Tlr2 Gene Deletion Delays Retinal Degeneration in Two Genetically Distinct Mouse Models of Retinitis Pigmentosa

Although considered a rare retinal dystrophy, retinitis pigmentosa (RP) is the primary cause of hereditary blindness. Given its diverse genetic etiology (>3000 mutations in >60 genes), there is an urgent need for novel treatments that target common features of the disease. TLR2 is a key activator of innate immune response. To examine its role in RP progression we characterized the expression profile of Tlr2 and its adaptor molecules and the consequences of Tlr2 deletion in two genetically distinct models of RP: Pde6brd10/rd10 (rd10) and RhoP23H/+ (P23H/+) mice. In both models, expression levels of Tlr2 and its adaptor molecules increased in parallel with those of the proinflammatory cytokine Il1b. In rd10 mice, deletion of a single Tlr2 allele had no effect on visual function, as evaluated by electroretinography. However, in both RP models, complete elimination of Tlr2 attenuated the loss of visual function and mitigated the loss of photoreceptor cell numbers. In Tlr2 null rd10 mice, we observed decreases in the total number of microglial cells, assessed by flow cytometry, and in the number of microglia infiltrating the photoreceptor layers. Together, these results point to TLR2 as a mutation-independent therapeutic target for RP

The multiple dimensions of health and disease of the ecobiopsychosocial being in A monster calls (2016)

Connor O'Malley is a 12-year-old boy suffering from caregiver syndrome due to his mother's terminal illness; his fears materialize and come to life in a fantastic way constituting a fearsome monster whose purpose is to bring to light his deepest fears and feelings. Every terminally ill patient, when becoming no longer independent, requires care from caregivers who may ensure their well-being, and in many cases the caregivers are family members. Caregiver Syndrome is a condition caused by the strenuous care of a dependent family member. This syndrome manifests in response to emotional stress and is characterized by both physical and psychological exhaustion. By establishing itself as an ecobiopsychosocial entity, human health is the result of well-being in each sphere, so that, when only one of them is affected, the health of an individual can be affected, as occurs in caregiver syndrome. The caregiver syndrome in Connor is the subject of this article, as are the potential means for its approach.Connor O'Malley es un chico de 12 años que padece del síndrome del cuidador debido a la enfermedad terminal de su madre; sus temores se materializan y cobran vida constituyendo de manera fantástica un temible monstruo que tiene como propósito sacar a la luz sus más profundos temores y sentimientos. Todo paciente con enfermedad terminal al dejar de ser independiente requiere atención de cuidadores que aseguren su bienestar y en muchas ocasiones los cuidadores son miembros de la familia. El síndrome del cuidador es una condición provocada por el cuidado extenuante de un familiar dependiente. Este síndrome se manifiesta en respuesta a un estrés emocional y se caracteriza por el agotamiento tanto físico como psicológico. Al constituirse como una entidad ecobiopsicosocial, la salud humana es resultado del bienestar en cada esfera, de modo que, cuando existe afectación de tan solo una de ellas, la salud de un individuo puede afectarse, como sucede en el síndrome del cuidador. El síndrome del cuidador en Connor es el tema del presente artículo, así como lo son los potenciales medios para su abordaje

Artificial Intelligence to evaluate the impact of COVID-19 disease on the elderly

Resumen del trabajo presentado a las II Jornadas Científicas PTI+ Salud Global, celebradas en Valencia del 5 al 6 de octubre de 2022.Peer reviewe

The gut microbiota, a hallmark of human aging, could implicate risk and effect of COVID19 in the elderly

Resumen del trabajo presentado a las II Jornadas Científicas PTI+ Salud Global, celebradas en Valencia del 5 al 6 de octubre de 2022.Peer reviewe

Longitudinal study of the immune response after

Resumen del trabajo presentado a las II Jornadas Científicas PTI+ Salud Global, celebradas en Valencia del 5 al 6 de octubre de 2022.Peer reviewe

