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Background: The 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. Purpose: To 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. Method: Qualitative 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. Results: Sixty-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. Conclusions: The 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. [ABSTRACT FROM AUTHOR]

Abstract: 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 6million. 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 735.4million Euros. Of this figure, 21.2% corresponded to direct costs, including 41million Euros in primary care (5.6%), 8.1million Euros in mental health specialised care (1.1%), 5.6million Euros due to hospitalisation (0.8%) and 101.1million Euros due to pharmacological care (13.7%); and 78.8% to indirect costs due to productivity loss. 3.7million work days were lost to temporary disability for depression with a cost of 199.6million Euros (27.1%), and 353.3million Euros due to permanent disability (48%). Mortality attributed to suicide accounted for 26.9million 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. [Copyright &y& Elsevier]

Background: Constitutional MLH1 epimutations are characterised by monoallelic methylation of the MLH1 promoter throughout normal tissues, accompanied by allele-specific silencing. The mechanism underlying primary MLH1 epimutations is currently unknown. The aim of this study was to perform an in-depth characterisation of constitutional MLH1 epimutations targeting the aberrantly methylated region around MLH1 and other genomic loci.Methods: Twelve MLH1 epimutation carriers, 61 Lynch syndrome patients, and 41 healthy controls, were analysed by Infinium 450 K array. Targeted molecular techniques were used to characterise the MLH1 epimutation carriers and their inheritance pattern.Results: No nucleotide or structural variants were identified in-cis on the epimutated allele in 10 carriers, in which inter-generational methylation erasure was demonstrated in two, suggesting primary type of epimutation. CNVs outside the MLH1 locus were found in two cases. EPM2AIP1-MLH1 CpG island was identified as the sole differentially methylated region in MLH1 epimutation carriers compared to controls.Conclusion: Primary constitutional MLH1 epimutations arise as a focal epigenetic event at the EPM2AIP1-MLH1 CpG island in the absence of cis-acting genetic variants. Further molecular characterisation is needed to elucidate the mechanistic basis of MLH1 epimutations and their heritability/reversibility. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Alcohol is recognized as a direct hepatotoxin, but the precise molecular pathways that are important for the initiation and progression of alcohol-induced tissue injury are not completely understood. The current understanding of alcohol toxicity to organs suggests that alcohol initiates injury by generation of oxidative and nonoxidative ethanol metabolites and via translocation of gut-derived endotoxin. These processes lead to cellular injury and stimulation of the inflammatory responses mediated through a variety of molecules. With continuing alcohol abuse, the injury progresses through impairment of tissue regeneration and extracellular matrix (ECM) turnover, leading to fibrogenesis and cirrhosis. Several cell types are involved in this process, the predominant being stellate cells, macrophages, and parenchymal cells. In response to alcohol, growth factors and cytokines activate many signaling cascades that regulate fibrogenesis. This mini-review brings together research focusing on the underlying mechanisms of alcohol-mediated injury in a number of organs. It highlights the various processes and molecules that are likely involved in inflammation, immune modulation, susceptibility to infection, ECM turnover and fibrogenesis in the liver, pancreas, and lung triggered by alcohol abuse. [ABSTRACT FROM AUTHOR]

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. As this systematic review is based on published data, approval from the local ethics committee was not required. • Twelve trial-based health-economic evaluations to prevent depression are presented • Nine of these 12 studies were CUAs of which 6 were cost-effective • The remaining 3 studies were CEAs of which 2 were cost-effective • Psychological interventions have the potential to be cost-effective • More economic evaluations should be conducted for priority setting [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The causal mechanism for cancer predisposition in Lynch-like syndrome (LLS) remains unknown. Our aim was to elucidate the constitutional basis of mismatch repair (MMR) deficiency in LLS patients throughout a comprehensive (epi)genetic analysis. One hundred and fifteen LLS patients harboring MMR-deficient tumors and no germline MMR mutations were included. Mutational analysis of 26 colorectal cancer (CRC)-associated genes was performed. Pathogenicity of MMR variants was assessed by splicing and multifactorial likelihood analyses. Genome-wide methylome analysis was performed by the Infinium Human Methylation 450K Bead Chip. The multigene panel analysis revealed the presence of two MMR gene truncating mutations not previously found. Of a total of 15 additional MMR variants identified, five -present in 6 unrelated individuals- were reclassified as pathogenic. In addition, 13 predicted deleterious variants in other CRC-predisposing genes were found in 12 probands. Methylome analysis detected one constitutional MLH1 epimutation, but no additional differentially methylated regions were identified in LLS compared to LS patients or cancer-free individuals. In conclusion, the use of an ad-hoc designed gene panel combined with pathogenicity assessment of variants allowed the identification of deleterious MMR mutations as well as new LLS candidate causal genes. Constitutional epimutations in non-LS-associated genes are not responsible for LLS. [ABSTRACT FROM AUTHOR]

