2-arachidonoylglycerol metabolism is differently modulated by oligomeric and fibrillar conformations of amyloid beta in synaptic terminals

Alzheimer´s disease (AD) is the most prevalent disorder of senile dementia mainly characterized by amyloid-beta peptide (Aβ) deposits in the brain. Cannabinoids are relevant to AD as they exert several beneficial effects in many models of this disease. Still, whether the endocannabinoid system is either up- or down-regulated in AD has not yet been fully elucidated. Thus, the aim of the present paper was to analyze endocannabinoid 2-arachidonoylglycerol (2-AG) metabolism in cerebral cortex synaptosomes incubated with Aβ oligomers or fibrils. These Aβ conformations were obtained by "aging" the 1-40 fragment of the peptide under different agitation and time conditions. A diminished availability of 2-AG resulting from a significant decrease in diacylglycerol lipase (DAGL) activity was observed in the presence of large Aβ1-40 oligomers along with synaptosomal membrane damage, as judged by transmission electron microscopy and LDH release. Conversely, a high availability of 2-AG resulting from an increase in DAGL and lysophosphatidic acid phosphohydrolase activities occurred in the presence of Aβ1-40 fibrils although synaptosomal membrane disruption was also observed. Interestingly, neither synaptosomal mitochondrial viability assayed by MTT reduction nor membrane lipid peroxidation assayed by TBARS formation measurements were altered by Aβ1-40 oligomers or fibrils. These results show a differential effect of Aβ1-40 peptide on 2-AG metabolism depending on its conformation.Fil: Pascual, Ana Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Gaveglio, Virginia Lucía. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Giusto, Norma Maria. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Pasquaré, Susana Juana. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentin

The paradoxical effect of COVID-19 outbreak on loneliness

As in previous periods of quarantine, lockdown confinement measures dictated to control SARS-CoV-2 would be expected to negatively affect mental health. We investigated the immediate effects (over a 10 day period) of a strict nationwide stay-at-home order imposed in Spain, one of the countries most affected by the COVID-19 pandemic. Focusing our analysis on the feelings of loneliness, we obtained our measures within a social context characterised by strong and continuous public and governmental support for increasing social bonds and cooperation in order to face the common public threat. Leveraging data from the Barcelona Brain Health Initiative, a prospective population-based study cohort, the short UCLA Loneliness Scale was administered to 1604 participants 2 years and 1 year before the stay-at-home lockdown and repeated, on average, 10 days after the official confinement order issued by the Spanish government. Ratings of loneliness remained stable during the 2 years before lockdown; however, they decreased significantly during the early stages of home confinement. This effect was particularly significant for the item 'feeling excluded from others' and was also observed among individuals who were confined alone. Overall, the results suggest that gestures and manifestations of appreciation by people for the labour and efforts of certain individuals, along with official campaigns designed to promote feelings of inclusion and belonging, may have beneficial effects on feelings of loneliness, a negative emotional state strongly regarded as a risk factor for impaired mental and general health status. Further assessments during the later stages of home confinement are now warranted

Social and health services offer in Primary Care attention of people older than 65

Rincón científico.La consolidación de poblaciones envejecidas en los países desarrollados, y concretamente en España, ha situado en primer plano la preocupación por la atención que recibe este grupo demográfico, tanto en lo que se refiere al aspecto social como al sanitario. El objetivo de este estudio es describir los servicios sociosanitarios y programas ofertados para la atención en domicilio de la población a partir de los 65 años. Este es un estudio descriptivo transversal realizado en 190 una muestra de conveniencia en las comunidades autónomas (CC.AA.) de Aragón, Baleares, Castilla y León, Navarra, Madrid y Cataluña durante el año 2004 a través de un cuestionario semiestructurado destinado a identificar servicios sanitarios y servicios sociales. En conjunto los programas y servicios sociosanitarios ofertados a esta población son muy similares en las CC.AA. estudiadas, pero existen diferencias en el grado de implantación de los mismos. Esto podría indicar que los cuidados llegan a la población de forma desigual según su lugar de residencia, con las consiguientes desigualdades en la atención recibida y por tanto con posibles desigualdades en salud, calidad de vida y bienestar.El presente trabajo forma parte del Proyecto Científico de la Red Temática de Investigación Cooperativa en Cuidados a Personas Mayores RIMARED (2003-2005) y financiado por el Fondo de Investigación Sanitaria. (G03/100).S

The Barcelona brain health initiative: A cohort study to define and promote determinants of brain health.

