Multiple sclerosis-related trigeminal neuralgia: a prospective series of 43 patients treated with gamma knife surgery with more than one year of follow-up.

BACKGROUND: Trigeminal neuralgia (TN) related to multiple sclerosis (MS) is more difficult to manage pharmacologically and surgically. OBJECTIVE: This article aims to evaluate the safety and efficacy of Gamma Knife surgery (GKS) in this special group of patients. METHODS: Between July 1992 and November 2010, 43 cases with more than 1 year of follow-up were operated with GKS for TN related to MS and prospectively evaluated in the Timone University Hospital, Marseille, France. Radiosurgery using the Gamma Knife (model B or C or Perfexion) was performed. A single 4-mm isocenter was positioned at a median distance of 8 mm (range 5.7-14.7) anterior to the emergence of the nerve. A median maximum dose of 85 Gy (range 75-90) was delivered. RESULTS: The median follow-up period was 53.8 months (12-157.1). Thirty-nine patients (90.7%) were initially pain free. Their actuarial probability of remaining pain free without medication at 6 months, 1, 3, 5 and 10 years was 87.2, 71.8, 43.1, 38.3 and 20.5%, respectively, and remained stable till 12 years. The hypoesthesia actuarial rate at 6 months, 1 and 2 years was 11.5, 11.5 and 16%, and remained stable till 12 years. CONCLUSIONS: GKS proved safe and effective in this special group of patients.

Role of the NALP3 Inflammasome in the Development of Two-Kidney, One Clip Hypertension in Mice

Objective: The NALP3 inflammasome functions as a sensor of danger signals and triggers processing and release of IL-1b. Mutations of NALP3 are responsible for the cryopyrin associated periodic syndromes, a group of autoinflammatory disorders that respond to IL1 inhibition. Genetic studies have also linked NALP3 to hypertension in man, but the mechanism is not understood. The aim of this study is to investigate the role of NAPL3 inflammasome in the development of hypertension in an animal model. Design and Method: Six-week old male WT and NALP3 KO mice were used for generating a two-kidney, one clip (2K1C) renovascular hypertension. A U-shaped stainless steel clip (O^ ¼0.12mm) was placed on left renal artery under anaesthesia. The same surgery without clipping was performed in sham mice. At week 6 and 12 after the clipping, intra-arterial blood pressure (BP) was measured in conscious mice. Blood was collected for plasma renin analysis. Heart and kidney were excised and stored for molecular and morphological examinations. n¼5-6 mice per group. Data are mean_SEM. Results: Mean BP was significantly increased at week 6 and 12 in WT-2K1C mice compared to WT-sham group (MBPweek6: 138_2 vs.124_3 mmHg, p<0.01 and MBPweek12: 141_5 vs.122_3 mmHg, p<0.01) followed with an significant increase in heart weight (HW) and a decrease in clipped kidney weight indices in WT-2K1C mice compared to the WT-sham (HW/ BWweek6: 4.65_0.04 vs. 3.99_0.12 mg/g, p<0.001 and HW/BWweek12: 4.94_0.15 vs. 4.22_0.12 mg/g, p<0.001). Interestingly, NALP3 KO-2K1C mice did not develop hypertension. The MBP of KO-2K1C mice was comparable to the KO-sham (MBPweek6: 122_3 vs. 119_3 mmHg, p>0.05 and MBPweek6: 128_5 vs.122_4 mmHg, p>0.05). There was also no significant change in heart and kidney weight indices between KO- 2K1C and KO-sham mice. Conclusion: The preliminary results suggest that absence of NALP3 protects mice from the development of renin-dependent hypertension. Further molecular and morphological examinations are ongoing for the confirmation and mechanism explanation.

Effectiveness of career counseling: A one-year follow-up

The aim of this study was to analyze the psychometric properties of the Career Adapt-Abilities Scale (CAAS) in a French-speaking Swiss sample and its relationship with personality dimensions and work engagement. The heterogeneous sample of 391 participants (Mage = 39.59, SD = 12.30) completed the CAAS-International and a short version of the Utrecht Work Engagement Scale. To assess personality dimensions, participants completed either the Zuckerman-Kuhlman-Aluja Personality Questionnaire (n=283) or the NEO-FFI-R (n=108). The internal consistencies for the four subscales and total scores of the CAAS ranged from good to excellent, and skewness and kurtosis values indicated that scores were normally distributed. Gender differences and cor- relations with age were small or negligible. Several CFA models confirmed the factor structure of the French version of the CAAS-International, with loadings very similar to the ones observed for the international form. Adaptability was related to different personality dimensions, particularly neuroticism and conscientiousness, and also to work engagement. When predicting work engage- ment, career adaptability had a significant incremental validity over personality dimensions. Fi- nally, career adaptability partially moderated the relationship between personality and work engagement, suggesting that career adaptability also contributes to regulating the expression of personality dispositions.

