National Childrens Research Center

Dublin, Ireland

National Childrens Research Center

Dublin, Ireland
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McCarthy L.K.,National Maternity Hospital | McCarthy L.K.,National Childrens Research Center | McCarthy L.K.,University College Dublin | Molloy E.J.,National Maternity Hospital | And 5 more authors.
Pediatrics | Year: 2013

BACKGROUND AND OBJECTIVE: Hypothermia on admission to the NICU is associated with increased mortality in preterm infants. Many newborns are hypothermic on admission despite using polyethylene bags (PBs). Using exothermic mattresses (EMs) in addition to PBs may reduce hypothermia but increase hyperthermia. We wished to determine whether placing preterm newborns in PBs on EMs in the DR results in more infants with rectal temperature outside the range 36.5 to 37.5°C on NICU admission. METHODS: Infants <31 weeks were randomly assigned before birth to treatment with or without an EM. All infants were placed in a PB and under radiant heat immediately after birth and brought to NICU in a transport incubator. Infants randomly assigned to EM were placed on a mattress immediately after delivery and remained on it until admission. Randomization was stratified by gestational age. Rectal temperature was measured with a digital thermometer on NICU admission. RESULTS: The data safety monitoring committee recommended stopping for efficacy after analyzing data from half the planned sample. We report data for 72 infants enrolled at this time. Fewer infants in PBs on EMs had temperatures within the target range (15/37 [41%] vs 27/35 [77%], P = .002) and more had temperatures >37.5°C (17/37 [46%] vs 6/35 [17%], P = .009). CONCLUSIONS: In very preterm newborns, using EMs in addition to PBs in the DR resulted in more infants with temperatures outside the normal range and more hyperthermia on NICU admission. Pediatrics 2013;132:e135-e141. Copyright © 2013 by the American Academy of Pediatrics.

O'Donovan S.M.,University College Cork | O'B. Hourihane J.,University College Cork | Murray D.M.,University College Cork | Kenny L.C.,University College Cork | And 6 more authors.
Journal of Allergy and Clinical Immunology | Year: 2016

Background Early nutrition and adiposity have been linked to atopic dermatitis (AD) development. Objective We sought to describe risk factors for AD in the first year of life in infants participating in the Cork BASELINE birth cohort study (n = 1537). Methods Prospective data on early-life events, infant feeding, and nutritional and environmental exposures were collected at 15 weeks' gestation, birth, and 2, 6, and 12 months of age. Body composition was assessed by using air displacement plethysmography at day 2 and 2 months. The primary outcome, persistent AD, was determined if the UK Working Party Diagnostic Criteria were satisfied at both 6 and 12 months. Results At 6 and 12 months, the point prevalence of AD was 14.2% (99% CI, 10.5% to 17.8%) and 13.7% (99% CI, 10.3% to 17.6%), respectively; 7.5% (99% CI, 5.0% to 9.9%) of infants had AD at both 6 and 12 months of age. At hospital discharge, 35% of infants were exclusively breast-fed, decreasing to 14% by 2 months. Complementary feeding was commenced at a median of 19 weeks (interquartile range, 17-22 weeks; 19% at <17 weeks and 6% at ≥26 weeks). Median fat mass at day 2 was 0.35 kg (interquartile range, 0.25-0.48 kg). A parental history of atopic disease was self-reported by 43% of mothers and 34% of fathers. Risk factors for AD at 6 and 12 months were maternal atopy (adjusted odds ratio, 2.99; 99% CI, 1.35-6.59; P =.0004) and fat mass of the 80th percentile or greater at day 2 (adjusted odds ratio, 2.31; 99% CI, 1.02-2.25; P =.009). Conclusion This is the first report of neonatal adiposity as a predictor of AD at 6 and 12 months of age in a well-characterized atopic disease-specific birth cohort. © 2015 American Academy of Allergy, Asthma & Immunology.