The Barcelona Brain Health Initiative (BBHI) is an ongoing prospective longitudinal study focused on identifying determinants of brain health. The main objectives are: (i) to characterize lifestyle, cognitive, behavioral and environmental markers related to a given individual's cognitive and mental functions in middle to old age, (ii) to assess the biological determinants predictive of maintenance of brain health, and (iii) to evaluate the impact of a controlled multi-dimensional lifestyle intervention on improving and maintaining brain health. The BBHI cohort consists of >4500 healthy participants aged 40-65 years followed through online questionnaires (Phase I) assessing participants' self-perceived health and lifestyle factors in seven different domains: overall health, physical exercise, cognitive activity, sleep, nutrition, social interactions, and life purpose. In Phase II a sub-group of 1,000 individuals is undergoing detailed in-person evaluations repeated at two-yearly intervals. These evaluations will provide deep phenotyping of brain function, including medical, neurological and psychiatric examinations, assessment of physical fitness, neuropsychological assessments, structural and functional brain magnetic resonance imaging, electroencephalography and perturbation-based non-invasive brain stimulation evaluations of brain activity, as well as collection of biological samples. Finally, in Phase III a further sub-group of 500 participants will undergo a similar in-person assessment before and after a multi-dimensional intervention to optimize lifestyle habits and evaluate its effects on cognitive and brain structure and function. The intervention group will receive remote supervision through an ICT-based solution, with the support of an expert in health and lifestyle coaching strategies aimed at promoting adherence. On the other hand, the control group will not have this coaching support, and will only receive education and recommendations about healthy habits. Results of this three-part initiative shall critically contribute to a better understanding of the determinants to promote and maintain brain health over the lifespan

Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1

Genetic Alzheimer’s disease (AD) risk factors associate with reduced defensive amyloid β plaque-associated microglia (AβAM), but the contribution of modifiable AD risk factors to microglial dysfunction is unknown. In AD mouse models, we observe concomitant activation of the hypoxia-inducible factor 1 (HIF1) pathway and transcription of mitochondrial-related genes in AβAM, and elongation of mitochondria, a cellular response to maintain aerobic respiration under low nutrient and oxygen conditions. Overactivation of HIF1 induces microglial quiescence in cellulo, with lower mitochondrial respiration and proliferation. In vivo, overstabilization of HIF1, either genetically or by exposure to systemic hypoxia, reduces AβAM clustering and proliferation and increases Aβ neuropathology. In the human AD hippocampus, upregulation of HIF1α and HIF1 target genes correlates with reduced Aβ plaque microglial coverage and an increase of Aβ plaque-associated neuropathology. Thus, hypoxia (a modifiable AD risk factor) hijacks microglial mitochondrial metabolism and converges with genetic susceptibility to cause AD microglial dysfunction.Instituto de Salud Carlos III CD09/0007, PI18/01556, PI18/01557Ministerio de Educación, Cultura y Deporte FPU14/02115, AP2010‐1598, FPU16/02050, FPU15/02898, BES-2010-033886Ministerio de Economia, Industria y Competitividad SAF2012‐33816, SAF2015‐64111‐R, SAF2017-90794-REDT, PIE13/0004, BFU2016-76872-R, BES-2011-047721Junta de Andalucía P12‐CTS‐2138, P12‐CTS‐2232, UMA18-FEDERJA-211, US‐126273

