[Incremental impact of population dispersion on health personnel resources in Primary Care]. / Impacto incremental de la dispersión poblacional sobre los recursos de personal sanitario en Atención Primaria.

OBJECTIVE: To quantify the incremental impact that population dispersion has on the number of health personnel in Primary Care in Alto Aragón, using a reproducible method. METHOD: Descriptive observational study that compares health the number of health personnel (family medicine, pediatrics and nursing) in EAP and PA emergencies in 2019 in an unpopulated and dispersed territory such as Huesca, with the number that would correspond to it by applying population ratios per professional of hypothetical constructs with different population densities. RESULTS: Huesca, with respect to the national average, has 39% more PA health personnel. There are 239 additional professionals (112 in family medicine, 2 in pediatrics and 115 in nursing), 130 in emergencies and 109 in EAP. With the average of the five most densely populated provinces, it would reduce this staff by 49%, and with the average of the five least densely populated provinces, it would increase it by 12%. CONCLUSIONS: There is a relationship between low population density and a greater number of family medicine and PC nurses, but not with pediatrics. The powerful incremental effect that dispersion has on health care spending gives it a relevant role in the regional financing system. Comparing PC health personnel in scenarios with different population density is a useful method for quantifying the impact of dispersion.

La mielinización como un factor modulador de los circuitos de memoria / Myelination as a modulating factor in memory circuitry

Introducción: La mielina se ha conceptualizado durante muchos años como un componente estático que regula la velocidad de transmisión del impulso nervioso. Sin embargo, cada vez son más los trabajos que defienden un papel dinámico y dependiente de la experiencia. Esto ha permitido el desarrollo de un nuevo concepto denominado plasticidad mielínica, que contribuye, junto con la plasticidad sináptica, a los cambios a largo plazo que se dan en los circuitos neuronales durante el aprendizaje y la memoria. Por tanto, en esta revisión se abordarán los últimos datos publicados en relación con el papel de la mielinización con la memoria. Desarrollo: La evidencia a partir de estudios de neuroimagen en humanos demuestra que la mielinización puede cambiar debido a la modulación dependiente de la actividad, de forma que los aprendizajes pueden modificar la mielinización de los axones. Alternativamente, también se ha demostrado que interferir sobre la mielinización, utilizando para ello modelos transgénicos de roedores, deteriora significativamente los procesos de memoria. Esto tiene importantes implicaciones en alteraciones tan graves como la enfermedad de Alzheimer, en la que comienzan a describirse cambios transcripcionales y en el fenotipo de las células asociadas al proceso de mielinización. Conclusiones:Los nuevos descubrimientos apoyan el concepto de plasticidad mielínica y sus implicaciones con la memoria, lo que abre una nueva oportunidad para el tratamiento de los déficits que afectan a esta función cognitiva.(AU)

Introduction: Myelin has been understood for many years as a static component that regulates the speed of electrical impulse transmission. However, multiple works defend a dynamic role dependent on experience. This has allowed the development of a new concept called myelin plasticity that contributes, together with synaptic plasticity, to the long-term changes that occur in neuronal circuits during learning and memory. Therefore, this review will address the latest published data regarding the role of myelination with memory. Development: Evidence from human neuroimaging studies demonstrates that myelination can change due to activity-dependent modulation, such that learning can modify the axon myelination. Alternatively, it has also been shown that interfering with myelination, using transgenic rodent models, significantly impairs memory processes. This has important implications in alterations as severe as Alzheimer’s disease, where transcriptional changes and in the phenotype of cells associated with the myelination process begin to be described. Conclusions: The new knowledge supports the concept of myelin plasticity and its implications for memory, which opens a new opportunity for the treatment of deficits that affect this cognitive function.(AU)

[Myelination as a modulating factor in memory circuitry]. / La mielinización como un factor modulador de los circuitos de memoria.

INTRODUCTION: Myelin has been understood for many years as a static component that regulates the speed of electrical impulse transmission. However, multiple works defend a dynamic role dependent on experience. This has allowed the development of a new concept called myelin plasticity that contributes, together with synaptic plasticity, to the long-term changes that occur in neuronal circuits during learning and memory. Therefore, this review will address the latest published data regarding the role of myelination with memory. DEVELOPMENT: Evidence from human neuroimaging studies demonstrates that myelination can change due to activity-dependent modulation, such that learning can modify the axon myelination. Alternatively, it has also been shown that interfering with myelination, using transgenic rodent models, significantly impairs memory processes. This has important implications in alterations as severe as Alzheimer's disease, where transcriptional changes and in the phenotype of cells associated with the myelination process begin to be described. CONCLUSIONS: The new knowledge supports the concept of myelin plasticity and its implications for memory, which opens a new opportunity for the treatment of deficits that affect this cognitive function.

TITLE: La mielinización como un factor modulador de los circuitos de memoria.Introducción. La mielina se ha conceptualizado durante muchos años como un componente estático que regula la velocidad de transmisión del impulso nervioso. Sin embargo, cada vez son más los trabajos que defienden un papel dinámico y dependiente de la experiencia. Esto ha permitido el desarrollo de un nuevo concepto denominado plasticidad mielínica, que contribuye, junto con la plasticidad sináptica, a los cambios a largo plazo que se dan en los circuitos neuronales durante el aprendizaje y la memoria. Por tanto, en esta revisión se abordarán los últimos datos publicados en relación con el papel de la mielinización con la memoria. Desarrollo. La evidencia a partir de estudios de neuroimagen en humanos demuestra que la mielinización puede cambiar debido a la modulación dependiente de la actividad, de forma que los aprendizajes pueden modificar la mielinización de los axones. Alternativamente, también se ha demostrado que interferir sobre la mielinización, utilizando para ello modelos transgénicos de roedores, deteriora significativamente los procesos de memoria. Esto tiene importantes implicaciones en alteraciones tan graves como la enfermedad de Alzheimer, en la que comienzan a describirse cambios transcripcionales y en el fenotipo de las células asociadas al proceso de mielinización. Conclusiones. Los nuevos descubrimientos apoyan el concepto de plasticidad mielínica y sus implicaciones con la memoria, lo que abre una nueva oportunidad para el tratamiento de los déficits que afectan a esta función cognitiva.

