Imbalance between pro and anti-oxidant mechanisms in perivascular adipose tissue aggravates long-term high-fat diet-derived endothelial dysfunction

Background: The hypothesis of this study is that long-term high-fat diets (HFD) induce perivascular adipose tissue (PVAT) dysfunction characterized by a redox imbalance, which might contribute to aggravate endothelial dysfunction in obesity. Methods and Results: C57BL/6J mice were fed either control or HFD (45% kcal from fat) for 32 weeks. Body weight, lumbar and mesenteric adipose tissue weights were significantly higher in HFD animals compared to controls. The anticontractile effect of PVAT in mesenteric arteries (MA) was lost after 32 week HFD and mesenteric endothelial-dependent relaxation was significantly impaired in presence of PVAT in HFD mice (Emax = 71.0±5.1 vs Emax = 58.5±4.2, p<0.001). The inhibitory effect of L-NAME on Ach-induced relaxation was less intense in the HFD group compared with controls suggesting a reduction of endothelial NO availability. Expression of eNOS and NO bioavailability were reduced in MA and almost undetectable in mesenteric PVAT of the HFD group. Superoxide levels and NOX activity were higher in PVAT of HFD mice. Apocynin only reduced contractile responses to NA in HFD animals. Expression of ec-SOD and total SOD activity were significantly reduced in PVAT of HFD mice. No changes were observed in Mn-SOD, Cu/Zn-SOD or catalase. The ratio [GSSG]/([GSH]+[GSSG]) was 2-fold higher in the mesenteric PVAT from HFD animals compared to controls. Conclusions: We suggest that the imbalance between pro-oxidant (NOX, superoxide anions, hydrogen peroxide) and antioxidant (eNOS, NO, ecSOD, GSSG) mechanisms in PVAT after long-term HFD might contribute to the aggravation of endothelial dysfunctionThis work was supported by grants from Ministerio de Ciencia e Investigación (BFU2011-25303), Ministerio de Economía y Competitividad (SAF2009- 09714, SAF2011-25303, BFU2012-35353), Grupos Universidad Complutense de Madrid (UCM; GR-921641), Fundación Universitaria San Pablo-CEU, Fundación Mutua Madrileña and Sociedad para el Estudio de la Salud Cardiometabólica (SESCAMET). MGO and CFG-P are supported by Ministerio de Educación y Cienci

Fetal undernutrition is associated with perinatal sex-dependent alterations in oxidative status

This is the published version of a work that was accepted for publication in The Journal of Nutritional Biochemestry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in The Journal of Nutritional Biochemestry 26.12 (2015). DOI: 10.1016/jnubio.2015.09.004Intrauterine growth retardation predisposes to hypertension development, known as fetal programming. Females are less susceptible, which has been mainly attributed to estrogen influence. We hypothesize that perinatal differences in oxidative status might also contribute. We studied 21-day-old (prepuberal) and 6-month-old male and female Intrauterine growth retardation predisposes to hypertension development, known as fetal programming. Females are less susceptible, which has been mainly attributed to estrogen influence. We hypothesize that perinatal differences in oxidative status might also contribute. We studied 21-day-old (prepuberal) and 6-month-old male and female offspring from rats fed ad libitum during gestation (Control) or with 50% of Control daily intake from day 10 to delivery (maternal undernutrition, MUN). We assessed in vivo blood pressure and the following plasma biomarkers of oxidative status: protein carbonyls, thiols, reduced glutathione (GSH), total antioxidant capacity, superoxide anion scavenging activity (SOSA) and catalase activities; we calculated a global score (oxy-score) from them. Estradiol and melatonin concentration was measured in young rats. Prepuberal MUN males were normotensive but already exhibited increased carbonyls and lower thiols, GSH, SOSA and melatonin; oxy-score was significantly lower compared to Control males. Prepuberal MUN females only exhibited reduced SOSA compared to Control females. Adult rats from all experimental groups showed a significant increase in carbonyls and a decrease in antioxidants compared to prepuberal rats; oxy-score was negative in adult rats suggesting the development of a prooxidative status as rat age. Adult MUN males were hypertensive and exhibited the highest increase in carbonyls despite similar or even higher antioxidant levels compared to Controls. Adult MUN females remained normotensive and did not exhibit differences in any of the biomarkers compared to Controls. The better global antioxidant status developed by MUN females during perinatal life could contribute to their protection against hypertension programming.offspring from rats fed ad libitum during gestation (Control) or with 50% of Control daily intake from day 10 to delivery (maternal undernutrition, MUN). We assessed in vivo blood pressure and the following plasma biomarkers of oxidative status: protein carbonyls, thiols, reduced glutathione (GSH), total antioxidant capacity, superoxide anion scavenging activity (SOSA) and catalase activities; we calculated a global score (oxy-score) from them. Estradiol and melatonin concentration was measured in young rats. Prepuberal MUN males were normotensive but already exhibited increased carbonyls and lower thiols, GSH, SOSA and melatonin; oxy-score was significantly lower compared to Control males. Prepuberal MUN females only exhibited reduced SOSA compared to Control females. Adult rats from all experimental groups showed a significant increase in carbonyls and a decrease in antioxidants compared to prepuberal rats; oxy-score was negative in adult rats suggesting the development of a prooxidative status as rat age. Adult MUN males were hypertensive and exhibited the highest increase in carbonyls despite similar or even higher antioxidant levels compared to Controls. Adult MUN females remained normotensive and did not exhibit differences in any of the biomarkers compared to Controls. The better global antioxidant status developed by MUN females during perinatal life could contribute to their protection against hypertension programming.This work was supported by Ministerio de Economía y Competitividad Spain (grant number FEM2012-37634-C03-01 to S. M. Arribas) and Universidad Autónoma de Madrid Banco - Santander (Interuniversity Cooperation Project, Center for Latin American Studies, Santander, USA 2013–2014 to M. A. Martín-Cabrejas)

Differential Deleterious Impact of Highly Saturated Versus Monounsaturated Fat Intake on Vascular Function, Structure, and Mechanics in Mice

Vegetable oils such as palm oil (enriched in saturated fatty acids, SFA) and high-oleic-acid sunflower oil (HOSO, containing mainly monounsaturated fatty acids, MUFA) have emerged as the most common replacements for trans-fats in the food industry. The aim of this study is to analyze the impact of SFA and MUFA-enriched high-fat (HF) diets on endothelial function, vascular remodeling, and arterial stiffness compared to commercial HF diets. Five-week-old male C57BL6J mice were fed a standard (SD), a HF diet enriched with SFA (saturated oil-enriched Food, SOLF), a HF diet enriched with MUFA (unsaturated oil-enriched Food, UOLF), or a commercial HF diet for 8 weeks. Vascular function was analyzed in the thoracic aorta. Structural and mechanical parameters were assessed in mesenteric arteries by pressure myography. SOLF, UOLF, and HF diet reduced contractile responses to phenylephrine and induced endothelial dysfunction in the thoracic aorta. A significant increase in the β-index, and thus in arterial stiffness, was also detected in mesenteric arteries from the three HF groups, due to enhanced deposition of collagen in the vascular wall. SOLF also induced hypotrophic inward remodeling. In conclusion, these data demonstrate a deleterious effect of HF feeding on obesity-related vascular alterations that is exacerbated by SFA

Rationale and design of the Concordance study between FFR and iFR for the assessment of lesions in the left main coronary artery. The ILITRO-EPIC-07 Trial

Introduction and objectives: Patients with left main coronary artery (LMCA) stenosis have been excluded from the trials that support the non-inferiority of the instantaneous wave-free ratio (iFR) compared to the fractional flow reserve (FFR) in the decision-making process of coronary revascularization. This study proposes to prospectively assess the concordance between the two indices in LMCA lesions and to validate the iFR cut-off value of 0.89 for clinical use. Methods: National, prospective, and observational multicenter registry of 300 consecutive patients with intermediate lesions in the LMCA (angiographic stenosis, 25% to 60%. A pressure gudiewire study and determination of the RFF and the iFR will be performed: in the event of a negative concordant result (FFR > 0.80/iFR > 0.89), no treatment will be performed; in case of a positive concordant result (FFR 0.80/iFR 0.89), an intravascular echocardiography will be performed and revascularization will be delayed if the minimum lumen area is > 6 mm(2). The primary clinical endpoint will be a composite of cardiovascular death, LMCA lesion-related non-fatal infarction or need for revascularization of the LMCA lesion at 12 months. Conclusions: Confirm that an iFR-guided decision-making process in patients with intermediate LMCA stenosis is clinically safe and would have a significant clinical impact. Also, justify its systematic use when prescribing treatment in these potentially high-risk patients

La participación de ayudantes alumnos en el Ciclo de Nivelación: una estrategia de formación y colaboración en procesos de enseñanza

8 p.El conocimiento en educación y en investigación en Ciencias de la Salud, generó nuevas perspectivas de análisis en el ámbito de la formación en salud humana. A partir del cambio curricular en la Facultad de Ciencias Médicas (UNC), el Departamento de Admisión implementó el Programa de Mejoramiento del Ciclo de Nivelación de la Carrera de Medicina, cuya definición incluyó estrategias para su continua revalorización académica. En este marco, se consideró prioritaria la formación de ayudantes alumnos como un espacio que afianza el estudio del alumno, el aprendizaje autónomo y la participación en grupos de trabajo académico. El ingreso a la formación universitaria implica el aprendizaje de reglas propias del estudio superior, la autonomía en el aprendizaje es una facultad que requiere ser construida, no nace con los sujetos, es por ello que, como institución educativa, la universidad debe promover su construcción y potenciación. Como una característica esencial del aprendizaje en la universidad, los ayudantes alumnos constituyen un nexo especial entre docentes y alumnos. Reconociendo la particular importancia que cobra este nexo entre docentes y aspirantes a la carrera de Medicina en el Ciclo de Nivelación y valorando la enseñanza situada, que destaca la actividad y el contexto para el aprendizaje, el Departamento de Admisión permite a los ayudantes alumnos aprender involucrándose en el mismo tipo de actividades que enfrentan los expertos en diferentes campos del conocimiento. Promueve asimismo su participación en actividades como seguimiento del Ámbito Virtual y el desarrollo de diferentes proyectos de investigación. Estas acciones se concretan a través de un curso anual que aborda dos áreas: la pedagógico-didáctica y la investigación y ambas líneas de profundización se fundamentan en la utilidad de las herramientas del campo pedagógico para lograr un aprendizaje autónomo e integrar grupos de trabajo académico. En este marco la formación didáctica de los ayudantes se sostiene como un pilar fundamental tanto en su proceso formativo como su participación en las actividades vinculadas a la enseñanza de objetivos específicos en el área de las ciencias de la salud en el Ciclo de Nivelación.http://creativecommons.org/licenses/by-sa/2.5/ar/deed.es_ARFil: Lucchese, Marcela Susana María. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Área de Admisión; Argentina.Fil: Novella, María de Lourdes. Universidad Nacional de Córdoba. Facultad de Cienicas Médicas. Área de Admisión; Argentina.Fil: Fernández, Alicia Ruth. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Área de Admisión; Argentina.Fil: Bollati, Alicia M. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Área de Admisión; Argentina.Fil: Enders, Julio E. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Escuela de Salud Pública y Ambiente; Argentina.Fil: Burrone, María Soledad. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Área de Admisión; Argentina.Fil: Frestes, Ricardo Emilio. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Cátedra de Biología Celular, Histología y Embriología; Argentina.Fil: Triquell, María Fernanda. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Instituto de Biología Celular, Histología y Embriología; Argentina.Fil: Antuña, Ana. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Departamento de Enseñanza Práctica; Argentina.Fil: Trucchia, Silvina. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Cátedra de Medicina Antropológica; Argentina.Fil: Reginatto, Gabriel Alfonso. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Departamento de Admisión; Argentina.Fil: Tomatis, Cristal. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Departamento de Admisión; Argentina.Fil: Picone, Alicia. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Departamento de Admisión; Argentina.Fil: Olivero, Mariano. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Departamento de Admisión; Argentina.Fil: Balzi, Marcela. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Departamento de Admisión; Argentina.Fil: Misana, Antonella. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Departamento de Admisión; Argentina.Otras Ciencias de la Educació

Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor

AbstractDespite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio