Preservation of the metabolic rate of oxygen in preterm infants during indomethacin therapy for closure of the ductus arteriosus

Background:The aim of this study was to assess and quantify the effects of indomethacin on cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO 2) in preterm infants undergoing treatment for a patent ductus arteriosus (PDA).Methods:CBF and CMRO 2 were measured before and after the first dose of a 3-d course of indomethacin to close hemodynamically significant PDA in preterm neonates. Indocyanine-green (ICG) concentration curves were acquired before and after indomethacin injection to quantify CBF and CMRO 2.Results:Eight preterm neonates (gestational age, 27.6 ± 0.5 wk; birth weight, 992 ± 109 g; 6 males:2 females) were treated at a median age of 4.5 d (range, 4-21 d). Indomethacin resulted in an average CBF decrease of 18% (pre- and post-CBF = 12.9 ± 1.3 and 10.6 ± 0.8 ml/100 g/min, respectively) and an OEF increase of 11% (pre- and post-OEF = 0.38 ± 0.02 and 0.42 ± 0.02, respectively) but no significant change in CMRO 2 (pre- and post-CMRO 2 = 0.83 ± 0.07 and 0.76 ± 0.07 ml O 2 /100 g/min, respectively). Corresponding mean blood pressure (BP), arterial oxygen saturation (S a O 2), heart rate, and end-tidal carbon dioxide tension levels remained unchanged.Conclusion:Indomethacin resulted in significant reduction in CBF but did not alter CMRO 2 because of a compensatory increase in OEF. Copyright © 2013 International Pediatric Research Foundation, Inc

Machine Learning Identifies Clinical and Genetic Factors Associated With Anthracycline Cardiotoxicity in Pediatric Cancer Survivors

BACKGROUND Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging. OBJECTIVES This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors. METHODS We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 case patients with reduced left ventricular ejection fraction despite low-dose doxorubicin (\u3c= 250 mg/m(2)), and 106 control patients with preserved left ventricular ejection fraction despite doxorubicin \u3e250 mg/m(2) were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between case patients and control patients. The expression levels of 5 top-ranked genes were evaluated in human induced pluripotent stem cell-derived cardiomyocytes, and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed. RESULTS Thirty-one genes were differentially enriched for variants between case patients and control patients (p \u3c 0.001). Only 42.6% case patients harbored a variant in these genes compared to 89.6% control patients (odds ratio: 0.09; 95% confidence interval: 0.04 to 0.17; p = 3.98 x 10(-15)). A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical-only model. In vitro inhibition of gene-associated pathways (PI3KR2, ZNF827) provided protection from cardiotoxicity in cardiomyocytes. CONCLUSIONS Our study identified variants in cardiac injury pathway genes that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and it also provided new targets in autophagy genes for the development of cardio-protective drugs

Exome Sequencing Identifies Rare Variants in Multiple Genes in Atrioventricular Septal Defect

Purpose The genetic etiology of atrioventricular septal defect (AVSD) is unknown in 40% cases. Conventional sequencing and arrays have identified the etiology in only a minority of non-syndromic individuals with AVSD. Methods: Whole exome sequencing was performed in 81 unrelated probands with AVSD to identify potentially causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD. Results: A significant enrichment of rare and rare/damaging variants was identified in the gene set, compared with controls (odds ratio 1.52, 95% confidence interval 1.35–1.71, p = 4.8 x 10-11). The enrichment was specific to AVSD probands compared with a non-AVSD cohort with tetralogy of Fallot (odds ratio 2.25, 95% confidence interval 1.84-2.76, p = 2.2 x 10-16). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2 and MDM4) were enriched for rare variants in AVSD compared to controls, including three syndrome-associated genes (NIPBL, CHD7, CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands. Conclusion: Mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD even in those with isolated heart disease. The identification of a gene set associated with AVSD will facilitate targeted genetic screening in this cohort

Indomethacin Induced and Prostaglandin Relieved Coarctation of the Aorta in Right Aortic Arch With Left Arterial Duct: a Case Report

We describe the case of an infant with DiGeorge syndrome born with a right aortic arch and left arterial duct. Despite the remote location of the right aortic arch from the left arterial duct, he developed coarctation of the aorta during treatment with indomethacin. This was relieved by prostaglandin treatment. This case highlights the fact that, even in the absence of an arterial duct, ductal tissue can still be present in the aorta, and cause coarctation when exposed to indomethacin. We also demonstrate the utility of prostaglandin for relief of this type of obstruction

Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect

The genetic etiology of atrioventricular septal defect (AVSD) is unknown in 40% cases. Conventional sequencing and arrays have identified the etiology in only a minority of nonsyndromic individuals with AVSD. Whole-exome sequencing was performed in 81 unrelated probands with AVSD to identify potentially causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD. A significant enrichment of rare and rare damaging variants was identified in the gene set, compared with controls (odds ratio (OR): 1.52; 95% confidence interval (CI): 1.35-1.71; P = 4.8 × 10(-11)). The enrichment was specific to AVSD probands, compared with a cohort without AVSD with tetralogy of Fallot (OR: 2.25; 95% CI: 1.84-2.76; P = 2.2 × 10(-16)). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2, and MDM4) were enriched for rare variants in AVSD compared with controls, including three syndrome-associated genes (NIPBL, CHD7, and CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands. Mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD, even in those with isolated heart disease. The identification of a gene set associated with AVSD will facilitate targeted genetic screening in this cohor

Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect

The genetic etiology of atrioventricular septal defect (AVSD) is unknown in 40% cases. Conventional sequencing and arrays have identified the etiology in only a minority of nonsyndromic individuals with AVSD.status: publishe