Domingo-Fernandez R.,Royal College of Surgeons in Ireland | Domingo-Fernandez R.,National Childrens Research Center | Lindner S.,Childrens Hospital Essen | Mestdagh P.,Ghent University | And 17 more authors.
Nature Genetics | Year: 2012

LIN28B regulates developmental processes by modulating microRNAs (miRNAs) of the let-7 family. A role for LIN28B in cancer has been proposed but has not been established in vivo. Here, we report that LIN28B showed genomic aberrations and extensive overexpression in high-risk neuroblastoma compared to several other tumor entities and normal tissues. High LIN28B expression was an independent risk factor for adverse outcome in neuroblastoma. LIN28B signaled through repression of the let-7 miRNAs and consequently resulted in elevated MYCN protein expression in neuroblastoma cells. LIN28B-let-7-MYCN signaling blocked differentiation of normal neuroblasts and neuroblastoma cells. These findings were fully recapitulated in a mouse model in which LIN28B expression in the sympathetic adrenergic lineage induced development of neuroblastomas marked by low let-7 miRNA levels and high MYCN protein expression. Interference with this pathway might offer therapeutic perspectives. © 2012 Nature America, Inc. All rights reserved.

Hawkes C.P.,University College Cork | Hawkes C.P.,Cork University Maternity Hospital | Hourihane J.O'B.,University College Cork | Kenny L.C.,University College Cork | And 4 more authors.
Pediatrics | Year: 2011

BACKGROUND: There is increasing evidence that in utero growth has both immediate and far-reaching influence on health. Birth weight and length are used as surrogate measures of in utero growth. However, these measures poorly reflect neonatal adiposity. Air-displacement plethysmography has been validated for the measurement of body fat in the neonatal population. OBJECTIVE: The goal of this study was to show the normal reference values of percentage body fat (%BF) in infants during the first 4 days of life. METHODS: As part of a large population-based birth cohort study, fat mass, fat-free mass, and %BF were measured within the first 4 days of life using air-displacement plethsymography. Infants were grouped into gestational age and gender categories. RESULTS: Of the 786 enrolled infants, fat mass, fat-free mass, and %BF were measured in 743 (94.5%) infants within the first 4 days of life. %BF increased significantly with gestational age. Mean (SD) %BF at 36 to 37 6/7 weeks' gestation was 8.9% (3.5%); at 38 to 39 6/7 weeks' gestation, 10.3% (4%); and at 40 to 41 6/7 weeks' gestation, 11.2% (4.3%) (P < .001). Female infants had significantly increased mean (SD) %BF at 38 to 39 6/7(11.1% [3.9%] vs 9.8% [3.9%]; P = .012) and at 40 to 41 6/7 (12.5% [4.4%] vs 10% [3.9%]; P < .001) weeks' gestation compared with male infants. Gender- and gestational age-specific centiles were calculated, and a normative table was generated for reference. CONCLUSION: %BF at birth is influenced by gestational age and gender. We generated accurate %BF centiles from a large population-based cohort. Copyright © 2011 by the American Academy of Pediatrics.

Kelleher M.,University College Cork | Dunn-Galvin A.,University College Cork | Hourihane J.O.,University College Cork | Hourihane J.O.,National Childrens Research Center | And 7 more authors.
Journal of Allergy and Clinical Immunology | Year: 2015

Background Loss-of-function mutations in the skin barrier protein filaggrin (FLG) are a major risk for atopic dermatitis (AD). The pathogenic sequence of disturbances in skin barrier function before or during the early development of AD is not fully understood. A more detailed understanding of these events is needed to develop a clearer picture of disease pathogenesis. A robust, noninvasive test to identify babies at high risk of AD would be important in planning early intervention and/or prevention studies. Objectives To ascertain whether a noninvasive measurement of skin barrier function at day 2 after birth and at 2 months predicts the development of AD at 1 year. Furthermore, to determine whether increases in transepidermal water loss (TEWL) predate the development of clinical AD. Methods A total of 1903 infants were enrolled in the Cork Babies After Scope: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints Birth Cohort study from July 2009 to October 2011. Measurements of TEWL were made at birth (day 2) and at 2 and 6 months. The presence of AD was ascertained at 6 and 12 months, and disease severity was assessed by using the SCORing Atopic Dermatitis clinical tool at 6 months and by using both the SCORing Atopic Dermatitis clinical tool and Nottingham Severity Score at 12 months. A total of 1300 infants were genotyped for FLG mutations. Results At 6 months, 18.7% of the children had AD, and at 12 months, 15.53%. In a logistic regression model, day 2 upper quartile TEWL measurement was significantly predictive of AD at 12 months (area under the receiver operating characteristic curve, 0.81; P <.05). Lowest quartile day 2 TEWL was protective against AD at 12 months. An upper quartile 2 month TEWL was also strongly predictive of AD at 12 months (area under the receiver operating characteristic curve, 0.84; P <.05). At both ages, this effect was independent of parental atopy, FLG status, or report of an itchy flexural rash at 2 months. Associations were increased when parental atopy status or child FLG mutation status was added into the linear regression model. Conclusions Impairment of skin barrier function at birth and at 2 months precedes clinical AD. In addition to providing important mechanistic insights into disease pathogenesis, these findings have implications for the optimal timing of interventions for the prevention of AD. © 2015 The Authors.

McCarthy L.K.,National Maternity Hospital | McCarthy L.K.,National Childrens Research Center | McCarthy L.K.,University College Dublin | O'Donnell C.P.F.,National Maternity Hospital | And 2 more authors.
Acta Paediatrica, International Journal of Paediatrics | Year: 2011

Aims: To compare the admission temperature of infants treated with polyethylene bags alone to infants treated with exothermic mattresses in addition to bags in the delivery room. Methods: We prospectively studied infants born at <31 weeks' gestation who were placed in bags at birth. Some infants were also placed on mattresses. Admission axillary temperatures were measured in all infants on admission to the neonatal intensive care. We compared the temperatures of infants treated with bags alone to those treated with mattresses and bags. Results: We studied 43 infants: 15 were treated with bags while 28 were treated with a bag and mattress. Mean admission temperature was similar between the groups. Hypothermia and hyperthermia occurred more frequently in infants treated with a bag and mattress, and more infants treated with a bag had admission temperatures 36.5-37.5°C. Conclusion: The use of exothermic mattresses in addition to polyethylene bags, particularly in younger, smaller newborns, may result in more hypothermia and hyperthermia on admission. A randomised controlled trial is necessary to determine which strategy results in more infants having admission temperatures in the normal range. © 2011 Foundation Acta Pædiatrica.

Hensey C.C.,National Maternity Hospital | Hayden E.,National Maternity Hospital | O'Donnell C.P.F.,National Maternity Hospital | O'Donnell C.P.F.,National Childrens Research Center | O'Donnell C.P.F.,University College Dublin
Archives of Disease in Childhood: Fetal and Neonatal Edition | Year: 2013

Objective: To compare the efficacy of low-flow oxygen, low-flow air and sham treatment given via nasal cannulae in preventing desaturation (falls in oxygen saturation (SpO2)) in preterm infants. Study design: Infants born at <33 weeks gestation receiving gas at flow rates <1 l/min via nasal cannulae were eligible for inclusion. Enrolled infants received three treatments - 0.1 l/min 100% oxygen, 0.1 l/min air, (21% oxygen) and sham (tubing disconnected from flow-meter) - via nasal cannulae, each for 3 h. Treatments were given in a randomly assigned order and caregivers were masked to treatment. Infants were monitored with a pulse oximeter that recorded SpO2 and heart rate every 2 s. Treatment was stopped before 3 h if infants reached prespecified failure criteria. We compared the rates of failure and the frequency and duration of desaturation episodes that occurred during each treatment. Results: Of 14 infants enrolled, 2 (14%) reached failure criteria during treatment with oxygen compared with 7 (50%) during treatment with air and sham. Among infants who completed the 3-h study periods, there were fewer episodes and shorter duration of desaturation with oxygen compared with air and sham. Conclusions: At a flow rate of 0.1 l/min via nasal cannulae, air is no better than sham treatment in preventing desaturation in preterm infants, while 100% oxygen is superior to both.

Hawkes C.P.,Children's Hospital of Philadelphia | Hawkes C.P.,National Childrens Research Center | Schnellbacher S.,Children's Hospital of Philadelphia | Singh R.J.,Mayo Medical School | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context: Vitamin D intoxication is characterized by elevated serum 25-hydroxyvitamin D (25(OH)D) and suppressed serum 1,25-dihydroxvitamin D (1,25(OH)2D). We evaluated two adolescents with hypercalcemia due to vitamin D intoxication; both had elevated serum 1,25(OH)2D by Diasorin RIA, but normal serum 1,25(OH)2D concentrations by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Objective: This study aimed to determine the effect of 25(OH)D2 and 25(OH)D3 on 1,25(OH)2D concentration determined using RIA and LC-MS/MS. Methods: Pools of normal serum and an artificial serum matrix were prepared and aliquots were spiked with >99% pure 25(OH)D2 or 25(OH)D3 (50-700 ng/mL). Samples were maintained at 4°C or heated to 56°C, and the concentrations of vitamin D metabolites were measured by LC-MS/MS and Diasorin RIA. Results: Median 1,25(OH)2 D increased by 114% with RIA and 21% with LC-MS/MS with addition of 100 ng/mL 25(OH)D3, and 349% (RIA) and 117% (LC-MS/MS) with 700 ng/mL of 25(OH)D3. Each 1-ng/mL increase in 25(OH)D3 increased 1,25(OH)2D by 0.231 pg/mL (RIA) and 0.121 pg/mL (LC-MS/MS). Spiking with 25(OH)D2 led to similar changes. Heat inactivation of serum, and using an artificial serum matrix, were associated with similar effects of 25(OH)D on 1,25(OH)2D assays. Conclusions: Vitamin D intoxication with high serum levels of 25(OH)D2 or 25(OH)D3 can be associated with elevated levels of 1,25(OH)2D due to interference in a commonly used RIA. A similar but attenuated effect also occurs when 1,25(OH)2 D is measured using LC-MS/MS but does not seem to be clinically significant. The basis for this effect on the LC-MS/MS assay is presently uncertain. Copyright © 2015 by the Endocrine Society.

Hawkes C.P.,Children's Hospital of Philadelphia | Hawkes C.P.,National Childrens Research Center | Levine M.A.,Children's Hospital of Philadelphia | Levine M.A.,University of Pennsylvania
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: The ketogenic diet is increasingly used in refractory epilepsy and is associated with clinically significant effectsonboneandmineral metabolism. Although hypercalciuriaandloss ofbone mineral density are common in patients on the ketogenic diet, hypercalcemia has not previously been described. Objective: The aim of the study was to describe three childrenwhodeveloped hypercalcemia while on the ketogenic diet. Design: A retrospective chart review of three children on the ketogenic with severe hypercalcemia was conducted. Results: We describe three children on the ketogenic diet for refractory seizures who presented with hypercalcemia. Case 1 was a 5.5-year-old male with an undiagnosed, rapidly progressive seizure disorder associated with developmental regression. Case 2 was a 2.5-year-old male with a chromosomal deletion of 2q24.3, and case 3 was a 4.6-year-old male with cerebral cortex dysplasia. Patients had been on a ketogenic diet for 6 to 12 months before presentation. Daily intake of calcium and vitaminDwas not excessive, and all three patients were not acidotic because they were taking supplemental bicarbonate. Each child had elevated serum levels of calcium and normal serum phosphate levels, moderately elevated urinary calcium excretion, and low levels of serum alkaline phosphatase, PTH, and 1,25-dihydroxyvitamin D. All patients responded to calcitonin. Conclusions: Hypercalcemia is an uncommon complication of the ketogenic diet, and these children may represent the severe end of a clinical spectrum of disordered mineral metabolism. The mechanism for hypercalcemia is unknown but is consistent with excess bone resorption and impaired calcium excretion. © 2014 by the Endocrine Society.

Gegenbauer K.,University College Dublin | Gegenbauer K.,National Childrens Research Center | Gegenbauer K.,Trinity College Dublin | Nagy Z.,University College Dublin | Smolenski A.,University College Dublin
PLoS ONE | Year: 2013

Regulator of G-protein signaling 18 (RGS18) is a GTPase-activating protein that turns off Gq signaling in platelets. RGS18 is regulated by binding to the adaptor protein 14-3-3 via phosphorylated serine residues S49 and S218 on RGS18. In this study we confirm that thrombin, thromboxane A2, or ADP stimulate the interaction of RGS18 and 14-3-3 by increasing the phosphorylation of S49. Cyclic AMP- and cyclic GMP-dependent kinases (PKA, PKG) inhibit the interaction of RGS18 and 14-3-3 by phosphorylating S216. To understand the effect of S216 phosphorylation we studied the phosphorylation kinetics of S49, S216, and S218 using Phos-tag gels and phosphorylation site-specific antibodies in transfected cells and in platelets. Cyclic nucleotide-induced detachment of 14-3-3 from RGS18 coincides initially with double phosphorylation of S216 and S218. This is followed by dephosphorylation of S49 and S218. Dephosphorylation of S49 and S218 might be mediated by protein phosphatase 1 (PP1) which is linked to RGS18 by the regulatory subunit PPP1R9B (spinophilin). We conclude that PKA and PKG induced S216 phosphorylation triggers the dephosphorylation of the 14-3-3 binding sites of RGS18 in platelets. © 2013 Gegenbauer et al.

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