Protecting the underscreened women in developed countries: the value of HPV test

Background: Poor attendance to cervical cancer (CC) screening is a major risk factor for CC. Efforts to capture underscreened women are considerable and once women agree to participate, the provision of longitudinal validity of the screening test is of paramount relevance. We evaluate the addition of high risk HPV test (HPV) to cervical cytology as a primary screening test among underscreened women in the longitudinal prediction of intraepithelial lesions grade 2 or worse (CIN2+). Methods: Women were included in the study if they were older than 39 years and with no evidence of cervical cytology in the previous five years within the Public Primary Health Care System in Catalonia (Spain). 1,832 underscreened women from eight public primary health areas were identified during 2007-2008 and followed-up for over three years to estimate longitudinal detection of CIN2+. Accuracy of each screening test and the combination of both to detect CIN2+ was estimated. The risk of developing CIN2+ lesions according to histology data by cytology and HPV test results at baseline was estimated using the Kaplan-Meier method. Results: At baseline, 6.7% of participants were HPV positive, 2.2% had an abnormal cytology and 1.3% had both tests positive. At the end of follow-up, 18 out of 767 (2.3%) underscreened women had a CIN2+, two of which were invasive CC. The three-year longitudinal sensitivity and specificity estimates to detect CIN2+ were 90.5% and 93.0% for HPV test and 38.2% and 97.8% for cytology. The negative predictive value was >99.0% for each test. No additional gains in validity parameters of HPV test were observed when adding cytology as co-test. The referral to colposcopy was higher for HPV but generated 53% higher detection of CIN2+ compared to cytology. Conclusions: Underscreened women had high burden of cervical disease. Primary HPV screening followed by cytology triage could be the optimal strategy to identify CIN2+ leading to longer and safe screen intervals

The micro as active policy: Proposals to transversalize the gender perspective at the UNC

Este trabajo pretende contribuir con la búsqueda y fomento de la equidad de géneros en el ámbito de la educación universitaria, puntualmente en la Universidad Nacional de Córdoba. Basándonos en el ODS 4 y ODS 5, se apunta a reformular el programa de la asignatura Sociología Jurídica perteneciente al cuarto año de la carrera de Abogacía, de la Facultad de Derecho en base a una metodología cualitativa de análisis documental. En función de los contenidos mínimos que la asignatura debe brindar, nos atrevemos a reflexionar sobre las posibilidades y los límites de lo que implicaría una transversalización de la perspectiva de género que habilite un diálogo con la sociología clásica; proponiendo elementos y estrategias que entendemos centrales para el rediseño de este programa en clave de equidad de género.This work aims to contribute to the search for and promotion of gender equity in the field of university education, specifically at the National University of Cordoba. Based on SDG 4 and SDG 5, the aim is to reformulate the syllabus of the subject Sociology of Law, which belongs to the fourth year of the Law Degree at the Faculty of Law, based on a qualitative methodology of documentary analysis. In terms of the minimum content that the subject should provide, we dare to reflect on the possibilities and limits of what a mainstreaming of the gender perspective that enables a dialogue with classical sociology would imply; proposing elements and strategies that we understand to be central to the redesign of this programme in terms of gender equity.Fil: Bonavitta, Paola. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Centro de Investigaciones María Saleme Burnichón; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Maritano, Ornella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad. Universidad Nacional de Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad; ArgentinaFil: Schnell, Rocío. Universidad Nacional de Córdoba. Facultad de Psicología; ArgentinaFil: Gastiazoro, Maria Eugenia. Universidad Nacional de Córdoba. Centro de Investigaciones Jurídicas y Sociales. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones Jurídicas y Sociales; ArgentinaFil: Coseani, Daniela. Universidad Nacional de Cordoba. Facultad de Ciencias Sociales; ArgentinaFil: Johnson, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad. Universidad Nacional de Córdoba. Centro de Investigaciones y Estudios sobre Cultura y Sociedad; ArgentinaFil: de Garay Hernández, Jimena. Universidade do Estado de Rio do Janeiro; BrasilFil: Deangeli, Melina Andrea. Universidad Nacional de Córdoba. Facultad de Derecho y Ciencias Sociales. Centro de Investigaciones Juridícas y Sociales; ArgentinaFil: Menoyo, Sofía Gabriela. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades; ArgentinaFil: Presman, Clara. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades; ArgentinaFil: Muñoz-Rodríguez, Luisa. Universidad Manuela Beltrán; ColombiaFil: Scarpino, Pascual. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba. Centro de Estudios Avanzados; Argentin

