Extracellular superoxide dismutase (EC-SOD) is a tetramer composed of either intact (Trpfor Gly enabled us to test these hypotheses. The mutation does not prevent proteolysis of the ECM-binding region but prevents a carboxypeptidase B-like enzyme from trimming residues beyond Gly 213 . The R213G mutation is located in the ECM-binding region, and individuals carrying this mutation have an increased concentration of EC-SOD in the circulatory system. In this study, we purified the R213G EC-SOD variant from heterozygous or homozygous individuals and determined the C-terminal residue of the processed subunit to be Gly 213 . This finding supports the two-step processing mechanism and indicates that the R213G mutation does not disturb the initial endoproteinase cleavage event but perturbs the subsequent trimming of the C terminus.

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The characteristics that predict progression to overt chronic obstructive pulmonary disease (COPD) in smokers without spirometric airflow obstruction are not clearly defined.We conducted a post hoc analysis of 849 current and former smokers (≽20 pack-years) with preserved spirometry from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort who had baseline computed tomography (CT) scans of lungs and serial spirometry. We examined whether CT-derived lung volumes representing air trapping could predict adverse respiratory outcomes and more rapid decline in spirometry to overt COPD using mixed-effect linear modelling. Among these subjects with normal forced expiratory volume in 1 s (FEV 1 ) to forced vital capacity (FVC) ratio, CT-measured residual volume (RV CT ) to total lung capacity (TLC CT ) ratio varied widely, from 21% to 59%. Over 2.5±0.7 years of follow-up, subjects with higher RV CT /TLC CT had a greater differential rate of decline in FEV 1 /FVC; those in the upper RV CT /TLC CT tertile had a 0.66% (95% CI 0.06%-1.27%) faster rate of decline per year compared with those in the lower tertile (p=0.015) regardless of demographics, baseline spirometry, respiratory symptoms score, smoking status (former versus current) or smoking burden (pack-years). Accordingly, subjects with higher RV CT /TLC CT were more likely to develop spirometric COPD (OR 5.7 (95% CI 2.4-13.2) in upper versus lower RV CT /TLC CT tertile; p<0.001). Other CT indices of air trapping showed similar patterns of association with lung function decline; however, when all CT indices of air trapping, emphysema, and airway disease were included in the same model, only RV CT /TLC CT retained its significance.Increased air trapping based on radiographic lung volumes predicts accelerated spirometry decline and progression to COPD in smokers without obstruction.

Background Imaging based assessment of cardiovascular structure and function provides clinically relevant information in smokers. Non-cardiac gated thoracic computed tomographic (CT) scanning is increasingly leveraged for clinical care and lung cancer screening. We sought to determine if more comprehensive measures of ventricular geometry could be obtained from CT using an atlas based surface model of the heart. Methods Subcohorts of 24 subjects with cardiac MRI and 262 subjects with echocardiography were identified from COPDGene, a longitudinal observational study of smokers. A surface model of the heart was manually initialized, and then automatically optimized to fit the epicardium for each CT. Estimates of right and left ventricular (RV and LV) volume and free wall curvature were then calculated and compared with structural and functional metrics obtained from MRI and echocardiograms. Results CT measures of RV dimension and curvature correlated with similar measures obtained using MRI. RV and LV volume obtained from CT were inversely related with echocardiogrambased estimates of right ventricular systolic pressure using tricuspid regurgitation jet velocity (RVSP) and LV ejection fraction (LVEF) respectively. Patients with evidence of RV or LV dysfunction on echocardiogram had larger RV and LV dimensions on CT. Logistic regression models based on demographics and ventricular measures from CT had an area under the curve (AUC) of > 0.7 for the prediction of elevated RVSP and ventricular failure. These data suggest that non-cardiac gated, non-contrast enhanced thoracic CT scanning may provide insight into cardiac structure and function in smokers.

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