Biomarcadores de las formas clínicas de esclerosis múltiple: desarrollo de estrategias personalizadas basadas en perfiles inmunológicos de la vía del interferón de tipo I

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Microbiología I, leída el 10/04/2013Multiple sclerosis (MS) is a highly heterogeneous disease and to date reliable plasma biomarkers that enable to distinguish among the different clinical forms of MS are lacking. The present work has identified blood biomarkers in 182 subjects (129 MS patients and 53 healthy controls) that were consecutively recruited as two independent cohorts. We found a significant lower expression of dipeptydil peptidase 4 (DPP4) and DPP activity in the plasma of MS patients with respect to healthy controls and DPP activity correlated inversely with clinical disability score in MS. Our results demonstrate that the divergent clinical and histology-based MS forms are associated with distinct profiles of circulating biomarkers, mostly chemokines and growth/angiogenic factors (HGF, Eotaxin/CCL11, MCP-1/CCL2, Rantes/CCL5, EGF, MIP-1β/CCL4, VEGF and FGFb); and with different gene expression levels in PBMCs of patients (CLU, IRF2 and LDLR). Responder patients to type I IFN displayed high levels of plasma IP10 and MCP-1, and a specific expression pattern of IFN stimulated genes.La esclerosis múltiple (EM) es una enfermedad muy heterogénea clínicamente que carece de biomarcadores plasmáticos que distingan entre formas clínicas. Este trabajo ha identificado biomarcadores de EM en sangre periférica en 182 sujetos (129 pacientes con EM y 53 controles sanos) reclutados en dos cohortes consecutivas. La expresión de dipeptidil peptidasa 4 (DPP4) y la actividad DPP están significativamente disminuidas en el plasma de nuestros pacientes con EM con respecto a los controles sanos y la actividad DPP se correlaciona inversamente con la escala de discapacidad clínica en EM. Nuestros resultados demuestran que las fases recurrente-remitente y la progresiva se asocian con distintos perfiles de biomarcadores circulantes, en su mayor parte quimiocinas y factores de crecimiento/angiogénicos (HGF, Eotaxin/CCL11, MCP-1/CCL2, Rantes/CCL5, EGF, MIP-1β/CCL4, VEGF y FGFb); y con diferentes niveles de expresión génica en sus PBMCs (CLU, IRF2 y LDLR). Los pacientes respondedores a IFN de tipo I presentan niveles elevados de IP10 y MCP-1 en plasma, así como una expresión específica de los genes estimulados por IFN.Depto. de Inmunología, Oftalmología y ORLFac. de MedicinaTRUEunpu

Didáctica de la geometría en Educación Infantil a través de las áreas de expresión

La enseñanza de la geometría en Educación infantil es de vital importancia ya que permite a los niños de esta etapa comprender mejor el espacio que les rodea y construir un pensamiento espacial que les permita hacer frente a los constantes retos que se les presentan en su vida cotidiana. Trabajar la geometría y el espacio a través de la expresión artística y corporal hace que los niños participen de manera activa en su proceso de aprendizaje, siendo protagonistas del mismo y obteniendo aprendizajes más significativos. Tras realizar un análisis sobre la didáctica de las matemáticas en Educación Infantil y más concretamente del aprendizaje de la geometría; procederé a la exposición de una propuesta de actividades prácticas sobre el tema, relacionadas con las áreas de expresión que servirán como recursos que puede emplear cualquier docente durante su labor educativa.Grado en Educación Infanti

Ten Reasons Why People With Down Syndrome are Protected From the Development of Most Solid Tumors - A Review.

