Enfermedad y sociedad en la obra de B. Pérez Galdós

Tesis doctoral inédita. Universidad Autónoma de Madrid. Facultad de Medicina, Departamento de Medicina Preventiva. Fecha de lectura:6-4-94

Desarrollo y caracterización de un modelo ex ovo para el desarrollo de glioblastoma multiforme

El cáncer sigue siendo una de las principales causas de muerte en el mundo. El glioblastoma multiforme (GBM) es el tumor más agresivo y prevalente del sistema nervioso central, con una de supervivencia de tan solo 15 a 18 meses desde su diagnóstico. Pese a que se ha observado que su incidencia varía en relación con factores como la edad, la raza o el sexo, el GBM puede desarrollarse en cualquier persona. Además, la efectividad de los tratamientos tradicionales está condicionada por factores como el microambiente tumoral y el subtipo molecular de GBM que se desarrolle, siendo necesaria la búsqueda de nuevas terapias dirigidas y específicas a cada paciente. Por estos motivos, la presente investigación se centró en el desarrollo de un nuevo modelo preclínico para el estudio del GBM basado en embriones de pollo ex ovo. En base a estudios previos de este grupo de investigación, se seleccionó la línea celular de GBM humana GB-39, para la generación de un xenoinjerto derivado de paciente (PDX) en el cerebro de los embriones de pollo. Los embriones manifestaron un desarrollo morfológico normal en el tiempo que duraron los experimentos y los tumores generados en ellos fueron capaces de injertarse y proliferar, recapitulando las características de los tumores de GBM humanos. Además, el análisis de los marcadores de células microgliales Iba1 y CD11B sí confirmaron una activación moderada de la microglía que se correspondía con la progresión normal del tumor. Los análisis con los marcadores específicos GLAST y CD44, revelaron que los tumores no presentaban patrones de crecimiento invasivos ni infiltración con transición epitelio-mesénquima que pudiera derivar en metástasis. Por último, se llevó a cabo una prueba de concepto, que consistió en la inyección e integración de exosomas, para comprobar el potencial del modelo en el estudio de la vehiculiazación de fármacos. Los datos recogidos en este proyecto confirman que el modelo desarrollado puede ser usado como modelo preclínico para testar in vivo tratamientos contra el GBM humano, pudiendo utilizarse en futuros estudios experimentales en el campo de la biomedicina.Cancer remains one of the leading causes of death in the world. Glioblastoma multiforme (GBM) is the most aggressive and prevalent tumor of the central nervous system, reaching a survival period of only 15 to 18 months after diagnosis. Although it has been observed that its incidence varies in relation to factors such as age, race or gender, GBM can be developed by any person. Furthermore, the effectiveness of traditional treatments is conditioned by factors such as the tumor microenvironment and the molecular subtype of GBM, making necessary the search for new targeted therapies specific to each patient. For these reasons, the present research focused on the development of a new preclinical model to study of GBM that is based on chicken embryos ex ovo. According to previous studies of this research group, the GBM human derived cell line GB-39 was selected for the generation of a patient-derived xenograft (PDX) in the brain of chicken embryos. In this study, we observed that the embryos showed a normal morphological development during all experimental process. It was also possible to confirm, by histological and immunohistochemical analysis of the markers KI67, GFAP and S100B, that the PDX-generated tumors were able to engraft and proliferate, recapitulating the characteristics of human GBM tumors. In addition, analysis with GLAST and CD44 specific markers revealed that the tumors did not exhibit invasive growth patterns or infiltration with epithelial-mesenchymal transition that could lead to metastasis. However, analysis of the microglial cell markers Iba1 and CD11B did confirm moderate microglial activation consistent with normal tumor progression. Finally, a proof of concept, consisting of the injection and integration of exosomes, was carried out to test the potential of the model in the study of drug delivery. The data collected in this project confirm that the developed model can be used as a preclinical model to test in vivo human GBM treatments, which will contribute to future experimental studies in the field of biomedicine

Tareas domésticas, cuidado de hijos y variables de salud psicosocial en función del género de profesores y no profesores

The main objective of this exploratory study is to discover differences between men and women in performing housework and childcare, analyzing possible relationships with psychosocial health variables. In addition, it seeks to find out if there are also differences based on gender inside and outside the teaching profession. A total of 79 participants who live with their partner (38 teachers and 45 tertiary sector workers) participate in this study. The work design is descriptive-comparative and cross-sectional. The results indicate that women, regardless of their profession, have a higher degree of involvement in childcare. In addition, the group of women also presented higher levels of depression and physical fatigue and worse mood than men. By profession, it is observed that men teachers are less involved than their partners in their children's food, rest, leisure, education and hygiene. All the results are discussed emphasizing the need to implement measures that help improve the women’s well-being and encourage a real co-responsibility between men and women.El objetivo principal del presente estudio exploratorio es descubrir diferencias entre hombres y mujeres en la realización de las tareas domésticas y el cuidado de los hijos, analizando posibles relaciones con variables de salud psicosocial. Además, se persigue averiguar si también existen diferencias en función del género dentro y fuera de la profesión docente. Un total de 79 participantes que viven con su pareja (38 docentes y 45 trabajadores del sector terciario) participan en este estudio. El diseño del trabajo es descriptivo-comparativo y de corte transversal. Los resultados señalan que las mujeres, independientemente de su profesión, presentan mayor grado de implicación en el cuidado de los hijos. Además, el grupo de mujeres también presenta mayores niveles de depresión y de fatiga física y un peor estado de ánimo que los hombres. Por profesiones, se observa que los profesores presentan una menor implicación que sus parejas en la alimentación, el descanso, el ocio, la educación y la higiene de sus hijos. Todos los resultados se discuten enfatizando la necesidad de poner en marcha medidas que ayuden a mejorar el bienestar de las mujeres y favorezcan una corresponsabilidad real entre hombres y mujeres

Tareas domésticas, cuidado de hijos y variables de salud psicosocial en función del género de profesores y no profesores

The main objective of this exploratory study is to discover differences between men and women in performing housework and childcare, analyzing possible relationships with psychosocial health variables. In addition, it seeks to find out if there are also differences based on gender inside and outside the teaching profession. A total of 79 participants who live with their partner (38 teachers and 45 tertiary sector workers) participate in this study. The work design is descriptive-comparative and cross-sectional. The results indicate that women, regardless of their profession, have a higher degree of involvement in childcare. In addition, the group of women also presented higher levels of depression and physical fatigue and worse mood than men. By profession, it is observed that men teachers are less involved than their partners in their children's food, rest, leisure, education and hygiene. All the results are discussed emphasizing the need to implement measures that help improve the women’s well-being and encourage a real co-responsibility between men and women.El objetivo principal del presente estudio exploratorio es descubrir diferencias entre hombres y mujeres en la realización de las tareas domésticas y el cuidado de los hijos, analizando posibles relaciones con variables de salud psicosocial. Además, se persigue averiguar si también existen diferencias en función del género dentro y fuera de la profesión docente. Un total de 79 participantes que viven con su pareja (38 docentes y 45 trabajadores del sector terciario) participan en este estudio. El diseño del trabajo es descriptivo-comparativo y de corte transversal. Los resultados señalan que las mujeres, independientemente de su profesión, presentan mayor grado de implicación en el cuidado de los hijos. Además, el grupo de mujeres también presenta mayores niveles de depresión y de fatiga física y un peor estado de ánimo que los hombres. Por profesiones, se observa que los profesores presentan una menor implicación que sus parejas en la alimentación, el descanso, el ocio, la educación y la higiene de sus hijos. Todos los resultados se discuten enfatizando la necesidad de poner en marcha medidas que ayuden a mejorar el bienestar de las mujeres y favorezcan una corresponsabilidad real entre hombres y mujeres

Physical activity and self-reported health status among adolescents: A cross-sectional population-based study

Objectives: Little is known about the dose–response relationship between physical activity and health benefits among young people. Our objective was to analyse the association between the frequency of undertaking moderate-to-vigorous physical activity (MVPA) and the self-reported health status of the adolescent population. Design: Cross-sectional study. Setting: All regions of Spain. Participants: Students aged 11–18 years participating in the Spanish Health Behaviour in School-aged Children survey 2006. A total of 375 schools and 21 188 students were selected. Main outcomes: The frequency of undertaking MVPA was measured by a questionnaire, with the following four health indicators: self-rated health, health complaints, satisfaction with life and health-related quality of life. Linear and logistic regression models were used to analyse the association, adjusting for potential confounding variables and the modelling of the dose–response relationship. Results: As the frequency of MVPA increased, the association with health benefits was stronger. A linear trend (p<0.05) was found for self-rated health and health complaints in males and females and for satisfaction with life among females; for health-related quality of life this relationship was quadratic for both sexes ( p<0.05). For self-reported health and health complaints, the effect was found to be of greater magnitude in males than in females and, in all scales, the benefits were observed from the lowest frequencies of MVPA, especially in males. Conclusions: A protective effect of MVPA was found in both sexes for the four health indicators studied, and this activity had a gradient effect. Among males, health benefits were detected from very low levels of physical activity and the magnitude of the relationship was greater than that for females.g This study has been funded by the Consejo Superior de Deportes (National Sports Council) and the Ministerio de Sanidad, Servicios Sociales e Igualdad (Ministry of Health and Social Policy

Physical activity and self-reported health status among adolescents: a cross-sectional population-based study

Objectives: Little is known about the dose–response relationship between physical activity and health benefits among young people. Our objective was to analyse the association between the frequency of undertaking moderate-to-vigorous physical activity (MVPA) and the self-reported health status of the adolescent population. Design: Cross-sectional study. Setting: All regions of Spain. Participants: Students aged 11–18 years participating in the Spanish Health Behaviour in School-aged Children survey 2006. A total of 375 schools and 21.188 students were selected. Main outcomes: The frequency of undertaking MVPA was measured by a questionnaire, with the following four health indicators: self-rated health, health complaints, satisfaction with life and health-related quality of life. Linear and logistic regression models were used to analyse the association, adjusting for potential confounding variables and the modelling of the dose–response relationship. Results: As the frequency of MVPA increased, the association with health benefits was stronger. A linear trend (p<0.05) was found for self-rated health and health complaints in males and females and for satisfaction with life among females; for health-related quality of life this relationship was quadratic for both sexes ( p<0.05). For self-reported health and health complaints, the effect was found to be of greater magnitude in males than in females and, in all scales, the benefits were observed from the lowest frequencies of MVPA, especially in males. Conclusions: A protective effect of MVPA was found in both sexes for the four health indicators studied, and this activity had a gradient effect. Among males, health benefits were detected from very low levels of physical activity and the magnitude of the relationship was greater than that for females

Incidence and prevalence of ischaemic heart disease and cerebrovascular disease in Spain: a systematic review of the literature

Cardiovascular disease morbidity is not well documented in Spain, due to the fact that there is no comprehensive and reliable data source. This study sought to describe the population frequency of ischaemic heart disease and cerebrovascular disease in Spain. We used bibliographic search strategies in four different databases to identify scientific studies published in Spanish medical journals or by Spanish authors after 1990. We then selected studies drawn from population-based registers, prevalence surveys and cohort studies, from which age-adjusted incidence and/or prevalence rates could be extracted. We identified 19 papers published in the period 1993-2005, containing valid information on cardiovascular diseases population incidence or prevalence in Spain. Acute myocardial infarction incidence rates per 100,000 population ranged between 135-210 and 29-61 new cases annually for men and women aged 25-74 years, respectively. Acute myocardial infarction prevalence rates were not available, but a study of prevalence of angina showed rates of 7.3% in men and 7.5% in women. Cerebrovascular disease incidence rates per 100,000 population ranged between 364 for men and 169 women, in aged 69 years and over rising to 2.371 in men and 1.493 in women. Prevalence rates in population aged 65 years and over would be estimated in 7% in men and 6% in women. Although currently available information may serve as an initial reference, monitoring of the incidence and prevalence of these diseases will nevertheless call for an effort which exceeds the capacity of isolated research teams. La morbilidad de las enfermedades cardiovasculares no es bien conocida en España. Esta carencia de información se debe a que no existe una fuente de datos que sea estable, exhaustiva y fiable. El objetivo de este trabajo es describir la frecuencia poblacional de cardiopatía isquémica y enfermedad cerebrovascular en España. Se identificaron como fuentes de información los estudios científicos publicados en revistas médicas españolas o por autores españoles con fecha posterior al año 1990, mediante estrategias de búsqueda bibliográfica en cuatro bases de datos distintas. Se seleccionaron los estudios derivados de registros poblacionales, encuestas de prevalencia y estudios de cohortes de los que fue posible extraer tasas de incidencia y/o prevalencia ajustadas por edad. Se identificaron 19 trabajos publicados entre 1993 y 2005, con información válida sobre incidencia o prevalencia de cardiopatía isquémica o enfermedad cerebrovascular en España a nivel poblacional. Morbilidad por cardiopatía isquémica: Las tasas de incidencia de infarto agudo de miocardio oscilaron entre 135-210 nuevos casos anuales por cada 100.000 varones y entre 29-61 por cada 100.000 mujeres entre 25 y 74 años. No existen datos de prevalencia de cardiopatía isquémica, solamente hay un estudio de prevalencia de angina en la que ésta se estima en el 7,3% en hombres y 7,5% en mujeres. Las tasas de incidencia de enfermedad cerebrovascular por 100.000 habitantes se estiman en 364 en hombres y 169 en mujeres. Si la incidencia se midiera en población mayor de 69 años las tasas se elevarían a 2.371 en hombres y 1.493 en mujeres. La prevalencia de ictus en población mayor de 65 años en España podría estimarse en un 7% en hombres y un 6% en mujeres. La información disponible en la actualidad puede servir como referencia inicial, pero sería necesario un esfuerzo de estandarización metodológica y de coordinación que excede la capacidad de grupos de investigación aislados

