Short-term effects of opioids during therapeutic hypothermia for neonatal encephalopathy.

Objective: To examine the effects of opioids during therapeutic hypothermia (TH) on short-term outcomes in neonates with neonatal encephalopathy (NE).

Methods: Multicenter retrospective study of neonates with moderate/severe NE from Jan. 2013-Feb 2021.

Placenta and Intestinal Injury in Preterm Infants.

Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal conditions affecting 6 to 10% of low-birth-weight infants and remains a leading cause of death. The risk factors associated with NEC are complex and multifactorial, including preterm birth and intrauterine exposure to inflammation and hypoxia. Chorioamnionitis has been associated with intestinal injury in animal and human clinical studies.

The Current State of Neonatal Neurodevelopmental Follow-up Programs in North America: A Children's Hospitals Neonatal Consortium Report.

Objective:  This study aimed to determine neonatal neurodevelopmental follow-up (NDFU) practices across academic centers.

Study Design:  This study was a cross-sectional survey that addressed center-specific neonatal NDFU practices within the Children's Hospitals Neonatal Consortium (CHNC).

Results:  Survey response rate was 76%, and 97% of respondents had a formal NDFU program.

Outcomes by disease onset, sex, and intervention in neonates with SIP and surgical NEC.

Background: Outcomes of infants following surgical necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) categorized by the age of onset, interventions, and sex are not well defined.

Methods: Retrospective comparison of infants categorized by age of onset (NEC at <10, 10-20, and >20 days) and SIP at <7 versus ≥7 days), sex, and intervention [Penrose Drain (PD) vs. laparotomy].

Association of Hospital Resource Utilization With Neurodevelopmental Outcomes in Neonates With Hypoxic-Ischemic Encephalopathy.

Importance: Intercenter variation exists in the management of hypoxic-ischemic encephalopathy (HIE). It is unclear whether increased resource utilization translates into improved neurodevelopmental outcomes.

Objective: To determine if higher resource utilization during the first 4 days of age, quantified by hospital costs, is associated with survival without neurodevelopmental impairment (NDI) among infants with HIE.

CpG methylation patterns in placenta and neonatal blood are differentially associated with neonatal inflammation.

Background: Infants born extremely premature are at increased risk for health complications later in life for which neonatal inflammation may be a contributing biological driver. Placental CpG methylation provides mechanistic information regarding the relationship between prenatal epigenetic programming, prematurity, neonatal inflammation, and later-in-life health.

Methods: We contrasted CpG methylation in the placenta and neonatal blood spots in relation to neonatal inflammation in the Extremely Low Gestational Age Newborn (ELGAN) cohort.

New body composition reference charts for preterm infants.

Background: The American Academy of Pediatrics (AAP) has recommended that nutritional management of the preterm infant should aim to achieve body composition that replicates the in utero fetus, but intrauterine body composition reference charts for preterm infants are lacking.

Objective: Our objective was to create body composition reference curves for preterm infants that approximate the body composition of the in utero fetus from 30 to 36 wk of gestation.

Design: A total of 223 ethnically diverse infants born at 30 + 0 to 36 + 6 wk of gestation were enrolled.

Regulation of fibroblast growth factor 2 expression in oxygen-induced retinopathy.

Purpose: Fibroblast growth factor (FGF) 2 is a potent endothelial cell mitogen and survival factor that is postulated to participate in the pathogenesis of retinopathy of prematurity (ROP). The purpose of the current study was to determine the transcriptional and translational regulation of FGF2 expression in oxygen-induced retinopathy (OIR), the animal model of ROP.

Methods: We examined FGF2 protein and mRNA expression and optokinetic visual responses in transgenic mice possessing a dual-luciferase bicistronic transgene containing a 5'-internal ribosome entry site (IRES) of FGF2.

Potential influence of total parenteral nutrition on body composition at discharge in preterm infants.

Objective: This study was undertaken to assess the potential influence of total parenteral nutrition (TPN) on body composition (BC) in preterm infants.

Study Design: This prospective, observational study of infants born <35 weeks measured BC at discharge using air displacement plethysmography. The % body fat (BF) at discharge was correlated with variables gestational age (GA), severity of illness, days on oxygen, time to regain birth weight and duration of TPN.

Hyperglycemia mediates a shift from cap-dependent to cap-independent translation via a 4E-BP1-dependent mechanism.

Diabetes and its associated hyperglycemia induce multiple changes in liver function, yet we know little about the role played by translational control of gene expression in mediating the responses to these conditions. Here, we evaluate the hypothesis that hyperglycemia-induced O-GlcNAcylation of the translational regulatory protein 4E-BP1 alters hepatic gene expression through a process involving the selection of mRNA for translation. In both streptozotocin (STZ)-treated mice and cells in culture exposed to hyperglycemic conditions, expression of 4E-BP1 and its interaction with the mRNA cap-binding protein eIF4E were enhanced in conjunction with downregulation of cap-dependent and concomitant upregulation of cap-independent mRNA translation, as assessed by a bicistronic luciferase reporter assay.

Hyperoxia-induced alterations in the pulmonary proteome of juvenile rats.