People with Down syndrome have unique characteristics as a result of the presence of an extra chromosome 21. Regarding cancer, they present a unique pattern of tumors, which has not been fully explained to date. Globally, people with Down syndrome have a similar lifetime risk of developing cancer compared to the general population. However, they have a very increased risk of developing certain tumors (e.g., acute leukemia, germ cell tumors, testicular tumors and retinoblastoma) and, on the contrary, there are some other tumors which appear only exceptionally in this syndrome (e.g., breast cancer, prostate cancer, medulloblastoma, neuroblastoma and Wilms tumor). Various hypotheses have been developed to explain this situation. The genetic imbalance secondary to the presence of an extra chromosome 21 has molecular consequences at several levels, not only in chromosome 21 but also throughout the genome. In this review, we discuss the different proposed mechanisms that protect individuals with trisomy 21 from developing solid tumors: genetic dosage effect, tumor suppressor genes overexpression, disturbed metabolism, impaired neurogenesis and angiogenesis, increased apoptosis, immune system dysregulation, epigenetic aberrations and the effect of different microRNAs, among others. More research into the molecular pathways involved in this unique pattern of malignancies is still needed.post-print1107 K

Questions and answers in the management of children with medulloblastoma over the time. How did we get here? A systematic review.

Introduction: Treatment of children with medulloblastoma (MB) includes surgery, radiation therapy (RT) and chemotherapy (CT). Several treatment protocols and clinical trials have been developed over the time to maximize survival and minimize side effects. Methods: We performed a systematic literature search in May 2023 using PubMed. We selected all clinical trials articles and multicenter studies focusing on MB. We excluded studies focusing exclusively on infants, adults, supratentorial PNETs or refractory/relapsed tumors, studies involving different tumors or different types of PNETs without differentiating survival, studies including <10 cases of MB, solely retrospective studies and those without reference to outcome and/or side effects after a defined treatment. Results: 1. The main poor-prognosis factors are: metastatic disease, anaplasia, MYC amplification, age younger than 36 months and some molecular subgroups. The postoperative residual tumor size is controversial. 2. MB is a collection of diseases. 3. MB is a curable disease at diagnosis, but survival is scarce upon relapse. 4. Children should be treated by experienced neurosurgeons and in advanced centers. 5. RT is an essential treatment for MB. It should be administered craniospinal, early and without interruptions. 6. Craniospinal RT dose could be lowered in some low-risk patients, but these reductions should be done with caution to avoid relapses. 7. Irradiation of the tumor area instead of the entire posterior fossa is safe enough. 8. Hyperfractionated RT is not superior to conventional RT 9. Both photon and proton RT are effective. 10. CT increases survival, especially in high-risk patients. 11. There are multiple drugs effective in MB. The combination of different drugs is appropriate management. 12. CT should be administered after RT. 13. The specific benefit of concomitant CT to RT is unknown. 14. Intensified CT with stem cell rescue has no benefit compared to standard CT regimens. 15. The efficacy of intraventricular/intrathecal CT is controversial. 16. We should start to think about incorporating targeted therapies in front-line treatment. 17. Survivors of MB still have significant side effects. Conclusion: Survival rates of MB improved greatly from 1940-1970, but since then the improvement has been smaller. We should consider introducing targeted therapy as front-line therapy. 1 Introductionpost-print5468 K

