TRIM17 and TRIM28 antagonistically regulate the ubiquitination and anti-apoptotic activity of BCL2A1

International audienceBCL2A1 is an anti-apoptotic member of the BCL-2 family that contributes to chemoresistance in a subset of tumors. BCL2A1 has a short half-life due to its constitutive processing by the ubiquitin-proteasome system. This constitutes a major tumor-suppressor mechanism regulating BCL2A1 function. However, the enzymes involved in the regulation of BCL2A1 protein stability are currently unknown. Here, we provide the first insight into the regulation of BCL2A1 ubiquitination. We present evidence that TRIM28 is an E3 ubiquitin-ligase for BCL2A1. Indeed, endogenous TRIM28 and BCL2A1 bind to each other at the mitochondria and TRIM28 knock-down decreases BCL2A1 ubiquitination. We also show that TRIM17 stabilizes BCL2A1 by blocking TRIM28 from binding and ubiquitinating BCL2A1, and that GSK3 is involved in the phosphorylation-mediated inhibition of BCL2A1 degradation. BCL2A1 and its close relative MCL1 are thus regulated by common factors but with opposite outcome. Finally, overexpression of TRIM28 or knock-out of TRIM17 reduced BCLA1 protein levels and restored sensitivity of melanoma cells to BRAF-targeted therapy. Therefore, our data describe a molecular rheostat in which two proteins of the TRIM family antagonistically regulate BCL2A1 stability and modulate cell death

A Study of the Real-World Effectiveness of Group Psychoeducation for Bipolar Disorders: Is Change in Illness Perception a Key Mediator of Benefit?

International audienceBACKGROUND: Findings from efficacy trials of group psychoeducation (PE) for bipolar disorders (BD) led to its inclusion in evidence-based guidelines as a first-line mandatory treatment. However, pragmatic trials and observational studies are needed to determine its real-world effectiveness, impact on outcomes deemed important to patients and to clarify potential mediators of any benefits. METHODS: Individuals with BD were offered the opportunity to participate in 20h of PE and asked to complete pre- and post-intervention ratings of symptoms, knowledge about BD, medication adherence, and illness perception. A priori, two key patient outcomes were identified (social functioning and self-esteem); sample attrition due to dropout or relapse was recorded. RESULTS: Of 156 individuals who completed the pre-PE assessments, 103 completed the program and post-PE assessments. Only 4 of 53 dropouts were associated with BD relapse. Post-intervention, the PE completers demonstrated a statistically significant improvement in social functioning (p = 0.003, Effect Size (ES) = 0.26) and a trend towards improved self-esteem (ES = 0.14). Whilst there were significant changes in medication adherence (p = 0.002, ES = 0.28), knowledge of BD (p < 0.001, ES = 1.20), and illness perception (p < 0.001, ES = -0.37), mediational analysis demonstrated that only change in illness perception was associated to change in functioning (p=0.03) with no contribution from changes in knowledge of BD or medication adherence. CONCLUSIONS: In real-world settings, over 60% individuals completed 10-session course of PE. After controlling for demography and baseline clinical state, change in illness perception, rather than change in knowledge or medication adherence, emerged as a potential mediator of some benefits of PE

Use of a serious game to strengthen medication adherence in euthymic patients with bipolar disorder following a psychoeducational programme: A randomized controlled trial

International audienceAlthough psychoeducation programmes are the gold-standard intervention in bipolar disorder (BD), more innovative tools are needed to broaden and consolidate their effects, especially on treatment adherence. Serious games could be an option. Methods: We carried out a two-arm open randomized controlled trial to compare the add-on use of the serious game BIPOLIFE® for one month (n = 20) vs. treatment as usual (TAU; n = 21) following the completion of a psychoeducation programme in euthymic adults with BD. The primary outcome was the percentage of adherent patients (i.e., patients with a Medication Adherence Rating Scale, MARS, total score >7) at 4 months after the end of the psychoeducation programme. We also measured the changes in therapeutic adherence and beliefs on pharmacological treatments (Drug Attitude Inventory, DAI) between study inclusion and the 1-month (end of BIPOLIFE® use) and 4-month visits, healthcare use during the study period, and BIPOLIFE® acceptability.Results: The percentage of adherent patients was lower in the BIPOLIFE® group than in the TAU group at inclusion (p = 0.02). Conversely, the absolute variation of the MARS and DAI scores was higher in the BIPOLIFE® than in the TAU group at the 1-month visit (p = 0.03 and p = 0.002, respectively) but not at the 4-month visit (p = 0.22 and p = 0.07, respectively).Limitations: Small sample size, and low frequency of connexion to BIPOLIFE® declared by the patients.Conclusion: BIPOLIFE® may help patients with BD to increase their confidence in medications, if used regularly

Clinical features associated with trait-impulsiveness in euthymic bipolar disorder patients.

