Implicación de los receptores TLR4 en el daño cerebral causado por el consumo de alcohol

El abuso de alcohol puede causar daño cerebral y en ciertos casos cursa con neurodegeneración, aunque los mecanismos moleculares de estos efectos se desconocen. El Sistema Nervioso Central (SNC) ha sido considerado, hasta muy recientemente, como un sistema inmunológicamente privilegiado (Galea et al., 2007). Sin embargo, estudios de los últimos años indican que el cerebro coordina y regula numerosos aspectos de la respuesta inmune innata, y que la inflamación representa un factor crítico y esencial para muchas enfermedades del SNC, como son las enfermedades neurodegenerativas (Wild et al., 2008). Igualmente, la respuesta del sistema inmune innato también desempeña un papel crucial en el daño causado por numerosas enfermedades autoinmunes, y colabora en otras enfermedades tales como el cáncer, diabetes y daños cardiovasculares (Dalgleish and O'Byrne, 2006; Tedgui and Mallat, 2006). Los receptores TLRs (toll-like receptors), son los que fundamentalmente participan en la respuesta innata inmune, y responden ante procesos patogénicos. Recientemente, se ha demostrado que los TLRs se expresan en el SNC y que la neuroinflamación asociada a la activación de los receptores TLRs, participa en muchos procesos neuropatológicos y neurodegenerativos (Babcock et al., 2006; Chen et al., 2007). Además, se ha demostrado que la eliminación de los receptores TLR4 en ratones TLR4-KO, previene la isquemia y el daño cerebral (Cao et al., 2007). Es importante señalar, que aunque un incremento transitorio de dicha respuesta inmune puede ser beneficiosa para paliar condiciones patogénicas (Rivest, 2003), una activación exacerbada de la inmunidad innata puede conllevar a procesos implicados en neurodegeneración (Campbell, 2004). Aunque los procesos neuropatológicos por los que el etanol induce daño en cerebro no están esclarecidos, estudios de nuestro laboratorio ya habían demostrado que la administración crónica de alcohol en la rata, activaba vías de señalización asociadas a la respuesta de los receptores IL-1RI y TLR4 y causaba muerte neural en células gliales en cultivo (Valles et al., 2004). Estos resultados sugerían que el etanol puede causar daño a través de neuroinflamación (Blanco and Guerri, 2007). Además, datos del mismo laboratorio indicaban que el etanol, a concentraciones con relevancia a nivel fisiológico, y en ausencia de los ligando IL-1 o LPS, era capaz de activar la vía de señalización IL-1RI/ TLR4 no sólo en astrocitos (Blanco et al., 2005; Blanco et al., 2008) sino también en microglía y macrófagos de ratón (Fernandez-Lizarbe et al., 2008), sugiriendo que la activación de la respuesta de TLR4 inducida por etanol, podría ser de importancia en mecanismos de neuroinflamación (Blanco and Guerri, 2007). En base a los anteriores resultados y considerando el papel crítico de los TLR4 en la neuroinflamación, daño cerebral y neurodegeneración (Okun et al., 2009), el principal objetivo de este trabajo ha sido establecer el papel potencial de la respuesta de TLR4/IL1RI inducida por el etanol, tanto en la activación astroglial, daño cerebral y neurodegeneración causada por el consumo de alcohol, así como evaluar si éste daño cerebral causado por el consumo de alcohol se asociaba con alteraciones cognitivas tras la retirada del alcohol y los posibles mecanismos epigenéticos involucrados en dichas alteraciones. Por tanto, el presente trabajo se ha abordado la hipótesis de que los receptores TLR4 poseen un papel crucial en la neuroinflamación, daño cerebral y posible neurodegeneración inducida por el consumo de alcohol y que el inflamasoma participa en el daño neural causado por el consumo de alcohol. El inflamasoma, es una plataforma multiprotéica citosólica que permite la activación de las caspasas proinflamatorias, específicamente de la caspasa-1 que procesa el precursor de la interleucina-1beta (pro-IL-1beta) a la forma activa (IL-1) así como a otros miembros de la misma familia como la IL-18, conduciendo a una poderosa respuesta inflamatoria. Desconocemos cómo se produce la activación de los inflamasomas y los mecanismos por los cuáles se logra la respuesta inmunoprotectora, sin embargo, sabemos que el ensamblaje y la activación del inflamasoma es un proceso esencial en los mecanismos naturales de defensa inmune. El inflamasoma más estudiado ha sido el NLRP3 (criopirina), ya que se producen mutaciones en el gen que codifica algunas proteínas que lo conforman, participando en ciertas patologías autoinmunes. Los resultados obtenidos demuestran que el consumo crónico de alcohol en ratones, causa una activación en la señalización del TLR4 (MAPK, NF-kB/p65), estimula la microglía y astroglía, aumenta los niveles de citoquinas y mediadores proinflamatorios e incluso activa la actividad de la caspasa-3, causando degeneración y muerte neuronal en corteza cerebral de ratones. La deficiencia de la función de los receptores TLR4 en ratones (TLR4-KO) protege de la neuroinflamación y de gran parte de los efectos deletéreos que causa el consumo de alcohol en cerebro. Además, demostramos que los co-receptores del TLR4, CD14 y MD-2, participan en la activación del TLR4 por el etanol, ya que el silenciamiento de estos co-receptores, mediante el uso de siRNAs, bloquea la respuesta del TLR4 inducida por el etanol en astrocitos. Los resultados también demuestran que el inflamasoma NLRP3 participa en la neuroinflamación causada por el consumo de alcohol. De hecho, la administración de alcohol en ratones activa el complejo citosólico del inflamasoma NLRP3/Casp1, en astrocitos en cultivo y en la corteza cerebral e hipocampo de ratones TLR4+/+. Dicha activación es muy leve en animales TLR4-KO. Los resultados indican que los TLR4 potencian la respuesta neuroinflamatoria del complejo NLRP3/Casp1, y que los TLR4 son necesarios pero no suficientes para que el alcohol produzca una activación completa de este complejo citosólico. Además, también observamos que el consumo crónico de alcohol, causa una leve infiltración celular de polimorfonucleados (leucocitos, neutrófilos, etc.) y macrófagos en cerebro, que se conoce como infiltrado inflamatorio en cerebro. Es interesante resaltar que la activación de los receptores TLR4 y neuroinflamación se asocia con procesos de desmielinización, que se observan en alcohólicos con un abuso de alcohol. De hecho, demostramos que la activación del TLR4 tras el consumo de alcohol, causa una reducción en los niveles de diferentes proteínas de mielina, alteraciones morfológicas, cambios estructurales de las fibras mielínicas, notable reducción en la materia blanca, degeneración axonal y muerte neuronal asociada. La eliminación de la función de los TLR4, no sólo protege de gran parte de la neuroinflamación, sino que también de las alteraciones en la mielina y el daño neuronal asociado con el abuso de alcohol. En correlación con nuestros estudios, mediante técnicas de neuroimagen y en necropsias de cerebros de individuos alcohólicos, se ha observado una atrofia cerebral y agrandamiento ventricular, junto con una reducción del volumen de la sustancia blanca hemisférica cerebral. Finalmente, demostramos que la neuroinflamación y la neurodegeneración que induce el consumo crónico de alcohol, causa cambios epigenéticos en la acetilación de histonas y estos cambios, se correlacionan con alteraciones cognitivas y conductuales a largo plazo tras el consumo de alcohol. En resumen, aunque los mecanismos por los que el alcohol causa daño cerebral son complejos, la activación del sistema innato inmune y de los receptores TLR4 en el cerebro, desempeña un papel crucial en la neuroinflamación y en el daño cerebral que conlleva el abuso de alcohol. Por tanto, los receptores TLR4 pueden representar una nueva diana terapéutica para paliar o tratar ciertas patologías asociadas al consumo de alcohol, como la hepatopatía, la reducción en la materia blanca, el daño cerebral y las alteraciones cognitivas y conductuales asociadas con el abuso de alcohol.Alcohol abuse can cause brain damage and in some cases, neurodegeneration, but the molecular mechanism remains unknown. The Central Nervous System (CNS) has been considered, until recently, to be immunologically privileged system (Galea et al., 2007), but it is it is now well accepted however that immune surveillance occurs in the normal CNS and that inflammatory responses can take place in the context of disease. Indeed, recent studies indicate that the brain is the organ that coordinates and regulates all factors involved in the innate immune response, and inflammation is considered to be a critical event for several CNS diseases, as neurodegenerative disorders (Wild et al., 2008). Likewise, the innate immune system response is also involved in the damage associated to numerous autoimmune disorders, and also participates in other diseases as cancer, diabetes and cardiovascular diseases (Dalgleish and O'Byrne, 2006; Tedgui and Mallat, 2006). The toll-like receptors (TLRs) are the receptors implicated in the innate immune response to infection or damage. Recent evidence, demonstrates that TLRs are expressed in the CNS and neuroinflammation induced by the TLR activation, participates in brain injury and neurodegenerative processes (Babcock et al., 2006; Chen et al., 2007). Indeed, elimination of the TLR4 receptors, by using TLR4-KO mice, prevents ischemia and brain damage (Cao et al., 2007). It is important to highlight that although the innate immune response can be beneficial for some pathogenic conditions (Rivest, 2003), an exacerbate activation in the Innate Immunity can lead to neurodegeneration (Campbell, 2004). Notably, previous studies have been demonstrated that chronic ethanol intake induces the activation of the signalling pathways associated to the IL-1RI/TLR4 immune response in rat brain and even can cause cell death