National Jewish Health

About: National Jewish Health is a healthcare organization based out in Denver, Colorado, United States. It is known for research contribution in the topics: T cell & Asthma. The organization has 883 authors who have published 833 publications receiving 79201 citations. The organization is also known as: National Jewish Medical and Research Center.

Brain activation changes before and after PAP treatment in obstructive sleep apnea.

Abstract: study objectives : Obstructive sleep apnea syndrome (OSAS) is asso- ciated with cognitive and functional deficits, most of which are corrected after positive airway pressure (PAP) treatment. Previous studies inves- tigating the neural underpinnings of OSAS failed to provide consistent results both on the cerebral substrates underlying cognitive deficits and on the effect of treatment on these anomalies. The aims of the study were a) to investigate whether never-treated OSA patients demonstrat- ed differences in brain activation compared to healthy controls during a cognitive task; and b) to investigate whether any improvements in cognitive functioning found in OSA patients after treatment reflected a change in the underlying cerebral activity. Design : OSA patients and healthy controls underwent functional mag- netic resonance imaging (fMRI) scanning. They were compared on per- formance and brain activation during a 2-back working-memory task. Patients were also re-evaluated after 3 months treatment with PAP. Cognitive functions were evaluated using neurocognitive tests. Sleepi- ness (ESS), mood (Beck Depression Inventory) and, quality-of-life (SF- 36) were also assessed. setting : The Sleep Disorders Center and CERMAC at the Vita-Salute San Raffaele University. Patients or Participants : 17 OSA patients and 15 age- and education- matched healthy controls. interventions : PAP treatment for 3 months. Measurements and results : Compared to controls, never-treated OSA patients showed increased activations in the left frontal cortex, medial precuneus, and hippocampus, and decreased activations in the caudal pons. OSA patients showed decreases in activation with treat- ment in the left inferior frontal gyrus and anterior cingulate cortex, and bilaterally in the hippocampus. Most neurocognitive domains, impaired at baseline, showed significant improvement after treatment. conclusions : OSA patients showed an overrecruitment of brain re- gions compared to controls, in the presence of the same level of performance on a working-memory task. Decreases of activation in prefrontal and hippocampal structures were observed after treatment in comparison to baseline. These findings may reflect a neural com - pensation mechanism in never-treated patients, which is reduced by

Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: integrated analysis of cumulative data from 5 clinical trials

Abstract: Background Pirfenidone is an oral antifibrotic agent that has been shown to reduce the decline in lung function in patients with idiopathic pulmonary fibrosis (IPF). We performed an integrated analysis of safety data from five clinical trials evaluating pirfenidone in patients with IPF. Methods All patients treated with pirfenidone in the three multinational Phase 3 studies (CAPACITY (studies 004 and 006), ASCEND (study 016)) and two ongoing open-label studies (study 002 and study 012 (RECAP)) were included in the analysis. Safety outcomes were assessed during the period from the first dose until 28 days after the last dose of study drug. Results A total of 1299 patients were included in the analysis. The cumulative total exposure to pirfenidone was 3160 person exposure years (PEY). The median duration of exposure was 1.7 years (range 1 week to 9.9 years), and the mean (±SD) daily dose was 2053.8 (±484.9) mg. Gastrointestinal events (nausea (37.6%), diarrhoea (28.1%), dyspepsia (18.4%), vomiting (15.9%)) and rash (25.0%) were the most common adverse events; these were generally mild to moderate in severity and without significant clinical consequence. Elevations in alanine aminotransferase or aspartate aminotransferase greater than three times the upper limit of normal occurred in 40/1299 (3.1%) patients (adjusted incidence, 2.3 per 100 PEY). Elevations were generally transient and reversible with dose modification or discontinuation. Conclusions A comprehensive analysis of safety outcomes in a large and well-defined cohort of 1299 patients with IPF who were followed prospectively for up to 9.9 years demonstrated that long-term treatment with pirfenidone is safe and generally well tolerated. Trial registration numbers NCT00287716, NCT00287729, NCT00662038, NCT01366209.

