Vascular O-GlcNAcylation augments reactivity to constrictor stimuli by prolonging phosphorylated levels of the myosin light chain

O-GlcNAcylation is a modification that alters the function of numerous proteins. We hypothesized that augmented O-GlcNAcylation levels enhance myosin light chain kinase (MLCK) and reduce myosin light chain phosphatase (MLCP) activity, leading to increased vascular contractile responsiveness. The vascular responses were measured by isometric force displacement. Thoracic aorta and vascular smooth muscle cells (VSMCs) from rats were incubated with vehicle or with PugNAc, which increases O-GlcNAcylation. In addition, we determined whether proteins that play an important role in the regulation of MLCK and MLCP activity are directly affected by O-GlcNAcylation. PugNAc enhanced phenylephrine (PE) responses in rat aortas (maximal effect, 14.2±2 vs 7.9±1 mN for vehicle, n=7). Treatment with an MLCP inhibitor (calyculin A) augmented vascular responses to PE (13.4±2 mN) and abolished the differences in PE-response between the groups. The effect of PugNAc was not observed when vessels were preincubated with ML-9, an MLCK inhibitor (7.3±2 vs 7.5±2 mN for vehicle, n=5). Furthermore, our data showed that differences in the PE-induced contractile response between the groups were abolished by the activator of AMP-activated protein kinase (AICAR; 6.1±2 vs 7.4±2 mN for vehicle, n=5). PugNAc increased phosphorylation of myosin phosphatase target subunit 1 (MYPT-1) and protein kinase C-potentiated inhibitor protein of 17 kDa (CPI-17), which are involved in RhoA/Rho-kinase-mediated inhibition of myosin phosphatase activity. PugNAc incubation produced a time-dependent increase in vascular phosphorylation of myosin light chain and decreased phosphorylation levels of AMP-activated protein kinase, which decreased the affinity of MLCK for Ca2+/calmodulin. Our data suggest that proteins that play an important role in the regulation of MLCK and MLCP activity are directly affected by O-GlcNAcylation, favoring vascular contraction.

Determinación de la sensibilidad a insecticidas organofosforados, carbamato y piretroides en poblaciones de Aedes aegypti Linneaus, 1762 ( Díptera: Culicidae ) de Panamá / Determining the status of susceptibility to organophosphate, carbamate and pyrethroids insecticides in populations of Aedes aegypti Linneaus, 1762 ( Diptera: Culicidae ) in Panamá

Introducción. Se llevó a cabo un estudio para determinar la sensibilidad de Aedes aegypti provenientes de regiones de alto riesgo de transmisión de dengue en Panamá, a insecticidas organofosforados, carbamatos y piretroides. Objetivo. Evaluar la sensibilidad a insecticidas piretroides, organofosforados y carbamatos en poblaciones de Ae. aegypti provenientes de ocho sitios pertenecientes a siete municipios de Panamá. Materiales y métodos. Se recolectaron poblaciones de Ae. aegypti en diferentes tipos de criaderos localizados en áreas urbanas y se criaron en condiciones controladas de laboratorio. Con la generación F 1 de cada una de las cepas se hicieron bioensayos de sensibilidad siguiendo la metodología estandarizada por la Organización Mundial de la Salud para larvas y adultos. Resultados. Las ocho cepas de Ae. aegypti resultaron sensibles a los insecticidas piretroides deltametrina, lambdacihalotrina y ciflutrina, el organofosforado fenitrotión y los carbamato propoxur y bendiocarb. Solo la cepa CHITRE resultó con resistencia moderada al insecticida deltametrina en larvas (FR 50 =5x). Sin embargo, en adultos resultó sensible. Conclusiones. Es necesaria la vigilancia periódica de la sensibilidad de las poblaciones de Ae. aegypti de los municipios evaluados, con el propósito de conservar en las poblaciones el carácter sensible a estos insecticidas. Los insecticidas aplicados para el control de Ae. aegypti pueden seguir siendo utilizados en los municipios evaluados, pero depende de la sensibilidad de los mosquitos en el área específica.

