CD5L promotes M2 macrophage polarization through autophagy-mediated upregulation of ID3

CD5L (CD5 molecule-like) is a secreted glycoprotein that controls key mechanisms in inflammatory responses, with involvement in processes such as infection, atherosclerosis, and cancer. In macrophages, CD5L promotes an anti-inflammatory cytokine profile in response to TLR activation. In the present study, we questioned whether CD5L is able to influence human macrophage plasticity, and drive its polarization toward any specific phenotype. We compared CD5L-induced phenotypic and functional changes to those caused by IFN/LPS, IL4, and IL10 in human monocytes. Phenotypic markers were quantified by RT-qPCR and flow cytometry, and a mathematical algorithm was built for their analysis. Moreover, we compared ROS production, phagocytic capacity, and inflammatory responses to LPS. CD5L drove cells toward a polarization similar to that induced by IL10. Furthermore, IL10- and CD5L-treated macrophages showed increased LC3-II content and colocalization with acidic compartments, thereby pointing to the enhancement of autophagy-dependent processes. Accordingly, siRNA targeting ATG7 in THP1 cells blocked CD5L-induced CD163 and Mer tyrosine kinase mRNA and efferocytosis. In these cells, gene expression profiling and validation indicated the upregulation of the transcription factor ID3 by CD5L through ATG7. In agreement, ID3 silencing reversed polarization by CD5L. Our data point to a significant contribution of CD5L-mediated autophagy to the induction of ID3 and provide the first evidence that CD5L drives macrophage polarization.Peer ReviewedPostprint (published version

RESISTENCIA DIURÉTICA EN INSUFICIENCIA CARDÍACA AGUDA CONGESTIVA.

La expansión del volumen de líquido extracelular es fundamental para la fisiopatología de la insuficiencia cardíaca. Dicho aumento conduce a presiones elevadas de llenado intracardíaco, dando como resultado un conjunto de signos y síntomas conocido como congestión. Los diuréticos siguen siendo la piedra angular del tratamiento de la insuficiencia cardíaca aguda congestiva, fundamentalmente, diuréticos de asa administrados vía intravenosa, en especial la furosemida. A pesar de su amplio uso y recomendación, existen pocas evidencias científicas respecto a la dosis y vía de administración óptimas. Una comprensión detallada de la farmacocinética de los diuréticos es esencial para el uso seguro y eficaz de la terapia diurética en la insuficiencia cardíaca aguda. La resistencia diurética, definida como una cantidad inadecuada de natriuresis a pesar de un tratamiento diurético intenso, es un desafío clínico que obliga a la necesidad de buscar alternativas terapéuticas para superarla como la reciente estrategia de terapia diurética guiada por diuresis. Entre las alternativas al tratamiento diurético convencional se han propuesto técnicas de depuración extracorpórea como la ultrafiltración, el uso de dopamina a dosis bajas en combinación con diuréticos, la asociación de suero salino hipertónico y dosis altas de furosemida, y antagonistas de los receptores de vasopresina, en especial el tolvaptán, si bien, ninguna de ellas cumple plenamente los objetivos de seguridad y eficacia a un coste razonable. Por tanto, es de especial importancia conocer los diferentes mecanismos renales implicados en la resistencia diurética y hacer nuevos ensayos clínicos que aporten datos concluyentes acerca del uso óptimo de los diuréticos en estos pacientes. <br /

El rol mediador de la pobreza en la asociación entre factores ambientales y el desempeño cognitivo de preescolares

La asociación entre los factores ambientales y el desempeño cognitivo durante la infancia podría estar mediada por la pertenencia a hogares pobres (i.e., hogares con necesidades básicas insatisfechas o satisfechas). Este estudio exploró tal mediación en preescolares de diferentes contextos socioeconómicos. Para tal fin, se administraron tareas que demandaron atención ejecutiva, memoria de trabajo, control inhibitorio, planificación y razonamiento fluido a 250 niños/as de 4 y 5 años. Los resultados sugirieron que la pobreza medió los efectos de la composición familiar, la salud infantil, los factores de riesgo para la salud, cantidad de niños/as y adultos en el hogar, la edad materna y las actividades de alfabetización sobre la atención ejecutiva, el razonamiento fluido y el control inhibitorio. Estos resultados contribuyen a la comprensión de la relación entre los factores ambientales y el desarrollo cognitivo a través de la identificación de la pobreza como variable mediadora.The association between environmental factors and cognitive performance during childhood could be mediated by poverty (i.e., households with Unsatisfied or Satisfied Basic Needs). This study explored such mediating roles in preschoolers from different socioeconomic backgrounds. Tasks to assess executive attention, working memory, inhibitory control, planning, and fluid reasoning were administered to 250 children aged 4 and 5 years. The results suggested that poverty mediated the effects of family composition, child health, health risk factors, children and adults at home, maternal age, and literacy activities on the performance of executive attention, fluid reasoning, and inhibitory control. These results contribute to our understanding of the relationship between environmental factors and cognitive development through the identification of the mediating role of poverty.Fil: Fracchia, Carolina Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Segretin, María Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Hermida, Maria Julia. Universidad Nacional de Hurlingham; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Prats, Lucía María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Lipina, Sebastián Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentin

Empathy for others' suffering and its mediators in mental health professionals

Empathy is a complex cognitive and affective process that allows humans to experience concern for others, comprehend their emotions, and eventually help them. In addition to studies with healthy subjects and various neuropsychiatric populations, a few reports have examined this domain focusing on mental health workers, whose daily work requires the development of a saliently empathic character. Building on this research line, the present population-based study aimed to (a) assess different dimensions of empathy for pain in mental health workers relative to general-physicians and non-medical workers; and (b) evaluate their relationship with relevant factors, such as moral profile, age, gender, years of experience, and workplace type. Relative to both control groups, mental health workers exhibited higher empathic concern and discomfort for others' suffering, and they favored harsher punishment to harmful actions. Furthermore, this was the only group in which empathy variability was explained by moral judgments, years of experience, and workplace type. Taken together, these results indicate that empathy is continuously at stake in mental health care scenarios, as it can be affected by contextual factors and social contingencies. More generally, they highlight the importance of studying this domain in populations characterized by extreme empathic demands.Fil: Santamaria Garcia, Hernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Báez Buitrago, Sandra Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: García, Adolfo Martín. Instituto de Neurología Cognitiva. Laboratorio de Psicología Experimental y Neurociencia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina. Universidad Nacional de Cuyo. Facultad de Educación Elemental y Especial; ArgentinaFil: Flichtentrei, Daniel. Intramed; ArgentinaFil: Prats, Lucía María. Intramed; Argentina. Centro de Educaciones Médicas e Investigación Clínica "Norberto Quirno"; ArgentinaFil: Mastandueno, Ricardo. Intramed; ArgentinaFil: Sigman, Mariano. Universidad Torcuato di Tella; ArgentinaFil: Matallana, Diana. Pontificia Universidad Javeriana; ColombiaFil: Cetkovich Bakmas, Marcelo Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Ibanez Barassi, Agustin Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentin

Disposition of d-penicillamine, a promising drug for preventing alcohol-relapse. Influence of dose, chronic alcohol consumption and age: studies in rats

Pharmacokinetic studies concerning D-penicillamine (an acetaldehyde sequestering agent) are scarce and have not evaluated the influence of chronic ethanol consumption and age on its disposition. Since recent preclinical studies propose D-penicillamine as a promising treatment for alcohol relapse, the main aim of the present work was to evaluate the influence of these two factors on D-penicillamine disposition in order to guide future clinical studies on the anti-relapse efficacy of this drug in alcoholism. Additionally, the effect of the administered dose was also evaluated. To this end, three studies were carried out. Study 1 assessed the influence of dose on D-penicillamine disposition, whereas studies 2 and 3 evaluated, respectively, the influence of chronic alcohol consumption and age. Rapid intravenous administrations of 2, 10 and 30 mg/kg of D-penicillamine were performed using young or adult ethanol-naïve rats or adult ethanol-experienced (subjected to a long-term ethanol self-administration protocol) rats. Pharmacokinetic parameters were derived from the biexponential model. Statistical analysis of CL, normalized AUC0 ∞, V1 and k10 revealed that disposition, in the range plasma concentrations assayed, is non-linear both in young ethanol-naïve and in adult ethanol-experienced rats. Notably, no significant changes in t1/2 were detected. Chronic ethanol consumption significantly reduced CL values by 35% without affecting t1/2. D-Penicillamine disposition was equivalent in young and adult animals. In conclusion, although DP pharmacokinetics is non-linear, the lack of significant alterations of the t1/2 would potentially simplify the clinical use of this drug. Chronic consumption of ethanol also alters D-penicillamine disposition but, again, does not modify t1/2. Copyright © 2014 John Wiley & Sons, Ltd.Peer ReviewMedicin

