Gender-Specific Modulation of the Response to Arterial Injury by Soluble Guanylate Cyclase α1

Objective: Soluble guanylate cyclase (sGC), a heterodimer composed of α and β subunits, synthesizes cGMP in response to nitric oxide (NO). NO modulates vascular tone and structure but the relative contributions of cGMP-dependent versus cGMP-independent mechanisms remain uncertain. We studied the response to vascular injury in male (M) and female (F) mice with targeted deletion of exon 6 of the sGCα1 subunit (sGCα1-/-), resulting in a non-functional heterodimer. Methods: We measured aortic cGMP levels and mRNA transcripts encoding sGC α1, α2, and β1 subunits in wild type (WT) and sGCa1-/- mice. To study the response to vascular injury, BrdU-incorporation and neointima formation (maximum intima to media (I/M) ratio) were determined 5 and 28 days after carotid artery ligation, respectively. Results: Aortic cGMP levels were 4-fold higher in F than in M mice in both genotypes, and, within each gender, 4-fold higher in WT than in sGCa1-/-. In contrast, sGCα1, sGCα2, and sGCβ1 mRNA expression did not differ between groups. 3H-thymidine incorporation in cultured sGCa1-/- smooth muscle cells (SMC) was 27%±12% lower than in WT SMC and BrdU-incorporation in carotid arteries 5 days after ligation was significantly less in sGCa1-/- M than in WT M. Neointima area and I/M 28 days after ligation were 65% and 62% lower in sGCa1-/- M than in WT M mice (p<0,05 for both) but were not different in F mice. Conclusion: Functional deletion of sGCa1 resulted in reduced cGMP levels in male sGCa1-/- mice and a gender-specific effect on the adaptive response to vascular injury

Oxygenated machine perfusion at room temperature as an alternative for static cold storage in porcine donor hearts

Background There is a continued interest in ex situ heart perfusion as an alternative strategy for donor heart preservation. We hypothesize that oxygenated machine perfusion of donor hearts at a temperature that avoids both normothermia and deep hypothermia offers adequate and safe preservation. Methods Cardioplegia-arrested porcine donor hearts were randomly assigned to six hours of preservation using cold storage (CS, n = 5) or machine perfusion using an oxygenated acellular perfusate at 21 degrees C (MP, n = 5). Subsequently, all grafts were evaluated using the Langendorff method for 120 min. Metabolic parameters and histology were analyzed. Systolic function was assessed by contractility and elastance. Diastolic function was assessed by lusitropy and stiffness. Results For both groups, in vivo baseline and post-Langendorff biopsies were comparable, as were lactate difference and myocardial oxygen consumption. Injury markers gradually increased and were comparable. Significant weight gain was seen in MP (p = 0.008). Diastolic function was not impaired in MP, and lusitropy was superior from 30 min up to 90 min of reperfusion. Contractility was superior in MP during the first hour of evaluation. Conclusion We conclude that the initial functional outcome of MP-preserved hearts was transiently superior compared to CS, with no histological injury post-Langendorff. Our machine perfusion strategy could offer feasible and safe storage of hearts prior to transplantation. Future studies are warranted for further optimization

Oxygenated machine perfusion at room temperature as an alternative for static cold storage in porcine donor hearts

Background There is a continued interest in ex situ heart perfusion as an alternative strategy for donor heart preservation. We hypothesize that oxygenated machine perfusion of donor hearts at a temperature that avoids both normothermia and deep hypothermia offers adequate and safe preservation. Methods Cardioplegia-arrested porcine donor hearts were randomly assigned to six hours of preservation using cold storage (CS, n = 5) or machine perfusion using an oxygenated acellular perfusate at 21 degrees C (MP, n = 5). Subsequently, all grafts were evaluated using the Langendorff method for 120 min. Metabolic parameters and histology were analyzed. Systolic function was assessed by contractility and elastance. Diastolic function was assessed by lusitropy and stiffness. Results For both groups, in vivo baseline and post-Langendorff biopsies were comparable, as were lactate difference and myocardial oxygen consumption. Injury markers gradually increased and were comparable. Significant weight gain was seen in MP (p = 0.008). Diastolic function was not impaired in MP, and lusitropy was superior from 30 min up to 90 min of reperfusion. Contractility was superior in MP during the first hour of evaluation. Conclusion We conclude that the initial functional outcome of MP-preserved hearts was transiently superior compared to CS, with no histological injury post-Langendorff. Our machine perfusion strategy could offer feasible and safe storage of hearts prior to transplantation. Future studies are warranted for further optimization.</p

