Publications by authors named "James F Padbury"

99 Publications

Translational Research: The Time is Now.

Authors:
James F Padbury Bongsup P Cho

R I Med J (2013) 2021 Apr 1;104(3):16. Epub 2021 Apr 1.

Professor of Pharmacy, University of Rhode Island, Program Director of Rhode Island IDeA Network of Biomedical Research Excellence (RI-INBRE), Kingston, RI.

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April 2021

50 Years Ago in TheJournalofPediatrics: Diazoxide-Induced Hyperosmolar Nonketotic Coma: Contemporary Genetic Insights.

Authors:
Lauren E Boudreau James F Padbury

J Pediatr 2021 Mar;230:31

Division of Neonatal-Perinatal Medicine, Women and Infant's Hospital of Rhode Island, Providence, Rhode Island.

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http://dx.doi.org/10.1016/j.jpeds.2020.10.046DOI Listing
March 2021

Serious neonatal morbidities are associated with differences in DNA methylation among very preterm infants.

Authors:
Todd M Everson T Michael O'Shea Amber Burt Karen Hermetz Brian S Carter Jennifer Helderman Julie A Hofheimer Elisabeth C McGowan Charles R Neal Steven L Pastyrnak Lynne M Smith Antoine Soliman Sheri A DellaGrotta Lynne M Dansereau James F Padbury Barry M Lester Carmen J Marsit

Clin Epigenetics 2020 10 19;12(1):151. Epub 2020 Oct 19.

Gangarosa Department of Environmental Health, Emory University Rollins School of Public Health, Atlanta, GA, USA.

Background: Infants born very preterm are more likely to experience neonatal morbidities compared to their term peers. Variations in DNA methylation (DNAm) associated with these morbidities may yield novel information about the processes impacted by these morbidities.

Methods: This study included 532 infants born < 30 weeks gestation, participating in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants study. We used a neonatal morbidity risk score, which was an additive index of the number of morbidities experienced during the NICU stay, including bronchopulmonary dysplasia (BPD), severe brain injury, serious neonatal infections, and severe retinopathy of prematurity. DNA was collected from buccal cells at discharge from the NICU, and DNAm was measured using the Illumina MethylationEPIC. We tested for differential methylation in association with the neonatal morbidity risk score then tested for differentially methylated regions (DMRs) and overrepresentation of biological pathways.

Results: We identified ten differentially methylated CpGs (α Bonferroni-adjusted for 706,278 tests) that were associated with increasing neonatal morbidity risk scores at three intergenic regions and at HPS4, SRRD, FGFR1OP, TNS3, TMEM266, LRRC3B, ZNF780A, and TENM2. These mostly followed dose-response patterns, for 8 CpGs increasing DNAm associated with increased numbers of morbidities, while for 2 CpGs the risk score was associated with decreasing DNAm. BPD was the most substantial contributor to differential methylation. We also identified seven potential DMRs and over-representation of genes involved in Wnt signaling; however, these results were not significant after Bonferroni adjustment for multiple testing.

Conclusions: Neonatal DNAm, within genes involved in fibroblast growth factor activities, cellular invasion and migration, and neuronal signaling and development, are sensitive to the neonatal health complications of prematurity. We hypothesize that these epigenetic features may be representative of an integrated marker of neonatal health and development and are promising candidates to integrate with clinical information for studying developmental impairments in childhood.
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http://dx.doi.org/10.1186/s13148-020-00942-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574188PMC
October 2020

Epigenome-wide analysis identifies genes and pathways linked to acoustic cry variation in preterm infants.

Authors:
Ghazal Aghagoli Stephen J Sheinkopf Todd M Everson Carmen J Marsit Hannah Lee Amber A Burt Brian S Carter Jennifer B Helderman Julie A Hofheimer Elisabeth C McGowan Charles R Neal T Michael O'Shea Steven L Pastyrnak Lynne M Smith Antoine Soliman Lynne M Dansereau Sheri A DellaGrotta James F Padbury Barry M Lester

Pediatr Res 2020 Sep 23. Epub 2020 Sep 23.

Brown Center for the Study of Children at Risk, Providence, RI, USA.

Background: Preterm birth places infants at higher risk of adverse long-term behavioral and cognitive outcomes. Combining biobehavioral measures and molecular biomarkers may improve tools to predict the risk of long-term developmental delays.

Methods: The Neonatal Neurobehavior and Outcomes in Very Preterm Infants study was conducted at nine neonatal intensive care units between April 2014 and June 2016. Cries were recorded and buccal swabs collected during the neurobehavioral exam. Cry episodes were extracted and analyzed using a computer system and the data were summarized using factor analysis. Genomic DNA was extracted from buccal swabs, quantified using the Qubit Fluorometer, and aliquoted into standardized concentrations. DNA methylation was measured with the Illumina MethylationEPIC BeadArray, and an epigenome-wide association study was performed using cry factors (n = 335).

Results: Eighteen CpGs were associated with the cry factors at genome-wide significance (α = 7.08E - 09). Two CpG sites, one intergenic and one linked to gene TCF3 (important for B and T lymphocyte development), were associated with acoustic measures of cry energy. Increased methylation of TCF3 was associated with a lower energy-related cry factor. We also found that pitch (F) and hyperpitch (F > 1 kHz) were associated with DNA methylation variability at 16 CpG sites.

