Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis.

RATIONALE: Systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) portends worse outcome than other forms of PAH. Vasoconstrictive and vascular remodeling actions of endothelin (ET) 1 and angiotensin (Ang) II via endothelin receptor type A (ETAR) and Ang receptor type-1 (AT1R) activation are implicated in PAH pathogenesis. OBJECTIVES: We hypothesized that stimulating autoantibodies (Abs) targeting and activating AT1R and ETAR may contribute to SSc-PAH pathogenesis, and tested their functional and biomarker relevance. METHODS: Anti-AT1R and -ETAR Abs were detected by ELISA in different cohorts of patients and tested in vitro and in an animal model for their pathophysiological effects. MEASUREMENTS AND MAIN RESULTS: The Abs were significantly higher and more prevalent in patients with SSc-PAH (n = 81) and connective tissue disease-associated PAH (n = 110) compared with other forms of PAH/pulmonary hypertension (n = 106). High anti-AT1R and anti-ETAR Abs predicted development of SSc-PAH and SSc-PAH-related mortality in a prospective analysis. Both Abs increased endothelial cytosolic Ca(2+) concentrations in isolated perfused rat lungs, which could be blocked by respective specific receptor antagonists. Ab-mediated stimulation of intralobar pulmonary rat artery ring segments increased vasoconstrictive responses to Ang II and ET-1, and implicated cross-talk between both pathways demonstrated by reciprocal blockade with respective antagonists. Transfer of SSc-IgG containing both autoantibodies into healthy C57BL/6J mice led to more abundant vascular and airway α-smooth muscle actin expression and inflammatory pulmonary vasculopathy. CONCLUSIONS: Anti-AT1R and -ETAR Abs are more frequent in SSc-PAH/connective tissue disease-PAH compared with other forms of pulmonary hypertension, and serve as predictive and prognostic biomarkers in SSc-PAH. Both antibodies may contribute to SSc-PAH via increased vascular endothelial reactivity and induction of pulmonary vasculopathy.

Experimental study on high-purity hydrogen generation from synthetic biogas in a 10 kW fixed-bed chemical looping system.

The utilization of locally available renewable resources is crucial for the creation of a sustainable energy system in the future. Biogas, a product of the anaerobic digestion of biogenic residues, exhibits great potential as feedstock to generate hydrogen for fuel cell mobility applications. A 10 kW fixed-bed chemical looping research system, to-date the largest in the world, was operated to prove the applicability of this versatile process for synthetic biogas utilization. In this experimental study, the focus was laid on examining the influence of different operating parameters (biogas composition, steam co-feeding, process temperature) on the attainable hydrogen purity and system efficiency. The generated hydrogen, between 90 to 230 g per cycle, was characterized online by ppm-range gas analysis and exhibited a product gas quality between 99.8% and 99.998%. The difference observed is attributed to carbon deposition if synthetic biogas with an increased share of carbon dioxide was supplied. This study involved the longest uninterrupted period of operation of a lab prototype system for fixed-bed chemical looping with 250 hours of time-on-stream, four months of discontinuous service and 50 consecutive experimental cycles.

Prostate Cancer Prevention Trial risk calculator 2.0 for the prediction of low- vs high-grade prostate cancer.

OBJECTIVE: To modify the Prostate Cancer Prevention Trial risk calculator (PCPTRC) to predict low- vs high-grade (Gleason grade≥7) prostate cancer and incorporate percent free-prostate-specific antigen (PSA). METHODS: Data from 6664 Prostate Cancer Prevention Trial placebo arm biopsies (5826 individuals), where prostate-specific antigen and digital rectal examination results were available within 1 year before the biopsy and PSA was ≤10 ng/mL, were used to develop a nominal logistic regression model to predict the risk of no vs low-grade (Gleason grade<7) vs high-grade cancer (Gleason grade≥7). Percent free-PSA was incorporated into the model based on likelihood ratio analysis of a San Antonio Biomarkers of Risk cohort. Models were externally validated on 10 Prostate Biopsy Collaborative Group cohorts and 1 Early Detection Research Network reference set. RESULTS: Of all the Prostate Cancer Prevention Trial biopsies, 5468 (82.1%) were negative for prostate cancer, 942 (14.1%) detected low-grade, and 254 (3.8%) detected high-grade disease. Significant predictors were (log base 2) PSA (odds ratio for low-grade vs no cancer, 1.29*; high-grade vs no cancer, 2.02*; high-grade vs low-grade cancer, 1.57*), digital rectal examination (0.96, 1.49*, 1.55*, respectively), age (1.02*, 1.05*, 1.03*, respectively), African American race (1.13, 2.83*, 2.51*, respectively), prior biopsy (0.63*, 0.81, 1.27, respectively), and family history (1.31*, 1.25, 0.95, respectively), where * indicates P value<.05. The new PCPTRC 2.0 either with or without percent free-PSA (also significant by the likelihood ratio method) validated well externally. CONCLUSION: By differentiating the risk of low- vs high-grade disease on biopsy, PCPTRC 2.0 better enables physician-patient counseling concerning whether to proceed to biopsy.