Airway allergy causes alveolar macrophage death, profound alveolar disorganization and surfactant dysfunction.

Respiratory disorders caused by allergy have been associated to bronchiolar inflammation leading to life-threatening airway narrowing. However, whether airway allergy causes alveolar dysfunction contributing to the pathology of allergic asthma remains unaddressed. To explore whether airway allergy causes alveolar dysfunction that might contribute to the pathology of allergic asthma, alveolar structural and functional alterations were analyzed during house dust mite (HDM)-induced airway allergy in mice, by flow cytometry, light and electron microscopy, monocyte transfer experiments, assessment of intra-alveolarly-located cells, analysis of alveolar macrophage regeneration in Cx3cr1 cre:R26-yfp chimeras, analysis of surfactant-associated proteins, and study of lung surfactant biophysical properties by captive bubble surfactometry. Our results demonstrate that HDM-induced airway allergic reactions caused severe alveolar dysfunction, leading to alveolar macrophage death, pneumocyte hypertrophy and surfactant dysfunction. SP-B/C proteins were reduced in allergic lung surfactant, that displayed a reduced efficiency to form surface-active films, increasing the risk of atelectasis. Original alveolar macrophages were replaced by monocyte-derived alveolar macrophages, that persisted at least two months after the resolution of allergy. Monocyte to alveolar macrophage transition occurred through an intermediate stage of pre-alveolar macrophage and was paralleled with translocation into the alveolar space, Siglec-F upregulation, and downregulation of CX3CR1. These data support that the severe respiratory disorders caused by asthmatic reactions not only result from bronchiolar inflammation, but additionally from alveolar dysfunction compromising an efficient gas exchange.

Resident macrophage-dependent immune cell scaffolds drive anti-bacterial defense in the peritoneal cavity.

Peritoneal immune cells reside unanchored within the peritoneal fluid in homeostasis. Here, we examined the mechanisms that control bacterial infection in the peritoneum using a mouse model of abdominal sepsis following intraperitoneal Escherichia coli infection. Whole-mount immunofluorescence and confocal microscopy of the peritoneal wall and omentum revealed that large peritoneal macrophages (LPMs) rapidly cleared bacteria and adhered to the mesothelium, forming multilayered cellular aggregates composed by sequentially recruited LPMs, B1 cells, neutrophils, and monocyte-derived cells (moCs). The formation of resident macrophage aggregates (resMφ-aggregates) required LPMs and thrombin-dependent fibrin polymerization. E. coli infection triggered LPM pyroptosis and release of inflammatory mediators. Resolution of these potentially inflammatory aggregates required LPM-mediated recruitment of moCs, which were essential for fibrinolysis-mediated resMφ-aggregate disaggregation and the prevention of peritoneal overt inflammation. Thus, resMφ-aggregates provide a physical scaffold that enables the efficient control of peritoneal infection, with implications for antimicrobial immunity in other body cavities, such as the pleural cavity or brain ventricles.

Discovery of small-molecule enzyme activators by activity-based protein profiling.

Activity-based protein profiling (ABPP) has been used extensively to discover and optimize selective inhibitors of enzymes. Here, we show that ABPP can also be implemented to identify the converse-small-molecule enzyme activators. Using a kinetically controlled, fluorescence polarization-ABPP assay, we identify compounds that stimulate the activity of LYPLAL1-a poorly characterized serine hydrolase with complex genetic links to human metabolic traits. We apply ABPP-guided medicinal chemistry to advance a lead into a selective LYPLAL1 activator suitable for use in vivo. Structural simulations coupled to mutational, biochemical and biophysical analyses indicate that this compound increases LYPLAL1's catalytic activity likely by enhancing the efficiency of the catalytic triad charge-relay system. Treatment with this LYPLAL1 activator confers beneficial effects in a mouse model of diet-induced obesity. These findings reveal a new mode of pharmacological regulation for this large enzyme family and suggest that ABPP may aid discovery of activators for additional enzyme classes.

