Exendin-4 protects against post-myocardial infarction remodelling via specific actions on inflammation and the extracellular matrix

Glucagon-like peptide-1 (GLP-1) is an insulin-releasing hormone clinically exploited for glycaemic control in diabetes, which also confers acute cardioprotection and benefits in experimental/clinical heart failure. We specifically investigated the role of the GLP-1 mimetic, exendin-4, in post-myocardial infarction (MI) remodelling, which is a key contributor to heart failure. Adult female normoglycaemic mice underwent coronary artery ligation/sham surgery prior to infusion with exendin-4/vehicle for 4 weeks. Metabolic parameters and infarct sizes were comparable between groups. Exendin-4 protected against cardiac dysfunction and chamber dilatation post-MI and improved survival. Furthermore, exendin-4 modestly decreased cardiomyocyte hypertrophy/apoptosis but markedly attenuated interstitial fibrosis and myocardial inflammation post-MI. This was associated with altered extracellular matrix (procollagen IαI/IIIαI, connective tissue growth factor, fibronectin, TGF-β3) and inflammatory (IL-10, IL-1β, IL-6) gene expression in exendin-4-treated mice, together with modulation of both Akt/GSK-3β and Smad2/3 signalling. Exendin-4 also altered macrophage response gene expression in the absence of direct actions on cardiac fibroblast differentiation, suggesting cardioprotective effects occurring secondary to modulation of inflammation. Our findings indicate that exendin-4 protects against post-MI remodelling via preferential actions on inflammation and the extracellular matrix independently of its established actions on glycaemic control, thereby suggesting that selective targeting of GLP-1 signalling may be required to realise its clear therapeutic potential for post-MI heart failure.

Metabolic signatures of human Alzheimer's disease (AD): H-1 NMR analysis of the polar metabolome of post-mortem brain tissue

Brain tissue from so-called Alzheimer's disease (AD) mouse models has previously been examined using H-1 NMR-metabolomics, but comparable information concerning human AD is negligible. Since no animal model recapitulates all the features of human AD we undertook the first H-1 NMR-metabolomics investigation of human AD brain tissue. Human post-mortem tissue from 15 AD subjects and 15 age-matched controls was prepared for analysis through a series of lyophilised, milling, extraction and randomisation steps and samples were analysed using H-1 NMR. Using partial least squares discriminant analysis, a model was built using data obtained from brain extracts. Analysis of brain extracts led to the elucidation of 24 metabolites. Significant elevations in brain alanine (15.4 %) and taurine (18.9 %) were observed in AD patients (p ≤ 0.05). Pathway topology analysis implicated either dysregulation of taurine and hypotaurine metabolism or alanine, aspartate and glutamate metabolism. Furthermore, screening of metabolites for AD biomarkers demonstrated that individual metabolites weakly discriminated cases of AD [receiver operating characteristic (ROC) AUC <0.67; p < 0.05]. However, paired metabolites ratios (e.g. alanine/carnitine) were more powerful discriminating tools (ROC AUC = 0.76; p < 0.01). This study further demonstrates the potential of metabolomics for elucidating the underlying biochemistry and to help identify AD in patients attending the memory clinic

Financial reintegration assistance for veterans of the Irish revolution (1916-23): post-conflict policy in an historical setting

In the aftermath of the Irish revolution and Civil War the governments of independent Ireland introduced various compensation schemes to provide financial reintegration assistance to revolutionary veterans. This would be recognised today as part of a programme for DDR. This paper will examine various service and disability pensions paid to veterans in the context of literature on post-conflict reintegration. It will examine various challenges to reintegration in an effort to analyse the success of revolutionary compensation as a post-conflict reintegration mechanism in independent Ireland after 1922.

Authenticity, Identity and Sustainability in Post-war Iraq: Reshaping the Urban Form of Erbil City

Issues of authenticity and identity are particularly significant in cities where social and cultural change is shaping active transformation of its urban fabric and structure in the post-war condition. In search of sustainable future, Iraqi cities are stretched between the two ends of the spectrum, authentic quarters with its traditional fabric and modern districts with their global sense of living. This paper interrogates the reciprocal influences, distinct qualities and sustainable performance of both authentic and modern quarters of Erbil, the
capital of the Iraqi province of Kurdistan, as factors in shaping sustainable urban forms for Iraqi cities. In doing so, the paper, firstly, seeks to highlight the urban identity as an effective factor in relation to sustainable urban form. Secondly, the city of Erbil in Iraq has been chosen as a field study, due to its regional, social, political and historical role in the region. Thirdly, the study emphasises the dynamic activities and performance of residential projects according to rational sustainable criteria. The research concludes that urban identity and the sense of place in traditional and historical places should inform design strategies in order to achieve a more sustainable urban context.

Impact of electric vehicles on a carbon constrained power system—a post 2020 case study

Electric vehicles (EVs) offer great potential to move from fossil fuel dependency in transport once some of the technical barriers related to battery reliability and grid integration are resolved. The European Union has set a target to achieve a 10% reduction in greenhouse gas emissions by 2020 relative to 2005 levels. This target is binding in all the European Union member states. If electric vehicle issues are overcome then the challenge is to use as much renewable energy as possible to achieve this target. In this paper, the impacts of electric vehicle charged in the all-Ireland single wholesale electricity market after the 2020 deadline passes is investigated using a power system dispatch model. For the purpose of this work it is assumed that a 10% electric vehicle target in the Republic of Ireland is not achieved, but instead 8% is reached by 2025 considering the slow market uptake of electric vehicles. Our experimental study shows that the increasing penetration of EVs could contribute to approach the target of the EU and Ireland government on emissions reduction, regardless of different charging scenarios. Furthermore, among various charging scenarios, the off-peak charging is the best approach, contributing 2.07% to the target of 10% reduction of Greenhouse gas emissions by 2025.

Efficacy response in CF patients treated with ivacaftor: Post-hoc analysis

Clinical studies in patients with cystic fibrosis and G551D-CFTR showed that the group treated with ivacaftor had improved clinical outcomes. To better understand the effect of ivacaftor therapy across the distribution of individual FEV1 responses, data from Phase 3 studies (STRIVE/ENVISION) were re-examined. In this post-hoc analysis of patients (n=209) who received 48 weeks of ivacaftor or placebo, patients were assigned to tertiles according to FEV1 response. These groups were then used to evaluate response (FEV1, sweat chloride, weight, CFQ-R, and pulmonary exacerbation). The number needed to treat (NNT) was calculated for specific thresholds for each outcome. Across all tertiles, numerical improvements in FEV1, sweat chloride, CFQ-R and the frequency of pulmonary exacerbations were observed in ivacaftor-treated patients: the treatment difference versus placebo was statistically significant for all outcomes in the upper tertile and for some outcomes in the lower and middle tertiles. The NNT for a≥5% improvement in %predicted FEV1 was 1.90, for a≥5% body weight increase was 5.74, and to prevent a pulmonary exacerbation was 3.85. This analysis suggests that the majority of patients with clinical characteristics similar to STRIVE/ENVISION patients have the potential to benefit from ivacaftor therapy.