Explore the vast range of titles available.

Asthma is a heterogeneous disease with variability among patients in characteristics such as lung function, symptoms and control, body weight, markers of inflammation, and responsiveness to glucocorticoids (GC). Cluster analysis of well-characterized cohorts can advance understanding of disease subgroups in asthma and point to unsuspected disease mechanisms. We utilized an hypothesis-free cluster analytical approach to define the contribution of obesity and related variables to asthma phenotype. In a cohort of clinical trial participants (n = 250), minimum-variance hierarchical clustering was used to identify clinical and inflammatory biomarkers important in determining disease cluster membership in mild and moderate persistent asthmatics. In a subset of participants, GC sensitivity was assessed via expression of GC receptor alpha (GCRα) and induction of MAP kinase phosphatase-1 (MKP-1) expression by dexamethasone. Four asthma clusters were identified, with body mass index (BMI, kg/m(2)) and severity of asthma symptoms (AEQ score) the most significant determinants of cluster membership (F = 57.1, p<0.0001 and F = 44.8, p<0.0001, respectively). Two clusters were composed of predominantly obese individuals; these two obese asthma clusters differed from one another with regard to age of asthma onset, measures of asthma symptoms (AEQ) and control (ACQ), exhaled nitric oxide concentration (F(E)NO) and airway hyperresponsiveness (methacholine PC(20)) but were similar with regard to measures of lung function (FEV(1) (%) and FEV(1)/FVC), airway eosinophilia, IgE, leptin, adiponectin and C-reactive protein (hsCRP). Members of obese clusters demonstrated evidence of reduced expression of GCRα, a finding which was correlated with a reduced induction of MKP-1 expression by dexamethasone Obesity is an important determinant of asthma phenotype in adults. There is heterogeneity in expression of clinical and inflammatory biomarkers of asthma across obese individuals. Reduced expression of the dominant functional isoform of the GCR may mediate GC insensitivity in obese asthmatics.

Pulmonary arterial hypertension (PAH) is a chronic condition of elevated pulmonary arterial pressures with associated increases in pulmonary vascular resistance leading to right ventricular failure, which was almost uniformly fatal prior to the introduction of pulmonary hypertension specific therapy. Systemic prostacyclin analogs are the first PAH-specific therapies to be made available and are typically recommended as first-line therapy for subjects with severe disease. Treprostinil is a newer prostacyclin analog similar to epoprostenol in its mechanism of action and relative efficacy with the advantage of a longer half life in human serum and room temperature stability. It is unique in that it is available in multiple formulations for alternative routes of delivery, including subcutaneous, intravenous and inhalational routes. Additionally, oral treprostinil is currently under investigation. Both subcutaneous and intravenous forms of treprostinil have demonstrated efficacy in short-term clinical trials and are currently approved for use in subjects with PAH and New York Heart Association functional class (NYHA FC) II–IV symptoms in the USA and for subjects with NYHA FC III and IV in Europe. Inhaled treprostinil has also demonstrated efficacy in short-term clinical trials primarily as add-on therapy and is currently approved for use in subjects with PAH and NYHA FC III–IV symptoms in the USA and Europe. The different formulations of treprostinil have significantly increased the treatment options and opportunities for treatment of patients with PAH.

E. RAND SUTHERLAND, ELENA GOLEVA, TONYA S. KING, ERIK LEHMAN, ALLEN D. STEVENS, LEISA P. JACKSON, AMANDA R. STREAM, JOHN V. FAHY, and DONALD Y. M. LEUNG FOR THE ASTHMA CLINICAL RESEARCH NETWORK11.1 INTRODUCTIONCluster analyses of cross-sectional data from clinical populations have identified phenotypic subsets of patients with asthma, and the assessment of BMI in recent asthma cluster analyses has allowed assessment of the relationship of BMI to clinical features of asthma. Haldar and colleagues reported that obesity was associated with increased symptom expression, reduced eosinophilic airway inflammation, adult age of onset, and female sex, while also being associated with reduced clinical responsiveness to inhaled corticosteroids (ICS) [1]. A separate cluster analysis of patients participating in the NIH Severe Asthma Research Program indicated that elevated body mass index (BMI) was associated with specific clinical features in severe asthma, with the identification of a cluster of patients inwhom elevated BMI was associated with female sex, adult onset asthma, a greater likelihood of complicated asthma treatment regimens, and more frequent health care utilization and need for systemic glucocorticoids (GC) [2]. These two studies have supported the conclusion that asthma phenotype is relatively homogenous in obese patients, with high symptom expression, low atopy and airway eosinophilia, and relative insensitivity to GC, a phenomenon that has been reported by others in both clinical [3]–[5] and in vitro [6] settings.