Thyroid transcription factor 1 (TTF-1), encoded by the gene NKX2-1 (Entrez gene identifi cation number 7080 ), is expressed in the thyroid gland, brain, and lung. In the lung, it is an early marker of lung differentiation and is important for structural development M utations in genes encoding surfactant protein-B ( SFTPB ), member A3 of the ATP-binding cassette family of transporters ( ABCA3 ), and surfactant protein-C ( SFTPC ) cause neonatal respiratory distress syndrome (RDS) or childhood interstitial and diffuse lung disease (ChILD). 1 Considerable overlap in the clinical and histologic features of the lung disease associated with these mutations exists, which are collectively referred to as surfactant dysfunction disorders. Children with fi ndings of surfactant dysfunction but without identifi able mutations in the SFTPB , SFTPC, or ABCA3 genes have been reported. 2,3 Background: Mutations in the gene encoding thyroid transcription factor, NKX2-1 , result in neurologic abnormalities, hypothyroidism, and neonatal respiratory distress syndrome (RDS) that together are known as the brain-thyroid-lung syndrome. To characterize the spectrum of associated pulmonary phenotypes, we identifi ed individuals with mutations in NKX2-1 whose primary manifestation was respiratory disease. Methods: Retrospective and prospective approaches identifi ed infants and children with unexplained diffuse lung disease for NKX2-1 sequencing. Histopathologic results and electron micrographs were assessed, and immunohistochemical analysis for surfactant-associated proteins was performed in a subset of 10 children for whom lung tissue was available.

Implementation of the asthma CPM was associated with improved compliance with CAC-3 and with a delayed, yet significant and sustained decrease in hospital asthma readmission rates, validating CAC-3 as a quality measure. Due to high baseline compliance, CAC-1 and CAC-2 are of questionable value as quality measures.

Major basic protein (MBP) is a highly cationic protein found in the granules of eosinophils. It has been postulated that MBP may participate in the pathogenesis of airway hyperresponsiveness exhibited by asthmatic patients. Accordingly, we used a rat model to investigate the effect of human MBP instillation on airway responsiveness and the possible role of cationic charge in the determination of this effect. Dose-response characteristics to inhaled methacholine (MDRC) were determined at baseline, and the animals were allowed to recover. Then animals in the experimental group received 100 micrograms of purified human MBP via direct instillation into the trachea. One hour after instillation, the MDRC were again assessed. Control animals received (in lieu of MBP) buffer from the void volume pool of the same chromatography column used to purify the MBP. One hour after instillation of MBP there was a significant increase in airway responsiveness to inhaled methacholine, whereas control animals exhibited no increase in airway responsiveness. Some animals from the MBP group were restudied 48 h after MBP instillation, by which time airway responsiveness had returned to baseline level. The effect of the polycations poly-L-arginine and poly-L-lysine on airway responsiveness was also examined. As with MBP, airway responsiveness to inhaled methacholine increased 1 h after the instillation of either polycation. In addition, acetylation of the charged groups on poly-L-lysine resulted in a loss of this effect. Histologic examination of the airways failed to reveal airway epithelial shedding 1 h after MBP or polycation instillation.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhaled irritants activate transient receptor potential ankyrin-1 (TRPA1), resulting in cough, bronchoconstriction, and inflammation/edema. TRPA1 is also implicated in the pathogenesis of asthma. Our hypothesis was that particulate materials activate TRPA1 via a mechanism distinct from chemical agonists and that, in a cohort of children with asthma living in a location prone to high levels of air pollution, expression of uniquely sensitive forms of TRPA1 may correlate with reduced asthma control. Variant forms of TRPA1 were constructed by mutating residues in known functional elements and corresponding to single-nucleotide polymorphisms in functional domains. TRPA1 activity was studied in transfected HEK-293 cells using allyl-isothiocynate, a model soluble electrophilic agonist; 3,5-ditert butylphenol, a soluble nonelectrophilic agonist and a component of diesel exhaust particles; and insoluble coal fly ash (CFA) particles. The N-terminal variants R3C and R58T exhibited greater, but not additive, activity with all three agonists. The ankyrin repeat domain-4 single nucleotide polymorphisms E179K and K186N exhibited decreased response to CFA. The predicted N-linked glycosylation site residues N747A and N753A exhibited decreased responses to CFA, which were not attributable to differences in cellular localization. The pore-loop residue R919Q was comparable to wild-type, whereas N954T was inactive to soluble agonists but not CFA. These data identify roles for ankyrin domain-4, cell surface N-linked glycans, and selected pore-loop domain residues in the activation of TRPA1 by insoluble particles. Furthermore, the R3C and R58T polymorphisms correlated with reduced asthma control for some children, which suggest that TRPA1 activity may modulate asthma, particularly among individuals living in locations prone to high levels of air pollution.

BACKGROUND AND OBJECTIVES: Gaps exist in inpatient asthma care. Our aims were to assess the impact of an evidence-based care process model (EB-CPM) 5 years after implementation at Primary Children's Hospital (PCH), a tertiary care facility, and after its dissemination to 7 community hospitals.METHODS: Participants included asthmatics 2 to 17 years admitted at 8 hospitals between 2003 and 2013. The EB-CPM was implemented at PCH between January 2008 and March 2009, then disseminated to 7 community hospitals between January and June 2011. We measured compliance using a composite score (CS) for 8 quality measures. Outcomes were compared between preimplementation and postimplementation periods. Confounding was addressed through multivariable regression analyses.RESULTS: At PCH, the CS increased and remained at .90% for 5 years after implementation. We observed sustained reductions in asthma readmissions (P = .026) and length of stay (P , .001), a trend toward reduced costs (P = .094), and no change in hospital resource use, ICU transfers, or deaths. The CS also increased at the 7 community hospitals, reaching 80% to 90% and persisting .2 years after dissemination, with a slight but not significant readmission reduction (P = .119), a significant reduction in length of stay (P , .001) and cost (P = .053), a slight increase in hospital resource use (P = .032), and no change in ICU transfers or deaths.CONCLUSIONS: Our intervention resulted in sustained, long-term improvement in asthma care and outcomes at the tertiary care hospital and successful dissemination to community hospitals.