G20 2014: reform of the international organisations, financial regulation, trade, accountability and anti-corruption

This issue of the G20 Monitor discusses the reform of international economic institutions, financial regulation, and the trade, accountability and anti-corruption agendas at the forthcoming Brisbane G20 Summit. It also provides a summary of the key ideas from the ‘G20 Conference: Strengthening Accountability and Effectiveness’ hosted by the Lowy Institute. Key findings: If the G20 is truly to be the world’s premier forum for international economic cooperation, fostering the reform of international economic institutions needs to be a fundamental objective. Ex ante regulatory impact assessments are an important tool for strengthening financial regulation and fostering financial stability globally. Trade, anti-corruption, and the accountability of the G20 are important agenda items for the forthcoming Brisbane Summit and go to the heart of the G20’s aim to boost growth and resilience

Dynamical nonequilibrium molecular dynamics reveals the structural basis for allostery and signal propagation in biomolecular systems

A dynamical approach to nonequilibrium molecular dynamics (D-NEMD), proposed in the 1970s by Ciccotti et al., is undergoing a renaissance and is having increasing impact in the study of biological macromolecules. This D-NEMD approach, combining MD simulations in stationary (in particular, equilibrium) and nonequilibrium conditions, allows for the determination of the time-dependent structural response of a system using the Kubo–Onsager relation. Besides providing a detailed picture of the system’s dynamic structural response to an external perturbation, this approach also has the advantage that the statistical significance of the response can be assessed. The D-NEMD approach has been used recently to identify a general mechanism of inter-domain signal propagation in nicotinic acetylcholine receptors, and allosteric effects in β-lactamase enzymes, for example. It complements equilibrium MD and is a very promising approach to identifying and analysing allosteric effects. Here, we review the D-NEMD approach and its application to biomolecular systems, including transporters, receptors, and enzymes

Impact of carvedilol on the mitochondrial damage induced by hypoxanthine and xantine oxidase: what role in myocardial ischemia and reperfusion?

OBJECTIVES: The cardioprotective effects of carvedilol (CV) may be explained in part by interactions with heart mitochondria. The objective of this work was to study the protection afforded by CV against oxidative stress induced in isolated heart mitochondria by hypoxanthine and xanthine oxidase (HX/XO), a well-known source of reactive oxygen species (ROS) in the cardiovascular system. METHODS: Mitochondria were isolated from Wistar rat hearts (n = 8) and incubated with HX/XO in the presence and in the absence of calcium. Several methods were used to assess the protection afforded by CV: evaluation of mitochondrial volume changes (by measuring changes in the optical density of the mitochondrial suspension), calcium uptake and release (with a fluorescent probe, Calcium Green 5-N) and mitochondrial respiration (with a Clark-type oxygen electrode). RESULTS: CV decreased mitochondrial damage associated with ROS production by HX and XO, as verified by the reduction of mitochondrial swelling and increase in mitochondrial calcium uptake. In the presence of HX and XO, CV also ameliorated mitochondrial respiration in the active phosphorylation state and prevented decrease in the respiratory control ratio (p < 0.05) and in mitochondrial phosphorylative efficiency (p < 0.001). CONCLUSIONS: The data indicate that CV partly protected heart mitochondria from oxidative damage induced by HX and XO, which may be useful during myocardial ischemia and reperfusion. It is also suggested that mitochondria may be a priority target for the protective action of some compounds

Treatable Traits in COPD - A Proposed Approach

The well-recognized individual heterogeneity within COPD patients has led to a growing interest in greater personalization in the approach of these patients. Thus, the treatable traits strategy has been proposed as a further step towards precision medicine in the management of chronic airway disease, both in stable phase and acute exacerbations. The aim of this paper is to perform a critical review on the treatable traits strategy and propose a guide to approach COPD patients in the light of this new concept. An innovative stepwise approach is proposed - a multidisciplinary model based on two distinct phases, with the potential to be implemented in both primary care and hospital settings. The first phase is the initial and focused assessment of a selected subset of treatable traits, which should be addressed in all COPD patients in both settings (primary care and hospital). As some patients may present with advanced disease at diagnosis or may progress despite this initial treatment requiring a more specialized assessment, they should progress to a second phase, in which a broader approach is recommended. Beyond stable COPD, we explore how the treatable traits strategy may be applied to reduce the risk of future exacerbations and improve the management of COPD exacerbations. Since many treatable traits have already been related to exacerbation risk, the strategy proposed here represents an opportunity to be proactive. Although it still lacks prospective validation, we believe this is the way forward for the future of the COPD approach.info:eu-repo/semantics/publishedVersio

