Clustering based on clinicophysiologic parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.

U-BIOPRED cohort n=91 epithelial brushings or biopsies IL-17 High Clinical phenotype Nasal polyps Smoking Antibiotic use Epithelial Gene Expression Profile Clinical phenotype FeNO Exacerbations Gene expression shared with psoriasis IDO1 IL1B DEFB4B S100A8, S100A9 PI3 CXCL3, CXCL8 CXCL10, CCL20 Gene signature SERPINB2 POSTN CLCA1 IL-13 High T cell infiltration Neutrophilia Eosinophilia IL-17-high asthma with features of a psoriasis immunophenotype From a the Respiratory,

Dunn MJ, Shattock MJ. Characterization of the phospholemman knockout mouse heart: depressed left ventricular function with increased Na-K-ATPase activity. Am J Physiol Heart Circ Physiol 294: H613-H621, 2008. First published December 7, 2007 doi:10.1152/ajpheart.01332.2007, abundantly expressed in the heart, is the primary cardiac sarcolemmal substrate for PKA and PKC. Evidence supports the hypothesis that PLM is part of the cardiac Na-K pump complex and provides the link between kinase activity and pump modulation. PLM has also been proposed to modulate Na/Ca exchanger activity and may be involved in cell volume regulation. This study characterized the phenotype of the PLM knockout (KO) mouse heart to further our understanding of PLM function in the heart. PLM KO mice were bred on a congenic C57/BL6 background. In vivo conductance catheter measurements exhibited a mildly depressed cardiac contractile function in PLM KO mice, which was exacerbated when hearts were isolated and Langendorff perfused. There were no significant differences in action potential morphology in paced Langendorff-perfused hearts. Depressed contractile function was associated with a mild cardiac hypertrophy in PLM KO mice. Biochemical analysis of crude ventricular homogenates showed a significant increase in Na-K-ATPase activity in PLM KO hearts compared with wild-type controls. SDS-PAGE and Western blot analysis of ventricular homogenates revealed small, nonsignificant changes in Na-K-ATPase subunit expression, with two-dimensional gel (isoelectric focusing, SDS-PAGE) analysis revealing minimal changes in ventricular protein expression, indicating that deletion of PLM was the primary reason for the observed PLM KO phenotype. These studies demonstrate that PLM plays an important role in the contractile function of the normoxic mouse heart. Data are consistent with the hypothesis that PLM modulates Na-K-ATPase activity, indirectly affecting intracellular Ca and hence contractile function. FXYD1; contractile function; intracellular sodium regulation IN EXCITABLE TISSUES, the activity of the plasma membrane Na-K-ATPase is vital for the maintenance of normal electrical activity, ionic homeostasis, cell volume control, and substrate and amino acid transport and for setting cellular Ca load and hence contractility. Interventions that influence Na-K-ATPase activity and/or the transmembrane Na gradient can therefore profoundly affect myocardial function. In essence, the Na-KATPase not only influences a wide range of transmembrane transport processes but also indirectly controls myocardial contractility.It has recently been recognized that the FXYD family of small single transmembrane-spanning proteins are tissue-specific regulators of the Na-K-ATPase (3-5, 28). Phospholemman (PLM, FXYD1) is expressed in excitable tissues and is unique among the FXYD proteins in that it contains a cytoplasmic region with consensus phosphorylation sites for kinases that include PKC and PKA (21, 30). In fact, PLM was originally identified as the primary sarcolemmal ...