International audienceBACKGROUND: A strong association has been reported between trait-impulsiveness and bipolar disorder (BD). Much attention has been focused on this association, but subgroup analysis has generated conflicting results, raising questions about the role of trait-impulsiveness in suicidal behavior and substance misuse in bipolar patients. METHOD: We compared Barratt Impulsiveness Scale-10 scores between 385 euthymic bipolar patients and 185 healthy controls. We then investigated possible association between impulsiveness scores and the following clinical characteristics: suicide attempt (SA), lifetime alcohol/cannabis misuse, rapid cycling and mixed episodes. RESULTS: Bipolar patients and healthy controls had significantly different BIS-10 total score and subscores (motor, attentional and nonplanning impulsiveness) (all p values <0.0001). No association was observed between BIS-10 total score, personal history of SA, number of SA, age at first SA and history of violent SA. Higher BIS-10 total scores were associated with alcohol misuse (p=0.005), cannabis misuse (p<0.0001), with an additive effect for these two substances (p=0.005). Higher BIS-10 total scores were also associated with rapid cycling (p=0.006) and history of mixed episodes (p=0.002), with an additive effect of these two variables (p=0.0006). LIMITATIONS: We used only one clinical measurement of impulsiveness and did not carry out cognitive assessment. CONCLUSION: This study demonstrates that trait-impulsiveness may be considered as a dimensional feature associated with BD and with a more severe clinical expression of the disease, characterized by a history of substance misuse, rapid cycling and mixed episodes. We found no association between impulsiveness and SA characteristics in bipolar patients, confirming some previous negative results

Clinical expression of bipolar disorder type I as a function of age and polarity at onset: convergent findings in samples from France and the United States.

International audienceBACKGROUND: The clinical presentation, course, and comorbidities of bipolar disorder type I are highly heterogeneous, and this variability remains poorly predictable. Certain onset characteristics (eg, age and polarity at onset) may delineate subgroups differing in clinical expression and outcome. METHOD: We retrospectively investigated the association between both age and polarity at onset and the clinical characteristics of bipolar I disorder (DSM-IV) in 2 independent adult samples: 480 French patients assessed in 1992-2006 (patients had been recruited from 3 university-affiliated psychiatry departments) and 714 US patients assessed in 1991-2003 (data were extracted from the Bipolar Disorder Phenome Database). RESULTS: Polarity at onset correlated with subsequent predominance (P < .001). Most patients experienced a depressive onset (57.9% in France vs 71.0% in the United States; P < .001) associated with a higher density of depressive episodes, suicidal behavior, and alcohol misuse. A manic onset was associated with a higher density of manic episodes. Early onset was frequent in both countries (42% in France vs 68% in the United States; P < .001) and was associated with suicidal behavior and cannabis and cocaine/opiate misuse. Sensitivity for the prediction of clinical characteristics was 1%-35% for age at onset and 26%-47% for polarity at onset. CONCLUSIONS: Onset characteristics are associated with subsequent predominant polarity, suicidal behavior, and substance misuse in bipolar I disorder. These findings may facilitate personalized treatment strategies based on type of onset and may also facilitate early focused strategies for preventing comorbidity. Given the relatively low sensitivity and specificity of these onset characteristics for predicting clinical variables, the relevance of age and polarity at onset as specifiers in nosographical classifications will require further studies. However, polarity at onset may be the more relevant specifier, with further investigation required for age at onset

Duration of untreated bipolar disorder: missed opportunities on the long road to optimal treatment.

International audienceOBJECTIVE: Duration of untreated illness represents a potentially modifiable component of any diagnosis-treatment pathway. In bipolar disorder (BD), this concept has rarely been systematically defined or not been applied to large clinically representative samples. METHOD: In a well-characterized sample of 501 patients with BD, we estimated the duration of untreated bipolar disorder (DUB: the interval between the first major mood episode and first treatment with a mood stabilizer). Associations between DUB and clinical onset and the temporal sequence of key clinical milestones were examined. RESULTS: The mean DUB was 9.6 years (SD 9.7; median 6). The median DUB for those with a hypomanic onset (14.5 years) exceeded that for depressive (13 years) and manic onset (8 years). Early onset BD cases have the longest DUB (P < 0.0001). An extended DUB was associated with more mood episodes (P < 0.0001), more suicidal behaviour (P = 0.0003) and a trend towards greater lifetime mood instability (e.g. rapid cycling, possible antidepressant-induced mania). CONCLUSION: Duration of untreated bipolar disorder (DUB) will only be significantly reduced by more aggressive case finding strategies. Reliable diagnosis (especially for BD-II) and/or instigation of recommended treatments is currently delayed by insufficient awareness of the early, polymorphous presentations of BD, lack of systematic screening and/or failure to follow established guidelines

Personal protection against biting insects and ticks.

International audienceRecent events with the first cases of local transmission of chikungunya and dengue fever virus in southern France by Aedes albopictus, adding to the nuisance and potential vectors that can be encountered when traveling in tropical or sub-tropical countries, has shown the value of a reflection on the Personal protection against vectors (PPAV). It is seen during an outbreak of vector-borne disease, or simply because of nuisance arthropods, that our fellow citizens try to protect themselves individually by using an arsenal of resources available on the market. Yet most of these means have been neither checked for effectiveness or safety tests, however, essential. Travellers, staff on mission or assignment, are looking for specific information on how to protect themselves or their families. Health workers had at their disposal so far indications that vary widely from one source to another. Therefore it seemed important to the Society of Travel Medicine (SMV) and the French Society of Parasitology (SFP) to initiate a reflection on this theme. This reflection took the form of recommendations for good practice, following the outline established by the French High Health Authority (HAS). The aim was to gather all relevant information, verified and validated and the format to be used not only by health personnel (doctors, pharmacists, nurses), but also by travel agents and individuals. This document highlights the need to take into account the risk of vector-borne diseases, some deadly, and the benefit of various methods of personal protection. The choice of methods is clearly oriented towards those whose effectiveness has been proven and potential risks assessed. The paper finally proposes two decision trees based on the transmission type (day or night) and kind of stay (short or roaming, long and steady). It concerns travellers, but also expatriates, residents and nomads