Objective: Although evidence supports the effectiveness of psychological interventions for prevention of anxiety, little is known about their cost-effectiveness. The aim of this study was to conduct a systematic review of health-economic evaluations of psychological interventions for anxiety prevention., Methods: PubMed, PsycInfo, Web of Science, Embase, Cochrane Central Register of Controlled Trials, EconLit, National Health Service (NHS) Economic Evaluations Database, NHS Health Technology Assessment, and OpenGrey databases were searched electronically on December 23, 2022. Included studies focused on economic evaluations based on randomized controlled trials of psychological interventions to prevent anxiety. Study data were extracted, and the quality of the selected studies was assessed by using the Consensus on Health Economic Criteria and the Cochrane risk-of-bias tool., Results: All included studies (N=5) had economic evaluations that were considered to be of good quality. In two studies, the interventions showed favorable cost-effectiveness compared with usual care groups. In one study, the intervention was not cost-effective. Findings from another study cast doubt on the cost-effectiveness of the intervention, and the cost-effectiveness of the intervention in the remaining study could not be established., Conclusions: Although the findings suggest some preliminary evidence of cost-effectiveness of psychological interventions for preventing anxiety, they were limited by the small number of included studies. Additional research on the cost-effectiveness of psychological interventions for anxiety in different countries and populations is required., Competing Interests: The authors report no financial relationships with commercial interests.

Despite the occurrence of wildfires quadrupling over the past four decades, the health effects associated with wildfire smoke exposures during pregnancy remains unknown. Particulate matter less than 2.5 μ ms (PM 2.5 ) is among the major pollutants emitted in wildfire smoke. Previous studies found PM 2.5 associated with lower birthweight, however, the relationship between wildfire-specific PM 2.5 and birthweight is uncertain. Our study of 7923 singleton births in San Francisco between January 1, 2017 and March 12, 2020 examines associations between wildfire smoke exposure during pregnancy and birthweight. We linked daily estimates of wildfire-specific PM 2.5 to maternal residence at the ZIP code level. We used linear and log-binomial regression to examine the relationship between wildfire smoke exposure by trimester and birthweight and adjusted for gestational age, maternal age, race/ethnicity, and educational attainment. We stratified by infant sex to examine potential effect modification. Exposure to wildfire-specific PM 2.5 during the second trimester of pregnancy was positively associated with increased risk of large for gestational age ( OR = 1.13; 95% CI: 1.03, 1.24), as was the number of days of wildfire-specific PM 2.5 above 5 μ g m -3 in the second trimester ( OR = 1.03; 95% CI: 1.01, 1.06). We found consistent results with wildfire smoke exposure in the second trimester and increased continuous birthweight-for-gestational age z -score. Differences by infant sex were not consistent. Counter to our hypothesis, results suggest that wildfire smoke exposures are associated with increased risk for higher birthweight. We observed strongest associations during the second trimester. These investigations should be expanded to other populations exposed to wildfire smoke and aim to identify vulnerable communities. Additional research is needed to clarify the biological mechanisms in this relationship between wildfire smoke exposure and adverse birth outcomes., (© 2023 The Author(s). Published by IOP Publishing Ltd.)

Despite successes on the Sustainable Development Goals for access to improved water sources and sanitation, many low and middle-income countries (LMICs) continue to struggle with high rates of diarrheal disease. In Guatemala, 98% of water sources are estimated to have E. coli contamination. This project moves toward a novel low-cost approach to bridge the gap between the microbiologic identification of E. coli and the vast impact that this pathogen has on human health within marginalized communities using co-designed community-based tools, low-cost technology, and AI. An agile co-design process was followed with water quality stakeholders, community staff, and local graphic design artists to develop a community water quality education mobile app. A series of alpha- and beta-testers completed interactive demonstration, feedback, and in-depth interview sessions. A microbiology lab in Guatemala developed and piloted field protocols with lay community workers to collect and process water samples. A preliminary artificial intelligence (AI) algorithm was developed to detect the presence of E. coli in images generated from community-derived water samples. The mobile app emerged as a pictorial and audio-driven community-facing tool. The field protocol for water sampling and testing was successfully implemented by lay community workers. Feedback from the community workers indicated both desire and ability to conduct the water sampling and testing protocol under field conditions. However, images derived from the low-cost $2 microscope in field conditions were not of a suitable quality for AI object detection of E. coli, and additional low-cost technologies are being considered. The preliminary AI object detection algorithm from lab-derived images performed at 94% accuracy in identifying E. coli in comparison to the Chromocult gold-standard., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Hall-Clifford et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Depression is strongly associated with obesity among other chronic physical diseases. The latest mega- and meta-analysis of genome-wide association studies have identified multiple risk loci robustly associated with depression. In this study, we aimed to investigate whether a genetic-risk score (GRS) combining multiple depression risk single nucleotide polymorphisms (SNPs) might have utility in the prediction of this disorder in individuals with obesity. A total of 30 depression-associated SNPs were included in a GRS to predict the risk of depression in a large case-control sample from the Spanish PredictD-CCRT study, a national multicentre, randomized controlled trial, which included 104 cases of depression and 1546 controls. An unweighted GRS was calculated as a summation of the number of risk alleles for depression and incorporated into several logistic regression models with depression status as the main outcome. Constructed models were trained and evaluated in the whole recruited sample. Non-genetic-risk factors were combined with the GRS in several ways across the five predictive models in order to improve predictive ability. An enrichment functional analysis was finally conducted with the aim of providing a general understanding of the biological pathways mapped by analyzed SNPs. We found that an unweighted GRS based on 30 risk loci was significantly associated with a higher risk of depression. Although the GRS itself explained a small amount of variance of depression, we found a significant improvement in the prediction of depression after including some non-genetic-risk factors into the models. The highest predictive ability for depression was achieved when the model included an interaction term between the GRS and the body mass index (BMI), apart from the inclusion of classical demographic information as marginal terms (AUC = 0.71, 95% CI = [0.65, 0.76]). Functional analyses on the 30 SNPs composing the GRS revealed an over-representation of the mapped genes in signaling pathways involved in processes such as extracellular remodeling, proinflammatory regulatory mechanisms, and circadian rhythm alterations. Although the GRS on its own explained a small amount of variance of depression, a significant novel feature of this study is that including non-genetic-risk factors such as BMI together with a GRS came close to the conventional threshold for clinical utility used in ROC analysis and improves the prediction of depression. In this study, the highest predictive ability was achieved by the model combining the GRS and the BMI under an interaction term. Particularly, BMI was identified as a trigger-like risk factor for depression acting in a concerted way with the GRS component. This is an interesting finding since it suggests the existence of a risk overlap between both diseases, and the need for individual depression genetics-risk evaluation in subjects with obesity. This research has therefore potential clinical implications and set the basis for future research directions in exploring the link between depression and obesity-associated disorders. While it is likely that future genome-wide studies with large samples will detect novel genetic variants associated with depression, it seems clear that a combination of genetics and non-genetic information (such is the case of obesity status and other depression comorbidities) will still be needed for the optimization prediction of depression in high-susceptibility individuals., (© 2022. The Author(s).)