Conclusions: Acoustic cry characteristics are related to variation in DNA methylation in preterm infants.

Impact: Preterm birth is a major public health problem and its long-term impact on health is not well understood. Cry acoustics, related to prematurity, has been linked to a variety of medical conditions. Biobehavioral measures and molecular biomarkers can improve prediction tools for long-term developmental risks of preterm birth. Variation in epigenetic modulation in preterm infants provides a potential link between preterm birth and unfavorable developmental outcomes.
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http://dx.doi.org/10.1038/s41390-020-01172-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985041PMC
September 2020

The Effects of Delayed Cord Clamping on 12-Month Brain Myelin Content and Neurodevelopment: A Randomized Controlled Trial.

Authors:
Judith S Mercer Debra A Erickson-Owens Sean C L Deoni Douglas C Dean Iii Richard Tucker Ashley B Parker Sarah Joelson Emily N Mercer Jennifer Collins James F Padbury

Am J Perinatol 2020 Jul 21. Epub 2020 Jul 21.

Department of Pediatrics, Women and Infants Hospital of Rhode Island, Providence, Rhode Island.

Objective:  This study aimed to determine if delayed cord clamping (DCC) affected brain myelin water volume fraction (VFm) and neurodevelopment in term infants.

Study Design:  This was a single-blinded randomized controlled trial of healthy pregnant women with term singleton fetuses randomized at birth to either immediate cord clamping (ICC) (≤ 20 seconds) or DCC (≥ 5 minutes). Follow-up at 12 months of age consisted of blood work for serum iron indices and lead levels, a nonsedated magnetic resonance imaging (MRI), followed within the week by neurodevelopmental testing.

Results:  At birth, 73 women were randomized into one of two groups: ICC (the usual practice) or DCC (the intervention). At 12 months, among 58 active participants, 41 (80%) had usable MRIs. There were no differences between the two groups on maternal or infant demographic variables. At 12 months, infants who had DCC had increased white matter brain growth in regions localized within the right and left internal capsules, the right parietal, occipital, and prefrontal cortex. Gender exerted no difference on any variables. Developmental testing (Mullen Scales of Early Learning, nonverbal, and verbal composite scores) was not significantly different between the two groups.

Conclusion:  At 12 months of age, infants who received DCC had greater myelin content in important brain regions involved in motor function, visual/spatial, and sensory processing. A placental transfusion at birth appeared to increase myelin content in the early developing brain.

Key Points: · DCC resulted in higher hematocrits in newborn period.. · DCC appears to increase myelin at 12 months.. · Gender did not influence study outcomes..
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http://dx.doi.org/10.1055/s-0040-1714258DOI Listing
July 2020

DNA methylation in children with prenatal methamphetamine exposure and environmental adversity.

Authors:
Oluwadamilola O Oni-Orisan Lynne M Dansereau Carmen J Marsit Lynne M Smith Charles R Neal Sheri A Della Grotta James F Padbury Barry M Lester

Pediatr Res 2020 Jul 14. Epub 2020 Jul 14.

Brown Center for the Study of Children at Risk, Women and Infants Hospital of Rhode Island, Providence, RI, USA.

Background: Methamphetamine (MA) use during pregnancy is a significant public health concern in the United States and affects long-term brain and behavioral development in children. We hypothesized that prenatal MA exposure would be related to greater DNA methylation of HSD11B2 and postnatal environmental stress.

Methods: The Infant Development, Environment, and Lifestyle Study (IDEAL), a longitudinal study of prenatal MA exposure enrolled mother-infant dyads in California, Hawaii, Iowa, and Oklahoma. Prenatal exposure was defined by maternal self-report and/or meconium toxicology screening. At ages 10-11 years, 100 children were assessed for drug exposure and DNA methylation of HSD11B2. Hierarchical linear models were used to determine the association between prenatal MA exposure and methylation of HSD11B2 at four CpG sites.

Results: Prenatal MA exposure (1.4% vs 0.31%, P < 0.01) and early childhood adversity (3.0 vs 2.0, P < 0.01) were associated with greater DNA methylation of HSD11B2 at the CpG2 site. The statistically significant effects of early childhood adversity (B = 0.11, P < 0.01) and prenatal MA exposure (B = 0.32, P = 0.03) on DNA methylation remained after adjusting for covariates.

Conclusions: Prenatal MA exposure is related to postnatal childhood adversity and epigenetic alterations in HSD11B2, an important gene along the stress response pathway suggesting prenatal and postnatal programming effects.

Impact: Prenatal methamphetamine exposure has been associated with developmental issues in newborns, yet little is known about the stress pathophysiology of methamphetamine on neurobehavior.This is the first evidence that prenatal methamphetamine exposure acts as a stressor, confirming the third pathophysiology of methamphetamine exposure.
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http://dx.doi.org/10.1038/s41390-020-1058-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855315PMC
July 2020

Get the most out of your data.

Authors:
James F Padbury

J Pediatr 2020 Mar;218:1-4

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http://dx.doi.org/10.1016/j.jpeds.2020.01.027DOI Listing
March 2020

Social Stress-Related Epigenetic Changes Associated With Increased Heart Rate Variability in Infants.

Authors:
Ghazal Aghagoli Elisabeth Conradt James F Padbury Stephen J Sheinkopf Hasmik Tokadjian Lynne M Dansereau Edward Z Tronick Carmen J Marsit Barry M Lester

Front Behav Neurosci 2019 15;13:294. Epub 2020 Jan 15.

Brown Center for the Study of Children at Risk, Brown University, Providence, RI, United States.

Early life stress can result in persistent alterations of an individual's stress regulation through epigenetic modifications. Epigenetic alteration of the gene is associated with changes in the stress response system during infancy as measured by cortisol reactivity. Although autonomic nervous system (ANS) reactivity is a key component of the stress response, we have a limited understanding of the effects of DNA methylation on ANS reactivity. To examine this relation, ANS stress responses of term, 4-5-month-old healthy infants were elicited using the face-to-face still-face paradigm, which involved five, 2-min episodes. Two of these episodes were the "still-face" in which the mother was non-responsive to her infant. EKG was acquired continuously and analyzed in 30 s-intervals. Cheek swabs were collected, and DNA was extracted from buccal cells. Respiratory sinus arrhythmia (RSA) was measured as heart rate variability (HRV). Mean HRV was calculated for each 30-s "face to face" episode. DNA methylation of was calculated using bisulfite pyrosequencing. Percent DNA methylation was computed for each of the 13 CpG sites. The relations between mean HRV for each "face to face" episode and percent DNA methylation was examined averaged over CpG sites 1-6 and 7-13 and at each individual CpG site. Higher HRV at baseline, first reunion, and second still-face was related to greater methylation of CpG sites 1-6. Higher HRV at the second reunion was related to greater methylation of CpG sites 12 and 13. These data provide evidence that increased methylation of at CpG sites 12 and 13 are associated with increased activation of parasympathetic pathways as represented by increased HRV.
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http://dx.doi.org/10.3389/fnbeh.2019.00294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974792PMC
January 2020

Evidence for lysosomal biogenesis proteome defect and impaired autophagy in preeclampsia.

Authors:
Akitoshi Nakashima Shi-Bin Cheng Masahito Ikawa Tamotsu Yoshimori Warren J Huber Ramkumar Menon Zheping Huang Jamie Fierce James F Padbury Yoel Sadovsky Shigeru Saito Surendra Sharma

Autophagy 2020 10 26;16(10):1771-1785. Epub 2019 Dec 26.

Departments of Pediatrics, Obstetrics and Gynecology and Pathology, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University , Providence, RI, USA.

The etiology of preeclampsia (PE), a serious pregnancy complication, remains an enigma. We have demonstrated that proteinopathy, a pathologic feature of neurodegenerative diseases, is a key observation in the placenta and serum from PE patients. We hypothesize that the macroautophagy/autophagy machinery that mediates degradation of aggregated proteins and damaged organelles is impaired in PE. Here, we show that TFEB (transcription factor EB), a master transcriptional regulator of lysosomal biogenesis, and its regulated proteins, LAMP1, LAMP2, and CTSD (cathepsin D), were dysregulated in the placenta from early and late onset PE deliveries. Primary human trophoblasts and immortalized extravillous trophoblasts (EVTs) showed reduced TFEB expression and nuclear translocation as well as lysosomal protein content in response to hypoxia. Hypoxia-exposed trophoblasts also showed decreased PPP3/calcineurin phosphatase activity and increased XPO1/CRM1 (exportin 1), events that inhibit TFEB nuclear translocation. These proteins were also dysregulated in the PE placenta. These results are supported by observed lysosomal ultrastructural defects with decreased number of autolysosomes in hypoxia-treated primary human trophoblasts. Autophagy-deficient human EVTs exhibited poor TFEB nuclear translocation, reduced lysosomal protein expression and function, and increased MTORC1 activity. Sera from PE patients induced these features and protein aggregation in EVTs. Importantly, trophoblast-specific conditional knockout mice exhibited reduced TFEB expression with increased deposition of protein aggregates in the placenta. These results provide compelling evidence for a regulatory link between accumulation of protein aggregates and TFEB-mediated impaired lysosomal biogenesis and autophagy in the placenta of PE patients. : autophagy related 7; CTSD: cathepsin D; ER: endoplasmic reticulum; EVTs: extravillous trophoblasts; KRT7: keratin 7; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; mSt: mStrawberry; MTORC1: mechanistic target of rapamycin complex 1; NP: normal pregnancy; NPS: normal pregnancy serum; PE: preeclampsia; PES: preeclampsia serum; p-RPS6KB: phosphorylated ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; XPO1/CRM1: exportin 1.
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http://dx.doi.org/10.1080/15548627.2019.1707494DOI Listing
October 2020

How old am I really?

Authors:
James F Padbury

J Pediatr 2019 Dec;215:1-3

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http://dx.doi.org/10.1016/j.jpeds.2019.10.057DOI Listing
December 2019

Effect of prematurity on genome wide methylation in the placenta.

Authors:
Jessica Schuster Alper Uzun Joan Stablia Christoph Schorl Mari Mori James F Padbury

BMC Med Genet 2019 06 28;20(1):116. Epub 2019 Jun 28.

Pediatrics, Center for Computational Molecular Biology, Brown Medical School, Brown University, Providence, Rhode Island, 02906, USA.