Consenso: seguridad del paciente y las metas internacionales / Patient safety and the international goals: Consensus document

La seguridad del paciente es una de las dimensiones de la atención. Los avances médicos han tornado los procesos de atención cada vez más complejos, y, usualmente, hay una conjunción de circunstancias que confluyen para que ocurran errores. Los eventos adversos constituyen un problema grave de salud pública al ocasionar daños de diversos grados al paciente y a su familia, lo cual, además, lleva a incrementar el costo del proceso de atención y la estancia hospitalaria.La mayoría de los eventos adversos se producen en los hospitales, ya que, por su complejidad, su población está sometida a un mayor riesgo asociado a la atención. Se presenta este consenso con el objetivo de ofrecer herramientas cuya implementación contribuya a brindar una atención más segura.

Patient safety is one of the dimensions of care. Medical advances have made assistance processes more and more complex, and there isusually a combination of circumstances that converge for errors to occur. Adverse events constitute a serious public health problem, causing damages of varying degrees to the patient and his family, which also leads to an increase in the cost of the care process and hospital stay. Most of the adverse events occur in hospitals because their complexity is subject to a greater risk associated with care. That is why we present this consensus with the aim of offering tools whose implementation can contribute to provide a safer healthcare.

[Patient safety and the international goals: Consensus document]. / Consenso: seguridad del paciente y las metas internacionales.

Patient safety is one of the dimensions of care. Medical advances have made assistance processes more and more complex, and there is usually a combination of circumstances that converge for errors to occur. Adverse events constitute a serious public health problem, causing damages of varying degrees to the patient and his family, which also leads to an increase in the cost of the care process and hospital stay. Most of the adverse events occur in hospitals because their complexity is subject to a greater risk associated with care. That is why we present this consensus with the aim of offering tools whose implementation can contribute to provide a safer healthcare.

La seguridad del paciente es una de las dimensiones de la atención. Los avances médicos han tornado los procesos de atención cada vez más complejos, y, usualmente, hay una conjunción de circunstancias que confluyen para que ocurran errores. Los eventos adversos constituyen un problema grave de salud pública al ocasionar daños de diversos grados al paciente y a su familia, lo cual, además, lleva a incrementar el costo del proceso de atención y la estancia hospitalaria. La mayoría de los eventos adversos se producen en los hospitales, ya que, por su complejidad, su población está sometida a un mayor riesgo asociado a la atención. Se presenta este consenso con el objetivo de ofrecer herramientas cuya implementación contribuya a brindar una atención más segura.

PGRMC2 is an intracellular haem chaperone critical for adipocyte function.

Haem is an essential prosthetic group of numerous proteins and a central signalling molecule in many physiologic processes1,2. The chemical reactivity of haem means that a network of intracellular chaperone proteins is required to avert the cytotoxic effects of free haem, but the constituents of such trafficking pathways are unknown3,4. Haem synthesis is completed in mitochondria, with ferrochelatase adding iron to protoporphyrin IX. How this vital but highly reactive metabolite is delivered from mitochondria to haemoproteins throughout the cell remains poorly defined3,4. Here we show that progesterone receptor membrane component 2 (PGRMC2) is required for delivery of labile, or signalling haem, to the nucleus. Deletion of PGMRC2 in brown fat, which has a high demand for haem, reduced labile haem in the nucleus and increased stability of the haem-responsive transcriptional repressors Rev-Erbα and BACH1. Ensuing alterations in gene expression caused severe mitochondrial defects that rendered adipose-specific PGRMC2-null mice unable to activate adaptive thermogenesis and prone to greater metabolic deterioration when fed a high-fat diet. By contrast, obese-diabetic mice treated with a small-molecule PGRMC2 activator showed substantial improvement of diabetic features. These studies uncover a role for PGRMC2 in intracellular haem transport, reveal the influence of adipose tissue haem dynamics on physiology and suggest that modulation of PGRMC2 may revert obesity-linked defects in adipocytes.

