Mutations in Membrin/GOSR2 Reveal Stringent Secretory Pathway Demands of Dendritic Growth and Synaptic Integrity.

Mutations in the Golgi SNARE (SNAP [soluble NSF attachment protein] receptor) protein Membrin (encoded by the GOSR2 gene) cause progressive myoclonus epilepsy (PME). Membrin is a ubiquitous and essential protein mediating ER-to-Golgi membrane fusion. Thus, it is unclear how mutations in Membrin result in a disorder restricted to the nervous system. Here, we use a multi-layered strategy to elucidate the consequences of Membrin mutations from protein to neuron. We show that the pathogenic mutations cause partial reductions in SNARE-mediated membrane fusion. Importantly, these alterations were sufficient to profoundly impair dendritic growth in Drosophila models of GOSR2-PME. Furthermore, we show that Membrin mutations cause fragmentation of the presynaptic cytoskeleton coupled with transsynaptic instability and hyperactive neurotransmission. Our study highlights how dendritic growth is vulnerable even to subtle secretory pathway deficits, uncovers a role for Membrin in synaptic function, and provides a comprehensive explanatory basis for genotype-phenotype relationships in GOSR2-PME

Altered Gene Expression in Pulmonary Tissue of Tryptophan Hydroxylase-1 Knockout Mice: Implications for Pulmonary Arterial Hypertension

The use of fenfluramines can increase the risk of developing pulmonary arterial hypertension (PAH) in humans, but the mechanisms responsible are unresolved. A recent study reported that female mice lacking the gene for tryptophan hydroxylase-1 (Tph1(−/−) mice) were protected from PAH caused by chronic dexfenfluramine, suggesting a pivotal role for peripheral serotonin (5-HT) in the disease process. Here we tested two alternative hypotheses which might explain the lack of dexfenfluramine-induced PAH in Tph1(−/−) mice. We postulated that: 1) Tph1(−/−) mice express lower levels of pulmonary 5-HT transporter (SERT) when compared to wild-type controls, and 2) Tph1(−/−) mice display adaptive changes in the expression of non-serotonergic pulmonary genes which are implicated in PAH. SERT was measured using radioligand binding methods, whereas gene expression was measured using microarrays followed by quantitative real time PCR (qRT-PCR). Contrary to our first hypothesis, the number of pulmonary SERT sites was modestly up-regulated in female Tph1(−/−) mice. The expression of 51 distinct genes was significantly altered in the lungs of female Tph1(−/−) mice. Consistent with our second hypothesis, qRT-PCR confirmed that at least three genes implicated in the pathogenesis of PAH were markedly up-regulated: Has2, Hapln3 and Retlna. The finding that female Tph1(−/−) mice are protected from dexfenfluramine-induced PAH could be related to compensatory changes in pulmonary gene expression, in addition to reductions in peripheral 5-HT. These observations emphasize the intrinsic limitation of interpreting data from studies conducted in transgenic mice that are not fully characterized

Parents' concerns about children are highly prevalent but often not confirmed by child doctors and nurses

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to assess the prevalence in the general population of parents' concerns about the development of their child, to identify groups at risk and to assess the association between parents' concerns and professional judgement.</p> <p>Methods</p> <p>We obtained cross-sectional data on a Dutch nationally representative sample of children aged 14 months, 3 3/4, 5–6 and 8–12 years within the setting of routine well-child visits provided to the entire population. A total of 4,107 participated (response rate 85.3%). Data were about concerns that parents reported by questionnaire before the visit regarding behavioural and emotional problems, developmental delay, consequences of disease and contact with peers that needed professional assistance, and about the assessment of these domains by doctors and nurses during the visit. Moreover, we obtained data on parent-reported psychosocial problems using the Infant-Toddler Social and Emotional Assessment and the Child Behavior Checklist.</p> <p>Results</p> <p>Of all parents, 49.3% reported some concerns and 8.7% reported frequent concerns, most frequently on child behaviour. Frequent concerns were most likely to refer to young children, children from labour immigrant families, with fathers of medium educational level and in low-income families. The prevalence rates of professional-assessed parenting problems were much lower than parent-reported ones. The rates of psychosocial problems were highest in the case of shared concerns, but also higher if parents expressed concerns that were not confirmed by professionals.</p> <p>Conclusion</p> <p>A very large proportion of parents of young children have concerns regarding their child, but agreement on these concerns with child health professionals is relatively low.</p

