The single-scattering properties of black carbon aggregates determined from the geometric-optics surface-wave approach and the T-matrix method

The single-scattering properties of eight black carbon (BC, soot) fractal aggregates, composed of primary spheres from 7 to 600, computed by the geometric-optics surface-wave (GOS) approach coupled with the Rayleigh-Gans-Debye (RGD) adjustment for size parameters smaller than approximately 2, are compared with those determined from the superposition T-matrix method. We show that under the condition of random orientation, the results from GOS/RGD are in general agreement with those from T-matrix in terms of the extinction and absorption cross-sections, the single-scattering co-albedo, and the asymmetry factor. When compared with the specific absorption (m(2)/g) measured in the laboratory, we illustrate that using the observed radii of primary spheres ranging from 3.3 to 25 nm, the theoretical values determined from GOS/RGD for primary sphere numbers of 100-600 are within the range of measured values. The GOS approach can be effectively applied to aggregates composed of a large number of primary spheres (e.g., > 6000) and large size parameters (>> 2) in terms of computational efforts

Associations of oxygenated hemoglobin with disease burden and prognosis in stable COPD : Results from COSYCONET

We studied whether in patients with stable COPD blood gases (BG), especially oxygenated hemoglobin (OxyHem) as a novel biomarker confer information on disease burden and prognosis and how this adds to the information provided by the comorbidity pattern and systemic inflammation. Data from 2137 patients (GOLD grades 1–4) of the baseline dataset of the COSYCONET COPD cohort were used. The associations with dyspnea, exacerbation history, BODE-Index (cut-off ≤2) and all-cause mortality over 3 years of follow-up were determined by logistic and Cox regression analyses, with sex, age, BMI and pack years as covariates. Predictive values were evaluated by ROC curves. Capillary blood gases included SaO2, PaO2, PaCO2, pH, BE and the concentration of OxyHem [haemoglobin (Hb) x fractional SaO2, g/dL] as a simple-to-measure correlate of oxygen content. Inflammatory markers were WBC, CRP, IL-6 and -8, TNF-alpha and fibrinogen, and comorbidities comprised a broad panel including cardiac and metabolic disorders. Among BG, OxyHem was associated with dyspnoea, exacerbation history, BODE-Index and mortality. Among inflammatory markers and comorbidities, only WBC and heart failure were consistently related to all outcomes. ROC analyses indicated that OxyHem provided information of a magnitude comparable to that of WBC, with optimal cut-off values of 12.5 g/dL and 8000/µL, respectively. Regarding mortality, OxyHem also carried independent, additional information, showing a hazard ratio of 2.77 (95% CI: 1.85–4.15, p  8000/µL was 2.33 (95% CI: 1.60–3.39, p < 0.0001). In stable COPD, the concentration of oxygenated hemoglobin provided additional information on disease state, especially mortality risk. OxyHem can be calculated from hemoglobin concentration and oxygen saturation without the need for the measurement of PaO2. It thus appears well suited for clinical use with minimal equipment, especially for GPs

Interferon regulatory factor 8-deficiency determines massive neutrophil recruitment but T cell defect in fast growing granulomas during tuberculosis

Following Mycobacterium tuberculosis (Mtb) infection, immune cell recruitment in lungs is pivotal in establishing protective immunity through granuloma formation and neogenesis of lymphoid structures (LS). Interferon regulatory factor-8 (IRF-8) plays an important role in host defense against Mtb, although the mechanisms driving anti-mycobacterial immunity remain unclear. In this study, IRF-8 deficient mice (IRF-8−/−) were aerogenously infected with a low-dose Mtb Erdman virulent strain and the course of infection was compared with that induced in wild-type (WT-B6) counterparts. Tuberculosis (TB) progression was examined in both groups using pathological, microbiological and immunological parameters. Following Mtb exposure, the bacterial load in lungs and spleens progressed comparably in the two groups for two weeks, after which IRF-8−/− mice developed a fatal acute TB whereas in WT-B6 the disease reached a chronic stage. In lungs of IRF-8−/−, uncontrolled growth of pulmonary granulomas and impaired development of LS were observed, associated with unbalanced homeostatic chemokines, progressive loss of infiltrating T lymphocytes and massive prevalence of neutrophils at late infection stages. Our data define IRF-8 as an essential factor for the maintenance of proper immune cell recruitment in granulomas and LS required to restrain Mtb infection. Moreover, IRF-8−/− mice, relying on a common human and mouse genetic mutation linked to susceptibility/severity of mycobacterial diseases, represent a valuable model of acute TB for comparative studies with chronically-infected congenic WT-B6 for dissecting protective and pathological immune reactions

