La regulación del Spindle Assembly Checkpoint en Schizosaccharomyces pombe

Motivación: Durante la mitosis, el huso mitótico formado por microtúbulos y moléculas asociadas, se encarga de la correcta segregación de los cromosomas. La pérdida o ganancia de cromosomas durante la mitosis puede promover cambios genéticos que predispongan al cáncer. Las células eucariotas tienen mecanismos que proporcionan a la célula un tiempo extra cuando existen problemas para capturar los cromosomas de forma adecuada. Este mecanismo, conservado de levaduras a humanos, se denomina Checkpoint del huso mitótico o Spindle Assembly Checkpoint (SAC). Una observación inicial mostró que las rutas de estrés son esenciales para el funcionamiento del Checkpoint del huso. Consistente con esta observación se comprobó que Bub1, una quinasa esencial para el funcionamiento del SAC, presenta sitios consenso de fosforilación por las MAPKs. En este proyecto se estudió la relevancia funcional de los sitios de fosforilación por MAPK de Bub1 en la levadura S. pombe.Métodos: Para estudiar la regulación del SAC, se usó el análisis genético y microscópico de la división celular en mutantes defectivos de este sistema de control en mitosis. Técnicas como la transformación y la clonación también fueron utilizadas.Resultados: Hemos demostrado que el SAC está regulado por la ruta de estrés de la MAPK pmk1 en S. pombe. La inactivación de la ruta MAPK a través de la deleción de pmk1, hace que las células sean sensibles a una droga que induce despolimerización en los microtúbulos del spindle, indicativo de defectos en el SAC. Mediante análisis genético, encontramos que este mecanismo es dependiente de bub1, un regulador central del SAC. Además, se ha estudiado la división celular en un mutante de Bub1 en el que se han eliminado 5 sitios putativos de fosforilación por MAPKs observándose, que dicho mutante es incapaz de llevar a cabo una segregación cromosómica correcta.Conclusiones: Se ha determinado que la ruta de la MAPK pmk1 se requiere para la supervivencia de S. pombe en condiciones en las que se compromete la función del huso mitótico así como la importancia de los sitios de fosforilación consenso de MAPK presentes en la quinasa Bub1. Nuestro estudio revela una conexión entre las rutas de MAPKs y el correcto funcionamiento del SAC. La pérdida total o parcial de esta regulación da lugar a eventos de aneuploidía. Este estudio puede ser relevante para entender cómo las células eucariotas evitan la aneuploidía, una de las características más comunes en tumores y que suelen modificar la progresión tumoral hacia diferentes estados de malignidad

A purine metabolic checkpoint that prevents autoimmunity and autoinflammation.

Still's disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of function of the purine nucleoside enzyme FAMIN is the sole known cause for monogenic Still's disease. Here we discovered that a FAMIN-enabled purine metabolon in dendritic cells (DCs) restrains CD4+ and CD8+ T cell priming. DCs with absent FAMIN activity prime for enhanced antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in excessive influenza A virus-specific responses. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ∼6% of mankind is homozygous. FAMIN controls membrane trafficking and restrains antigen presentation in an NADH/NAD+-dependent manner by balancing flux through adenine-guanine nucleotide interconversion cycles. FAMIN additionally converts hypoxanthine into inosine, which DCs release to dampen T cell activation. Compromised FAMIN consequently enhances immunosurveillance of syngeneic tumors. FAMIN is a biochemical checkpoint that protects against excessive antiviral T cell responses, autoimmunity, and autoinflammation

Academic literacy study at the School of Veterinary Sciences of the National University of La Plata

Cuando nos referimos a alfabetización académica, hacemos referencia a los conocimientos necesarios para aprender en la universidad. Habiéndose realizado una evaluación diagnóstica en el curso de Patología General Veterinaria, se estudió esta problemática en los cursos de segundo año de la carrera de Medicina Veterinaria de la Facultad de Ciencias Veterinarias de la UNLP. Los objetivos del estudio incluyeron conocer qué importancia se da en los cursos de segundo año a la lectura y a la escritura, indagar en las ideas de los docentes al respecto, analizar las actividades de lectoescritura propuestas a los estudiantes y conocer las dificultades que éstos enfrentan ante la lectura y escritura de textos académicos. Para ello se analizaron las planificaciones y evaluaciones curriculares de cada curso, relatos de clases y textos escritos por estudiantes. Se realizaron observaciones de clase y se encuestó a docentes y estudiantes de segundo año. Los resultados muestran qué actividades de lectura y escritura están presentes, tanto en el curriculum práctico como en el formal, hallándose las actividades de escritura preponderantemente en la instancia de evaluación. Las encuestas docentes revelan ideas en transición entre la postura que no reconoce responsabilidad de la universidad en la alfabetización académica y la que sí lo hace. Las encuestas a estudiantes revelaron múltiples dificultades en la lectura, mientras que el análisis de sus escritos mostró dificultades en la escritura. El conocimiento de la situación actual permitirá diseñar proyectos de intervención tendientes a mejorarla, facilitando el proceso de incorporación de los estudiantes a la cultura académica.Academic literacy refers to the knowledge required for learning in college. Taken into account a previous diagnostic study in the Veterinary General Pathology course, in the present work we performed an evaluation of the academic literacy in the remaining courses of second year of the Veterinary Medicine Career, School of Veterinary Sciences, UNLP. Our objectives were to know the relevance given in the courses to reading and writing, to inquire into the teacher conceptions about the academic literacy, to analyze the literacy activities proposed, and to know the challenges they should go through during reading and writing academic texts. Here we analyze planning and evaluation of each course, class descriptions and texts written by students. Class observations and surveys directed to teachers and second-year students were made. The results showed that reading and writing activities are present in the practical curriculum as in the formal one. The writing activities are predominantly present in the evaluations. Surveys directed to teachers reveal teachers that recognize responsibility of the university in the academic literacy and teachers who do not. In addition, surveys directed to students revealed many difficulties in reading, while the analysis of writing showed some difficulties. Knowledge of the current situation will allow designing intervention projects aimed to facilitating the process of incorporation of students to the academic culture.Facultad de Ciencias Veterinaria

Academic literacy study at the School of Veterinary Sciences of the National University of La Plata

Cuando nos referimos a alfabetización académica, hacemos referencia a los conocimientos necesarios para aprender en la universidad. Habiéndose realizado una evaluación diagnóstica en el curso de Patología General Veterinaria, se estudió esta problemática en los cursos de segundo año de la carrera de Medicina Veterinaria de la Facultad de Ciencias Veterinarias de la UNLP. Los objetivos del estudio incluyeron conocer qué importancia se da en los cursos de segundo año a la lectura y a la escritura, indagar en las ideas de los docentes al respecto, analizar las actividades de lectoescritura propuestas a los estudiantes y conocer las dificultades que éstos enfrentan ante la lectura y escritura de textos académicos. Para ello se analizaron las planificaciones y evaluaciones curriculares de cada curso, relatos de clases y textos escritos por estudiantes. Se realizaron observaciones de clase y se encuestó a docentes y estudiantes de segundo año. Los resultados muestran qué actividades de lectura y escritura están presentes, tanto en el curriculum práctico como en el formal, hallándose las actividades de escritura preponderantemente en la instancia de evaluación. Las encuestas docentes revelan ideas en transición entre la postura que no reconoce responsabilidad de la universidad en la alfabetización académica y la que sí lo hace. Las encuestas a estudiantes revelaron múltiples dificultades en la lectura, mientras que el análisis de sus escritos mostró dificultades en la escritura. El conocimiento de la situación actual permitirá diseñar proyectos de intervención tendientes a mejorarla, facilitando el proceso de incorporación de los estudiantes a la cultura académica.Academic literacy refers to the knowledge required for learning in college. Taken into account a previous diagnostic study in the Veterinary General Pathology course, in the present work we performed an evaluation of the academic literacy in the remaining courses of second year of the Veterinary Medicine Career, School of Veterinary Sciences, UNLP. Our objectives were to know the relevance given in the courses to reading and writing, to inquire into the teacher conceptions about the academic literacy, to analyze the literacy activities proposed, and to know the challenges they should go through during reading and writing academic texts. Here we analyze planning and evaluation of each course, class descriptions and texts written by students. Class observations and surveys directed to teachers and second-year students were made. The results showed that reading and writing activities are present in the practical curriculum as in the formal one. The writing activities are predominantly present in the evaluations. Surveys directed to teachers reveal teachers that recognize responsibility of the university in the academic literacy and teachers who do not. In addition, surveys directed to students revealed many difficulties in reading, while the analysis of writing showed some difficulties. Knowledge of the current situation will allow designing intervention projects aimed to facilitating the process of incorporation of students to the academic culture.Facultad de Ciencias Veterinaria

Guía de práctica clínica para el tratamiento farmacológico y psicológico de los pacientes adultos con trastorno bipolar y un diagnóstico comórbido de trastorno por uso de sustancias

This review synthesizes the pharmacological and psychosocial interventions that have been conducted in comorbid bipolar disorder (BD) and substance use disorders (SUDs) while also providing clinical recommendations about which intervention elements are helpful for addressing substance use versus mood symptoms in patients with these co-occurring conditions. The best evidence from randomized controlled trials was used to evaluate treatment options. The strength of recommendations was described using the GRADE approach. Very few of the randomized trials performed so far have provided consistent evidence for the management of both mood symptoms and substance use in patients with a BD. No clinical trials are available for bipolar patients using cannabis. Some treatments have shown benefit for mood symptoms without benefits for alcohol or illicit substance use. Our results suggest that 1) we can (weakly) recommend the use of adjuvant valproate or naltrexone to improve symptoms of alcohol use disorder; 2) Lamotrigine add-on therapy seems to reduce cocaine-related symptoms and is therefore recommended (moderate strength); and 3) Varenicline is (weakly) recommended to improve nicotine abstinence. Integrated group therapy is the most-well validated and efficacious approach on substance use outcomes if substance use is targeted in an initial treatment phaseEsta revisión resume las intervenciones farmacológicos y psicosociales que se han realizado en trastorno bipolar (TB) y un diagnóstico comórbido de trastorno por uso de sustancias (TUS) y además proporciona recomendaciones clínicas respecto de cuáles elementos de intervención son útiles para hacer frente a los síntomas del uso de sustancias versus los síntomas de estado de ánimo en pacientes con estas afecciones concurrentes. Se utilizó la mejor evidencia de ensayos controlados aleatorizados para evaluar las opciones de tratamiento. La fuerza de las recomendaciones se describió mediante el enfoque GRADE. Muy pocos de los ensayos aleatorizados realizados hasta la fecha han proporcionado evidencia consistente para el manejo tanto de los síntomas de estado de ánimo como del uso de sustancias en pacientes con TB. No hay disponibilidad de ensayos clínicos para pacientes con TB que utilizan el cannabis. Algunos tratamientos han mostrado beneficios para los síntomas de estado de ánimo sin beneficios para el uso de alcohol o sustancias ilícitas. Nuestros resultados sugieren que 1) podemos (débilmente) recomendar el uso de ácido valproico o naltrexona adyuvante para aliviar los síntomas del trastorno por consumo de alcohol; 2) el tratamiento complementario con lamotrigina parece reducir los síntomas relacionados con la cocaína y, por tanto, es recomendable (fuerza moderada); y 3) la vareniclina es recomendable (débilmente) para mejorar la abstinencia de la nicotina. La terapia grupal integrada es el enfoque con más validación y eficacia sobre los resultados en el uso de sustancias cuando este uso es abordado durante la fase inicial de tratamientoS

Correction : Chaparro et al. Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain: Large-Scale Epidemiological Study. J. Clin. Med. 2021, 10, 2885

The authors wish to make the following corrections to this paper [...]

Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain : Large-Scale Epidemiological Study

(1) Aims: To assess the incidence of inflammatory bowel disease (IBD) in Spain, to describe the main epidemiological and clinical characteristics at diagnosis and the evolution of the disease, and to explore the use of drug treatments. (2) Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD-Crohn's disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)-during 2017 in Spain were included and were followed-up for 1 year. (3) Results: We identified 3611 incident cases of IBD diagnosed during 2017 in 108 hospitals covering over 22 million inhabitants. The overall incidence (cases/100,000 person-years) was 16 for IBD, 7.5 for CD, 8 for UC, and 0.5 for IBD-U; 53% of patients were male and median age was 43 years (interquartile range = 31-56 years). During a median 12-month follow-up, 34% of patients were treated with systemic steroids, 25% with immunomodulators, 15% with biologics and 5.6% underwent surgery. The percentage of patients under these treatments was significantly higher in CD than UC and IBD-U. Use of systemic steroids and biologics was significantly higher in hospitals with high resources. In total, 28% of patients were hospitalized (35% CD and 22% UC patients, p < 0.01). (4) Conclusion: The incidence of IBD in Spain is rather high and similar to that reported in Northern Europe. IBD patients require substantial therapeutic resources, which are greater in CD and in hospitals with high resources, and much higher than previously reported. One third of patients are hospitalized in the first year after diagnosis and a relevant proportion undergo surgery

Effectiveness and Safety of the Sequential Use of a Second and Third Anti-TNF Agent in Patients With Inflammatory Bowel Disease: Results From the Eneida Registry

Background: The effectiveness of the switch to another anti-tumor necrosis factor (anti-TNF) agent is not known. The aim of this study was to analyze the effectiveness and safety of treatment with a second and third anti-TNF drug after intolerance to or failure of a previous anti-TNF agent in inflammatory bowel disease (IBD) patients. Methods: We included patients diagnosed with IBD from the ENEIDA registry who received another anti-TNF after intolerance to or failure of a prior anti-TNF agent. Results: A total of 1122 patients were included. In the short term, remission was achieved in 55% of the patients with the second anti-TNF. The incidence of loss of response was 19% per patient-year with the second anti-TNF. Combination therapy (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.8-3; P < 0.0001) and ulcerative colitis vs Crohn's disease (HR, 1.6; 95% CI, 1.1-2.1; P = 0.005) were associated with a higher probability of loss of response. Fifteen percent of the patients had adverse events, and 10% had to discontinue the second anti-TNF. Of the 71 patients who received a third anti-TNF, 55% achieved remission. The incidence of loss of response was 22% per patient-year with a third anti-TNF. Adverse events occurred in 7 patients (11%), but only 1 stopped the drug. Conclusions: Approximately half of the patients who received a second anti-TNF achieved remission; nevertheless, a significant proportion of them subsequently lost response. Combination therapy and type of IBD were associated with loss of response. Remission was achieved in almost 50% of patients who received a third anti-TNF; nevertheless, a significant proportion of them subsequently lost response

Clinical guideline for the treatment of dual pathology in the adult population

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Effectiveness of an intervention for improving drug prescription in primary care patients with multimorbidity and polypharmacy:Study protocol of a cluster randomized clinical trial (Multi-PAP project)

This study was funded by the Fondo de Investigaciones Sanitarias ISCIII (Grant Numbers PI15/00276, PI15/00572, PI15/00996), REDISSEC (Project Numbers RD12/0001/0012, RD16/0001/0005), and the European Regional Development Fund ("A way to build Europe").Background: Multimorbidity is associated with negative effects both on people's health and on healthcare systems. A key problem linked to multimorbidity is polypharmacy, which in turn is associated with increased risk of partly preventable adverse effects, including mortality. The Ariadne principles describe a model of care based on a thorough assessment of diseases, treatments (and potential interactions), clinical status, context and preferences of patients with multimorbidity, with the aim of prioritizing and sharing realistic treatment goals that guide an individualized management. The aim of this study is to evaluate the effectiveness of a complex intervention that implements the Ariadne principles in a population of young-old patients with multimorbidity and polypharmacy. The intervention seeks to improve the appropriateness of prescribing in primary care (PC), as measured by the medication appropriateness index (MAI) score at 6 and 12months, as compared with usual care. Methods/Design: Design:pragmatic cluster randomized clinical trial. Unit of randomization: family physician (FP). Unit of analysis: patient. Scope: PC health centres in three autonomous communities: Aragon, Madrid, and Andalusia (Spain). Population: patients aged 65-74years with multimorbidity (≥3 chronic diseases) and polypharmacy (≥5 drugs prescribed in ≥3months). Sample size: n=400 (200 per study arm). Intervention: complex intervention based on the implementation of the Ariadne principles with two components: (1) FP training and (2) FP-patient interview. Outcomes: MAI score, health services use, quality of life (Euroqol 5D-5L), pharmacotherapy and adherence to treatment (Morisky-Green, Haynes-Sackett), and clinical and socio-demographic variables. Statistical analysis: primary outcome is the difference in MAI score between T0 and T1 and corresponding 95% confidence interval. Adjustment for confounding factors will be performed by multilevel analysis. All analyses will be carried out in accordance with the intention-to-treat principle. Discussion: It is essential to provide evidence concerning interventions on PC patients with polypharmacy and multimorbidity, conducted in the context of routine clinical practice, and involving young-old patients with significant potential for preventing negative health outcomes. Trial registration: Clinicaltrials.gov, NCT02866799Publisher PDFPeer reviewe