Background: Preterm birth is a significant clinical problem and an enormous burden on society, affecting one in eight pregnant women and their newborns. Despite decades of research, the molecular mechanism underlying its pathogenesis remains unclear. Many studies have shown that preterm birth is associated with health risks across the later life course. The "fetal origins" hypothesis postulates that adverse intrauterine exposures are associated with later disease susceptibility. Our recent studies have focused on the placental epigenome at term. We extended these studies to genome-wide placental DNA methylation across a wide range of gestational ages. We applied methylation dependent immunoprecipitation/DNA sequencing (MeDIP-seq) to 9 placentas with gestational age from 25 weeks to term to identify differentially methylated regions (DMRs).

Results: Enrichment analysis revealed 427 DMRs with nominally significant differences in methylation between preterm and term placentas (p < 0.01) and 21 statistically significant DMRs after multiple comparison correction (FDR p < 0.05), of which 62% were hypo-methylated in preterm placentas vs term placentas. The majority of DMRs were in distal intergenic regions and introns. Significantly enriched pathways identified by Ingenuity Pathway Analysis (IPA) included Citrulline-Nitric Oxide Cycle and Fcy Receptor Mediated Phagocytosis in macrophages. The DMR gene set overlapped placental gene expression data, genes and pathways associated evolutionarily with preterm birth.

Conclusion: These studies form the basis for future studies on the epigenetics of preterm birth, "fetal programming" and the impact of environment exposures on this important clinical challenge.
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http://dx.doi.org/10.1186/s12881-019-0835-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599230PMC
June 2019

Epigenome-wide Analysis Identifies Genes and Pathways Linked to Neurobehavioral Variation in Preterm Infants.

Authors:
Todd M Everson Carmen J Marsit T Michael O'Shea Amber Burt Karen Hermetz Brian S Carter Jennifer Helderman Julie A Hofheimer Elisabeth C McGowan Charles R Neal Steven L Pastyrnak Lynne M Smith Antoine Soliman Sheri A DellaGrotta Lynne M Dansereau James F Padbury Barry M Lester

Sci Rep 2019 04 19;9(1):6322. Epub 2019 Apr 19.

Department of Pediatrics, Brown Alpert Medical School and Women and Infants Hospital, Providence, RI, United States.

Neonatal molecular biomarkers of neurobehavioral responses (measures of brain-behavior relationships), when combined with neurobehavioral performance measures, could lead to better predictions of long-term developmental outcomes. To this end, we examined whether variability in buccal cell DNA methylation (DNAm) associated with neurobehavioral profiles in a cohort of infants born less than 30 weeks postmenstrual age (PMA) and participating in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study (N = 536). We tested whether epigenetic age, age acceleration, or DNAm levels at individual loci differed between infants based on their NICU Network Neurobehavioral Scale (NNNS) profile classifications. We adjusted for recruitment site, infant sex, PMA, and tissue heterogeneity. Infants with an optimally well-regulated NNNS profile had older epigenetic age compared to other NOVI infants (β = 0.201, p-value = 0.026), but no significant difference in age acceleration. In contrast, infants with an atypical NNNS profile had differential methylation at 29 CpG sites (FDR < 10%). Some of the genes annotated to these CpGs included PLA2G4E, TRIM9, GRIK3, and MACROD2, which have previously been associated with neurological structure and function, or with neurobehavioral disorders. These findings contribute to the existing evidence that neonatal epigenetic variations may be informative for infant neurobehavior.
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http://dx.doi.org/10.1038/s41598-019-42654-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474865PMC
April 2019

Genetic disorders of lung development.

Authors:
James F Padbury

J Pediatr 2019 Mar;206

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http://dx.doi.org/10.1016/j.jpeds.2019.01.020DOI Listing
March 2019

Doc, my tummy hurts.

Authors:
James F Padbury

J Pediatr 2019 Feb;205

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http://dx.doi.org/10.1016/j.jpeds.2018.12.019DOI Listing
February 2019

Effects of Delayed Cord Clamping on 4-Month Ferritin Levels, Brain Myelin Content, and Neurodevelopment: A Randomized Controlled Trial.

Authors:
Judith S Mercer Debra A Erickson-Owens Sean C L Deoni Douglas C Dean Jennifer Collins Ashley B Parker Meijia Wang Sarah Joelson Emily N Mercer James F Padbury

J Pediatr 2018 12 6;203:266-272.e2. Epub 2018 Jul 6.

Pediatrics, Alpert School of Medicine, Brown University, Providence, RI; Department of Pediatrics, Women and Infants Hospital of Rhode Island, Providence, RI.

Objective: To evaluate whether placental transfusion influences brain myelination at 4 months of age.

Study Design: A partially blinded, randomized controlled trial was conducted at a level III maternity hospital in the US. Seventy-three healthy term pregnant women and their singleton fetuses were randomized to either delayed umbilical cord clamping (DCC, >5 minutes) or immediate clamping (ICC, <20 seconds). At 4 months of age, blood was drawn for ferritin levels. Neurodevelopmental testing (Mullen Scales of Early Learning) was administered, and brain myelin content was measured with magnetic resonance imaging. Correlations between myelin content and ferritin levels and group-wise DCC vs ICC brain myelin content were completed.

