A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models

Progressive kidney diseases are often associated with scarring of the kidney’s filtration unit, a condition called focal segmental glomerulosclerosis (FSGS). This scarring is due to loss of podocytes, cells critical for glomerular filtration, and leads to proteinuria and kidney failure. Inherited forms of FSGS are caused by Rac1-activating mutations, and Rac1 induces TRPC5 ion channel activity and cytoskeletal remodeling in podocytes. Whether TRPC5 activity mediates FSGS onset and progression is unknown. We identified a small molecule, AC1903, that specifically blocks TRPC5 channel activity in glomeruli of proteinuric rats. Chronic administration of AC1903 suppressed severe proteinuria and prevented podocyte loss in a transgenic rat model of FSGS. AC1903 also provided therapeutic benefit in a rat model of hypertensive proteinuric kidney disease. These data indicate that TRPC5 activity drives disease and that TRPC5 inhibitors may be valuable for the treatment of progressive kidney diseases.National Institutes of Health (U.S.) (Grant DK095045)National Institutes of Health (U.S.) (Grant DK099465)National Institutes of Health (U.S.) (Grant DK103658)National Institutes of Health (U.S.) (Grant DK083511)National Institutes of Health (U.S.) (Grant DK093746

Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch

Intragranular pH rapidly modulates exocytosis in adrenal chromaffin cells

Several drugs produce rapid changes in the kinetics of exocytosis of catecholamines, as measured at the single event level with amperometry. This study is intended to unveil whether the mechanism(s) responsible for these effects involve changes in the intravesicular pH. Cell incubation with bafilomycin A1, a blocker of the vesicular proton pump, caused both a deceleration in the kinetics of exocytosis and a reduction in the catecholamine content of vesicle. These effects were also observed upon reduction of proton gradient by nigericin or NH4Cl. pH measurements using fluorescent probes (acridine orange, quinacrine or enhanced green fluorescent protein-synaptobrevin) showed a strong correlation between vesicular pH and the kinetics of exocytosis. Hence, all maneuvers tested that decelerated exocytosis also alkalinized secretory vesicles and vice versa. On the other hand, calcium entry caused a transient acidification of granules. We therefore propose that the regulation of vesicular pH is, at least partially, a necessary step in the modulation of the kinetics of exocytosis and quantal size operated by some cell signals.MC andMSM are recipients of a fellowship from the Spanish Ministerio de Ciencia y Tecnologia. This work is supported in part by a grant from Spanish Ministerio de Ciencia y Tecnologia to RB (DGCYTBFI2001-3531 and Gobierno de Canarias) and Spanish Ministerio de Educacion (PM98-0097/PM98-0104) and Generalitat Valenciana (Ctidib/2002/138 and GRUPOS03/038) to MC.Peer reviewe

Betabloqueante fluorescente (+/-) RCTM-3 de los receptores adrenergéticos de tipo Beta

Betabloqueante fluorecente (+/-)-RCTM-3 y sus formas enantioméricas de los receptores andrenérgicos de tipo Beta que corresponde a la estructura química del propanolol sustituyéndose el anillo 1-naftol por el 9-hydroxy-4-methoxyacridine. El compuesto resultante es una base débil con una liposolubilidad elevada y una estructura que lo hace fuertemente fluorescente y estable químicamente. Además presenta una eficiencia cuántica lumínica muy alta. Es un marcador de organelas secretoras muy eficiente para su uso en microscopía de epifluorescencia estándar. Su enorme eficiencia cuántica hace posible obtener imágenes de gran calidad con los láseres habituales en microscopía confocal o de onda evanescente.Peer reviewedUniversidad de La Laguna, Consejo Superior de Investigaciones Científicas (España)B2 Patente con examen previ

La mirada pedagógica para el siglo XXI : teoría, temas y prácticas en cuestión. Reflexiones de un encuentro

La Maestría en Educación: Pedagogías Críticas y Problemátias Socioeducativas tiene entre sus objetivos recuperar el espacio de lo pedagógico en el debate disciplinar de las Ciencias de la Educación, a fin de contribuir a superar visiones fragmentadas del objeto de estudio. El centro de interés está puesto en la reflexión sobre algunos núcleos que permitan articular la presencia dispersa, compleja y problemática de lo pedagógico en los desarrollos teóricos, las temáticas y las prácticas contemporáneas. Por eso consideramos central contextualizar los temas y habilitar fuertemente la reflexión de las experiencias argentina y latinoamericana. Las Jornadas objeto de esta publicación propusieron, tanto en sus aspectos temáticos como en su propuesta organizativa, materializar el deseo de jerarquizar la pregunta, la reflexión y el intercambio como prácticas colectivas de enriquecimiento mutuo. Fueron denominadas Jornadas de Debate y Producción. Debate, porque sostenemos que en la circulación de la palabra, la expresión de ideas diversas, la argumentación, la fundamentación y la discusión respetuosa avanza la construcción de lo público. Producción, porque pensamos que es posible generar instancias de construcción colectiva que estimulen la reflexión profunda. Y en nuestra práctica permanente, creemos que la Maestría no es solo un espacio de transmisión, sino también de elaboración y generación de conocimiento de los docentes, investigadores y cursantes, conocimiento que debe difundirse, compartirse, contrastarse, a fin de aportar a la solución de los problemas de nuestra educación y nuestra patria.A modo de presentación. Silvia Llomovatte 9; Primera parte: Mesas Redondas 13; i. Lo pedagógico en las teorías y corrientes sobre la educación 15; Presentación. Julia Silber 17; Algo nos pasa hoy con el conocimiento: pedagogía ¿dónde habitas? Carlos Cullen 22, La pedagogía como efecto de pensamiento. María Silvia Serra 27; Pedagogía, Ciencias de la educación y Teoría crítica de la Sociedad, un abordaje posible. Margarita Sgró 33; Lo implícito y lo explicito en los componentes pedagógicos de las teorías criticas en educación. Luis Rigal 40; ii. Lo pedagógico en las nuevas temáticas educativas 51; Presentación. Inés Cappellacci 53; Pedagogía y Ciencias Sociales. Herramientas teóricas para abordar la cuestión del conocimiento en la universidad pública. Sandra Carli 60; Gubernamentalidad, pedagogía y subjetividad: Políticas de escolarización y territorio en las sociedades de gerenciamiento. Silvia Grinberg 66; Sobre la tolerancia, los umbrales y los miedos: Las transformaciones en la sensibilidad sobre la violencia en la educación escolar. Carina V. Kaplan 75; La educación sexual integral como expresión del debate pedagógico. Graciela Morgade 85; Notas sobre la estética escolar como objeto de investigación histórico-educativa. Pablo Pineau 95; iii. Lo pedagógico en las prácticas educativas 105; Presentación. Daniel Suárez 107; Los docentes como sujetos del campo pedagógico: una mirada desde las políticas educativas. Myriam Feldfeber 103; Pedagogía y movimientos sociales: Lo pedagógico y lo político en sus propuestas educativas. Anahí Guelman 120; Reflexiones pedagógicas en torno a procesos de escolarización de chicos y chicas en situación de calle. María Paula Montesinos y Ana Pagano 131; Algunas metáforas para pensar la especificidad de la intervención socio-pedagógica. Mónica Paso 139; La Investigación Acción Participativa y la educación Popular: su encuadre pedagógica. María Teresa Sirvent 150; Segunda parte: Relatorías 177; Grupo 1 Armando Belmes (coordinador), Judith Naidorf, Judith Wischnevsky y Laura Tarrio (relatoras) 179; Grupo 2 Víctor Piaggio (coordinador), Sofía Thisted, Gloria Zelaya (relatoras) 181; Grupo 3 Malena Charovsky (coordinadora), Nora Graziano, Fernanda Saforcada (relatoras) 184; Grupo 4 Silvia Sunsi (coordinadora), Maura Ramos (relatora) 188; Grupo 5 Silvia González (coordinadora), Claudia Loyola, Silvia Satulovsky (relatoras) 192; Grupo 6 Lidia Roccella (coordinadora), Mónica Descalzo, Mariana Vázquez (relatoras) 195; Grupo 7 Flavia Gispert (coordinadora), Alejandro Vassiliades, María Gabriela Hernando (relatores) 197; Grupo 8 César Linietsky (coordinador), Victoria Orce, Egle Pitton (relatoras) 200; A modo de Conclusión. Flora M. Hillert 20

Safety of hospital discharge before return of bowel function after elective colorectal surgery

Background: Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function.Methods: A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien-Dindo classification system.Results: A total of 3288 patients were included in the analysis, of whom 301 (9.2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4-7) and 7 (6-8) days respectively (P &lt; 0.001). There were no significant differences in rates of readmission between these groups (6.6 versus 8.0 per cent; P = 0.499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0.90, 95 per cent c.i. 0.55 to 1.46; P = 0.659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34.7 versus 39.5 per cent; major 3.3 versus 3.4 per cent; P = 0.110).Conclusion: Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients

Timing of nasogastric tube insertion and the risk of postoperative pneumonia: an international, prospective cohort study

Aim: Aspiration is a common cause of pneumonia in patients with postoperative ileus. Insertion of a nasogastric tube (NGT) is often performed, but this can be distressing. The aim of this study was to determine whether the timing of NGT insertion after surgery (before versus after vomiting) was associated with reduced rates of pneumonia in patients undergoing elective colorectal surgery. Method: This was a preplanned secondary analysis of a multicentre, prospective cohort study. Patients undergoing elective colorectal surgery between January 2018 and April 2018 were eligible. Those receiving a NGT were divided into three groups, based on the timing of the insertion: routine NGT (inserted at the time of surgery), prophylactic NGT (inserted after surgery but before vomiting) and reactive NGT (inserted after surgery and after vomiting). The primary outcome was the development of pneumonia within 30 days of surgery, which was compared between the prophylactic and reactive NGT groups using multivariable regression analysis. Results: A total of 4715 patients were included in the analysis and 1536 (32.6%) received a NGT. These were classified as routine in 926 (60.3%), reactive in 461 (30.0%) and prophylactic in 149 (9.7%). Two hundred patients (4.2%) developed pneumonia (no NGT 2.7%; routine NGT 5.2%; reactive NGT 10.6%; prophylactic NGT 11.4%). After adjustment for confounding factors, no significant difference in pneumonia rates was detected between the prophylactic and reactive NGT groups (odds ratio 1.03, 95% CI 0.56–1.87, P = 0.932). Conclusion: In patients who required the insertion of a NGT after surgery, prophylactic insertion was not associated with fewer cases of pneumonia within 30 days of surgery compared with reactive insertion

Safety of hospital discharge before return of bowel function after elective colorectal surgery

© 2020 BJS Society Ltd Published by John Wiley & Sons LtdBackground: Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function. Methods: A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien–Dindo classification system. Results: A total of 3288 patients were included in the analysis, of whom 301 (9·2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4–7) and 7 (6–8) days respectively (P < 0·001). There were no significant differences in rates of readmission between these groups (6·6 versus 8·0 per cent; P = 0·499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0·90, 95 per cent c.i. 0·55 to 1·46; P = 0·659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34·7 versus 39·5 per cent; major 3·3 versus 3·4 per cent; P = 0·110). Conclusion: Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients

Prevalence and Clinical Outcomes of Poor Immune Response Despite Virologically Suppressive Antiretroviral Therapy Among Children and Adolescents With Human Immunodeficiency Virus in Europe and Thailand: Cohort Study

International audienceIn human immunodeficiency virus (HIV)-positive adults, low CD4 cell counts despite fully suppressed HIV-1 RNA on antiretroviral therapy (ART) have been associated with increased risk of morbidity and mortality. We assessed the prevalence and outcomes of poor immune response (PIR) in children receiving suppressive ART