A microRNA network regulates expression and biosynthesis of wild-type and DeltaF508 mutant cystic fibrosis transmembrane conductance regulator.

Production of functional proteins requires multiple steps, including gene transcription and posttranslational processing. MicroRNAs (miRNAs) can regulate individual stages of these processes. Despite the importance of the cystic fibrosis transmembrane conductance regulator (CFTR) channel for epithelial anion transport, how its expression is regulated remains uncertain. We discovered that miRNA-138 regulates CFTR expression through its interactions with the transcriptional regulatory protein SIN3A. Treating airway epithelia with an miR-138 mimic increased CFTR mRNA and also enhanced CFTR abundance and transepithelial Cl(-) permeability independent of elevated mRNA levels. An miR-138 anti-miR had the opposite effects. Importantly, miR-138 altered the expression of many genes encoding proteins that associate with CFTR and may influence its biosynthesis. The most common CFTR mutation, ΔF508, causes protein misfolding, protein degradation, and cystic fibrosis. Remarkably, manipulating the miR-138 regulatory network also improved biosynthesis of CFTR-ΔF508 and restored Cl(-) transport to cystic fibrosis airway epithelia. This miRNA-regulated network directs gene expression from the chromosome to the cell membrane, indicating that an individual miRNA can control a cellular process more broadly than recognized previously. This discovery also provides therapeutic avenues for restoring CFTR function to cells affected by the most common cystic fibrosis mutation.

Quantitative measurement of retinal hemorrhages in suspected victims of child abuse.

PURPOSE: Child abuse is one of the leading causes of death in early childhood. The presence of retinal hemorrhages often supports the diagnosis. The purpose of this study was to determine whether the specific measurement of retinal hemorrhages when present on fundus photography correlates with other clinical findings typically seen in children suspected of having been abused. METHODS: The medical records of children with retinal hemorrhages who were suspected of being victims of abusive head trauma from June 2003 to June 2013 and who had widefield retinal photography performed were retrospectively reviewed. Data collected included hemorrhage-covered percentage (HCP) of the central retina (posterior pole or 40° circle centered on fovea) measured by ImageJ in relation to death, length of hospital stay, presence of abnormal findings on neuroimaging or skeletal survey, and definite versus possible abuse. RESULTS: Significant difference in retinal hemorrhage measured on fundus photography was found in patients with axial skeletal fracture (P = 0.016), signs of severe brain trauma on neuroimaging (P = 0.014) and definite versus possible abuse (P = 0.023). No correlation of quantitative measurement of the retinal hemorrhage to length of hospital stay, death, or the presence of skull fracture was found in this cohort. CONCLUSIONS: The quantitative measurement of total retinal hemorrhage when present on fundus photography centered on posterior pole in children suspected of having been abused correlated with some but not all findings typically seen in abused children.