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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The pathophysiology resulting in cerebral edema in pediatric diabetic ketoacidosis (DKA) is unknown. To investigate the changes in white matter microstructure in this disease, we measured diffusion tensor imaging (DTI) parameters, including apparent diffusion coefficient (ADC), fractional anisotropy (FA), and radial and axial diffusivity in children with DKA at two time points during treatment. ⋯ Consistent DTI changes occurred during DKA treatment over a short time frame. These findings describe widespread water diffusion abnormalities in DKA, supporting an association between clinical illness and DTI markers of microstructural change in white matter.