Characterization of the memory immune response to viruses

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 11-12-2018Esta tesis tiene embargado el acceso al texto completo hasta el 11-06-2020La vacunación es la estrategia más eficiente para conferir protección frente a patógenos humanos. Sin embargo, actualmente no hay vacunas disponibles frente a patógenos crónicos de alto impacto sanitario. Nuestro objetivo fue el estudio de la respuesta inmunitaria frente a infecciones virales para obtener información útil en el diseño de nuevas estrategias de vacunación, centrándonos en el virus vaccinia (VACV) y el citomegalovirus murino (MCMV). VACV es uno de los mejores modelos para estudiar las interacciones entre hospedador y patógeno, ya que fue el agente utilizado para erradicar la viruela. MCMV es uno de los candidatos más prometedores en el desarrollo de vacunas basadas en linfocitos T CD8+, útiles frente a patógenos que dependen de una respuesta inmunitaria celular para su eliminación. Comenzamos estudiando la iniciación de la respuesta inmunitaria celular y la respuesta humoral tras la infección por VACV en modelos de ratón con deficiencias genéticas asociadas a defectos en la inmunidad celular. Nuestra observación más relevante fue el hecho de que la ausencia de PARP-2 en linfocitos T combinada con una deficiencia sistémica en PARP-1 causa una fuerte reducción de la respuesta de anticuerpos frente a VACV. Como PARP-1 y PARP-2 son dianas terapéuticas en cáncer debido a su papel en la reparación del DNA y el mantenimiento de la estabilidad genómica, esto podría ser relevante para efectos secundarios potenciales en pacientes. Posteriormente analizamos la capacidad protectora de los vectores vacunales de MCMV en un modelo de ratón que presenta un defecto en la respuesta de linfocitos T CD8+ de memoria, observando que MCMV puede superar situaciones de deficiencia en la respuesta inmunitaria de memoria. Para describir el mecanismo molecular de este fenómeno, hemos analizado en detalle la respuesta de linfocitos T CD8+ inducida por los vectores vacunales de MCMV en estos animales centrándonos en su fenotipo, cinética y función; junto con los títulos virales de MCMV en órganos y el fenotipo y la función de las células dendríticas y de las células NK. Además, hemos analizado la respuesta de linfocitos T CD8+ inducida por un MCMV que carece de una proteína de evasión inmunitaria que interfiere con la presentación de antígenos restringida por MHC de clase I, observando alteraciones en la magnitud y en la cinética de la respuesta de linfocitos T CD8+ frente a varios epítopos. Estas observaciones pueden contribuir a la descripción de los mecanismos de generación de respuestas de linfocitos T CD8+ frente a MCMV, que son únicas debido a su potencia y persistencia.Vaccination is the most efficient strategy to confer protection against various human pathogens. However, to this date there are still no vaccines available against some chronic pathogens of high sanitary impact. Our goal was to study immune responses against viral infections in order to obtain potentially useful information for the design of new vaccination strategies, focusing on vaccinia virus (VACV) and murine cytomegalovirus (MCMV) vectors. As VACV was the vaccination agent used for the eradication of smallpox, it is one of the best models to study host-pathogen interactions. MCMV is one of the most promising candidates in order to develop CD8+ T lymphocyte-based vaccines, which are necessary against pathogens that depend on a cellular immune response for their elimination. First, we studied the initiation of the cellular immune response and the humoral response after VACV infection in different mouse models with genetic deficiencies associated with impaired cellular immunity. Our most relevant finding was that the absence of PARP-2 in T lymphocytes in a PARP-1 deficient background causes a strong reduction of anti-VACV antibody responses. Since PARP-1 and PARP-2 are targets for cancer therapy as they are involved in DNA repair and in maintenance of genomic stability, this might be relevant for potential side effects in patients. Then, we analyzed the capacity of MCMV vaccine vectors to induce protection in a mouse model of defective CD8+ T lymphocyte memory responses, observing that MCMV can overcome situations of deficient immune memory. In order to describe the molecular mechanism of this phenomenon, we have analyzed in detail the CD8+ T lymphocyte response induced by MCMV vectors in these animals in terms of phenotype, kinetics and function; together with MCMV viral titers in organs and the phenotype and function of dendritic cells and NK cells. Furthermore, we analyzed the CD8+ T lymphocyte response induced by an MCMV lacking an immune evasion protein that interferes with MHC class I-restricted antigen presentation, observing alterations in the magnitude and kinetics of the CD8+ T lymphocyte response against several epitopes. These findings might contribute to describe the mechanisms behind the generation of anti-MCMV CD8+ T lymphocyte responses, which are unique due to their strength and persistence

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research