Experience with tocilizumab in severe COVID-19 pneumonia after 80 days of follow-up: A retrospective cohort study

Objectives: To describe the clinical characteristics and predictors of major outcomes in patients treated with tocilizumab (TCZ) for severe COVID-19 pneumonia.Patients and methods: Case series of all sequential patients with severe COVID-19 pneumonia treated with TCZ at an Academic Spanish hospital (March 12 - May 2, 2020). Clinical outcomes: death, length of hospital stay. An early clinical response to TCZ (48-72 h after the administration) was assessed by variations in respiratory function markers, Brescia COVID Respiratory Severity Scale (BCRSS), inflammatory parameters, and patients' and physicians' opinion. Associations were tested by multiple logistic regression.Results: From a cohort of 236 patients, 77 patients treated with TCZ were included (median age 62 years (IQR 53.0-72.0), 64.9% were males), 42.9% had Charlson index ≥3; hypertension (41.6%), obesity (34.7%), and diabetes (20.8%). Median follow-up was 83.0 days (78.0-86.5), no patient was readmitted. ICU admission was required for 42 (54.5%), invasive mechanical ventilation in 38 (49.4%) and 10 patients died (12.9% global, 23.8% at ICU admitted). After multivariate adjustment, TCZ response by BCRSS (OR 0.03 (0.01-0.68), p = 0.028), and Charlson index (OR 3.54 (1.20-10.44), p = 0.022) has been identified as independent factors associated with mortality. Median of hospital stay was 16.0 days (11.0-23.0); BCRSS, physician subjective and D-dimer response were associated with shorter hospitalization stay.Conclusions: In a Mediterranean cohort, use of tocilizumab for severe COVID-19 show 12.9% of mortality. Early TCZ-response by BCRSS and low comorbidity were associated with increased survival. Early TCZ-response was related to shorter median hospital stay

Paraneoplastic cerebellar ataxia and antibodies to metabotropic glutamate receptor 2

To report the presence of a new neuronal surface antibody against the metabotropic glutamate receptor 2 antibody (mGluR2-Ab) in 2 patients with paraneoplastic cerebellar ataxia.mGluR2-Abs were initially characterized by immunohistochemistry on the rat brain and confirmed by immunofluorescence on HEK293 cells transfected with mGluR2. Additional studies included analysis of potential cross-reactivity with other mGluRs, expression of mGluR2 in patients' tumors, and the effects of mGluR2-Abs on cultures of rat hippocampal neurons.Patient 1 was a 78-year-old woman with progressive cerebellar ataxia with an initial relapsing-remitting course who developed a small-cell tumor of unknown origin. Patient 2 was a 3-year-old girl who presented a steroid-responsive acute cerebellitis preceding the diagnosis of an alveolar rhabdomyosarcoma. Patients' serum and CSF showed a characteristic immunostaining of the hippocampus and cerebellum in rat brain sections and immunolabeled the cell surface of live rat hippocampal neurons. HEK293 cells transfected with mGluR1, 2, 3, and 5 confirmed that patients' antibodies only recognized mGluR2. mGluR2-Abs were not detected in 160 controls, 120 with paraneoplastic, autoimmune, or degenerative ataxias, and 40 with autoimmune encephalitis and antibodies against mGluR5 or unknown antigens. Expression of mGluR2 in tumors was confirmed by immunohistochemistry using a commercial mGluR2-Ab. Incubation of live rat hippocampal neurons with CSF of patient 2 did not modify the density of surface mGluR2 clusters.mGluR2-Abs are a novel biomarker of paraneoplastic cerebellar ataxia. The potential pathogenic effect of the antibodies is not mediated by downregulation or internalization of neuronal surface mGluR2.Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology