time-2), but not with air.
Conclusions
Significantly, the recruitment frequency of PRS and PLESRR increases with maturation, liquid is a superior medium for evoking such swallowing reflexes, and stimulus-response relationships for these reflexes are evident. These changes in aerodigestive protective reflexive activity may indicate differences in modulation of excitatory and inhibitory pathways during longitudinal postnatal maturation.
doi:10.1038/pr.2014.147
PMCID: PMC4268006  PMID: 25279989
7.  Impaired epithelial Na+ channels activity contributes to cystogenesis and development of autosomal recessive polycystic kidney disease in PCK rats 
Pediatric research  2014;77(0):64-69.
BACKGROUND
Autosomal recessive polycystic kidney disease (ARPKD) is a genetic disorder characterized by the development of renal cysts of the tubular epithelial cell origin. Epithelial Na+ channel (ENaC) is responsible for sodium reabsorption in the aldosterone-sensitive distal nephron. Here we investigated the ENaC expression and activity in cystic tissue taken from rats with ARPKD.
METHODS
PCK rats were treated with the selective ENaC inhibitor benzamil given in the drinking water, and after 4 or 12 weeks the severity of morphological malformations in the kidneys was assessed. ENaC and AQP2 expression and ENaC activity were tested with immunohistochemistry and patch clamp electrophysiology, respectively.
RESULTS
Treatment with benzamil exacerbated development of cysts compared to the vehicle-treated animals. In contrast, the 12 weeks treatment with a loop diuretic furosemide had no effect on cystogenesis. Single channel patch clamp analysis revealed that ENaC activity in the freshly isolated cystic epithelium was significantly lower than in the non-cystic collecting ducts isolated from PCK or normal Sprague-Dawley rats. Immunohistochemical analysis confirmed that β-ENaC and AQP2 expressions in cysts are decreased compared to non-dilated tubules from PCK rat kidneys.
CONCLUSION
We demonstrated that cystic epithelium exhibits low ENaC activity and this phenomenon can contribute to cyst progression.
doi:10.1038/pr.2014.145
PMCID: PMC4268054  PMID: 25279988
8.  Respiratory Inductance Plethysmography calibration for pediatric upper airway obstruction: an animal model 
Pediatric research  2014;77(0):75-83.
Background
To determine optimal methods of Respiratory Inductance Plethysmography (RIP) flow calibration for application to pediatric post-extubation upper airway obstruction.
Methods
We measured RIP, spirometry, and esophageal manometry in spontaneously breathing, intubated Rhesus monkeys with increasing inspiratory resistance. RIP calibration was based on: ΔµVao ≈ M[ΔµVRC + K(ΔµVAB)] where K establishes the relationship between the uncalibrated rib cage (ΔµVRC) and abdominal (ΔµVAB) RIP signals. We calculated K during: (1) isovolume maneuvers during a negative inspiratory force (NIF) (2) Quantitative Diagnostic Calibration (QDC) during (a) tidal breathing, (b) continuous positive airway pressure (CPAP), and (c) increasing degrees of UAO. We compared the calibrated RIP flow waveform to spirometry quantitatively and qualitatively.
Results
Isovolume calibrated RIP flow tracings were more accurate (against spirometry) both quantitatively and qualitatively than those from QDC (p<0.0001), with bigger differences as UAO worsened. Isovolume calibration yielded nearly identical clinical interpretation of inspiratory flow limitation as spirometry.
Conclusions
In an animal model of pediatric UAO, Isovolume calibrated RIP flow tracings are accurate against spirometry. QDC during tidal breathing yields poor RIP flow calibration, particularly as UAO worsens. Routine use of a NIF maneuver before extubation affords the opportunity to use RIP to study post extubation UAO in children.
doi:10.1038/pr.2014.144
PMCID: PMC4268304  PMID: 25279987
9.  Maternal influences on fetal microbial colonization and immune development 
Pediatric research  2014;77(0):189-195.
While critical for normal development, the exact timing of establishment of the intestinal microbiome is unknown. For example, although preterm labor and birth have been associated with bacterial colonization of the amniotic cavity and fetal membranes for many years, the prevailing dogma of a sterile intrauterine environment during normal term pregnancies has been challenged more recently. While found to be a key contributor of evolution in the animal kingdom, maternal transmission of commensal bacteria may also constitute a critical process during healthy pregnancies in humans with yet unclear developmental importance. Metagenomic sequencing has elucidated a rich placental microbiome in normal term pregnancies likely providing important metabolic and immune contributions to the growing fetus. Conversely, an altered microbial composition during pregnancy may produce aberrant metabolites impairing fetal brain development and life-long neurological outcomes. Here we review the current understanding of microbial colonization at the feto-maternal interface and explain how normal gut colonization drives a balanced neonatal mucosal immune system, while dysbiosis contributes to aberrant immune function early in life and beyond. We discuss how maternal genetics, diet, medications, and probiotics inform the fetal microbiome in preparation for perinatal and postnatal bacterial colonization.
doi:10.1038/pr.2014.163
PMCID: PMC4289016  PMID: 25310759
10.  Obesity-Associated Biomarkers and Executive Function in Children 
Pediatric research  2014;77(0):143-147.
There is a growing focus on links between obesity and cognitive decline in adulthood, including Alzheimer’s disease. It is also increasingly recognized that obesity in youth is associated with poorer cognitive function, specifically executive functioning skills such as inhibitory control and working memory, which are critical for academic achievement. Emerging literature provides evidence for possible biological mechanisms driven by obesity; obesity-associated biomarkers such as adipokines, obesity-associated inflammatory cytokines, and obesity-associated gut hormones have been associated with learning, memory, and general cognitive function. To date, examination of obesity-associated biology with brain function has primarily occurred in animal models. The few studies examining such biologically-mediated pathways in adult humans have corroborated the animal data, but this body of work has gone relatively unrecognized by the pediatric literature. Despite the fact that differences in these biomarkers have been found in association with obesity in children, the possibility that obesity-related biology could affect brain development in children has not been actively considered. We review obesity-associated biomarkers that have shown associations with neurocognitive skills, specifically executive functioning skills which have far-reaching implications for child development. Understanding such gut-brain associations early in the lifespan may yield unique intervention implications.
doi:10.1038/pr.2014.158
PMCID: PMC4416088  PMID: 25310758
11.  Transgenic sickle cell disease mice have high mortality and dysregulated immune responses after vaccination 
Pediatric research  2013;74(2):141-147.
Background
Children with sickle cell disease (SCD) are susceptible to recurrent infections, which are often life threatening and necessitate frequent vaccinations. Given the altered baseline immunity and proinflammatory state associated with SCD, we sought to determine the relative safety and efficacy of vaccination in transgenic SCD mice.
Methods
Eight week-old SCD mice were vaccinated with ovalbumin (OVA) and aluminum hydroxide weekly for three weeks by the intraperitoneal (IP) or intramuscular (IM) route. One week after the third vaccination, serum cytokines/chemokines, immunoglobulins, and bronchoalveolar lavage (BAL) fluid cytokines were measured.
Results
Only SCD mice were prone to mortality associated with vaccination as 40% of the animals died after the IP vaccinations and 50% died after the IM vaccinations. Serum IgG2b and IgM were significantly lower in SCD than C57Bl/6 mice after vaccination, but OVA-specific IgE was significantly higher. Serum interleukin 1 alpha (IL-1α), IL-2, IL-5, macrophage inflammatory protein 1 alpha (MIP-1α), and granulocyte macrophage-colony stimulating factor (GM-CSF) were significantly lower in SCD mice than C57Bl/6 mice after vaccination, whereas BAL fluid IL-1β and IL-6 were elevated.
Conclusions
Mice with SCD appear to have a dysregulated immune response to vaccination. Thus, the relative safety and immunogenicity of vaccination should be studied in greater detail in the context of SCD.
doi:10.1038/pr.2013.85
PMCID: PMC4487511  PMID: 23728384
12.  A Pharmacokinetic and Dosing Study of Intravenous Insulin-Like Growth Factor-I and IGF-Binding Protein-3 Complex to Preterm Infants 
Pediatric research  2009;65(5):574-579.