Take home messagePeople with asthma and healthcare professionals provide strong support for mHealth for asthma self-management. 2 ABSTRACTRationale: mHealth has the potential to revolutionise the self-management of long-term medical conditions such as asthma. A user-centred design is integral if mHealth is to be embraced by patients and healthcare professionals. Objective: Determine the perspectives of individuals with asthma and healthcare professionals on the use of mHealth for asthma selfmanagement. Methods: A sequential exploratory mixed methods design was used; focus groups informed the development of questionnaires, which were disseminated to individuals with asthma and healthcare professionals. Results: Focus group participants (18 asthma patients and five healthcare professionals) identified 12 potential uses of mHealth.Questionnaire results showed that individuals with asthma (n=186) most frequently requested a mHealth system to monitor asthma over time (72%) and to collect data to present to healthcare teams (70%). In contrast, a system alerting patients to deteriorating asthma control (86%) and advising them when to seek medical attention (87%) was most frequently selected by healthcare professionals (n=63). Individuals with asthma were less likely than healthcare professionals (P<0.001) to believe that assessing medication adherence and inhaler technique could improve asthma control. Conclusion: Our data provide strong support for mHealth for asthma self-management, but highlight fundamental differences between the perspectives of patients and healthcare professionals.3

In the heart, Na/K-ATPase regulates intracellular Na+ and Ca2 + (via NCX), thereby preventing Na+ and Ca2 + overload and arrhythmias. Here, we test the hypothesis that nitric oxide (NO) regulates cardiac intracellular Na+ and Ca2 + and investigate mechanisms and physiological consequences involved. Effects of both exogenous NO (via NO-donors) and endogenously synthesized NO (via field-stimulation of ventricular myocytes) were assessed in this study. Field stimulation of rat ventricular myocytes significantly increased endogenous NO (18 ± 2 μM), PKCε activation (82 ± 12%), phospholemman phosphorylation (at Ser-63 and Ser-68) and Na/K-ATPase activity (measured by DAF-FM dye, western-blotting and biochemical assay, respectively; p < 0.05, n = 6) and all were abolished by Ca2 +-chelation (EGTA 10 mM) or NOS inhibition l-NAME (1 mM). Exogenously added NO (spermine-NONO-ate) stimulated Na/K-ATPase (EC50 = 3.8 μM; n = 6/grp), via decrease in Km, in PLMWT but not PLMKO or PLM3SA myocytes (where phospholemman cannot be phosphorylated) as measured by whole-cell perforated-patch clamp. Field-stimulation with l-NAME or PKC-inhibitor (2 μM Bis) resulted in elevated intracellular Na+ (22 ± 1.5 and 24 ± 2 respectively, vs. 14 ± 0.6 mM in controls) in SBFI-AM-loaded rat myocytes. Arrhythmia incidence was significantly increased in rat hearts paced in the presence of l-NAME (and this was reversed by l-arginine), as well as in PLM3SA mouse hearts but not PLMWT and PLMKO. We provide physiological and biochemical evidence for a novel regulatory pathway whereby NO activates Na/K-ATPase via phospholemman phosphorylation and thereby limits Na+ and Ca2 + overload and arrhythmias. This article is part of a Special Issue entitled “Na+ Regulation in Cardiac Myocytes”.

No abstract

The diagnosis of asthma is currently based on clinical history, physical examination and lung function, and to date, there are no accurate objective tests either to confirm the diagnosis or to discriminate between different types of asthma. This consensus exercise reviews the state of the art in asthma diagnosis to identify opportunities for future investment based on the likelihood of their successful development, potential for widespread adoption and their perceived impact on asthma patients. Using a two-stage e-Delphi process and a summarizing workshop, a group of European asthma experts including health professionals, researchers, people with asthma and industry representatives ranked the potential impact of research investment in each technique or tool for asthma diagnosis and monitoring. After a systematic review of the literature, 21 statements were extracted and were subject of the two-stage Delphi process. Eleven statements were scored 3 or more and were further discussed and ranked in a face-to-face workshop. The three most important diagnostic/predictive tools ranked were as follows: "New biological markers of asthma (eg genomics, proteomics and metabolomics) as a tool for diagnosis and/or monitoring," "Prediction of future asthma in preschool children with reasonable accuracy" and "Tools to measure volatile organic compounds (VOCs) in exhaled breath."

No abstract