Functional characterisation of the amyotrophic lateral sclerosis risk locus GPX3/TNIP1

Background: Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this. // Methods: The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (Ncases = 20,806, Ncontrols = 59,804) with ‘omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray Ntotal = 942, protein Ntotal = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO). // Results: SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10−6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10−3, adjusted R2 = 0.042, Beffect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all < 0.0001), which were rescued with gpx3 expression, with no phenotype identified with tnip1 KD or gpx3 overexpression. // Conclusions: These results support GPX3 as a lead ALS risk gene in this locus, with more data needed to confirm/reject a role for TNIP1. This has implications for understanding disease mechanisms (GPX3 acts in the same pathway as SOD1, a well-established ALS-associated gene) and identifying new therapeutic approaches. Few previous examples of in-depth investigations of risk loci in ALS exist and a similar approach could be applied to investigate future expected GWAS findings

Effectiveness of a web-based self-help smoking cessation intervention: protocol of a randomised controlled trial

BACKGROUND: Cigarette smoking is a major risk factor for many chronic and fatal illnesses. Stopping smoking directly reduces those risks. The aim of this study is to investigate the effectiveness of a web-based interactive self-help programme for smoking cessation, known as the StopSite, by comparing it to an online self-help guide. Both interventions were based on cognitive-behavioural and self-control principles, but the former provided exercises, feedback and interactive features such as one-to-one chatrooms and a user forum, which facilitated mutual support and experience sharing. METHODS AND DESIGN: We conducted a randomised controlled trial to compare the interactive intervention with the self-help guide. The primary outcome measure was prolonged abstinence from smoking. Secondary outcomes were point-prevalence abstinence, number of cigarettes smoked, and incidence of quit attempts reported at follow-up assessments. Follow-up assessments took place three and six months after a one-month grace period for starting the intervention after baseline. Analyses were based on intention-to-treat principles using a conservative imputation method for missing data, whereby non-responders were classified as smokers. DISCUSSION: The trial should add to the body of knowledge on the effectiveness of web-based self-help smoking cessation interventions. Effective web-based programmes can potentially help large numbers of smokers to quit, thus having a major public health impact. TRIAL REGISTRATION: ISRCTN7442376

Delivery of a Small for Gestational Age Infant and Greater Maternal Risk of Ischemic Heart Disease

Background: Delivery of a small for gestational age (SGA) infant has been associated with increased maternal risk of ischemic heart disease (IHD). It is uncertain whether giving birth to SGA infant is a specific determinant of later IHD, independent of other risk factors, or a marker of general poor health. The purpose of this study was to investigate the association between delivery of a SGA infant and maternal risk for IHD in relation to traditional IHD risk factors. Methods and Findings: Risk of maternal IHD was evaluated in a population based cross-sectional study of 6,608 women with a prior live term birth who participated in the National Health and Nutrition Examination Survey (1999–2006), a probability sample of the U.S. population. Sequence of events was determined from age at last live birth and at diagnosis of IHD. Delivery of a SGA infant is strongly associated with greater maternal risk for IHD (age adjusted OR; 95 % CI: 1.8; 1.2, 2.9; p = 0.012). The association was independent of the family history of IHD, stroke, hypertension and diabetes (family historyadjusted OR; 95 % CI: 1.9; 1.2, 3.0; p = 0.011) as well as other risk factors for IHD (risk factor-adjusted OR; 95 % CI: 1.7; 1.1, 2.7; p = 0.025). Delivery of a SGA infant was associated with earlier onset of IHD and preceded it by a median of 30 (interquartile range: 20, 36) years. Conclusions: Giving birth to a SGA infant is strongly and independently associated with IHD and a potential risk factor that precedes IHD by decades. A pregnancy that produces a SGA infant may induce long-term cardiovascular changes tha