in glial cells in culture (Valles et al., 2004). Other results further demonstrate that low/moderate ethanol concentrations, in absence of IL-1 or LPS, are capable to activate the IL-1RI/TLR4 signalling pathways in astrocytes (Blanco et al., 2005; Blanco et al., 2008) and even in cultured microglia and in mice peritoneal macrophages (Fernandez-Lizarbe et al., 2008). These results suggest that the activation of ethanol-induced TLR4 immune response could be critical factor in the neuroinflammation processes induced by ethanol (Blanco and Guerri, 2007). On the basis on the above studies, and considering the critical role of TLR4 in the neuroinflammation and brain damage (Okun et al., 2009), the main objective of the present work has been to establish whether TLR4 receptors play an in vivo role in the ethanol-induced neuroinflammation, brain damage and possible neurodegeneration and if other immune systems, as inflammasome, participate in the neuroinflammation caused by alcohol consumption. The inflammasome is a multiproteic cytosolic platform that allows to the proinflammatory caspases, specifically caspase-1 to cleavage the interleuquin-1 beta and interleuquin 18 precursors (pro-IL-1beta and pro-IL-18, respectively) to the active forms (IL-1 and IL-18), triggering an important inflammatory response. Although, the molecular mechanisms involved in the inflammasome activation and whether the immune response are protective or induced inflammation is still uncertain, we know that inflammasome recruitment and activation is considered crucial in the natural innate immune response mechanism. One of the best characterized inflammasome is the NLRP3 inflammasome or criopirin, since it is involved in many autoimmune diseases. The results of the this work demonstrate that in vivo chronic ethanol intake triggers the activation of the TLR4 signalling pathway(MAPK, NF-kB/p65) in mice brain, activates microglial and astroglial cells, increases cytokines and proinflammatory mediators levels, and induces caspase-3 activation that leads to neuronal death in the brain cortex from TLR4 mice. The deficiency in the TLR4 function (TLR4-KO mice) protects from neuroinflammation, reactive gliosis and neuronal death. We further show that the TLR4 co-receptors as CD14 and MD-2, participate in the ethanol-induced TLR4 activation, since the down-regulation of these proteins, by using siRNAs, abolishes ethanol-induced TLR4 response in astrocytes in culture. Our findings also reveal that NLRP3-inflammasome participates in the alcohol induced-neuroinflammation. Thus, we demonstrate that chronic ethanol administration induces the activation of the cytosolic complex NLRP3/Casp1 inflammasome in both cultured astrocytes, brain (cortex and hippocampus) of TLR4+/+ mice. However, NLRP3 activation is absent or weak in brain of TLR4-KO animals. Our results also indicate that TLR4 receptors potentiate the neuroinflammatory response of the NLRP3/Casp1 inflammasome complex. Moreover, we observe that chronic alcohol treatment induces a weak polymorfonucleated infiltration (e.g. leucocytes, neutrophils) and even macrophages, events that could contribute to the activation of TLR4+/+ and NLRP3-inflammasome. Also, we highlight the relationship of the TLR4 immune response activation and neuroinflammation with the demyelination processes observed in alcoholics with alcohol abuse. In fact, we demonstrate that chronic ethanol treatment in mice concomitantly with the TLR4 activation and neuroinflammation; we also observed a reduction in the different myelin protein levels, as well as myelin morphological alterations, such as structural changes in the myelin sheats, and an important reduction of the white matter, axonal degeneration and neuronal death. The elimination of the TLR4 function, not only protects from neuroinflammation processes, but also eliminates most of the myelin alterations and neuronal damage associated to alcohol abuse. Corroborating our results, neuroimaging and postmortem studies in alcoholics´brain have been observed brain atrophy and ventricular growth with an important white matter reduction in the brain. Finally, we demonstrate that neuroinflammation and neurodegeneration processes induced by chronic alcohol intake, can cause epigenetic changes related to histone acetilation. These changes correlate with long term cognitive and behavioural dysfunctions in ethanol-treated animals. In summary, although molecular mechanisms implicated in the alcohol-induced brain damage are complex, the innate immune system and TLR4 activation in the brain play a critical role in the neuroinflammation and brain damage induced by alcohol abuse. Our results indicate that TLR4 receptors can represent a novel therapeutic target for the pathologies associated with alcohol consumption, like alcoholic hepatophaty, cortical white matter reduction, brain damage and cognitive and behavioural disorders associated to alcohol abuse

