Soluble receptor for advanced glycation end products in COPD: relationship with emphysema and chronic cor pulmonale: a case-control study

<p>Abstract</p> <p>Background</p> <p>The receptor for advanced glycation end products (RAGE) is a multiligand signal transduction receptor that can initiate and perpetuate inflammation. Its soluble isoform (sRAGE) acts as a decoy receptor for RAGE ligands, and is thought to afford protection against inflammation. With the present study, we aimed at determining whether circulating sRAGE is correlated with emphysema and chronic cor pulmonale in chronic obstructive pulmonary disease (COPD).</p> <p>Methods</p> <p>In 200 COPD patients and 201 age- and sex-matched controls, we measured lung function by spirometry, and sRAGE by ELISA method. We also measured the plasma levels of two RAGE ligands, N-epsilon-carboxymethyl lysine and S100A12, by ELISA method. In the COPD patients, we assessed the prevalence and severity of emphysema by computed tomography (CT), and the prevalence of chronic cor pulmonale by echocardiography. Multiple quantile regression was used to assess the effects of emphysema, chronic cor pulmonale, smoking history, and comorbid conditions on the three quartiles of sRAGE.</p> <p>Results</p> <p>sRAGE was significantly lower (p = 0.007) in COPD patients (median 652 pg/mL, interquartile range 484 to 1076 pg/mL) than in controls (median 869 pg/mL, interquartile range 601 to 1240 pg/mL), and was correlated with the severity of emphysema (p < 0.001), the lower the level of sRAGE the greater the degree of emphysema on CT. The relationship remained statistically significant after adjusting for smoking history and comorbid conditions. In addition, sRAGE was significantly lower in COPD patients with chronic cor pulmonale than in those without (p = 0.002). Such difference remained statistically significant after adjusting for smoking history, comorbidities, and emphysema severity. There was no significant difference in the plasma levels of the two RAGE ligands between cases and controls.</p> <p>Conclusions</p> <p>sRAGE is significantly lower in patients with COPD than in age- and sex-matched individuals without airflow obstruction. Emphysema and chronic cor pulmonale are independent predictors of reduced sRAGE in COPD.</p

Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5)

Abstract Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA) focuses on the integrated care of chronic diseases. Area 5 (Care Pathways) was initiated using chronic respiratory diseases as a model. The chronic respiratory disease action plan includes (1) AIRWAYS integrated care pathways (ICPs), (2) the joint initiative between the Reference site MACVIA-LR (Contre les MAladies Chroniques pour un VIeillissement Actif) and ARIA (Allergic Rhinitis and its Impact on Asthma), (3) Commitments for Action to the European Innovation Partnership on Active and Healthy Ageing and the AIRWAYS ICPs network. It is deployed in collaboration with the World Health Organization Global Alliance against Chronic Respiratory Diseases (GARD). The European Innovation Partnership on Active and Healthy Ageing has proposed a 5-step framework for developing an individual scaling up strategy: (1) what to scale up: (1-a) databases of good practices, (1-b) assessment of viability of the scaling up of good practices, (1-c) classification of good practices for local replication and (2) how to scale up: (2-a) facilitating partnerships for scaling up, (2-b) implementation of key success factors and lessons learnt, including emerging technologies for individualised and predictive medicine. This strategy has already been applied to the chronic respiratory disease action plan of the European Innovation Partnership on Active and Healthy Ageing

Altered effector function of peripheral cytotoxic cells in COPD

<p>Abstract</p> <p>Background</p> <p>There is mounting evidence that perforin and granzymes are important mediators in the lung destruction seen in COPD. We investigated the characteristics of the three main perforin and granzyme containing peripheral cells, namely CD8⁺T lymphocytes, natural killer (NK; CD56⁺CD3^-) cells and NKT-like (CD56⁺CD3⁺) cells.</p> <p>Methods</p> <p>Peripheral blood mononuclear cells (PBMCs) were isolated and cell numbers and intracellular granzyme B and perforin were analysed by flow cytometry. Immunomagnetically selected CD8+ T lymphocytes, NK (CD56⁺CD3^-) and NKT-like (CD56⁺CD3⁺) cells were used in an LDH release assay to determine cytotoxicity and cytotoxic mechanisms were investigated by blocking perforin and granzyme B with relevant antibodies.</p> <p>Results</p> <p>The proportion of peripheral blood NKT-like (CD56⁺CD3⁺) cells in smokers with COPD (COPD subjects) was significantly lower (0.6%) than in healthy smokers (smokers) (2.8%, p < 0.001) and non-smoking healthy participants (HNS) (3.3%, p < 0.001). NK (CD56⁺CD3^-) cells from COPD subjects were significantly less cytotoxic than in smokers (16.8% vs 51.9% specific lysis, p < 0.001) as were NKT-like (CD56⁺CD3⁺) cells (16.7% vs 52.4% specific lysis, p < 0.001). Both cell types had lower proportions expressing both perforin and granzyme B. Blocking the action of perforin and granzyme B reduced the cytotoxic activity of NK (CD56⁺CD3^-) and NKT-like (CD56⁺CD3⁺) cells from smokers and HNS.</p> <p>Conclusion</p> <p>In this study, we show that the relative numbers of peripheral blood NK (CD56⁺CD3^-) and NKT-like (CD56⁺CD3⁺) cells in COPD subjects are reduced and that their cytotoxic effector function is defective.</p