Proyecto Nube

La baja tolerancia a la frustración es un problema que ocurre en casi todas las aulas de todos los Centros Educativos, no solo interrumpe el ritmo normal de la clase, sino que también afecta negativamente en el alumno/a que la sufre en su desarrollo como persona, ya que le generará ansiedad, tristeza, miedo… también, hemos decidido que la autoestima es un factor influyente en la baja tolerancia a la frustración, ya que tener una baja autoestima dificulta el rendimiento del alumno/a, y, por ende, conlleva a sentirse frustrado por no conseguir los objetivos que se marque. Es muy importante concienciar, no solo a los docentes del Centro, sino también a los familiares, de que trabajar en mejorar la tolerancia a la frustración no solo mejorará el rendimiento del alumno/a tanto cognitivamente, sino que también socialmente. Es por eso que, en este proyecto, queremos que la familia participe y se anime a trabajar actividades o pautas y claves que hemos desarrollado tras buscar consejos y autores recomendados. Este Proyecto Profesionalizador está dirigido al profesorado de Educación Infantil que pueda tener en sus aulas niños/as con baja tolerancia a la frustración, para así, facilitar y proporcionar información, herramientas y actividades para intentar solventar el problema que les afecta. También, puede ser utilizado por la familia, ya que no hay actividades específicas solo para el aula.Low tolerance to frustration is an issue that occurs in early every classroom of every Schools, not only it interrupts the normal rhythm of the class, but also affect in a negative way in their development as a person when they suffer it because it will cause anxiety, sadness, fear… Also, we decided that self-esteem is an influent factor in the low tolerance to frustration because it hampers the children performance, and thereby, it involves to children to feel frustrated because they cannot get their targets. Is very important to educate, not only to the teachers, but their families, with the aim of improving the children tolerance to frustration, because it not only improve their scholar performance, but also their sociability. That’s why, in this project, we want that families participate as well, doing activities at home, or read the tips and keys that we have developed after we have searched many authors and advice. This project is aims to all teachers of Children Education that may have any student with those characteristics for facilitate and provide information, tools and activities for trying to solve the problem. Families can use this project as well because it does not have a specific activity just for the classroom

Reseña histórica del Hospital Psiquiátrico ¨Crisanto Betancourt Hernández¨ de Mayabeque

La atención al enfermo mental ha estado centrada en el hospital psiquiátrico, eje fundamental del tratamiento a enfermedades mentales.Con la reorientación de la psiquiatría, los hospitales psiquiátricos desarrollan una labor comunitaria coordinada entre el nivel de atención primario y el secundario. El Hospital Psiquiátrico ¨Crisanto Betancourt Hernández¨, representa a este tipo de entidad, lo que motiva a explorar su evolución histórica.  Las referencias se obtienen de las entrevistas a los fundadores, los vecinos, la exploración de documentos, las fotos, los reconocimientos y las condecoraciones .Se constata que ha crecido en la calidad de los servicios, la transformación de nuevas  instalaciones; la reducción de camas acorde al desarrollo de la reorientación de la especialidad, la proyección comunitaria en el primer nivel de atención; la formación del personal idóneo para la realización de esta labor y su superación científica

CCN2 Binds to Tubular Epithelial Cells in the Kidney

Cellular communication network-2 (CCN2), also called connective tissue growth factor (CTGF), is considered a fibrotic biomarker and has been suggested as a potential therapeutic target for kidney pathologies. CCN2 is a matricellular protein with four distinct structural modules that can exert a dual function as a matricellular protein and as a growth factor. Previous experiments using surface plasmon resonance and cultured renal cells have demonstrated that the C-terminal module of CCN2 (CCN2(IV)) interacts with the epidermal growth factor receptor (EGFR). Moreover, CCN2(IV) activates proinflammatory and profibrotic responses in the mouse kidney. The aim of this paper was to locate the in vivo cellular CCN2/EGFR binding sites in the kidney. To this aim, the C-terminal module CCN2(IV) was labeled with a fluorophore (Cy5), and two different administration routes were employed. Both intraperitoneal and direct intra-renal injection of Cy5-CCN2(IV) in mice demonstrated that CCN2(IV) preferentially binds to the tubular epithelial cells, while no signal was detected in glomeruli. Moreover, co-localization of Cy5-CCN2(IV) binding and activated EGFR was found in tubules. In cultured tubular epithelial cells, live-cell confocal microscopy experiments showed that EGFR gene silencing blocked Cy5-CCN2(IV) binding to tubuloepithelial cells. These data clearly show the existence of CCN2/EGFR binding sites in the kidney, mainly in tubular epithelial cells. In conclusion, these studies show that circulating CCN2(IV) can directly bind and activate tubular cells, supporting the role of CCN2 as a growth factor involved in kidney damage progression