Associações entre temperamento regulação do cortisol em pré-escolares de lares pobres

El presente trabajo propone analizar las asociaciones entre el temperamento y la regulación del cortisol en una muestra de 46 niños y niñas de 5 años de edad, de hogares pobres; así como el rol modulador del sexo y las condiciones socio-ambientales de los hogares, en tales asociaciones. Los resultados sugieren una mayor proporción de descenso del cortisol matutino durante la noche para las niñas con niveles más bajos de afectividad negativa, los niños con niveles más altos de esfuerzo de control, así como para las niñas y los niños de hogares con mejores condiciones socio-ambientales y con niveles más altos de esfuerzo de control. Asimismo, se identificaron asociaciones específicas entre los valores de regulación del cortisol y un conjunto de 12 ítems del cuestionario de temperamento, en su mayoría correspondientes a la dimensión afectividad negativa. Estos resultados aportan evidencia al estudio de las diferencias individuales del desarrollo autorregulatorio en la niñez, considerando diferentes niveles de organización.The present work proposes to analyze the associations between temperament and cortisol regulation in a sample of 46 boys and girls of 5years-old, from poor homes; as well as the modulating role of sex and the socio-environmental conditions of households in such associations. The results suggest a higher proportion of morning cortisol decline during the night for girls with lower levels of negative affectivity, boys with higher levels of effortful control, as well as for children from homes with better socio-environmental conditions, and with higher levels of effortful control. Likewise, specific associations were identified between cortisol regulation and a set of 12 items of the temperament questionnaire, most of them corresponding to the negative affectivity dimension. These results provide evidence for the study of self-regulatory development in childhood, considering different levels of organization.Este artigo propõe analisar as associações entre temperamento e regulação do cortisol em uma amostra de 46 meninos e meninas de 5 anos de idade de famílias pobres; bem como o papel modulador do sexo e as condições socioambientais das famílias, nessas associações. Os resultados sugerem uma proporção maior de declínio matinal do cortisol durante a noite para meninas com níveis mais baixos de afetividade negativa, meninos com níveis mais altos de esforço de controle, assim como meninas e meninos em domicílios com melhores condições socioeconómicas - ambientais e com níveis mais altos de esforço de controle. Da mesma forma, foram identificadas associações específicas entre os valores de regulação do cortisol e um conjunto de 12 itens do questionário de temperamento, correspondendo principalmente à dimensão afetiva negativa. Esses resultados evidenciam o estudo das diferenças individuais do desenvolvimento autorregulador na infância, considerando diferentes níveis de organização.Fil: Segretin, María Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Prats, Lucía María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Lipina, Sebastián Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentin

Disposition of d-penicillamine, a promising drug for preventing alcohol-relapse. Influence of dose, chronic alcohol consumption and age: studies in rats

Pharmacokinetic studies concerning d-penicillamine (an acetaldehyde sequestering agent) are scarce and have not evaluated the influence of chronic ethanol consumption and age on its disposition. Since recent preclinical studies propose d-penicillamine as a promising treatment for alcohol relapse, the main aim of the present work was to evaluate the influence of these two factors on d-penicillamine disposition in order to guide future clinical studies on the anti-relapse efficacy of this drug in alcoholism. Additionally, the effect of the administered dose was also evaluated. To this end, three studies were carried out. Study 1 assessed the influence of dose on d-penicillamine disposition, whereas studies 2 and 3 evaluated, respectively, the influence of chronic alcohol consumption and age. Rapid intravenous administrations of 2, 10 and 30 mg/kg of d-penicillamine were performed using young or adult ethanol-naïve rats or adult ethanol-experienced (subjected to a long-term ethanol self-administration protocol) rats. Pharmacokinetic parameters were derived from the biexponential model. Statistical analysis of CL, normalized AUC0∞, V1 and k10 revealed that disposition, in the range plasma concentrations assayed, is non-linear both in young ethanol-naïve and in adult ethanol-experienced rats. Notably, no significant changes in t1/2 were detected. Chronic ethanol consumption significantly reduced CL values by 35% without affecting t1/2. d-Penicillamine disposition was equivalent in young and adult animals. In conclusion, although DP pharmacokinetics is non-linear, the lack of significant alterations of the t1/2 would potentially simplify the clinical use of this drug. Chronic consumption of ethanol also alters d-penicillamine disposition but, again, does not modify t1/2

