Caracterización de la función de Dyrk1A como modulador del comportamiento de las células madre neurales, normales y cancerosas

El gen DYRK1A se localiza en el cromosoma 21 en la región llamada “Región Crítica del Síndrome de Down”. Dyrk1A participa en diferentes vías de señalización y está implicado durante el desarrollo en la proliferación y diferenciación de progenitores neurales, pero se desconoce si esta función se mantiene en el individuo adulto. En la década de los 90 se demostró que existe neurogénesis en el cerebro adulto, residiendo las células madre que la mantienen en dos nichos o regiones cerebrales que son la zona sub-ependimaria (SEZ) adyacente a los ventrículos laterales y la zona sub-granular del giro dentado del hipocampo. Estas NSCs están reguladas por diferentes factores moleculares y celulares que mantienen su homeostasis y existen cada vez más evidencias de que su desregulación puede conducir a situaciones patológicas. Estas células se pueden aislar y crecer in vitro en ausencia de sustrato y presencia de los mitógenos EGF y FGF, formando unos agregados llamados neuroesferas. Por otro lado los glioblastomas (GBMs) son tumores muy agresivos con una supervivencia a cinco años menor del 2% de los pacientes. Fue en los GBMs donde se aislaron por primera vez en tumores sólidos unas células con características de célula madre que se consideran responsables de la formación y mantenimiento del tumor. Además se ha propuesto que algunas de las vías que controlan el comportamiento de las NSCs puedan también estar regulando a las TICs. Por todo esto nos propusimos estudiar el efecto de Dyrk1A sobre la regulación de las NSCs y de las células madre iniciadoras de tumor (TICs). Realizamos un análisis de expresión que reveló que las NSCs de la SEZ expresan Dyrk1A tanto in vivo como in vitro. Para el estudio de la regulación de Dyrk1A sobre las NSCs utilizamos un modelo murino de haploinsuficiencia para Dyrk1A. La heterocigosis de Dyrk1A produce una disminución del porcentaje de NSCs en la SEZ. El estudio del comportamiento in vitro de estas NSCs reveló que las células heterocigotas para Dyrk1A tienen disminuida la capacidad de auto-renovación, y que esta disminución se produce en respuesta exclusivamente al mitógeno EGF. Este defecto en auto-renovación se corresponde con una disminución de la cantidad de EGFR en estas células heterocigotas. Los experimentos de estabilidad del EGFR demostraron que la disminución de la dosis de Dyrk1A conlleva un aumento de la tasa de degradación del receptor. Además esta regulación de los niveles del EGFR por Dyrk1A se produce (al menos en parte) a través de la fosforilación del modulador de los receptores de tirosina quinasa Sprouty2. Análogamente a las NSCs, las TICs de GBMs se pueden crecer ausencia de suero y presencia de EGF y FGF formando agregados esferoides. Estos cultivos de TICs de GBMs expresan DYRK1A, aunque de una manera variable. La reducción de los niveles de DYRK1A mediante RNA de interferencia produce un descenso en la capacidad de auto-renovación de estas células in vitro, que se corresponde con una reducción en los niveles de EGFR. Por último estas células interferidas para DYRK1A tienen menor capacidad de formación de tumores in vivo. En conclusión Dyrk1A es un regulador de la auto-renovación tanto de NSCs como de TICs de GBMs en respuesta a EGF y una diana terapéutica interesante para el tratamiento de los GBMs

Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth

Glioblastomas (GBMs) are very aggressive tumors that are resistant to conventional chemo- and radiotherapy. New molecular therapeutic strategies are required to effectively eliminate the subpopulation of GBM tumor-initiating cells that are responsible for relapse. Since EGFR is altered in 50% of GBMs, it represents one of the most promising targets; however, EGFR kinase inhibitors have produced poor results in clinical assays, with no clear explanation for the observed resistance. We uncovered a fundamental role for the dual-specificity tyrosine phosphorylation-regulated kinase, DYRK1A, in regulating EGFR in GBMs. We found that DYRK1A was highly expressed in these tumors and that its expression was correlated with that of EGFR. Moreover, DYRK1A inhibition promoted EGFR degradation in primary GBM cell lines and neural progenitor cells, sharply reducing the self-renewal capacity of normal and tumorigenic cells. Most importantly, our data suggest that a subset of GBMs depends on high surface EGFR levels, as DYRK1A inhibition compromised their survival and produced a profound decrease in tumor burden. We propose that the recovery of EGFR stability is a key oncogenic event in a large proportion of gliomas and that pharmacological inhibition of DYRK1A could represent a promising therapeutic intervention for EGFR-dependent GBMs.This work was supported by grants from the Ministerio de Educación y Ciencia (MEC; SAF2008-04531), the Ministerio de Ciencia e Innovación (MICINN, PLE2009-0115), and the Ministerio de Asuntos Exteriores y Cooperación (MAEC-AECID A/023963/09; to P. Sánchez-Gómez), as well as by grants from the Fondo de Investigación Sanitaria (FIS-PS09-01977) and Fundación Mutua-madrileña grants (FMM 2007/057, to J.R. Ricoy; and FMM2011/89, to J.M. Sepúlveda).S

Modelling the consumption of anxiolytics and its addictive behaviour

Background: Population-based anxiolytics consumption (AX) is a widely debated subject because long-term AX may lead to tolerance and addiction. This study aims to obtain mathematical models that identify the various behaviours in AX prescription in accordance with gender, age and the continuous prescription of other drugs associated with chronic diseases.Methods: Data were obtained from an electronic prescriptions database (n=12,211,992) received by patients (n=504,224) visiting the Primary Health Care Centres in the province of Castellón (East Spain) in 2009. A linear regression model was used to explain the number of defined daily doses (DDD) of AX prescribed in accordance with age, gender and more than 5 prescriptions of any drug associated with chronic diseases other than AX. We used the logistic regression model to quantify the joint influence of the explanatory variables on the likelihood (L) of prescribing increasingly high DDD of AX.Results: The mean annual DDD per patient was 133.13, and the DDD prescribed was 38.06 day/1000 inhabitants. Few differences, although significant, in prescriptions per gender were observed; males received fewer prescriptions than females. Conversely, differences in age groups were substantial; the older subjects become, the higher the prescribed DDD, although these differences disappeared after the age of 65. AX use was also positively associated with the presence of comorbidity: depression, psychosis and epilepsy. Sporadic AX prescriptions were not associated with any factor, except continuous use.Conclusions: The prevalence of prescribing AX in the general population visiting the primary health centres in Castellón is over 16%. Prescriptions and the DDD of AX are barely higher for females than for males, and age is the most influential factor; the older the patient, the higher the number of prescribed DDD. The likelihood of potentially addictive behaviours is higher among the elderly and patients with comorbidity, mainly those patients with other chronic psychiatric conditions. © 2010 Elsevier Ltd.Guadalajara Olmeda, MN.; Barrachina Martínez, I.; De La Poza, E.; Vivas Consuelo, DJJ.; Caballer Tarazona, M. (2011). Modelling the consumption of anxiolytics and its addictive behaviour. Mathematical and Computer Modelling. 54(7):1626-1633. https://doi.org/10.1016/j.mcm.2010.12.036S1626163354

Suppressive Antibiotic Therapy in Prosthetic Joint Infections: A Multicentre Cohort Study

Objectives: The aim was to describe the effectiveness of suppressive antibiotic treatment (SAT) in routine clinical practice when used in situations in which removal of a prosthetic implant is considered essential for the eradication of an infection, and it cannot be performed. Methods: This was a descriptive retrospective and multicentre cohort study of prosthetic joint infection (PJI) cases managed with SAT. SAT was considered to have failed if a fistula appeared or persisted, if debridement was necessary, if the prosthesis was removed due to persistence of the infection or if uncontrolled symptoms were present. Results: In total, 302 patients were analysed. Two hundred and three of these patients (67.2%) received monotherapy. The most commonly used drugs were tetracyclines (39.7% of patients) (120/302) and cotrimoxazole (35.4% of patients) (107/302). SAT was considered successful in 58.6% (177/302) of the patients (median time administered, 36.5 months; IQR 20.75-59.25). Infection was controlled in 50% of patients at 5 years according to Kaplan-Meier analysis. Resistance development was documented in 15 of 65 (23.1%) of the microbiologically documented cases. SAT failure was associated with age <70 years (sub-hazard ratio (SHR) 1.61, 95% CI 1.1-2.33), aetiology other than Gram-positive cocci (SHR 1.56, 95% CI 1.09-2.27) and location of the prosthesis in the upper limb (SHR 2.4, 95% CI 1.5-3.84). SAT suspension was necessary due to adverse effects in 17 of 302 patients (5.6%). Conclusions: SAT offers acceptable results for patients with PJI when surgical treatment is not performed or when it fails to eradicate the infection