HD 191939 revisited: New and refined planet mass determinations, and a new planet in the habitable zone

HD 191939 (TOI-1339) is a nearby (d=54pc), bright (V=9mag), and inactive Sun-like star (G9 V) known to host a multi-planet transiting system. Ground-based spectroscopic observations confirmed the planetary nature of the three transiting sub-Neptunes (HD 191939 b, c, and d) originally detected by TESS and were used to measure the masses for planets b and c with 3$\sigma$ precision. These previous observations also reported the discovery of an additional Saturn-mass planet (HD 191939 e) and evidence for a further, very long-period companion (HD 191939 f). Here, we report the discovery of a new non-transiting planet in the system and a refined mass determination of HD 191939 d. The new planet, HD 191939 g, has a minimum mass of 13.5$\pm$2.0 M$_\oplus$ and a period of about 280 d. This period places the planet within the conservative habitable zone of the host star, and near a 1:3 resonance with HD 191939 e. The compilation of 362 radial velocity measurements with a baseline of 677 days from four different high-resolution spectrographs also allowed us to refine the properties of the previously known planets, including a 4.6$\sigma$ mass determination for planet d, for which only a 2$\sigma$ upper limit had been set until now. We confirm the previously suspected low density of HD 191939 d, which makes it an attractive target for attempting atmospheric characterisation. Overall, the planetary system consists of three sub-Neptunes interior to a Saturn-mass and a Uranus-mass planet plus a high-mass long-period companion. This particular configuration has no counterpart in the literature and makes HD 191939 an exceptional multi-planet transiting system with an unusual planet demographic worthy of future observation.Comment: Accepted for publication in A&A. 20 pages, 8 figure

HD 191939 revisited: New and refined planet mass determinations, and a new planet in the habitable zone

HD 191939 (TOI-1339) is a nearby (d = 54 pc), bright (V = 9 mag), and inactive Sun-like star (G9 V) known to host a multi-planet transiting system. Ground-based spectroscopic observations confirmed the planetary nature of the three transiting sub-Neptunes (HD 191939 b, c, and d) originally detected by TESS and were used to measure the masses for planets b and c with 3\ucf precision. These previous observations also reported the discovery of an additional Saturn-mass planet (HD 191939 e) and evidence for a further, very long-period companion (HD 191939 f). Here, we report the discovery of a new non-transiting planet in the system and a refined mass determination of HD 191939 d. The new planet, HD 191939 g, has a minimum mass of 13.5\ub12.0 M- and a period of about 280 days. This period places the planet within the conservative habitable zone of the host star, and near a 1:3 resonance with HD 191939 e. The compilation of 362 radial velocity measurements with a baseline of 677 days from four different high-resolution spectrographs also allowed us to refine the properties of the previously known planets, including a 4.6\ucf mass determination for planet d, for which only a 2\ucf upper limit had been set until now. We confirm the previously suspected low density of HD 191939 d, which makes it an attractive target for attempting atmospheric characterisation. Overall, the planetary system consists of three sub-Neptunes interior to a Saturn-mass and a Uranus-mass planet plus a high-mass long-period companion. This particular configuration has no counterpart in the literature and makes HD 191939 an exceptional multi-planet transiting system with an unusual planet demographic worthy of future observation

HIV testing within general practices in Europe : A mixed-methods systematic review

Funding Information: This work was supported by IWT (Belgium) and the ANRS (France) through the framework of HIVERA JTC 2014. Publisher Copyright: © 2018 The Author(s).Background: Late diagnosis of HIV infection remains a key challenge in Europe. It is acknowledged that general practitioners (GPs) may contribute greatly to early case finding, yet there is evidence that many diagnostic opportunities are being missed. To further promote HIV testing in primary care and to increase the utility of available research, the existing evidence has been synthesised in a systematic review adhering to the PRISMA guidelines. Methods: The databases PubMed, Scopus and Embase were searched for the period 2006-2017. Two authors judged independently on the eligibility of studies. Through a mixed-methods systematic review of 29 studies, we provide a description of HIV testing in general practices in Europe, including barriers and facilitators. Results: The findings of the study show that although various approaches to target patients are used by GPs, most tests are still carried out based on the patient's request. Several barriers obstruct HIV testing in general practice. Included are a lack of communication skills on sexual health, lack of knowledge about HIV testing recommendations and epidemic specificities, difficulties with using the complete list of clinical HIV indicator diseases and lack of experience in delivering and communicating test results. The findings also suggest that the provision of specific training, practical tools and promotion programmes has an impact on the testing performance of GPs. Conclusions: GPs could have an increased role in provider-initiated HIV-testing for early case finding. To achieve this objective, solutions to the reported barriers should be identified and testing criteria adapted to primary healthcare defined. Providing guidance and training to better identify priority groups for HIV testing, as well as information on the HIV epidemic's characteristics, will be fundamental to increasing awareness and testing by GPs.publishersversionPeer reviewe

Immunomodulatory strategies prevent the development of autoimmune emphysema

<p>Abstract</p> <p>Background</p> <p>The presence of anti-endothelial cell antibodies and pathogenic T cells may reflect an autoimmune component in the pathogenesis of emphysema. Whether immune modulatory strategies can protect against the development of emphysema is not known.</p> <p>Methods</p> <p>Sprague Dawley rats were immunized with human umbilical vein endothelial cells (HUVEC) to induce autoimmune emphysema and treated with intrathymic HUVEC-injection and pristane. Measurements of alveolar airspace enlargement, cytokine levels, immuno histochemical, western blot analysis, and T cell repertoire of the lung tissue were performed.</p> <p>Results</p> <p>The immunomodulatory strategies protected lungs against cell death as demonstrated by reduced numbers of TUNEL and active caspase-3 positive cells and reduced levels of active caspase-3, when compared with lungs from HUVEC-immunized rats. Immunomodulatory strategies also suppressed anti-endothelial antibody production and preserved CNTF, IL-1alpha and VEGF levels. The immune deviation effects of the intrathymic HUVEC-injection were associated with an expansion of CD4+CD25+Foxp3+ regulatory T cells. Pristane treatment decreased the proportion of T cells expressing receptor beta-chain, Vβ16.1 in the lung tissue.</p> <p>Conclusions</p> <p>Our data demonstrate that interventions classically employed to induce central T cell tolerance (thymic inoculation of antigen) or to activate innate immune responses (pristane treatment) can prevent the development of autoimmune emphysema.</p

CD8 positive T cells express IL-17 in patients with chronic obstructive pulmonary disease

<p>Abstract</p> <p>Background</p> <p>Chronic obstructive pulmonary disease (COPD) is a progressive and irreversible chronic inflammatory disease of the lung. The nature of the immune reaction in COPD raises the possibility that IL-17 and related cytokines may contribute to this disorder. This study analyzed the expression of IL-17A and IL-17F as well as the phenotype of cells producing them in bronchial biopsies from COPD patients.</p> <p>Methods</p> <p>Bronchoscopic biopsies of the airway were obtained from 16 COPD subjects (GOLD stage 1-4) and 15 control subjects. Paraffin sections were used for the investigation of IL-17A and IL-17F expression in the airways by immunohistochemistry, and frozen sections were used for the immunofluorescence double staining of IL-17A or IL-17F paired with CD4 or CD8. In order to confirm the expression of IL-17A and IL-17F at the mRNA level, a quantitative RT-PCR was performed on the total mRNA extracted from entire section or CD8 positive cells selected by laser capture microdissection.</p> <p>Results</p> <p>IL-17F immunoreactivity was significantly higher in the bronchial biopsies of COPD patients compared to control subjects (<it>P </it>< 0.0001). In the submucosa, the absolute number of both IL-17A and IL-17F positive cells was higher in COPD patients (<it>P </it>< 0.0001). After adjusting for the total number of cells in the submucosa, we still found that more cells were positive for both IL-17A (<it>P </it>< 0.0001) and IL-17F (<it>P </it>< 0.0001) in COPD patients compared to controls. The mRNA expression of IL-17A and IL-17F in airways of COPD patients was confirmed by RT-PCR. The expression of IL-17A and IL-17F was co-localized with not only CD4 but also CD8, which was further confirmed by RT-PCR on laser capture microdissection selected CD8 positive cells.</p> <p>Conclusion</p> <p>These findings support the notion that Th17 cytokines could play important roles in the pathogenesis of COPD, raising the possibility of using this mechanism as the basis for novel therapeutic approaches.</p