Photochromic performance of a dithienylethene–indolinooxazolidine hybrid

The synthesis and the photochromic performance of a single-molecule system based on the covalent combination of dithienylperfluorocyclopentene and indolino[2,1-b]oxazolidine are described. The photoinduced interconversion between four states was shown to be deeply dependent on solvent and can be selectively controlled by adjusting the irradiation wavelength in chlorobenzene solutions. The color can be switched between colorless, yellow, pink and green on demand. This biphotochromic hybrid compound, despite poor fatigue resistance properties of the most conjugated colored isomer, displays large contrasts in structure, switching between zwitterionic and neutral character, independent chromophores and highly conjugated π systems

Randomised controlled trial of adjunctive inspiratory muscle training for patients with COPD.

BACKGROUND: This study aimed to investigate whether adjunctive inspiratory muscle training (IMT) can enhance the well-established benefits of pulmonary rehabilitation (PR) in patients with COPD. METHODS: 219 patients with COPD (FEV1: 42%±16% predicted) with inspiratory muscle weakness (PImax: 51±15 cm H2O) were randomised into an intervention group (IMT+PR; n=110) or a control group (Sham-IMT+PR; n=109) in this double-blind, multicentre randomised controlled trial between February 2012 and October 2016 (ClinicalTrials.gov NCT01397396). Improvement in 6 min walking distance (6MWD) was a priori defined as the primary outcome. Prespecified secondary outcomes included respiratory muscle function and endurance cycling time. FINDINGS: No significant differences between the intervention group (n=89) and the control group (n=85) in improvements in 6MWD were observed (0.3 m, 95% CI -13 to 14, p=0.967). Patients who completed assessments in the intervention group achieved larger gains in inspiratory muscle strength (effect size: 1.07, p<0.001) and endurance (effect size: 0.79, p<0.001) than patients in the control group. 75 s additional improvement in endurance cycling time (95% CI 1 to 149, p=0.048) and significant reductions in Borg dyspnoea score at isotime during the cycling test (95% CI -1.5 to -0.01, p=0.049) were observed in the intervention group. INTERPRETATION: Improvements in respiratory muscle function after adjunctive IMT did not translate into additional improvements in 6MWD (primary outcome). Additional gains in endurance time and reductions in symptoms of dyspnoea were observed during an endurance cycling test (secondary outcome) TRIAL REGISTRATION NUMBER: NCT01397396; Results

Performance-based financing as a health system reform : mapping the key dimensions for monitoring and evaluation

Peer reviewedPublisher PD

Standardisation of clinical assessment, management and follow-up of acute hospitalised exacerbation of copd: A europe-wide consensus

Background: Despite hospitalization for exacerbation being a high-risk event for morbidity and mortality, there is little consensus globally regarding the assessment and management of hospitalised exacerbations of COPD. We aimed to establish a consensus list of symptoms, physiological measures, clinical scores, patient questionnaires and investigations to be obtained at time of hospitalised COPD exacerbation and follow-up. Methods: A modified Delphi online survey with pre-defined consensus of importance, feasibility and frequency of measures at hospitalisation and follow-up of a COPD exacerbation was undertaken. Findings: A total of 25 COPD experts from 18 countries contributed to all 3 rounds of the survey. Experts agreed that a detailed history and examination were needed. Experts also agreed on which treatments are needed and how soon these should be delivered. Experts recommended that a full blood count, renal function, C-reactive protein and cardiac blood biomarkers (BNP and troponin) should be measured within 4 hours of admission and that the modified Medical Research Council dyspnoea scale (mMRC) and COPD assessment test (CAT) should be performed at time of exacerbation and follow-up. Experts encouraged COPD clinicians to strongly consider discussing palliative care, if indicated, at time of hospitalisation. Interpretation: This Europe-wide consensus document is the first attempt to standardise the assessment and care of patients hospitalised for COPD exacerbations. This should be regarded as the starting point to build knowledge and evidence on patients hospitalised for COPD exacerbations