Use of mental health services among disaster survivors: predisposing factors

<p>Abstract</p> <p>Background</p> <p>Given the high prevalence of mental health problems after disasters it is important to study health services utilization. This study examines predictors for mental health services (MHS) utilization among survivors of a man-made disaster in the Netherlands (May 2000).</p> <p>Methods</p> <p>Electronic records of survivors (n = 339; over 18 years and older) registered in a mental health service (MHS) were linked with general practice based electronic medical records (EMRs) of survivors and data obtained in surveys. EMR data were available from 16 months pre-disaster until 3 years post-disaster. Symptoms and diagnoses in the EMRs were coded according to the International Classification of Primary Care (ICPC). Surveys were carried out 2–3 weeks and 18 months post-disaster, and included validated questionnaires on psychological distress, post-traumatic stress reactions and social functioning. Demographic and disaster-related variables were available. Predisposing factors for MHS utilization 0–18 months and 18–36 months post-disaster were examined using multiple logistic regression models.</p> <p>Results</p> <p>In multiple logistic models, adjusting for demographic and disaster related variables, MHS utilization was predicted by demographic variables (young age, immigrant, public health insurance, unemployment), disaster-related exposure (relocation and injuries), self-reported psychological problems and pre- and post-disaster physician diagnosed health problems (chronic diseases, musculoskeletal problems). After controlling for all health variables, disaster intrusions and avoidance reactions (OR:2.86; CI:1.48–5.53), hostility (OR:2.04; CI:1.28–3.25), pre-disaster chronic diseases (OR:1.82; CI:1.25–2.65), injuries as a result of the disaster (OR:1.80;CI:1.13–2.86), social functioning problems (OR:1.61;CI:1.05–2.44) and younger age (OR:0.98;CI:0.96–0.99) predicted MHS utilization within 18 months post-disaster. Furthermore, disaster intrusions and avoidance reactions (OR:2.29;CI:1.04–5.07) and hostility (OR:3.77;CI:1.51–9.40) predicted MHS utilization following 18 months post-disaster.</p> <p>Conclusion</p> <p>This study showed that several demographic and disaster-related variables and self-reported and physician diagnosed health problems predicted post-disaster MHS-use. The most important factors to predict post-disaster MHS utilization were disaster intrusions and avoidance reactions and symptoms of hostility (which can be identified as symptoms of PTSD) and pre-disaster chronic diseases.</p

Secondary prevention of heart disease – knowledge among cardiologists and Ω-3 (Omega-3) fatty acid prescribing behaviors in Karachi, Pakistan

<p>Abstract</p> <p>Background</p> <p>The use of omega-3 fatty acids is a currently proven strategy for secondary prevention of heart disease. The prescription practices for this important nutraceutical is not currently known. It is imperative to assess the knowledge of cardiologists regarding the benefits of omega-3 fatty acids and to determine the frequency of its prescription. The aim of the study was to determine the practices and associations of dietary fish prescribing among cardiologists of Karachi and to assess their knowledge of fish oil supplementation and attitudes toward dietary practices.</p> <p>Methods</p> <p>A cross sectional survey was conducted during the period of January to March, 2008. A self report questionnaire was employed. All practicing cardiologists of Karachi were included in the study. Multiple logistic regression analysis was performed to determine the independent factors associated with high fish prescribers.</p> <p>Results</p> <p>The sample comprised of a total of 163 cardiologists practicing in Karachi, Pakistan. Most (73.6%) of the cardiologists fell in the age range of 28 – 45 years and were male (90.8%). High fish prescribers only comprised 36.2% of the respondents. After adjusting for age and gender, multivariate analysis revealed that only the variable of knowledge about fish oil's role in reducing sudden cardiac death was independently associated with high fish prescribers OR = 6.38 [95% CI 2.58–15.78].</p> <p>Conclusion</p> <p>The level of knowledge about the benefits of omega-3 fatty acids is high and the cardiologists harbor a favorable attitude towards dispensing dietary fish advice. However, the prescription practices are less than optimal and not concordant with recommendations of organisations such as the American Heart Association and National Heart Foundation of Australia. The knowledge of prevention of sudden cardiac death in CVD patients has been identified as an important predictor of high fish prescription. This particular life-saving property of omega-3 fatty acids should be the focus of any implemented educational strategy targeted to improve secondary CVD prevention via omega-3 fatty acid supplementation.</p

Disrupting the rhythm of depression using Mobile Cognitive Therapy for recurrent depression: randomized controlled trial design and protocol

Background: Major depressive disorder (MDD) is projected to rank second on a list of 15 major diseases in terms of burden in 2030. The major contribution of MDD to disability and health care costs is largely due to its highly recurrent nature. Accordingly, efforts to reduce the disabling effects of this chronic condition should shift to preventing recurrence, especially in patients at high risk of recurrence. Given its high prevalence and the fact that interventions are necessary during the remitted phase, new approaches are needed to prevent relapse in depression. Methods/design: The best established effective and available psychological intervention is cognitive therapy. However, it is costly and not available for most patients. Therefore, we will compare the effectiveness and cost-effectiveness of self-management supported by online CT accompanied by SMS based tele-monitoring of depressive symptomatology, i.e. Mobile Cognitive Therapy (M-CT) versus treatment as us usual (TAU). Remitted patients (n = 268) with at least two previous depressive episodes will be recruited and randomized over (1) M-CT in addition to TAU versus (2) TAU alone, with follow-ups at 3, 12, and 24 months. Randomization will be stratified for number of previous episodes and type of treatment as usual. Primary outcome is time until relapse/recurrence over 24 months using DSM-IV-TR criteria as assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). For the economic evaluation the balance between costs and health outcomes will be compared across strategies using a societal perspective. Discussion: Internet-based interventions might be helpful in empowering patients to become their own disease managers in this lifelong recurrent disorder. This is, as far as we are aware of, the first study that examines the (cost) effectiveness of an E-mental health program using SMS monitoring of symptoms with therapist support to prevent relapse in remitted recurrently depressed patient

PRegnancy Outcomes after a Maternity Intervention for Stressful EmotionS (PROMISES): study protocol for a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>There is ample evidence from observational prospective studies that maternal depression or anxiety during pregnancy is a risk factor for adverse psychosocial outcomes in the offspring. However, to date no previous study has demonstrated that treatment of depressive or anxious symptoms in pregnancy actually could prevent psychosocial problems in children. Preventing psychosocial problems in children will eventually bring down the huge public health burden of mental disease. The main objective of this study is to assess the effects of cognitive behavioural therapy in pregnant women with symptoms of anxiety or depression on the child's development as well as behavioural and emotional problems. In addition, we aim to study its effects on the child's development, maternal mental health, and neonatal outcomes, as well as the cost-effectiveness of cognitive behavioural therapy relative to usual care.</p> <p>Methods/design</p> <p>We will include 300 women with at least moderate levels of anxiety or depression at the end of the first trimester of pregnancy. By including 300 women we will be able to demonstrate effect sizes of 0.35 or over on the total problems scale of the child behavioural checklist 1.5-5 with alpha 5% and power (1-beta) 80%.</p> <p>Women in the intervention arm are offered 10-14 individual cognitive behavioural therapy sessions, 6-10 sessions during pregnancy and 4-8 sessions after delivery (once a week). Women in the control group receive care as usual.</p> <p>Primary outcome is behavioural/emotional problems at 1.5 years of age as assessed by the total problems scale of the child behaviour checklist 1.5 - 5 years.</p> <p>Secondary outcomes will be mental, psychomotor and behavioural development of the child at age 18 months according to the Bayley scales, maternal anxiety and depression during pregnancy and postpartum, and neonatal outcomes such as birth weight, gestational age and Apgar score, health care consumption and general health status (economic evaluation).</p> <p>Trial Registration</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2242">NTR2242</a></p

Disrupting the rhythm of depression: design and protocol of a randomized controlled trial on preventing relapse using brief cognitive therapy with or without antidepressants

Background: Maintenance treatment with antidepressants is the leading strategy to prevent relapse and recurrence in patients with recurrent major depressive disorder (MDD) who have responded to acute treatment with antidepressants (AD). However, in clinical practice most patients (up to 70-80%) are not willing to take this medication after remission or take too low dosages. Moreover, as patients need to take medication for several years, it may not be the most cost-effective strategy. The best established effective and available alternative is brief cognitive therapy (CT). However, it is unclear whether brief CT while tapering antidepressants (AD) is an effective alternative for long term use of AD in recurrent depression. In addition, it is unclear whether the combination of AD to brief CT is beneficial.Methods/design: Therefore, we will compare the effectiveness and cost-effectiveness of brief CT while tapering AD to maintenance AD and the combination of CT with maintenance AD. In addition, we examine whether the prophylactic effect of CT was due to CT tackling illness related risk factors for recurrence such as residual symptoms or to its efficacy to modify presumed vulnerability factors of recurrence (e.g. rigid explicit and/or implicit dysfunctional attitudes). This is a multicenter RCT comparing the above treatment scenarios. Remitted patients on AD with at least two previous depressive episodes in the past five years (n = 276) will be recruited. The primary outcome is time related proportion of depression relapse/recurrence during minimal 15 months using DSM-IV-R criteria as assessed by the Structural Clinical Interview for Depression. Secondary outcome: economic evaluation (using a societal perspective) and number, duration and severity of relapses/recurrences.Discussion: This will be the first trial to investigate whether CT is effective in preventing relapse to depression in recurrent depression while tapering antidepressant treatment compared to antidepressant treatment alone and the combination of both. In addition, we explore explicit and implicit mediators of CT.Trial registration: Netherlands Trial Register (NTR): NTR1907