Nutritional imbalances in a Mexican vegan group: urgent need for country-specific dietary guidelines / Desequilibrios nutricionales en un grupo mexicano de veganos: necesidad de guías alimentarias para cada país

Introduction: vegan diets exclude the consumption of animal-derived products, and health advantages have been reported when followed. However, heterogeneous eating habits, food availability, and sociocultural characteristics among regions could lead to different physiological results Case reports: twelve patients following a strict vegan diet for an uninterrupted period of ≥ 3 years were subjected to clinical assessment. Patients significantly exceeded the suggested intake for sugar, presented six mineral deficiencies, and exhibited three vitamins below the recommended consumption. We further identified hyperglycemia, hypertriglyceridemia, subnormal serum vitamin B12 concentrations, as well as macrocytosis and microcytic anemia in several participants. Discussion: this Mexican vegan diet is strongly influenced by endemic and cultural adaptations that could limit the benefits reported in other populations. Professional guidance is required to avoid specific deficiencies with potential repercussions. We urge country-specific vegan guidelines considering local eating habits, food availability, and sociocultural perspectives around food (AU)

Introducción: la dieta vegana excluye el consumo de productos de origen animal y se ha vinculado con una disminución del riesgo de morbimortalidad. Sin embargo, los distintos hábitos alimentarios entre países podrían condicionar los beneficios reportados para las dietas basadas en vegetales. Casos clínicos: doce pacientes siguiendo una estricta dieta vegana por ≥ 3 años se sometieron a una evaluación clínica. Exhibieron una ingestión de azúcar que supera el consumo sugerido, presentaron tres deficiencias vitamínicas y seis de minerales. Se identificó la presencia de hiperglucemia, hipertrigliceridemia, concentraciones séricas subnormales de vitamina B12, macrocitosis y anemia microcítica en varios participantes. Discusión: la dieta vegana de este grupo resultó fuertemente influenciada por adaptaciones culturales que podrían limitar los beneficios reportados en otras poblaciones. Se requiere orientación profesional para evitar desequilibrios nutricionales. Enfatizamos la necesidad del desarrollo de guías alimentarias y de práctica clínica que consideren los hábitos alimentarios locales, la disponibilidad de alimentos en la región y las perspectivas socioculturales en torno a la dieta vegana (AU)

Agentes hemostáticos tópicos de uso quirúrgico / Topical hemostatic agents for surgical use

Introducción: La morbilidad, mortalidad y costes tras la cirugía se hallan influenciados en gran medida por la pérdida hemática o hemorragia y las consecuencias derivadas de la misma. Para controlar la hemorragia, es frecuente el uso de agentes hemostáticos tópicos en combinación o en adyuvancia a otras técnicas hemostáticas, cuando éstas resultan ineficaces o impracticables. Material y métodos: Se realizó una revisión sistemática en Cochrane y MEDLINE desde el año 2000 a 2017 para identificar las publicaciones relacionadas con el uso de hemostáticos pasivos, activos y sellantes en comparación con otros agentes hemostáticos en todos los tipos de intervenciones quirúrgicas. Resultados: Se seleccionaron 20 ensayos clínicos. La variable principal de eficacia en el 95% fue el tiempo hasta la hemostasia y en el 5% la disminución del sangrado. Las intervenciones quirúrgicas más frecuentes fueron; cirugía hepática (30%), vascular (20%), cardíaca (10%), espinal (10%), general (5%), plástica (5%), y otros tipos de cirugía (20%).Los estudios se dividieron en 7 grupos, en función del tipo de agente hemostático a estudio y el comparador: a) hemostáticos mixtos versus pasivos (10%), b) sellantes de fibrina versus hemostáticos activos (5%), c) sellantes de fibrina versus hemostáticos pasivos (50%), d) hemostáticos mixtos entre sí (15%), e) sellantes de fibrina entre sí (5%), f) hemostáticos pasivos entre sí (5%), g) hemostáticos activos entre sí (10%).Conclusiones: Los hemostáticos activos, mixtos y sellantes de fibrina demuestran superioridad frente a los pasivos en términos de eficacia clínica, con un coste superior y un perfil de efectos adversos similar. (AU)

Introduction: Morbidity, mortality, and costs after surgery are greatly influenced by blood loss or bleeding and the consequences of it.To control bleeding, the use of topical hemostatic agents in combination or adjuvant to other hemostatic techniques is frequent, when these are ineffective or impractical.Method: A systematic review was conducted in Cochrane and PubMed from 2000 to 2017 to identify publications related to the use of passive, active and sealant hemostatics compared to other hemostatic agents in all types of surgical interventions.Results: Twenty clinical trials were selected. The main variable of efficacy in 95% was the time to hemostasis and in 5% the decrease in bleeding.The most frequent surgical interventions were; liver surgery (30%), vascular (20%), cardiac (10%), spinal (10%), general (5%), plastic (5%), and other types of surgery (20%).The studies were divided into 7 groups, depending on the type of hemostatic agent under study and the comparator: a) mixed hemostatic versus passive (10%), b) fibrin sealants versus active hemostatic agents (5%), c) fibrin sealants versus passive hemostatic (50%), d) mixed hemostatic with each other (15%), e) fibrin sealants with each other (5%), f) passive hemostatic with each other (5%), g) active hemostatic with each other (10%).Conclusions: Active and mixed hemostatics and fibrin sealants showed superiority over the passive hemostatics in terms of clinical efficacy, with a higher cost and a similar profile of side effects. (AU)

Implantación de un nuevo modelo organizativo en la atención al proceso musculoesquelético: ¿mejora la capacidad de resolución de los procesos? / Implementation of a new referral model for the musculoskeletal care pathway: does it improve healthcare outcomes?