Executive summary of the Consensus Document of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) and of the Spanish Association of Surgeons (AEC) in antibiotic prophylaxis in surgery

[ES] La profilaxis antibiótica en cirugía es una de las medidas más eficaces para la prevención de la infección de localización quirúrgica, aunque su uso es con frecuencia inadecuado, pudiendo incrementar el riesgo de infección, toxicidades y resistencias bacterianas. Debido al avance en las técnicas quirúrgicas y la emergencia de microorganismos multirresistentes las actuales pautas de profilaxis precisan ser revisadas. La Sociedad Española de Enfermedades Infecciosas (SEIMC), conjuntamente con la Asociación Española de Cirujanos (AEC) ha revisado y actualizado las recomendaciones de profilaxis antimicrobiana para adaptarlas a cada tipo de intervención quirúrgica y a la epidemiología actual. En este documento se recogen las recomendaciones de los antimicrobianos utilizados en profilaxis en los diferentes procedimientos, las dosis, la duración, la profilaxis en huéspedes especiales, y en situación epidemiológica de multirresistencia, de tal forma que permitan un manejo estandarizado, un uso racional, seguro y efectivo de los mismos en la cirugía electiva.[EN] Antibiotic prophylaxis in surgery is one of the most effective measures for preventing surgical site infection, although its use is frequently inadequate and may even increase the risk of infection, toxicities and antimicrobial resistance. As a result of advances in surgical techniques and the emergence of multidrug-resistant organisms, the current guidelines for prophylaxis need to be revised. The Sociedad Española de Enfermedades Infecciosas (Spanish Society of Infectious Diseases and Clinical Microbiology) (SEIMC) together with the Asociación Española de Cirujanos (Spanish Association of Surgeons) (AEC) have revised and updated the recommendations for antibiotic prophylaxis in surgery to adapt them to any type of surgical intervention and to current epidemiology. This document gathers together the recommendations on antimicrobial prophylaxis in the various procedures, with doses, duration, prophylaxis in special patient groups, and in epidemiological settings of multidrug resistance to facilitate standardized management and the safe, effective and rational use of antibiotics in elective surgery

A Large Multicenter Prospective Study of Community-Onset Healthcare Associated Bacteremic Urinary Tract Infections in the Era of Multidrug Resistance: Even Worse than Hospital Acquired Infections?

Introduction: Healthcare-associated (HCA) infections represent a growing public health problem. The aim of this study was to compare community-onset healthcare associated (CO-HCA) bacteremic urinary tract infections (BUTI) and hospital-acquired (HA)-BUTI with special focus on multidrug resistances (MDR) and outcomes. Methods: ITUBRAS-project is a prospective multicenter cohort study of patients with HCA-BUTI. All consecutive hospitalized adult patients with CO-HCA-BUTI or HA-BUTI episode were included in the study. Exclusion criteria were: patients \ 18 years old, non-hospitalized patients, bacteremia from another source or primary bacteremia, non-healthcare related infections and infections caused by unusual pathogens of the urinary tract. Th main outcome variable was 30-day all-cause mortality with day 1 as the first day of positive blood culture. Logistic regression was used to analyze factors associated with clinical cure at hospital discharge and with receiving inappropriate initial antibiotic treatment. Cox regression was used to evaluate 30-day all-cause mortality. Results: Four hundred forty-three episodes were included, 223 CO-HCA-BUTI. Patients with CO-HCA-BUTI were older (p \ 0.001) and had more underlying diseases (p = 0.029) than those with HA-BUTI. The severity of the acute illness (Pitt score) was also higher in CO-HCABUTI (p = 0.026). Overall, a very high rate of MDR profiles (271/443, 61.2%) was observed, with no statistical differences between groups. In multivariable analysis, inadequate empirical treatment was associated with MDR profile (aOR 3.35; 95% CI 1.77?6.35), Pseudomonas aeruginosa (aOR 2.86; 95% CI 1.27?6.44) and Charlson index (aOR 1.11; 95% CI 1.01?1.23). Mortality was not associated with the site of acquisition of the infection or the presence of MDR profile. However, in the logistic regression analyses patients with CO-HCA-BUTI (aOR 0.61; 95% CI 0.40?0.93) were less likely to present clinical cure. Conclusion: The rate of MDR infections was worryingly high in our study. No differences in MDR rates were found between CO-HCA-BUTI and HA-BUTI, in the probability of receiving inappropriate empirical treatment or in 30-day mortality. However, CO-HCA-BUTIs were associated with worse clinical cure.Funding. This study and the journal’s Rapid Service Fee are sponsored and funded by MSD Spain. The study was also supported by Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0004, RD16/ 0016/0005, RD16/0016/0007, RD16/0016/0010, RD16/0016/0011 and RD16/0016/0015), co-financed by the European Development Regional Fund ‘A way to achieve Europe’ (ERDF), Operative program Intelligent Growth 2014–2020

A Large Multicenter Prospective Study of Community-Onset Healthcare Associated Bacteremic Urinary Tract Infections in the Era of Multidrug Resistance: Even Worse than Hospital Acquired Infections?

Introduction: Healthcare-associated (HCA) infections represent a growing public health problem. The aim of this study was to compare community-onset healthcare associated (CO-HCA) bacteremic urinary tract infections (BUTI) and hospital-acquired (HA)-BUTI with special focus on multidrug resistances (MDR) and outcomes. Methods: ITUBRAS-project is a prospective multicenter cohort study of patients with HCA-BUTI. All consecutive hospitalized adult patients with CO-HCA-BUTI or HA-BUTI episode were included in the study. Exclusion criteria were: patients < 18 years old, non-hospitalized patients, bacteremia from another source or primary bacteremia, non-healthcare-related infections and infections caused by unusual pathogens of the urinary tract. The main outcome variable was 30-day all-cause mortality with day 1 as the first day of positive blood culture. Logistic regression was used to analyze factors associated with clinical cure at hospital discharge and with receiving inappropriate initial antibiotic treatment. Cox regression was used to evaluate 30-day all-cause mortality. Results: Four hundred forty-three episodes were included, 223 CO-HCA-BUTI. Patients with CO-HCA-BUTI were older (p < 0.001) and had more underlying diseases (p = 0.029) than those with HA-BUTI. The severity of the acute illness (Pitt score) was also higher in CO-HCA-BUTI (p = 0.026). Overall, a very high rate of MDR profiles (271/443, 61.2%) was observed, with no statistical differences between groups. In multivariable analysis, inadequate empirical treatment was associated with MDR profile (aOR 3.35; 95% CI 1.77–6.35), Pseudomonas aeruginosa (aOR 2.86; 95% CI 1.27–6.44) and Charlson index (aOR 1.11; 95% CI 1.01–1.23). Mortality was not associated with the site of acquisition of the infection or the presence of MDR profile. However, in the logistic regression analyses patients with CO-HCA-BUTI (aOR 0.61; 95% CI 0.40–0.93) were less likely to present clinical cure. Conclusion: The rate of MDR infections was worryingly high in our study. No differences in MDR rates were found between CO-HCA-BUTI and HA-BUTI, in the probability of receiving inappropriate empirical treatment or in 30-day mortality. However, CO-HCA-BUTIs were associated with worse clinical cure. © 2021, The Author(s)

Resumen ejecutivo de tratamiento de las infecciones de prótesis articulares. Guia clínica práctica de la Sociedad Española de Enfermedades Infecciosas y Microbiologia Clínica

[EN] The incidence of prosthetic joint infection (PJI) is expected to increase in the coming years. PJI has serious consequences for patients, and high costs for the health system. The complexity of these infections makes it necessary to organize the vast quantity of information published in the last several years. The indications for the choice of a given surgical strategy and the corresponding antimicrobial therapy are specifically reviewed. The authors selected clinically relevant questions and then reviewed the available literature in order to give recommendations according to a pre-determined level of scientific evidence. The more controversial aspects were debated, and the final composition was agreed at an ad hoc meeting. Before its final publication, the manuscript was made available online in order that all SEIMC members were able to read it and make comments and suggestions.[ES] Se prevé un incremento de la incidencia de infección de las prótesis articulares (IPA) en los próximos años. Las IPA plantean graves consecuencias para los pacientes y un alto coste el sistema sanitario. La complejidad de estas infecciones hace que sea necesario organizar la inmensa cantidad de información publicada en los últimos años. En estas guías se revisan específicamente las indicaciones para la elección de una estrategia quirúrgica dada y el tratamiento antimicrobiano correspondiente. Los autores seleccionaron las preguntas clínicamente relevantes y revisaron la literatura disponible con el fin de proporcionar recomendaciones de acuerdo con un grado de evidencia científica predeterminada. Los aspectos más controvertidos fueron debatidos y la redacción final se acordó en una reunión ad hoc. Antes de su publicación, el manuscrito estuvo abierto a comentarios y sugerencias de los miembros de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica.Peer reviewe

Infestación experimental de Cernuella (Xeromagna) cespitum arigonis (Mollusca) por Dicrocoelium dendriticum (Trematoda)

1 página.-- Trabajo presentado a la X Reunión anual de la Asociación de Parasitólogos Españoles ( Sitges, Barcelona, 23 al 24 de septiembre, 1994).Para contribuir al entendimiento de los datos obtenidos en la naturaleza, sobre la transmisión parasitaria de Dicrocoelium dendriticum (Rudolphi, 1819) en los moluscos primeros hospedadores intermediarios, se siguió el desarrollo experimental del parásito en Cernuella (Xeromagna) cespitum arigonis (Schmidt, 1853), especie importante en la epidemiología de la dicroceliosis...Estudio financiado por la Junta de Castilla y León Proyecto n° 0701/89 por la CICYT Proyecto n° AGF92-0588.Peer reviewe

Open lung approach versus standard protective strategies : Effects on driving pressure and ventilatory efficiency during anesthesia - A pilot, randomized controlled trial

Background: Low tidal volume (VT) during anesthesia minimizes lung injury but may be associated to a decrease in functional lung volume impairing lung mechanics and efficiency. Lung recruitment (RM) can restore lung volume but this may critically depend on the post-RM selected PEEP. This study was a randomized, two parallel arm, open study whose primary outcome was to compare the effects on driving pressure of adding a RM to low-VT ventilation, with or without an individualized post-RM PEEP in patients without known previous lung disease during anesthesia. Methods: Consecutive patients scheduled for major abdominal surgery were submitted to low-VT ventilation (6 ml.kg(-1)) and standard PEEP of 5 cmH(2)O (pre-RM, n = 36). After 30 min estabilization all patients received a RM and were randomly allocated to either continue with the same PEEP (RM-5 group, n = 18) or to an individualized open-lung PEEP (OL-PEEP) (Open Lung Approach, OLA group, n = 18) defined as the level resulting in maximal Cdyn during a decremental PEEP trial. We compared the effects on driving pressure and lung efficiency measured by volumetric capnography. Results: OL-PEEP was found at 8 +/- 2 cmH(2)O. 36 patients were included in the final analysis. When compared with pre-RM, OLA resulted in a 22% increase in compliance and a 28% decrease in driving pressure when compared to pre-RM. These parameters did not improve in the RM-5. The trend of the DP was significantly different between the OLA and RM-5 groups (p = 0.002). VDalv/VTalv was significantly lower in the OLA group after the RM (p = 0.035). Conclusions: Lung recruitment applied during low-VT ventilation improves driving pressure and lung efficiency only when applied as an open-lung strategy with an individualized PEEP in patients without lung diseases undergoing major abdominal surgery