Mutational dynamics of murine angiogenin duplicates

<p>Abstract</p> <p>Background</p> <p>Angiogenin (Ang) is a protein involved in angiogenesis by inducing the formation of blood vessels. The biomedical importance of this protein has come from findings linking mutations in Ang to cancer progression and neurodegenerative diseases. These findings highlight the evolutionary constrain on Ang amino acid sequence. However, previous studies comparing human Angiogenin with homologs from other phylogenetically related organisms have led to the conclusion that Ang presents a striking variability. Whether this variability has an adaptive value <it>per se </it>remains elusive. Understanding why many functional Ang paralogs have been preserved in mouse and rat and identifying functional divergence mutations at these copies may explain the relationship between mutations and function. In spite of the importance of testing this hypothesis from the evolutionarily and biomedical perspectives, this remains yet unaccomplished. Here we test the main mutational dynamics driving the evolution and function of Ang paralogs in mammals.</p> <p>Results</p> <p>We analysed the phylogenetic asymmetries between the different Ang gene copies in mouse and rat in the context of vertebrate Ang phylogeny. This analysis shows strong evidence in support of accelerated evolution in some Ang murine copies (mAng). This acceleration is not due to non-functionalisation because constraints on amino acid replacements remain strong. We identify many of the amino acid sites involved in signal localization and nucleotide binding by Ang to have evolved under diversifying selection. Compensatory effects of many of the mutations at these paralogs and their key structural location in or nearby important functional regions support a possible functional shift (functional divergence) in many Ang copies. Similarities between 3D-structural models for mAng copies suggest that their divergence is mainly functional.</p> <p>Conclusions</p> <p>We identify the main evolutionary dynamics shaping the variability of Angiogenin in vertebrates and highlight the plasticity of this protein after gene duplication. Our results suggest functional divergence among mAng paralogs. This puts forward mAng as a good system candidate for testing functional plasticity of such an important protein while stresses caution when using mouse as a model to infer the consequences of mutations in the single Ang copy of humans.</p

A survey of domestic wells and pit latrines in rural settlements of Mali: Implications of on-site sanitation on the quality of water supplies

On-site sanitation is generally advocated as a means to eradicate the health hazards associated with open defecation. While this has provided a welcome upgrade to the livelihoods of millions of people in low-income countries, improved sanitation facilities are increasingly becoming a threat to domestic groundwater-based supplies. Within this context, a survey of pit latrines, domestic wells and improved water sources was carried out in a large rural village of southern Mali. All households were surveyed for water, sanitation and hygiene habits. Domestic wells and improved water sources were georeferenced and sampled for water quality (pH, electric conductivity, temperature, turbidity, total dissolved solids, thermotolerant coliforms, chloride and nitrate) and groundwater level, while all latrines were inspected and georeferenced. A GIS database was then used to evaluate the proportion of water points within the influence area of latrines, as well as to underpin multiple regression models to establish the determinants for fecal contamination in drinking supplies. Moreover, an appraisal of domestic water treatment practices was carried out. This revealed that nearly two-thirds of the population uses bleach to purify drinking supplies, but also that domestic-scale treatment as currently implemented by the population is far from effective. It is thus concluded that existing habits could be enhanced as a means to make water supplies safer. Furthermore, population, well and latrine density were all identified as statistically significant predictors for fecal pollution at different spatial scales. These findings are policy-relevant in the context of groundwater-dependent human settlements, since many countries in the developing world currently pursue the objective of eliminating open defecation

NADPH oxidase and reactive oxygen species contribute to alcohol-induced microglial activation and neurodegeneration

<p>Abstract</p> <p>Background</p> <p>Activation of microglia causes the production of proinflammatory factors and upregulation of NADPH oxidase (NOX) that form reactive oxygen species (ROS) that lead to neurodegeneration. Previously, we reported that 10 daily doses of ethanol treatment induced innate immune genes in brain. In the present study, we investigate the effects of chronic ethanol on activation of NOX and release of ROS, and their contribution to ethanol neurotoxicity.</p> <p>Methods</p> <p>Male C57BL/6 and NF-κB enhanced GFP mice were treated intragastrically with water or ethanol (5 g/kg, i.g., 25% ethanol w/v) daily for 10 days. The effects of chronic ethanol on cell death markers (activated caspase-3 and Fluoro-Jade B), microglial morphology, NOX, ROS and NF-κB were examined using real-time PCR, immunohistochemistry and hydroethidine histochemistry. Also, Fluoro-Jade B staining and NOX gp91^phoximmunohistochemistry were performed in the orbitofrontal cortex (OFC) of human postmortem alcoholic brain and human moderate drinking control brain.</p> <p>Results</p> <p>Ethanol treatment of C57BL/6 mice showed increased markers of neuronal death: activated caspase-3 and Fluoro-Jade B positive staining with Neu-N (a neuronal marker) labeling in cortex and dentate gyrus. The OFC of human post-mortem alcoholic brain also showed significantly more Fluoro-Jade B positive cells colocalized with Neu-N, a neuronal marker, compared to the OFC of human moderate drinking control brain, suggesting increased neuronal death in the OFC of human alcoholic brain. Iba1 and GFAP immunohistochemistry showed activated morphology of microglia and astrocytes in ethanol-treated mouse brain. Ethanol treatment increased NF-κB transcription and increased NOX gp91^phoxat 24 hr after the last ethanol treatment that remained elevated at 1 week. The OFC of human postmortem alcoholic brain also had significant increases in the number of gp91^phox+ immunoreactive (IR) cells that are colocalized with neuronal, microglial and astrocyte markers. In mouse brain ethanol increased gp91^phoxexpression coincided with increased production of O₂^-and O₂^-- derived oxidants. Diphenyleneiodonium (DPI), a NOX inhibitor, reduced markers of neurodegeneration, ROS and microglial activation.</p> <p>Conclusions</p> <p>Ethanol activation of microglia and astrocytes, induction of NOX and production of ROS contribute to chronic ethanol-induced neurotoxicity. NOX-ROS and NF-κB signaling pathways play important roles in chronic ethanol-induced neuroinflammation and neurodegeneration.</p

Prefrontal response and frontostriatal functional connectivity to monetary reward in abstinent alcohol-dependent young adults

Although altered function in neural reward circuitry is widely proposed in models of addiction, more recent conceptual views have emphasized the role of disrupted response in prefrontal regions. Changes in regions such as the orbitofrontal cortex, medial prefrontal cortex, and dorsolateral prefrontal cortex are postulated to contribute to the compulsivity, impulsivity, and altered executive function that are central to addiction. In addition, few studies have examined function in these regions during young adulthood, when exposure is less chronic than in typical samples of alcohol-dependent adults. To address these issues, we examined neural response and functional connectivity during monetary reward in 24 adults with alcohol dependence and 24 psychiatrically healthy adults. Adults with alcohol dependence exhibited less response to the receipt of monetary reward in a set of prefrontal regions including the medial prefrontal cortex, lateral orbitofrontal cortex, and dorsolateral prefrontal cortex. Adults with alcohol dependence also exhibited greater negative correlation between function in each of these regions and that in the nucleus accumbens. Within the alcohol-dependent group, those with family history of alcohol dependence exhibited lower mPFC response, and those with more frequent drinking exhibited greater negative functional connectivity between the mPFC and the nucleus accumbens. These findings indicate that alcohol dependence is associated with less engagement of prefrontal cortical regions, suggesting weak or disrupted regulation of ventral striatal response. This pattern of prefrontal response and frontostriatal connectivity has consequences for the behavior patterns typical of addiction. Furthermore, brain-behavior findings indicate that the potential mechanisms of disruption in frontostriatal circuitry in alcohol dependence include family liability to alcohol use problems and more frequent use of alcohol. In all, these findings build on the extant literature on reward-circuit function in addiction and suggest mechanisms for disrupted function in alcohol dependence. © 2014 Forbes et al

Post-traumatic anxiety associates with failure of the innate immune receptor TLR9 to evade the pro-inflammatory NFκB pathway

Post-traumatic anxiety notably involves inflammation, but its causes and functional significance are yet unclear. Here, we report that failure of the innate immune system Toll-like receptor 9 (TLR9) to limit inflammation is causally involved with anxiety-associated inflammation and that peripheral administration of specific oligonucleotide activators of TLR9 may prevent post-traumatic consequences in stressed mice. Suggesting involvement of NFκB-mediated enhancement of inflammatory reactions in the post-traumatic phenotype, we found association of serum interleukin-1β increases with symptoms severity and volumetric brain changes in post-traumatic stress disorder patients. In predator scent-stressed mice, the moderate NFκB-activating oligonucleotides mEN101 and its human ortholog BL-7040, but not the canonic NFκB activator oligonucleotide ODN1826, induced anxiolytic effects. In stressed mice, peripherally administered mEN101 prevented delayed stress-inducible serum interleukin-1β increases while limiting stress-characteristic hippocampal transcript modifications and the anxiety-induced EGR1-mediated neuronal activation. Attesting to the TLR9 specificity of this response, BL-7040 suppressed NFκB-mediated luciferase in transfected cells co-expressing TLR9, but not other TLRs. Furthermore, TLR9−/− mice were mEN101 and BL-7040 resistant and presented unprovoked anxiety-like behavior and anxiety-characteristic hippocampal transcripts. Our findings demonstrate functional relevance of TLR9 in protecting stressed mammals from overreacting to traumatic experiences and suggest using oligonucleotide-mediated peripheral TLR9 activation to potentiate the innate immune system and prevent post-traumatic inflammation and anxiety

The choroid plexus as a sex hormone target: Functional implications

The choroid plexuses (CPs) are highly vascularized branched structures that protrude into the ventricles of the brain, and form a unique interface between the blood and the cerebrospinal fluid (CSF). In recent years, novel functions have been attributed to this tissue such as in immune and chemical surveillance of the central nervous system, brain development, adult neurogenesis and circadian rhythm regulation. Sex hormones (SH) are widely recognized as modulators in several neurodegenerative diseases, and there is evidence that estrogens and androgens regulate several fundamental biological functions in the CPs. Therefore, SH are likely to affect the composition of the CSF impacting on brain homeostasis. This review will look at implications of the CPs' sex-related specificities.Portuguese Foundation for Science and Technology (FCT, Portugal – http://www.fct.pt) project grants (PTDC/SAU-NEU/114800/2009); and by FEDER funds through the POCI – COMPETE 2020 – Operational Programme Competitiveness and Internationalisation in Axis I – Strengthening research, technological development and innovation (Project No. 007491) and National Funds by FCT – Foundation for Science and Technology (Project UID/Multi/00709). Joana Tomás was supported by a grant from CENTRO-07-ST24-FEDER-002015. Telma Quintela is a recipient of a FCT fellowship (SFRH/BPD/70781/2010). The work at ICVS/3B’s has the support of Portuguese North Regional Operational Program (ON.2 – O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER). Fernanda Marques is a recipient of a FCT Investigator award (IF/00231/2013) of the Fundação para a Ciência e Tecnologia (FCT, Portugal)info:eu-repo/semantics/publishedVersio

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Opportunities for the Development of Neuroimmune Therapies in Addiction

Studies have implicated neuroinflammatory processes in the pathophysiology of various psychiatric conditions, including addictive disorders. Neuroimmune signaling represents an important and relatively poorly understood biological process in drug addiction. The objective of this review is to update the field on recent developments in neuroimmune therapies for addiction. First, we review studies of neuroinflammation in relation to alcohol and methamphetamine dependence followed by a section on neuroinflammation and accompanying neurocognitive dysfunction in HIV infection and concomitant substance abuse. Second, we provide a review of pharmacotherapies with neuroimmune properties and their potential development for the treatment of addictions. Pharmacotherapies covered in this review include ibudilast, minocycline, doxycycline, topiramate, indomethacin, rolipram, anakinra (IL-1Ra), peroxisome proliferator-activated receptor agonists, naltrexone, and naloxone. Lastly, summary and future directions are provided with recommendations for how to efficiently translate preclinical findings into clinical studies that can ultimately lead to novel and more effective pharmacotherapies for addiction