In preterm infants, low levels of Insulin like growth factor 1 (IGF-I) have been associated with impaired growth and retinopathy of prematurity. Our objective was to study safety and pharmacokinetics of i.v. administered rhIGF-I with its binding protein 3 (rhIGFBP-3) to preterm infants. At 3 d chronological age, an i.v. 3 h infusion of rhIGF-I/rhIGFBP-3 was administered followed by serial measurements of IGF-I and IGFBP-3. Infants were evaluated for physiologic safety measurements. The individual dose of rhIGF-I ranged from 1 to 12 µg/kg. The study was conducted at Queen Silvia Children’s Hospital, Gothenburg, Sweden, between January and November 2007. Five patients (3 F) with mean (range) post menstrual age 27 wk (26–29) and birth weight 1022 g (810 –1310) participated. IGF-I and IGFBP-3 levels before infusion were median (range) 18 (12–28) and 771 (651–1047) ng/mL, respectively. Immediately after study drug infusion, serum IGF-I and IGFBP-3 levels were 38 (25–59) and 838 (754 –1182) ng/mL, respectively. Median (range) half-life for IGF-I and IGFBP-3 was 0.79 (0.59 –1.42) and 0.87 (0.85– 0.94) hours, respectively. Blood glucose, insulin, sodium, potassium, and physiologic safety measures were within normal ranges. The rhIGF-I/rhIGFBP-3 equimolar proportion was effective in increasing serum IGF-I levels and administration under these study conditions was safe and well tolerated.
doi:10.1203/PDR.0b013e31819d9e8c
PMCID: PMC4486044  PMID: 19190540
13.  Childhood Malnutrition and the Intestinal Microbiome Malnutrition and the microbiome 
Pediatric research  2014;77(0):256-262.
Malnutrition contributes to almost half of all deaths in children under the age of 5 years, particularly those who live in resource-constrained areas. Those who survive frequently suffer from long-term sequelae including growth failure and neurodevelopmental impairment. Malnutrition is part of a vicious cycle of impaired immunity, recurrent infections and worsening malnutrition. Recently, alterations in the gut microbiome have also been strongly implicated in childhood malnutrition. It has been suggested that malnutrition may delay the normal development of the gut microbiota in early childhood or force it towards an altered composition that lacks the required functions for healthy growth and/or increases the risk for intestinal inflammation. This review addresses our current understanding of the beneficial contributions of gut microbiota to human nutrition (and conversely the potential role of changes in that community to malnutrition), the process of acquiring an intestinal microbiome, potential influences of malnutrition on the developing microbiota and the evidence directly linking alterations in the intestinal microbiome to childhood malnutrition. We review recent studies on the association between alterations in the intestinal microbiome and early childhood malnutrition and discuss them in the context of implications for intervention or prevention of the devastation caused by malnutrition.
doi:10.1038/pr.2014.179
PMCID: PMC4476274  PMID: 25356748
14.  Anesthetic use in newborn infants: the urgent need for rigorous evaluation 
Pediatric Research  2015;78(1):2-6.
Approximately 1.5 million neonates receive general anesthesia each year for a surgical procedure. Despite this being an essential practice, a number of recent studies now indicate that anesthetic exposure could cause toxicity and neuronal apoptosis in the developing brain. This could potentially influence long-term neurodevelopmental outcome, especially premature infants in need of multiple surgical procedures. Most anesthetic drugs routinely administered to neonates have not been adequately tested for safety or efficacy. Given the number of confounders, dosing is often extrapolated from adults. This is concerning since many different drugs can be administered concurrently, with few of these agents actually approved for use by the Food and Drug Administration. Since 1997, legislation has been passed in the United States and abroad encouraging more drug investigation in infants and children. This has resulted in over 500 labeling changes to products regarding safety and efficacy in various pediatric age groups. However, only three drugs routinely used as anesthetic agents in newborn infants have had any updated labeling (none in very premature infants). This “off-label” use without adequate testing must be addressed. Therefore, more clinical trials of common anesthetic agents used alone and in combination in neonates are urgently needed.
doi:10.1038/pr.2015.58
PMCID: PMC4471569  PMID: 25790274
15.  Lipopolysaccharide-Induced Human Enterocyte Tolerance to Cytokine-Mediated Interleukin-8 Production May Occur Independently of TLR-4/MD-2 Signaling 
Pediatric research  2005;59(1):89-95.
Intestinal epithelial cells (IEC) are constantly exposed to bacterial components, such as LPS, without triggering proinflammatory immune responses. This study demonstrates that chronic exposure of human-derived IEC to LPS induces tolerance to an endogenous inflammatory cytokine (IL-1β) activated IL-8 response that occurs independently of TLR-4/MD-2 signaling. IL-8 production in response to activation by unrelated TNF-α and PMA signaling pathways is also inhibited, indicating a broad-spanning tolerance. Quantitative rtPCR and IL-8 promoter-luciferase assays demonstrate that tolerance is regulated at the transcriptional level and occurs independently of IEC cytodifferentiation. By contrast, LPS does not significantly alter other proinflammatory signaling cascades in IEC that function independently of IL-8 production, e.g., IL-6 secretion and PEEC (Hepoxilin A3)-induced neutrophil transepithelial migration in response to invasive Salmonella typhimurium. Human IEC have therefore developed LPS-induced signaling cascades that promote an IL-8 hyporesponsiveness to proinflammatory cytokines while LPS exposure does not compromise the ability of IEC to mount other proinflammatory immune responses to invasive enteropathogens.
doi:10.1203/01.pdr.0000195101.74184.e3
PMCID: PMC4465784  PMID: 16326999
16.  Lactobacillus rhamnosus GG and its SpaC pilus adhesin modulate inflammatory responsiveness and TLR-related gene expression in the fetal human gut 
Pediatric research  2015;77(4):528-535.
Background
Bacterial contact in utero modulates fetal and neonatal immune responses. Maternal probiotic supplementation reduces the risk of immune-mediated disease in the infant. We investigated the immunomodulatory properties of live Lactobacillus rhamnosus GG and its SpaC pilus adhesin in human fetal intestinal models.
Methods
TNF-α mRNA expression was measured by qPCR in a human fetal intestinal organ culture model exposed to live L. rhamnosus GG and proinflammatory stimuli. Binding of recombinant SpaC pilus protein to intestinal epithelial cells was assessed in human fetal intestinal organ culture and the human fetal intestinal epithelial cell line H4 by immunohistochemistry and immunofluorescence, respectively. TLR-related gene expression in fetal ileal organ culture after exposure to recombinant SpaC was assessed by qPCR.
Results
Live L. rhamnosus GG significantly attenuates pathogen-induced TNF-α mRNA expression in the human fetal gut. Recombinant SpaC protein was found to adhere to the fetal gut and to modulate varying levels of TLR-related gene expression.
Conclusion
The human fetal gut is responsive to luminal microbes. L. rhamnosus GG significantly attenuates fetal intestinal inflammatory responses to pathogenic bacteria. The L. rhamnosus GG pilus adhesin SpaC binds to immature human intestinal epithelial cells and directly modulates intestinal epithelial cell innate immune gene expression.
doi:10.1038/pr.2015.5
PMCID: PMC4465787  PMID: 25580735
17.  B-type natriuretic peptide: a prognostic marker in congenital diaphragmatic hernia 
Pediatric research  2014;76(6):549-554.
Background
B-type natriuretic peptide (BNP) has not been evaluated in newborns with congenital diaphragmatic hernia (CDH). We hypothesized that BNP and severity of pulmonary hypertension (PH) would predict clinical outcome in these infants.
Methods
We measured BNP levels and assessed severity of PH by echocardiography at one day and one week of life. Outcome was classified by status at 56 days (or prior discharge): Good (n=13) if alive on room air and Poor (n=14) if expired or receiving respiratory support. We estimated area under the curve (AUC) and 95% confidence interval (CI).
Results
BNP levels were higher at one day in newborns with Poor outcome (median 220 pg/mL versus 55 pg/mL, P<0.01). At one week, there was no significant difference in BNP level (median 547 pg/mL versus 364 pg/mL, P=0.70, for Poor and Good outcomes). At one day, BNP level predicted outcome (AUC 0.91, 95% CI 0.77–1.0), but this relationship dissipated by one week (AUC 0.55, 95% CI 0.31–0.79). Severity of PH did not predict outcome at one day (AUC 0.51, 95% CI 0.27–0.74), but prediction improved at one week (AUC 0.80, 95% CI 0.61–0.99).