Gene expression in lungs of mice lacking the 5-hydroxytryptamine transporter gene

<p>Abstract</p> <p>Background</p> <p>While modulation of the serotonin transporter (5HTT) has shown to be a risk factor for pulmonary arterial hypertension for almost 40 years, there is a lack of in vivo data about the broad molecular effects of pulmonary inhibition of 5HTT. Previous studies have suggested effects on inflammation, proliferation, and vasoconstriction. The goal of this study was to determine which of these were supported by alterations in gene expression in serotonin transporter knockout mice.</p> <p>Methods</p> <p>Eight week old normoxic mice with a 5-HTT knock-out (5HTT-/-) and their heterozygote(5HTT+/-) or wild-type(5HTT+/+) littermates had right ventricular systolic pressure(RVSP) assessed, lungs collected for RNA, pooled, and used in duplicate in Affymetrix array analysis. Representative genes were confirmed by quantitative RT-PCR and western blot.</p> <p>Results</p> <p>RVSP was normal in all groups. Only 124 genes were reliably changed between 5HTT-/- and 5HTT+/+ mice. More than half of these were either involved in inflammatory response or muscle function and organization; in addition, some matrix, heme oxygenase, developmental, and energy metabolism genes showed altered expression. Quantitative RT-PCR for examples from each major group confirmed changes seen by array, with an intermediate level in 5HTT +/- mice.</p> <p>Conclusion</p> <p>These results for the first time show the in vivo effects of 5HTT knockout in lungs, and show that many of the downstream mechanisms suggested by cell culture and ex vivo experiments are also operational in vivo. This suggests that the effect of 5HTT on pulmonary vascular function arises from its impact on several systems, including vasoreactivity, proliferation, and immune function.</p

A multivariate hierarchical Bayesian approach to measuring agreement in repeated measurement method comparison studies

Background. Assessing agreement in method comparison studies depends on two fundamentally important components; validity (the between method agreement) and reproducibility (the within method agreement). The Bland-Altman limits of agreement technique is one of the favoured approaches in medical literature for assessing between method validity. However, few researchers have adopted this approach for the assessment of both validity and reproducibility. This may be partly due to a lack of a flexible, easily implemented and readily available statistical machinery to analyse repeated measurement method comparison data. Methods. Adopting the Bland-Altman framework, but using Bayesian methods, we present this statistical machinery. Two multivariate hierarchical Bayesian models are advocated, one which assumes that the underlying values for subjects remain static (exchangeable replicates) and one which assumes that the underlying values can change between repeated measurements (non-exchangeable replicates). Results. We illustrate the salient advantages of these models using two separate datasets that have been previously analysed and presented; (i) assuming static underlying values analysed using both multivariate hierarchical Bayesian models, and (ii) assuming each subject's underlying value is continually changing quantity and analysed using the non-exchangeable replicate multivariate hierarchical Bayesian model. Conclusion. These easily implemented models allow for full parameter uncertainty, simultaneous method comparison, handle unbalanced or missing data, and provide estimates and credible regions for all the parameters of interest. Computer code for the analyses in also presented, provided in the freely available and currently cost free software package WinBUGS

A primary care, multi-disciplinary disease management program for opioid-treated patients with chronic non-cancer pain and a high burden of psychiatric comorbidity

