Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes

Amyloid; Multiphoton microscopy; PrediabetesAmiloide; Microscòpia multifotònica; PrediabetisAmiloide; Microscopía multifotónica; PrediabetesBackground While aging is the main risk factor for Alzheimer´s disease (AD), emerging evidence suggests that metabolic alterations such as type 2 diabetes (T2D) are also major contributors. Indeed, several studies have described a close relationship between AD and T2D with clinical evidence showing that both diseases coexist. A hallmark pathological event in AD is amyloid-β (Aβ) deposition in the brain as either amyloid plaques or around leptomeningeal and cortical arterioles, thus constituting cerebral amyloid angiopathy (CAA). CAA is observed in 85–95% of autopsy cases with AD and it contributes to AD pathology by limiting perivascular drainage of Aβ. Methods To further explore these alterations when AD and T2D coexist, we have used in vivo multiphoton microscopy to analyze over time the Aβ deposition in the form of plaques and CAA in a relevant model of AD (APPswe/PS1dE9) combined with T2D (db/db). We have simultaneously assessed the effects of high-fat diet-induced prediabetes in AD mice. Since both plaques and CAA are implicated in oxidative-stress mediated vascular damage in the brain, as well as in the activation of matrix metalloproteinases (MMP), we have also analyzed oxidative stress by Amplex Red oxidation, MMP activity by DQ™ Gelatin, and vascular functionality. Results We found that prediabetes accelerates amyloid plaque and CAA deposition, suggesting that initial metabolic alterations may directly affect AD pathology. T2D significantly affects vascular pathology and CAA deposition, which is increased in AD-T2D mice, suggesting that T2D favors vascular accumulation of Aβ. Moreover, T2D synergistically contributes to increase CAA mediated oxidative stress and MMP activation, affecting red blood cell velocity. Conclusions Our data support the cross-talk between metabolic disease and Aβ deposition that affects vascular integrity, ultimately contributing to AD pathology and related functional changes in the brain microvasculature.University of Cadiz Predoctoral Fellowship (CHB). This study is part of the current project (RECOGNISED; Clinical Trials gov registration no. NCT04281186) funded by the European Commission (H2020 programme-GA 847749) focusing on common mechanisms in the pathogenesis of diabetic retinopathy, brain pathology and cognitive impairment, with special interest in the neurovascular unit, in the T2D population. Agencia Estatal de Investigacion. Ministerio de Ciencia e Innovacion. Programa Estatal de Generacion de Conocimiento y Fortalecimiento Cientifico y Tecnologico del Sistema de I + D + i y del Programa Estatal de I + D + i Orientada a los Retos de la Sociedad, del Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion (PID2020-115499RB-I00/AEI/10.130 39/501100011033). Programa Estatal de I + D + I orientada a los Retos de la Sociedad (BFU 2016-75038-R), financed by the Agencia Estatal de Investigacion (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER), Ministerio de Economia y Competitividad. Proyectos de I + D + i, en regimen de concurrencia competitiva, destinadas a las universidades y entidades publicas de investigacion calificadas como agentes del Sistema Andaluz del Conocimiento, en el ambito del Plan Andaluz de Investigacion, Desarrollo e Innovación (PAIDI 2020). Andalucia se mueve con Europa (P20-00928)

Disruption of cortical cell type composition and function underlies diabetes-associated cognitive decline