Randomized phase III trial of bleomycin, vindesine, mitomycin-C, and cisplatin (BEMP) versus cisplatin (P) in disseminated squamous-cell carcinoma of the uterine cervix: an EORTC Gynecological Cancer Cooperative Group study

PURPOSE: Three previous mitomycin-cisplatin-based chemotherapy trials conducted within the EORTC Gynecological Cancer Cooperative Group (GCCG) in patients with disseminated squamous-cell carcinoma of the uterine cervix (SCCUC) suggested that with such regimens a higher overall response rate and a higher complete response rate could be obtained compared to what might have been expected from cisplatin alone. In that respect the combination of bleomycin, vindesine (Eldesine), mitomycin C and cisplatin (BEMP) was the most promising. In the present study BEMP has been compared with the best single agent, cisplatin (P) in the expectation that improved response rates might translate into a better survival. PATIENTS AND METHODS: Eligible patients were those with SCCUC and disseminated measurable disease outside previously irradiated areas, aged < or = 75 years, with a WHO performance status < or = 2 and adequate bone marrow, renal, hepatic and pulmonary function, who gave consent according to regulations followed in individual institutions. Patients were randomized to BEMP: E 3 mg/m2 day 1, P 50 mg/m2 day 1, B 15 mg (24-hour infusion) day 2-4 and M 8 mg/m2 (at alternate cycles), or P 50 mg/m2. The first four cycles were given every 3 weeks (induction phase). Subsequent cycles were given every four weeks (maintenance phase), during which B was deleted from BEMP (MEP). Patients failing on P could be treated with BEM. Of the 287 patients entered, 235 were eligible and 201 evaluable for response. RESULTS: BEMP induced a significantly higher response rate than P (42% vs. 25%, P = 0.006). There was no difference in complete response rate (11% vs. 7%). BEMP was significantly more toxic than P (+/- BEM), both with respect to hematologic and nonhematologic toxicities. After a median follow-up of 6.1 years, survival curves were not significantly different. Median progression-free survival and overall survival were 5.3 and 10.1 months with BEMP and 4.5 and 9.3 months with P (+/- BEM), respectively. In a multivariate analysis of prognostic factors for survival, a lower age (P = 0.003), a lower performance status (P = 0.0001) and a short (<1 year) interval since diagnosis (P = 0.0152) were all associated with an increased risk of dying. For progression-free survival, lower age, prior radiotherapy, locoregional involvement and no prior surgery were associated with a high risk. Treatment with BEMP or P had no significant impact on survival, but for progression-free survival there was a trend in favor of BEMP (P = 0.0893). Adjusting for prognostic factors did not change the effect of treatment. CONCLUSIONS: Combination chemotherapy with BEMP produces more toxicity and more responses compared with cisplatin alone in patients with disseminated SCCUC, but this does not translate into a better survival. Therefore, in the palliative setting single-agent cisplatin should remain the standard therapy for these patients

Morphological Changes of the Internal Carotid Artery: Prevalence and Characteristics. A Clinical and Ultrasonographic Study in a Series of 19 804 Patients Over 25 Years Old

Background and purpose: Morphological changes of the internal carotid arteries (McICA) are frequently found during cervical ultrasound studies. However, the etiology of McICA remains controversial. During this study, the prevalence and demographic characteristics of McICA, such as kinking, coiling or looping identified by Doppler ultrasound, were analysed and its relationship with vascular risk factors and stroke was assessed. Methods: A retrospective study was performed by analysing 19 804 patients who were subjected to cervical ultrasonographic study between January 2000 and June 2012. The data were statistically analysed with SPSS® 20 and a multivariate logistic regression was performed. Statistical significance was accepted for P < 0.05 and 95% confidence intervals (CIs) were used. Results: Morphological changes of the internal carotid arteries were present in 2678 patients (13.5%) and were unilateral in 61.6% of these cases. Carotid kinking was found in 80% of the patients, coiling in 16% and looping in 1%. In multivariate analysis, the presence of McICA was related to older groups (1.04; 95% CI, 1.04-1.05; P < 0.01), female gender (1.78; 95% CI, 1.64-1.94; P < 0.01), patients with hyperlipidemia (1.28; 95% CI, 1.17-1.40; P < 0.01), carotid thickness (1.22; 95% CI, 1.13-1.33; P < 0.01) and cardiac or cardioembolic disease (1.11; 95% CI, 1.01-1.21; P = 0.02). The results of this study indicate that kinking in the carotid artery was associated with ipsilateral cerebral ischemic events (1.43; 95% CI, 1.040-1.958; P < 0.05). Conclusion: Morphological changes of the internal carotid arteries were associated with aging, female gender and patients with hyperlipidemia, hypertension, diabetes and heart disease. Kinking was associated with ipsilateral cerebral ischemia.info:eu-repo/semantics/publishedVersio

Advantages in the use of carvedilol versus propranolol for the protection of cardiac mitochondrial function

BACKGROUND: Carvedilol is a neurohormonal antagonist of multiple action which is used in clinical practice for the treatment of congestive heart failure, mild to moderate hypertension and myocardial infarction. Previous results from our group have demonstrated that one of the main targets for the protective effect of carvedilol is the cardiac mitochondrial network. In-this work, we compare the effect of carvedilol with propranolol in different models of mitochondrial dysfunction and in the generation of transmembrane electric potential (EP). We further tested if carvedilol was able to inhibit the mitochondrial permeability transition (MPT) induced by doxorubicin and calcium-dependent cytochrome c release, a phenomenon frequently associated with apoptotic cell death. METHODS: Cardiac mitochondria were isolated by differential centrifugation. Oxygen consumption and mitochondrial EP were determined using an oxygen electrode and a tetraphenylphosphonium-sensitive electrode, respectively. Changes in mitochondrial volume and the release of cytochrome c were measured with spectrophotometric techniques. RESULTS: Propranolol, compared with carvedilol, had only a marginal effect, not only in protection against MPT induction, but also against oxygen consumption linked to the oxidation of external NADH, a process that is considered by several authors as key in the cardiotoxicity of doxorubicin. Regarding EP generation, propranolol had no effect, in contrast to carvedilol, which was confirmed to act as a protonophore. For the first time we also show that carvedilol inhibits the MPT induced by doxorubicin and calcium-dependent cytochrome c release. CONCLUSIONS: With this work, we further support the notion that carvedilol is effective in several models of mitochondrial dysfunction, particularly those involving oxidative stress. The results demonstrate that for some pathological conditions, carvedilol and propranolol have different mechanisms of action at the sub-cellular level, as propranolol seems to lack effectiveness in the protection of cardiac mitochondria

Externally validated model predicting gait independence after stroke showed fair performance and improved after updating

ObjectiveTo externally validate recent prognostic models that predict independent gait following stroke.Study design and settingA systematic search identified recent models (ResultsThree prognostic models met our criteria, all with high Risk of Bias. Validation data was only available for the Australian model. This model used National Institute of Health Stroke Scale (NIHSS) and age to predict independent gait, using Motor Assessment Scale (MAS) walking item. For validation, Scandinavian Stroke Scale (SSS) was a proxy for NIHSS, and Functional Independence Measure (FIM) locomotion item was a proxy for MAS. The Area Under the Curve was 0.77 (0.74-0.80) and had good calibration in the validation dataset. Adjustment of the intercept and regression coefficients slightly improved discrimination. By adding paretic leg strength, the model further improved (AUC 0.82).ConclusionExternal validation of the Australian model with proxies showed fair discrimination and good calibration. Updating the model by adding paretic leg strength further improved model performance