Conclusion
BNP is a strong predictor of clinical outcome in newborns with CDH at one day of life.
doi:10.1038/pr.2014.136
PMCID: PMC4232979  PMID: 25188741
18.  Herpes simplex virus serotype and entry receptor availability alter CNS disease in a mouse model of neonatal HSV 
Pediatric research  2014;76(6):528-534.
Background
Outcomes of neonates with herpes simplex virus (HSV) encephalitis are worse after infection with HSV-2 when compared with HSV-1. The proteins herpes virus entry mediator (HVEM) and nectin-1 mediate HSV entry into susceptible cells. Prior studies have shown receptor-dependent differences in pathogenesis that depend on route of inoculation and host developmental age.
Methods
We investigated serotype-related differences in HSV disease and their relationship to entry receptor availability in a mouse model of encephalitis.
Results
Mortality was attenuated in seven-day-old wild-type (WT) mice inoculated with HSV-1(F) when compared with HSV-2(333). No serotype-specific differences were seen after inoculation of adult mice. HSV-1 pathogenesis was also attenuated relative to HSV-2 in newborn but not adult mice lacking HVEM or nectin-1. HSV-2 requires nectin-1 for encephalitis in adult but not newborn mice; in contrast, nectin-1 was important for HSV-1 pathogenesis in both age groups. Early viral replication was independent of age, viral serotype, or mouse genotype, suggesting host responses influence outcomes. In this regard, significantly greater amounts of inflammatory mediators were detected in brain homogenates from WT newborns 2 days after infection compared with adults and receptor-knockout newborns.
Conclusion
Dysregulation of inflammatory responses induced by infection may influence the severity of HSV encephalitis.
doi:10.1038/pr.2014.135
PMCID: PMC4233006  PMID: 25198371
19.  A Detailed Comparison of Mouse and Human Cardiac Development 
Pediatric research  2014;76(6):500-507.
Background
Mouse mutants are used to model human congenital cardiovascular disease. Little is published comparing normal cardiovascular development in mice versus humans. We carried out a systematic comparative analysis of mouse and human fetal cardiovascular development.
Methods
Episcopic fluorescence image capture (EFIC) was performed on 66 wild type mouse embryos from embryonic day (E) 9.5-birth; 2D and 3D datasets were compared with EFIC and magnetic resonance images (MRI) from a study of 52 human fetuses (Carnegie Stage (CS) 13–23).
Results
Time course of atrial, ventricular and outflow septation were outlined, and followed a similar sequence in both species. Bilateral vena cavae and prominent atrial appendages were seen in the mouse fetus; in human fetuses, atrial appendages were small, and a single right superior vena cava was present. In contrast to humans with separate pulmonary vein orifices, a pulmonary venous confluence with one orifice enters the left atrium in mice.
Conclusions
The cardiac developmental sequences observed in mouse and human fetuses are comparable, with minor differences in atrial and venous morphology. These comparisons of mouse and human cardiac development strongly support that mouse morphogenesis is a good model for human development.
doi:10.1038/pr.2014.128
PMCID: PMC4233008  PMID: 25167202
20.  Relationship Between Patterns of Intermittent Hypoxia and Retinopathy of Prematurity in Preterm Infants 
Pediatric research  2012;72(6):606-612.
Background
We have previously shown an increased incidence of intermittent hypoxemic events (IH) in preterm infants with severe retinopathy of prematurity (ROP). Animal models suggest that patterns of IH events may play a role in ROP severity as well. We hypothesize that specific IH patterns are associated with ROP in preterm infants.
Methods
Variability in IH duration, severity and the time interval between IH (≤80%, ≥10 seconds and ≤3min) along with the frequency spectrum of the oxygen saturation (SpO2) waveform were assessed.
Results
Severe ROP was associated with 1) an increased mean and standard deviation of the duration of IH (p<0.005), 2) more variability (Histogram Entropy) of the time interval between IH (p<0.005), 3) a higher IH nadir (p<0.05), 4) a time interval between IH of 1–20min (p<0.05) and 5) increased spectral power in the range of 0.002–0.008Hz (p<.05), corresponding to SpO2 waveform oscillations of 2–8 minutes in duration. Spectral differences were detected as early as 14 days of life.
Conclusions
Severe ROP was associated with more variable, longer, and less severe IH events. Identification of specific spectral components in the SpO2 waveform may assist in early identification of infants at risk for severe ROP.
doi:10.1038/pr.2012.132
PMCID: PMC4433009  PMID: 23037873
21.  Elevated blood levels of inflammation-related proteins are associated with an attention problem at age 24 months in extremely preterm infants 
Pediatric research  2014;75(6):781-787.
Background
Extremely preterm birth is associated with subsequent behavioral problems. We hypothesized that perinatal systemic inflammation, a risk factor for cerebral white matter injury and cognitive impairment, is associated with behavior problems observed at 2 years.
Methods
In a cohort of 600 children born before 28 weeks gestation, we measured 25 inflammation-related proteins in blood collected on postnatal days 1, 7, and 14, and identified behavior problems using parent responses to the Child Behavior Checklist for Ages 1.5–5 (CBCL/1.5-5) at two years of age. A persistent or recurrent protein elevation was defined as a concentration in the highest quartile (for gestational age and postnatal age) on at least two days approximately one week apart. Behavior problems were defined by CBCL/1.5-5 subscale scores at or above the 93rd percentile.
Results
A single-day elevation of ICAM-3 was associated with an increased risk of an attention problem, as were persistent or recurrent elevations of MPO, IL-6, TNF-RI, IL-8, ICAM-3, VEGF-R1, and VEGF-R2. These associations persisted among infants without white matter injury and cognitive impairment.
Conclusion
Among children born extremely prematurely, recurrent or persistent elevations of inflammation-related proteins in blood during in the first two postnatal weeks are associated with an attention problem at age 2 years.
doi:10.1038/pr.2014.41
PMCID: PMC4429865  PMID: 24614800
22.  PHARMACODYNAMICALLY OPTIMIZED ERYTHROPOIETIN TREATMENT COMBINED WITH PHLEBOTOMY REDUCTION PREDICTED TO ELIMINATE BLOOD TRANSFUSIONS IN SELECTED PRETERM INFANTS 
Pediatric research  2013;75(2):336-342.
BACKGROUND
Preterm very low birth weight (VLBW) infants weighing <1.5 kg at birth develop anemia requiring red blood cell transfusions (RBCTx). Because laboratory blood loss is a primary cause of anemia leading to RBCTx in VLBW infants, our goal was to simulate the extent to which RBCTx can be reduced or eliminated by reducing laboratory blood loss in combination with pharmacodynamically optimized erythropoietin (Epo) treatment.
METHODS
26 VLBW infants receiving RBCTx were studied during the first month of life. Simulated RBCTx were based on previously published RBCTx criteria and data-driven Epo pharmacodynamic optimization using literature-derived RBC lifespan and blood volume data with correction for phlebotomy loss.
RESULTS
Simulated pharmacodynamic optimization of Epo administration and reduction in laboratory phlebotomies by ≥55% predicted a complete elimination of RBCTx in 1.0–1.5 kg infants. In infants <1.0 kg with 100% reduction in phlebotomy, RBCTx is predicted to be reduced by 45%. The mean volume of laboratory blood drawn from all infants was 63 mL/kg, of which 33% was required for analysis and 67% discarded.
CONCLUSION
When reducing laboratory blood loss and optimized Epo treatment are combined, marked reductions in RBCTx in VLBW infants were predicted, particularly among those with birth weights >1.0 kg.
doi:10.1038/pr.2013.213
PMCID: PMC4418561  PMID: 24216541
23.  Intraamniotic LPS modulates expression of antimicrobial peptides in the fetal sheep lung 
Pediatric research  2014;76(5):441-447.
Background
Damage-associated molecular patterns (DAMPs) and antimicrobial peptides (AMPs) are components of pulmonary innate immunity and tissue repair. We hypothesized that DAMPs and AMPs would increase in response to fetal pulmonary inflammation caused by chorioamnionitis in a time-dependent manner.