Results: In the DCC and ICC groups, clamping time was 172 ± 188 seconds vs 28 ± 76 seconds (P < .002), respectively; the 48-hour hematocrit was 57.6% vs 53.1% (P < .01). At 4 months, infants with DCC had significantly greater ferritin levels (96.4 vs 65.3 ng/dL, P = .03). There was a positive relationship between ferritin and myelin content. Infants randomized to the DCC group had greater myelin content in the internal capsule and other early maturing brain regions associated with motor, visual, and sensory processing/function. No differences were seen between groups in the Mullen testing.

Conclusion: At 4 months, infants born at term receiving DCC had greater ferritin levels and increased brain myelin in areas important for early life functional development. Endowment of iron-rich red blood cells obtained through DCC may offer a longitudinal advantage for early white matter development.

Trial Registration: ClinicalTrials.gov: NCT01620008.
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http://dx.doi.org/10.1016/j.jpeds.2018.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6259583PMC
December 2018

Turning a negative into a positive.

Authors:
James F Padbury

J Pediatr 2018 12;203:1-2

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http://dx.doi.org/10.1016/j.jpeds.2018.10.010DOI Listing
December 2018

Epigenetic Programming by Maternal Behavior in the Human Infant.

Authors:
Barry M Lester Elisabeth Conradt Linda L LaGasse Edward Z Tronick James F Padbury Carmen J Marsit

Pediatrics 2018 10;142(4)

Emory University, Atlanta, Georgia.

: media-1vid110.1542/5804912859001PEDS-VA_2017-1890 OBJECTIVES: We sought to determine if variations in maternal care alter DNA methylation in term, healthy, 5-month-old infants. This work was based on landmark studies in animal models demonstrating that nurturing care by dams would alter their newborns' stress responses through epigenetic mechanisms. We used breastfeeding as a proxy for animal maternal behavior. We hypothesized alterations in DNA methylation of the glucocorticoid receptor gene and less hypothalamic stress response in infants of mothers who breastfed their infants versus infants of mothers who did not breastfeed.

Methods: A cohort study of term, healthy infants and their mothers who did ( = 21) or did not ( = 21) breastfeed for the first 5 months was used in this analysis. Cortisol stress reactivity was measured in infant saliva by using a mother-infant interaction procedure and DNA methylation of an important regulatory region of the glucocorticoid receptor gene. Changes in DNA methylation of this gene in humans were compared to homologous regions of the rat gene. DNA samples were prepared from cheek swabs and subjected to quantitative analysis of the extent of methylation by using sensitive sequencing techniques.

Results: Breastfeeding was associated with decreased DNA methylation of the glucocorticoid receptor promoter and decreased cortisol reactivity in 5-month-old infants. Decreased DNA methylation occurred in the promoter region involved in regulation of the hypothalamic-pituitary-adrenal and immune system responses.

Conclusions: Maternal care in humans may impact the hypothalamic-pituitary-adrenal stress response through behavioral programming and manifest as offspring epigenetic change. These results explain, in part, some of the positive effects observed in children who are breastfed.
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http://dx.doi.org/10.1542/peds.2017-1890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192679PMC
October 2018

Vitamin D and associated perinatal-neonatal outcomes among extremely low-birth-weight infants.

Authors:
Birju A Shah James F Padbury Michael P Anderson Michael F Holick Edgardo Szyld Catherine M Gordon

J Perinatol 2018 10 14;38(10):1318-1323. Epub 2018 Aug 14.

Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Objective: To evaluate vitamin D inadequacy among extremely low-birth-weight (ELBW, <1000 g) infants and the association between circulating vitamin D concentrations and perinatal-neonatal outcomes.

Study Design: Prospective cohort study of ELBW infants in the neonatal ICU. Blood was collected within the first 3 days after birth after obtaining informed consent. Circulating 25-hydroxyvitamin D concentrations (25(OH)D) were quantified using liquid chromatography-tandem mass spectroscopy and classified as vitamin D deficient, insufficient, or adequate ( < 20, 20-30, or > 30 ng/mL, respectively). Associations between 25(OH)D and perinatal-neonatal outcomes were determined by multivariable regression, adjusted for covariates that differ in the bivariate analysis.

Results: Of the 60 ELBW infants enrolled, 13 (22%) were vitamin D deficient, 15 (25%) were insufficient, and 32 (53%) were adequate. 25(OH)D levels were positively associated with fetal growth restriction and prolonged rupture of the membranes.

Conclusions: Vitamin D inadequacy was frequent among ELBW infants. Circulating vitamin D concentrations were significantly associated with perinatal outcomes in this contemporary cohort.
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http://dx.doi.org/10.1038/s41372-018-0203-yDOI Listing
October 2018

Enhancing the Development and Retention of Physician-Scientists in Academic Pediatrics: Strategies for Success.

Authors:
Cristina M Alvira Robin H Steinhorn William F Balistreri Jeffrey R Fineman Peter E Oishi James F Padbury John P Kinsella Steven H Abman

J Pediatr 2018 09 25;200:277-284. Epub 2018 Jul 25.

Section of Pulmonary Medicine, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO.

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http://dx.doi.org/10.1016/j.jpeds.2018.06.019DOI Listing
September 2018

Delayed Cord Clamping in Infants with Suspected Intrauterine Growth Restriction.

Authors:
Meijia Wang Judith S Mercer James F Padbury

J Pediatr 2018 10 25;201:264-268. Epub 2018 Jun 25.

