Calcium as a key player in arrhythmogenic cardiomiopathy : adhesion disorder or intracellular alteration?

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease characterized by sudden death in young people and featured by fibro-adipose myocardium replacement, malignant arrhythmias, and heart failure. To date, no etiological therapies are available. Mutations in desmosomal genes cause abnormal mechanical coupling, trigger pro-apoptotic signaling pathways, and induce fibro-adipose replacement. Here, we discuss the hypothesis that the ACM causative mechanism involves a defect in the expression and/or activity of the cardiac Ca2+ handling machinery, focusing on the available data supporting this hypothesis. The Ca2+ toolkit is heavily remodeled in cardiomyocytes derived from a mouse model of ACM defective of the desmosomal protein plakophilin-2. Furthermore, ACM-related mutations were found in genes encoding for proteins involved in excitation\u2012contraction coupling, e.g., type 2 ryanodine receptor and phospholamban. As a consequence, the sarcoplasmic reticulum becomes more eager to release Ca2+, thereby inducing delayed afterdepolarizations and impairing cardiac contractility. These data are supported by preliminary observations from patient induced pluripotent stem-cell-derived cardiomyocytes. Assessing the involvement of Ca2+ signaling in the pathogenesis of ACM could be beneficial in the treatment of this life-threatening disease

Connecting Galaxy Evolution, Star Formation and the X-ray Background

As a result of deep hard X-ray observations by Chandra and XMM-Newton a significant fraction of the cosmic X-ray background (CXRB) has been resolved into individual sources. These objects are almost all active galactic nuclei (AGN) and optical followup observations find that they are mostly obscured Type 2 AGN, have Seyfert-like X-ray luminosities (i.e., L_X ~ 10^{43-44} ergs s^{-1}), and peak in redshift at z~0.7. Since this redshift is similar to the peak in the cosmic star-formation rate, this paper proposes that the obscuring material required for AGN unification is regulated by star-formation within the host galaxy. We test this idea by computing CXRB synthesis models with a ratio of Type 2/Type 1 AGN that is a function of both z and 2-10 keV X-ray luminosity, L_X. The evolutionary models are constrained by parameterizing the observed Type 1 AGN fractions from the recent work by Barger et al. The parameterization which simultaneously best accounts for Barger's data, the CXRB spectrum and the X-ray number counts has a local, low-L_X Type 2/Type 1 ratio of 4, and predicts a Type 2 AGN fraction which evolves as (1+z)^{0.3}. Models with no redshift evolution yielded much poorer fits to the Barger Type 1 AGN fractions. This particular evolution predicts a Type 2/Type 1 ratio of 1-2 for log L_X > 44, and thus the deep X-ray surveys are missing about half the obscured AGN with these luminosities. These objects are likely to be Compton thick. Overall, these calculations show that the current data strongly supports a change to the AGN unification scenario where the obscuration is connected with star formation in the host galaxy rather than a molecular torus alone. The evolution of the obscuration implies a close relationship between star formation and AGN fueling, most likely due to minor mergers or interactions.Comment: 36 pages, 8 figures, ApJ in press. Minor changes to match published versio

Novas variedades de Cana-de-Açúcar

The authors carried out joint analyses of data referring to six experiments with varieties of sugar cane, carried out by SEGALLA and ALVAREZ in six locations in the State of S. Paulo, Brasil. The analyses showed that for cane or sugar yield, either for plant-cane or for plant-cane together with the first two ratoons, the best five varieties were CB 40-69, CB 41-76, CB 40-13, CB 40-19 and Co 419. The yield of sugar cane/for all varieties studied is given below, in metric tons produced in plant cane and the first two ratoons. Varieties Yield of sugar cane (tons/hectare) CB 40-69 205.2 CB 41-76 204.5 CB 40-13 199.4 CB 40-19 192.4 Co 419 192.1 CB 38-30 182.1 CB 41-70 181.5 Co 413 177.5 CB 38-22 174.4 CB 36-14 172.8 Co 290 166.6 CB 41-35 147.9 The least significant difference by Tukey's test, at the 5% level of probability, is A = 28.3 metric tons/hectare

The BeppoSAX High Energy Large Area Survey -V. The nature of the hard X-ray source populations and its evolution

We present optical spectroscopic identifications of hard X-ray (5-10 keV) selected sources belonging to the HELLAS sample obtained with BeppoSAX down to a 5-10 keV flux limit of f_{5-10 keV}~3x10^-14 erg cm^-2 s^-1. The sample consists of 118 sources. 25 sources have been identified trough correlations with catalogues of known sources. 49 have been searched for spectroscopic identification at the telescope. 13 fields resulted empty down to R=21. 37 sources have been identified with type 1 AGN and 9 with type 2 AGN. The remaining are: 5 narrow emission line galaxies, 6 Clusters, 2 BL Lac, 1 Radio Galaxy and 1 Star. Combining these objects with other hard X-ray selected AGNs from ASCA and HEAO1, we find that the local luminosity function of type 1 AGN in the 2-10 keV band is fairly well represented by a double-power-law-function. There is evidence for significant cosmological evolution according to a pure luminosity evolution (PLE) model L_X(z)~(1+z)^k, with k=2.12 and k=2.22 in a (Omega_m,Omega_lambda)=(1.0,0.0) and in a (Omega_m,Omega_lambda)=(0.3,0.7) cosmology, respectively. The data show an excess of faint high redshift type 1 AGN which is well modeled by a luminosity dependent density evolution (LDDE), similarly to what observed in the soft X-rays. However, in both cosmologies, the statistic is not significant enough to distinguish between the PLE and LDDE models. The fitted models imply a contribution of AGN1 to the 2-10 keV X-ray background from 35% up to 60%.Comment: 16 pages, 12 figures. Emulateapj version. To appear on ApJ, v570, May 1 200

The BeppoSAX High Energy Large Area Survey HELLAS, II: Number counts and X-ray spectral properties

The BeppoSAX High Energy Large Area Survey (HELLAS) has surveyed about 85 deg^2 of sky in the 5-10 keV band down to a flux of 4-5 10^-14 erg cm-2 s-1. The source surface density of 16.9+-6.4 deg$^{-2}$ at the survey limit corresponds to a resolved fraction of the 5-10 keV X-ray background (XRB) of the order of 20-30 %. Hardness ratios analysis indicates that the spectra of a substantial fraction of the HELLAS sources (at least one third) are harder than a alpha_E = 0.6 power law. This hardness may be due to large absorbing columns. The hardness ratio analysis also indicates that many HELLAS sources may have a spectrum more complex than a single absorbed power law. A soft component, superimposed to a strongly cut-off power law, is likely to be present in several sources.Comment: to appear in MNRA

Characteristics of structured physical training currently provided in cardiac patients: insights from the Exercise Training in Cardiac Rehabilitation (ETCR) Italian survey

Uncertainty exists about current delivery levels of exercise training (ET) during Cardiac Rehabilitation (CR) programmes. The aim of this study was to evaluate ET modalities in the real world of CR facilities in Italy. This was an observational survey of aggregate data, collected from CR facilities on a voluntary basis. Snapshots of a single working day at a local site were made, in terms of characteristics of patients and ET programmes delivered. Overall, 612 patients from 26 CR units were included, with an in-patient vs out-patient ratio of 3:1. Coronary artery disease (57.6%), heart failure (20.3%), and valve disease/surgery (22.1%) were the most represented target groups. The prevalence of endurance continuous training, interval training, and resistance/strength training was 66.7%, 11.1%, and 9.0%; other non-aerobic endurance and non-resistance training modalities such as respiratory muscle training and calisthenics were reported in 39.9% and 42.9% of cases respectively. Workloads for endurance exercise training were determined by cardiopulmonary test, conventional 12-leads ECG exercise testing, 6minwalking test, theoretical determination of heart rate, and rating of perceived exertion in 9%, 8%, 27%, 9%, and 40% of cases respectively. The average duration of the programmes (on an intention to treat basis) was 25 sessions of 42±11 min, with a frequency of >4 sessions/week in 67% of patients. Despite advances in CR interventions, there is a significant need for improvement of functional evaluation and exercise training prescription, and consideration of a wider range of training modalities in Ital

miR-34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase).

Objective- Vascular calcification (VC) is age dependent and a risk factor for cardiovascular and all-cause mortality. VC involves the senescence-induced transdifferentiation of vascular smooth muscle cells (SMCs) toward an osteochondrogenic lineage resulting in arterial wall mineralization. miR-34a increases with age in aortas and induces vascular SMC senescence through the modulation of its target SIRT1 (sirtuin 1). In this study, we aimed to investigate whether miR-34a regulates VC. Approach and Results- We found that miR-34a and Runx2 (Runt-related transcription factor 2) expression correlates in young and old mice. Mir34a <sup>+/+</sup> and Mir34a <sup>-/-</sup> mice were treated with vitamin D, and calcium quantification revealed that Mir34a deficiency reduces soft tissue and aorta medial calcification and the upregulation of the VC Sox9 (SRY [sex-determining region Y]-box 9) and Runx2 and the senescence p16 and p21 markers. In this model, miR-34a upregulation was transient and preceded aorta mineralization. Mir34a <sup>-/-</sup> SMCs were less prone to undergo senescence and under osteogenic conditions deposited less calcium compared with Mir34a <sup>+/+</sup> cells. Furthermore, unlike in Mir34a <sup>+/+</sup> SMC, the known VC inhibitors SIRT1 and Axl (AXL receptor tyrosine kinase) were only partially downregulated in calcifying Mir34a <sup>-/-</sup> SMC. Strikingly, constitutive miR-34a overexpression to senescence-like levels in human aortic SMCs increased calcium deposition and enhanced Axl and SIRT1 decrease during calcification. Notably, we also showed that miR-34a directly decreased Axl expression in human aortic SMC, and restoration of its levels partially rescued miR-34a-dependent growth arrest. Conclusions- miR-34a promotes VC via vascular SMC mineralization by inhibiting cell proliferation and inducing senescence through direct Axl and SIRT1 downregulation, respectively. This miRNA could be a good therapeutic target for the treatment of VC

Isolation and characterization of cardiac mesenchymal stromal cells from endomyocardial bioptic samples of arrhythmogenic cardiomyopathy patients

A normal adult heart is composed of several different cell types, among which cardiac mesenchymal stromal cells represent an abundant population. The isolation of these cells offers the possibility of studying their involvement in cardiac diseases, and, in addition, provides a useful primary cell model to investigate biological mechanisms. Here, the method for the isolation of C-MSC from arrhythmogenic cardiomyopathy patients\u2019 bioptic samples is described. The endomyocardial biopsy sampling is guided in the right ventricular areas adjacent to the scar visualized by electro-anatomical mapping. The digestion of the biopsies in collagenase and their plating on a plastic dish in culture medium to allow C-MSC growth is described. The isolated cells can be expanded in culture for several passages. To confirm their mesenchymal phenotype, the description of immuno-phenotypical characterization is provided. C-MSC are able to differentiate into several cell types like adipocytes, chondrocytes, and osteoblasts: in the context of ACM, characterized by adipocyte deposits in patients\u2019 hearts, the protocols for the adipogenic differentiation of C-MSC and the characterization of lipid droplet accumulation are described