Cognitive decline; Cortex; MetabolismDeclivi cognitiu; Còrtex; MetabolismeDeterioro cognitivo; Corteza; MetabolismoAims/hypothesis Type 2 diabetes is associated with increased risk of cognitive decline although the pathogenic basis for this remains obscure. Deciphering diabetes-linked molecular mechanisms in cells of the cerebral cortex could uncover novel therapeutic targets. Methods Single-cell transcriptomic sequencing (scRNA-seq) was conducted on the cerebral cortex in a mouse model of type 2 diabetes (db/db mice) and in non-diabetic control mice in order to identify gene expression changes in distinct cell subpopulations and alterations in cell type composition. Immunohistochemistry and metabolic assessment were used to validate the findings from scRNA-seq and to investigate whether these cell-specific dysfunctions impact the neurovascular unit (NVU). Furthermore, the behavioural and cognitive alterations related to these dysfunctions in db/db mice were assessed via Morris water maze and novel object discrimination tests. Finally, results were validated in post-mortem sections and protein isolates from individuals with type 2 diabetes. Results Compared with non-diabetic control mice, the db/db mice demonstrated disrupted brain function as revealed by losses in episodic and spatial memory and this occurred concomitantly with dysfunctional NVU, neuronal circuitry and cerebral atrophy. scRNA-seq of db/db mouse cerebral cortex revealed cell population changes in neurons, glia and microglia linked to functional regulatory disruption including neuronal maturation and altered metabolism. These changes were validated through immunohistochemistry and protein expression analysis not just in the db/db mouse cerebral cortex but also in post-mortem sections and protein isolates from individuals with type 2 diabetes (74.3 ± 5.5 years) compared with non-diabetic control individuals (87.0 ± 8.5 years). Furthermore, metabolic and synaptic gene disruptions were evident in cortical NVU cell populations and associated with a decrease in vascular density. Conclusions/interpretation Taken together, our data reveal disruption in the cellular and molecular architecture of the cerebral cortex induced by diabetes, which can explain, at least in part, the basis for progressive cognitive decline in individuals with type 2 diabetes

Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy

Fibrosi hepàtica; Cèl·lules T; Teràpia de citocinesFibrosis hepática; Células T; Terapia de citocinasLiver fibrosis; T cells; Cytokine therapyBackground & aims HCV CD4+ and CD8+ specific T cells responses are functionally impaired during chronic hepatitis C infection. DAAs therapies eradicate HCV infection in more than 95% of treated patients. However, the impact of HCV elimination on immune responses remain controversial. Here, we aimed to investigate whether HCV cure by DAAs could reverse the impaired immune response to HCV. Methods We analyzed 27 chronic HCV infected patients undergoing DAA treatment in tertiary care hospital, and we determined the phenotypical and functional changes in both HCV CD8+ and CD4+ specific T-cells before and after viral clearance. PD-1, TIM-3 and LAG-3 cell-surface expression was assessed by flow cytometry to determine CD4+ T cell exhaustion. Functional responses to HCV were analyzed by IFN-Ɣ ELISPOT, intracellular cytokine staining (IL-2 and IFN-Ɣ) and CFSE-based proliferation assays. Results We observed a significant decrease in the expression of PD-1 in CD4+ T-cells after 12 weeks of viral clearance in non-cirrhotic patients (p = 0.033) and in treatment-naive patients (p = 0.010), indicating a partial CD4 phenotype restoration. IFN-Ɣ and IL-2 cytokines production by HCV-specific CD4+ and CD8+ T cells remained impaired upon HCV eradication. Finally, a significant increase of the proliferation capacity of both HCV CD4+ and CD8+ specific T-cells was observed after HCV elimination by DAAs therapies. Conclusions Our results show that in chronically infected patients HCV elimination by DAA treatment lead to partial reversion of CD4+ T cell exhaustion. Moreover, proliferative capacity of HCV-specific CD4+ and CD8+ T cells is recovered after DAA’s therapies.This study was funded by Instituto de Salud Carlos III, cofinanced by the European Regional Development Fund (ERDF): grant numbers PI16/00337, PI18/00210 and PI19/00301. C.P. is supported by the Miguel Servet program of the Instituto de Salud Carlos III (CP14/00121 and CPII19/00001) cofinanced by the European Regional Development Fund (ERDF)

Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy

Background & aims: HCV CD4+ and CD8+ specific T cells responses are functionally impaired during chronic hepatitis C infection. DAAs therapies eradicate HCV infection in more than 95% of treated patients. However, the impact of HCV elimination on immune responses remain controversial. Here, we aimed to investigate whether HCV cure by DAAs could reverse the impaired immune response to HCV. Methods: We analyzed 27 chronic HCV infected patients undergoing DAA treatment in tertiary care hospital, and we determined the phenotypical and functional changes in both HCV CD8+ and CD4+ specific T-cells before and after viral clearance. PD-1, TIM-3 and LAG-3 cell-surface expression was assessed by flow cytometry to determine CD4+ T cell exhaustion. Functional responses to HCV were analyzed by IFN-Ɣ ELISPOT, intracellular cytokine staining (IL-2 and IFN-Ɣ) and CFSE-based proliferation assays. Results: We observed a significant decrease in the expression of PD-1 in CD4+ T-cells after 12 weeks of viral clearance in non-cirrhotic patients (p = 0.033) and in treatment-naive patients (p = 0.010), indicating a partial CD4 phenotype restoration. IFN-Ɣ and IL-2 cytokines production by HCV-specific CD4+ and CD8+ T cells remained impaired upon HCV eradication. Finally, a significant increase of the proliferation capacity of both HCV CD4+ and CD8+ specific T-cells was observed after HCV elimination by DAAs therapies. Conclusions: Our results show that in chronically infected patients HCV elimination by DAA treatment lead to partial reversion of CD4+ T cell exhaustion. Moreover, proliferative capacity of HCV-specific CD4+ and CD8+ T cells is recovered after DAA's therapies

