Mild and short-term caloric restriction prevents obesity-induced cardiomyopathy in young zucker rats without changing in metabolites and fatty acids cardiac profile

Caloric restriction (CR) ameliorates cardiac dysfunction associated with obesity. However, most of the studies have been performed under severe CR (30-65% caloric intake decrease) for several months or even years in aged animals. Here, we investigated whether mild (20% food intake reduction) and short-term (2-weeks) CR prevented the obese cardiomyopathy phenotype and improved the metabolic profile of young (14 weeks of age) genetically obese Zucker fa/fa rats. Heart weight (HW) and HW/tibia length ratio was significantly lower in fa/fa rats after 2 weeks of CR than in counterparts fed ad libitum. Invasive pressure measurements showed that systolic blood pressure, maximal rate of positive left ventricle (LV) pressure, LV systolic pressure and LV end-diastolic pressure were all significantly higher in obese fa/fa rats than in lean counterparts, which were prevented by CR. Magnetic resonance imaging revealed that the increase in LV end-systolic volume, stroke volume and LV wall thickness observed in fa/fa rats was significantly lower in animals on CR diet. Histological analysis also revealed that CR blocked the significant increase in cardiomyocyte diameter in obese fa/fa rats. High resolution magic angle spinning magnetic resonance spectroscopy analysis of the LV revealed a global decrease in metabolites such as taurine, creatine and phosphocreatine, glutamate, glutamine and glutathione, in obese fa/fa rats, whereas lactate concentration was increased. By contrast, fatty acid concentrations in LV tissue were significantly elevated in obese fa/fa rats. CR failed to restore the LV metabolomic profile of obese fa/fa rats. In conclusion, mild and short-term CR prevented an obesity-induced cardiomyopathy phenotype in young obese fa/fa rats independently of the cardiac metabolic profile.This study was supported by grants from Spanish Ministry of Science and Innovation (BFU2011-25303), Spanish Institute of Health Carlos III (CP15/00129), UCM groups (GR-921641), SESCAMET, Fundación Mutua Madrileña, Fundación Eugenio Rodríguez Pascual and Fondos FEDER.Peer Reviewe

Psychometric properties of the Internalized Stigma of Mental Illness scale adapted for people who use psychoactive substances.

Background: People who consume psychoactive substances may experience situations of social stigma on the part of the society in general, and also situations of internalized-stigma derived from their own consumption of substances. The Internalized Stigma of Mental Illness (ISMI) scale has been shown to be valid and reliable to evaluate the internalized-stigma in people with severe mental disorders, but in Argentina there is no a Spanish version of this scale for use with people who use psychoactive substances. The objective of this work was to evaluate the psychometric properties of the Spanish version of the Internalized Stigma of Mental Illness instrument adapted for people who use psychoactive substances.Method: The work was carried out on a sample of 200 patients older than 18 years under treatment of rehabilitation by consumption of psychoactive substances in a public institution of the city of Córdoba (Argentina) between the years 2014 and 2016. The instrument used was the Internalized Stigma of Mental Illness (ISMI) previously adapted for use in these groups of patients. It was determined the reliability of the scale through Cronbach’s coefficients ? and factorial structure was analyzed through an exploratory factor analysis.Results: The obtained coefficients showed a high reliability, while in the factorial structure emerged the 4 theoretical dimensions described by Ritsher, namely: social isolation, perceived discrimination, alienation and stereotyping. Conclusion: It is concluded that the scale adapted for people who use psychoactive substances is reliable and with an adequate factorial structure.</p

Regulation of BDNF Release by ARMS/Kidins220 through Modulation of Synaptotagmin-IV Levels

