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Psychological interventions have been proven to be effective to prevent depression, however, little is known on the cost-effectiveness of psychological interventions for the prevention of depression in various populations. A systematic review was conducted using PubMed, PsycINFO, Web of Science, Embase, Cochrane Central Register of Controlled Trials, Econlit, NHS Economic Evaluations Database, NHS Health Technology Assessment and OpenGrey up to January 2021. Only health-economic evaluations based on randomized controlled trials of psychological interventions to prevent depression were included. Independent evaluators selected studies, extracted data and assessed the quality using the Consensus on Health Economic Criteria and the Cochrane Risk of Bias Tool. Twelve trial-based economic evaluations including 5929 participants from six different countries met the inclusion criteria. Overall, the quality of most economic evaluations was considered good, but some studies have some risk of bias. Setting the willingness-to-pay upper limit to US$40,000 (2018 prices) for gaining one quality adjusted life year (QALY), eight psychological preventive interventions were likely to be cost-effective compared to care as usual. The likelihood of preventive psychological interventions being more cost-effective than care as usual looks promising, but more economic evaluations are needed to bridge the many gaps that remain in the evidence-base. ETHICS: As this systematic review is based on published data, approval from the local ethics committee was not required.

OBJETIVO: Analizar las propuestas sanitarias de las políticas públicas y los planes de salud que abordan la violencia contra las mujeres. MÉTODOS: Estudio descriptivo y comparativo de las políticas y planes de salud en Cataluña y Costa Rica del 2005 al 2011. Se utilizó una metodología cualitativa con análisis documental. Se clasificó por temas comunes y se describieron e interpretaron los contenidos. Se consideraron dimensiones como: principios, estrategias, concepción de violencia contra las mujeres, tendencias en salud y evaluación. RESULTADOS: Se analizaron 13 documentos de políticas públicas de género para abordar la violencia contra las mujeres. La desigualdad de género fue concebida como origen de la violencia contra las mujeres en ambos contextos. Las estrategias comunes fueron el cambio cultural y la acción interinstitucional. Las actuaciones sanitarias se ampliaron en planes específicos y en los protocolos y normas de actuación. La prioridad del tema y la especificidad de las actuaciones en los planes de salud fue un rasgo diferenciador entre Cataluña y Costa Rica. CONCLUSIONES: Entre los rasgos comunes están la inclusión de la violencia hacia las mujeres en los planes de salud, el uso de protocolos, tareas de detección, atención y recuperación para las mujeres y el autocuidado profesional. Cataluña no contempla acciones sanitarias con agresores. Hay menor especificidad en la conceptualización y en pautas protocolarias así como carencia de actualización de normas sanitarias en Costa Rica con respecto a Cataluña OBJECTIVE: To analyze the content of policies and action plans within the public healthcare system that addresses the issue of violence against women. METHODS: A descriptive and comparative study was conducted on the health policies and plans in Catalonia and Costa Rica from 2005 to 2011. It uses a qualitative methodology with documentary analysis. It is classified by topics that describe and interpret the contents. We considered dimensions, such as principles, strategies, concepts concerning violence against women, health trends, and evaluations. RESULTS: Thirteen public policy documents were analyzed. In both countries' contexts, we have provided an overview of violence against women as a problem whose roots are in gender inequality. The strategies of gender policies that address violence against women are cultural exchange and institutional action within the public healthcare system. The actions of the healthcare sector are expanded into specific plans. The priorities and specificity of actions in healthcare plans were the distinguishing features between the two countries. CONCLUSIONS: The common features of the healthcare plans in both the counties include violence against women, use of protocols, detection tasks, care and recovery for women, and professional self-care. Catalonia does not consider healthcare actions with aggressors. Costa Rica has a lower specificity in conceptualization and protocol patterns, as well as a lack of updates concerning health standards in Catalonia

BackgroundIn the predictD-intervention, GPs used a personalised biopsychosocial programme to prevent depression. This reduced the incidence of major depression by 21.0%, although the results were not statistically significant.AimTo determine whether the predictD-intervention is effective at preventing anxiety in primary care patients without depression or anxiety.Design and settingSecondary study of a cluster randomised trial with practices randomly assigned to either the predictD-intervention or usual care. This study was conducted in seven Spanish cities from October 2010 to July 2012.MethodIn each city, 10 practices and two GPs per practice, as well as four to six patients every recruiting day, were randomly selected until there were 26–27 eligible patients for each GP. The endpoint was cumulative incidence of anxiety as measured by the PRIME-MD screening tool over 18 months.ResultsA total of 3326 patients without depression and 140 GPs from 70 practices consented and were eligible to participate; 328 of these patients were removed because they had an anxiety syndrome at baseline. Of the 2998 valid patients, 2597 (86.6%) were evaluated at the end of the study. At 18 months, 10.4% (95% CI = 8.7% to 12.1%) of the patients in the predictD-intervention group developed anxiety compared with 13.1% (95% CI = 11.4% to 14.8%) in the usual-care group (absolute difference = −2.7% [95% CI = −5.1% to −0.3%]; P = 0.029).ConclusionA personalised intervention delivered by GPs for the prevention of depression provided a modest but statistically significant reduction in the incidence of anxiety.

Introduction: Long QT syndrome is the main arrhythmogenic disease responsible for sudden death in infants, especially in the first days of life. Performing an electrocardiogram in newborns could enable early diagnosis and adoption of therapeutic measures focused on preventing lethal arrhythmogenic events. However, the inclusion of an electrocardiogram in neonatal screening protocols still remains a matter of discussion. To comprehensively analyse the potential clinical value of performing an electrocardiogram and subsequent follow-up in a cohort of newborns. Methods: Electrocardiograms were performed in 685 neonates within the first week of life. One year follow-up was performed if QTc > 450 ms identified. Comprehensive genetic analysis using massive sequencing was performed in all cases with QTc > 470 ms. Results: We identified 54 neonates with QTc > 450 ms/ 480 ms at birth and, if persistent, pharmacological treatment was administrated during follow-up. A rare variant was identified as the potential cause of long QT syndrome in five cases. Three cases showed a family history of sudden arrhythmogenic death. Conclusions: Our prospective study identifies 0.14% of cases with a definite long QT, supporting implementation of electrocardiograms in routine pediatric protocols. It is an effective, simple and non-invasive approach that can help prevent sudden death in neonates and their relatives. Genetic analyses help to unravel the cause of arrhythmogenic disease in diagnosing neonates. Further, clinical assessment and genetic analysis of relatives allowed early identification of family members at risk of arrhythmias helping to adopt preventive personalized measures This work was supported by Fundació La Marato TV3 (358/U/2015), Sociedad Española Cardiología (Proyecto FEC para investigación clínica en Cardiología 2018), Obra Social La Caixa Foundation (LCF/PR/GN16/50290001 and LCF/PR/GN19/50320002), Fondo de Investigación Sanitaria (FIS, PI17/01690) from Instituto de Salud Carlos III (ISCIII) -Cofunded by European Regional Development Fund/European Social Fund A way to make Europe/Investing in your future, and Fundació Privada Daniel Bravo Andreu. CIBERCV is an initiative of the ISCIII, Spanish Ministry of Economy and Competitiveness. Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report

Background Housing is a social determinant of health. Extensive research has highlighted its adverse effects on health. However, less is known about the effects of cohousing typology on health, which has the potential to create lively social networks and healthy communities and environments. We report the findings of a scoping study designed to gather and synthesise all known evidence on the relationship between cohousing and wellbeing and health. Method Using the scoping review method, we conducted a literature review in PubMed, ProQuest, Scopus, Web of Science, Science Direct and JSTOR in May 2019 and selected articles published from 1960 onwards, with no geographical limit and no design restrictions. Retrieved articles underwent three sequential screening phases. The results were described through a narrative synthesis of the evidence. Results Of the 2560 articles identified, we selected 25 full-text articles analysing 77 experiences. All of them were conducted in high-income countries. Ten studies analysed the impact of cohousing on physical and mental health or quality of life and wellbeing. Eight of the 10 studies found a positive association. In addition, 22 studies analysed one or more psychosocial determinants of health (such as social support, sense of community and physical, emotional and economic security) and most found a positive association. Through these determinants, quality of life, wellbeing and health could be improved. However, the quality of the evidence was low. Discussion The cohousing model could enhance health and wellbeing mediated by psychosocial determinants of health. However, extreme caution should be exercised in drawing any conclusions due to the dearth of data identified and the designs used in the included studies, with most being cross-sectional or qualitative studies, which precluded causal-based interpretations. Because housing is a major social determinant of health, more evidence is needed on the impact of this model on health through both psychosocial and material pathways.

IntroductionLynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability (MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues.Materials and methodsBlood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers.ResultsThe hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (pMSH2 carriers (n=5) compared with MSH6 carriers (n=15). The hs-MSI analysis did not detect a difference between LS and control blood samples (p=0.564).ConclusionsThe hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations.

Normal procalcitonin (PCT) levels have been reported in adult pulmonary tuberculosis (TB) but have not been previously investigated in children. We aimed to assess PCT levels at diagnosis of TB in young children in a low-burden setting. In a cross-sectional observational study in a referral pediatric center in Barcelona (Spain), we assessed the value of PCT and other inflammatory markers (leucocyte counts, C-reactive protein, and erythrocyte sedimentation rate) in the diagnosis of TB in pre-school children ( 6 years at diagnosis, n = 45), as compared with two control groups (pneumococcal pneumonia, n = 25; and healthy controls, n = 49). Normal PCT levels were observed at diagnosis of TB in most cases, while C-reactive protein values and leucocyte counts were slightly elevated when compared to healthy controls. All three inflammatory biomarkers were significantly higher in children with pneumococcal pneumonia.In our study, PCT was not a useful diagnostic test for TB in young children. In a low-burden TB setting, PCT may be of some value in distinguishing pulmonary TB from pneumococcal pneumonia. What is Known: • Diagnosis of pediatric tuberculosis on clinical evidence is difficult, particularly in infants and small children. • Studies in adults with tuberculosis have mostly reported normal procalcitonin levels at diagnosis. What is New: • In pre-scholars with tuberculosis, erythrocyte sedimentation rate and white blood cell counts were higher than in healthy controls, but procalcitonin was not. • Procalcitonin may be useful in the differential diagnosis of intrathoracic tuberculosis and pneumococcal pneumonia.

Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature of NPC disease is the intracellular accumulation of cholesterol and gangliosides, predominantly in endolysosomes, mitochondrial cholesterol accumulation has also been reported. As accumulation of cholesterol in mitochondria is known to impair the transport of GSH into mitochondria, resulting in mitochondrial GSH (mGSH) depletion, we investigated the impact of mGSH recovery in NPC disease. We show that GSH ethyl ester (GSH-EE), but not N-acetylcysteine (NAC), restored the mGSH pool in liver and brain of Npc1-/- mice and in fibroblasts from NPC patients, while both GSH-EE and NAC increased total GSH levels. GSH-EE but not NAC increased the median survival and maximal life span of Npc1-/- mice. Moreover, intraperitoneal therapy with GSH-EE protected against oxidative stress and oxidant-induced cell death, restored calbindin levels in cerebellar Purkinje cells and reversed locomotor impairment in Npc1-/- mice. High-resolution respirometry analyses revealed that GSH-EE improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1-/- mice. Lipidomic analyses showed that GSH-EE treatment had not effect in the profile of most sphingolipids in liver and brain, except for some particular species in brain of Npc1-/- mice. These findings indicate that the specific replenishment of mGSH may be a potential promising therapy for NPC disease, worth exploring alone or in combination with other options., Graphical abstract fx1, Highlights • GSH-EE but not NAC restores mitochondrial GSH stores and protects against oxidative stress in NPC disease. • GSH-EE treatment improves motor coordination and extends survival in Npc1-/- mice. • GSH-EE therapy rescues cerebellar mitochondrial dysfunction in Npc1-/- mice. • GSH-EE treatment attenuates the liver phenotype in Npc1-/- mice.

Background Depression is viewed as a major and increasing public health issue, as it causes high distress in the people experiencing it and considerable financial costs to society. Efforts are being made to reduce this burden by preventing depression. A critical component of this strategy is the ability to assess the individual level and profile of risk for the development of major depression. This paper presents the cost-effectiveness of a personalized intervention based on the risk of developing depression carried out in primary care, compared with usual care. Methods Cost-effectiveness analyses are nested within a multicentre, clustered, randomized controlled trial of a personalized intervention to prevent depression. The study was carried out in 70 primary care centres from seven cities in Spain. Two general practitioners (GPs) were randomly sampled from those prepared to participate in each centre (i.e. 140 GPs), and 3326 participants consented and were eligible to participate. The intervention included the GP communicating to the patient his/her individual risk for depression and personal risk factors and the construction by both GPs and patients of a psychosocial programme tailored to prevent depression. In addition, GPs carried out measures to activate and empower the patients, who also received a leaflet about preventing depression. GPs were trained in a 10- to 15-h workshop. Costs were measured from a societal and National Health care perspective. Qualityadjustedlife years were assessed using the EuroQOL five dimensions questionnaire. The time horizon was 18 months. Results With a willingness-to-pay threshold of €10,000 (£8568) the probability of cost-effectiveness oscillated from 83% (societal perspective) to 89% (health perspective). If the threshold was increased to €30,000 (£25,704), the probability of being considered cost-effective was 94% (societal perspective) and 96%, respectively (health perspective). The sensitivity analysis confirmed these results. Conclusions Compared with usual care, an intervention based on personal predictors of risk of depression implemented by GPs is a cost-effective strategy to prevent depression. This type of personalized intervention in primary care should be further developed and evaluated. Trial registration ClinicalTrials.gov, NCT01151982. Registered on June 29, 2010

Scope Flavonoids and related compounds seem to have favorable effects on nonalcoholic fatty liver disease (NAFLD) progression, although the exact mechanisms implicated are poorly understood. In this study, we aimed to investigate the effect of the flanovol quercetin on gene expression deregulation involved in the development of NAFLD, as well as the possible implication of phosphatidylinositol 3-kinase (PI3K)/AKT pathway modulation. Methods and results We used an in vivo model based on methionine- and choline-deficient (MCD) diet-fed mice and an in vitro model consisting of Huh7 cells incubated with MCD medium. MCD-fed mice showed classical pathophysiological characteristics of nonalcoholic steatohepatitis, associated with altered transcriptional regulation of fatty acid uptake- and trafficking-related gene expression, with increased lipoperoxidation. PI3K/AKT pathway was activated by MCD and triggered gene deregulation causing either activation or inhibition of all studied genes as demonstrated through cell incubation with the PI3K-inhibitor LY294002. Treatment with quercetin reduced AKT phosphorylation, and oxidative/nitrosative stress, inflammation and lipid metabolism-related genes displayed a tendency to normalize in both in vivo and in vitro models. Conclusion These results place quercetin as a potential therapeutic strategy for preventing NAFLD progression by attenuating gene expression deregulation, at least in part through PI3K/AKT pathway inactivation.

[This corrects the article DOI: 10.1371/journal.pone.0167358.].

BackgroundThe predictD intervention, a multicomponent intervention delivered by family physicians (FPs), reduced the incidence of major depression by 21% versus the control group and was cost-effective. A qualitative methodology was proposed to identify the mechanisms of action of these complex interventions.PurposeTo seek the opinions of these FPs on the potential successful components of the predictD intervention for the primary prevention of depression in primary care and to identify areas for improvement.MethodQualitative study with FPs who delivered the predictD intervention at 35 urban primary care centres in seven Spanish cities. Face-to-face semi-structured interviews adopting a phenomenological approach. The data was triangulated by three investigators using thematic analysis and respondent validation was carried out.ResultsSixty-seven FPs were interviewed and they indicated strategies used to perform the predictD intervention, including specific communication skills such as empathy and the activation of patient resources. They perceived barriers such as lack of time and facilitators such as prior acquaintance with patients. FPs recognized the positive consequences of the intervention for FPs, patients and the doctor-patient relationship. They also identified strategies for future versions and implementations of the predictD intervention.ConclusionsThe FPs who carried out the predictD intervention identified factors potentially associated with successful prevention using this program and others that could be improved. Their opinions about the predictD intervention will enable development of a more effective and acceptable version and its implementation in different primary health care settings.

PMCID: PMC3779525.-- et al., [Background & Aims]: The pathogenesis of alcohol-induced liver disease (ALD) is poorly understood. Here, we examined the role of acid sphingomyelinase (ASMase) in alcohol induced hepatic endoplasmic reticulum (ER) stress, a key mechanism of ALD. [Methods]: We examined ER stress, lipogenesis, hyperhomocysteinemia, mitochondrial cholesterol (mChol) trafficking and susceptibility to LPS and concanavalin-A in ASMase-/- mice fed alcohol. [Results]: Alcohol feeding increased SREBP-1c, DGAT-2, and FAS mRNA in ASMase+/+ but not in ASMase-/- mice. Compared to ASMase+/+ mice, ASMase-/- mice exhibited decreased expression of ER stress markers induced by alcohol, but the level of tunicamycin-mediated upregulation of ER stress markers and steatosis was similar in both types of mice. The increase in homocysteine levels induced by alcohol feeding was comparable in both ASMase+/+ and ASMase-/- mice. Exogenous ASMase, but not neutral SMase, induced ER stress by perturbing ER Ca2+ homeostasis. Moreover, alcohol-induced mChol loading and StARD1 overexpression were blunted in ASMase-/- mice. Tunicamycin upregulated StARD1 expression and this outcome was abrogated by tauroursodeoxycholic acid. Alcohol-induced liver injury and sensitization to LPS and concanavalin-A were prevented in ASMase-/- mice. These effects were reproduced in alcohol-fed TNFR1/R2-/- mice. Moreover, ASMase does not impair hepatic regeneration following partial hepatectomy. Of relevance, liver samples from patients with alcoholic hepatitis exhibited increased expression of ASMase, StARD1, and ER stress markers. [Conclusions]: Our data indicate that ASMase is critical for alcohol-induced ER stress, and provide a rationale for further clinical investigation in ALD. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved., The work was supported by CIBEREHD, Fundació la Marató de TV3, la Mutua Madrileña, and grants PI10/02114, PI09/0056 and PI09/1164 (Instituto de Salud Carlos III), SAF2008-02199, SAF2009-11417, SAF2010-15760, SAF2011-23031, SAF2012-34831, and BFU2010-18826 (Plan Nacional de I+D), Spain; and P50-AA-11999 (Research Center for Liver and Pancreatic Diseases, NIAAA/NIH).

BACKGROUND: Not enough is known about universal prevention of depression in adults. OBJECTIVE: To evaluate the effectiveness of an intervention to prevent major depression. DESIGN: Multicenter, cluster randomized trial with sites randomly assigned to usual care or an intervention. (ClinicalTrials.gov: NCT01151982) SETTING: 10 primary care centers in each of 7 cities in Spain. PARTICIPANTS: Two primary care physicians (PCPs) and 5236 nondepressed adult patients were randomly sampled from each center; 3326 patients consented and were eligible to participate. INTERVENTION: For each patient, PCPs communicated individual risk for depression and personal predictors of risk and developed a psychosocial program tailored to prevent depression. MEASUREMENTS: New cases of major depression, assessed every 6 months for 18 months. RESULTS: At 18 months, 7.39% of patients in the intervention group (95% CI, 5.85% to 8.95%) developed major depression compared with 9.40% in the control (usual care) group (CI, 7.89% to 10.92%) (absolute difference, −2.01 percentage points [CI, −4.18 to 0.16 percentage points]; P = 0.070). Depression incidence was lower in the intervention centers in 5 cities and similar between intervention and control centers in 2 cities. LIMITATION: Potential self-selection bias due to nonconsenting patients. CONCLUSION: Compared with usual care, an intervention based on personal predictors of risk for depression implemented by PCPs provided a modest but nonsignificant reduction in the incidence of major depression. Additional study of this approach may be warranted. PRIMARY FUNDING SOURCE: Institute of Health Carlos III

Background Sudden unexplained death may be the first manifestation of an unknown inherited cardiac disease. Current genetic technologies may enable the unraveling of an etiology and the identification of relatives at risk. The aim of our study was to define the etiology of natural deaths, younger than 50 years of age, and to investigate whether genetic defects associated with cardiac diseases could provide a potential etiology for the unexplained cases. Methods and Findings Our cohort included a total of 789 consecutive cases (77.19% males)

The use of services for mental problems is generally reported as being relatively low. However, the methods used for data collection in surveys may have influenced the quality of self-reported service use. This study compares the information on recourse to physicians for mental problems reported in different sections of a survey conducted in six European countries. Thus, 5545 respondents were asked questions on contacts with physicians at least twice: (1) after the symptoms checklist in any completed diagnostic section, and (2) in a section devoted to use of care for mental problems. Of these 39.3% reported contacts with physicians about mental problems in the diagnostic sections, whereas 29.5% did so in the use-of-care section. Inconsistencies concerned 20.1% of participants, among whom those reporting consultations in diagnostic sections without reporting them in the use-of-care section represented the majority (74.4%). Multiple logistic regression analysis revealed that age, marital status, educational level and country were associated with under-reporting in the use-of-care section, as well as having mood or sleep problems. In conclusion, services used for mental health reasons when measured through a question referring to use of care due to the presence of a mental problem may underestimate the care people received for their problems.

Objective To estimate the cost of depression for the adult population in Catalonia (Spain) for 2006. Method The total adult population of Catalonia for the reference year was close to 6 million. A cross-design synthesis study was conducted, combining “top-down” and “bottom-up” data from secondary data sources, as well as expert opinion (nominal groups). A societal perspective was adopted. Estimates included direct health costs (hospital, primary, specialised and pharmacological care) and the indirect costs derived from the productivity lost due to morbidity and mortality. Sensitivity analyses were carried out for primary and specialised care resource utilisation. A Monte Carlo simulation model was developed to handle the uncertainty of the unit costs of primary care, specialised care and hospital visits. Results The total annual cost of depression in Catalonia for 2006 was 735.4 million Euros. Of this figure, 21.2% corresponded to direct costs, including 41 million Euros in primary care (5.6%), 8.1 million Euros in mental health specialised care (1.1%), 5.6 million Euros due to hospitalisation (0.8%) and 101.1 million Euros due to pharmacological care (13.7%); and 78.8% to indirect costs due to productivity loss. 3.7 million work days were lost to temporary disability for depression with a cost of 199.6 million Euros (27.1%), and 353.3 million Euros due to permanent disability (48%). Mortality attributed to suicide accounted for 26.9 million Euros (3.7%). The average annual cost of an adult with depression was close to 1800 Euros. Limitations The heterogeneity of the data sources, the uncertainty in several estimates (i.e. proportion of psychotropic expenditure attributed to the treatment of depression, suicide rate attributed to depression), and the difficulty in disaggregating anxiety and depressive disorders in a number of databases are study limitations. Conclusions The burden of depression for the Catalan public health system and society as a whole due to the consumption of resources and, more importantly, the loss of productivity is significant. Inefficiencies may be found in the overuse of pharmaceuticals and in the eligibility criteria of disability for work.

Recent studies conducted in the United States and in Europe have indicated that demand for care for common mental disorders has increased considerably in the last decades,1,2 although their prevalence has remained relatively stable.1–4 One of the reasons for this growing demand may be changes in public attitudes.5 Seeking help for nonpsychotic symptoms has become more acceptable and perceived stigma has declined. Recourse to health professionals for psychological problems, especially to mental health specialists, and its determinants are well documented in the literature. In particular, several studies have indicated that people who turn to mental health specialists for their problems are relatively young, with a higher educational level than those followed in general practice.6,7 However, other care providers, who are not in the conventional health care sector, may also be involved in the treatment of psychological problems, but little is known about them, and particularly about how their care articulates with more traditional medical follow-up. Recent national epidemiologic surveys have shown the particular importance of nonhealth professionals in the management of mental health problems in certain countries, notably the United States, where the proportion of the population seeking help from this sector is one of the highest in the world.8 The National Comorbidity Survey Replication revealed that 2.8% of Americans had turned at least once in the previous year to CAM providers, such as chiropractors and herbalists, and 3.4% turning to human services (that is, clergy and social workers or counsellors practising outside the specialty mental health sector) for problems with their emotions or nerves or their use of alcohol or drugs.7,8 Among the Americans surveyed who suffered from a mental condition, the proportion of users ranged from 4.5% to 6.8% for CAM, and was around 8.1% for human services.7,9 In addition, certain studies have indicated that the use of such providers may vary depending on the type of mental problem, notably with higher consultation rates for mood disorders.7,10 For Europe, the ESEMeD, which is part of the WHO WMH Survey Initiative, provides the opportunity to study recourse to this sector in 6 European countries and to compare extent of use with the United States, the definitions used for the 2 categories of nonhealth professionals being, however, slightly different. Although some information on prevalence rates has been published previously,8 no in-depth study has been performed. The specific aims of the present study were 3-fold: first, to assess the frequency of use of these professionals in the management of mental problems; second, to identify the personal, health-related, and social factors associated with the use of such care, and finally to determine if such services were complements to, or substitutes for, more traditional follow-up, in particular for people with a diagnosis of mental illness who are the most in need.

The pathogenesis and treatment of nonalcoholic steatohepatitis (NASH) are not well established. Feeding a diet deficient in both methionine and choline (MCD) is one of the most common models of NASH, which is characterized by steatosis, mitochondrial dysfunction, hepatocellular injury, oxidative stress, inflammation, and fibrosis. However, the individual contribution of the lack of methionine and choline in liver steatosis, advanced pathology and impact on mitochondrial S-adenosyl-l-methionine (SAM) and glutathione (GSH), known regulators of disease progression, has not been specifically addressed. Here, we examined the regulation of mitochondrial SAM and GSH and signs of disease in mice fed a MCD, methionine-deficient (MD), or choline-deficient (CD) diet. The MD diet reproduced most of the deleterious effects of MCD feeding, including weight loss, hepatocellular injury, oxidative stress, inflammation, and fibrosis, whereas CD feeding was mainly responsible for steatosis, characterized by triglycerides and free fatty acids accumulation. These findings were preceded by MCD- or MD-mediated SAM and GSH depletion in mitochondria due to decreased mitochondrial membrane fluidity associated with a lower phosphatidylcholine/phosphatidylethanolamine ratio. MCD and MD but not CD feeding resulted in increased ceramide levels by acid sphingomyelinase. Moreover, GSH ethyl ester or SAM therapy restored mitochondrial GSH and ameliorated hepatocellular injury in mice fed a MCD or MD diet. Thus, the depletion of SAM and GSH in mitochondria is an early event in the MCD model of NASH, which is determined by the lack of methionine. Moreover, therapy using permeable GSH prodrugs may be of relevance in NASH.

Objectives The aim of this study was to (1) to explore the validity of the depression diagnosis made by the general practitioner (GP) and factors associated with it, (2) to estimate rates of treatment adequacy for depression and factors associated with it and (3) to study how rates of treatment adequacy vary when using different assessment methods and criteria. Methods Epidemiological survey carried out in 77 primary care centres representative of Catalonia. A total of 3815 patients were assessed. Results GPs identified 69 out of the 339 individuals who were diagnosed with a major depressive episode according to the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) (sensitivity 0.22; kappa value: 0.16). The presence of emotional problems as the patients' primary complaint was associated with an increased probability of recognition. Rates of adequacy differed according to criteria: in the cases detected with the SCID-I interview, adequacy was 39.35% when using only patient self-reported data and 54.91% when taking into account data from the clinical chart. Rates of adequacy were higher when assessing adequacy among those considered depressed by the GP. Conclusion GPs adequately treat most of those whom they consider to be depressed. However, they fail to recognise depressed patients when compared to a psychiatric gold standard. Rates of treatment adequacy varied widely depending on the method used to assess them.

Dropping out from mental health treatment is a major problem because mental health treatments delivered for inadequate durations are ineffective. The aim of this study was to compare treatment dropout rates by type of provider, dropout risk by number of visit, and to ascertain factors associated with treatment dropout. A cross-sectional household survey of a representative sample of 626 out of 21,425 non-institutionalized adults from the general population of six European countries was carried out. Dropout was defined as terminating treatment before recommendation. Dropout from all treating providers during a 12-month period was 14%. Among psychiatrists, psychologists, and general practitioners figures were: 19.6, 20.3, and 20.3%, respectively. While the hazard risk for dropping out was higher during the first three visits to GPs and psychologists, it was stable for psychiatrists. Older age, female gender, and living in large or midsize urban areas were associated with a decreased risk of dropping out. Efforts for increasing patients’ proportion completing adequate courses of care for mental disorders in Europe should focus on the first visits, especially those made to the general medical care.

[Background/Aims]: Non-alcoholic fatty liver disease (NAFLD) pathogenesis remains unknown. Due to the emerging role of free cholesterol (FC) in NAFLD, our aim was to examine the correlation between FC accumulation in patients with NAFLD and the expression of enzymes that regulate cholesterol homeostasis., [Methods]: Filipin staining, indicative of FC accumulation, and real-time PCR analyses were performed in 31 NAFLD patients and in seven controls., [Results]: All NASH patients (n = 14) and 4 out of 17 patients with steatosis exhibited filipin staining compared to controls (0 out of 7 subjects with normal liver histology and BMI). Sterol regulatory element-binding protein-2 (SREBP-2) mRNA levels were 7- and 3-fold higher in NASH and steatosis patients, respectively, compared to controls. Since hydroxymethylglutaryl-CoA (HMG-CoA) reductase is the key enzyme in cholesterol synthesis and transcriptionally controlled by SREBP-2 we measured its mRNA levels, being 3- to 4-fold higher in NAFLD compared to controls, without any difference between NASH and steatosis patients. Fatty acid synthase (FAS) and SREBP-1c expression were not significantly induced in NAFLD, while ATP-binding cassette sub-family G member 1 (ABCG1), a transporter involved in cholesterol egress, and acyl-CoA-cholesterol acyltransferase mRNA levels were modestly increased (1.5- to 2.5-fold, p < 0.05), regardless of fibrosis. Interestingly, mRNA levels of steroidogenic acute regulatory protein (StAR), a mitochondrial-cholesterol transporting polypeptide, increased 7- and 15-fold in steatosis and NASH patients, respectively, compared to controls., [Conclusions]: FC increases in NASH and correlates with SREBP-2 induction. Moreover, StAR overexpression in NASH suggests that mitochondrial FC may be a player in disease progression and a novel target for intervention., This work was supported in part by the Research Center for Liver and Pancreatic Diseases Grant P50 AA 11999 from the US National Institute of Alcohol Abuse and Alcoholism (NIAAA), Plan Nacional de I + D Grants: SAF2005-03923, SAF2006-06780 and SAF2008-02199, and by the Spanish Fondo de Investigacion Sanitaria FIS: PI060085 and by the Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD) supported by the Instituto de Salud Carlos III.

Introduction and objectives Currently in Spain, 4 depot antipsychotics are available: flufenazine, pipotiazine, zuclopentixol and risperidone. The objectives of the present study are: a) to evaluate the efficacy of depot vs. oral forms of typical and atypical antipsychotics available in Spain for treating patients with schizophrenia; b) to compare the efficacy of different depot antipsychotics; c) to evaluate cost-effectiveness of typical and atypical depot and oral antipsychotics. Methods Systematic review of the literature between January 1980 and March 2007. Pharmaceutical companies of depot preparations were contacted aiming to include unpublished material. Results A total of 15 studies were included (13 journal manuscripts and 2 posters provided by the industry). Concordance between evaluators was moderate-high. The quality of selected studies was moderate-low. There were no differences in the efficacy between depot and oral risperidone. Efficacy of depot risperidone was higher than oral olanzapine (there were no differences regarding tolerability) and higher and better tolerated than oral zuclopentixol. The evidence was controversial when comparing the effi cacy of depot and oral flufenazine. There were no differences when comparing the efficacy between depot flufenazine and oral pimozide. Depot zuclopentixol was more effi cient than the oral preparation for treating patients with schizophrenia and violent behaviour. Finally, there were no differences regarding the effi cacy and tolerability between depot pipotiazine and depot flufenazine and between depot clopentixol and depot flufenazine. Conclusions There is few high-quality scientific evidence comparing depot and oral antipsychotics or different depot antipsychotics available in Spain. Selected evidence does not allow to conclude that depot antipsychotics are more effective and better tolerated than oral ones.

© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Autophagy is a process that maintains homeostasis during stress, although it also contributes to cell death under specific contexts. Ceramides have emerged as important effectors in the regulation of autophagy, mediating the crosstalk with apoptosis. Melatonin induces apoptosis of cancer cells; however, its role in autophagy and ceramide metabolism has yet to be clearly elucidated. This study was aimed to evaluate the effect of melatonin administration on autophagy and ceramide metabolism and its possible link with melatonin-induced apoptotic cell death in hepatocarcinoma (HCC) cells. Melatonin (2 mm) transiently induced autophagy in HepG2 cells through JNK phosphorylation, characterized by increased Beclin-1 expression, p62 degradation, and LC3II and LAMP-2 colocalization, which translated in decreased cell viability. Moreover, ATG5 silencing sensitized HepG2 cells to melatonin-induced apoptosis, suggesting a dual role of autophagy in cell death. Melatonin enhanced ceramide levels through both de novo synthesis and acid sphingomyelinase (ASMase) stimulation. Serine palmitoyltransferase (SPT) inhibition with myriocin prevented melatonin-induced autophagy and ASMase inhibition with imipramine-impaired autophagy flux. However, ASMase inhibition partially protected HepG2 cells against melatonin, while SPT inhibition significantly enhanced cell death. Findings suggest a crosstalk between SPT-mediated ceramide generation and autophagy in protecting against melatonin, while specific ASMase-induced ceramide production participates in melatonin-mediated cell death. Thus, dual blocking of SPT and autophagy emerges as a potential strategy to potentiate the apoptotic effects of melatonin in liver cancer cells., Raquel Ordoñez and Néstor Prieto-Domínguez are supported by the program ‘Formación del Profesorado Universitario’ (Becas FPU, references FPU12/01433 and FPU13/04173, respectively) from the Ministry of Education (Spain). CIBERehd is funded by Instituto de la Salud Carlos III, Spain. This work was supported in part by grants BFU2013-48141-R from Plan Nacional de I+D+I Spain, LE135U13 from Consejería de Educación de la Junta de Castilla y León, and SAF-2011-23031 and SAF-2012-34831 from Plan Nacional de I+D Spain; Fundació Marató de TV3, La Mutua Madrileña, and PI11/0325 (META) grant from the Instituto Salud Carlos III; and by the center grant P50-AA-11999 from Research Center for Liver and Pancreatic Diseases funded by NIAAA/NIH

Death from myocarditis requires the presence of myocardial inflammation, without any other structural heart disease, and is frequently associated with a viral infection [(1)][1]. We postulate that genetic defects in structural proteins cause the myocardium to become vulnerable and predisposed to

Background: Literature suggests that a high proportion of the population with mental disorders remains either untreated or poorly treated. This study aimed to describe the adequacy of treatment for Anxiety and Depressive disorders in Spain, how this differs between providers (primary versus specialised care) and which factors are associated with appropriate care. Method: Data were derived from the Spanish sample (N=5473) of the European Study of the Epidemiology of Mental Disorders (ESEMeD), a cross sectional study in a representative sample of adults. The subsample analyzed was composed by the 133 subjects with a mental disorder in the year prior to the interview who received treatment. Treatment adequacy was evaluated in two different ways: (1) considering definitions of minimally adequate treatment evidence based guidelines and criteria used in other epidemiological studies; (2) considering experts rating of treatment appropriateness based on the information contained in the case vignettes created from the CIDI answers. Generalised Estimating Equation (GEE) models and simple logistic regression were conducted to assess the correlates of adequate treatment. Results: Similar proportions of patients in specialty and general medical treatment received a minimally adequate treatment (31.8% and 30.5%, respectively). Associated factors to appropriateness were living in a large city, having a high educational level, and having a good self rated health state. Limitations: Treatment adequacy was based on simple information and criteria. Conclusions: Only one third of the mental health treatment in Spain met minimal adequacy criteria. More research is needed in order to find out reasons for these low rates.

Background We aimed to assess available evidence on risk factors associated with the onset of panic disorder (PD) and/or generalised anxiety disorder (GAD) in cohort studies in the general adult population. Methods Systematic review using MEDLINE, PsycINFO and Embase. Search terms included panic disorder, generalised anxiety disorder, cohort studies and risk factors. Results We finally selected 21 studies, involving 163,366 persons with a median follow-up of 5 years. 1) Sociodemographic factors: PD was associated with age, female gender, and few economic resources. GAD was associated with age, non-Hispanics and Blacks, being divorced or widowed, and few economic resources. 2) Psychosocial factors: PD was associated with smoking and alcohol problems. GAD was associated with stressful life events in childhood and adulthood, and personality. 3) Physical and mental health factors: PD was associated with the number of physical diseases suffered and the joint hypermobility syndrome. PD was also associated with a parental history of mental disorders, as well as with other anxiety disorders and other mental health problems in the person affected. GAD was associated with a parental history of mental disorders, as well as with other anxiety disorders and other mental health problems in the person affected, plus already having received psychiatric care. Limitations Few studies examined the same risk factors. Conclusions Sociodemographic, psychosocial and mental–physical health risk factors were determinant for the onset of PD and GAD in the general adult population. These findings could be useful for developing preventive interventions in PD and GAD.

Background: The ''predictD algorithm'' provides an estimate of the level and profile of risk of the onset of major depression in primary care attendees. This gives us the opportunity to develop interventions to prevent depression in a personalized way. We aim to evaluate the effectiveness, cost-effectiveness and cost-utility of a new intervention, personalized and implemented by family physicians (FPs), to prevent the onset of episodes of major depression.Methods/Design: This is a multicenter randomized controlled trial (RCT), with cluster assignment by health center and two parallel arms. Two interventions will be applied by FPs, usual care versus the new intervention predictD-CCRT. The latter has four components: a training workshop for FPs; communicating the level and profile of risk of depression; building up a tailored bio-psycho-family-social intervention by FPs to prevent depression; offering a booklet to prevent depression; and activating and empowering patients. We will recruit a systematic random sample of 3286 non-depressed adult patients (1643 in each trial arm), nested in 140 FPs and 70 health centers from 7 Spanish cities. All patients will be evaluated at baseline, 6, 12 and 18 months. The level and profile of risk of depression will be communicated to patients by the FPs in the intervention practices at baseline, 6 and 12 months. Our primary outcome will be the cumulative incidence of major depression (measured by CIDI each 6 months) over 18 months of follow-up. Secondary outcomes will be health-related quality of life (SF-12 and EuroQol), and measurements of cost-effectiveness and cost-utility. The inferences will be made at patient level. We shall undertake an intention-to-treat effectiveness analysis and will handle missing data using multiple imputations. We will perform multi-level logistic regressions and will adjust for the probability of the onset of major depression at 12 months measured at baseline as well as for unbalanced variables if appropriate. The economic evaluation will be approached from two perspectives, societal and health system.Discussion: To our knowledge, this will be the first RCT of universal primary prevention for depression in adults and the first to test a personalized intervention implemented by FPs. We discuss possible biases as well as other limitations.Trial registration: ClinicalTrials.gov identifier: NCT01151982.

BackgroundWithin the ICD and DSM review processes there is growing debate on the future classification and status of adjustment disorders, even though evidence on this clinical entity is scant, particularly outside specialised care.AimsTo estimate the prevalence of adjustment disorders in primary care; to explore whether there are differences between primary care patients with adjustment disorders and those with other mental disorders; and to describe the recognition and treatment of adjustment disorders by general practitioners (GPs).MethodParticipants were drawn from a cross-sectional survey of a representative sample of 3815 patients from 77 primary healthcare centres in Catalonia. The prevalence of current adjustment disorders and subtypes were assessed face to face using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). Multilevel logistic regressions were conducted to assess differences between adjustment disorders and other mental disorders. Recognition and treatment of adjustment disorders by GPs were assessed through a review of patients' computerised clinical histories.ResultsThe prevalence of adjustment disorders was 2.94%. Patients with adjustment disorders had higher mental quality-of-life scores than patients with major depressive disorder but lower than patients without mental disorder. Self-perceived stress was also higher in adjustment disorders compared with those with anxiety disorders and those without mental disorder. Recognition of adjustment disorders by GPs was low: only 2 of the 110 cases identified using the SCID-I were detected by the GP. Among those with adjustment disorders, 37% had at least one psychotropic prescription.ConclusionsAdjustment disorder shows a distinct profile as an intermediate category between no mental disorder and affective disorders (depression and anxiety disorders).

Objectives The objectives were to determine the levels of general practitioner (GP) recognition of anxiety disorders and examine associated factors. Methods An epidemiological survey was carried out in 77 primary care centers representative of Catalonia. A total of 3815 patients were assessed. Results GPs identified 185 of the 666 individuals diagnosed as meeting the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) criteria for any anxiety disorder (sensitivity 0.28). Regarding specific anxiety disorders, panic disorder was registered in just three of the patients who, according to the SCID-I, did not meet the criteria for this condition .Generalized anxiety disorder was recorded by the GP in 46 cases, 4 of them being concordant with the SCID-I (sensitivity 0.03). The presence of comorbid hypertension was associated with an increased probability of recognition. Emotional problems as the patients' main complaint and additional appointments with a mental health specialist were associated with both adequate and erroneous recognition. Being female, having more frequent appointments with the GP and having higher levels of self-perceived stress were related to false positives. As disability increased, the probability of being erroneously detected decreased. Conclusion GPs recognized anxiety disorders in some sufferers but still failed with respect to differentiating between anxiety disorder subtypes and disability assessment.

Childhood adversities (CAs) have consistently been associated with mental health problems in childhood and adulthood. However, few studies have employed appropriate statistical methods that take into account overlap among CAs, and many of the ones that did so were based on insufficiently complex models. The present paper studies the prevalence of a wide variety of CAs, as well as their relationship to the onset of mental disorders in a representative sample of a Spanish population.The study is part of the ESEMeD-Spain project, a cross-sectional household survey, which included a nationally representative sample of the Spanish adult population. CAs' associations with lifetime prevalence of mental disorders were estimated using discrete-time survival analysis with person-years as the unit of analysis.Of our sample, 20.6% reported at least one CA, of whom 24% reported more than one CA. Parental death, parental mental disorder, family violence, economic adversity, physical and sexual abuse were associated with different groups of mental disorders. CAs were associated with the onset of mental disorders during several stages of life. Simulations suggest that CAs were associated with 12.6% of all disorders, 10.8% of mood disorders, 5.8% of anxiety disorders, 27% of substance disorders and 29.7% of externalising disorders.Prevalences of CAs in the Spanish population are lower than those found in other high-income countries, especially when compared to the USA. In Spain, different CAs were associated with the onset of a number of mental disorders, although these associations were not as frequent as in other countries. Although lower than in other countries, the association between CAs and mental health in Spain should be considered relevant. Specific health policies and prevention programmes are needed in order to decrease this burden.

El pdf del artículo es la versión post-print., Background & Aims: Liver steatosis enhances ischemia/reperfusion (I/R) injury and is considered a primary factor in graft failure after liver transplantation. Although previous reports have shown a role for qualitative steatosis (macrovesicular vs. microvesicular) in hepatic I/R injury, no studies have compared side by side the specific contribution of individual lipids accumulating in fatty liver to I/R damage. Methods: We used nutritional and genetic models of micro and macrovesicular fatty livers exhibiting specific lipid profiles to assess their susceptibility to normothermic I/R injury. Results: Unlike choline-deficient (CD) diet-fed mice, characterized by predominant liver triglycerides/free fatty acids (TG/FFA) accumulation, mice fed a cholesterol-enriched (HC) diet, which exhibited enhanced hepatic cholesterol loading in mitochondria, were highly sensitive to I/R-induced liver injury. In vivo two-photon confocal imaging revealed enhanced mitochondrial depolarization and generation of reactive oxygen species following hepatic I/R in HC-fed but not in CD-fed mice, consistent with decreased mitochondrial GSH (mGSH) observed in HC-fed mice. Moreover, ob/ob mice, characterized by increased hepatic TG, FFA, and cholesterol levels, were as sensitive to I/R-mediated liver injury as mice fed the HC diet. Livers from ob/ob mice displayed increased StAR expression and mitochondrial cholesterol accumulation, resulting in mGSH depletion. Interestingly, atorvastatin therapy or squalene synthase inhibition in vivo attenuated StAR overexpression, mitochondrial cholesterol loading, and mGSH depletion, protecting ob/ob mice from I/R-mediated liver injury. Conclusions: Cholesterol accumulation, particularly in mitochondria, sensitizes to hepatic I/R injury, and thus represents a novel target to prevent the enhanced damage of steatotic livers to I/R-mediated damage. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved., The work was supported by grants SAF2006-06780, SAF2008-02199, SAF2008-04974 and SAF2009-11417 (Plan Nacional de I+D), PI070193 and PI09/00056 (Institut de Salud Carlos III), by CIBEREHD from the Institut Carlos III, the Fundación Mutua Madrileña and the center grant P50-AA-11999 Research Center for Liver and Pancreatic Diseases, US National Institute on Alcohol Abuse and Alcoholism, USA.

[Background]: Alcohol-induced liver injury is associated with decreased S-adenosyl-l-methionine (SAM)/S-adenosyl-l-homocysteine (SAH) ratio and mitochondrial glutathione (mGSH) depletion, which has been shown to sensitize hepatocytes to tumor necrosis factor (TNF)., [Aims]: As the effect of alcohol on mitochondrial SAM (mSAM) has been poorly characterized, our aim was to examine the status and transport of mSAM in relation to that of mGSH during alcohol intake., [Methods]: Sprague–Dawley rats were pair fed Lieber–DeCarli diets containing alcohol for 1 to 4 weeks and liver fractionated into cytosol and mitochondria to examine the mSAM transport and its sensitivity to membrane dynamics., [Results]: We found that cytosol SAM was depleted from the first week of alcohol feeding, with mSAM levels paralleling these changes. Cytosol SAH, however, increased during the first 3 weeks of alcohol intake, whereas its mitochondrial levels remained unchanged. mGSH depletion occurred by 3 to 4 weeks of alcohol intake due to cholesterol-mediated impaired transport from the cytosol. In contrast to this outcome, the transport of SAM into hepatic mitochondria was unaffected by alcohol intake and resistant to cholesterol-mediated perturbations in membrane dynamics; furthermore cytosolic SAH accumulation in primary hepatocytes by SAH hydrolase inhibition reproduced the mSAM depletion by alcohol due to the competition of SAH with SAM for mitochondrial transport. However, alcohol feeding did not potentiate the sensitivity to inhibition by SAH accumulation., [Conclusions]: Alcohol-induced mSAM depletion precedes that of mGSH and occurs independently of alcohol-mediated perturbations in membrane dynamics, disproving an inherent defect in the mSAM transport by alcohol. These findings suggest that the early mSAM depletion may contribute to the alterations of mitochondrial membrane dynamics and the subsequent mGSH down-regulation induced by alcohol feeding., The work presented was supported in part by the Research Center for Liver and Pancreatic Diseases, P50 AA 11999 funded by the U.S. National Institute on Alcohol Abuse and Alcoholism; Plan Nacional de I + D grants SAF (2005-03923, 2005-03943, 2006-06780) and CIBERehd supported by Instituto de Salud Carlos III, Spain. Anna Colell is a Ramón y Cajal investigator.

et al., The aim of this study was to demonstrate the existence of alterations in glutathione and cholesterol homeostasis in brain mitochondria from alcoholic rats. Glutathione concentration decreased, whereas oxidized glutathione and cholesterol contents increased in these organelles, suggesting the ethanol-induced generation of reactive oxygen species, and the impairment of mitochondrial uptake of glutathione, possibly due to the increase in cholesterol deposition. The release of apoptogenic proteins was increased after stimulating mitochondria from the brain of alcoholic rats with atractyloside. As a conclusion, chronic alcohol consumption might sensitize brain mitochondria to apoptotic stimuli, and promote the subsequent release of apoptotic proteins., This work was supported in part by Funds from Ministerio de Ciencia e Innovación (SAF 2007- 66801), Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+I), Ingenio 2010 initiative, RTA (Red de Transtornos Adictivos) and Consolider programms from Instituto de Salud Carlos III, Coopernicus-Santander Programm of the Universidad CEU- Cardenal Herrera, Dirección General de Drogodependencias (Generalitat Valenciana) and FEPAD (Fundación para el Estudio, Prevención y Ayuda a la Drogadicción).

To estimate the comorbidity of mental disorders with chronic physical conditions and to assess their independent and combined effects on health-related quality of life (HRQOL). Face-to-face cross-sectional survey of adult attendants to public primary care (PC) centres from Catalonia (Spain). A total of 3,815 out of 5,402 selected patients provided data for this study. We report frequency of chronic physical conditions among participants with mental disorders and the contribution of each mental disorder and chronic physical condition to HRQOL. Chronic pain is the most frequent condition among those with mental disorders (74.54%). The effect of chronic physical conditions on HRQOL is rather minor when compared to the effect of mental disorders (especially mood disorders). However, chronic pain plays an important role in HRQOL loss. Mood disorders and chronic pain negatively affect HRQOL of PC patients. Especial efforts should be made to detect and treat mental disorders and chronic pain at this level.

Comunicacion presentada en la Alzheimer's Association International Conference on Alzheimer's Disease, celebrada del 26 al 31 de julio de 2008 en Chicago (Estados Unidos)

The etiology of progression from steatosis to steatohepatitis (SH) remains unknown. Using nutritional and genetic models of hepatic steatosis, we show that free cholesterol (FC) loading, but not free fatty acids or triglycerides, sensitizes to TNF- and Fas-induced SH. FC distribution in endoplasmic reticulum (ER) and plasma membrane did not cause ER stress or alter TNF signaling. Rather, mitochondrial FC loading accounted for the hepatocellular sensitivity to TNF due to mitochondrial glutathione (mGSH) depletion. Selective mGSH depletion in primary hepatocytes recapitulated the susceptibility to TNF and Fas seen in FC-loaded hepatocytes; its repletion rescued FC-loaded livers from TNF-mediated SH. Moreover, hepatocytes from mice lacking NPC1, a late endosomal cholesterol trafficking protein, or from obese ob/ob mice, exhibited mitochondrial FC accumulation, mGSH depletion, and susceptibility to TNF. Thus, we propose a critical role for mitochondrial FC loading in precipitating SH, by sensitizing hepatocytes to TNF and Fas through mGSH depletion. © 2006 Elsevier Inc. All rights reserved., The work presented was supported in part by the Research Center for Liver and Pancreatic Diseases, P50 AA 11999; and grant 1R21 AA014135-01, funded by the US National Institute on Alcohol Abuse and Alcoholism; Plan Nacional de I+D grants SAF (2002-3564, 2003-04974, 2005-03923, 2005-03943, and 2006-0678); and Red Temática de Investigación Cooperativa G03/015, Red de Centros C03/02 PI 05/1285 and FIS (04/1039, 03/0426, 02/3057 and 02/0339) grants supported by Instituto de Salud Carlos III, Spain

[Background] The predictD study developed and validated a risk algorithm for predicting the onset of major depression in primary care. We aimed to explore the opinion of patients about knowing their risk for depression and the values and criteria upon which these opinions are based. [Methods] A maximum variation sample of patients was taken, stratified by city, age, gender, immigrant status, socio-economic status and lifetime depression. The study participants were 52 patients belonging to 13 urban health centres in seven different cities around Spain. Seven Focus Groups (FGs) were given held with primary care patients, one for each of the seven participating cities. [Results] The results showed that patients generally welcomed knowing their risk for depression. Furthermore, in light of available evidence several patients proposed potential changes in their lifestyles to prevent depression. Patients generally preferred to ask their General Practitioners (GPs) for advice, though mental health specialists were also mentioned. They suggested that GPs undertake interventions tailored to each patient, from a “patient-centred” approach, with certain communication skills, and giving advice to help patients cope with the knowledge that they are at risk of becoming depressed. [Conclusions] Patients are pleased to be informed about their risk for depression. We detected certain beliefs, attitudes, values, expectations and behaviour among the patients that were potentially useful for future primary prevention programmes on depression., This work was supported by grants from the Andalusian Council of Health [grant reference: 2008/0195][www.juntadeandalucia.es/fundacionprogres​oysalud]; the Department of Health of the Basque Government [grant reference: 2008/111021][www.osakidetza.euskadi.net]; the Spanish Network of Primary Care Research “redIAPP” (RD06/0018), the “Aragón group” (RD06/0018/0020), the “Sant Joan de Deu group” (RD07/0018/0017), “Bizkaya group” (RD07/0018/0018), “Castilla-León group” (RD07/0018/0027) and the “SAMSERAP group” (RD06/0018/0039 and CTS-587) [www.rediapp.org].

2 ) tests. ACox regression model was used to evaluate the Relapse Free Survival (RFS) and the Colon Cancer specific Survival. Results: MSI status could be determined by genotyping in 350 tumor samples. 48 patients (14%) had MSI high (MSI-H) tumors and 302 (86%) had microsatellite stable (MSS) tumor. BRAF status could be determined in 380 tumor samples. 58 cases (15%) were BRAF mutated tumors and 322 (85%) were BRAF wild type tumors. Tumor-stroma ratio was analyzed in 407 cases. 176 tumors (43%) had more than 50% intra-tumor stroma and were classified as stroma-high. MSI-H tumors were significantly located in the right colon (X 2 p-value = 1.03e-5), were poorly differentiated (X 2 p-value = 0.003) and had more than 12 lymph nodes resected (X 2 p-value = 0.037). MSI-H tumors were associated with BRAF mutation (X 2 p-value = 0.02) and stroma-low (X 2 p-value = 0.0005). When a molecular prognostic risk classification was performed, patients with MSI-H and stroma-low suggested a low risk of relapse comparing to MSI-H/stroma-high, MSS/stroma-low and MSS/ stroma-high (Hazard Ratio = 3.15; 95% CI, 0.76 - 13.1, p-value = 0.0602). Conclusion: MSI-H tumors are typically poorly differentiated, located in the right colon and have BRAF mutation as well as low intra-tumor stroma. Our results suggest that low-stroma could partly explain prognosis in patients with MSI-H stage II tumors.

3629 Background: Different clinico-pathological factors are used to define a group of patients with high-risk stage II colon cancer (CC) that may benefit of adjuvant treatment. Moreover, several molecular markers, such as microsatellite instability (MSI) and BRAF, have been widely investigated as prognostic factors. Recently a high stroma component (EMT+ subtypes) has also been associated with poor outcome. The aim of the study is to analyze the prognostic value of MSI, BRAF and tumor-stroma ratio in a prospective series of stage II CC patients. Methods: FFPE tissue from 432 stage II CC patients operated at Hospital Universitari de Bellvitge (1996 - 2006) were included in the study. MSI status was assessed by the analysis of 5 mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27). BRAF V600E mutation was analyzed by single strand conformation polymorphism technique. Tumor-stroma ratio was analyzed by immunohistochemistry. Associations between molecular factors and clinical features were assessed by Chi-Squared (X2) tests. A Cox regression model was used to evaluate the Relapse Free (RFS) and the Colon Cancer specific Survival. Results: MSI status could be determined in 350 patients. 48 (14%) had MSI high (MSI-H) tumor. BRAF status could be assessed in 380 cases. 58 (15%) cases were BRAF mutated. Tumor-stroma ratio was analyzed in 407 tumor samples. 176 (43%) tumors had more than 50% intra-tumor stroma and were classified as stroma-high. MSI-H tumors were significantly located in right colon (X2 p-value = 1.03e-5), were poorly differentiated (X2 p-value = 0.003) and had more than 12 lymph nodes resected (X2 p-value = 0.037). MSI-H tumors were associated with BRAF mutation (X2 p-value = 0.02) and stroma-low (X2 p-value = 0.0005). When a molecular prognostic risk classification was performed, patients with MSI-H /stroma-low suggested a low risk of relapse comparing to MSI-H/stroma-high, microsatellite stable (MSS)/stroma-low and MSS/stroma-high patients (HR = 3.15; 95 CI, 0.76 – 13.1, p-value = 0.0602). Conclusions: MSI-H tumors have BRAF mutation as well as low intra-tumor stroma. Our results suggest that tumor-stroma ratio can explain differential prognosis in MSI-H stage II tumors.