Intestinal bitter taste receptor activation alters hormone secretion and imparts metabolic benefits.

OBJECTIVES: Extracts of the hops plant have been shown to reduce weight and insulin resistance in rodents and humans, but elucidation of the mechanisms responsible for these benefits has been hindered by the use of heterogeneous hops-derived mixtures. Because hop extracts are used as flavoring agents for their bitter properties, we hypothesized that bitter taste receptors (Tas2rs) could be mediating their beneficial effects in metabolic disease. Studies have shown that exposure of cultured enteroendocrine cells to bitter tastants can stimulate release of hormones, including glucagon-like peptide 1 (GLP-1). These findings have led to the suggestion that activation of Tas2rs may be of benefit in diabetes, but this tenet has not been tested. Here, we have assessed the ability of a pure derivative of a hops isohumulone with anti-diabetic properties, KDT501, to signal through Tas2rs. We have further used this compound as a tool to systematically assess the impact of bitter taste receptor activation in obesity-diabetes. METHODS: KDT501 was tested in a panel of bitter taste receptor signaling assays. Diet-induced obese mice (DIO) were dosed orally with KDT501 and acute effects on glucose homeostasis determined. A wide range of metabolic parameters were evaluated in DIO mice chronically treated with KDT501 to establish the full impact of activating gut bitter taste signaling. RESULTS: We show that KDT501 signals through Tas2r108, one of 35 mouse Tas2rs. In DIO mice, acute treatment stimulated GLP-1 secretion and enhanced glucose tolerance. Chronic treatment caused weight and fat mass loss, increased energy expenditure, enhanced glucose tolerance and insulin sensitivity, normalized plasma lipids, and induced broad suppression of inflammatory markers. Chronic KDT501 treatment altered enteroendocrine hormone levels and bile acid homeostasis and stimulated sustained GLP-1 release. Combined treatment with a dipeptidyl peptidase IV inhibitor amplified the incretin-based benefits of this pure isohumulone. CONCLUSIONS: Activation of Tas2r108 in the gut results in a remodeling of enteroendocrine hormone release and bile acid metabolism that ameliorates multiple features of metabolic syndrome. Targeting extraoral bitter taste receptors may be useful in metabolic disease.

The Influence of a KDT501, a Novel Isohumulone, on Adipocyte Function in Humans.

OBJECTIVE: In a phase II clinical trial in nine obese, insulin-resistant humans, we observed that treatment with KDT501, a novel isohumulone drug, increased total and high-molecular weight (HMW) adiponectin in plasma. The objective was to determine whether KDT501 increased adiponectin secretion from subcutaneous white adipose tissue (SC WAT) and the underlying mechanism(s). METHODS: Nine obese participants with either prediabetes or with normal glucose tolerance plus three features of metabolic syndrome were part of the study. SC WAT biopsies were performed before and after 28 days of KDT501 treatment in a clinical research setting. In addition, a cold stimulus was used to induce thermogenic gene expression. Adiponectin secretion was measured, and gene expression of 130 genes involved in adipose tissue function was determined. The effect of KDT501 on adipocyte mitochondrial function was analyzed in vitro. RESULTS: SC WAT explants secreted more total and HMW adiponectin after KDT501 treatment (P < 0.05). After KDT501 treatment, a number of genes involved in thermogenesis and lipolysis were induced by cold (P < 0.05). KDT501 also potentiated ß-adrenergic signaling (P < 0.001) and enhanced mitochondrial function in adipocytes (P < 0.001). CONCLUSION: KDT501 induced adiponectin secretion posttranscriptionally and increased gene expression of thermogenic and lipolytic genes in response to cold stimulation. These beneficial effects on SC WAT may be explained by the ability of KDT501 to potentiate ß-adrenergic signaling and enhance mitochondrial function in adipocytes. CLINICAL TRIAL REGISTRATION: https://www.ClinicalTrials.gov, ID number: NCT02444910.

Diagnóstico de situación de seguridad del paciente en Argentina: Estudio transversal / The current status of patient safety in Argentina: Cross sectional study

Introducción. La seguridad de los pacientes es un objetivo prioritario de las organizaciones de salud. Objetivo. Conocer las actitudes, prácticas y condiciones de seguridad del paciente pediátrico en Argentina. Material y métodos. La Subcomisión de Calidad y Seguridad del Paciente de la Sociedad Argentina de Pediatría y Programa Nacional de Actualización Pediátrica elaboraron una encuesta sobre seguridad del paciente y prevención de errores (datos poblacionales, 9 dimensiones para internación, 5 para atención ambulatoria). El instrumento fue enviado a los alumnos de Programa Nacional de Actualización Pediátrica 2013, distribuidos en todo el país. Resultados. Encuesta administrada a 7438 alumnos; respondida por 6424 (86%). Población: edad: 42% de 30 a 40 años. Mujeres: 80%. Residencia/concurrencia en Pediatría: 83%. Formación en seguridad del paciente: 30%. Internación: 15% respondió que la institución donde trabajaba tenía Comité de Seguridad. El 74% carecía de sistemas de reporte de eventos; 70% no tenía identificación de pacientes; 32% debía prescribir según vademécum; 27% tenía programas de control de infecciones; 28% aplicaba la lista de verificación quirúrgica. Ambulatorio: 62% respondió que había lavatorios; 56%, que había jabón; y 63%, gel alcohólico disponible. El 70% contestó que los niños con enfermedades exantemáticas esperaban en lugares comunes. Conclusión. Este trabajo muestra que gran parte de los pediatras argentinos encuestados trabaja en condiciones en las que no se prioriza la seguridad del paciente, tanto en pediatría ambulatoria como de internación.

Background. Patient safety is a priority for healthcare organizations. For the PRONAP's 2013 final exam, the Quality & Patient Safety Subcommittee and the PRONAP managers designed a survey to be answered by pediatrician students nationwide. It was destined to evaluate attitudes, practices and safety conditions in which they worked. Aim. To assess the current state of practices in patient safety. Material and methods. Setting and sample: PRONAP students (7,438 pediatrician nationwide) who answered 2013 final exam. Instrument: Patient Safety Survey about pediatric inpatient (9 domains) and outpatient (5 domains) practices, and population data. Results. Patient Safety Survey: 6424 answered (86%). Population: age: 42% 30-40 years. Women: 80%. Residence in Pediatrics: 83%. Patient safety training: 30%. geographical origin: all provinces and CABA. Inpatient practices: 15% answered their institution had Patient Safety Committee. 74% of institutions did not have event reporting systems, 70% didn't have a patient's identification system. 32% answered that drug prescription should be done upon vademecum at their institution, and 27% had infection's control programs, 28% performed surgical checklist in operating room and 55% had a standardized patient hand-off. Outpatient practices: 62% said they had washbasins, 56% had soap available, and 63% alcohol gel. 70% answered children with a supposed infectious rash did not wait his turn separately. This study shows that most pediatricians in Argentine work without prioritizing patient safety, both in ambulatory and inpatient practice.

[The current status of patient safety in Argentina: Cross sectional study]. / Diagnóstico de situación de seguridad del paciente en Argentina. Estudio transversal.

BACKGROUND: Patient safety is a priority for healthcare organizations. For the PRONAP´s 2013 final exam, the Quality & Patient Safety Subcommittee and the PRONAP managers designed a survey to be answered by pediatrician students nationwide. It was destined to evaluate attitudes, practices and safety conditions in which they worked. AIM: To assess the current state of practices in patient safety. MATERIAL AND METHODS: Setting and sample: PRONAP students (7,438 pediatrician nationwide) who answered 2013 final exam. Instrument: Patient Safety Survey about pediatric inpatient (9 domains) and outpatient (5 domains) practices, and population data. RESULTS: Patient Safety Survey: 6424 answered (86%). Population: age: 42% 30-40 years. Women: 80%. Residence in Pediatrics: 83%. Patient safety training: 30%. geographical origin: all provinces and CABA. Inpatient practices: 15% answered their institution had Patient Safety Committee. 74% of institutions did not have event reporting systems, 70% didn´t have a patient´s identification system. 32% answered that drug prescription should be done upon vademecum at their institution, and 27% had infection´s control programs, 28% performed surgical checklist in operating room and 55% had a standardized patient hand-off. Outpatient practices: 62% said they had washbasins, 56% had soap available, and 63% alcohol gel. 70% answered children with a supposed infectious rash did not wait his turn separately. CONCLUSION: This study shows that most pediatricians in Argentine work without prioritizing patient safety, both in ambulatory and inpatient practice.

Introducción. La seguridad de los pacientes es un objetivo prioritario de las organizaciones de salud. Objetivo. Conocer las actitudes, prácticas y condiciones de seguridad del paciente pediátrico en Argentina. Material y métodos. La Subcomisión de Calidad y Seguridad del Paciente de la Sociedad Argentina de Pediatría y Programa Nacional de Actualización Pediátrica elaboraron una encuesta sobre seguridad del paciente y prevención de errores (datos poblacionales, 9 dimensiones para internación, 5 para atención ambulatoria). El instrumento fue enviado a los alumnos de Programa Nacional de Actualización Pediátrica 2013, distribuidos en todo el país. Resultados. Encuesta administrada a 7438 alumnos; respondida por 6424 (86%). Población: edad: 42% de 30 a 40 años. Mujeres: 80%. Residencia/concurrencia en Pediatría: 83%. Formación en seguridad del paciente: 30%. Internación: 15% respondió que la institución donde trabajaba tenía Comité de Seguridad. El 74% carecía de sistemas de reporte de eventos; 70% no tenía identificación de pacientes; 32% debía prescribir según vademécum; 27% tenía programas de control de infecciones; 28% aplicaba la lista de verificación quirúrgica. Ambulatorio: 62% respondió que había lavatorios; 56%, que había jabón; y 63%, gel alcohólico disponible. El 70% contestó que los niños con enfermedades exantemáticas esperaban en lugares comunes. Conclusión. Este trabajo muestra que gran parte de los pediatras argentinos encuestados trabaja en condiciones en las que no se prioriza la seguridad del paciente, tanto en pediatría ambulatoria como de internación

Integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes.

Phenotypic screening is making a comeback in drug discovery as the maturation of chemical proteomics methods has facilitated target identification for bioactive small molecules. A limitation of these approaches is that time-consuming genetic methods or other means are often required to determine the biologically relevant target (or targets) from among multiple protein-compound interactions that are typically detected. Here, we have combined phenotypic screening of a directed small-molecule library with competitive activity-based protein profiling to map and functionally characterize the targets of screening hits. Using this approach, we identify carboxylesterase 3 (Ces3, also known as Ces1d) as a primary molecular target of bioactive compounds that promote lipid storage in adipocytes. We further show that Ces3 activity is markedly elevated during adipocyte differentiation. Treatment of two mouse models of obesity-diabetes with a Ces3 inhibitor ameliorates multiple features of metabolic syndrome, illustrating the power of the described strategy to accelerate the identification and pharmacologic validation of new therapeutic targets.

FSHD muscular dystrophy region gene 1 binds Suv4-20h1 histone methyltransferase and impairs myogenesis.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy with a strong epigenetic component. It is associated with deletion of a macrosatellite repeat leading to over-expression of the nearby genes. Among them, we focused on FSHD region gene 1 (FRG1) since its over-expression in mice, Xenopus laevis and Caenorhabditis elegans, leads to muscular dystrophy-like defects, suggesting that FRG1 plays a relevant role in muscle biology. Here we show that, when over-expressed, FRG1 binds and interferes with the activity of the histone methyltransferase Suv4-20h1 both in mammals and Drosophila. Accordingly, FRG1 over-expression or Suv4-20h1 knockdown inhibits myogenesis. Moreover, Suv4-20h KO mice develop muscular dystrophy signs. Finally, we identify the FRG1/Suv4-20h1 target Eid3 as a novel myogenic inhibitor that contributes to the muscle differentiation defects. Our study suggests a novel role of FRG1 as epigenetic regulator of muscle differentiation and indicates that Suv4-20h1 has a gene-specific function in myogenesis.

Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances oxidative metabolism in skeletal muscle and adipose tissue.

Chromatin modifications are sensitive to environmental and nutritional stimuli. Abnormalities in epigenetic regulation are associated with metabolic disorders such as obesity and diabetes that are often linked with defects in oxidative metabolism. Here, we evaluated the potential of class-specific synthetic inhibitors of histone deacetylases (HDACs), central chromatin-remodeling enzymes, to ameliorate metabolic dysfunction. Cultured myotubes and primary brown adipocytes treated with a class I-specific HDAC inhibitor showed higher expression of Pgc-1α, increased mitochondrial biogenesis, and augmented oxygen consumption. Treatment of obese diabetic mice with a class I- but not a class II-selective HDAC inhibitor enhanced oxidative metabolism in skeletal muscle and adipose tissue and promoted energy expenditure, thus reducing body weight and glucose and insulin levels. These effects can be ascribed to increased Pgc-1α action in skeletal muscle and enhanced PPARγ/PGC-1α signaling in adipose tissue. In vivo ChIP experiments indicated that inhibition of HDAC3 may account for the beneficial effect of the class I-selective HDAC inhibitor. These results suggest that class I HDAC inhibitors may provide a pharmacologic approach to treating type 2 diabetes.

Site-directed mutagenesis to study the role of specific amino acids in the ligand binding domain of PPARs.

The role of certain amino acids in the interactions of ligands with their cognate nuclear receptors is usually achieved by the resolution of the crystal structure of the receptor complexed with the ligand. As a complementary functional approach, site-directed mutagenesis, a technique broadly used in molecular biology, allows the assessment of the role of a specific amino acid in determining the interaction with a specific ligand. This method makes it possible to evaluate several mutations of a key amino acid for ligand binding and to determine the relationship between protein structure and ligand interaction. Here, we describe an application of this technique to evaluate different point mutations on the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ) in the absence or presence of chemically different ligands.

Fluorescence resonance energy transfer techniques to study ligand-mediated interactions of PPARs with coregulators.

The capacity to induce the association of peroxisome proliferator-activated receptors (PPARs) with different transcriptional coregulators is determined by the peculiar 3D-structure that the receptors adopt when bound with a specific ligand. The fluorescence resonance energy transfer assay is a technique widely used to evaluate coregulator recruitment to nuclear receptors induced by ligands. With this assay it is possible to quantitatively determine the interaction and the affinity of coregulators with PPARs when these receptors are complexed with ligands. Here, we describe the use of this technique to assess the preferential interaction and the affinity of PPARγ with coregulators as a function of the chemical structure of the bound ligand.

Linking epigenetics to lipid metabolism: focus on histone deacetylases.

A number of recent studies revealed that epigenetic modifications play a central role in the regulation of lipid and of other metabolic pathways such as cholesterol homeostasis, bile acid synthesis, glucose and energy metabolism. Epigenetics refers to aspects of genome functions regulated in a DNA sequence-independent fashion. Chromatin structure is controlled by epigenetic mechanisms through DNA methylation and histone modifications. The main modifications are histone acetylation and deacetylation on specific lysine residues operated by two different classes of enzymes: Histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. The interaction between these enzymes and histones can activate or repress gene transcription: Histone acetylation opens and activates chromatin, while deacetylation of histones and DNA methylation compact chromatin making it transcriptionally silent. The new evidences on the importance of HDACs in the regulation of lipid and other metabolic pathways will open new perspectives in the comprehension of the pathophysiology of metabolic disorders.