BDNF is a growth factor with important roles in the nervous system in both physiological and pathological conditions, but the mechanisms controlling its secretion are not completely understood. Here, we show that ARMS/Kidins220 negatively regulates BDNF secretion in neurons from the CNS and PNS. Downregulation of the ARMS/Kidins220 protein in the adult mouse brain increases regulated BDNF secretion, leading to its accumulation in the striatum. Interestingly, two mouse models of Huntington's disease (HD) showed increased levels of ARMS/Kidins220 in the hippocampus and regulated BDNF secretion deficits. Importantly, reduction of ARMS/Kidins220 in hippocampal slices from HD mice reversed the impaired regulated BDNF release. Moreover, there are increased levels of ARMS/Kidins220 in the hippocampus and PFC of patients with HD. ARMS/Kidins220 regulates Synaptotagmin-IV levels, which has been previously observed to modulate BDNF secretion. These data indicate that ARMS/Kidins220 controls the regulated secretion of BDNF and might play a crucial role in the pathogenesis of HD.SIGNIFICANCE STATEMENT BDNF is an important growth factor that plays a fundamental role in the correct functioning of the CNS. The secretion of BDNF must be properly controlled to exert its functions, but the proteins regulating its release are not completely known. Using neuronal cultures and a new conditional mouse to modulate ARMS/Kidins220 protein, we report that ARMS/Kidins220 negatively regulates BDNF secretion. Moreover, ARMS/Kidins220 is overexpressed in two mouse models of Huntington's disease (HD), causing an impaired regulation of BDNF secretion. Furthermore, ARMS/Kidins220 levels are increased in brain samples from HD patients. Future studies should address whether ARMS/Kidins220 has any function on the pathophysiology of HD

Development of an activity disease score in patients with uveitis (UVEDAI)

To develop a disease activity index for patients with uveitis (UVEDAI) encompassing the relevant domains of disease activity considered important among experts in this field. The steps for designing UVEDAI were: (a) Defining the construct and establishing the domains through a formal judgment of experts, (b) A two-round Delphi study with a panel of 15 experts to determine the relevant items, (c) Selection of items: A logistic regression model was developed that set ocular inflammatory activity as the dependent variable. The construct "uveitis inflammatory activity" was defined as any intraocular inflammation that included external structures (cornea) in addition to uvea. Seven domains and 15 items were identified: best-corrected visual acuity, inflammation of the anterior chamber (anterior chamber cells, hypopyon, the presence of fibrin, active posterior keratic precipitates and iris nodules), intraocular pressure, inflammation of the vitreous cavity (vitreous haze, snowballs and snowbanks), central macular edema, inflammation of the posterior pole (the presence and number of choroidal/retinal lesions, vascular inflammation and papillitis), and global assessment from both (patient and physician). From all the variables studied in the multivariate model, anterior chamber cell grade, vitreous haze, central macular edema, inflammatory vessel sheathing, papillitis, choroidal/retinal lesions and patient evaluation were included in UVEDAI. UVEDAI is an index designed to assess the global ocular inflammatory activity in patients with uveitis. It might prove worthwhile to motorize the activity of this extraarticular manifestation of some rheumatic diseases

Ipsilesional Hippocampal GABA Is Elevated and Correlates With Cognitive Impairment and Maladaptive Neurogenesis After Cortical Stroke in Mice.

BACKGROUND Cognitive dysfunction is a frequent stroke sequela, but its pathogenesis and treatment remain unresolved. Involvement of aberrant hippocampal neurogenesis and maladaptive circuitry remodeling has been proposed, but their mechanisms are unknown. Our aim was to evaluate potential underlying molecular/cellular events implicated. METHODS Stroke was induced by permanent occlusion of the middle cerebral artery occlusion in 2-month-old C57BL/6 male mice. Hippocampal metabolites/neurotransmitters were analyzed longitudinally by in vivo magnetic resonance spectroscopy. Cognitive function was evaluated with the contextual fear conditioning test. Microglia, astrocytes, neuroblasts, interneurons, γ-aminobutyric acid (GABA), and c-fos were analyzed by immunofluorescence. RESULTS Approximately 50% of mice exhibited progressive post-middle cerebral artery occlusion cognitive impairment. Notably, immature hippocampal neurons in the impaired group displayed more severe aberrant phenotypes than those from the nonimpaired group. Using magnetic resonance spectroscopy, significant bilateral changes in hippocampal metabolites, such as myo-inositol or N-acetylaspartic acid, were found that correlated, respectively, with numbers of glia and immature neuroblasts in the ischemic group. Importantly, some metabolites were specifically altered in the ipsilateral hippocampus suggesting its involvement in aberrant hippocampal neurogenesis and remodeling processes. Specifically, middle cerebral artery occlusion animals with higher hippocampal GABA levels displayed worse cognitive outcome. Implication of GABA in this setting was supported by the amelioration of ischemia-induced memory deficits and aberrant hippocampal neurogenesis after blocking pharmacologically GABAergic neurotransmission, an intervention which was ineffective when neurogenesis was inhibited. These data suggest that GABA exerts its detrimental effect, at least partly, by affecting morphology and integration of newborn neurons into the hippocampal circuits. CONCLUSIONS Hippocampal GABAergic neurotransmission could be considered a novel diagnostic and therapeutic target for poststroke cognitive impairment.S