OBJETIVO: Evaluar el impacto de un cambio organizativo en la gestión del proceso musculoesquelético en nuestra Área de Gestión Sanitaria (AGS) estudiando los cambios en la capacidad de resolución de estos procesos mediante la derivación a la especialidad útil. DISEÑO: Estudio descriptivo prospectivo para evaluar las tendencias de las derivaciones de atención primaria (PAP) y atención hospitalaria (PAE) con procesos musculoesqueléticos en el periodo 2012-2018. MATERIAL Y MÉTODO: Se incluye a toda la población de referencia de nuestra AGS derivada a alguna de las 3 especialidades hospitalarias que atienden procesos musculoesqueléticos, sin determinación del tamaño muestral. Variables estudiadas: PAP, PAE, servicio de procedencia y de destino. Para el análisis estadístico se utilizó el programa SPSS; se presenta la evaluación de frecuencias absolutas. RESULTADOS: Las derivaciones totales realizadas desde atención primaria han pasado de 25.575 en 2012 a 24.871 en 2018. Las derivaciones PAE han pasado de 17.207 en 2012 a 9.803 en 2018. De las derivaciones PAP, el de mayor impacto ha sido el Servicio de Rehabilitación, que ha pasado de recibir el 8,2% de PAP en 2012 al 47% en 2018. De las derivaciones PAE por especialidad, la mayor reducción ha sido la del Servicio de Traumatología, que pasó de recibir 10.587 PAE en 2012 a 3.911 en 2018. CONCLUSIONES: El rediseño organizativo de la atención al proceso musculoesquelético ha conseguido mejorar la resolución de los procesos musculoesqueléticos. En este cambio organizativo, el Servicio de Rehabilitación ha asumido el liderazgo desde el punto de vista asistencial y de gestión del proceso musculoesquelético, lo que ha colaborado en la mejora de la resolución de estos procesos

OBJECTIVE: To evaluate the impact of an organisational change in the musculoskeletal referral pathway in our health management area (HMA) by identifying changes in the ability to improve healthcare outcomes by facilitating referral to the most suitable specialty. DESIGN: This prospective descriptive study aimed to evaluate referral trends from primary care services (PCS) and hospital care (PHS) to musculoskeletal services from 2012 to 2018. MATERIALS AND METHODS: We included all patients who were referred to any of the 3 musculoskeletal services from our HMA catchment area, without specifying sample size. The variables studied were PCS, PHS, service of origin and destination. We used the SPSS programme for the statistical analysis and obtained absolute frequency data. RESULTS: The total number of referrals from PCS increased from 25,575 in 2012 to 24,871 in 2018. PHS referrals decreased from 17,207 in 2012 to 9,803 in 2018. With regards to PCS referrals, the service most increasing the number of referrals to the musculoskeletal team was the Rehabilitation Service, from 8.2% in 2012 to 47% in 2018. Regarding PHSs referrals by specialty, the service that most reduced the number of referrals to the musculoskeletal team was the Traumatology Service, from 10,587 in 2012 to 3,911 in 2018. CONCLUSIONS: The redesign of the musculoskeletal referral pathway improved healthcare outcomes by improving the quality of the referral process. In this organisational change, the Rehabilitation Service took the leadership from the point of view of healthcare and management of the musculoskeletal process, collaborating in the improvement of the healthcare outcomes of these processes

[Implementation of a new referral model for the musculoskeletal care pathway: Does it improve healthcare outcomes?] / Implantación de un nuevo modelo organizativo en la atención al proceso musculoesquelético: ¿mejora la capacidad de resolución de los procesos?

OBJECTIVE: To evaluate the impact of an organisational change in the musculoskeletal referral pathway in our health management area (HMA) by identifying changes in the ability to improve healthcare outcomes by facilitating referral to the most suitable specialty. DESIGN: This prospective descriptive study aimed to evaluate referral trends from primary care services (PCS) and hospital care (PHS) to musculoskeletal services from 2012 to 2018. MATERIALS AND METHODS: We included all patients who were referred to any of the 3 musculoskeletal services from our HMA catchment area, without specifying sample size. The variables studied were PCS, PHS, service of origin and destination. We used the SPSS programme for the statistical analysis and obtained absolute frequency data. RESULTS: The total number of referrals from PCS increased from 25,575 in 2012 to 24,871 in 2018. PHS referrals decreased from 17,207 in 2012 to 9,803 in 2018. With regards to PCS referrals, the service most increasing the number of referrals to the musculoskeletal team was the Rehabilitation Service, from 8.2% in 2012 to 47% in 2018. Regarding PHSs referrals by specialty, the service that most reduced the number of referrals to the musculoskeletal team was the Traumatology Service, from 10,587 in 2012 to 3,911 in 2018. CONCLUSIONS: The redesign of the musculoskeletal referral pathway improved healthcare outcomes by improving the quality of the referral process. In this organisational change, the Rehabilitation Service took the leadership from the point of view of healthcare and management of the musculoskeletal process, collaborating in the improvement of the healthcare outcomes of these processes.

Valoración del dolor en personas con demencia y problemas de comunicación en España. Revisión sistemática / Pain assessment in individuals with dementia and communication problems in Spain. A systematic review

Antecedentes y objetivo: La valoración del dolor en personas con demencia avanzada y problemas de comunicación continúa siendo infradiagnosticada e infratratada debido a la dificultad que conlleva realizar esta valoración. Esta revisión pretende explorar y sintetizar cómo se está valorando el dolor en personas con demencia avanzada y problemas de comunicación en el contexto sanitario español. Materiales y métodos: Revisión sistemática de la literatura siguiendo los criterios PRISMA. Se revisaron las bases de datos Pubmed, Web of Science, Cinahl, Scopus, Dialnet y Cuitatge hasta diciembre de 2017. Cuatro revisores independientes identificaron los estudios que incluían instrumentos para evaluar el dolor en personas con demencia y problemas de comunicación, en el contexto sanitario español. Se realizó una síntesis narrativa de los artículos incluidos. Resultados: Después de aplicar los criterios de inclusión se seleccionaron 10 estudios. De estos 4 fueron estudios metodológicos de validaciones de escalas al español (Abbey, Algoplus, Doloplus y PAINAD-Sp) y uno del desarrollo de la escala original EDAD. Además, se identificaron 3 estudios realizados en España, que utilizaban una traducción de la PAINAD, un estudio que utilizó una traducción al español de la Doloplus2 y una publicación que incluyó el uso en España de una escala no validada para este perfil de pacientes (Pain-VAS). Conclusiones: Actualmente, existen varios instrumentos validados en español para valorar el dolor en personas con demencia avanzada y problemas de comunicación (Abbey, Algoplus, Doloplus y PAINAD-Sp). Aunque aún estos instrumentos no han sido muy utilizados en investigación y las propiedades psicométricas de los mismos pueden mejorar

Background and objective: Pain assessment in individuals with advanced dementia and communication problems continue to be underdiagnosed and undertreated due to the difficulty in performing this assessment. This review explores and synthesises how pain in individuals with advanced dementia and communication problems are being assessed in the context of Spanish healthcare. Materials and methods: A systematic review of the literature was conducted following the PRISMA criteria. We reviewed the databases of PubMed, Web of Science, Cinahl, Scopus, Dialnet and Cuitatge up to December 2017. Four independent reviewers identified studies that included instruments to assess pain in individuals with dementia and communication problems in the Spanish healthcare context. We performed a narrative synthesis of the included articles. Results: After applying the inclusion criteria, 10 studies were included. Of these, 4 were methodological studies validating Spanish versions of scales (Abbey, Algoplus, Doloplus and PAINAD-Sp), and 1 was on the development of the original EDAD scale. We also identified 3 studies conducted in Spain that used a translation of the PAINAD, 1 study that used a Spanish translation of Doloplus2 and 1 publication that included the use in Spain of a scale not validated for this patient profile (Pain-VAS). Conclusions: There are currently several instruments validated in Spanish to assess pain in individuals with advanced dementia and communication problems (Abbey, Algoplus, Doloplus y PAINAD-Sp). However, these instruments have still not been widely used in research, and their psychometric properties could be improved

Pain assessment in individuals with dementia and communication problems in Spain. A systematic review. / Valoración del dolor en personas con demencia y problemas de comunicación en España. Revisión sistemática.

BACKGROUND AND OBJECTIVE: Pain assessment in individuals with advanced dementia and communication problems continue to be underdiagnosed and undertreated due to the difficulty in performing this assessment. This review explores and synthesises how pain in individuals with advanced dementia and communication problems are being assessed in the context of Spanish healthcare. MATERIALS AND METHODS: A systematic review of the literature was conducted following the PRISMA criteria. We reviewed the databases of PubMed, Web of Science, Cinahl, Scopus, Dialnet and Cuitatge up to December 2017. Four independent reviewers identified studies that included instruments to assess pain in individuals with dementia and communication problems in the Spanish healthcare context. We performed a narrative synthesis of the included articles. RESULTS: After applying the inclusion criteria, 10 studies were included. Of these, 4 were methodological studies validating Spanish versions of scales (Abbey, Algoplus, Doloplus and PAINAD-Sp), and 1 was on the development of the original EDAD scale. We also identified 3 studies conducted in Spain that used a translation of the PAINAD, 1 study that used a Spanish translation of Doloplus2 and 1 publication that included the use in Spain of a scale not validated for this patient profile (Pain-VAS). CONCLUSIONS: There are currently several instruments validated in Spanish to assess pain in individuals with advanced dementia and communication problems (Abbey, Algoplus, Doloplus y PAINAD-Sp). However, these instruments have still not been widely used in research, and their psychometric properties could be improved.

Affective alterations in patients with Cushing's syndrome in remission are associated with decreased BDNF and cortisone levels.

OBJECTIVE: Affective alterations and poorer quality of life often persist in patients with Cushing's syndrome (CS) in remission. Brain-derived neurotrophic factor (BDNF) regulates the hypothalamic-pituitary-adrenal axis (HPA) and is highly expressed in brain areas controlling mood and response to stress. Our aims were to assess affective alterations after long-term remission of CS and evaluate whether they are associated with serum BDNF, salivary cortisol (SalF) and/or cortisone (SalE) concentrations. SUBJECTS AND METHODS: Thirty-six CS patients in remission (32 females/4 males; mean age (±s.d.), 48.8 ± 11.8 years; median duration of remission, 72 months) and 36 gender-, age- and BMI-matched controls were included. Beck Depression Inventory-II (BDI-II), Center for Epidemiological Studies Depression Scale (CES-D), Positive Affect Negative Affect Scale (PANAS), State-Trait Anxiety Inventory (STAI), Perceived Stress Scale (PSS) and EuroQoL and CushingQoL questionnaires were completed and measured to evaluate anxiety, depression, stress perception and quality of life (QoL) respectively. Salivary cortisol was measured using liquid chromatography/tandem mass spectrometry (LC/TMS). BDNF was measured in serum using an ELISA. RESULTS: Remitted CS patients showed worse scores in all questionnaires than controls: STAI (P < 0.001), BDI (P < 0.001), CES-D (P < 0.001), PANAS (P < 0.01), PSS (P < 0.01) and EuroQoL (P < 0.01). A decrease in BDNF was observed in CS vs controls (P = 0.038), and low BDNF was associated with more anxiety (r = -0.247, P = 0.037), depression (r = -0.249, P = 0.035), stress (r = -0.277, P = 0.019) and affective balance (r = 0.243, P = 0.04). Morning salivary cortisone was inversely associated with trait anxiety (r = -0.377, P = 0.040) and depressed affect (r = -0.392, P = 0.032) in CS patients. Delay to diagnosis was associated with depressive symptoms (BDI-II: r = 0.398, P = 0.036 and CES-D: r = 0.449, P = 0.017) and CushingQoL scoring (r = -0.460, P < 0.01). CONCLUSIONS: Low BDNF levels are associated with affective alterations in 'cured' CS patients, including depression, anxiety and impaired stress perception. Elevated levels of SalE might also be related to poor affective status in these patients.

White matter alterations in the brains of patients with active, remitted, and cured cushing syndrome: a DTI study.

BACKGROUND AND PURPOSE: Cushing syndrome appears after chronic exposure to elevated glucocorticoid levels. Cortisol excess may alter white matter microstructure. Our purpose was to study WM changes in patients with Cushing syndrome compared with controls by using DTI and the influence of hypercortisolism. MATERIALS AND METHODS: Thirty-five patients with Cushing syndrome and 35 healthy controls, matched for age, education, and sex, were analyzed through DTI (tract-based spatial statistics) for fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity (general linear model, family-wise error, and threshold-free cluster enhancement corrections, P < .05). Furthermore, the influence of hypercortisolism on WM DTI changes was studied by comparing 4 subgroups: 8 patients with Cushing syndrome with active hypercortisolism, 7 with Cushing syndrome with medication-remitted cortisol, 20 surgically cured, and 35 controls. Cardiovascular risk factors were used as covariates. In addition, correlations were analyzed among DTI values, concomitant 24-hour urinary free cortisol levels, and disease duration. RESULTS: There were widespread alterations (reduced fractional anisotropy, and increased mean diffusivity, axial diffusivity, and radial diffusivity values; P < .05) in patients with Cushing syndrome compared with controls, independent of the cardiovascular risk factors present. Both active and cured Cushing syndrome subgroups showed similar changes compared with controls. Patients with medically remitted Cushing syndrome also had reduced fractional anisotropy and increased mean diffusivity and radial diffusivity values, compared with controls. No correlations were found between DTI maps and 24-hour urinary free cortisol levels or with disease duration. CONCLUSIONS: Diffuse WM alterations in patients with Cushing syndrome suggest underlying loss of WM integrity and demyelination. Once present, they seem to be independent of concomitant hypercortisolism, persisting after remission/cure.

Optimización de la farmacoterapia en un hospital de Traumatología / Optimisation of pharmacotherapy in a trauma centre

Objetivo Evaluar los resultados de la implantación de un programa de atención farmacéutica dirigido a optimizar el tratamiento farmacoterapéutico individualizado en un hospital de Traumatología con historia clínica informatizada (HCI) y sistema integral de dispensación individualizada de medicamentos (SIDIM).Métodos Estudio retrospectivo observacional de 3 años de duración (2007-2009). Se realizó un seguimiento diario del tratamiento farmacoterapéutico de los pacientes ingresados en unidades de hospitalización con SIDIM. Mediante el registro en un documento normalizado, se clasificaron los problemas relacionados con los medicamentos (PRM) y/o errores de medicación (EM) identificados, así como las intervenciones farmacéuticas realizadas de acuerdo con la idoneidad y el grado de aceptación de las mismas. Para la identificación de pacientes con oportunidades de mejora en su farmacoterapia (PRM y/o EM) se empleó el método IASER®.Resultados Se realizaron 1.971 intervenciones farmacéuticas (IF) tras revisar 124.336 líneas de tratamiento correspondientes a 12 IF por cada 100 pacientes. La prevalencia de pacientes con PRM fue del 12% distribuidos de la siguiente manera: 50,66% categorizados en seguridad, 22,98% en indicación, 12,23% en efectividad y 14,13% en adherencia. Los grupos fármacológicos principalmente implicados fueron: antiinfecciosos (29%), fármacos para el aparato locomotor (..) (AU)

Objective To evaluate the results for implementing a pharmaceutical care programme aimed at optimising personalised pharmacotherapeutic treatment in a Trauma Centre with electronic medical records (EMR) and an integral system for personalised medication dispensing (ISPMD).Method A three-year observational, retrospective study (2007-2009). On a daily basis, we checked the pharmaceutical treatment of patients admitted to hospital units with ISPMD. The medication-related problems (MRP) and medication errors (ME) were identified and classified by recording them on a standardised document. We also recorded data on the Pharmaceutical Interventions performed in accordance with fitness and level of acceptance. We used the laser® method to identify patients with pharmacotherapy improvement opportunities (MRP and/or ME).Results One thousand nine-hundred and seventy-one pharmaceutical interventions (PI) were found after having reviewed 124 336 treatment lines, resulting in 12 PI for every 100 patients. The prevalence of patients with MRP was 12%, distributed as such: 50.66% were safety-related, 22.98% indication-related, 12.23% effectiveness-related and 14.13% adherence-related. The main drug groups involved were: anti-infectious agents (29%), drugs for the musculoskeletal system (21%), drugs for blood and haematopoietic organs (12%), and drugs for the nervous system (11%). The active ingredient that required most PI in 2007 was dexketoprofen (15.6%), followed by ketorolac (12.4%). In 2008, it was dexketoprofen (22.0%) followed by gentamicin (7.3%), and in 2009 enoxaparin (19.0%) followed by dexketoprofen (14.3%). The origin of MRP was due to ME in 91% of cases in 2007and 81% in 2008, decreasing (..) (AU)

[Optimisation of pharmacotherapy in a trauma centre]. / Optimización de la farmacoterapia en un hospital de Traumatología.