The impact of COPD on polyneuropathy : results from the German COPD cohort COSYCONET

Background: Peripheral neuropathy is a common comorbidity in COPD. We aimed to investigate associations between alterations commonly found in COPD and peripheral neuropathy, with particular emphasize on the distinction between direct and indirect effects. Methods: We used visit 4 data of the COPD cohort COSYCONET, which included indicators of polyneuropathy (repeated tuning fork and monofilament testing), excluding patients with diabetes a/o increased HbA1c. These indicators were analysed for the association with COPD characteristics, including lung function, blood gases, 6-min walk distance (6-MWD), timed-up-and-go-test (TUG), exacerbation risk according to GOLD, C-reactive protein (CRP), and ankle-brachial index (ABI). Based on the results of conventional regression analyses adjusted for age, BMI, packyears and gender, we utilized structural equation modelling (SEM) to quantify the network of direct and indirect relationships between parameters. Results: 606 patients were eligible for analysis. The indices of polyneuropathy were highly correlated with each other and related to base excess (BE), ABI and TUG. ABI was linked to neuropathy and 6-MWD, exacerbations depended on FEV1, 6-MWD and CRP. The associations could be summarized into a SEM comprising polyneuropathy as a latent variable (PNP) with three measured indicator variables. Importantly, PNP was directly dependent on ABI and particularly on BE. When also including patients with diabetes and/or elevated values of HbA1c (n = 742) the SEM remained virtually the same. Conclusion: We identified BE and ABI as major determinants of peripheral neuropathy in patients with COPD. All other associations, particularly those with lung function and physical capacity, were indirect. These findings underline the importance of alterations of the micromilieu in COPD, in particular the degree of metabolic compensation and vascular status

Associations of oxygenated hemoglobin with disease burden and prognosis in stable COPD: Results from COSYCONET

We studied whether in patients with stable COPD blood gases (BG), especially oxygenated hemoglobin (OxyHem) as a novel biomarker confer information on disease burden and prognosis and how this adds to the information provided by the comorbidity pattern and systemic inflammation. Data from 2137 patients (GOLD grades 1-4) of the baseline dataset of the COSYCONET COPD cohort were used. The associations with dyspnea, exacerbation history, BODE-Index (cut-off 8000/mu L was 2.33 (95% CI: 1.60-3.39, p<0.0001). In stable COPD, the concentration of oxygenated hemoglobin provided additional information on disease state, especially mortality risk. OxyHem can be calculated from hemoglobin concentration and oxygen saturation without the need for the measurement of PaO2. It thus appears well suited for clinical use with minimal equipment, especially for GPs

Enhanced M1 Macrophage Polarization in Human Helicobacter pylori-Associated Atrophic Gastritis and in Vaccinated Mice