Oxidative Stress and Cellular Senescence Are Involved in the Aging Kidney

Chronic kidney disease (CKD) can be considered as a clinical model for premature aging. However, non‐invasive biomarkers to detect early kidney damage and the onset of a senescent phenotype are lacking. Most of the preclinical senescence studies in aging have been done in very old mice. Furthermore, the precise characterization and over-time development of age-related senes-cence in the kidney remain unclear. To address these limitations, the age-related activation of cellular senescence-associated mechanisms and their correlation with early structural changes in the kidney were investigated in 3- to 18-month-old C57BL6 mice. Inflammatory cell infiltration was ob-served by 12 months, whereas tubular damage and collagen accumulation occurred later. Early activation of cellular-senescence-associated mechanisms was found in 12-month-old mice, character-ized by activation of the DNA-damage-response (DDR), mainly in tubular cells; activation of the antioxidant NRF2 pathway; and klotho downregulation. However, induction of tubular-cell-cycle-arrest (CCA) and overexpression of renal senescent-associated secretory phenotype (SASP) components was only found in 18-month-old mice. In aging mice, both inflammation and oxidative stress (marked by elevated lipid peroxidation and NRF2 inactivation) remained increased. These findings support the hypothesis that prolonged DDR and CCA, loss of nephroprotective factors (klotho), and dysfunctional redox regulatory mechanisms (NRF2/antioxidant defense) can be early drivers of age-related kidney-damage progressionThis research was funded by grants from the Instituto de Salud Carlos III (ISCIII); Fondos FEDER European Union (PI17/00119, PI20/00140; and DTS20/00083 to M.R.-O.; PI18/01133 to A.M.R.); Sara Borrell’ program from Instituto de Salud Carlos III (ISCIII) (grant number CD20/00042 to R.R.R.-D.); Red de Investigación Renal REDINREN: RD16/0009/0003 and RICORS program to RICORS2040 496 (RD21/0005), to M.R.-O., Sociedad Española de Nefrología; “NOVELREN-CM: Enfermedad renal crónica: nuevas Estrategias para la prevención, Diagnóstico y tratamiento” (B2017/BMD3751 to M.R.-O.); “Convocatoria Dinamización Europa Investigación 2019” MINECO (EIN2019-103294 to M.R.-O.); Juan de la Cierva incorporacion grant: IJC2018-035187-I to S.R.-M.; innovation program under the Marie Skłodowska-Curie grant of the European Union’s Horizon 2020 (IMProvePD ID: 812699) to M.R.-O.; and Fundacion Conchita Rabago to L.T.-

Epigenetic Modulation of Gremlin-1/NOTCH Pathway in Experimental Crescentic Immune-Mediated Glomerulonephritis

Crescentic glomerulonephritis is a devastating autoimmune disease that without early and properly treatment may rapidly progress to end-stage renal disease and death. Current immunosuppressive treatment provides limited efficacy and an important burden of adverse events. Epigenetic drugs are a source of novel therapeutic tools. Among them, bromodomain and extraterminal domain (BET) inhibitors (iBETs) block the interaction between bromodomains and acetylated proteins, including histones and transcription factors. iBETs have demonstrated protective effects on malignancy, inflammatory disorders and experimental kidney disease. Recently, Gremlin-1 was proposed as a urinary biomarker of disease progression in human anti-neutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis. We have now evaluated whether iBETs could regulate Gremlin-1 in experimental anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS) in mice, a model resembling human crescentic glomerulonephritis. In NTS-injected mice, the iBET JQ1 inhibited renal Gremlin-1 overexpression and diminished glomerular damage, restoring podocyte numbers. Chromatin immunoprecipitation assay demonstrated BRD4 enrichment of the Grem-1 gene promoter in injured kidneys, consistent with Gremlin-1 epigenetic regulation. Moreover, JQ1 blocked BRD4 binding and inhibited Grem-1 gene transcription. The beneficial effect of iBETs was also mediated by modulation of NOTCH pathway. JQ1 inhibited the gene expression of the NOTCH effectors Hes-1 and Hey-1 in NTS-injured kidneys. Our results further support the role for epigenetic drugs, such as iBETs, in the treatment of rapidly progressive crescentic glomerulonephritis