High inspired concentrations of oxygen (hyperoxia) are often necessary to counteract tissue hypoxia during the treatment of ARDS. Reactive oxygen species generated by hyperoxic therapy may influence the expression of the pulmonary proteome and the application of discovery proteomics to the hyperoxic lung has the potential to divulge mechanisms regulating the expression of specific proteins integral to lung injury and repair. The present study examined the proteome derived from 30-day-old Sprague-Dawley rats exposed to room air (RA) and 95% O2 (Ox) for 24-72 hours using 2-dimensional difference in-gel electrophoresis (2D-DIGE) coupled with MALDI-ToF/ToF mass spectrometry.

Hyperoxia-induced activation of the integrated stress response in the newborn rat lung.

Diverse environmental stresses stimulate eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, leading to a stress-resistant state characterized by global attenuation of protein synthesis and induction of cytoprotective genes. The signal transduction network culminating in these effects is referred to as the integrated stress response (ISR) or, when initiated by misfolded proteins within the endoplasmic reticulum (ER), the unfolded protein response (UPR). Given that we previously reported that exposure of 4-day-old Sprague-Dawley rats to 95% O(2) (Ox) diminishes global pulmonary protein synthesis and increases eIF2α phosphorylation, we conducted the current study to determine whether Ox activates the ISR or UPR.

Hyperoxia inhibits protein synthesis and increases eIF2α phosphorylation in the newborn rat lung.

Prolonged exposure to hyperoxia contributes to aberrant lung growth in premature infants. Of the deleterious effects induced by hyperoxia, alterations in protein synthesis are likely to be of great importance to the developing lung. Regulation of mRNA translation occurs predominantly at the level of initiation via control of mRNA/ribosome binding by proteins known as eukaryotic initiation factors (eIF).

Hydrogen peroxide impairs insulin-stimulated assembly of mTORC1.

Oxidants are well recognized for their capacity to reduce the phosphorylation of the mammalian target of rapamycin (mTOR) substrates, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and p70 S6 kinase 1 (S6K1), thereby hindering mRNA translation at the level of initiation. mTOR functions to regulate mRNA translation by forming the signaling complex mTORC1 (mTOR, raptor, GbetaL). Insulin signaling to mTORC1 is dependent upon phosphorylation of Akt/PKB and the inhibition of the tuberous sclerosis complex (TSC1/2), thereby enhancing the phosphorylation of 4E-BP1 and S6K1.

Roles of mitogen-activated protein kinase signal-integrating kinases 1 and 2 in oxidant-mediated eIF4E phosphorylation.

Oxidative stress alters cellular metabolic processes including protein synthesis. The eukaryotic initiation factor, eIF4E, acts in the rate-limiting steps of initiation and promotes nuclear export. Phosphorylation of eIF4E by mitogen activated protein kinase signal-integrating kinases 1 and 2 (Mnk) influences the affinity of eIF4E for the 5'-mRNA cap and fosters nuclear export activity.

Hyperoxia enhances VEGF release from A549 cells via post-transcriptional processes.

Exposure of animals to hyperoxia decreases lung VEGF mRNA expression concomitant with an acute increase in VEGF protein within the epithelial lining fluid (ELF). The VEGF concentration in ELF is in excess of that found in the plasma, leading to the hypothesis that hyperoxia stimulates the release of VEGF protein from stores within the extracellular matrix. To test this hypothesis in a cell culture system, we exposed A549 cells to 95% O(2) (Ox) for 48 h followed by recovery in room air (RA) for 24 h.

Cyclic stretch attenuates effects of hyperoxia on cell proliferation and viability in human alveolar epithelial cells.

The treatment of severe lung disease often requires the use of high concentrations of oxygen coupled with the need for assisted ventilation, potentially exposing the pulmonary epithelium to both reactive oxygen species and nonphysiological cyclic stretch. Whereas prolonged hyperoxia is known to cause increased cell injury, cyclic stretch may result in either cell proliferation or injury depending on the pattern and degree of exposure to mechanical deformation. How hyperoxia and cyclic stretch interact to affect the pulmonary epithelium in vitro has not been previously investigated.

Hyperoxia alters the expression and phosphorylation of multiple factors regulating translation initiation.

Hyperoxia is cytotoxic and depresses many cellular metabolic functions including protein synthesis. Translational control is exerted primarily during initiation by two mechanisms: 1) through inhibition of translation initiation complex formation via sequestration of the cap-binding protein, eukaryotic initiation factor (eIF) 4E, with inhibitory 4E-binding proteins (4E-BP); and 2) by prevention of eIF2-GTP-tRNA(i)(Met) formation and eIF2B activity by phosphorylated eIF2alpha. In this report, exposure of human lung fibroblasts to 95% O2 decreased the incorporation of thymidine into DNA at 6 h and the incorporation of leucine into protein beginning at 12 h.

Oxidant-induced hypertrophy of A549 cells is accompanied by alterations in eukaryotic translation initiation factor 4E and 4E-binding protein-1.

Control of protein synthesis resides at the level of eukaryotic translation initiation (eIF) complex formation. Complex formation is regulated by the mRNA cap-binding protein, eIF4E, whose activity is influenced by phosphorylation and binding to 4E-binding protein 1 (4E-BP1). To provide a link between alterations in protein synthesis and the pathogenesis of oxidant-mediated lung disease, we investigated the effect of hydrogen peroxide (H2O2) on actively growing A549 cells.