Modeling Disease Vector Occurrence when Detection Is Imperfect: Infestation of Amazonian Palm Trees by Triatomine Bugs at Three Spatial Scales

Blood-sucking bugs of the genus Rhodnius are major vectors of Chagas disease. Control and surveillance of Chagas disease transmission critically depend on ascertaining whether households and nearby ecotopes (such as palm trees) are infested by these vectors. However, no bug detection technique works perfectly. Because more sensitive methods are more costly, vector searches face a trade-off between technical prowess and sample size. We compromise by using relatively inexpensive sampling techniques that can be applied multiple times to a large number of palms. With these replicated results, we estimate the probability of failing to detect bugs in a palm that is actually infested. We incorporate this information into our analyses to derive an unbiased estimate of palm infestation, and find it to be about 50% – twice the observed proportion of infested palms. We are then able to model the effects of regional, landscape, and local environmental variables on palm infestation. Individual palm attributes contribute overwhelmingly more than landscape or regional covariates to explaining infestation, suggesting that palm tree management can help mitigate risk locally. Our results illustrate how explicitly accounting for vector, pathogen, or host detection failures can substantially improve epidemiological parameter estimation when perfect detection techniques are unavailable

Differential endothelial cell gene expression by African Americans versus Caucasian Americans: a possible contribution to health disparity in vascular disease and cancer

<p>Abstract</p> <p>Background</p> <p>Health disparities and the high prevalence of cardiovascular disease continue to be perplexing worldwide health challenges. This study addresses the possibility that genetic differences affecting the biology of the vascular endothelium could be a factor contributing to the increased burden of cardiovascular disease and cancer among African Americans (AA) compared to Caucasian Americans (CA).</p> <p>Methods</p> <p>From self-identified, healthy, 20 to 29-year-old AA (n = 21) and CA (n = 17), we established cultures of blood outgrowth endothelial cells (BOEC) and applied microarray profiling. BOEC have never been exposed to <it>in vivo </it>influences, and their gene expression reflects culture conditions (meticulously controlled) and donor genetics. Significance Analysis of Microarray identified differential expression of single genes. Gene Set Enrichment Analysis examined expression of pre-determined gene sets that survey nine biological systems relevant to endothelial biology.</p> <p>Results</p> <p>At the highly stringent threshold of False Discovery Rate (FDR) = 0, 31 single genes were differentially expressed in AA. <it>PSPH </it>exhibited the greatest fold-change (AA > CA), but this was entirely accounted for by a homolog (<it>PSPHL</it>) hidden within the <it>PSPH </it>probe set. Among other significantly different genes were: for AA > CA, <it>SOS1, AMFR, FGFR3; and for AA < CA, ARVCF, BIN3, EIF4B. </it>Many more (221 transcripts for 204 genes) were differentially expressed at the less stringent threshold of FDR <.05. Using the biological systems approach, we identified shear response biology as being significantly different for AA versus CA, showing an apparent tonic increase of expression (AA > CA) for 46/157 genes within that system.</p> <p>Conclusions</p> <p>Many of the genes implicated here have substantial roles in endothelial biology. Shear stress response, a critical regulator of endothelial function and vascular homeostasis, may be different between AA and CA. These results potentially have direct implications for the role of endothelial cells in vascular disease (hypertension, stroke) and cancer (via angiogenesis). Also, they are consistent with our over-arching hypothesis that genetic influences stemming from ancestral continent-of-origin could impact upon endothelial cell biology and thereby contribute to disparity of vascular-related disease burden among AA. The method used here could be productively employed to bridge the gap between information from structural genomics (for example, disease association) and cell function and pathophysiology.</p