Methods
Fetal sheep were exposed to intra-amniotic saline or LPS (10mg) between 5 hours and 15 days prior to preterm delivery at 125±2 days. Lung tissue mRNAs for pro-inflammatory cytokines; AMPs: myeloid antimicrobial peptide-29 (MAP29), dodecapeptide, sheep beta-defensin-1 (SBD1), sheep beta-defensin-2 (SBD2); DAMPs: IL-1α, lactoferrin, heat-shock protein-70 (HSP70), high-mobility group box protein-B1 (HMGB1), receptor for advanced glycation endproducts (RAGE) were measured by RT-qPCR. Immunohistochemistry of DAMPs and in situ hybridization of AMPs was performed.
Results
IL-1α, IL-1β, IL-6, IL-8, IL-10, MCP-1, and TNF-α mRNA increased after LPS exposure. MAP29, dodecapeptide, SBD1 and SBD2 mRNA were suppressed at 24 hours. MAP29 and dodecapeptide mRNA then increased at 8 days. Lactoferrin increased at 24 hours. There were no changes for HMGB1, HSP70 or RAGE. MAP29 and dodecapeptide localized to alveolar cells, increased 8 days after exposure to LPS.
Conclusion
AMPs are initially suppressed in the fetal lung by LPS-induced chorioamnionitis. The late induction of MAP29 and Dodecapeptide may be related to lung repair.
doi:10.1038/pr.2014.113
PMCID: PMC4213214  PMID: 25105257
24.  One Size Will Never Fit All: Clinical and Translational Research Gaps in Pediatric Transfusion Medicine 
Pediatric research  2014;76(5):425-431.
There is concern at the National Heart, Lung, and Blood Institute (NHLBI) and among transfusion medicine specialists regarding the small number of investigators and studies in the field of pediatric transfusion medicine (PTM). Accordingly, the objective of this article is to provide a snapshot of the clinical and translational PTM research considered to be of high priority by pediatricians, neonatologists, and transfusion medicine specialists. Included is a targeted review of three research areas of importance: 1) transfusion strategies, 2) short- and long-term clinical consequences, and 3) transfusion-transmitted infectious diseases. The recommendations by PTM and transfusion medicine specialists represent opportunities and innovative strategies to execute translational research, observational studies, and clinical trials of high relevance to PTM. With the explosion of new biomedical knowledge and increasingly sophisticated methodologies over the past decade, this is an exciting time to consider transfusion medicine as a paradigm for addressing questions related to fields such as cell biology, immunology, neurodevelopment, outcomes research and many others. Increased awareness of PTM as an, important, fertile field and the promotion of accompanying opportunities will help establish PTM as a viable career option and advance basic and clinical investigation to improve the health and wellbeing of children.
doi:10.1038/pr.2014.120
PMCID: PMC4408868  PMID: 25119336
25.  Serum creatinine concentration in very-low-birth-weight infants from birth to 34–36 wk postmenstrual age 
Pediatric Research  2015;77(5):696-702.
Background:
Serum creatinine (s[Cr]) reference ranges for very-low-birth-weight (VLBW) infants must account for physiologic changes in the first months of life.
Methods:
We retrospectively identified a sample of 218 appropriate-for-gestational age (GA) VLBW infants without risk factors for renal impairment, and classified into one of three GA groups: 25–27, 28–29, and 30–33 wk. We observed three phases of s[Cr] change (initial, decline, and equilibrium), whose characteristics varied by GA group. We used mixed-effects regression models to estimate mean and upper 95th prediction interval of s[Cr] for each GA group from birth to 34–36 wk post menstrual age (PMA).
Results:
In phase I, s[Cr] increased after birth, then returned slowly to baseline. The duration of phase I and the magnitude of s[Cr] rise decreased with increasing GA. In phase II, s[Cr] declined abruptly at a rate that increased with GA. A gradual transition to phase III, a steady-state equilibrium with similar s[Cr] among GA groups, began at approximately 34–36 wk PMA. We constructed GA group-specific nomograms depicting s[Cr] behaviour across the three phases.
Conclusion:
The reference ranges derived from a sample of infants without risk factors for renal impairment provide a context for quantitative interpretation of s[Cr] trends in VLBW infants.
doi:10.1038/pr.2015.25
PMCID: PMC4407015  PMID: 25675426

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