Department of Pediatrics, Women and Infants Hospital of Rhode Island, Providence, RI; Department of Pediatrics, Alpert School of Medicine, Brown University, Providence, RI.

We evaluated a subset of infants with suspected intrauterine growth restriction or birth weights small for gestational age enrolled in a study of delayed cord clamping for preterm infants. Compared with immediate clamping, delayed cord clamping was associated with no apparent harm and less suspected necrotizing enterocolitis.

Trial Registration: ClinicalTrials.gov: NCT00818220 and NCT01426698.
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http://dx.doi.org/10.1016/j.jpeds.2018.05.028DOI Listing
October 2018

Better beginnings.

Authors:
James F Padbury

J Pediatr 2017 11;190

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http://dx.doi.org/10.1016/j.jpeds.2017.09.034DOI Listing
November 2017

50 Years Ago in The Journal of Pediatrics: Cellular Growth of Human Placenta.

Authors:
Adrienne Bingham James F Padbury

J Pediatr 2017 09;188:69

Division of Neonatology Women and Infants Hospital of Rhode Island Providence, Rhode Island.

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http://dx.doi.org/10.1016/j.jpeds.2017.03.022DOI Listing
September 2017

Effects of human umbilical cord blood mononuclear cells on respiratory system mechanics in a murine model of neonatal lung injury.

Authors:
David R Mills Quanfu Mao Sharon Chu Kate Falcon Girard Morey Kraus James F Padbury Monique E De Paepe

Exp Lung Res 2017 03 29;43(2):66-81. Epub 2017 Mar 29.

a Department of Pathology , Women and Infants Hospital , Providence , Rhode Island , USA.

Background: Mononuclear cells (MNCs) have well-documented beneficial effects in a wide range of adult pulmonary diseases. The effects of human umbilical cord blood-derived MNCs on neonatal lung injury, highly relevant for potential autologous application in preterm newborns at risk for bronchopulmonary dysplasia (BPD), remain incompletely established. The aim of this study was to determine the long-term morphologic and functional effects of systemically delivered MNCs in a murine model of neonatal lung injury.

Materials And Methods: MNCs from cryopreserved cord blood (1 × 10 cells per pup) were given intravenously to newborn mice exposed to 90% O from birth; controls received cord blood total nucleated cells (TNCs) or granular cells, or equal volume vehicle buffer (sham controls). In order to avoid immune rejection, we used SCID mice as recipients. Lung mechanics (flexiVent™), engraftment, growth, and alveolarization were evaluated eight weeks postinfusion.

Results: Systemic MNC administration to hyperoxia-exposed newborn mice resulted in significant attenuation of methacholine-induced airway hyperreactivity, leading to reduction of central airway resistance to normoxic levels. These bronchial effects were associated with mild improvement of alveolarization, lung compliance, and elastance. TNCs had no effects on alveolar remodeling and were associated with worsened methacholine-induced bronchial hyperreactivity. Granular cell administration resulted in a marked morphologic and functional emphysematous phenotype, associated with high mortality. Pulmonary donor cell engraftment was sporadic in all groups.

Conclusions: These results suggest that cord blood MNCs may have a cell type-specific role in therapy of pulmonary conditions characterized by increased airway resistance, such as BPD and asthma. Future studies need to determine the active MNC subtype(s), their mechanisms of action, and optimal purification methods to minimize granular cell contamination.
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http://dx.doi.org/10.1080/01902148.2017.1300713DOI Listing
March 2017

Neutralizing anti-interleukin-1β antibodies reduce ischemia-related interleukin-1β transport across the blood-brain barrier in fetal sheep.

Authors:
Aparna Patra Xiaodi Chen Grazyna B Sadowska Jiyong Zhang Yow-Pin Lim James F Padbury William A Banks Barbara S Stonestreet

Neuroscience 2017 03 9;346:113-125. Epub 2017 Jan 9.

Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, United States. Electronic address:

Hypoxic ischemic insults predispose to perinatal brain injury. Pro-inflammatory cytokines are important in the evolution of this injury. Interleukin-1β (IL-1β) is a key mediator of inflammatory responses and elevated IL-1β levels in brain correlate with adverse neurodevelopmental outcomes after brain injury. Impaired blood-brain barrier (BBB) function represents an important component of hypoxic-ischemic brain injury in the fetus. In addition, ischemia-reperfusion increases cytokine transport across the BBB of the ovine fetus. Reducing pro-inflammatory cytokine entry into brain could represent a novel approach to attenuate ischemia-related brain injury. We hypothesized that infusions of neutralizing IL-1β monoclonal antibody (mAb) reduce IL-1β transport across the BBB after ischemia in the fetus. Fetal sheep were studied 24-h after 30-min of carotid artery occlusion. Fetuses were treated with placebo- or anti-IL-1β mAb intravenously 15-min and 4-h after ischemia. Ovine IL-1β protein expressed from IL-1β pGEX-2T vectors in Escherichia coli (E. coli) BL-21 cells was produced, purified, and radiolabeled with I. BBB permeability was quantified using the blood-to-brain transfer constant (K) with I-radiolabeled-IL-1β. Increases in anti-IL-1β mAb were observed in the brain of the mAb-treated group (P<0.001). Blood-to-brain transport of I-IL-1β was lower (P<0.04) across brain regions in the anti-IL-1β mAb-treated than placebo-treated ischemic fetuses. Plasma I-IL-1β counts were higher (P<0.001) in the anti-IL-1β mAb- than placebo-treated ischemic fetuses. Systemic infusions of anti-IL-1β mAb reduce IL-1β transport across the BBB after ischemia in the ovine fetus. Our findings suggest that conditions associated with increases in systemic pro-inflammatory cytokines and neurodevelopmental impairment could benefit from an anti-cytokine therapeutic strategy.
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http://dx.doi.org/10.1016/j.neuroscience.2016.12.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337150PMC
March 2017

Prenatal Major Depressive Disorder, Placenta Glucocorticoid and Serotonergic Signaling, and Infant Cortisol Response.