OBJECTIVE: To evaluate the results for implementing a pharmaceutical care programme aimed at optimising personalised pharmacotherapeutic treatment in a Trauma Centre with electronic medical records (EMR) and an integral system for personalised medication dispensing (ISPMD). METHOD: A three-year observational, retrospective study (2007-2009). On a daily basis, we checked the pharmaceutical treatment of patients admitted to hospital units with ISPMD. The medication-related problems (MRP) and medication errors (ME) were identified and classified by recording them on a standardised document. We also recorded data on the Pharmaceutical Interventions performed in accordance with fitness and level of acceptance. We used the laser method to identify patients with pharmacotherapy improvement opportunities (MRP and/or ME). RESULTS: One thousand nine-hundred and seventy-one pharmaceutical interventions (PI) were found after having reviewed 124 336 treatment lines, resulting in 12 PI for every 100 patients. The prevalence of patients with MRP was 12%, distributed as such: 50.66% were safety-related, 22.98% indication-related, 12.23% effectiveness-related and 14.13% adherence-related. The main drug groups involved were: anti-infectious agents (29%), drugs for the musculoskeletal system (21%), drugs for blood and haematopoietic organs (12%), and drugs for the nervous system (11%). The active ingredient that required most PI in 2007 was dexketoprofen (15.6%), followed by ketorolac (12.4%). In 2008, it was dexketoprofen (22.0%) followed by gentamicin (7.3%), and in 2009 enoxaparin (19.0%) followed by dexketoprofen (14.3%). The origin of MRP was due to ME in 91% of cases in 2007 and 81% in 2008, decreasing to 53% in 2009. PI fitness, as percentages (CI 95%) were considered: Important PI [30.29 (10.19-49.95)]; Very important PI [38.36 (35.45-73)]; Acceptable PI [82.10 (52.28-111.10)]. CONCLUSIONS: Optimising personalised pharmacotherapeutic treatment by implementing an interdisciplinary Pharmaceutical Care programme promotes team work, and as a result improves rational and safe medication dispensing.

PPARγ population shift produces disease-related changes in molecular networks associated with metabolic syndrome.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of adipocyte differentiation and has an important role in metabolic syndrome. Phosphorylation of the receptor's ligand-binding domain at serine 273 has been shown to change the expression of a large number of genes implicated in obesity. The difference in gene expression seen when comparing wild-type phosphorylated with mutant non-phosphorylated PPARγ may have important consequences for the cellular molecular network, the state of which can be shifted from the healthy to a stable diseased state. We found that a group of differentially expressed genes are involved in bi-stable switches and form a core network, the state of which changes with disease progression. These findings support the idea that bi-stable switches may be a mechanism for locking the core gene network into a diseased state and for efficiently propagating perturbations to more distant regions of the network. A structural analysis of the PPARγ-RXRα dimer complex supports the hypothesis of a major structural change between the two states, and this may represent an important mechanism leading to the differential expression observed in the core network.

High-resolution structural insights on the sugar-recognition and fusion tag properties of a versatile ß-trefoil lectin domain from the mushroom Laetiporus sulphureus.

In this work, we analyzed at high resolution the sugar-binding mode of the recombinant N-terminal ricin-B domain of the hemolytic protein LSLa (LSL(150)) from the mushroom Laetiporus sulphureus and also provide functional in vitro evidence suggesting that, together with its putative receptor-binding role, this module may also increase the solubility of its membrane pore-forming partner. We first demonstrate that recombinant LSL(150) behaves as an autonomous folding unit and an active lectin. We have determined its crystal structure at 1.47 Å resolution and also that of the [LSL(150):(lactose)ß, γ)] binary complex at 1.67 Å resolution. This complex reveals two lactose molecules bound to the ß and γ sites of LSL(150), respectively. Isothermal titration calorimetry indicates that LSL(150) binds two lactoses in solution with highly different affinities. Also, we test the working hypothesis that LSL(150) exhibits in vivo properties typical of solubility tags. With this aim, we have fused an engineered version of LSL(150) (LSL(t)) to the N-terminal end of various recombinant proteins. All the designed LSL(150)-tagged fusion proteins were successfully produced at high yield, and furthermore, the target proteins were purified by a straightforward affinity procedure on agarose-based matrices due to the excellent properties of LSL(150) as an affinity tag. An optimized protocol for target protein purification was devised, which involved removal of the LSL(150) tag through in-column cleavage of the fusion proteins with His(6)-tagged TEV endoprotease. These results permitted to set up a novel, lectin-based system for production and purification of recombinant proteins in E. coli cells with attractive biotechnological applications.

Additive effects of cannabinoid CB1 receptors blockade and cholecystokinin on feeding inhibition.

Cannabinoid CB1 receptor and cholecystokinin-1 (CCK(1)) receptors are located in peripheral nerve terminals of the gut, where they mediate satiety signals. Here we describe a detailed analysis of the interaction of both receptors in the control of feeding of food-deprived rats. Male Wistar rats were deprived for food 24h before testing. Rats were pre-treated with SR141716A (Rimonabant) or WIN 55,212-2 before CCK-8 sulphated administration and tested for food intake 60, 120 and 240 min after last drug injection. In parallel, the effect of Lorglumide--a CCK(1) receptor antagonist--pre-treatment was evaluated on feeding behaviour after SR141716A administration. Results show that SR141716A activates c-Fos expression in brainstem areas receiving vagal inputs. Blockade of CB1 receptors with SR141716A (1 mg/kg) reduces feeding and display additive satiety induction with the CCK(1) receptor agonist CCK-8 sulphated (5, 10, 25 µg/kg). The effect of SR141716A is not blocked by Lorglumide (10 mg/kg), indicating independent sites of action. Conversely, the administration of the CB1 agonist WIN 55,212-2 (2 mg/kg) reduced satiety induced by CCK-8. In conclusion, these results report additive anorectic actions for CCK1 activation and peripheral CB1 receptor blockade providing a framework for combined therapies in the treatment of eating disorders.

Structural models of DYNLL1 with interacting partners: African swine fever virus protein p54 and postsynaptic scaffolding protein gephyrin.