Enfermedad de Gaucher en Argentina: un informe del Registro Internacional de Gaucher y del Grupo Argentino de Diagnóstico y Tratamiento de la Enfermedad de Gaucher

La Enfermedad de Gaucher por su baja frecuencia está incluida dentro de las enfermedades huérfanas. En 1991 comenzó el ingreso de pacientes en el Registro Internacional de Gaucher. En 1992 se incorporaron los primeros dos pacientes de Latinoamérica. En 2006 se creó el Grupo Argentino de Diagnóstico y Tratamiento de la Enfermedad de Gaucher siendo sus objetivos principales el entendimiento de la prevalencia, presentación, manejo y tratamiento de la Enfermedad de Gaucher en Argentina. Hasta el 1 de febrero del 2013 ingresaron al Registro Internacional 5.986 pacientes provenientes de 60 países, de los cuales 133 (2.22%) fueron argentinos. El análisis de esta publicación fue realizado sobre 133 pacientes con Enfermedad de Gaucher. Esta es la primera publicación del Grupo Argentino de Diagnóstico y Tratamiento en base a los datos del Registro Internacional. La casuística argentina mostró un predominio femenino y la forma clínica más frecuente fue el tipo 1 (97.7%, n=128). El genotipo fue identificado en 57 pacientes (42.9%), siendo el más frecuente el N370S/ otro alelo (82.5%). Entre los pacientes con datos reportados, los síntomas basales predominantes, previos al inicio del tratamiento con Imiglucerasa que predominaron fueron la esplenomegalia (100%, n=13) y la hepatomegalia (88.9%, n=8) y como citopenias más frecuentes, la trombocitopenia (64.2%, n=34) y la anemia (45.9%, n=28). La infiltración de la médula ósea como un marcador específico de enfermedad ósea se encontró en el 50% de los pacientes. En total, el 85.7% de los pacientes argentinos reciben terapia de reemplazo enzimático con Imiglucerasa, lográndose las metas terapéuticas, en la mayoría de los casos, en la última evaluación. Las metas terapéuticas más frecuentemente alcanzadas resultaron: el control de las manifestaciones óseas (dolor óseo y crisis ósea, 81.9% y 99% respectivamente) y la normalización de la hemoglobina (86.5%). La terapia de reemplazo enzimática con Imiglucerasa, a largo plazo en la población argentina demostró ser una herramienta eficaz para mejorar los parámetros clínicos y bioquímicos de la Enfermedad de Gaucher tipo1.Fil: Drelichman, G.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Fernández Escobar, Nicolás. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Basack, Nora. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Kohan, R.. Registro Argentino de Gaucher; ArgentinaFil: Watman, N.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Bolesina, M.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Elena, G.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Veber, S. E.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Dragosky, M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Oncología Marie Curie; ArgentinaFil: Annetta, I.. Gobierno de la Ciudad de Buenos Aires. Hospital de Oncología Marie Curie; ArgentinaFil: Feliu, A.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Sciuccati, Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Cuello, María Fernanda. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fynn, Alcira. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; ArgentinaFil: Dodelson de Kremer, Raquel. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; ArgentinaFil: Angaroni, Celia Juana. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; ArgentinaFil: Giner Ayala, Alicia. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; ArgentinaFil: Del Valle Oller, Ana María. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Guelbert, Norberto Bernardo. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; ArgentinaFil: Delgado, María Andrea. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; ArgentinaFil: Becerra, Adriana Berónica. Provincia de Buenos Aires. Ministerio de Salud. Hospital de Niños "Sor María Ludovica" de la Plata; ArgentinaFil: Oliveri, María Beatriz. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Larroudé, M.. Centro Médico TIEMPO; ArgentinaFil: Masllorens, F.. Provincia de Buenos Aires. Ministerio de Salud. Hospital Nacional “Prof. Dr. A. Posadas"; ArgentinaFil: Szlago, M.. Fundación para el eEstudio de las Enfermedades Neurometabólicas; Argentina. Laboratorio de Neuroquímica “Dr. N. A. Chamoles”; ArgentinaFil: Schenone, A.. Laboratorio de Neuroquímica “Dr. N. A. Chamoles”; Argentina. Fundación para el eEstudio de las Enfermedades Neurometabólicas; Argentin