Non-productive angiogenesis disassembles Aß plaque-associated blood vessels

The human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD

Associations Between the Modified Food Standard Agency Nutrient Profiling System Dietary Index and Cardiovascular Risk Factors in an Elderly Population

Background: Helping consumers to improve the nutritional quality of their diet is a key public health action to prevent cardiovascular diseases (CVDs). The modified version of the Food Standard Agency Nutrient Profiling System Dietary Index (FSAm-NPS DI) underpinning the Nutri-Score front-of-pack label has been used in public health strategies to address the deleterious consequences of poor diets. This study aimed to assess the association between the FSAm-NPS DI and some CVD risk factors including body mass index (BMI), waist circumference, plasma glucose levels, triglyceride levels, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and diastolic and systolic blood pressure. Materials and Methods: Dietary intake was assessed at baseline and after 1 year of follow-up using a 143-item validated semi-quantitative food-frequency questionnaire. Dietary indices based on FSAm-NPS applied at an individual level were computed to characterize the diet quality of 5,921 participants aged 55-75 years with overweight/obesity and metabolic syndrome from the PREDIMED-plus cohort. Associations between the FSAm-NPS DI and CVD risk factors were assessed using linear regression models. Results: Compared to participants with a higher nutritional quality of diet (measured by a lower FSAm-NPS DI at baseline or a decrease in FSAm-NPS DI after 1 year), those participants with a lower nutritional quality of diet (higher FSAm-NPS DI or an increase in score) showed a significant increase in the levels of plasma glucose, triglycerides, diastolic blood pressure, BMI, and waist circumference (beta coefficient [95% confidence interval]; P for trend) (1.67 [0.43, 2.90]; <0.001; 6.27 [2.46, 10.09]; <0.001; 0.56 [0.08, 1.05]; 0.001; 0.51 [0.41, 0.60]; <0.001; 1.19 [0.89, 1.50]; <0.001, respectively). No significant associations in relation to changes in HDL and LDL-cholesterol nor with systolic blood pressure were shown. Conclusion: This prospective cohort study suggests that the consumption of food items with a higher FSAm-NPS DI is associated with increased levels of several major risk factors for CVD including adiposity, fasting plasma glucose, triglycerides, and diastolic blood pressure. However, results must be cautiously interpreted because no significant prospective associations were identified for critical CVD risk factors, such as HDL and LDL-cholesterol, and systolic blood pressure

Systemic and Local Hypoxia Synergize Through HIF1 to Compromise the Mitochondrial Metabolism of Alzheimer's Disease Microglia

Microglial cells are key contributors to Alzheimer’s disease (AD), constituting the first cellular line against Aß plaques. Local hypoxia and hypoperfusion, which are typically present in peripheral inflammatory foci, are also common in the AD brain. We describe here that Aß deposits are hypoxic and hypoperfused and that Aß plaque-associated microglia (AßAM) are characterized by the expression of hypoxia-inducible factor 1 (HIF1)-regulated genes. Notably, AßAM simultaneously upregulate the expression of genes involved in anaerobic glycolysis and oxidative mitochondrial metabolism, show elongated mitochondria surrounded by rough endoplasmic reticulum, and blunt the HIF1-mediated exclusion of pyruvate from the mitochondria through the pyruvate dehydrogenase kinase 1 (PDK1). Overstabilization of HIF1 –by genetic (von Hippel-Lindau deficient microglia) or systemic hypoxia (an AD risk factor)– induces PDK1 in microglia and reduces microglial clustering in AD mouse models. The human AD brain exhibits increased HIF1 activity and a hypoxic brain area shows reduced microglial clustering. The loss of the microglial barrier associates with augmented Aß neuropathology both in the chronic hypoxia AD mouse model and the human AD brain. Thus, the synergy between local and systemic AD risk factors converges with genetic susceptibility to cause microglial dysfunction.Peer reviewe