DYNLL1, the smallest dynein light chain, interacts with different cargos facilitating their cellular transport. Usually the sequence recognized in the targets is homologous to the GIQVD or the KXTQT motifs with a glutamine that is important for binding. Here we add two new examples of DYNLL1 targets that can be classified into these two groups: ASFV p54 and gephyrin. Using NMR we demonstrate the direct interaction between DYNLL1 and two peptides derived from their interacting sequences. We model the structure of both complexes and show that the overall binding mode is preserved as in other complexes despite differences at the residue-specific interactions.

Effect of temozolomide on the U-118 glioma cell line.

Glioblastomas (GBM) are the most lethal subtype of astrocytomas, with a mean patient survival rate of 12 months after diagnosis. The gold standard treatment of GBM, which includes surgery followed by the combination of radiotherapy and chemotherapy with temozolomide (TMZ), increases the survival rate to 14.6 months. The success of TMZ appears to be limited by the occurrence of chemoresistance that allows glioma cells to escape from death signaling pathways. However, the mechanism of TMZ action is yet to be clarified although some controversial results have been reported. Therefore, our aim was to evaluate the occurrence of apoptosis and autophagy in glioma cells treated with TMZ and to correlate TMZ action with the survival pathways Pi3K/Akt and ERK1/2 MAP kinase. Cell proliferation was evaluated by incorporation of bromodeoxyuridine. Apoptosis was studied by flow cytometry as well as by fluorescence confocal microscopy in order to evaluate the sub G0/G1 percentage of cells and chromatin condensation. The expression of the autophagy-associated protein, LC3, as well as Akt and ERK1/2 was performed by Western blotting. In TMZ-treated GBM cells the expression of LC3, the autophagy-associated protein was increased and only a reduced percentage of cells underwent apoptosis. In addition, we showed that the phosphorylation status of Pi3K/Akt and ERK1/2 MAP kinase was maintained during the treatment with TMZ, suggesting that glioma cells escape from TMZ-induced cell death due to these signaling pathways. The chemoresistance of U-118 cells to TMZ was partially eradicated when cells were simultaneously treated with specific inhibitors of Pi3K/Akt and ERK1/2 MAP kinase signaling pathways and TMZ. Therefore, we hypothesized that in order to induce glioma cell death it is essential to evaluate the activation of the survival pathways and establish a combined therapy using TMZ and inhibitors of those signaling pathways.

[Antineoplastic oral agents and drug-nutrient interactions: a sistematic review]. / Interacción de los antineoplásicos orales con los alimentos: revisión sistemática.

INTRODUCTION: Studies on bioavailability are part of the clinical development of drugs for oral use in order to identify potential drug-food interactions. For oral antitumor drugs, their clinical importance is currently recognized although regrettably the information available presents variability concerning the scientific evidence. OBJECTIVES: To review the available scientific evidence about oral anti-tumor medications and establish the recommendations for their administration with foods. METHODS: We carried out a bibliographic search in Medline and The Cochrane Library for the period January of 1966 to March of 2008, focused on identifying those publications about drug-food interactions with oral antitumor medications. The bibliographical analysis was made in two steps. During the first phase, we excluded those articles in which the title or their content did not correspond with the objective settled; during the second phase, we deleted all the references duplicated in both databases. The inclusion criteria to select the articles were: design (systematic reviews, meta-analysis, Phase I and Phase II randomized clinical trials), population (adult patients; >19 years of age), intervention evaluated (administration of oral anti-tumor drugs under fasting conditions or with food) and measurement of the iFA results (calculation of the 90% CI of the odds ratio between the geometric mean of the values under the curve of the plasma concentrations (ABC) or the maximal plasma concentration (Cmax) with and without foods). We excluded those publications that did not make reference to the bioequivalence dictamen established by the Food and Drugs Administration (FDA) in their outcomes measurement. A critical appraisal of the selected articles was done according to the recommendations that the FDA established to be met by these studies. RESULTS: At the initial search we obtained 850 references (98.5% Medline + and 1.4% Cochrane). During the first phase, we excluded 87.7% (746) of the articles, 100% of them corresponding to the search in Medline. During the second phase, 40 studies remained (5.2% of the initial ones) for full-text critical appraisal, to which four studies were added not indexed in Medline. From the critical appraisal of the 44 final articles, 25 were excluded (20 original articles, 4 short communications, and 1 meta-analysis) because they did not include as an outcome measure the bioequivalence dictamen. The 19 (2.2%) remaining articles provided information on 19 oral anti-tumor drugs in 210 patients and 146 healthy volunteers. Of these 19 drugs, 63% did not present drug-food interactions, with the possibility of administering them either with or without food; 21% have to be administered with foods and only 16% present drug-food interactions, so they have to be administered without foods. DISCUSSION: Currently, the clinical importance of drug-food interactions with oral anti-tumor drugs is identified more directly with the patient's safety than with the efficacy of the therapy. Given the development of these oral agents, their incorporation into the oncologic strategy displacing parenteral therapy, with monthly costs of thousands of Euros, it is necessary to perform well-designed studies on pharmacokinetics and pharmacodynamics. Their goal has to be comparing their bioavailability in the presence or absence of foods with the clinical response. In the meanwhile, to establish recommendations for their administration in relation to foods is inconsistent for some of these drugs and their results is uncertain given the lack of studies based on the FDA bioequivalence dictamen.

