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Palatable food and drugs of abuse activate common neurobiological pathways and numerous studies suggest that fat consumption increases vulnerability to drug abuse. In addition, preclinical reports show that palatable food may relieve craving for drugs, showing that an ad libitum access to a high-fat diet (HFD) can reduce cocaine-induced reinstatement. The main aim of the present study was to evaluate the effect of a limited and intermittent exposure to HFD administered during the extinction and reinstatement processes of a cocaine-induced conditioned place preference (CPP). Male and female mice underwent the 10 mg/kg cocaine CPP. From post-conditioning onwards, animals were divided into four groups: SD (standard diet); HFD-MWF with 2-h access to the HFD on Mondays, Wednesdays, and Fridays; HFD-24h, with 1-h access every day; and HFD-Ext with 1-h access to the HFD before each extinction session. Our results showed that all HFD administrations blocked reinstatement in males, while only the HFD-MWF was able to inhibit reinstatement in females. In addition, HFD-Ext males needed fewer sessions to extinguish the preference, which suggests that administration of fat before being exposed to the environmental cues is effective to extinguish drug-related memories. HFD did not affect Oprμ gene expression but increased CB1r gene expression in the striatum in HFD-Ext males. These results support that palatable food could act as an alternative reward to cocaine, accelerating extinction and blocking reinstatement, these effects being sex specific.

Background: The asymmetry of motor manifestations present in Parkinson’s disease (PD) suggests the existence of differences between both hemispheres. As a consequence, this asymmetry might contribute to different PD clinical phenotypes. Objective: To study the relationship between motor symptom laterality with motor, non-motor symptoms (NMS), freezing of gait (FOG), and quality of life (QoL) impairment in PD. Methods: In this cross-sectional study, we measured motor symptoms severity and complications with the Unified Parkinsons’ disease Rating Scale (UPDRS), FOG with the FOG questionnaire, QoL with the 39-item PD Quality of Life Questionnaire Summary Index, and NMS with the NMS, Visual Analogue Scales for Pain and Fatigue, Beck Depression Inventory-II, Impulsive-Compulsive Disorders, and PD Sleep and Cognitive Rating scales. We defined left and right motor laterality using the UPDRS part III. We used comparative, regression, and effect size analyses to evaluate the impact of asymmetry on motor and NMS, FOG, and QoL. Results: 342 left (LPD) and 310 right (RPD) patients, with a mean age of 62.0±8.8 years, were included. In multivariate regression analysis, LPD was associated with a greater motor (OR = 1,50, 95% CI 1.02–2.21), FOG (OR = 1.56, 95% CI 1.01–2.41), and overall NMS impairment (OR = 1.43, 95% CI 1.001–2.06), and better QoL (OR = 0.52 95% CI 0.32–0.85). Overall, only a mild effect size was found for all comparisons in which significant differences were present. Conclusion: In this large multicenter study, motor symptom laterality seems to carry a mild but significant impact on PD clinical manifestations, and QoL.

El uso de grupos (o paquetes) de barras presenta ventajas tales como la descongestión de barras. Sin embargo, el empalme de este tipo de barras requiere de mayor detalle tanto en el despiece como en la ejecución. El empalme más habitual en este tipo de barras es el empalme por solape (o traslapo), escalonando las barras individuales en la dirección longitudinal. El Eurocódigo 2 y la ACI-318-14 difieren en las formas de empalme por solape y en la longitud de solape necesaria. En esta nota técnica los autores analizamos la tolerancia mínima existente en función de los tipos de solape en paquetes de barras.

Alcohol is a neurotoxic compound and its abuse can induce brain damage and neurodegeneration. Evidence from the last decade demonstrates the critical role of the innate immune system in neuroinflammation associated with alcohol abuse. In this review, we discuss the role of miRNAs as regulators of immune Toll-like receptors (TLR4), the neuroimmune response associated with alcohol abuse, and the importance of glial extracellular vesicles in amplifying neuroinflammation. Current studies demonstrate the role of glial extracellular vesicles/exosomes in extending neuroinflammation, and the importance of miRNAs as key regulators of different biological functions. However, dysregulation of miRNAs also participates in neurological and neurodegenerative diseases associated with neuroinflammation. Recent findings indicate the possibility of circulating miRNAs being used as biomarkers to screen neurological and neuroinflammatory disorders as early diagnosis and therapy. This article highlights the role of miRNAs in regulating neuroinflammation associated with alcohol abuse and the importance of glial extracellular vesicles/exosomes in extending neuroinflammation.

Palliative sedation is used to relieve end-of-life refractory symptoms.The objective of this study was to describe the use of palliative sedation in patients who die in internal medicine departments.An observational, cross-sectional, retrospective, and multicenter clinical audit study was conducted in 145 hospitals in Spain and Argentina. Each hospital included the first 10 patients who died in the internal medicine department, starting on December 1, 2015.We included 1447 patients, and palliative sedation was administered to 701 patients (48.4%). Having a terminal illness (odds ratio [OR] 2.469, 95% CI 1.971-3.093, P 0.001) and the length of hospital stay (OR 1.011, 95% CI 1.002-1.021, P = 0.017) were independently associated with the use of palliative sedation. Consent was granted by the families of 582 (83%) patients. The most common refractory symptom was dyspnea, and the most commonly used drugs for sedation were midazolam (77%) and morphine (89.7%). An induction dose was administered in 25.7% of the patients. Rescue doses were scheduled for 70% of the patients, and hydration was maintained in 49.5%. Pain was more common in patients with cancer, whereas dyspnea was more common in those without cancer. Rescue doses were used more often for the patients with cancer (77.8% vs. 67.7%, P = 0.015). Monitoring the palliative sedation with a scale was more frequent in the patients with cancer (23.7% vs. 14.3%, P = 0.008).Palliative sedation is used more often for terminal patients. There are differences in the administration of palliative sedation between patients with and without cancer.

Introduction Meningiomas associating prominent cystic changes (CM) have challenged neurosurgeons since the beginning of this surgical discipline. We present the experience in the diagnostic and therapeutic management of this entity in our institution. Material and methods A review of our patient database was carried out, searching for those CM that were operated on in the last 15 years. Relevant clinical data were recorded and analysed for each case, with special emphasis in the correlation of radiological and pathological findings. Cystic changes were classified according to the scheme proposed by Nauta et al. Results A total of 11 patients were gathered, which represents 1.8% of the meningiomas operated on in our department during the period studied. All were adults, predominantly female patients (8 cases). Among the clinical symptoms a high rate of epileptic seizures was observed while only one patient developed acute intracranial hypertension. Morphologically, most tumours corresponded to type 2 CMs, followed by types 1, 3 and 4. In only five patients an unequivocal radiological diagnosis of meningioma could be made. All neoplasms were surgically removed and there were no records of recurrence (mean follow-up: 52.8 months). Microscopic findings were consistent with the pathological diagnosis of atypical meningioma in 4 cases, while the remaining tumours corresponded to OMS grade I neoplasms with variable microscopic patterns. Conclusions Meningiomas can exceptionally associate cystic changes, both intra and/or extratumoral, in variable number and size. When cystic changes become too prominent (a large number or big-sized cysts), a serious preoperative diagnostic dilemma may arise. The surgical management of those CMs displaying a peripheral, thin-walled cyst (types 2 and 3) is especially complex, as contrast enhancement of the tumour wall did not correlate strictly with neoplastic invasion; even in the absence of this feature free floating islands of meningothelial cells intermixed with cyst fluid can be found. Consequently both surgical biopsy of every suspicious tissue and copious irrigation of the surgical cavity are strongly recommended for these CM types.

Resumen Introduccion Los meningiomas que asocian cambios quisticos prominentes (MQ) han representado un reto diagnostico y terapeutico desde los origenes de la neurocirugia moderna. Presentamos la experiencia en el manejo clinico y quirurgico de esta entidad en nuestro Servicio. Material y metodos En este estudio descriptivo se incluyen los MQ intervenidos en nuestro Servicio en los ultimos 15 anos, evaluando las variables clinicas, diagnosticas y terapeuticas de este subgrupo de meningiomas, con especial enfasis en la correlacion de los hallazgos radiologicos y patologicos. Los tumores se clasificaron siguiendo el esquema propuesto por Nauta y sus colaboradores. Resultados Se identificaron 11 casos, lo que supone un 1,8% de los meningiomas intervenidos en ese periodo. Todos los pacientes eran adultos y 8 de ellos, mujeres. Entre los sintomas, destaco la alta frecuencia de crisis epilepticas, mientras que solo un caso desarrollo hipertension intracraneal aguda. La morfologia predominante fue el tipo 2, seguida de los tipos 1, 3 y 4. En 5 casos pudo establecerse un diagnostico radiologico inequivoco de meningioma. Todos los pacientes fueron tratados mediante cirugia, sin evidenciarse casos de recurrencia durante un seguimiento medio de 52,8 meses. Aunque la mayoria de las neoplasias correspondieron al grado i de la OMS, incluyendo subtipos variados, 4 de ellas fueron diagnosticadas como meningiomas atipicos. Conclusiones De forma excepcional, los meningiomas pueden desarrollar cambios quisticos, intra- o extratumorales, en numero y tamano variable. Estos constituyen hallazgos poco tipicos que pueden dificultar seriamente su diagnostico diferencial radiologico. Los meningiomas con quistes perifericos de capsula fina (tipos 2 y 3) suponen el escenario quirurgico mas complejo, pues el realce capsular en las pruebas de imagen no traduce necesariamente infiltracion tumoral, mientras que el quiste puede contener celulas neoplasicas. Por lo tanto, recomendamos realizar al menos biopsia de la capsula o seudocapsula, y lavado minucioso de la cavidad quirurgica especialmente en estos subtipos.

The present paper reports one of the first studies on the identification of natural resins and balsams in modern era drug formulations. Gas chromatography coupled with mass spectrometry (GC-MS) was applied to investigate the composition of ancient remedies and pharmaceutical formulations coming from the Spezieria di Santa Maria della Scala in Rome, founded at the end of the seventeenth century by the Discalced Carmelites. The obtained results highlight the presence of complex mixtures containing resinaceous and lipidic-based compounds. Thanks to the detection of characteristic markers, it was possible to identify several natural resins, such as guaiacum resin, ladano resin and scammony resin. Balsamic and aromatic compounds characteristic of essential oils were identified as well. In addition, an anti-inflammatory ointment, composed by mixing Venetian turpentine, a Pinaceae resin and a triterpene resin exudate of a plant from South America, was found among the analysed formulations. Combining the analytical results, the historical research and the botanical composition, it was possible to formulate compositional hypotheses of this historical medicine and provided some indications about their use in health. The study of historical drugs is not only important to know the practices handed down by apothecaries in the past, but also fundamental to reconstruct historical recipes that can inspire new dermatological, cosmetic, hygienic and current curative products.

The abuse of alcohol, one of the most popular psychoactive substances, can cause several pathological and psychological consequences, including alcohol use disorder (AUD). An impaired ability to stop or control alcohol intake despite adverse health or social consequences characterize AUD. While AUDs predominantly occur in men, growing evidence suggests the existence of distinct cognitive and biological consequences of alcohol dependence in women. The molecular and physiological mechanisms participating in these differential effects remain unknown. Transcriptomic technology permits the detection of the biological mechanisms responsible for such sex-based differences, which supports the subsequent development of novel personalized therapeutics to treat AUD. We conducted a systematic review and meta-analysis of transcriptomics studies regarding alcohol dependence in humans with representation from both sexes. For each study, we processed and analyzed transcriptomic data to obtain a functional profile of pathways and biological functions and then integrated the resulting data by meta-analysis to characterize any sex-based transcriptomic differences associated with AUD. Global results of the transcriptomic analysis revealed the association of decreased tissue regeneration, embryo malformations, altered intracellular transport, and increased rate of RNA and protein replacement with female AUD patients. Meanwhile, our analysis indicated that increased inflammatory response and blood pressure and a reduction in DNA repair capabilities associated with male AUD patients. In summary, our functional meta-analysis of transcriptomic studies provides evidence for differential biological mechanisms that AUD patients of differing sex.Abstract Figure

OBJECTIVESTo investigate the incidence of COVID-19 in a cohort of adult and paediatric patients with rheumatic diseases receiving targeted biologic and synthetic disease modifying anti-rheumatic drugs (tDMARDs) and to explore the possible effect of these treatments in the clinical expression of COVID-19.METHODSA cross-sectional study comprising of a telephone survey and electronic health records review was performed including all adult and paediatric patients with rheumatic diseases treated with tDMARDs in a large rheumatology tertiary centre in Barcelona, Spain. Demographics, disease activity, COVID-19 related symptoms and contact history data were obtained from the start of the 2020 pandemic. Cumulative incidence of confirmed cases (SARS-CoV-2 positive PCR test) was compared to the population estimates for the same city districts from a governmental COVID-19 health database. Suspected cases were defined following WHO criteria and compared to those without compatible symptoms.RESULTS959 patients with rheumatic diseases treated with tDMARDs were included. We identified 11 confirmed SARS-CoV-2 positive cases in the adult cohort and no confirmed positive cases in the paediatric cohort. All patients had a successful recovery and only one patient required admission in the intensive care unit. When using the same classification criteria (only COVID-19 positive cases with pneumonia), COVID-19 incidence rates of the rheumatic patient cohort were very similar to that of the general population [(0.48% (95% CI 0.09 to 8.65%)] and [0.58% (95% CI 5.62 to 5.99%)], respectively. We found significant differences in tDMARDs proportions between the suspected and non-suspected cases (p=0.002).CONCLUSIONAdult and paediatric patients with rheumatic diseases on tDMARDs do not seem to present a higher risk of COVID-19 or a more severe disease outcome when compared to general population. Our exploratory analysis suggests that the proportion of COVID-19 suspected cases differs between tDMARDs.

Verapamil is a phenylalkylamine class calcium channel blocker that for half a century has been used for the treatment of cardiovascular diseases. Nowadays, verapamil is also considered as a drug option for the treatment of several neurological and psychiatric disorders, such as cluster headache, bipolar disorders, epilepsy, and neurodegenerative diseases. Here, we review insights into the potential preventive and therapeutic role of verapamil on Alzheimer's disease (AD) based on limited experimental and clinical data. Pharmacological studies have shown that verapamil has a wide therapeutic spectrum, including antihypertensive, anti-inflammatory, and antioxidative effects, regulation of the blood-brain barrier function, due to its effect on P-glycoprotein, as well as adjustment of cellular calcium homeostasis, which may result in the delay of AD onset or ameliorate the symptoms of patients. However, the majority of the AD individuals are on polypharmacotherapy, and the interactions between verapamil and other drugs need to be considered. Therefore, for an appropriate and successful AD treatment, a personalized approach is more than necessary. A well-known narrow pharmacological window of verapamil efficacy may hinder this approach. It is therefore important to note that the verapamil efficacy may be conditioned by different factors. The onset, grade, and brain distribution of AD pathological hallmarks, the time-sequential appearances of AD-related cognitive and behavioral dysfunction, the chronobiologic and gender impact on calcium homeostasis and AD pathogenesis may somehow be influencing that success. In the future, such insights will be crucial for testing the validity of verapamil treatment on animal models of AD and clinical approaches.

Evidence obtained in recent decades has demonstrated that the brain still matures in adolescence. Changes in neural connectivity occur in different regions, including cortical and subcortical structures, which undergo modifications in white and gray matter densities. These alterations concomitantly occur in some neurotransmitter systems and hormone secretion, which markedly influence the refinement of certain brain areas and neural circuits. The immaturity of the adolescent brain makes it more vulnerable to the effects of alcohol and drug abuse, whose use can trigger long-term behavioral dysfunction. This article reviews the action of alcohol and drug abuse (cannabis, cocaine, opioids, amphetamines, anabolic androgenic steroids) in the adolescent brain, and their impact on both cognition and behavioral dysfunction, including predisposition to drug abuse in later life. It also discusses recent evidence that indicates the role of the neuroimmune system response and neuroinflammation as mechanisms that participate in many actions of ethanol and drug abuse in adolescence, including the neurotoxicity and alterations in neurocircuitry that contribute to the dysfunctional behaviors associated with addiction. The new data suggest the therapeutic potential of anti-inflammatory targets to prevent the long-term consequences of drug abuse in adolescence.

Introduction Adherence to somatotropin treatment is associated with increased growth velocity and improved adult height. The purpose of this study is to determine the adherence of patients undergoing treatment with an electronic device and its relationship with different variables (age, gender, duration of treatment, diagnosis, height, and growth rate). Material and methods Descriptive, longitudinal and retrospective study of children less than 14 years of age undergoing treatment with somatotropin administered with the Easypod® electronic device in the Paediatric Endocrinology Outpatient Clinic of the General University Hospital of Ciudad Real, Spain. Adherence was monitored for 12 months and was defined according to the equation: (days administered at the prescribed dose/prescribed days) × 100. The data analysis was performed using SPSS software. Results Data were collected from 30 patients, with a predominance of males (57%), a mean age of 6.09 years, with 51% of children less than 5 years old. The most common reasons for the treatment were: small for gestational age (55%) and growth hormone deficiency (38%). The mean duration of treatment was 4.3 years (3.6–5). A mean adherence of 92.3% (87.7–96.9) was observed, and there was a significant correlation with age (Pearson R = −0.384, P = 0.03), and duration of treatment (Pearson R = −0.537; P = 0.003). Conclusions The adherence in our patients with electronic device is high (92.3%), and is inversely associated with age and duration. The use of electronic devices allows monitoring of therapeutic compliance, which affects the optimisation of treatment.

Background Immunotherapy targeting the amyloid-β (Aβ) peptide is a promising strategy for the treatment of Alzheimer’s disease (AD); however, none of the active or passive vaccines tested have been demonstrated to be effective to date. We have developed the first active vaccine against the C-terminal end of Aβ40, ABvac40, and assessed its safety and tolerability in a phase I clinical trial. Methods A randomised, double-blind, placebo-controlled, parallel-group, phase I study of ABvac40 was conducted with patients aged 50–85 years with mild to moderate AD. Participants were entered into three separate groups according to time of study entry and were randomly allocated to receive ABvac40 or placebo (overall ratio 2:1). The first group received two half-doses of ABvac40 or placebo, whereas the second and third groups received two and three full doses, respectively. All treatments were administered subcutaneously at 4-week intervals. Patients, carers and investigators were blind to treatment allocation throughout the study. The primary objective was to assess the safety and tolerability of ABvac40 by registering all adverse events (AEs). All patients who received at least one dose of treatment were included in the safety analysis. The secondary objective was to evaluate the immunogenicity of ABvac40 by titration of specific anti-Aβ40 antibodies in plasma. Results Twenty-four patients were randomly allocated: 16 patients to the ABvac40 group and 8 patients to the placebo group. All randomised patients completed the study, therefore the intention-to-treat and safety populations were identical. Overall, 71 AEs affecting 18 patients were recorded: 11 (69%) in the ABvac40 group and 7 (88%) in the placebo group (p = 0.6214). Neither incident vasogenic oedema nor sulcal effusion (amyloid-related imaging abnormalities corresponding to vasogenic oedema and sulcal effusions) nor microhaemorrhages (amyloid-related imaging abnormalities corresponding to microhaemorrhages and hemosiderin deposits) were detected throughout the study period in the ABvac40-treated patients. Eleven of 12 (~92%) individuals receiving three injections of ABvac40 developed specific anti-Aβ40 antibodies. Conclusions ABvac40 showed a favourable safety and tolerability profile while eliciting a consistent and specific immune response. An ongoing phase II clinical trial is needed to confirm these results and to explore the clinical efficacy of ABvac40. Trial registration ClinicalTrials.gov, NCT03113812. Retrospectively registered on 14 April 2017.

The classic ketogenic diet is a diet high in fat, low in carbohydrates, and well-adjusted proteins. The reduction in glucose levels induces changes in the body’s metabolism, since the main energy source happens to be ketone bodies. Recent studies have suggested that nutritional interventions may modulate drug addiction. The present work aimed to study the potential effects of a classic ketogenic diet in modulating alcohol consumption and its rewarding effects. Two groups of adult male mice were employed in this study, one exposed to a standard diet (SD, n = 15) and the other to a ketogenic diet (KD, n = 16). When a ketotic state was stable for 7 days, animals were exposed to the oral self-administration paradigm to evaluate the reinforcing and motivating effects of ethanol. Rt-PCR analyses were performed evaluating dopamine, adenosine, CB1, and Oprm gene expression. Our results showed that animals in a ketotic state displayed an overall decrease in ethanol consumption without changes in their motivation to drink. Gene expression analyses point to several alterations in the dopamine, adenosine, and cannabinoid systems. Our results suggest that nutritional interventions may be a useful complementary tool in treating alcohol-use disorders.

Microgrids are one of the main drivers in achieving sustainable energy management in the context of smart cities and smart regions. In this way, multiple energy sources are employed and overall system performance is given by adequate information handling in terms of energy consumption requirements as well as user behavior profiles. This paper introduces a framework for wireless mesh communication, monitoring, and distributed energy management for domestic microgrids. A communication scheme based on a combination of sensors which describe energy consumption profiles (i.e., current probes, power consumption level at different loads), environmental factors (temperature, humidity and illumination level) and user behavior profiles (presence sensor detectors) is employed in order to provide an interactive scenario in terms of the management of multiple energy sources. Practical tests have been performed by using an XBee ZigBee network in a meshed configuration connected to an experimental microgrid implemented at the Public University of Navarre (UPNA). The system has been implemented in order to provide cloud-enabled data gathering, sending the required information via web services to a private cloud. These initial results are being scaled with the aim of providing a multi-microgrid communication and control scheme.

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.

Two technology opportunities, integration of renewable energy sources and the electrification of vehicles are being encouraged to reduce dependency on fossil fuels and pollution problems. Nevertheless, the huge increase of plug-in hybrid electric vehicles (PHEVs) on roads will cause an additional load in demand, especially at rush hours, and therefore, threatens the stability of existing power grids. Considering PHEV stay for several hours in the workplace, (i.e., university), this may provide an inimitable framework to charge PHEV from wind in the workplace. This paper introduces the possibility of introducing intelligent control of wind power and battery storage units as supplementary power sources for future PHEV charging demands during rush hours. The operation of the proposed algorithm is based on the priority levels of PHEVs charging, and fluctuations in DC link voltage levels due to the variation in wind speed. The priorities of PHEVs charging are developed according to their power requirements, maximum rating of distribution transformer and park duration of PHEVs in the workplace during wind speed. Various non-isolated proportional&ndash, integral controllers and improved intelligent fuzzy control are used to keep a minimum critical DC link voltage to permit the power conditioning system to operate a charging station uninterruptedly, even at low wind speed. The improved intelligent fuzzy controller also contributes to minimizing the stress on the DC bus and ensures quality output power. The performance of the proposed charging station is verified for the real PHEV under real-world record of wind speed. All the energy sources, electric charging station and their controllers are designed in MATLAB/Simulink. Finally, the feasibility of proposed charging station is checked experimentally in the laboratory.

Alcohol is a neurotoxic compound whose abuse can cause alterations in brain structure and functions, although these effects are more dramatic while the brain develops. The molecular mechanisms of neurotoxic effects of alcohol are complex and remain largely unknown. Current evidence from human and animal studies supports the role of the neuroimmune system in many actions of ethanol on the central nervous system, including neurotoxicity. Different studies have shown that, by activating innate immune receptors TLRs (Toll-like receptors) and (NOD)-like receptors (inflammasome NLRs) in glial cells, alcohol triggers signaling pathways which culminate in the production of pro-inflammatory cytokines and chemokines that lead to neuroinflammation and brain damage, and contribute to alcohol-induced neuropathology and neurobehavioral dysfunctions. In this chapter we review the evidence which demonstrates that the activation of the innate immune system and TLRs participates in not only the neuropathology associated with alcohol abuse in adults and adolescents with binge drinking, but also in the effects of alcohol exposure during fetal development. The potential therapies that target neuroimmune pathways to treat neuropathological and behavioral consequences of alcohol abuse are also discussed.

Heavy binge drinking in adolescence can cause long-term cognitive and behavioral dysfunctions. Recent experimental evidence indicates the participation of immune system activation in the effects of ethanol in the adolescent brain and suggests gender differences. The present study aims to assess plasma cytokine and chemokine levels in male and female adolescents and young adults during acute alcohol intoxication and to correlate these results with the toll-like receptor 4 (TLR4) response. The potential role of the TLR4 signaling response was also assessed in plasma and prefrontal cortex (PFC) of adolescent wild-type and TLR4-knockout male and female mice with binge ethanol treatment. The results showed that alcohol intoxication increased the plasma levels of several cytokine and chemokine [interferon-γ, interleukin (IL)-10, IL-17A, IL-1β, IL-2, IL-4, IL-6, IL-8, fractalkine, monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1α (MIP-1α)] and the upregulation of TLR4 mRNA levels occurred in intoxicated females, while elevation of colony-stimulating factor was only observed in the plasma of males. In wild-type female adolescent mice, intermittent ethanol treatment increased the levels of several cytokines (IL-17A and IL-1β) and chemokines (MCP-1, MIP-1α and fractalkine) in PFC and in serum (IL-17A, MCP-1 and MIP-1α), but significant differences in the fractalkine levels in PFC were observed only in male mice. No changes in serum or prefrontal cortex cytokine and chemokine levels were noted in ethanol-treated male or female TLR4-knockout mice. Our findings revealed that females are more vulnerable than males to inflammatory effects of binge ethanol drinking and suggested that TLR4 is an important target of ethanol-induced inflammation and neuroinflammation in adolescence.

Current studies evidence the role of miRNAs in extracellular vesicles (EVs) as key regulators of pathological processes, including neuroinflammation and neurodegeneration. As EVs can cross the blood&ndash, brain barrier, and EV miRNAs are very stable in peripheral circulation, we evaluated the potential gender differences in inflammatory-regulated miRNAs levels in human and murine plasma EVs derived from alcohol-intoxicated female and male adolescents, and whether these miRNAs could be used as biomarkers of neuroinflammation. We demonstrated that while alcohol intoxication lowers anti-inflammatory miRNA (mir-146a-5p, mir-21-5p, mir-182-5p) levels in plasma EVs from human and mice female adolescents, these EV miRNAs increased in males. In mice brain cortices, ethanol treatment lowers mir-146a-5p and mir-21-5p levels, while triggering a higher expression of inflammatory target genes (Traf6, Stat3, and Camk2a) in adolescent female mice. These results indicate, for the first time, that female and male adolescents differ as regards the ethanol effects associated with the inflammatory-related plasma miRNAs EVs profile, and suggest that female adolescents are more vulnerable than males to the inflammatory effects of binge alcohol drinking. These findings also support the view that circulating miRNAs in EVs could be useful biomarkers for screening ethanol-induced neuroinflammation and brain damage in adolescence.

