SSC 2016. Últimas recomendaciones en el paciente séptico

Se recomienda el uso de un protocolo de control de glucemia iniciando la administración de insulina cuando 2 niveles de glucemia consecutivos sean >180 mg/dL. El protocolo deberá perseguir un límite máximo de glucemia de 180 mg/dL, en lugar de intentar mantener niveles inferiores o iguales a 110 mg/dL. (Recomendación fuerte, alta calidad de la evidencia). Se recomienda la monitorización de la glucemia cada 1 ó 2 horas hasta que los niveles de glucosa y la administración de insulina se encuentren estables, a partir de entonces cada 4 horas, en todos los pacientes que reciben perfusión de insulina (BPS). Se recomienda la interpretación de los niveles de glucemia capilar de forma cautelosa, dado que tales mediciones pueden no estimar adecuadamente los valores reales en sangre arterial o en plasma (BPS) Sugieren el uso de sangre arterial en lugar de sangre capilar si los pacientes tienen catéteres arteriales. (Recomendación débil, baja calidad de la evidencia). Si bien las recomendaciones hacen referencia a que valor de glucemia se considera como límite para empezar con el tratamiento con insulina, no se establecen recomendaciones de rangos glucémicos de mantenimiento en el paciente séptico. Posteriormente en el texto se hace referencia a que los consensos publicados recomiendan mantener cifras de glucemia entre 140 -180 mg/dl, que es la que parece que menos hipoglucemias provoca. Otro rango recomendado es mantener glucemias 110-140 mg/dl en pacientes seleccionados y siempre que se pueda conseguir sin tener hipoglucemias significativas. En la unidad de los autores se aplica un protocolo con rango de 140-180 mg /dl y no observamos grandes oscilaciones en la glucemia, controlamos rápidamente la hiperglucemia y no suelen presentarse hipoglucemias significativas. Parece razonable que si la medición de glucemia capilar no es muy fiable, se recomienden determinaciones en sangre arterial. En nuestra unidad se aplica un protocolo de perfusión continua de insulina y las mediciones de glucemia se realizan en sangre arterial

Recomendaciones de manejo de la Gripe A en la Unidad de Cuidados Críticos

The Influenza A infection is a serious disease, as it is a leading cause of acute respiratory failure during epidemic seasons. Some patients develop serious complications because of it, and require mechanical ventilation and support measures for other organic failures which require admission to Critical Care Units. Awareness of information related to the complications arising from Influenza A and proper management of these patients decreases the morbidity and mortality associated with this infection. This document provides an overview of management guidelines extracted from consensus documents in order to synthesize current knowledge about managing   severe patients with Influenza A.  La infección por Gripe A es una enfermedad grave, siendo una causa principal de insuficiencia respiratoria aguda durante las estaciones epidémicas. Algunos pacientes desarrollan complicaciones graves, con necesidad de ventilación mecánica y medidas de soporte de otros fracasos orgánicos precisando ingreso en Unidades de Cuidados Críticos.  El conocimiento de las complicaciones y adecuado manejo de estos pacientes disminuye la morbimortalidad asociada a esta infección. Este documento proporciona pautas de manejo extraídas de documentos de consenso con el fin de sintetizar el conocimiento actual sobre el manejo del paciente grave con Gripe A.      

Distinct Microglial Responses in Two Transgenic Murine Models of TAU Pathology

Microglial cells are crucial players in the pathological process of neurodegenerative diseases, such as Alzheimer’s disease (AD). Microglial response in AD has been principally studied in relation to amyloid-beta pathology but, comparatively, little is known about inflammatory processes associated to tau pathology. In the hippocampus of AD patients, where tau pathology is more prominent than amyloid-beta pathology, a microglial degenerative process has been reported. In this work, we have directly compared the microglial response in two different transgenic tau mouse models: ThyTau22 and P301S. Surprisingly, these two models showed important differences in the microglial profile and tau pathology. Where ThyTau22 hippocampus manifested mild microglial activation, P301S mice exhibited a strong microglial response in parallel with high phospho-tau accumulation. This differential phospho-tau expression could account for the different microglial response in these two tau strains. However, soluble (S1) fractions from ThyTau22 hippocampus presented relatively high content of soluble phospho-tau (AT8-positive) and were highly toxic for microglial cells in vitro, whereas the correspondent S1 fractions from P301S mice displayed low soluble phosphotau levels and were not toxic for microglial cells. Therefore, not only the expression levels but the aggregation of phospho-tau should differ between both models. In fact, most of tau forms in the P301S mice were aggregated and, in consequence, forming insoluble tau species.We conclude that different factors as tau mutations, accumulation, phosphorylation, and/or aggregation could account for the distinct microglial responses observed in these two tau models. For this reason, deciphering the molecular nature of toxic tau species for microglial cells might be a promising therapeutic approach in order to restore the deficient immunological protection observed in AD hippocampus.CIBERNEDJunta de Andalucía. Consejería de Economía, Innovación, Ciencia y Empleo CTS-2035Fundación Tatiana Pérez de Guzmán el BuenoMinisterio de Ciencia, Innovación y UniversidadesInstituto de Salud Carlos III. Fondo de Investigación Sanitaria. PI15/00957 PI15/00796Fondo Europeo de Desarrollo Regional PI15/00957 PI15/0079

Estrategias de optimización de uso de betalactámicos: La importancia de conocer las particularidades fisiopatológicas del paciente crítico

There are several  strategies aimed at improving the use of antibiotics in critical patients. These strategies include de-escalation, cycling, early treatment or the use of pharmacokinetic / pharmacodynamic parameters to adjust the dosage. The pathophysiological changes that occur in the critical patient can condition the pharmacokinetics and pharmacodynamics paramethers of antibiotics, especially in beta-lactams. Therefore, anticipating the antimicrobial result based on their plasma concentrations in the place of action can be very difficult to establish, which, in turn, may have clinically relevant consequences. The pharmacodynamic profile of beta-lactams can be improved, through longer exposure with more frequent doses or with continuous or extended infusions, especially to treat multiresistant bacteria.Se han propuesto varias estrategias de mejora con la finalidad de optimizar el uso de antibióticos en los pacientes críticos. Entre ellas destacan la de-escalada, el ciclado, el tratamiento anticipado o el uso de parámetros farmacocinéticos/farmacodinámicos para ajustar la dosificación. Las alteraciones fisiopatológicas que ocurren en el paciente crítico condicionan la farmacocinética y la farmacodinamia de los antibióticos, especialmente de los betalactámicos. Por ello,  la predicción del resultado antimicrobiano basado en sus concentraciones plasmáticas, puede ser muy difícil de establecer en el lugar de acción, debido a dichas alteraciones, pudiendo tener esto consecuencias clínicamente relevantes. Se puede mejorar el perfil farmacodinámico de los betalactámicos, mediante una exposición más prolongada con dosis más frecuentes o con infusiones continuas o extendidas, especialmente para tratar bacterias multirresistentes

Utilidad de los cartuchos de hemoperfusión en el shock séptico.

Introduction: Septic shock is one of the most frequent entities observed in Intensive Care Units and is associated with high morbidity and mortality. Sepsis is characterized by a dysregulation of the immune system. In it, an imbalance occurs between pro-inflammatory substances and anti-inflammatory substances. Septic patients often have an elevation in endotoxin and cytokine levels. Elevated levels of cytokines in these patients have been associated with higher mortality. Hemoperfusion or hemoadsorption is a blood purification technique whose objective is to decrease the levels of cytokines in plasma. There are three devices on the market: the cytosorb, the polymyxin B, and the Oxiris cartridge. Discussion: With regard to cytosorb, there is no evidence that makes us advise the use of cytosorb routinely in patients with septic shock. Regarding polymyxin B, there is insufficient evidence available in the literature to advise the use of these cartridges in patients with septic shock on a routine basis. Finally, with the Oxiris cartridge there are no studies whose primary objective is the analysis of mortality, so its use cannot be recommended routinely. Conclusions: There is no conclusive evidence on which to base to advise the use of absorption therapies in patients in septic shock. There is only a subpopulation of patients with severe septic shock and high mortality (based on severity scales) in which these types of therapies may show certain benefits.  Introducción: El shock séptico es una de las entidades más frecuentes observadas en las Unidades de Cuidados Intensivos y está asociada a una elevada morbi-mortalidad. La sepsis se caracteriza por una desregulación del sistema inmune. En ella, se produce un desequilibrio entre sustancias proinflamatorias y sustancias antiinflamatorias. Los pacientes sépticos suelen tener una elevación en los niveles de endotoxinas y citoquinas. Niveles elevados de citoquinas en estos pacientes se ha asociado a mayor mortalidad. La hemoperfusión o hemoadsorción es una técnica de depuración de la sangre cuyo objetivo es disminuir los niveles de citoquinas en plasma. Existen tres dispositivos en el mercado: el cytosorb, la polimixina B y el cartucho Oxiris. Discusión: Con respecto al cytosorb, no hay evidencia que nos haga aconsejar la utilización de cytosorb de manera rutinaria en pacientes con shock séptico. Respecto a la polimixina B, no existe suficiente evidencia disponible en la literatura para aconsejar el uso de estos cartuchos en pacientes con shock séptico de manera rutinaria. Por último, con el cartucho Oxiris no hay estudios cuyo objetivo primario sea el análisis de mortalidad, por lo que no se puede aconsejar su uso de manera rutinaria. Conclusiones: No existen evidencias concluyentes en las que basarse para aconsejar el uso de las terapias de absorción en pacientes en shock séptico. Únicamente hay una subpoblación de pacientes con shock séptico grave y con alta mortalidad (basado en las escalas de gravedad) en los que puede que este tipo de terapias muestren ciertos beneficios

Should we open fire on microglia? Depletion models as tools to elucidate microglial role in health and alzheimer’s disease

Microglia play a critical role in both homeostasis and disease, displaying a wide variety in terms of density, functional markers and transcriptomic profiles along the different brain regions as well as under injury or pathological conditions, such as Alzheimer’s disease (AD). The generation of reliable models to study into a dysfunctional microglia context could provide new knowledge towards the contribution of these cells in AD. In this work, we included an overview of different microglial depletion approaches. We also reported unpublished data from our genetic microglial depletion model, Cx3cr1CreER /Csf1rflx/flx, in which we temporally controlled microglia depletion by either intraperitoneal (acute model) or oral (chronic model) tamoxifen administration. Our results reported a clear microglial repopulation, then pointing out that our model would mimic a context of microglial replacement instead of microglial dysfunction. Next, we evaluated the origin and pattern of microglial repopulation. Additionally, we also reviewed previous works assessing the effects of microglial depletion in the progression of Aβ and Tau pathologies, where controversial data are found, probably due to the heterogeneous and time-varying microglial phenotypes observed in AD. Despite that, microglial depletion represents a promising tool to assess microglial role in AD and design therapeutic strategies.La Marato-TV3 Foundation 20141432, 20141431Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas CB06/05/0094, CB06/05/1116Junta de Andalucía US-1262734, UMA18-FEDERJA-211, P18-RT-223

Diversity of plaque-associated myeloid cells subtypes in human alzheimer’s disease brain

Aims: Parenchymal microglia, as well other myeloid cells, have been postulated as a critical factor in Alzheimer´s disease (AD) pathogenesis since the identification of genetic risk factors related to their functions. However, the different phenotypes and the implication of the diverse immune cells in the human pathology have not been determined yet. In this work, we have further analyzed the phenotypic profile of the damage-associated myeloid cells in two AD vulnerable brain regions, the frontal cortex and hippocampus. Methods: Immunohistochemistry and image analysis approaches have been carried out in postmortem brain samples from patients with AD (Braak V-VI) and aged controls without neurological symptoms (Braak II). Results: Damage-associated microglial cells were clustered around amyloid plaques and expressed Iba1, TMEM119, CD68, Trem2 and CD45high. Moreover, AD brains exhibited parenchymal infiltration of CD163-positive monocyte-derived cells that invaded plaque near blood vessels. While the frontal cortex showed strong microglial activation similarly to that reported in amyloidogenic mice, the hippocampus of the same patients showed an attenuated microglial activation with a degenerative phenotype. Conclusions: These findings suggest the existence of different myeloid populations associated with Aβ plaques that correlates with disease severity. These results open the opportunity to design targeted therapies, not only to microglia, but also to the population of macrophages to modulate amyloid pathology and provide a better understanding of the immunological mechanisms underlying AD progression.Supported by ISCiii of Spain grants PI18/01557 (AG), PI18/01556 (JV) co-financed by FEDER funds from EU, by Junta de Andalucia grants UMA18-FEDERJA-211(AG), P18-RT-2233(AG) and US-1262734(JV) co-financed by Programa Operativo FEDER 2014-2020, and by B1-2019_07 Universidad de Malaga. Campus de Excelencia Internacional Andalucia Tech (ESM)

Investigación bibliométrica sobre la belleza y los consumidores

El estudio busca dar luz a la literatura existente en referencia al sector de la belleza y sus consumidores. Para llevar a cabo dicho estudio se ha realizado un análisis bibliométrico de los artículos proporcionados por la base de datos Web of Science Core Collection, permitiendo agrupar los datos y valores de los diferentes artículos. El análisis nos reporta diferentes resultados, en los últimos años ha habido un incremento exponencial de los artículos publicados en esta materia, así mismo, el número de citas es creciente a lo largo del tiempo. Los artículos han sido escritos por instituciones de gran prestigio y de diversos países, destacando la presencia de Inglaterra, Estados Unidos y China. El mapeo científico aporta futuras líneas de investigación relacionadas con el tema tratado, los artículos académicos relacionados con la belleza y los actores de la comunicación audiovisual es creciente, el estudio del desarrollo de marca y metodologías de consumo por parte de los usuarios de estos productos y las campañas de márquetin orientado a nuevas tecnologías en el mundo de la belleza

Disruption of Amyloid Plaques Integrity Affects the Soluble Oligomers Content from Alzheimer Disease Brains

The implication of soluble Abeta in the Alzheimer's disease (AD) pathology is currently accepted. In fact, the content of soluble extracellular Abeta species, such as monomeric and/or oligomeric Abeta, seems to correlate with the clinicopathological dysfunction observed in AD patients. However, the nature (monomeric, dimeric or other oligomers), the relative abundance, and the origin (extra-/intraneuronal or plaque-associated), of these soluble species are actually under debate. In this work we have characterized the soluble (defined as soluble in Trisbuffered saline after ultracentrifugation) Abeta, obtained from hippocampal samples of Braak II, Braak III-IV and Braak V-VI patients. Although the content of both Abeta40 and Abeta42 peptides displayed significant increase with pathology progression, our results demonstrated the presence of low, pg/mg protein, amount of both peptides. This low content could explain the absence (or below detection limits) of soluble Abeta peptides detected by western blots or by immunoprecipitation-western blot analysis. These data were in clear contrast to those published recently by different groups. Aiming to explain the reasons that determine these substantial differences, we also investigated whether the initial homogenization could mobilize Abeta from plaques, using 12-month-old PS1xAPP cortical samples. Our data demonstrated that manual homogenization (using Dounce) preserved the integrity of Abeta plaques whereas strong homogenization procedures (such as sonication) produced a vast redistribution of the Abeta species in all soluble and insoluble fractions. This artifact could explain the dissimilar and somehow controversial data between different groups analyzing human AD sample

Amyloid-β impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease

Reactive astrocytes and dystrophic neurites, most aberrant presynaptic elements, are found surrounding amyloid-β plaques in Alzheimer's disease (AD). We have previously shown that reactive astrocytes enwrap, phagocytose, and degrade dystrophic synapses in the hippocampus of APP mice and AD patients, but affecting less than 7% of dystrophic neurites, suggesting reduced phagocytic capacity of astrocytes in AD. Here, we aimed to gain insight into the underlying mechanisms by analyzing the capacity of primary astrocyte cultures to phagocytose and degrade isolated synapses (synaptoneurosomes, SNs) from APP (containing dystrophic synapses and amyloid-β peptides), Tau (containing AT8- and AT100-positive phosphorylated Tau) and WT (controls) mice. We found highly reduced phagocytic and degradative capacity of SNs-APP, but not AT8/AT100-positive SNs-Tau, as compared with SNs-WT. The reduced astrocyte phagocytic capacity was verified in hippocampus from 12-month-old APP mice, since only 1.60 ± 3.81% of peri-plaque astrocytes presented phagocytic structures. This low phagocytic capacity did not depend on microglia-mediated astrocyte reactivity, because removal of microglia from the primary astrocyte cultures abrogated the expression of microglia-dependent genes in astrocytes, but did not affect the phagocytic impairment induced by oligomeric amyloid-β alone. Taken together, our data suggest that amyloid-β, but not hyperphosphorylated Tau, directly impairs the capacity of astrocytes to clear the pathological accumulation of oligomeric amyloid-β, as well as of peri-plaque dystrophic synapses containing amyloid-β, perhaps by reducing the expression of phagocytosis receptors such as Mertk and Megf10, thus increasing neuronal damage in AD. Therefore, the potentiation or recovery of astrocytic phagocytosis may be a novel therapeutic avenue in AD.Centro de Invesitgacion Biomedica en Red Enfermedades Neurodegenetativas (CIBERNED). CB06/05/0094 y CB06/05/1116Instituto de Salud Carlos III y fondos FEDER de la Unión Europea. PI18/01556 y PI18/01557Consejería de Economía y Conocimiento de la Junta de Andalucía y el Programa Operativo FEDER 2014-2020. PY18-RT-2233, UMA18-FEDERJA-211 y US-1262734Fundación La Marató-TV3. 20141430, 20141431, 2014143