A 14 años de la desaparición forzada de Iván Torres Millacura : ¿qué ha cambiado?

A 14 años de la desaparición de Iván Torres Millacura, pese a la condena de la Corte Interamericana de Derechos Humanos y las condenas penales de dos de los autores, más la sanción del delito autónomo de desaparición forzada de personas en 2011, ésta práctica aberrante, sumada a las facultades policiales de detención por averiguación de antecedentes o identidad, sin control judicial, constituyen fuente permanente de hostigamiento por parte de funcionarios públicos a sectores vulnerables de la sociedad, principalmente jóvenes pobres. El funcionamiento violento de instituciones públicas es un fenómeno violatorio de derechos humanos que no sólo tienen como consecuencia la vulneración y violación de derechos fundamentales de las personas, sino que además son permeables a derivar rápidamente en la responsabilidad internacional del Estado, sino se piensa en medidas de prevención y fundamentalmente en sanciones adecuadas que impidan la impunidad de los casos y con ello la repetición de los mismos.Fil: Lecour, Lucas Jorge. Universidad Nacional de Cuyo. Facultad de Derech

P652The cardioprotective effect of exogenous sphingosine-1-phosphate requires the activation of endogenous sphingosine-1-phosphate via the sphingosine kinase 1

Purpose: Exogenous administration of sphingosine-1-phosphate (S1P) alone, or as part of high density lipoprotein, protects against myocardial infarction. S1P-induced cardioprotection targets the inhibition of the mitochondrial permeability transition pore via mechanisms that remain unclear. In the cell, the endogenous production of S1P from sphingosine is dependent on the activation of sphingosine kinases (SphK) 1 and 2. These two kinases play a role in cardioprotection against ischemia-reperfusion (IR) injury. Therefore, we hypothesised that the cardioprotective effect of exogenous S1P requires the activation of endogenous S1P via SphK. Methods: Isolated cardiomyocytes from adult wildtype mice were exposed to 2 hours of simulated ischemia (SI) in the presence of S1P (10nM) with/without N,N-dimethylsphingosine (DMS, a SphK1 and 2 inhibitor, 10μM) or SKI (a specific SphK1 inhibitor, 15μM). Cell viability was assessed using trypan blue staining and normalised to the normoxic control. Isolated perfused hearts from adult wildtype mice were exposed to 35 minutes of global ischemia followed by 45 minutes of reperfusion (IR) in the presence of S1P (10nM) with/without SKI (10μM). Infarct size (IS) was assessed using tripheyltetrazolium chloride staining and SphK1 activity using a specific biochemical fluorescence based assay kit. Both parameters were normalised to the IR control. Results: In isolated cardiomyocytes, viability under normoxic conditions was 76±1%. SI reduced viability to 52±1% (p< 0.001 vs. normoxia). Pre-treatment with S1P restored the viability to 75±1% (p<0.001 vs. SI). The beneficial effect of S1P was partially inhibited in the presence of DMS (67±4%) (ns vs. S1P) and totally abrogated with SKI pre-treatment (54±2%). Similarly, pre-treatment with S1P in isolated hearts reduced IS following IR from 50±1% (IR control) to 31±2% (S1P) (p<0.001 vs. control). Pre-treatment with SKI abrogated the cardioprotective effect of S1P (56±8%) (p<0.05 vs. S1P) as well as the S1P-induced increase in SphK1 activity (from S1P: 196±79 arbitrary units (AU) to SKI+S1P: 53±27 AU, p<0.05 vs. S1P). Conclusions: Our data, performed in both isolated cardiomyocytes and isolated hearts subjected to an ischemia/reperfusion insult, strongly suggest that exogenous sphingosine-1-phosphate-induced cardioprotection is dependent on the activation of endogenous sphingosine-1-phosphate via sphingosine kinase

When are pro-inflammatory cytokines SAFE in heart failure?

The cytokine hypothesis presently suggests that an excessive production of pro-inflammatory cytokines, such as tumour necrosis factor alpha (TNF) and interleukin 6 (IL6), contributes to the pathogenesis of heart failure. The concept, successfully proved in genetically modified animal models, failed to translate to humans. Recently, accumulation of apparently paradoxical experimental data demonstrates that, under certain conditions, production of pro-inflammatory cytokines can initiate the activation of a pro-survival cardioprotective signalling pathway. This novel path that involves the activation of a transcription factor, signal transducer and activator of transcription 3 (STAT3), has been termed the survival activating factor enhancement (SAFE) pathway. In this review, we will discuss whether targeting the SAFE pathway may be considered as a preventive and/or therapeutic measure for the treatment of heart failur

Studies of symbiotically important Rhizobium meliloti exopolysaccharides EPSII and succinoglycan

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Biology, 1999.Includes bibliographical references.by Louis LeCour, Jr.S.M