European Council of Legal Medicine (ECLM) accreditation of forensic pathology services in Europe.

Forensic experts play a major role in the legal process as they offer professional expert opinion and evidence within the criminal justice system adjudicating on the innocence or alleged guilt of an accused person. In this respect, medico-legal examination is an essential part of the investigation process, determining in a scientific way the cause(s) and manner of unexpected and/or unnatural death or bringing clinical evidence in case of physical, psychological, or sexual abuse in living people. From a legal perspective, these types of investigation must meet international standards, i.e., it should be independent, effective, and prompt. Ideally, the investigations should be conducted by board-certified experts in forensic medicine, endowed with a solid experience in this field, without any hierarchical relationship with the prosecuting authorities and having access to appropriate facilities in order to provide forensic reports of high quality. In this respect, there is a need for any private or public national or international authority including non-governmental organizations seeking experts qualified in forensic medicine to have at disposal a list of specialists working in accordance with high standards of professional performance within forensic pathology services that have been successfully submitted to an official accreditation/certification process using valid and acceptable criteria. To reach this goal, the National Association of Medical Examiners (NAME) has elaborated an accreditation/certification checklist which should be served as decision-making support to assist inspectors appointed to evaluate applicants. In the same spirit than NAME Accreditation Standards, European Council of Legal Medicine (ECLM) board decided to set up an ad hoc working group with the mission to elaborate an accreditation/certification procedure similar to the NAME's one but taking into account the realities of forensic medicine practices in Europe and restricted to post-mortem investigations. This accreditation process applies to services and not to individual practitioners by emphasizing policies and procedures rather than professional performance. In addition, the standards to be complied with should be considered as the minimum standards needed to get the recognition of performing and reliable forensic pathology service.

Perception of tobacco, cannabis, and alcohol use of others is associated with one's own use.

BACKGROUND: Interventions have been developed to reduce overestimations of substance use among others, especially for alcohol and among students. Nevertheless, there is a lack of knowledge on misperceptions of use for substances other than alcohol. We studied the prevalence of misperceptions of use for tobacco, cannabis, and alcohol and whether the perception of tobacco, cannabis, and alcohol use by others is associated with one's own use. METHODS: Participants (n=5216) in a cohort study from a census of 20-year-old men (N=11,819) estimated the prevalence of tobacco and cannabis use among peers of the same age and sex and the percentage of their peers drinking more alcohol than they did. Using the census data, we determined whether participants overestimated, accurately estimated, or underestimated substance use by others. Regression models were used to compare substance use by those who overestimated or underestimated peer substance with those who accurately estimated peer use. Other variables included in the analyses were the presence of close friends with alcohol or other drug problems and family history of substance use. RESULTS: Tobacco use by others was overestimated by 46.1% and accurately estimated by 37.3% of participants. Cannabis use by others was overestimated by 21.8% and accurately estimated by 31.6% of participants. Alcohol use by others was overestimated by more than half (53.4%) of participants and accurately estimated by 31.0%. In multivariable models, compared with participants who accurately estimated tobacco use by others, those who overestimated it reported smoking more cigarettes per week (incidence rate ratio [IRR] [95% CI], 1.17 [range, 1.05, 1.32]). There was no difference in the number of cigarettes smoked per week between those underestimating and those accurately estimating tobacco use by others (IRR [95% CI], 0.99 [range, 0.84, 1.17]). Compared with participants accurately estimating cannabis use by others, those who overestimated it reported more days of cannabis use per month (IRR [95% CI], 1.43 [range, 1.21, 1.70]), whereas those who underestimated it reported fewer days of cannabis use per month (IRR [95% CI], 0.62 [range, 0.23, 0.75]). Compared with participants accurately estimating alcohol use by others, those who overestimated it reported consuming more drinks per week (IRR [95% CI], 1.57 [range, 1.43, 1.72]), whereas those who underestimated it reported consuming fewer drinks per week (IRR [95% CI], 0.41 [range, 0.34, 0.50]). CONCLUSIONS: Perceptions of substance use by others are associated with one's own use. In particular, overestimating use by others is frequent among young men and is associated with one's own greater consumption. This association is independent of the substance use environment, indicating that, even in the case of proximity to a heavy-usage group, perception of use by others may influence one's own use. If preventive interventions are to be based on normative feedback, and their aim is to reduce overestimations of use by others, then the prevalence of overestimation indicates that they may be of benefit to roughly half the population; or, in the case of cannabis, to as few as 20%. Such interventions should take into account differing strengths of association across substances.