Impact of an active surveillance program and infection control measures on the incidence of carbapenem-resistant gram-negative bacilli in an intensive care unit

Hospital-acquired infections caused by carbapenem-resistant Gram-negative bacteria (CRGNB) have been increasingly reported worldwide and are associated with high rates of mortality especially in intensive care units(ICUs). Early identification through rectal surveillance cultures and implementation of infection control measures(ICM) including contact precautions, staff education on cleaning and hand hygiene may reduce the spread of these microorganisms. The aim of this work was to assess the impact of enhanced ICM on CRGNB colonization and to describe the molecular epidemiology of these bacteria in a polyvalent ICU in a tertiary level hospital. A prospective study including audits and active surveillance culture program, with molecular characterization, was conducted before and after the implementation of prevention programs and infection control measures. Microbiological screening was performed in chromogenic media; PCR targeting β-lactamases genes (blaKPC, blaNDM, blaVIM and blaOXA-48, blaSHV and blaCTX-M), molecular typing by PFGE; and MLST in K. pneumoniae were performed. CRGNB colonization was reduced from 16.92% to 9.67% upon implementing the infection control measures. In K. pneumoniae the most frequent carbapenemase type was KPC-2 associated with SHV-2 and CTX-M-15, and was disseminated in various STs (ST17, ST13, ST2256, ST353); there was no persistence of particular clones and virulence factors showed no association with hypervirulence. IMP-1 carbapenemase predominated in A. baumannii and the PFGE analysis individualized 3 clusters, assuming that the dissemination in the ICU was clonal. The early detection of patients colonized with CRBGN by using epidemiological surveillance cultures and the implementation of prophylactic measures are key to reducing the incidence of these microorganisms.Fil: Vargas, Juan Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Microbiología "Luis Verna". Cátedra de Bacteriología; ArgentinaFil: Moreno Mochi, María Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Microbiología "Luis Verna". Cátedra de Bacteriología; ArgentinaFil: Lopez, Carolina Graciela. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Microbiología "Luis Verna". Cátedra de Bacteriología; ArgentinaFil: Alarcón, Janet Alejandra. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Microbiología "Luis Verna". Cátedra de Bacteriología; ArgentinaFil: Acosta, Nancy. Gobierno de la Provincia de Tucumán. Hospital Ángel Padilla; ArgentinaFil: Soria, Karina. Gobierno de la Provincia de Tucumán. Hospital Ángel Padilla; ArgentinaFil: Nuñez, Juan Manuel. Gobierno de la Provincia de Tucumán. Hospital Ángel Padilla; ArgentinaFil: Villafañe, Sandra. Gobierno de la Provincia de Tucumán. Hospital Ángel Padilla; ArgentinaFil: Ramacciotti, Jorge. Gobierno de la Provincia de Tucumán. Hospital Ángel Padilla; ArgentinaFil: del Campo, Rosa. Instituto Ramón y Cajal de Investigación Sanitaria; EspañaFil: Jure, Maria Angela. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Microbiología "Luis Verna". Cátedra de Bacteriología; Argentin

Teoría política posfundacional. Presupuestos, métodos, apuestas

Las notas que presentamos a continuación sintetizan el trabajo de una comunidad abierta que ha intentado hacer de la política un lugar de pensamiento. Notas preliminares de una indagación inacabada que buscan precisar las dificultadescon las que nos hemos encontrado a lo largo de varios años. Al mismo tiempo, presentamos ciertos resultados provisorios, ciertas respuestas que hemos encontrado para tratar de definir una aproximación singular a la política; especificando los presupuestos, los métodos y las apuestas que constituyen una perspectiva específica.Fil: Biset, Emmanuel. 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: Martínez, Natalia María. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Centro de Investigaciones María Saleme Burnichón; ArgentinaFil: Soria, Ana Sofia. 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: Aznarez Carini, Gala. 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: Lorio, Natalia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Humanidades. Universidad Nacional de Córdoba. Instituto de Humanidades; ArgentinaFil: Moyano, Manuel Ignacio. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Centro de Investigaciones María Saleme Burnichón; ArgentinaFil: Llao, Marina Ivana. Universidad Nacional de Córdoba; ArgentinaFil: Romero, María Aurora. 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: Salamanca Agudelo, Katherine. Universidad Nacional de Córdoba. Centro de Estudios Avanzados; ArgentinaFil: Sosa, Pedro. 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: Vargas, Maria de Las Mercedes. Universidad Nacional de Santiago del Estero; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Farrán, Roque. 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; Argentin

Long-term care facilities (LTCF) for the elderly: the surveillance of communicable diseases as part of health care and protection

[ES] Durante las últimas décadas la asistencia sanitaria ha sufrido importantes cambios. La mayor esperanza de vida ha dado lugar a un envejecimiento de la población que, según las Naciones Unidas, está a punto de convertirse en una de las más importantes transformaciones sociales del siglo XXI. A nivel mundial, había 727 millones de personas de 65 años o más en 2020 (un 9,3% de la población total) y se estima que aumente al 16% en 2050 . En la Unión Europea (UE), el porcentaje de población de 65 años o más se ha incrementado de un 9,6% en 1960 a un 20,3% en 2019 y se proyecta que aumente a un 31,3% para 2100. Asistimos además a un proceso de envejecimiento de la población mayor, con una proporción de personas muy mayores (aquellas de 80 años y más) en la población total de la Unión Europea del 5,8% en 2019 . España es uno de los países con una mayor proporción de personas mayores, con un porcentaje de ciudadanos de 65 años o más en 2020 del 19,6% del total de la población, y con una proyección del 26,5% para 2035. Casi un tercio de esta población (6%) tienen 80 años o más. [EN] During the last decades, healthcare has undergone important changes. Increased life expectancy has given rise to an aging population that, according to the United Nations, is about to become one of the most important social transformations of the 21st century. Globally, there were 727 million people aged 65 or over in 2020 (9.3% of the total population) and this is estimated to increase to 16% by 2050 . In the European Union (EU), the percentage of the population aged 65 or over has increased from 9.6% in 1960 to 20.3% in 2019 and is projected to increase to 31.3% by 2100. We are also witnessing a process of aging of the elderly population, with a proportion of very old people (those aged 80 and over) in the total population of the European Union of 5.8% in 2019 . Spain is one of the countries with the highest proportion of older people, with a percentage of citizens aged 65 or over in 2020 of 19.6% of the total population, and with a projection of 26.5% for 2035. Almost a third of this population (6%) are 80 years or older.S

A collaboratively derived environmental research agenda for Galapagos

Galápagos is one of the most pristine archipelagos in the world and its conservation relies upon research and sensible management. In recent decades both the interest in, and the needs of, the islands have increased, yet the funds and capacity for necessary research have remained limited. It has become, therefore, increasingly important to identify areas of priority research to assist decision-making in Galápagos conservation. This study identified 50 questions considered priorities for future research and management. The exercise involved the collaboration of policy makers, practitioners and researchers from more than 30 different organisations. Initially, 360 people were consulted to generate 781 questions. An established process of preworkshop voting and three rounds to reduce and reword the questions, followed by a two-day workshop, was used to produce the final 50 questions. The most common issues raised by this list of questions were human population growth, climate change and the impact of invasive alien species. These results have already been used by a range of organisations and politicians and are expected to provide the basis for future research on the islands so that its sustainability may be enhanced. </jats:p

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Elective cancer surgery in COVID-19-free surgical pathways during the SARS-CoV-2 pandemic: An international, multicenter, comparative cohort study

PURPOSE As cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway. PATIENTS AND METHODS This international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation). RESULTS Of 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). CONCLUSION Within available resources, dedicated COVID-19–free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks