Pediatric research
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Genetic variations in the 17q21 locus are strongly associated with childhood nonallergic asthma. Expression of the 17q21 genes, orosomucoid like 3 (ORMDL3) and gasdermin B (GSMDB), is affected by these disease-associated variants. However, until recently, no functional connection of the protein products coded by these genes with asthma was known. ⋯ This includes dysregulation of the unfolded protein response (UPR) associated with airway remodeling and also an effect of ORMDL3-dysregulated sphingolipid synthesis on bronchial hyperreactivity. These findings are crucial for a better understanding of the mechanism of childhood asthma and may lead to asthma therapeutics that target pathways previously not thought to be related to this common pediatric respiratory disease. Furthermore, this may validate the unbiased genome-wide association study (GWAS) approach for complex diseases such as asthma, to better define pathomechanisms and drug targets.
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Abnormal ciliary axonemal structure and function are linked to the growing class of genetic disorders collectively known as ciliopathies, and our understanding of the complex genetics and functional phenotypes of these conditions has rapidly expanded. While progress in genetics and biology has uncovered numerous cilia-related syndromes, primary ciliary dyskinesia (PCD) remains the sole genetic disorder of motile cilia dysfunction. The first disease-causing mutation was described just 13 y ago, and since that time, the pace of gene discovery has quickened. ⋯ These findings have yielded novel insights into the processes involved in ciliary assembly, structure, and function, which will allow us to better understand the clinical manifestations of PCD. Moreover, advances in techniques for genetic screening and sequencing are improving diagnostic approaches. In this article, we will describe the structure, function, and emerging genetics of respiratory cilia, review the genotype-phenotype relationships of motor ciliopathies, and explore the implications of recent discoveries for diagnostic testing for PCD.
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Review Meta Analysis Historical Article
Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990.
Intrapartum hypoxic events ("birth asphyxia") may result in stillbirth, neonatal or postneonatal mortality, and impairment. Systematic morbidity estimates for the burden of impairment outcomes are currently limited. Neonatal encephalopathy (NE) following an intrapartum hypoxic event is a strong predictor of long-term impairment. ⋯ Intrapartum-related conditions are a large global burden, mostly due to high mortality in low-income countries. Universal coverage of obstetric care and neonatal resuscitation would prevent most of these deaths and disabilities. Rates of impairment are highest in middle-income countries where neonatal intensive care was more recently introduced, but quality may be poor. In settings without neonatal intensive care, the impairment rate is low due to high mortality, which is relevant for the scale-up of basic neonatal resuscitation.
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For nearly a decade, our research group has had the privilege of developing and mining a multicenter, microarray-based, genome-wide expression database of critically ill children (≤10 y of age) with septic shock. Using bioinformatic and systems biology approaches, the expression data generated through this discovery-oriented, exploratory approach have been leveraged for a variety of objectives, which are reviewed here. Fundamental observations include widespread repression of gene programs corresponding to the adaptive immune system and biologically significant differential patterns of gene expression across developmental age groups. ⋯ The data have also been leveraged for the discovery of novel therapeutic targets, as well as for the discovery and development of novel stratification and diagnostic biomarkers. Almost a decade of genome-wide expression profiling in pediatric septic shock is now demonstrating tangible results. The studies have progressed from an initial discovery-oriented and exploratory phase to a new phase in which the data are being translated and applied to address several areas of clinical need.
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Cardiac biomarkers are used to identify cardiac disease in term and preterm infants. This review discusses the roles of natriuretic peptides and cardiac troponins. Natriuretic peptide levels are elevated during atrial strain (atrial natriuretic peptide (ANP)) or ventricular strain (B-type natriuretic peptide (BNP)). ⋯ Furthermore, cardiac biomarkers can possibly be used to guide therapy and improve outcome. Natriuretic peptides and cardiac troponins are potential tools in the diagnosis and treatment of neonatal disease that is complicated by circulatory compromise. However, clear reference ranges need to be set and validation needs to be carried out in a population of interest.