Authors:
Laura R Stroud George D Papandonatos Stephanie H Parade Amy L Salisbury Maureen G Phipps Barry M Lester James F Padbury Carmen J Marsit

Psychosom Med 2016 Nov/Dec;78(9):979-990

From the Department of Psychiatry and Human Behavior (Stroud, Parade, Salisbury, Lester), Warren Alpert Medical School, Brown University; Providence, Rhode Island; Centers for Behavioral and Preventive Medicine (Stroud), The Miriam Hospital, Providence, Rhode Island; Department of Biostatistics, School of Public Health (Papandonatos), Brown University, Providence, Rhode Island; Bradley/Hasbro Children's Research Center (Parade), Providence, Rhode Island; Department of Pediatrics (Salisbury, Lester, Padbury), Warren Alpert Medical School, Brown University, Providence, Rhode Island; Women & Infants' Hospital of Rhode Island (Salisbury, Phipps, Lester, Padbury), Providence, Rhode Island; Department of Obstetrics and Gynecology (Phipps), Warren Alpert Medical School, Brown University, Providence, Rhode Island; and Department of Environmental Health (Marsit), Rollins School of Public Health, Emory University, Atlanta, Georgia.

Objectives: Extending prior studies of prenatal adversity and depressive symptoms, we tested associations between maternal prenatal major depressive disorder (MDD) and infant cortisol regulation. Based on prior findings by our group, we also tested placenta glucocorticoid (HSD11B2 methylation) and serotonin (SLC6A4 gene expression) signaling as moderators of links between prenatal MDD and infant cortisol.

Methods: Participants were 153 mother-infant pairs from a low-income, diverse sample (M [SD] age = 26 [6] years). Repeated structured diagnostic interviews were used to identify mothers with (a) prenatal MDD, (b) preconception-only MDD, and (c) controls. Placenta samples were assayed for HSD11B2 methylation and SLC6A4 gene expression. Infant salivary cortisol response to a neurobehavioral examination was assessed at 1 month.

Results: Daughters of prenatal MDD mothers had 51% higher baseline (ratio = 1.51; 95% confidence interval [CI] = 1.01-2.27; p = .045) and 64% higher stress responsive cortisol (ratio = 1.64; 95% CI = 1.05-2.56; p = .03) than daughters of controls and 75% higher stress-responsive cortisol (ratio = 1.75; 95% CI = 1.04-2.94; p = .04) than daughters of preconception-only MDD mothers. HSD11B2 methylation moderated links between prenatal MDD and baseline cortisol (p = .02), with 1% methylation decreases associated with 9% increased baseline cortisol in infants of prenatal MDD mothers (ratio = 1.09; 95% CI = 1.01-1.16). SLC6A4 expression moderated links between prenatal MDD and cortisol response among boys alone (p = .007), with 10-fold increases in expression associated with threefold increases in stress-responsive cortisol (ratio = 2.87; 95% CI = 1.39-5.93) in sons of control mothers.

Conclusions: Results highlight specificity of associations between prenatal versus preconception MDD and cortisol regulation and the importance and complexity of placenta glucocorticoid and serotonergic pathways underlying the intergenerational transmission of risk from maternal adversity.
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http://dx.doi.org/10.1097/PSY.0000000000000410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6541396PMC
July 2017

Gasping for air.

Authors:
James F Padbury

J Pediatr 2016 Oct;177:2-3

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http://dx.doi.org/10.1016/j.jpeds.2016.08.038DOI Listing
October 2016

Lymphocyte genetic diversity revealed by next generation sequencing.

Authors:
James F Padbury

J Pediatr 2016 Sep;176:1-4

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http://dx.doi.org/10.1016/j.jpeds.2016.07.018DOI Listing
September 2016

18-Month Follow-Up of Infants Cared for in a Single-Family Room Neonatal Intensive Care Unit.

Authors:
Barry M Lester Amy L Salisbury Katheleen Hawes Lynne M Dansereau Rosemarie Bigsby Abbot Laptook Marybeth Taub Linda L Lagasse Betty R Vohr James F Padbury

J Pediatr 2016 10 26;177:84-89. Epub 2016 Jul 26.

Departments of Pediatrics, Warren Alpert Medical School of Brown University, Providence, RI; Department of Pediatrics, Women and Infants Hospital of Rhode Island, Providence, RI.

Objectives: To determine whether the single-family room (SFR)-neonatal intensive care unit (NICU) is associated with improved 18-month neurodevelopmental outcome, especially in infants of mothers with high maternal involvement.