Regional differences in mu-opioid receptor-dependent modulation of basal dopamine transmission in rat striatum

The nigrostriatal dopamine system is implicated in the regulation of reward and motor activity. Dopamine (DA) release in dorsal striatum (DS) is controlled by the firing rate of DA neurons in substantia nigra pars compacta. However, influences at terminal level, such as those involving activation of mu opioid receptors (MORs), can play a key role in determining DA levels in striatum. Nonetheless, published data also suggest that the effect of opioid drugs on DA levels may differ depending on the DS subregion analysed. In this study, in vivo microdialysis in rats was used to explore this regional dependence. Changes in basal DA levels induced by local retrodialysis application of DAMGO (selective MORs agonist) in three different subregions of DS along the rostro-caudal axis were studied. Our results indicate that whereas administration of 10μM DAMGO into the rostral and caudal DS significantly reduced DA levels, in medial DS an increase in DA levels was observed. These data reveal a regional-dependent MOR modulation of DA release in DS, similar to that described in the ventral striatum. Our findings may lead to a better understanding of the nigrostriatal DA system regulation

Individuality and self-regulation in preschoolers

"Different ways of solving planning and spatial working memory tasks generate different taskperformance profiles. Tests were administered to 346 (planning) and 427 (spatial working memory) Argentinean children from different socioeconomic (SES) backgrounds. A cross-sectional design was performed to explore eventual variable profiles of performance that were associated with levels of success or failure on tasks that tapped working memory and planning demands and to evaluate their association with SES backgrounds. The results showed that (1) different task-performance profiles were identified: decreased, changeless, oscillated, or increased; (2) the total score for the tasks was significantly different among these profiles; and (3) there were significant differences in the total score among SES groups, which depended on type of profile. These findings suggested the importance of studying individual differences in the performance of tasks that demand self-regulatory processes of children with SES disadvantages. This is important for the understanding of how children solve problems, and how that behavior varies according to SES." (author's abstract)"Aufgaben zum Planen und zum Arbeitsgedächtnis können verschiedenartig gelöst werden. Argentinische Kinder mit unterschiedlichem sozioökonomischen Status (SES) haben Planungsaufgaben (n=346) und Aufgaben zum visuellen Arbeitsgedächtnis (n=427) gelöst. In einem Querschnittsdesign wurden Lösungsprofile identifiziert und in Verbindung mit dem SES gebracht. Die Ergebnisse zeigten: (1) es gibt unterschiedliche Lösungsprofile: abnehmend, gleichbleibend, oszillierend und zunehmend; (2) die Gesamtpunktzahl für die Aufgaben unterschied sich signifikant zwischen den Lösungsprofilen; (3) die Leistung unterschied sich zwischen den SES-Gruppen in Abhängigkeit der Lösungsprofile. Diese Ergebnisse unterstreichen die Wichtigkeit der Betrachtung individueller Unterschiede in der Bearbeitung von Aufgaben, die Selbstregulation erfassen. Das ist bedeutsam, um zu verstehen, wie Kinder diese Aufgaben lösen und wie sich ihr Verhalten in Abhängigkeit des SES unterscheidet." (Autorenreferat

Ambrisentan use in a HIV-1 infected patient with end-stage renal disease and pulmonary hypertension : minimal removal by hemodialysis - a case report

Ambrisentan is a selective endothelin receptor antagonist used for the treatment of pulmonary arterial hypertension (PAH). Little is known about ambrisentan removal by hemodialysis in patients with end-stage renal disease (ESRD). A 53-year-old woman with HIV/hepatitis C virus (HCV) co-infection, PAH and ESRD on regular hemodialyis was admitted in our hospital due to refractory heart failure while on treatment with bosentan (125 mg twice daily) and tadalafil (20 mg once daily) for PAH and antiretroviral treatment (cART) including darunavir/cobicistat (800/150 mg once daily). Excessive exposure to bosentan due to drug interactions between bosentan and darunavir/cobicistat was suspected. Bosentan was replaced by ambrisentan, with progressive improvement in her clinical condition. Pre- and postdialyzer cocentrations of ambrisentan in plasma were determined and hemodialysis extraction ratio for ambrisentan was 2%. Our results suggest that hemodialysis results in minimal ambrisentan removal, and therefore no specific ambrisentan dosage adjustment seems to be required in ESRD patients undergoing hemodialysis