Registries in rheumatological and musculoskeletal conditions. Paediatric Behçet's disease: an international cohort study of 110 patients. One-year follow-up data.

OBJECTIVE: To set-up an international cohort of patients suspected with Behçet's disease (BD). The cohort is aimed at defining an algorithm for definition of the disease in children. METHODS: International experts have defined the inclusion criteria as follows: recurrent oral aphthosis (ROA) plus one of following-genital ulceration, erythema nodosum, folliculitis, pustulous/acneiform lesions, positive pathergy test, uveitis, venous/arterial thrombosis and family history of BD. Onset of disease is <16 years, disease duration is ≤3 years, future follow-up duration is ≥4 years and informed consent is obtained. The expert committee has classified the included patients into: definite paediatric BD (PED-BD), probable PED-BD and no PED-BD. Statistical analysis is performed to compare the three groups of patients. Centres document their patients into a single database. RESULTS: At January 2010, 110 patients (56 males/54 females) have been included. Mean age at first symptom: 8.1 years (median 8.2 years). At inclusion, 38% had only one symptom associated with ROA, 31% had two and 31% had three or more symptoms. A total of 106 first evaluations have been done. Seventeen patients underwent the first-year evaluation, and 36 had no new symptoms, 12 had one and 9 had two. Experts have examined 48 files and classified 30 as definite and 18 as probable. Twenty-six patients classified as definite fulfilled the International Study Group criteria. Seventeen patients classified as probable did not meet the international criteria. CONCLUSION: The expert committee has classified the majority of patients in the BD group although they presented with few symptoms independently of BD classification criteria.

Erreur sur la personne? Considérations liminaires pour une étude des écrits personnels en Suisse romande au XVIIIe siècle

The current tendency tu study personal testimonials of all kinds is useful when doing research into the period of Enlightenment in Europe. The prolific production of such documents in 18th-century Switzerland offers the opportunity to ask whether there was a specifically Swiss form of Enlightenment. The answer in undoubtedly complex. One must first look into received ideas that would permit establishing a coherent link between the prevailing intellectual atmospere in Switzerland and personal writings. Secondly, the originality of these abundant writings is not the primary concern. It is more important to try to understand the relationship between the historical implications of these writings and the conception of the human person that is conveyed therein. In studying the testimonials, the challenge lies in determining the contextual situation of the first person narrator - a rhetorical device that typifies the genre.

Mortality among 24,865 workers exposed to polychlorinated biphenyls (PCBs) in three electrical capacitor manufacturing plants: a ten-year update.

The objective of this analysis was to evaluate mortality among a cohort of 24,865 capacitor-manufacturing workers exposed to polychlorinated biphenyls (PCBs) at plants in Indiana, Massachusetts, and New York and followed for mortality through 2008. Cumulative PCB exposure was estimated using plant-specific job-exposure matrices. External comparisons to US and state-specific populations used standardized mortality ratios, adjusted for gender, race, age and calendar year. Among long-term workers employed 3 months or longer, within-cohort comparisons used standardized rate ratios and multivariable Poisson regression modeling. Through 2008, more than one million person-years at risk and 8749 deaths were accrued. Among long-term employees, all-cause and all-cancer mortality were not elevated; of the a priori outcomes assessed only melanoma mortality was elevated. Mortality was elevated for some outcomes of a priori interest among subgroups of long-term workers: all cancer, intestinal cancer and amyotrophic lateral sclerosis (women); melanoma (men); melanoma and brain and nervous system cancer (Indiana plant); and melanoma and multiple myeloma (New York plant). Standardized rates of stomach and uterine cancer and multiple myeloma mortality increased with estimated cumulative PCB exposure. Poisson regression modeling showed significant associations with estimated cumulative PCB exposure for prostate and stomach cancer mortality. For other outcomes of a priori interest--rectal, liver, ovarian, breast, and thyroid cancer, non-Hodgkin lymphoma, Alzheimer disease, and Parkinson disease--neither elevated mortality nor positive associations with PCB exposure were observed. Associations between estimated cumulative PCB exposure and stomach, uterine, and prostate cancer and myeloma mortality confirmed our previous positive findings.