TLE3 is a dual-function transcriptional coregulator of adipogenesis.

PPARγ and Wnt signaling are central positive and negative regulators of adipogenesis, respectively. Here we identify the groucho family member TLE3 as a transcriptional integrator of the PPARγ and Wnt pathways. TLE3 is a direct target of PPARγ that participates in a feed-forward loop during adipocyte differentiation. TLE3 enhances PPARγ activity and functions synergistically with PPARγ on its target promoters to stimulate adipogenesis. At the same time, induction of TLE3 during differentiation provides a mechanism for termination of Wnt signaling. TLE3 antagonizes TCF4 activation by ß-catenin in preadipocytes, thereby inhibiting Wnt target gene expression and reversing ß-catenin-dependent repression of adipocyte gene expression. Transgenic expression of TLE3 in adipose tissue in vivo mimics the effects of PPARγ agonist and ameliorates high-fat-diet-induced insulin resistance. Our data suggest that TLE3 acts as a dual-function switch, driving the formation of both active and repressive transcriptional complexes that facilitate the adipogenic program.

Crystal structure of the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand binding domain complexed with a novel partial agonist: a new region of the hydrophobic pocket could be exploited for drug design.

The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors regulating glucose and lipid metabolism. The search for new PPAR ligands with reduced adverse effects with respect to the marketed antidiabetic agents thiazolidinediones (TZDs) and the dual-agonists glitazars is highly desired. We report the crystal structure and activity of the two enantiomeric forms of a clofibric acid analogue, respectively complexed with the ligand-binding domain (LBD) of PPARgamma, and provide an explanation on a molecular basis for their different potency and efficacy against PPARgamma. The more potent S-enantiomer is a dual PPARalpha/PPARgamma agonist which presents a partial agonism profile against PPARgamma. Docking of the S-enantiomer in the PPARalpha-LBD has been performed to explain its different subtype pharmacological profile. The hypothesis that partial agonists show differential stabilization of helix 3, when compared to full agonists, is also discussed. Moreover, the structure of the complex with the S-enantiomer reveals a new region of the PPARgamma-LBD never sampled before by other ligands.

Aspectos de la política nacional de medicamentos, ley de prescripción de medicamentos por su nombre genérico y Plan Remediar / Documentos de Trabajo

Este trabajo analiza dos aspectos de la Política Nacional de Medicamentos en la Argentina: la Ley sobre Prescripción de Medicamentos por su nombre Genérico y la implementación del Plan Remediar. La investigación apunta a evaluar el impacto económico de esta política sobre el gasto de las familias en salud, centrando el análisis en las patologías más frecuentes, especialmente en la franja más pobre de la población.

This research aims to analyze two components of the National Drug Policy in Argentina: The Generics Medicine Prescribing Law and The Remediar Programme. The study focuses on the evaluation of the economic impact of these policies on family health expenditures, emphasizing the effects on the most economically deprivedpopulation.

Aspectos de la política nacional de medicamentos, ley de prescripción de medicamentos por su nombre genérico y Plan Remediar / Documentos de Trabajo

Este trabajo analiza dos aspectos de la Política Nacional de Medicamentos en la Argentina: la Ley sobre Prescripción de Medicamentos por su nombre Genérico y la implementación del Plan Remediar. La investigación apunta a evaluar el impacto económico de esta política sobre el gasto de las familias en salud, centrando el análisis en las patologías más frecuentes, especialmente en la franja más pobre de la población. (AU)

This research aims to analyze two components of the National Drug Policy in Argentina: The Generics Medicine Prescribing Law and The Remediar Programme. The study focuses on the evaluation of the economic impact of these policies on family health expenditures, emphasizing the effects on the most economically deprivedpopulation. (AU)