Background: Infection with Helicobacter pylori triggers a chronic gastric inflammation that can progress to atrophy and gastric adenocarcinoma. Polarization of macrophages is a characteristic of both cancer and infection, and may promote progression or resolution of disease. However, the role of macrophages and their polarization during H. pylori infection has not been well defined. Methodology/Principal Findings: By using a mouse model of infection and gastric biopsies from 29 individuals, we have analyzed macrophage recruitment and polarization during H. pylori infection by flow cytometry and real-time PCR. We found a sequential recruitment of neutrophils, eosinophils and macrophages to the gastric mucosa of infected mice. Gene expression analysis of stomach tissue and sorted macrophages revealed that gastric macrophages were polarized to M1 after H. pylori infection, and this process was substantially accelerated by prior vaccination. Human H. pylori infection was characterized by a mixed M1/M2 polarization of macrophages. However, in H. pylori-associated atrophic gastritis, the expression of inducible nitric oxide synthase was markedly increased compared to uncomplicated gastritis, indicative of an enhanced M1 macrophage polarization in this pre-malignant lesion. Conclusions/Significance: These results show that vaccination of mice against H. pylori amplifies M1 polarization of gastric macrophages, and that a similar enhanced M1 polarization is present in human H. pylori-induced atrophic gastritis

Expiratory Venous Volume and Arterial Tortuosity are Associated with Disease Severity and Mortality Risk in Patients with COPD: Results from COSYCONET

Mircea Gabriel Stoleriu,1,2,&ast; Michael Pienn,3,4,&ast; Rudolf A Joerres,5 Peter Alter,6 Tamas Fero,7 Martin Urschler,8 Gabor Kovacs,3,9 Horst Olschewski,3,9 Hans-Ulrich Kauczor,7,10 Mark Wielpütz,7,10 Bertram Jobst,7,10 Tobias Welte,11 Jürgen Behr,2,12 Franziska C Trudzinski,10,13 Robert Bals,14,15 Henrik Watz,16 Claus F Vogelmeier,6 Jürgen Biederer,10,17,18,&ast; Kathrin Kahnert2,12,19,&ast; On behalf of the COSYCONET Study Group1Division for Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich (LMU) and Asklepios Medical Center; Munich-Gauting, Gauting, 82131, Germany; 2Institute for Lung Health and Immunity and Comprehensive Pneumology Center with the CPC-M bioArchive; Helmholtz Center Munich; Member of the German Lung Research Center (DZL), Munich, 81377, Germany; 3Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; 4Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 5Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Hospital of Ludwig-Maximilians-University Munich (LMU), Munich, 80336, Germany; 6Department of Medicine, Pulmonary and Critical Care Medicine, University of Marburg (UMR), Member of the German Center for Lung Research (DZL), Marburg, 35033, Germany; 7Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany; 8Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria; 9University Clinic for Internal Medicine, Medical University of Graz, Division of Pulmonology, Graz, Austria; 10Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research DZL, Heidelberg, Germany; 11Department of Respiratory Medicine and Infectious Disease, Member of the German Center of Lung Research, Hannover School of Medicine, Hannover, Germany; 12Department of Medicine V, LMU University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany; 13Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Heidelberg, Germany; 14Department of Internal Medicine V-Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg, 66421, Germany; 15Helmholtz Institute for Pharmaceutical Research, Saarbrücken, 66123, Germany; 16Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Centre North, German Centre for Lung Research, Großhansdorf, Germany; 17Faculty of Medicine, Christian-Albrechts-Universität Zu Kiel, Kiel, Germany; 18University of Latvia, Faculty of Medicine, Riga, LV-1586, Latvia; 19MediCenterGermering, Germering, Germany&ast;These authors contributed equally to this workCorrespondence: Mircea Gabriel Stoleriu, Division of Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich (LMU) and Asklepios Lung Clinic Munich-Gauting, Marchioninistr. 15, 81377 Munich and Robert-Koch-Allee 2, Gauting, 82131, Germany, Tel +49 89 85791 4201, Email [email protected]: The aim of this study was to evaluate the association between computed tomography (CT) quantitative pulmonary vessel morphology and lung function, disease severity, and mortality risk in patients with chronic obstructive pulmonary disease (COPD).Patients and Methods: Participants of the prospective nationwide COSYCONET cohort study with paired inspiratory-expiratory CT were included. Fully automatic software, developed in-house, segmented arterial and venous pulmonary vessels and quantified volume and tortuosity on inspiratory and expiratory scans. The association between vessel volume normalised to lung volume and tortuosity versus lung function (forced expiratory volume in 1 sec [FEV1]), air trapping (residual volume to total lung capacity ratio [RV/TLC]), transfer factor for carbon monoxide (TLCO), disease severity in terms of Global Initiative for Chronic Obstructive Lung Disease (GOLD) group D, and mortality were analysed by linear, logistic or Cox proportional hazard regression.Results: Complete data were available from 138 patients (39% female, mean age 65 years). FEV1, RV/TLC and TLCO, all as % predicted, were significantly (p < 0.05 each) associated with expiratory vessel characteristics, predominantly venous volume and arterial tortuosity. Associations with inspiratory vessel characteristics were absent or negligible. The patterns were similar for relationships between GOLD D and mortality with vessel characteristics. Expiratory venous volume was an independent predictor of mortality, in addition to FEV1.Conclusion: By using automated software in patients with COPD, clinically relevant information on pulmonary vasculature can be extracted from expiratory CT scans (although not inspiratory scans); in particular, expiratory pulmonary venous volume predicted mortality.Trial Registration: NCT01245933.Keywords: COPD, computed tomography, pulmonary vasculature, vessel volume, vessel tortuosity, lung functio