The PGE2-Stat3 interaction in doxorubicin-induced myocardial apoptosis

Aims Both cyclooxygenase-2 (COX-2) and the transcription factor signal transducer and activator of transcription 3 (Stat3) are involved in adaptive growth and survival of cardiomyocytes. In ventricular cardiomyocytes, prostaglandin E2 (PGE2), a major COX-2 product, leads to adaptive growth via Stat3 activation, but whether this transcription factor acts as a signalling molecule in PGE2-induced cell survival is unknown. Therefore, the purpose of this study was to determine whether PGE2 counteracts cardiac apoptosis induced by doxorubicin (DOX), and if so, whether Stat3 plays a critical role in this cardioprotective effect. Methods and results Neonatal rat ventricular cardiomyocytes were incubated with DOX (0.5 µM) and/or PGE2 (1 µM). Apoptosis was assessed by determining caspase3 activation and apoptotic DNA fragmentation. The role of Stat3 was evaluated in vitro and in vivo by transfecting cardiomyocytes with siRNA targeting rat Stat3 and by using cardiomyocyte-restricted Stat3 knockout (Stat3 KO) mice, respectively. Incubation of ventricular cardiomyocytes with PGE2 led to a time-dependent decrease in the DOX-induced caspase3 activation, reaching a maximal inhibition of 70 ± 5% after 4 h. Similarly, PGE2 inhibited DOX-induced DNA fragmentation by 58 ± 5% after 24 h. This antiapoptotic action of PGE2 was strongly reduced by the ERK1/2 inhibitor, U0126, whereas the p38 MAP kinase inhibitor, SB203580, had no effect. Depleting Stat3 expression by 50-60% in isolated ventricular cardiomyocytes markedly reduced the protective effect of PGE2 on DOX-induced caspase3 activation and DNA fragmentation. Likewise, the stable PGE2 analogue, 16,16-dimethyl-PGE2, was unable to counteract cardiac apoptosis induced by DOX in Stat3 KO mice. Conclusion Our results demonstrate that PGE2 prevents myocardial apoptosis induced by DOX. This protection requires the activation of the prosurvival pathways of Stat3 and ERK1/

Analysis of a Local HIV-1 Epidemic in Portugal Highlights Established Transmission of non-B and -G Subtypes

The existing data supports Portugal as the Western Europe country with highest HIV-1 subtype diversity. However, detailed phylogenetic studies of Portuguese HIV-1 epidemics are still scarce. Thus, our main goal was to analyze the phylodynamics of a local HIV-1 infection in the Portuguese region of Minho. Molecular epidemiological analysis was applied to data from 289 HIV-1 infected individuals followed in the reference Hospital of the province of Minho, Portugal, in which isolated viruses had been sequenced between 2000 and 2012. Viruses of the G (29.1%) and B (27.0%) subtypes were the most frequent, followed by recombinant forms (17.6%), C (14.5%), F1 (7.3%) and A1 (4.2%) subtypes. Multinomial logistic regression revealed that the odds of being infected with A1 and F1 subtype increased over the years when compared with B, G, C or recombinant viruses. As expected, polyphyletic patterns suggesting multiple and old introductions of subtypes B and G were found. However, transmission clusters of non-B and -G viruses among native individuals were also found with the dates of the most recent common ancestor estimated to the early 2000s. Our study supports that the HIV-1 subtype diversity in the Portuguese region of Minho is high and has been increasing in a manner that is apparently driven by factors other than immigration and international travel. Infections with A1 and F1 viruses in the region of Minho are becoming established and were mainly found in sexually transmitted clusters, reinforcing the need for more efficacious control measures targeting this infection route

Improving Reconstituted HDL Composition for Efficient Post-Ischemic Reduction of Ischemia Reperfusion Injury.

BACKGROUND: New evidence shows that high density lipoproteins (HDL) have protective effects beyond their role in reverse cholesterol transport. Reconstituted HDL (rHDL) offer an attractive means of clinically exploiting these novel effects including cardioprotection against ischemia reperfusion injury (IRI). However, basic rHDL composition is limited to apolipoprotein AI (apoAI) and phospholipids; addition of bioactive compound may enhance its beneficial effects. OBJECTIVE: The aim of this study was to investigate the role of rHDL in post-ischemic model, and to analyze the potential impact of sphingosine-1-phosphate (S1P) in rHDL formulations. METHODS AND RESULTS: The impact of HDL on IRI was investigated using complementary in vivo, ex vivo and in vitro IRI models. Acute post-ischemic treatment with native HDL significantly reduced infarct size and cell death in the ex vivo, isolated heart (Langendorff) model and the in vivo model (-48%, p&lt;0.01). Treatment with rHDL of basic formulation (apoAI + phospholipids) had a non-significant impact on cell death in vitro and on the infarct size ex vivo and in vivo. In contrast, rHDL containing S1P had a highly significant, protective influence ex vivo, and in vivo (-50%, p&lt;0.01). This impact was comparable with the effects observed with native HDL. Pro-survival signaling proteins, Akt, STAT3 and ERK1/2 were similarly activated by HDL and rHDL containing S1P both in vitro (isolated cardiomyocytes) and in vivo. CONCLUSION: HDL afford protection against IRI in a clinically relevant model (post-ischemia). rHDL is significantly protective if supplemented with S1P. The protective impact of HDL appears to target directly the cardiomyocyte

The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection—evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology

Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury