Severe pulmonary arterial hypertension is characterized by increased neutrophil elastase and relative elafin deficiency

BACKGROUND: Preclinical evidence implicates neutrophil elastase (NE) in PAH pathogenesis, and the NE inhibitor elafin is under early therapeutic investigation. RESEARCH QUESTION: Are circulating NE and elafin levels abnormal in PAH and associated with clinical severity? STUDY DESIGN/METHODS: . In an observational Stanford University PAH cohort (N=249), plasma NE and elafin were measured in comparison to healthy controls (N=106) then related to clinical features and relevant ancillary biomarkers. Cox regression models were fitted with cubic spline functions to associate NE and elafin with survival. To validate prognostic relationships, we analyzed two United Kingdom cohorts (N=75, N=357). Mixed effects models evaluated NE and elafin changes during disease progression. Finally, we studied effects of NE/elafin balance on pulmonary artery endothelial cells (PAECs) from PAH patients. RESULTS: Relative to controls, patients had increased NE (205.1 [123.6-387.3] vs. 97.6 [74.4-126.6] ng/mL, P168.5 ng/mL portended increased mortality risk after adjustment for known clinical predictors (HR 2.52, CI 1.36-4.65, P=0.003) or prognostic cytokines (HR 2.63, CI 1.42-4.87, P=0.001), and NE added incremental value to established PAH risk scores. Similar prognostic thresholds were identified in validation cohorts. Longitudinal NE changes tracked with clinical trends and outcomes. PAH-PAECs exhibited increased apoptosis and attenuated angiogenesis when exposed to NE at the level observed in patients' blood. Elafin rescued PAEC homeostasis, yet the required dose exceeded levels found in patients. INTERPRETATION: NE is increased and elafin deficient across PAH subtypes. NE associates with disease severity and outcomes, and this target-specific biomarker could facilitate therapeutic development of elafin

Patient characteristics, comorbidities, and medication use for children with ADHD with and without a co-occurring reading disorder: A retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) often have a co-occurring reading disorder (RD). The purpose of this research was to assess differences between children with ADHD without RD (ADHD-only) and those with ADHD and co-occurring RD (ADHD+RD).</p> <p>Methods</p> <p>Using data from the U.S. Thomson Reuter Marketscan^®Databases for the years 2005 through 2007, this analysis compared the medical records--including patient demographics, comorbidities, and medication use--of children (age < 18) with ADHD-only to those with ADHD+RD.</p> <p>Results</p> <p>Patients with ADHD+RD were significantly younger, more likely to have received a procedure code associated with formal psychological or non-psychological testing, and more likely to have been diagnosed with comorbid bipolar disorder, conduct disorder, or depression. They were no more likely to have received an antidepressant, anti-manic (bipolar), or antipsychotic, and were significantly less likely to have received a prescription for a stimulant medication.</p> <p>Conclusions</p> <p>Relying on a claims database, there appear to be differences in the patient characteristics, comorbidities, and medication use when comparing children with ADHD-only to those with ADHD+RD.</p

Coxiella burnetii, the Agent of Q Fever, Replicates within Trophoblasts and Induces a Unique Transcriptional Response

Q fever is a zoonosis caused by Coxiella burnetii, an obligate intracellular bacterium typically found in myeloid cells. The infection is a source of severe obstetrical complications in humans and cattle and can undergo chronic evolution in a minority of pregnant women. Because C. burnetii is found in the placentas of aborted fetuses, we investigated the possibility that it could infect trophoblasts. Here, we show that C. burnetii infected and replicated in BeWo trophoblasts within phagolysosomes. Using pangenomic microarrays, we found that C. burnetii induced a specific transcriptomic program. This program was associated with the modulation of inflammatory responses that were shared with inflammatory agonists, such as TNF, and more specific responses involving genes related to pregnancy development, including EGR-1 and NDGR1. In addition, C. burnetii stimulated gene networks organized around the IL-6 and IL-13 pathways, which both modulate STAT3. Taken together, these results revealed that trophoblasts represent a protective niche for C. burnetii. The activation program induced by C. burnetii in trophoblasts may allow bacterial replication but seems unable to interfere with the development of normal pregnancy. Such pathophysiologocal processes should require the activation of immune placental cells associated with trophoblasts