Study Design: An 18-month follow-up was undertaken that compared infants born <30 weeks gestational age; 123 from a SFR-NICU vs 93 from an open-bay NICU. Infants were divided into high vs low maternal involvement based on days/week of kangaroo care, breast/bottle feeding, and maternal care. Infants with high vs low maternal involvement in the SFR and open-bay NICUs were compared on the Bayley Cognitive, Language, and Motor scores and Pervasive Developmental Disorders autism screen.

Results: There were more mothers in the high maternal involvement SFR than in the high maternal involvement open-bay group (P = .002). Infants with high maternal involvement in both NICUs had greater Cognitive (P = .029) and Language (P < .000) scores than infants with low maternal involvement. Effect sizes within NICU were moderate to large in the SFR-NICU for Language scores and moderate for the Language composite in the open-bay NICU. The number of days of maternal involvement was greater in the SFR than open-bay NICU (P < .000), and length of stay was shorter in the high maternal involvement SFR than high maternal involvement open-bay NICU (P = .024). Kangaroo and maternal care predicted Cognitive (kangaroo, P = .003) and Language scores (P = .015, P = .032, respectively). Infants with ≥1 symptom of autism were more likely to be in the open-bay low maternal involvement group vs the SFR high maternal involvement group (OR = 4.91, 95% CI = 2.2-11.1).

Conclusions: High maternal involvement is associated with improved 18-month neurodevelopmental outcome, especially in infants cared for in a SFR-NICU.
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http://dx.doi.org/10.1016/j.jpeds.2016.06.069DOI Listing
October 2016

Prenatal Programming of Infant Neurobehaviour in a Healthy Population.

Authors:
Allison A Appleton Megan A Murphy Devin C Koestler Corina Lesseur Alison G Paquette James F Padbury Barry M Lester Carmen J Marsit

Paediatr Perinat Epidemiol 2016 07 23;30(4):367-75. Epub 2016 Mar 23.

Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH.

Background: Identifying the prenatal origins of mental conditions is of increasing interest, yet most studies have focused on high-risk populations and cannot disentangle prenatal and postnatal programming effects. Thus, we examined whether profiles of neurobehaviour indicative of future risk could be identified in healthy 1-3-day-old infants, and examined associations with perinatal risk factors.

Methods: Participants included 627 healthy mothers and term infants from a population-based US cohort. Neurobehaviour was assessed within 24-72 h after delivery with the NICU Network Neurobehavioural Scales (NNNS). A model-based clustering algorithm was used to derive neurobehavioural profiles from NNNS scores. Maternal health histories, pregnancy conditions and behaviours, labour/delivery factors, and infant attributes were examined in relation to the neurobehavioural profiles.

Results: Seven discrete neurobehavioural profiles were identified, including one average functioning profile, and two inversely patterned below and above average profiles. Higher pregnancy weight gain (OR 1.44, 95% CI 1.10, 1.88) and birthweight percentiles (OR 1.46, 95% CI 1.10, 1.95) were associated with greater odds of below average newborn neurobehaviour. Above average neurobehaviour was associated with experiencing longer gestations (OR 1.29, 95% CI 1.02, 1.64) and higher 5-min APGAR scores (OR 2.43, 95% CI 1.07, 5.52). Maternal pregnancy alcohol use (OR 0.54, 95% CI 0.33, 0.89), and fetal distress (OR 0.10, 95% CI 0.01, 0.72) were associated with lower likelihood of having average neurobehaviour.

Conclusion: Distinct profiles of neurobehaviour can be derived in a healthy population of newborns, with different sets of perinatal factors predicting different patterns of neurobehaviour. These findings suggest a potential in utero origin for mental health risk.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054721PMC
http://dx.doi.org/10.1111/ppe.12294DOI Listing
July 2016

dbPEC: a comprehensive literature-based database for preeclampsia related genes and phenotypes.

Authors:
Alper Uzun Elizabeth W Triche Jessica Schuster Andrew T Dewan James F Padbury

Database (Oxford) 2016 5;2016. Epub 2016 Mar 5.

Department of Pediatrics, Women & Infants Hospital of Rhode Island, Providence, RI, USA Department of Pediatrics, Brown Alpert Medical School, Providence, RI, USA Center for Computational Molecular Biology, Brown University, Providence, RI, USA.

Preeclampsia is one of the most common causes of fetal and maternal morbidity and mortality in the world. We built a Database for Preeclampsia (dbPEC) consisting of the clinical features, concurrent conditions, published literature and genes associated with Preeclampsia. We included gene sets associated with severity, concurrent conditions, tissue sources and networks. The published scientific literature is the primary repository for all information documenting human disease. We used semantic data mining to retrieve and extract the articles pertaining to preeclampsia-associated genes and performed manual curation. We deposited the articles, genes, preeclampsia phenotypes and other supporting information into the dbPEC. It is publicly available and freely accessible. Previously, we developed a database for preterm birth (dbPTB) using a similar approach. Using the gene sets in dbPTB, we were able to successfully analyze a genome-wide study of preterm birth including 4000 women and children. We identified important genes and pathways associated with preterm birth that were not otherwise demonstrable using genome-wide approaches. dbPEC serves not only as a resources for genes and articles associated with preeclampsia, it is a robust source of gene sets to analyze a wide range of high-throughput data for gene set enrichment analysis. Database URL: http://ptbdb.cs.brown.edu/dbpec/.
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http://dx.doi.org/10.1093/database/baw006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779341PMC
October 2016