Interferon Gamma Activated Macrophages Kill Mycobacteria by Nitric Oxide Induced Apoptosis

Mycobacterium tuberculosis is an intracellular pathogen of macrophages and escapes the macrophages' bactericidal effectors by interfering with phagosome-lysosome fusion. IFN-γ activation renders the macrophages capable of killing intracellular mycobacteria by overcoming the phagosome maturation block, nutrient deprivation and exposure to microbicidal effectors including nitric oxide (NO). While the importance about NO for the control of mycobacterial infection in murine macrophages is well documented, the underlying mechanism has not been revealed yet. In this study we show that IFN-γ induced apoptosis in mycobacteria-infected macrophages, which was strictly dependent on NO. Subsequently, NO-mediated apoptosis resulted in the killing of intracellular mycobacteria independent of autophagy. In fact, killing of mycobacteria was susceptible to the autophagy inhibitor 3-methyladenine (3-MA). However, 3-MA also suppressed NO production, which is an important off-target effect to be considered in autophagy studies using 3-MA. Inhibition of caspase 3/7 activation, as well as NO production, abolished apoptosis and elimination of mycobacteria by IFN-γ activated macrophages. In line with the finding that drug-induced apoptosis kills intracellular mycobacteria in the absence of NO, we identified NO-mediated apoptosis as a new defense mechanism of activated macrophages against M. tuberculosis

The chemokine receptor CXCR5 is pivotal for ectopic mucosa-associated lymphoid tissue neogenesis in chronic Helicobacter pylori-induced inflammation

Ectopic lymphoid follicles are a key feature of chronic inflammatory autoimmune and infectious diseases, such as rheumatoid arthritis, Sjögren's syndrome, and Helicobacter pylori-induced gastritis. Homeostatic chemokines are considered to be involved in the formation of such tertiary lymphoid tissue. High expression of CXCL13 and its receptor, CXCR5, has been associated with the formation of ectopic lymphoid follicles in chronic infectious diseases. Here, we defined the role of CXCR5 in the development of mucosal tertiary lymphoid tissue and gastric inflammation in a mouse model of chronic H. pylori infection. CXCR5-deficient mice failed to develop organized gastric lymphoid follicles despite similar bacterial colonization density as infected wild-type mice. CXCR5 deficiency altered Th17 responses but not Th1-type cellular immune responses to H. pylori infection. Furthermore, CXCR5-deficient mice exhibited lower H. pylori-specific serum IgG and IgA levels and an overall decrease in chronic gastric immune responses. In conclusion, the development of mucosal tertiary ectopic follicles during chronic H. pylori infection is strongly dependent on the CXCL13/CXCR5 signaling axis, and lack of de novo lymphoid tissue formation attenuates chronic immune responses