Interacción de los antineoplásicos orales con los alimentos: revisión sistemática / Antineoplastic oral agents and drug-nutrient interactions: a sistematic review

Introducción: Los estudios de biodisponibilidad son parte integrante del desarrollo clínico de medicamentos para administración oral con el fin de identificar potenciales interacciones fármaco-alimento (iFA). Actualmente, para los antineoplásicos orales se empieza a reconocer su importancia clínica, aun cuando lamentablemente, la información disponible presenta variabilidad en su evidencia científica. Objetivos: Revisar la evidencia científica disponible sobre las interacciones de los alimentos con medicamentos antineoplásicos orales y establecer recomendaciones para su administración. Métodos: Se realizó una búsqueda bibliográfica en Medline y The Cochrane Library para el periodo comprendido entre enero de 1966 a marzo de 2008, enfocada a identificar las publicaciones sobre interacciones fármaco alimento con antineoplásicos orales. El análisis bibliográfico consta de dos fases. En la primera fase se excluyeron los artículos que por título y contenido del resumen no se correspondían con el objetivo planteado; en la segunda fase se eliminaron las referencias duplicadas en ambas bases de datos. Los criterios de inclusión para seleccionar los artículos fueron: diseño (revisiones sistemáticas, metaanálisis, ensayos clínicos randomizados Fase I y II), población (pacientes adultos; >19 años de edad), intervención evaluada (administración de antineoplásicos orales bajo condiciones de ayuno o con alimentos) y medida del resultado de la iFA (cálculo del IC90% de la razón entre la media geométrica de valores del área bajo la curva de concentraciones plasmáticas (ABC) o la concentración plasmática máxima (Cmax) con y sin alimentos). Se excluyeron las publicaciones que como medida de resultado no hacían referencia al dictamen de bioequivalencia establecido por la Food and Drugs Administration (FDA). La valoración crítica de los artículos seleccionados se realizó según las recomendaciones que de acuerdo con la FDA deben cumplir estos estudios. Resultados: En la búsqueda inicial se obtuvieron 850 referencias (98,5% Medline + y 1,4% Cochrane). En la primera fase se excluyeron el 87,7% (746) de los artículos, correspondiendo el 100% a la búsqueda en Medline. En la segunda fase, quedaron 40 artículos (5,2% de los iniciales) para su lectura crítica a texto completo, a los que se añadieron cuatro más no indexados en Medline. De la lectura crítica de los 44 artículos finales, se excluyeron 25 artículos (20 artículos originales, 4 comunicaciones cortas y 1 metanálisis) por no incluir como medida de resultado el dictamen de bioequivalencia. Los 19 (2,2%) artículos restantes proporcionaron información sobre 19 fármacos antineoplásicos orales, en 210 pacientes y 146 voluntarios sanos. De estos 19 fármacos, el 63% no presentan iFA o interacciones fármaco-alimento, pudiéndose administrar indistintamente con/sin alimentos; el 21% se deben administrar con alimentos y sólo el 16% presentan interacción fármaco alimento, por lo que se deben administrar sin alimentos. Discusión: Actualmente, la importancia clínica de las interacciones fármaco alimento con antineoplásicos orales se identifica más directamente con la seguridad del paciente que con la efectividad del tratamiento. Ante el desarrollo de estos agentes orales, su irrupción en la terapia oncológica desplazando a la terapia parenteral, con costes mensuales de miles de euros, hay necesidad de realizar estudios farmacocinéticos y farmacodinámicos bien diseñados. Su objetivo debe de ser comparar su biodisponibilidad en presencia o ausencia de alimentos con la respuesta clínica. Mientras tanto, establecer recomendaciones para su administración en relación con los alimentos, es inconsistente para algunos de estos fármacos y su resultado incierto por la falta de estudios fundamentados en el dictamen de bioequivalencia establecido por la FDA (AU)

Introduction: studies on bioavailability are part of the clinical development of drugs for oral use in order to identify potential drug-food interactions. For oral antitumor drugs, their clinical importance is currently recognized although regrettably the information available presents variability concerning the scientific evidence. Objectives: To review the available scientific evidence about oral anti-tumor medications and establish the recommendations for their administration with foods. Methods: We carried out a bibliographic search in Medline and The Cochrane Library for the period January of 1966 to March of 2008, focused on identifying those publications about drug-food interactions with oral antitumor medications. The bibliographical analysis was made in two steps. During the first phase, we excluded those articles in which the title or their content did not correspond with the objective settled; during the second phase, we deleted all the references duplicated in both databases. The inclusion criteria to select the articles were: design (systematic reviews, meta-analysis, Phase I and Phase II randomized clinical trials), population (adult patients; >19 years of age), intervention evaluated (administration of oral anti-tumor drugs under fasting conditions or with food) and measurement of the iFA results (calculation of the 90% CI of the odds ratio between the geometric mean of the values under the curve of the plasma concentrations (ABC) or the maximal plasma concentration (Cmax) with and without foods). We excluded those publications that did not make reference to the bioequivalence dictamen established by the Food and Drugs Administration (FDA) in their outcomes measurement. A critical appraisal of the selected articles was done according to the recommendations that the FDA established to be met by these studies. Results: At the initial search we obtained 850 references (98.5% Medline + and 1.4% Cochrane). During the first phase, we excluded 87.7% (746) of the articles, 100% of them corresponding to the search in Medline. During the second phase, 40 studies remained (5.2% of the initial ones) for full-text critical appraisal, to which four studies were added not indexed in Medline. From the critical appraisal of the 44 final articles, 25 were excluded (20 original articles, 4 short communications, and 1 meta-analysis) because they did not include as an outcome measure the bioequivalence dictamen. The 19 (2.2%) remaining articles provided information on 19 oral anti-tumor drugs in 210 patients and 146 healthy volunteers. Of these 19 drugs, 63% did not present drugfood interactions, with the possibility of administering them either with or without food; 21% have to be administered with foods and only 16% present drug-food interactions, so they have to be administered without foods. Discussion: Currently, the clinical importance of drugfood interactions with oral anti-tumor drugs is identified more directly with the patient's safety than with the efficacy of the therapy. Given the development of these oral agents, their incorporation into the oncologic strategy displacing parenteral therapy, with monthly costs of thousands of Euros, it is necessary to perform well-designed studies on pharmacokinetics and pharmacodynamics. Their goal has to be comparing their bioavailability in the presence or absence of foods with the clinical response. In the meanwhile, to establish recommendations for their administration in relation to foods is inconsistent for some of these drugs and their results is uncertain given the lack of studies based on the FDAbioequivalence dictamen (AU)