Teaching methodologies that university faculty use are varied but in Spain, traditionally, the lecture has been the main method used. This is where the teacher has been the focus of teaching and the student is a mere receiver of knowledge, but in other places such as England, other techniques have been introduced to help students actively participate, helping the learning process significantly. This has been a great help for adaptation to the European Higher Education Area with the implementation of the Bologna Process. That is why countries with long traditions of theoretical teaching, as is the case in Spain, have undergone a complex and traumatic process during the adaptation period. In Spain there has been a change of roles by both the faculty as well as the students and that has led to some mistakes when implementing new working tools such as seminars and workshops. The research presented makes a comparison between the faculty teaching in the Primary School Teaching Degrees at two universities; one Spanish and one English, for the Bologna process to check the similarities and differences when working and thereby obtain information needed to improve the process in Spain.

Adolescence is a critical stage of brain maturation in which important plastic and dynamic processes take place in different brain regions, leading to development of the adult brain. Ethanol drinking in adolescence disrupts brain plasticity and causes structural and functional changes in immature brain areas (prefrontal cortex, limbic system) that result in cognitive and behavioral deficits. These changes, along with secretion of sexual and stress-related hormones in adolescence, may impact self-control, decision making, and risk-taking behaviors that contribute to anxiety and initiation of alcohol consumption. New data support the participation of the neuroimmune system in the effects of ethanol on the developing and adult brain. This article reviews the potential pathological bases that underlie the effects of alcohol on the adolescent brain, such as the contribution of genetic background, the perturbation of epigenetic programming, and the influence of the neuroimmune response. Special emphasis is given to the actions of ethanol in the innate immune receptor toll-like receptor 4 (TLR4), since recent studies have demonstrated that by activating the inflammatory TLR4/NFκB signaling response in glial cells, binge drinking of ethanol triggers the release of cytokines/chemokines and free radicals, which exacerbate the immune response that causes neuroinflammation/neural damage as well as short- and long-term neurophysiological, cognitive, and behavioral dysfunction. Finally, potential treatments that target the neuroimmune response to treat the neuropathological and behavioral consequences of adolescent alcohol abuse are discussed.

Resumen Introduccion La aparicion de anomalias congenitas a nivel del atlas es frecuente en pacientes con alteraciones neurales, como en el sindrome de Down. La presencia de estenosis clinica por alteracion en el arco posterior de C1 sin que existiera una subluxacion atlantoaxial previa no ha sido descrita en la literatura hasta el momento. Caso clinico Presentamos un caso excepcional de mielopatia por compresion a nivel del atlas en un nino de 5 anos con sindrome de Down provocado por una anomalia del desarrollo del arco posterior de C1. Se realizo una laminectomia posterior a ese nivel con mejoria de la sintomatologia previa. Conclusiones Se debe prestar especial atencion a los ninos con sindromes asociados a alteraciones de la condrogenesis, como es el caso de los que presentan sindrome de Down, para poder beneficiarse de un tratamiento precoz, ya que en la mayoria de las ocasiones son diagnosticados cuando los sintomas son muy severos.

Santos-García, Diego et al.-- COPPADIS Study Group, [Background] Parkinson's disease (PD) is a progressive neurodegenerative disorder causing motor and non-motor symptoms that can affect independence, social adjustment and the quality of life (QoL) of both patients and caregivers. Studies designed to find diagnostic and/or progression biomarkers of PD are needed. We describe here the study protocol of COPPADIS-2015 (COhort of Patients with PArkinson's DIsease in Spain, 2015), an integral PD project based on four aspects/concepts: 1) PD as a global disease (motor and non-motor symptoms); 2) QoL and caregiver issues; 3) Biomarkers; 4) Disease progression., [Methods/design] Observational, descriptive, non-interventional, 5-year follow-up, national (Spain), multicenter (45 centers from 15 autonomous communities), evaluation study. Specific goals: (1) detailed study (clinical evaluations, serum biomarkers, genetic studies and neuroimaging) of a population of PD patients from different areas of Spain, (2) comparison with a control group and (3) follow-up for 5 years. COPPADIS-2015 has been specifically designed to assess 17 proposed objectives. Study population: approximately 800 non-dementia PD patients, 600 principal caregivers and 400 control subjects. Study evaluations: (1) baseline includes motor assessment (e.g., Unified Parkinson's Disease Rating Scale part III), non-motor symptoms (e.g., Non-Motor Symptoms Scale), cognition (e.g., Parkinson's Disease Cognitive Rating Scale), mood and neuropsychiatric symptoms (e.g., Neuropsychiatric Inventory), disability, QoL (e.g., 39-item Parkinson's disease Quality of Life Questionnaire Summary-Index) and caregiver status (e.g., Zarit Caregiver Burden Inventory); (2) follow-up includes annual (patients) or biannual (caregivers and controls) evaluations. Serum biomarkers (S-100b protein, TNF-α, IL-1, IL-2, IL-6, vitamin B12, methylmalonic acid, homocysteine, uric acid, C-reactive protein, ferritin, iron) and brain MRI (volumetry, tractography and MTAi [Medial Temporal Atrophy Index]), at baseline and at the end of follow-up, and genetic studies (DNA and RNA) at baseline will be performed in a subgroup of subjects (300 PD patients and 100 control subjects). Study periods: (1) recruitment period, from November, 2015 to February, 2017 (basal assessment); (2) follow-up period, 5 years; (3) closing date of clinical follow-up, May, 2022. Funding: Public/Private., [Discussion] COPPADIS-2015 is a challenging initiative. This project will provide important information on the natural history of PD and the value of various biomarkers., Diego Santos-García has received honoraria for educational presentations by Abbvie, UCB Pharma and Lundbeck. Pablo Mir has received honoraria for lecturing or advisory boards from AbbVie, UCB, Zambon, Allergan and Merz, and research grants from the Ministerio de Economía y Competitividad de España [SAF2007-60700], the Instituto de Salud Carlos III [PI10/01674, CP08/00174, PI13/01461], the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [PI-0377/2007, PI-0741/2010, PI-0437-2012], the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation and the Fundación Alicia Koplowitz. Esther Cubo has received travel funding from Abbvie, Allergan and UCB Pharmaceuticals, and received research support from the Movement Disorder Society, World Federation of Neurology and Junta de Castilla y León. Lydia Vela has received honoraria for educational presentations by Abbvie, UCB Pharma and Lundbeck. Maria C Rodriguez-Oroz has received payment for lectures, travel and accommodation to attend scientific meetings from UCB, Lundbeck, Abbvie and Boston Scientific. She has received grants from CIBERNED, Government of Basque Country and Guipuzcoa, Spanish Health Institute and Era-net. Maria J Marti has received speaking fees from Ipsen, Merz, Allergan and UCB Pharma and research grants from Ministery of Health and Social Services, Marató TV3, Centro Investigacion Biomedica en Red and Michael J Fox Foundation for Parkinson’s research. Jose M Arbelo has received honoraria for educational presentations or clinical studies participation by Abbvie, UCB Pharma and Italfarmaco. Jon Infante has received honoraria as a speaker from UCB Pharma and traveling grants from Abbvie. Jaime Kulisevsky has received honoraria for lecturing or advisoring from Abbvie, UCB and Zambon. Pablo Martínez-Martin has received honorarium from Abbvie for a symposium and participation in the Advisory Board for an epidemiological study, Editorial Viguera for a master course, UCB for lecturing in International University Menendez Pelayo summer course.Santos-García

The impact of apathy on health-related quality of life (HRQOL) in recently diagnosed Parkinson's disease (PD) has not been systematically investigated. The objective of this cross-sectional survey (ANIMO study) was to examine the contribution of apathy to HRQOL in a Spanish sample of recently diagnosed PD patients. PD patients, diagnosed within 2 years of inclusion, were recruited at 102 outpatient clinics in 82 communities throughout Spain. Apathy was quantified using the Lille Apathy Rating Scale and HRQOL with the EuroQol-5D questionnaire. A mean EuroQol-5D index score of 0.89 obtained from population references in Spain was used as the cutoff for this study. The relationship between apathy and the dichotomized EuroQol-5D index score (

El embolismo aéreo constituye una situación de emergencia en neurocirugía pediátrica. La posición quirúrgica sedente es un factor de riesgo para su desarrollo. Presentamos el caso de un paciente pediátrico que se intervino para una exéresis de un tumor de fosa posterior en posición sedente. Durante el procedimiento presentó dos episodios de embolia aérea con repercusión hemodinámica; en este artículo describimos su curso y su manejo. El objetivo de este trabajo es por un lado, describir el caso clínico presentado y por otro lado, revisar el manejo anestésico del embolismo aéreo así como el papel de la monitorización no invasiva para su diagnóstico precoz. ABSTRACT Air embolism constitutes an emergency situation in pediatric neurosurgery. The sedentary surgical position is a risk factor for its development. We present the case of a pediatric patient who underwent an exeresis of a posterior fossa tumor in a sitting position. During the procedure, the patient presented two episodes of air embolism with hemodynamic repercussion. In this article we describe its course and its management. The objective of this work is, on the one hand, to describe the clinical case presented and, on the other hand, to review the anesthetic management of air embolism as well as the role of non-invasive monitoring for early diagnosis.

This article provides a definition and description of grief, its characteristics, and the current explanatory models of this phenomenon (the stage model, task model, constructivist model and dual process model). The authors argue that a state of mourning in advance is produced in the process of dementia as a result of significant relational loss before death and describe the risk factors for complicated grief in caregivers: overload, lack of personal and material resources, delegation of care, and complex feelings such as guilt. The need for healthcare organizations to provide professional caregivers with the appropriate means to help with grief and to develop their own measures to prevent burnout is stressed. These measures could include protocols that provide bereavement intervention with the family, the primary caregiver, other patients and/or residents and the professional caregiving team. Finally, losses in persons with dementia must be taken into consideration, avoiding phenomena such as silencing and overprotection and encouraging acceptance and emotional support of their pain so that organic and emotional complications do not occur.

This article represents the proceedings of a symposium presented at the 2004 annual meeting of the International Society for Biomedical Research on Alcoholism, held in Mannheim, Germany. The presentations were as follows: 1) “Antioxidants Prevent Ethanol-Induced Cell Death in Developing Brain and in Cultured Neural Cells” by M. Pascual, M. C. Garcia-Minguillan, and Consuelo Guerri; 2) “Rational Development of Ethanol Antagonists” by Michael E. Charness and Michael F. Wilkemeyer; 3) “Choline Supplementation as a Treatment for Fetal Alcohol Effects” by Jennifer D. Thomas and Hector D. Dominguez; 4) “Cerebellar and Cortical Plasticity After Neonatal Alcohol Exposure: Model of Intervention” by Anna Y. Klintsova, Charles R. Goodlett, and William T. Greenough; and 5) “Circadian Rhythms in Prenatally Ethanol-Exposed Rats” by Hiromi Sakata-Haga.

Considerable evidence has demonstrated that women are more vulnerable than men to the toxic effects of alcohol, although the results as to whether gender differences exist in ethanol-induced brain damage are contradictory. We have reported that ethanol, by activating the neuroimmune system and Toll-like receptors 4 (TLR4), can cause neuroinflammation and brain injury. However, whether there are gender differences in alcohol-induced neuroinflammation and brain injury are currently controversial. Using the brains of TLR4(+/+) and TLR4(-/-) (TLR4-KO) mice, we report that chronic ethanol treatment induces inflammatory mediators (iNOS and COX-2), cytokines (IL-1 beta, TNF-alpha), gliosis processes, caspase-3 activation and neuronal loss in the cerebral cortex of both female and male mice. Conversely, the levels of these parameters tend to be higher in female than in male mice. Using an in vivo imaging technique, our results further evidence that ethanol treatment triggers higher GFAP levels and lower MAP-2 levels in female than in male mice, suggesting a greater effect of ethanol-induced astrogliosis and less MAP-2(+) neurons in female than in male mice. Our results further confirm the pivotal role of TLR4 in alcohol-induced neuroinflammation and brain damage since the elimination of TLR4 protects the brain of males and females against the deleterious effects of ethanol. In short, the present findings demonstrate that, during the same period of ethanol treatment, females are more vulnerable than males to the neurotoxic/neuroinflammatory effects of ethanol, thus supporting the view that women are more susceptible than men to the medical consequences of alcohol abuse. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Until quite recently, the central nervous system (CNS) has been considered an autonomous unit nourished by blood and shielded not only from circulating immune cells but also from pathogens and toxins originating from circulation. However, it is now well established that immune surveillance occurs in the normal CNS and that inflammatory responses can take place in the neural plasticity and disease context. The CNS presents a well-organized series of innate immune reactions in response to systematic bacterial and viral infections and to cerebral injury [1, 2]. Activation of the innate immune system is an important component of inflammatory response.

TLRs (Toll-like receptors) play an important role in the innate immune response, and are also involved in brain injury and neurodegeneration. We have shown that ethanol by activating TLR4 response on glial cells causes the release of cytokines and inflammatory mediators, inducing neuroinflammation and neural damage. We have also shown …

The effect of treatment with thyroxine (T4) on the hepatic deiodinase (5′D-I) activity and triiodothyronine (T3) content and on insulin-like growth factor-I (IGF-I) secretion and mRIMA hepatic expression were studied in neonatal and adult diabetic (D) rats and compared with 4 thyroidectomized (Tx) groups: neonatal and adult Tx rats treated or not with T4. Serum T3 and T4 decreased by 92% in both Tx populations and by 80% to 70% in D adults according to the severity of diabetes: -70 mg/kg body weight (BW) (D70) or 50 mg/kg BW (D50) of streptozotocin (STZ) injected, whereas only a 30% to 33% decrease was found in D neonates. A similar decrease of liver 5′D-I activity and T3 concentrations was found in neonatal and adult Tx rats, whereas a significant reduction in those parameters was observed only in adult diabetics, either D70 or D50, but not in D neonates. Serum levels and liver mRNA expression of IGF-I determined by ribonuclease protection assay, plasma and pituitary growth hormone (GH), plasma insulin, and glycemia were also measured in both D populations. A decrease in circulating IGF-I, previously reported for Tx adult rats, was also found in both D populations. T4 treatment recovered IGF-I and liver T3 in both Tx groups and D neonates, but not in D adults. These results show an age-dependent adaptation of the liver thyroid economy in diabetes, as hepatic 5′D-I does not respond to diabetes in neonates and IGF-I is insensitive to T4 treatment in adult diabetics and suggest a positive correlation between hepatic T3 content and IGF-I expression in conditions of diabetes and Tx. © 2003 Elsevier Inc. All rights reserved.

Nutrional status is an important factor with regard to glucose tolerance and insulin release. Modifications observed in over and undernourished men and experimental animals have been the subject of numerous studies. It is well known that a relatioship exists between obesity and some types of diabetes, in fact, it was the first risk factor for diabetes to be identified. Overnutrition causes glucose intolerance because of a defect in stimulus-secretion coupling in the beta cell and insulin resistance (1).

The neo-T4 syndrome was induced by sc administration of high doses (30 microgram) of L-T4 (T4) during 5 consecutive days in the early postnatal period. Rats were injected starting on the 3rd or 6th day of life. Blood glucose and insulin levels as well as liver glycogen levels were determined between the 5th and 20th days of life. This covers the critical period for brain development (the 7th to 12th day) during which most myelination takes place. Blood glucose and insulin and liver glycogen started to decrease after the second injection of T4 and remained quite low until 2 days after the last injection. Glucose tolerance testing was performed on 8- and 12-day-old neo-T4 rats; treatment was started at 3 days of age. After 70 min of fasting, 200 mg glucose/100 g BW were injected ip. Low plasma insulin levels were found after a glucose load. Plasma ketone bodies were higher in neo-T4 rats than in controls after 4 or 5 days of treatment. The rats appeared to be in a severe catabolic state and were using up their reserves. These alterations in carbohydrate metabolism in suckling rats should be considered when interpreting the brain damage produced by large doses of T4 during the early neonatal period.