Background: In 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., Aim: To determine whether the predictD-intervention is effective at preventing anxiety in primary care patients without depression or anxiety., Design and Setting: Secondary 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., Method: In 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., Results: A 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)., Conclusion: A personalised intervention delivered by GPs for the prevention of depression provided a modest but statistically significant reduction in the incidence of anxiety., (© The Authors.)

Introduction: Lynch 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 Methods: Blood 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., Results: The hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p<0.001). This finding was confirmed in the validation set, reaching 100% specificity and sensitivity. Higher hs-MSI scores were detected in biallelic MSH2 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)., Conclusions: The 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Three loose housing systems for lactating cows (compost bedded pack, CBP; conventional bedded pack, BP; and freestalls, FS) were assessed on one farm in terms of cow behavior and welfare. An on-farm welfare assessment based on the Welfare Quality protocols was used four times every three months on 757 cows. Video recordings taken twice over four days were used to assess behavior patterns at resting areas. Cows in CBP and BP were dirtier than those in FS ( p < 0.0001). Fewer integument alterations were recorded for CBP and BP than FS ( p < 0.001). Cows in BP were quicker to lie down and stand up compared to those in CBP or FS ( p < 0.001). Percentages of cows needing more attempts before rising were higher for FS ( p < 0.01). However, a higher frequency of kneeling was observed in CBP ( p = 0.033). A lower percentage of cows lying in the resting area was recorded for FS (56%) than CBP or BP (97 or 84%, respectively, p < 0.05). Overall, in this study, cows kept in bedded pack barns were dirtier but had fewer integument alterations and spent more time lying down in the resting area than cows housed in freestalls., Competing Interests: The authors declare no conflict of interest.

A significant proportion of DNA-mismatch repair (MMR) variants are classified as of unknown significance, precluding diagnosis. The in vitro MMR assay is used to assess their MMR capability, likely the most important function of an MMR protein. However, the robustness of the assay, crucial for its use in the clinical setting, has been rarely evaluated. The aim of the present work was to validate an in vitro MMR assay approach to the functional characterization of MMR variants, as a first step to meeting quality standards of diagnostic laboratories. The MMR assay was optimized by testing a variety of reagents and experimental conditions. Reference materials and standard operating procedures were established. To determine the intra- and interexperimental variability of the assay and its reproducibility among centers, independent transfections of six previously characterized MLH1 variants were performed in two independent laboratories. Reagents and conditions optimal for performing the in vitro MMR assay were determined. The validated assay demonstrated no significant intra- or interexperimental variability and good reproducibility between centers. We set up a robust in vitro MMR assay that can provide relevant in vitro functional evidence for MMR variant pathogenicity assessment, eventually improving the molecular diagnosis of hereditary cancer syndromes associated with MMR deficiency., (Copyright © 2020 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

The presence of nanomaterials in our everyday life is ever increasing, and so too are concerns about the possible health consequences of exposure to them. While evidence of their biological activity is growing, there is still scant knowledge of the epigenetic mechanisms that could be at play in these processes. Moreover, the great variability in the chemical and physical structures of these compounds handicaps the study of their possible health risks. Here we have synthesized reduced graphene oxide (rGO) through the thermal exfoliation/reduction of graphite oxide, and characterized the resulting material. We have then made use of Illumina's MethylationEPIC arrays and bisulphite pyrosequencing to analyse the genome-wide and global DNA methylation dynamics associated with the medium-term exposure of human lung epithelial cells to rGO at concentrations of 1 and 10 µg/mL. The results show no genome-wide or global DNA methylation changes associated with either condition. Our observations thus suggest that medium-term rGO exposure does not have significant effects on the DNA methylation patterns of human lung epithelial cells.

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.

In a proportion of patients presenting mismatch repair (MMR)-deficient tumors, no germline MMR mutations are identified, the so-called Lynch-like syndrome (LLS). Recently, MMR-deficient tumors have been associated with germline mutations in POLE and MUTYH or double somatic MMR events. Our aim was to elucidate the molecular basis of MSH2-deficient LS-suspected cases using a comprehensive analysis of colorectal cancer (CRC)-associated genes at germline and somatic level. Fifty-eight probands harboring MSH2-deficient tumors were included. Germline mutational analysis of MSH2 (including EPCAM deletions) and MSH6 was performed. Pathogenicity of MSH2 variants was assessed by RNA analysis and multifactorial likelihood calculations. MSH2 cDNA and methylation of MSH2 and MSH6 promoters were studied. Matched blood and tumor DNA were analyzed using a customized next generation sequencing panel. Thirty-five individuals were carriers of pathogenic or probably pathogenic variants in MSH2 and EPCAM. Five patients harbored 4 different MSH2 variants of unknown significance (VUS) and one had 2 novel MSH6 promoter VUS. Pathogenicity assessment allowed the reclassification of the 4 MSH2 VUS and 6 probably pathogenic variants as pathogenic mutations, enabling a total of 40 LS diagnostics. Predicted pathogenic germline variants in BUB1, SETD2, FAN1 and MUTYH were identified in 5 cases. Three patients had double somatic hits in MSH2 or MSH6, and another 2 had somatic alterations in other MMR genes and/or proofreading polymerases. In conclusion, our comprehensive strategy combining germline and somatic mutational status of CRC-associated genes by means of a subexome panel allows the elucidation of up to 86% of MSH2-deficient suspected LS tumors., (© 2017 UICC.)

The clinical spectrum of germline mismatch repair (MMR) gene variants continues increasing, encompassing Lynch syndrome, Constitutional MMR Deficiency (CMMRD), and the recently reported MSH3-associated polyposis. Genetic diagnosis of these hereditary cancer syndromes is often hampered by the presence of variants of unknown significance (VUS) and overlapping phenotypes. Two PMS2 VUS, c.2149G>A (p.V717M) and c.2444C>T (p.S815L), were identified in trans in one individual diagnosed with early-onset colorectal cancer (CRC) who belonged to a family fulfilling clinical criteria for hereditary cancer. Clinico-pathological data, multifactorial likelihood calculations and functional analyses were used to refine their clinical significance. Likelihood analysis based on cosegregation and tumor data classified the c.2444C>T variant as pathogenic, which was supported by impaired MMR activity associated with diminished protein expression in functional assays. Conversely, the c.2149G>A variant displayed MMR proficiency and protein stability. These results, in addition to the conserved PMS2 expression in normal tissues and the absence of germline microsatellite instability (gMSI) in the biallelic carrier ruled out a CMMRD diagnosis. The use of comprehensive strategies, including functional and clinico-pathological information, is mandatory to improve the clinical interpretation of naturally occurring MMR variants. This is critical for appropriate clinical management of cancer syndromes associated to MMR gene mutations.

Importance: To our knowledge, no systematic reviews or meta-analyses have been conducted to assess the effectiveness of preventive psychological and/or educational interventions for anxiety in varied populations., Objective: To evaluate the effectiveness of preventive psychological and/or educational interventions for anxiety in varied population types., Data Sources: A systematic review and meta-analysis was conducted based on literature searches of MEDLINE, PsycINFO, Web of Science, EMBASE, OpenGrey, Cochrane Central Register of Controlled Trials, and other sources from inception to March 7, 2017., Study Selection: A search was performed of randomized clinical trials assessing the effectiveness of preventive psychological and/or educational interventions for anxiety in varying populations free of anxiety at baseline as measured using validated instruments. There was no setting or language restriction. Eligibility criteria assessment was conducted by 2 of us., Data Extraction and Synthesis: Data extraction and assessment of risk of bias (Cochrane Collaboration's tool) were performed by 2 of us. Pooled standardized mean differences (SMDs) were calculated using random-effect models. Heterogeneity was explored by random-effects meta-regression., Main Outcomes and Measures: Incidence of new cases of anxiety disorders or reduction of anxiety symptoms as measured by validated instruments., Results: Of the 3273 abstracts reviewed, 131 were selected for full-text review, and 29 met the inclusion criteria, representing 10 430 patients from 11 countries on 4 continents. Meta-analysis calculations were based on 36 comparisons. The pooled SMD was -0.31 (95% CI, -0.40 to -0.21; P < .001) and heterogeneity was substantial (I2 = 61.1%; 95% CI, 44% to 73%). There was evidence of publication bias, but the effect size barely varied after adjustment (SMD, -0.27; 95% CI, -0.37 to -0.17; P < .001). Sensitivity analyses confirmed the robustness of effect size results. A meta-regression including 5 variables explained 99.6% of between-study variability, revealing an association between higher SMD, waiting list (comparator) (β = -0.33 [95% CI, -0.55 to -0.11]; P = .005) and a lower sample size (lg) (β = 0.15 [95% CI, 0.06 to 0.23]; P = .001). No association was observed with risk of bias, family physician providing intervention, and use of standardized interviews as outcomes., Conclusions and Relevance: Psychological and/or educational interventions had a small but statistically significant benefit for anxiety prevention in all populations evaluated. Although more studies with larger samples and active comparators are needed, these findings suggest that anxiety prevention programs should be further developed and implemented.

Endoplasmic reticulum (ER) is a dynamic organelle that participates in a number of cellular functions by controlling lipid metabolism, calcium stores, and proteostasis. Under stressful situations, the ER environment is compromised, and protein maturation is impaired; this causes misfolded proteins to accumulate and a characteristic stress response named unfolded protein response (UPR). UPR protects cells from stress and contributes to cellular homeostasis re-establishment; however, during prolonged ER stress, UPR activation promotes cell death. ER stressors can modulate autophagy which in turn, depending of the situation, induces cell survival or death. Interactions of different autophagy- and apoptosis-related proteins and also common signaling pathways have been found, suggesting an interplay between these cellular processes, although their dynamic features are still unknown. A number of pathologies including metabolic, neurodegenerative and cardiovascular diseases, cancer, inflammation, and viral infections are associated with ER stress, leading to a growing interest in targeting components of the UPR as a therapeutic strategy. Melatonin has a variety of antioxidant, anti-inflammatory, and antitumor effects. As such, it modulates apoptosis and autophagy in cancer cells, neurodegeneration and the development of liver diseases as well as other pathologies. Here, we review the effects of melatonin on the main ER stress mechanisms, focusing on its ability to regulate the autophagic and apoptotic processes. As the number of studies that have analyzed ER stress modulation by this indole remains limited, further research is necessary for a better understanding of the crosstalk between ER stress, autophagy, and apoptosis and to clearly delineate the mechanisms by which melatonin modulates these responses., (© 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., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Disrupted cholesterol homeostasis has been reported in Alzheimer disease and is thought to contribute to disease progression by promoting amyloid β (Aβ) accumulation. In particular, mitochondrial cholesterol enrichment has been shown to sensitize to Aβ-induced neurotoxicity. However, the molecular mechanisms responsible for the increased cholesterol levels and its trafficking to mitochondria in Alzheimer disease remain poorly understood. Here, we show that endoplasmic reticulum (ER) stress triggered by Aβ promotes cholesterol synthesis and mitochondrial cholesterol influx, resulting in mitochondrial glutathione (mGSH) depletion in older age amyloid precursor protein/presenilin-1 (APP/PS1) mice. Mitochondrial cholesterol accumulation was associated with increased expression of mitochondrial-associated ER membrane proteins, which favor cholesterol translocation from ER to mitochondria along with specific cholesterol carriers, particularly the steroidogenic acute regulatory protein. In vivo treatment with the ER stress inhibitor 4-phenylbutyric acid prevented mitochondrial cholesterol loading and mGSH depletion, thereby protecting APP/PS1 mice against Aβ-induced neurotoxicity. Similar protection was observed with GSH ethyl ester administration, which replenishes mGSH without affecting the unfolded protein response, thus positioning mGSH depletion downstream of ER stress. Overall, these results indicate that Aβ-mediated ER stress and increased mitochondrial cholesterol trafficking contribute to the pathologic progression observed in old APP/PS1 mice, and that ER stress inhibitors may be explored as therapeutic agents for Alzheimer disease., (Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

This study evaluated the rate of Hispanic children who have grandparents involved in caretaking and whether grandparents' involvement had a negative impact on feeding practices, children's physical activity, and body mass index (BMI). One-hundred and 99 children and their parents were recruited at an elementary school. Parents completed a questionnaire regarding their children's grandparents' involvement as caretakers and the feeding and physical activity practices of that grandparent when with the child. Children's height and weight were measured and zBMI scores were calculated. Forty-three percent of parents reported that there was a grandparent involved in their child's caretaking. Grandparents served a protective role on zBMI for youth of Hispanic descent, except for the Cuban subgroup. There was no relationship between grandparent involvement and feeding and physical activity behaviors. In some cases grandparents may serve a protective function for childhood obesity. These results highlight the need for future research on grandparents and children's health, especially among Hispanic subgroups., ((PsycINFO Database Record (c) 2013 APA, all rights reserved).)

Current evidence indicates that excess brain cholesterol regulates amyloid-β (Aβ) deposition, which in turn can regulate cholesterol homeostasis. Moreover, Aβ neurotoxicity is potentiated, in part, by mitochondrial glutathione (mGSH) depletion. To better understand the relationship between alterations in cholesterol homeostasis and Alzheimer's disease (AD), we generated a triple transgenic mice featuring sterol regulatory element-binding protein-2 (SREBP-2) overexpression in combination with APPswe/PS1ΔE9 mutations (APP/PS1) to examine key biochemical and functional characteristics of AD. Unlike APP/PS1 mice, APP/PS1/SREBP-2 mice exhibited early mitochondrial cholesterol loading and mGSH depletion. Moreover, β-secretase activation and Aβ accumulation, correlating with oxidative damage and neuroinflammation, were accelerated in APP/PS1/SREBP-2 mice compared with APP/PS1 mice. Triple transgenic mice displayed increased synaptotoxicity reflected by loss of synaptophysin and neuronal death, resulting in early object-recognition memory impairment associated with deficits in spatial memory. Interestingly, tau pathology was present in APP/PS1/SREBP-2 mice, manifested by increased tau hyperphosphorylation and cleavage, activation of tau kinases and neurofibrillary tangle (NFT) formation without expression of mutated tau. Importantly, in vivo treatment with the cell permeable GSH ethyl ester, which restored mGSH levels in APP/PS1/SREBP-2 mice, partially prevented the activation of tau kinases, reduced abnormal tau aggregation and Aβ deposition, resulting in attenuated synaptic degeneration. Taken together, these results show that cholesterol-mediated mGSH depletion is a key event in AD progression, accelerating the onset of key neuropathological hallmarks of the disease. Thus, therapeutic approaches to recover mGSH may represent a relevant strategy in the treatment of AD.

Objective: Studies indicate general psychological stress plays a role in the glycemic control of individuals with type 1 diabetes mellitus (T1DM). Disease-specific rather than general measures may be more closely related to measures of health outcomes. Therefore, measurement of diabetes-related stress is needed to advance knowledge of significant relationships between stress and glycemic control. The objective of this study was to evaluate the psychometric properties of a measure of diabetes-related stress for youth with T1DM., Research Design and Methods: A 65-item diabetes stress questionnaire for youths (DSQY) was previously developed for use with older children and adolescents. The DSQY was completed by 417 youths with T1DM and the results were analyzed to determine the factor structure and psychometric properties of the questionnaire, as well as relationships of diabetes stress with demographic and clinical variables., Results: A factor analysis of the DSQY yielded an eight-factor solution with acceptable internal consistencies. Significant relationships were observed between glycemic control and stress related to parents and dietary issues. While age and socioeconomic status were unrelated with DSQY scores, higher stress was associated with longer diabetes duration, female gender, and racial/ethnic minority status., Conclusions: The DSQY is a reliable and valid measure for assessment of diabetes-specific stress in youths with T1DM., (© 2012 John Wiley & Sons A/S.)

Background: Within 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., Aims: To 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)., Method: Participants 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., Results: The 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., Conclusions: Adjustment disorder shows a distinct profile as an intermediate category between no mental disorder and affective disorders (depression and anxiety disorders).

Risk analysis tools can be applied in the early stages of the research, development, and innovation of pharmaceutical drugs. We used a risk ranking and filtering method to optimize time resources in internal audits of project development documents in order to ensure traceability in a university pilot plant. Data gathered during audits undertaken over a 14 month period were classified according to risk factors at several levels. Consequently, time resources for this type of internal audit can be optimised by focusing on aspects that are objectively determined to be critical to traceability. In addition, quality can be ensured by paying more attention to the most critical aspects, rather than the most commonly observed findings in historical data., Lay Abstract: One of the most important issue for a research, development, and innovation centre is the traceability of both experimental tasks and their documentation. This study describes an analysis of the findings revealed during internal audits carried out over a 14 month period, in order to establish its criticality and to highlight those important aspects to consider in future audits, while saving both personnel and time resources to carry out internal audits on development of projects.

Purpose: 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., Methods: 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., Results: 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., Conclusions: 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.

Neurocognitive functioning may be compromised in children with type 1 diabetes mellitus (T1DM). The factor most consistently implicated in the long-term neurocognitive functioning of children with T1DM is age of onset. The pediatric literature suggests that glycemic extremes may have an effect on the neurocognitive functioning of children, but findings are mixed. The purpose of this study was to compare the neurocognitive functioning of young children with T1DM diagnosed before 6 yr of age and healthy children (i.e., without chronic illness). Additionally, in the children with T1DM, we examined the relationship between their neurocognitive functioning and glycemic control. Sixty-eight (36 with T1DM and 32 without chronic illness) preschool-age children (M age = 4.4 yr ) were recruited and administered a battery of instruments to measure cognitive, language, and fine motor skills. Children with T1DM performed similar to the healthy controls and both groups' skills fell in the average range. Among children with diabetes, poor glycemic control [higher hemoglobin A1c (HbA1c)] was related to lower general cognitive abilities (r = -0.44,p < 0.04), slower fine motor speed (r = -0.64,p < 0.02), and lower receptive language scores (r = -0.39,p < 0.04). Such findings indicate that young children with T1DM already demonstrate some negative neurocognitive effects in association with chronic hyperglycemia.

The purpose of this study was to examine youths' knowledge of the hemoglobin A1c (HbA1c) test and glycemic control. Seventy youths (11-16 year olds) with type 1 diabetes were interviewed concerning their knowledge of the HbA1c test, health risks associated with particular HbA1c values, and their own glycemic goals. Results revealed that only 13% of youths accurately described the HbA1c test. Fewer correctly identified the HbA1c ranges for good, fair, and poor glycemic control. The majority of youths did not know the blood glucose values corresponding to specific HbA1c results. Only a small number of youth correctly estimated the short-term and long-term risks associated with maintenance of HbA1c of 7% and 12%. In this sample of mostly lower-income, minority youths with type 1 diabetes, there was a significant lack of knowledge concerning the meaning and implications of the HbA1c test. Findings suggest that interventions for this patient population should use the HbA1c test results to help young patients to better understand and set goals for their glycemic control.

Background: The World Health Organization (WHO) has stated that the three leading causes of burden of disease in 2030 are projected to include HIV/AIDS, unipolar depression and ischaemic heart disease., Aims: To estimate health-related quality of life (HRQoL) and quality-adjusted life-year (QALY) losses associated with mental disorders and chronic physical conditions in primary healthcare using data from the diagnosis and treatment of mental disorders in primary care (DASMAP) study, an epidemiological survey carried out with primary care patients in Catalonia (Spain)., Method: A cross-sectional survey of a representative sample of 3815 primary care patients. A preference-based measure of health was derived from the 12-item Short Form Health Survey (SF-12): the Short Form-6D (SF-6D) multi-attribute health-status classification. Each profile generated by this questionnaire has a utility (or weight) assigned. We used non-parametric quantile regressions to model the association between both mental disorders and chronic physical condition and SF-6D scores., Results: Conditions associated with SF-6D were: mood disorders, beta = -0.20 (95% CI -0.18 to -0.21); pain, beta = -0.08 (95%CI -0.06 to -0.09) and anxiety, beta = -0.04 (95% CI -0.03 to -0.06). The top three causes of QALY losses annually per 100 000 participants were pain (5064), mood disorders (2634) and anxiety (805)., Conclusions: Estimation of QALY losses showed that mood disorders ranked second behind pain-related chronic medical conditions.

Purpose: 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)., Methods: 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., Results: 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., Conclusions: 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.

The molecular mechanisms of Alzheimer's disease (AD) are not fully understood. Extensive evidence from experimental models has involved the overgeneration and accumulation of toxic amyloid beta peptides (Abeta) in the onset and progression of the disease. The amyloidogenic processing of amyloid precursor protein into pathogenic Abeta fragments is thought to occur in specific domains of the plasma membrane and favored by cholesterol enrichment. Intracellular Abeta accumulation is known to induce oxidative stress, predominantly via mitochondria targeting of toxic Abeta. Recent evidence using mouse models of cholesterol loading has demonstrated that the specific mitochondrial cholesterol pool sensitizes neurons to Abeta-induced oxidant cell death and caspase-independent apoptosis due to selective mitochondrial GSH (mGSH) depletion induced by cholesterol-mediated perturbation of mitochondrial membrane dynamics. mGSH replenishment by permeable precursors such as glutathione ethyl ester protected against Abeta-mediated neurotoxicity and inflammation. Thus, these novel data expand the pathogenic role of cholesterol in AD indicating that in addition to fostering Abeta generation, mitochondrial cholesterol determines Abeta neurotoxicity via mGSH regulation.

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.

Background & Aims: Nuclear factor kappaB (NF-kappaB) is the master regulator of tumor necrosis factor (TNF) susceptibility. Although mitochondrial glutathione (mGSH) depletion was shown to sensitize hepatocytes to TNF despite NF-kappaB activation, the mechanisms involved, particularly the role of Bax oligomerization and mitochondrial outer membrane (MOM) permeabilization, 2 critical steps in cell death, remained unexplored., Methods: TNF signaling at the premitochondrial and mitochondrial levels was analyzed in primary mouse hepatocytes with or without mGSH depletion., Results: Unexpectedly, we observed that TNF activates caspase-8 independently of NF-kappaB inactivation, causing Bid cleavage and mitochondrial Bax oligomerization. However, their predicted consequences on MOM permeabilization, cytochrome c release, caspase-3 activation, and hepatocellular death occurred only on mGSH depletion. These events were preceded by stimulated mitochondrial reactive oxygen species that predominantly oxidized cardiolipin, changes not observed in acidic sphingomyelinase (ASMase)(-/-) hepatocytes. Oxidized cardiolipin potentiated oligomerized Bax-induced MOM-like liposome permeabilization by restructuring the lipid bilayer, without effect on membrane Bax insertion or oligomerization. ASMase(-/-) mice with mGSH depletion by cholesterol loading were resistant to TNF-induced liver injury in vivo., Conclusions: Thus, MOM-localized oligomeric Bax is not sufficient for TNF-induced MOM permeabilization and cell death requiring mGSH-controlled ASMase-mediated mitochondrial membrane remodeling by oxidized cardiolipin generation.

The pathogenesis of alcohol-induced liver disease (ALD) is still poorly understood. One of the clues to its progression relates to the alcohol-mediated susceptibility of hepatocytes to cell death by reactive oxygen species (ROS) and inflammatory cytokines. Tumor necrosis factor alpha (TNF) has been considered a key ALD mediator with acidic sphingomyelinase (ASMase)-mediated ceramide generation playing a critical role. TNF receptor 1 and 2 knock-out mice or ASMase(-/-) mice exhibit resistance to alcohol-mediated fatty liver and cell death. Furthermore, alcohol feeding has been shown to sensitize hepatocytes to TNF due to the limitation of mitochondrial glutathione (mGSH) through impaired import of GSH from the cytosol due to altered membrane order parameter caused by mitochondrial cholesterol increase. Selective pharmacological depletion of mGSH sensitizes hepatocytes to TNF-mediated cell death, which reproduces the observations found with alcohol feeding. TNF signaling analyses in hepatocytes with or without mGSH depletion indicate that mGSH prevents cardiolipin peroxidation (CLOOH) formation by TNF-induced ROS via ASMase and that CLOOH cooperates with oligomerized Bax to cause mitochondrial outer membrane permeabilization through destabilization of the lipid bilayer via increased bilayer-to-inverted hexagonal phase transitions. Thus, activation of ASMase and cholesterol-mediated mGSH depletion both collaborate to promote alcohol-induced TNF-mediated hepatocellular damage, suggesting novel therapeutic opportunities in ALD.

Objective: Acute Stress Disorder (ASD) and subclinical symptoms of acute stress (SAS) may be a useful framework for understanding the psychological reactions of mothers and fathers of children newly diagnosed with a pediatric malignancy., Patients and Methods: Mothers (N = 129) and fathers (N = 72) of 138 children newly diagnosed with cancer completed questionnaires assessing acute distress, anxiety, and family functioning. Demographic data were also gathered. Inclusion criteria were: a confirmed diagnosis of a pediatric malignancy in a child under the age of 18 years without prior chronic or life threatening illness and fluency in English or Spanish., Results: Descriptive statistics and multiple linear regressions were used to examine predictors of SAS. Fifty-one percent (N = 66) of mothers and 40% (N = 29) of fathers met DSM-IV diagnostic criteria for ASD. The majority of the sample reported experiencing at least one SAS. General anxiety, but not family functioning, was a strong predictor of SAS in both mothers and fathers even after controlling for demographic characteristics., Conclusions: Immediately following their child's diagnosis of cancer, most mothers and fathers experience SAS, with a subsample meeting criteria for ASD. More anxious parents are at heightened risk of more intense reactions. The findings support the need for evidence-based psychosocial support at diagnosis and throughout treatment for families who are at risk for acute distress reactions., ((c) 2007 Wiley-Liss, Inc.)

Unlabelled: Purpose Psychometric properties of the Psychosocial Assessment Tool 2.0 (PAT2.0), a brief screener for psychosocial risk in families of children with cancer, are presented., Methods: Female (N = 132) and male (N = 72) caregivers of 141 children newly diagnosed with cancer completed the PAT2.0 and measures of child behavior symptoms, anxiety, acute stress, and family functioning to establish validity. Internal consistency and test-retest reliability of the PAT2.0 were also examined., Results: Internal consistency and two-week test-retest for the PAT2.0 Total score was strong. Validity for the PAT2.0 was supported by significant correlations between the PAT2.0 subscales and measures of corresponding constructs. PAT2.0 Total scores were correlated with acute stress and child behavior symptoms for both mothers and fathers. Receiver-Operating Characteristic curves provided preliminary support for the proposed cutoffs., Conclusion: The PAT2.0 Total score is a useful screening tool for family psychosocial risk in the pediatric oncology population.

Background and Objective: Suicide is a public health problem and it is increasing in Spain. The objective of this study is to analyze the prevalence and risk factors of suicide related outcomes (ideation, plan and attempt) using data from the ESEMeD-Spain project., Subjects and Method: This is a face-to-face household survey carried out in a probability representative sample of the adult general population of Spain. 5,473 subjects were interviewed using the Composite International Diagnostic Interview (CIDI 3.0), developed by the World Mental Health Survey Initiative., Results: Lifetime prevalence of suicide ideation and attempts was 4.4% and 1.5%, respectively. Risk of suicide related outcomes was significantly higher among women (odds ratio [OR] = 2.3-2.7), younger cohorts (OR = 21.3-86), and lower education levels (OR = 5.3-6.4). Having a mental disorder was associated to an increased risk in all diagnostic categories, but especially in major depressive episode (OR = 5.3-6.8). Risk of suicide attempt was higher during the first year since the onset of ideation (OR = 30.2), decreasing thereafter., Conclusions: The prevalence of suicide related outcomes is low when compared with other countries. Results identified groups with higher risk (women, young, subjects with a mental disorder, psychiatric comorbidity and recent suicidal ideation) in which suicide prevention could show benefits.