Pirfenidone for Idiopathic Pulmonary Fibrosis and Beyond

Pirfenidone (PFD) slows the progression of idiopathic pulmonary fibrosis (IPF) by inhibiting the exaggerated fibrotic response and possibly through additional mechanisms, such as anti-inflammatory effects. PFD has also been evaluated in other fibrosing lung diseases. Myocardial fibrosis is a common feature of several heart diseases and the progressive deposition of extracellular matrix due to a persistent injury to cardiomyocytes may trigger a vicious cycle that leads to persistent structural and functional alterations of the myocardium. No primarily antifibrotic medications are used to treat patients with heart failure. There is some evidence that PFD has antifibrotic actions in various animal models of cardiac disease and a phase II trial on patients with heart failure and preserved ejection fraction has yielded positive results. This review summarises the evidence about the possible mechanisms of IPF and modulation by PFD, the main results about IPF or non-IPF interstitial pneumonias and also data about PFD as a potential protective cardiac drug

Pathophysiological Rationale and Clinical Evidence for Neurohormonal Modulation in Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome resulting from the interaction between cardiac diseases, comorbidities and ageing. HFpEF is characterised by the activation of neurohormonal axes, namely of the renin-angiotensin-aldosterone system and the sympathetic nervous system, although to a lesser extent compared with heart failure with reduced ejection fraction. This provides a rationale for neurohormonal modulation as a therapeutic approach for HFpEF. Nonetheless, randomised clinical trials have failed to demonstrate a prognostic benefit from neurohormonal modulation therapies in HFpEF, with the sole exception of patients with left ventricular ejection fraction in the lower range of normality, for whom the American guidelines suggest that such therapies may be considered. In this review, the pathophysiological rationale for neurohormonal modulation in HFpEF is summarised and the clinical evidence on pharmacological and nonpharmacological approaches backing current recommendations discussed

Perspectives in noninvasive imaging for chronic coronary syndromes

Both the latest European guidelines on chronic coronary syndromes and the American guidelines on chest pain have underlined the importance of noninvasive imaging to select patients to be referred to invasive angiography. Nevertheless, although coronary stenosis has long been considered the main determinant of inducible ischemia and symptoms, growing evidence has demonstrated the importance of other underlying mechanisms (e.g., vasospasm, microvascular disease, energetic inefficiency). The search for a pathophysiology-driven treatment of these patients has therefore emerged as an important objective of multimodality imaging, integrating "anatomical" and "functional" information. We here provide an up-to-date guide for the choice and the interpretation of the currently available noninvasive anatomical and/or functional tests, focusing on emerging techniques (e.g., coronary flow velocity reserve, stress-cardiac magnetic resonance, hybrid imaging, functional-coronary computed tomography angiography, etc.), which could provide deeper pathophysiological insights to refine diagnostic and therapeutic pathways in the next future

NT-proBNP for Risk Prediction in Heart Failure:Identification of Optimal Cutoffs Across Body Mass Index Categories

OBJECTIVES The goal of this study was to assess the predictive power of N-terminal pro–B-type natriuretic peptide (NT-proBNP) and the decision cutoffs in heart failure (HF) across body mass index (BMI) categories. BACKGROUND  Concentrations of NT-proBNP predict outcome in HF. Although the influence of BMI to reduce levels of NT-proBNP is known, the impact of obesity on prognostic value remains uncertain. METHODS Individual data from the BIOS (Biomarkers In Heart Failure Outpatient Study) consortium were analyzed. Patients with stable HF were classified as underweight (BMI = 40 kg/m(2)) obese. The prognostic rote of NT-proBNP was tested for the endpoints of all-cause and cardiac death. RESULTS The study population included 12,763 patients (mean age 66 +/- 12 years; 25% women; mean left ventricular ejection fraction 33% 113%). Most patients were overweight (n = 5,176), followed by normal weight (n = 4,299), mildly obese (n = 2,157), moderately obese (n = 612), severely obese (n = 314), and underweight (n = 205). NT-proBNP inversely correlated with BMI (beta = -0.174 for 1 kg/m(2); P < 0.001). Adding NT-proBNP to clinical models improved risk prediction across BMI categories, with the exception of severely obese patients. The best cutoffs of NT-proBNP for 5-year all-cause death prediction were lower as BMI increased (3,785 ng/L, 2,193 ng/L, 1,554 ng/L, 1,045 ng/L, 755 ng/L, and 879 ng/L, for underweight, normal weight, overweight, and mildly, moderately, and severely obese patients, respectively) and were higher in women than in men. CONCLUSIONS NT-proBNP maintains its independent prognostic value up to 40 kg/m(2) BMI, and tower optimal risk-prediction cutoffs are observed in overweight and obese patients