The Vacuolar Pathway in Macrophages Plays a Major Role in Antigen Cross-Presentation Induced by the Pore-Forming Protein Sticholysin II Encapsulated Into Liposomes

Cross-presentation is an important mechanism for the differentiation of effector cytotoxic T lymphocytes (CTL) from naïve CD8+ T-cells, a key response for the clearance of intracellular pathogens and tumors. The liposomal co-encapsulation of the pore-forming protein sticholysin II (StII) with ovalbumin (OVA) (Lp/OVA/StII) induces a powerful OVA-specific CTL activation and an anti-tumor response in vivo. However, the pathway through which the StII contained in this preparation is able to induce antigen cross-presentation and the type of professional antigen presenting cells (APCs) involved have not been elucidated. Here, the ability of mouse bone marrow-derived dendritic cells (BM-DCs) and macrophages (BM-MΦs) stimulated with Lp/OVA/StII to activate SIINFEKL-specific B3Z CD8+ T cells was evaluated in the presence of selected inhibitors. BM-MΦs, but not BM-DCs were able to induce SIINFEKL-specific B3Z CD8+ T cell activation upon stimulation with Lp/OVA/StII. The cross-presentation of OVA was markedly decreased by the lysosome protease inhibitors, leupeptin and cathepsin general inhibitor, while it was unaffected by the proteasome inhibitor epoxomicin. This process was also significantly reduced by phagocytosis and Golgi apparatus function inhibitors, cytochalasin D and brefeldin A, respectively. These results are consistent with the concept that BM-MΦs internalize these liposomes through a phagocytic mechanism resulting in the cross-presentation of the encapsulated OVA by the vacuolar pathway. The contribution of macrophages to the CTL response induced by Lp/OVA/StII in vivo was determined by depleting macrophages with clodronate-containing liposomes. CTL induction was almost completely abrogated in mice depleted of macrophages, demonstrating the relevance of these APCs in the antigen cross-presentation induced by this formulation

Raicilla clúster de turismo

Es importante mencionar que este proyecto corresponde al seguimiento de los ciclos anteriores, Primavera y Verano 2022. Enunciando el plan de continuidad que se tuvo, se avanzó con la creación de un taller de capacitación para la profesionalización de las experiencias, llevando a la existencia la estructura y contenido que se presentará con el objetivo de que durante la siguiente etapa (Primavera 2023) se pueda llevar a cabo. Durante el actual semestre, se realizaron diversos productos, levantamientos de información y entregas que derivaron en la creación del “Taller de Profesionalización de Experiencias Turísticas para la Ruta de la Raicilla.” Los objetivos de este producto son crear interés entre los raicilleros y taberneros a través de la información y el conocimiento del potencial turístico que tiene la raicilla no solo como un objeto de evento, sino como un producto turístico. Además, se crearon productos para redes sociales que sirvieran como guía para aquellas tabernas que busquen impulsar sus marcas y productos a través de campañas de comunicación en estos medios, el objetivo de estos productos fue unificar la manera en que las marcas de raicilla se comunican con sus potenciales clientes y el público interesado.ITESO, A.C

Comprehensive Analysis of NRG1 Common and Rare Variants in Hirschsprung Patients

Hirschsprung disease (HSCR, OMIM 142623) is a developmental disorder characterized by the absence of ganglion cells along variable lengths of the distal gastrointestinal tract, which results in tonic contraction of the aganglionic gut segment and functional intestinal obstruction. The RET proto-oncogene is the major gene for HSCR with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology. Many other genes have been described to be associated with the pathology, as NRG1 gene (8p12), encoding neuregulin 1, which is implicated in the development of the enteric nervous system (ENS), and seems to contribute by both common and rare variants. Here we present the results of a comprehensive analysis of the NRG1 gene in the context of the disease in a series of 207 Spanish HSCR patients, by both mutational screening of its coding sequence and evaluation of 3 common tag SNPs as low penetrance susceptibility factors, finding some potentially damaging variants which we have functionally characterized. All of them were found to be associated with a significant reduction of the normal NRG1 protein levels. The fact that those mutations analyzed alter NRG1 protein would suggest that they would be related with HSCR disease not only in Chinese but also in a Caucasian population, which reinforces the implication of NRG1 gene in this pathology

Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. Methods: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.Peer reviewe