Metabolomic analysis of human disease and its application to the eye

Metabolomics, the analysis of the metabolite profile in body fluids or tissues, is being applied to the analysis of a number of different diseases as well as being used in following responses to therapy. While genomics involves the study of gene expression and proteomics the expression of proteins, metabolomics investigates the consequences of the activity of these genes and proteins. There is good reason to think that metabolomics will find particular utility in the investigation of inflammation, given the multi-layered responses to infection and damage that are seen. This may be particularly relevant to eye disease, which may have tissue specific and systemic components. Metabolomic analysis can inform us about ocular or other body fluids and can therefore provide new information on pathways and processes involved in these responses. In this review, we explore the metabolic consequences of disease, in particular ocular conditions, and why the data may be usefully and uniquely assessed using the multiplexed analysis inherent in the metabolomic approach

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Regime Type, Inequality, and Redistributive Transfers in Developing Countries

The debate on whether democracy and inequality increase the level of redistribution in a country is still ongoing. We construct a model that predicts a higher probability of redistribution in democracies than in autocracies. Further, with higher initial inequality, there should be more redistribution in democracies but not necessarily in autocracies. We test these predictions using data on social transfers in developing countries for the period 1960-2010. We confirm that democracy increases redistribution and, to some extent, that there is more redistribution with rising inequality. Hence, on the basis of a direct measure of redistribution, we present evidence to confirm the median voter theorem

Evaluation of a real-time virtual intervention to empower persons living with HIV to use therapy self-management: study protocol for an online randomized controlled trial

Background: Living with HIV makes considerable demands on a person in terms of self-management, especially as regards adherence to treatment and coping with adverse side-effects. The online HIV Treatment, Virtual Nursing Assistance and Education (Virus de I'immunodeficience Humaine-Traitement Assistance Virtuelle Infirmiere et Enseignement; VIH-TAVIE (TM)) intervention was developed to provide persons living with HIV (PLHIV) with personalized follow-up and real-time support in managing their medication intake on a daily basis. An online randomized controlled trial (RCT) will be conducted to evaluate the efficacy of this intervention primarily in optimizing adherence to combination anti-retroviral therapy (ART) among PLHIV.Methods/design: A convenience sample of 232 PLHIV will be split evenly and randomly between an experimental group that will use the web application, and a control group that will be handed a list of websites of interest. Participants must be aged 18 years or older, have been on ART for at least 6 months, and have internet access. The intervention is composed of four interactive computer sessions of 20 to 30 minutes hosted by a virtual nurse who engages the PLHIV in a skills-learning process aimed at improving self-management of medication intake. Adherence constitutes the principal outcome, and is defined as the intake of at least 95% of the prescribed tablets. The following intermediary measures will be assessed: self-efficacy and attitude towards antiretroviral medication, symptom-related discomfort, and emotional support. There will be three measurement times: baseline (T0), after 3 months (T3) and 6 months (T6) of baseline measurement. The principal analyses will focus on comparing the two groups in terms of treatment adherence at the end of follow-up at T6. An intention-to-treat (ITT) analysis will be carried out to evaluate the true value of the intervention in a real context.Discussion: Carrying out this online RCT poses various challenges in terms of recruitment, ethics, and data collection, including participant follow-up over an extended period. Collaboration between researchers from clinical disciplines (nursing, medicine), and experts in behavioral sciences information technology and media will be crucial to the development of innovative solutions to supplying and delivering health services

Industry agglomeration, sub-national institutions and the profitability of foreign subsidiaries

This study investigates the impact of agglomeration and its interaction with subnational institutions on the profitability of multinational enterprises (MNEs) subsidiaries operating in an emerging economy. We argue that in an emerging economy like China, competition in product and factor markets is more intense between foreign firms than between foreign and domestic firms owing to market segmentation. Consequently, agglomerating with other foreign firms has negative impact on the profitability of foreign subsidiaries. In contrast, foreign firms agglomerating with domestic firms may reap gains owing to less competition and improved access to local resources and knowledge. We find that these effects are more pronounced to domestic-market-oriented foreign firms. Furthermore, sub-national institutions moderate the above relationships. Our arguments are supported by the empirical analysis based on a comprehensive dataset of foreign firms operating in China over the period of 1999-2005