Loss of Direct Vascular Contact to Astrocytes in the Hippocampus as an Initial Event in Alzheimer's Disease. Evidence from Patients, In Vivo and In Vitro Experimental Models.

Alzheimer's disease (AD) is characterized by the accumulation of aggregated amyloid peptides in the brain parenchyma and within the walls of cerebral vessels. The hippocampus-a complex brain structure with a pivotal role in learning and memory-is implicated in this disease. However, there is limited data on vascular changes during AD pathological degeneration in this susceptible structure, which has distinctive vascular traits. Our aim was to evaluate vascular alterations in the hippocampus of AD patients and PDAPP-J20 mice-a model of AD-and to determine the impact of Aß40 and Aß42 on endothelial cell activation. We found a loss of physical astrocyte-endothelium interaction in the hippocampus of individuals with AD as compared to non-AD donors, along with reduced vascular density. Astrocyte-endothelial interactions and levels of the tight junction protein occludin were altered early in PDAPP-J20 mice, preceding any signs of morphological changes or disruption of the blood-brain barrier in these mice. At later stages, PDAPP-J20 mice exhibited decreased vascular density in the hippocampus and leakage of fluorescent tracers, indicating dysfunction of the vasculature and the BBB. In vitro studies showed that soluble Aß40 exposure in human brain microvascular endothelial cells (HBMEC) was sufficient to induce NFκB translocation to the nucleus, which may be linked with an observed reduction in occludin levels. The inhibition of the membrane receptor for advanced glycation end products (RAGE) prevented these changes in HBMEC. Additional results suggest that Aß42 indirectly affects the endothelium by inducing astrocytic factors. Furthermore, our results from human and mouse brain samples provide evidence for the crucial involvement of the hippocampal vasculature in Alzheimer's disease.

Expression of TGFß-family signalling components in ageing cartilage: age-related loss of TGFß and BMP receptors.

OBJECTIVE: Ageing is the main risk factor for osteoarthritis (OA). We investigated if expression of transforming growth factor ß (TGFß)-family components, a family which is crucial for the maintenance of healthy articular cartilage, is altered during ageing in cartilage. Moreover, we investigated the functional significance of selected age-related changes. DESIGN: Age-related changes in expression of TGFß-family members were analysed by quantitative PCR in healthy articular cartilage obtained from 42 cows (age: ¾-10 years). To obtain functional insight of selected changes, cartilage explants were stimulated with TGFß1 or bone morphogenetic protein (BMP) 9, and TGFß1 and BMP response genes were measured. RESULTS: Age-related cartilage thinning and loss of collagen type 2a1 expression (∼256-fold) was observed, validating our data set for studying ageing in cartilage. Expression of the TGFß-family type I receptors; bAlk2, bAlk3, bAlk4 and bAlk5 dropped significantly with advancing age, whereas bAlk1 expression did not. Of the type II receptors, expression of bBmpr2 decreased significantly. Type III receptor expression was unaffected by ageing. Expression of the ligands bTgfb1 and bGdf5 also decreased with age. In explants, an age-related decrease in TGFß1-response was observed for the pSmad3-dependent gene bSerpine1 (P = 0.016). In contrast, ageing did not affect BMP9 signalling, an Alk1 ligand, as measured by expression of the pSmad1/5 dependent gene bId1. CONCLUSIONS: Ageing negatively affects both the TGFß-ALK5 and BMP-BMPR signalling routes, and aged chondrocytes display a lowered pSmad3-dependent response to TGFß1. Because pSmad3 signalling is essential for cartilage homeostasis, we propose that this change contributes to OA development.

The high affinity ALK1-ligand BMP9 induces a hypertrophy-like state in chondrocytes that is antagonized by TGFß1.

OBJECTIVE: In osteoarthritic cartilage, expression of the receptor ALK1 correlates with markers of deleterious chondrocyte hypertrophy. Recently, bone morphogenetic protein 9 (BMP9) was identified as a high affinity ligand for ALK1. Therefore, we studied if BMP9 signaling results in expression of hypertrophy markers in chondrocytes. Furthermore, because transforming growth factorß1 (TGFß1) is a well known anti-hypertrophic factor, the interaction between BMP9 and TGFß1 signaling was also studied. DESIGN: Primary chondrocytes were isolated from bovine cartilage and stimulated with BMP9 and/or TGFß1 to measure intracellular signaling via pSmads with the use of Western blot. Expression of Smad-responsive genes or hypertrophy-marker genes was measured using qPCR. To confirm observations on TGFß/Smad3 responsive genes, a Smad3-dependent CAGA12-luc transcriptional reporter assay was performed in the chondrocyte G6 cell line. RESULTS: In primary chondrocytes, BMP9 potently induced phosphorylation of Smad1/5 and Smad2 to a lesser extent. BMP9-induced Smad1/5 phosphorylation was rapidly (2 h) reflected in gene expression, whereas Smad2 phosphorylation was not. Remarkably, BMP9 and TGFß1 dose-dependently synergized on Smad2 phosphorylation, and showed an additive effect on expression of Smad3-dependent genes like bSerpine1 after 24 h. The activation of the TGFß/Smad3 signaling cascade was confirmed using the CAGA12-luc transcriptional reporter. BMP9 selectively induced bAlpl and bColX expression, which are considered early markers of cellular hypertrophy, but this was potently antagonized by addition of a low dose of TGFß1. CONCLUSIONS: This study shows that in vitro in chondrocytes, BMP9 potently induces pSmad1/5 and a chondrocyte hypertrophy-like state, which is potently blocked by TGFß1. This observation underlines the importance of TGFß1 in maintenance of chondrocyte phenotype.

Physical activity below the minimum international recommendations improves oxidative stress, ADMA levels, resting heart rate and small artery endothelial function

Background: A moderate level of physical activity (PA), such as a daily 30-min walk, reduces cardiovascular risk. There is a lack of evidence about the cardiovascular benefits of PA below this recommendation of minimum PA level. Objective: We aimed to study the impact of a lower level of PA on cardiovascular health. Design: Sixty-four overweight/obese men and women were enrolled in a community programme consisting of 4 months of 1h, low-intensity PA two days per week. Before and after the intervention, PA level (METs/h/wk), endogenous antioxidant status (SOD and GPX concentration and activity and oxidised LDL), ADMA concentrations, endothelial function by small artery reactive hyperaemia index (saRHI), and resting heart rate (RHR) were assessed. Results: After the intervention, significant increases in saRHI (P=0.031), SOD and GPX activities, and a decrease in ADMA plasma concentrations, and RHR (P < 0.001 for all) were observed. Increases in PA were positively associated with increases in saRHI (r = 0.341, P = 0.022), GPx (r = 0.303, P = 0.047) and decreases in RHR (r=−0.302, P=0.047). Multivariate analyses showed that independent predictors of saRHI improvement were an increase in PA (2.65, 95%CI: 1.21–4.01), decrease in RHR (1.91, 95%CI: 1.01–4.98), and an increase in GPx (2.61, 95%CI: 1.16–5.01). Conclusion: In obese and overweight men and women, an increase in PA, even below the minimal international recommendations, improves antioxidant capacity, RHR and peripheral small artery reactivity

Introducción: Los niveles moderados de actividad física (AF), 30 min al día de caminar, reducen el riesgo cardiovascular. No existe evidencia si los niveles bajos de actividad física, por debajo de las recomendaciones internacionales, afectan la salud cardiovascular. Objetivo: Estudiar el efecto de los niveles bajos de actividad física sobre la salud cardiovascular Diseño: Se seleccionaron 64 hombres y mujeres con sobrepeso u obesidad para completar un programa comunitario de actividad física consistente en 1h, 2 días a la semana, durante 4 meses, de AF de intensidad baja. Antes y después del programa se evaluó la AF (MET/h/semana), el estado antioxidante endógeno (SOD y GPX concentración y actividad), las concentraciones de ADMA, la función endotelial de pequeña arteria mediante el índice de hiperemia reactiva (saRHI) y la frecuencia cardíaca (FC) en reposo. Resultados: Después de la intervención se observó un aumento significativo en el saRHI (p=0,031), en la actividad de la SOD y la GPX, y una disminución de las concentraciones plasmáticas de ADMA y de la FC (p<0,001 para todos). El aumento en la AF se asoció directamente con el aumento del saRHI (r = 0,341, p = 0,022), GPx (r = 0,303, p = 0,047) y disminución en FC (r = -0.297, p = 0,047). Los predictores independientes de la mejora del saRHI fueron un aumento en la AF (2,65; IC95%: 1,21-4,01), la disminución de la FC (1,91; IC95%:1,01-4,98) y el aumento de la GPx (2,61; IC95%:1,16-5,01). Conclusiones: Un aumento de la AF, incluso por debajo de las recomendaciones internacionales de AF, mejoró la capacidad antioxidante, la FC y la función endotelial de las pequeñas arterias en hombres y mujeres con sobrepeso u obesidad

Physical activity below the minimum international recommendations improves oxidative stress, ADMA levels, resting heart rate and small artery endothelial function.

BACKGROUND: A moderate level of physical activity (PA), such as a daily 30-min walk, reduces cardiovascular risk. There is a lack of evidence about the cardiovascular benefits of PA below this recommendation of minimum PA level. OBJECTIVE: We aimed to study the impact of a lower level of PA on cardiovascular health. DESIGN: Sixty-four overweight/obese men and women were enrolled in a community programme consisting of 4 months of 1h, low-intensity PA two days per week. Before and after the intervention, PA level (METs/h/wk), endogenous antioxidant status (SOD and GPX concentration and activity and oxidised LDL), ADMA concentrations, endothelial function by small artery reactive hyperaemia index (saRHI), and resting heart rate (RHR) were assessed. RESULTS: After the intervention, significant increases in saRHI (P=0.031), SOD and GPX activities, and a decrease in ADMA plasma concentrations, and RHR (P<0.001 for all) were observed. Increases in PA were positively associated with increases in saRHI (r=0.341, P=0.022), GPx (r=0.303, P=0.047) and decreases in RHR (r=-0.302, P=0.047). Multivariate analyses showed that independent predictors of saRHI improvement were an increase in PA (2.65, 95%CI: 1.21-4.01), decrease in RHR (1.91, 95%CI: 1.01-4.98), and an increase in GPx (2.61, 95%CI: 1.16-5.01). CONCLUSION: In obese and overweight men and women, an increase in PA, even below the minimal international recommendations, improves antioxidant capacity, RHR and peripheral small artery reactivity.

[Terminal illness. Death... in the words of professionals. A qualitative study based on in-depth interviews with health professionals]. / Enfermedad terminal, muerte... en palabras de los profesionales (y II). Un estudio cualitativo de entrevistas en profundidad a profesionales de la salud.

This article is the second part of an interesting qualitative research project which presents and interprets opinions made by diverse medical and nursing professionals regarding care provided to terminal patients and relationships with patients' relatives.

Condicionamientos de la sobreactuación terapéutica. Papel de la familia / No disponible

Objetivos: identificar dificultades y obstáculos de los profesionales médicos y enfermeros en relación con la sobreactuación terapéutica; explorar la diversidad de experiencias. Método: estudio cualitativo de tipo fenomenológico basado en entrevistas individuales a profesionales médicos y enfermeros que trabajan con enfermos terminales y familia, en hospitales y centros de salud de zonas urbanas y rurales de Granada y provincia, grabadas y transcritas, y asistidos en el análisis de la información por el software Atlas.tí, con una muestra de 42 entrevistas (20 médicos, 21 enfermeros y 1 psicólogo) sobre 48, y 6 rechazadas por no cumplir criterios de triangulación de la información. Resultados: aunque los profesionales son contrarios a alargar la agonía de los enfermos admiten que la presión que soportan de las familias les lleva a intervenir. Aparecen diferencias de posicionamiento y matiz entre profesionales en hospitales y en centros de salud, y entre profesionales médicos y enfermeros, sin embargo, para todos ellos, el trabajo con la familia es un problema. Conclusiones: desde la perspectiva del profesional, las demandas familiares condicionan la presencia de sobreactuación. Ausente la consideración de los deseos y opiniones de los pacientes en la toma de decisiones. Dificultades para reconocer la situación de enfermedad terminal y para transmitirla, así como identificar enfermo terminal y enfermo agónico explican comportamientos sobreactuantes. El trabajo con los familiares para acordar y consensuar medidas terapéuticas requiere un entorno de relación terapéutica que no se puede improvisar en el último momento (AU)

Objetive: to identify the difficulties and obstacles that professional doctors and nurses face in relation to therapeutic obstinacy. To explore experience diversity. Method: qualitative phenomenological research based on individual interviews (recorded and transcribed) to doctors and nurses working with terminally ill patients and their families in hospitals and health centers in the suburbs and rural areas of Granada and its province. The analysis of data has been supported by the Atlas.tí software. The sample consists of 48 interviews, 42 of them to 20 doctors, 21 nurses, and 1 psychologist; the remaining 6 were rejected because of unmet criteria for information triangulation. Results: despite the fact that professionals are opposed to prolonging the agony of patients, they recognize that pressure from family demands eventually leads them to intervene. Attitudes and stance show differences between professionals in hospitals and health centers, and between doctors and nurses. Nevertheless, working with patient families is a problem. Conclusions: from a professional’s point of view, family requests condition the presence of therapeutic obstinacy. Patient wishes and opinions are not considered when a decision is to be made. There are difficulties in recognizing and reporting on illness status, as well as difficulties in identifying a terminally ill patient from an agonizing one. These difficulties explain obstinate behaviors. Working with families to arrange for therapeutic decisions requires a therapeutic relationship environment, which cannot be improvised at the last minute (AU)

Adherencia terapéutica en hipertensos. Estudio cualitativo / Treatment adherence of hypertensive patients: a qualitative study

La prevalencia de la hipertensión en España se sitúa en torno al 25% de la población adulta. Los profesionales de la salud disponen de un amplio arsenal terapéutico y conocen los criterios higiénico-dietéticos que mantendrían los niveles arteriales dentro de la normalidad. La falta de observancia de la pauta terapéutica es común en todo proceso crónico. En el caso de la hipertensión arterial las cifras de no cumplidores alcanzan límites realmente preocupantes, cerca del 40% para el tratamiento farmacológico y entre el 60-90% en las medidas higiénico-dietéticas. Por ahora, se sabe poco sobre las opiniones y expectativas que los pacientes tienen sobre la hipertensión y su tratamiento. Para tratar esta cuestión, hemos diseñado un estudio cualitativo basado en la técnica de los grupos focales. El objetivo ha sido identificar desde la perspectiva de los usuarios las dificultades del cumplimiento, así como los factores relacionados con este fenómeno. Constatamos la dificultad a la hora de seguir las prescripciones médicas, en gran medida porque no se sienten tratados de forma individualizada para establecer el tratamiento, las medidas adecuadas y el modo de llevarlo a cabo. Consideramos que es fundamental optimizar la relación del profesional de la salud con el paciente

The prevalence of hypertension among adults in Spain reaches around 25%. Health professionals have many therapeutic means at their disposal and know all hygienic and dietetic measures needed to keep arterial levels within normality. Non-adherence to therapy is a common observable fact in all chronic processes. Concerning arterial hypertension, non-adherence percentages reach alarming levels: nearly 40% non-adherence to drug treatment and between 60-90% non-adherence to hygienic and dietetic measures. So far, little is known about patients' expectations and opinions about hypertension and its treatment. To deal with this subject, a qualitative study was designed based on the focal groups' technique. The aim was to identify adherence difficulties according to patients, as well as other factors related to this phenomenon. We have detected treatment adherence difficulties, mainly due to a lack of individual treatments, measures and application methods. We believe it is essential for health professionals to optimize their relations with their patients

Influencia del estilo de vida en el perfil lipídico / Influence of life style in the lipidic profile

En este trabajo se ha analizado la relación entre el estilo de vida y el perfil lipídico, como factor de riesgo para la salud. Se han seleccionado 15 sujetos deportistas “senior” sanos, atletas especialistas en carrera de fondo, con una media de edad de 51 años, 69 Kg como peso medio y 1,69m como estatura media. Su participación en el estudio fue voluntaria, junto a la de otros 12 sujetos sedentarios y de similares características socioculturales, que configuraron el grupo control, con una media de edad de 49 años, un peso medio de 83 Kg y una talla de 1,72 m. Se ha utilizado el cuestionario de estilos de vida de Heyward sobre hábitos relacionados con la bebida, tabaco, ejercicio físico y dieta, así como la determinación de los niveles de lípidos en sangre (TG, Colesterol total, HDL, LDL, VLDL, y cociente LDL/ HDL Se han comparado los niveles basales de lípidos en ambos grupos con relación al estilo de vida. Los resultados de nuestro trabajo muestran hábitos menos saludables en el grupo de sujetos sedentarios, con mayor ingesta de alcohol y tabaco y significativamente menor realización de ejercicio físico que en el grupo de atletas. El perfil lipídico muestra valores inferiores de colesterol total, triglicéridos, LDL,VLDL, LDL/HDL y mayores de HDL en el grupo de atletas cuyo consumo de alcohol es menor, no consumen tabaco y entrenan de forma regular. El ejercicio físico en nuestro estudio se constituye como el hábito de mayor relevancia en la configuración de unas características antropométricas y un perfil lipídico óptimos para la promoción de la salud y desarrollo de estilos de vida saludables (AU)