BACKGROUND: Chronic non-cancer pain is a common problem that is often accompanied by psychiatric comorbidity and disability. The effectiveness of a multi-disciplinary pain management program was tested in a 3 month before and after trial. METHODS: Providers in an academic general medicine clinic referred patients with chronic non-cancer pain for participation in a program that combined the skills of internists, clinical pharmacists, and a psychiatrist. Patients were either receiving opioids or being considered for opioid therapy. The intervention consisted of structured clinical assessments, monthly follow-up, pain contracts, medication titration, and psychiatric consultation. Pain, mood, and function were assessed at baseline and 3 months using the Brief Pain Inventory (BPI), the Center for Epidemiological Studies-Depression Scale scale (CESD) and the Pain Disability Index (PDI). Patients were monitored for substance misuse. RESULTS: Eighty-five patients were enrolled. Mean age was 51 years, 60% were male, 78% were Caucasian, and 93% were receiving opioids. Baseline average pain was 6.5 on an 11 point scale. The average CESD score was 24.0, and the mean PDI score was 47.0. Sixty-three patients (73%) completed 3 month follow-up. Fifteen withdrew from the program after identification of substance misuse. Among those completing 3 month follow-up, the average pain score improved to 5.5 (p = 0.003). The mean PDI score improved to 39.3 (p < 0.001). Mean CESD score was reduced to 18.0 (p < 0.001), and the proportion of depressed patients fell from 79% to 54% (p = 0.003). Substance misuse was identified in 27 patients (32%). CONCLUSIONS: A primary care disease management program improved pain, depression, and disability scores over three months in a cohort of opioid-treated patients with chronic non-cancer pain. Substance misuse and depression were common, and many patients who had substance misuse identified left the program when they were no longer prescribed opioids. Effective care of patients with chronic pain should include rigorous assessment and treatment of these comorbid disorders and intensive efforts to insure follow up

Comparison of a one-time educational intervention to a teach-to-goal educational intervention for self-management of heart failure: design of a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Heart failure (HF) is common, costly and associated with significant morbidity and poor quality of life, particularly for patients with low socioeconomic status. Self-management training has been shown to reduce HF related morbidity and hospitalization rates, but there is uncertainty about how best to deliver such training and what patients benefit. This study compares a single session self-management HF training program against a multiple session training intervention and examines whether their effects differ by literacy level.</p> <p>Methods/Design</p> <p>In this randomized controlled multi-site trial, English and Spanish-speaking patients are recruited from university-affiliated General Internal Medicine and Cardiology clinics at 4 sites across the United States. Eligible patients have HF with New York Heart Association class II-IV symptoms and are prescribed a loop diuretic. Baseline data, including literacy level, are collected at enrollment and follow-up surveys are conducted at 1, 6 and 12 months</p> <p>Upon enrollment, both the control and intervention groups receive the same 40 minute, literacy-sensitive, in-person, HF education session covering the 4 key self-management components of daily self assessment and having a plan, salt avoidance, exercise, and medication adherence. All participants also receive a literacy-sensitive workbook and a digital bathroom scale. After the baseline education was completed, patients are randomly allocated to return to usual care or to receive ongoing education and training. The intervention group receives an additional 20 minutes of education on weight and symptom-based diuretic self-adjustment, as well as periodic follow-up phone calls from the educator over the course of 1 year. These phone calls are designed to reinforce the education, assess participant knowledge of the education and address barriers to success.</p> <p>The primary outcome is the combined incidence of all cause hospitalization and death. Secondary outcomes include HF-related quality of life, HF-related hospitalizations, knowledge regarding HF, self-care behavior, and self-efficacy. The effects of each intervention will be stratified by patient literacy, in order to identify any differential effects.</p> <p>Discussion</p> <p>Enrollment of the proposed 660 subjects will continue through the end of 2009. Outcome assessments are projected to be completed by early 2011.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <url>http://www.clinicaltrials.gov/</url> NCT00378950</p

Synergistic interaction effect between job control and social support at work on general psychological distress

Purpose Little is known about the interaction between job control and social support at work on common mental disorders. To examine whether there is a synergistic interaction effect between job control and social support at work on general psychological distress and whether it differs by the level of job demands. Methods About 1,940 male and female workers from the Malmo Shoulder and Neck Study were chosen for this cross-sectional study. Job control, social support at work, and job demands were measured by the Swedish version of the Job Content Questionnaire, and general psychological distress was assessed by the General Health Questionnaire. Results A significant excessive risk increase for general psychological distress was observed when workers had both low job control and low social support at work in both men and women. The synergistic effect was stronger in women, when job demands were low (Rothman's synergy index was 2.16 vs. 1.51 when job demands were high). However, in male workers, while a strong synergistic effect between job control and social support at work was found when job demands were low (synergy index was 9.25), there was an antagonistic effect when job demands were high (synergy index was 0.52). Conclusions There was a synergistic interaction effect between job control and social support at work on general psychological distress, but the synergistic effect or its effect size differed by the level of job demands and gender. An atomic, additive approach to the risk assessment of the psychosocial work characteristics on common mental disorders could be misleading or lead to a risk underestimation