Forward-central two-particle correlations in p-Pb collisions at root s(NN)=5.02 TeV

Two-particle angular correlations between trigger particles in the forward pseudorapidity range (2.5 2GeV/c. (C) 2015 CERN for the benefit of the ALICE Collaboration. Published by Elsevier B. V.Peer reviewe

Event-shape engineering for inclusive spectra and elliptic flow in Pb-Pb collisions at root(NN)-N-S=2.76 TeV

Peer reviewe

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Nouveaux états quantiques induits sous champ : étude microscopique par résonance magnétique nucléaire de l'azurite

We present a Nuclear Magnetic Resonance (NMR) study of azurite, Cu3(CO3)2(OH)2, a quantum spin system. This compound has been recognised as a model system for a quasi-1D, frustrated, ‘diamond' chain of S=1/2 spins beared by Cu2+ ions. In the magnetisation curve as a function of magnetic field it presents, between 11 and 30 T and at very low temperatures, a plateau at 1/3 of the saturation magnetisation. We performed Cu NMR measurements in azurite at T=1.5 K in order to determine its microscopic magnetic structure. The obtained results show that the ‘dimer' of two more strongly coupled spins is approximately in a singlet state while the third spin (the ‘monomer') is almost fully polarised. This confirms that the electronic configuration of the 1/3 plateau is a new quantum state without classical analogue [F. Aimo et al., Phys. Rev. Lett. 102, 127205, (2009)]. By very high magnetic field proton NMR, between 31 and 34 T and at T=0.6 K, we have also studied the transition region between the 1/3 plateau and the full polarisation of the system in order to test for the possible existence of a 2/3 plateau. This plateau is expected in rather exceptional case when longitudinal spin correlations are dominant and stabilise an incommensurable longitudinal order. However, our analysis showed that the symmetric splitting of NMR spectra corresponds to an antiferromagnetic transverse and not longitudinal order, which is incompatible with the existence of a 2/3 plateau.Nous présentons une étude par Résonance Magnétique Nucléaire (RMN) de l'azurite, Cu3(CO3)2(OH)2, un système de spins quantiques. Ce composé peut être modélisé comme une chaine quasi-unidimensionnelle, frustrée, ‘de type diamant', de spins électroniques S=1/2 portés par les ions de cuivre Cu2+. Il présente dans sa courbe de l'aimantation en fonction du champ magnétique, entre 11 et 30 T et à très basse température, un plateau à 1/3 de l'aimantation à saturation. Nous avons effectué des mesures RMN du cuivre dans l'azurite à T=1.5 K afin de déterminer sa structure magnétique microscopique. Les résultats obtenus dans le plateau démontrent que le ‘dimère' des deux spins qui sont plus fortement couplés est approximativement dans l'état singulet, tandis que le troisième spin (le ‘monomère') est presque complètement polarisé. Cela confirme que la configuration électronique du plateau à 1/3 est un nouvel état quantique qui n'a pas d'équivalent classique [F. Aimo et al., Phys. Rev. Lett. 102 127205, (2009)]. Par RMN du proton à très haut champ magnétique, entre 31 et 34 T à T=0.6 K, nous avons aussi étudié le passage depuis le plateau à 1/3 vers la polarisation complète du système, afin de confirmer ou infirmer l'existence éventuelle d'un plateau à 2/3. Ce plateau est attendu dans le cas exceptionnel où les corrélations longitudinales de spins sont dominantes et stabilisent un ordre incommensurable longitudinal. L'analyse détaillée du dédoublement très symétrique des spectres RMN nous amène à conclure que c'est un ordre antiferromagnétique transverse et non longitudinal qui est établi, ce qui est incompatible avec l'existence du plateau à 2/3