Introduction: We studied the susceptibility to organophosphate, carbamate and pyrethroid insecticides of Aedes aegypti from different regions of high transmission risk for dengue in Panama. Objective: To evaluate the susceptibility to organophosphate, carbamate and pyrethroid insecticides in Ae. aegypti from eight sites belonging to seven municipalities in Panamá. Materials and methods: We collected Ae. aegypti larval populations in different types of breeding sites located in urban areas. Insects were reared in laboratory control conditions. With the F 1 generation of each strain we performed susceptibility bioassays using WHO standardized methodology for larvae and adults. Results: The eight Ae. Aegypti strains were susceptible to the pyrethroid insecticides: deltamethrin, lambdacyhalothrin and cifluthrin, to the organophosphate fenitrothrion, and to the carbamates propoxur and bendiocarb. Only the CHITRE strain exhibited a moderate resistance to the insecticide deltamethrin in larvae (FR 50 =5x). However, adults were susceptible. Conclusions: It is necessary to perform periodic surveillance to evaluate the susceptibility of Ae. aegypti populations in the studied municipalities with the purpose of preserving their susceptible. The insecticides applied for Ae. aegypti control can still be used in the evaluated municipalities; however it will depend on the susceptibility of the mosquitoes in the specific area.

Medicamentos utilizados para trastornos cognitivos: Análisis de un millón y medio de prescripciones en la Argentina / Drugs used for cognitive impairment: Analysis of 1.5 million prescriptions in Argentina

Los costos originados por trastornos cognitivos y demencias son significativos para los sistemas de salud. Según guías nacionales e internacionales, los fármacos recomendados para su tratamiento son inhibidores de colinesterasa (donepecilo, galantamina y rivastigmina) y memantina. En la Argentina también son utilizados otros nootrópicos, galantamina, rivastigmina, vasodilatadores, vitaminas y antioxidantes. El objetivo del presente estudio es describir y comparar el patrón de prescripción de drogas para el tratamiento de trastornos cognitivos y demencias en las distintas regiones del país. Se realizó un estudio observacional retrospectivo a partir de las prescripciones (1 814 108 envases) realizadas en la práctica clínica habitual durante el segundo semestre del 2008 y el primer y segundo semestre del 2009. El trabajo fue realizado sobre la población total del Instituto Nacional de Servicios Sociales para Jubilados y Pensionados. Se analizaron variables demográficas, cantidad y tasa de prescripciones, presentaciones y dosis utilizadas por regiones. Considerando todo el país, memantina fue la droga más prescripta en esos períodos, con un total de 570 893 envases. Memantina, donepecilo, rivastigmina e idebenona presentaron un incremento en las tasas de prescripción 2008-2009. Analizando los cambios regionales en tasas de prescripción, la memantina aumentó en el Noroeste y Noreste argentino, la idebenona en el Noroeste y la Patagonia y el donepecilo en el Noreste. Grupos de fármacos no recomendados fueron altamente prescriptos en todas las regiones del país. Algunos fueron indicados en adultos jóvenes o de mediana edad.

Cognitive impairment and dementia treatment costs are significant for health systems. According to national and international guidelines, recommended drugs for treatment of dementias are cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine. Despite these guidelines recommendations, other nootropics, vasodilators and antioxidants are often used in Argentina. The purpose of this study was to describe and compare the prescription pattern of commonly used drugs for the treatment of cognitive disorders and dementia in different regions of Argentina. An observational, retrospective study of 1 814 108 recipes prescribed to National Institute of Social Services for Retired and Pensioners outpatients during the during the second half of 2008 and the first and second half of 2009 was performed, taking in count the whole country and also different Argentina´s regions. Demographic variables, quantity and rate of prescriptions, dosage forms and strengths were analyzed. Considering the entire country, memantine was the most prescribed drug in these periods (570 893 packages). An increase in the memantine, donepezil, rivastigmine and idebenone rates of prescription was observed. Prescription rate of memantine increased in the North-West and North-East regions, that of idebenone in the North-East region and Patagonia and donepezil in the North-East region. Non recommended drugs were highly prescribed in all the analyzed regions. Some of them were indicated to young and middle-aged patients.