Impact of Interview Mode on Accuracy of Child and Parent Report of Adherence With Asthma-Controller Medication

Abstract: OBJECTIVES. Parents and children often overreport adherence to treatment regimens, which in turn complicates interpretation and application of clinical trial findings. The objective of this investigation was to test the effect of reporting mode on accuracy of inhaled corticosteroid-adherence reporting in children with asthma and their parents under conditions similar to those of an asthma clinical trial. PATIENTS AND METHODS. Participants included 104 children who were being treated with an inhaled corticosteroid delivered by a metered-dose inhaler for asthma diagnosed by their health care provider. Each parent and child dyad was randomly assigned to 1 of 3 self-report adherence-assessment modes: (1) audio computer-assisted self-interviewing; (2) face-to-face interview with study staff; or (3) self-administered paper-and-pencil questionnaire. At the 4 monthly visits, the parent and child were interviewed separately and asked questions about adherence on the previous day and in the past week. Electronic devices were attached to the each participant9s metered-dose inhaler to provide an objective record of actual daily medication activations. RESULTS. Both children and parents greatly overreported their inhaled corticosteroid adherence when queried about either time frame (1 day or 1 week) in any of the 3 interview modes. One of 3 responses reported full adherence when no medication had been taken. Inconsistent with the study hypothesis, discrepancy between self-report and objectively measured adherence was greatest in the computer-interview condition. In the optimal circumstance where children were interviewed by study staff about their adherence within the previous 24 hours, reported adherence was within the ±25% accuracy range for only half of the participants. Larger discrepancy scores were observed for both parents and children when reporting by computer or questionnaire. CONCLUSIONS. Under the best of conditions in this study, accuracy of self-report was insufficient to provide a stand-alone measure of adherence. Verification of treatment adherence by objective measures remains necessary.

Cationic Proteins Induce Airway Hyperresponsiveness Dependent on Charge Interactions

Abstract: It has previously been demonstrated that human eosinophil-derived granule major basic protein (MBP) can increase airway responsiveness after intratracheal administration in the rat. This effect was mimicked by synthetic polycations, suggesting that charge interactions may be important in the development of airway hyperresponsiveness (AHR). To support this hypothesis, we investigated whether two other cationic proteins, platelet factor 4 (PF4) and cathepsin G, were capable of inducing AHR. Furthermore, to determine whether these effects were dependent on their positive charge, the charge of these proteins was neutralized with low molecular weight heparin. In addition, we have examined whether the effect of a synthetic polycation, poly-l-lysine could be inhibited by low molecular weight heparin, albumin, or dextran sulphate.MBP, PF4, or cathepsin G induced a 2- to 3-fold increase in airway responsiveness 1 h after instillation, as assessed by the dose of inhaled methacholine required to increase total lung ...

MEK-1 phosphorylation by MEK kinase, Raf, and mitogen-activated protein kinase: analysis of phosphopeptides and regulation of activity.

Abstract: MEK-1 is a dual threonine and tyrosine recognition kinase that phosphorylates and activates mitogen-activated protein kinase (MAPK). MEK-1 is in turn activated by phosphorylation. Raf and MAPK/extracellular signal-regulated kinase kinase (MEKK) independently phosphorylate and activate MEK-1. Recombinant MEK-1 is also capable of autoactivation. Purified recombinant wild type MEK-1 and a mutant kinase inactive MEK-1 were used as substrates for MEKK, Raf, and autophosphorylation. MEK-1 phosphorylation catalyzed by Raf, MEKK, or autophosphorylation resulted in activation of MEK-1 kinase activity measured by phosphorylation of a mutant kinase inactive MAPK. Phosphoamino acid analysis and peptide mapping identified similar MEK-1 tryptic phosphopeptides after phosphorylation by MEK kinase, Raf, or MEK-1 autophosphorylation. MEK-1 is phosphorylated by MAPK at sites different from that for Raf and MEKK. Phosphorylation of MEK-1 by MAPK does not affect MEK-1 kinase activity. Several phosphorylation sites present in MEK-1 immunoprecipitated from 32P-labeled cells after stimulation with epidermal growth factor were common to the in vitro phosphorylated enzyme. The major site of MAPK phosphorylation in MEK-1 is threonine 292. Mutation of threonine 292 to alanine eliminates 90% of MAPK catalyzed phosphorylation of MEK-1 but does not influence MEK-1 activity. The results demonstrate that MEKK and Raf regulate MEK-1 activity by phosphorylation of common residues and thus, two independent protein kinases converge at MEK-1 to regulate the activity of MAPK.