Spare non-occupational HIV post-exposure prophylaxis by active contacting and testing of the source person.

OBJECTIVE: HIV-1 post-exposure prophylaxis (PEP) is frequently prescribed after exposure to source persons with an undetermined HIV serostatus. To reduce unnecessary use of PEP, we implemented a policy including active contacting of source persons and the availability of free, anonymous HIV testing ('PEP policy'). METHODS: All consultations for potential non-occupational HIV exposures i.e. outside the medical environment) were prospectively recorded. The impact of the PEP policy on PEP prescription and costs was analysed and modelled. RESULTS: Among 146 putative exposures, 47 involved a source person already known to be HIV positive and 23 had no indication for PEP. The remaining 76 exposures involved a source person of unknown HIV serostatus. Of 33 (43.4%) exposures for which the source person could be contacted and tested, PEP was avoided in 24 (72.7%), initiated and discontinued in seven (21.2%), and prescribed and completed in two (6.1%). In contrast, of 43 (56.6%) exposures for which the source person could not be tested, PEP was prescribed in 35 (81.4%), P &lt; 0.001. Upon modelling, the PEP policy allowed a 31% reduction of cost for management of exposures to source persons of unknown HIV serostatus. The policy was cost-saving for HIV prevalence of up to 70% in the source population. The availability of all the source persons for testing would have reduced cost by 64%. CONCLUSION: In the management of non-occupational HIV exposures, active contacting and free, anonymous testing of source persons proved feasible. This policy resulted in a decrease in prescription of PEP, proved to be cost-saving, and presumably helped to avoid unnecessary toxicity and psychological stress.

Activation mechanisms of the protease MALT1 and cleavage of one of its targets - the ribonuclease Regnase-1- in lymphocytes and lymphoma cell lines

Persistent infection induces an adaptive immune response that is mediated by T and B lymphocytes. Upon triggering with an antigen, these cells become activated and turn into fast expanding cells able to efficiently defend the host. Lymphocyte activation is controlled by a complex composed of CARMA1, BCL10 and MALT1 which regulates the NF-KB signaling pathway upon antigen triggering. Abnormally high expression or activity of either one of these three proteins can favor the development of lymphomas, while genetic defects in the pathway are associated with immunodeficiency. MALT1 was identified as a paracaspase sharing homology with other cysteine proteases, namely caspases and metacaspases. In order to be active, caspases need to dimerize. Based on their sequence similarity with MALT1, we hypothesized that dimerization might also be a mechanism of activation employed by MALT1. To address this assumption, we performed a bioinformatics modelling based on the crystal structures of several caspases. Our model suggested that the MALT1 caspase-like domain can indeed form dimers. This finding was later confirmed by several published crystal structures of MALT1. In the dimer interface of our model, we noticed the presence of charged amino acids that could potentially form salt bridges and thereby hold both monomers together. Mutation of one of these residues, E549, into alanine completely blocked the catalytic activity of MALT1. Additionally, we provided evidence for a role of E549 in promoting the MALTl-dependent growth of cells derived from diffuse large B cell lymphoma (DLBCL) of the aggressive B cell-like type (ABC). To our initial surprise, the E549A mutation showed only a partial defect in dimerization, indicating that additional residues are essential to form a stable dimer. The MALT1 crystal structures revealed a key function for E549 in stabilizing the catalytic site of the protease via its interaction with an arginine which is located next to the catalytic active cysteine. In an additional study, we discovered that MALT1 monoubiquitination is required for the catalytic activity of the protease. Interestingly, we found that the MALT1 dimer interface mutant E549A could not be monoubiquitinated. Based on these findings, we suggest that correct formation of the dimer interface is a prerequisite for monoubiquitination. In a second project, we discovered a novel target of the protease MALT1, the ribonuclease Regnase¬la It was described that the RNase activity of Regnase-1 negatively regulates immune responses. We could show that in ABC DLBCL cell lines, Regnase-1 is not only cleaved by MALT1 but also phosphorylated, at least in part, by the inhibitor of KB kinase (IKK). Both regulations appear to restrain the RNase function of Regnase-1 and thereby allow the production of pro-survival proteins. In conclusion, our studies further highlight and explain the importance of the catalytic activity of MALT1 for the activation of lymphocytes and provide additional knowledge for the development of specific drugs targeting the catalytic activity of MALT1 for immunomodulation and treatment of lymphomas.  SUMMARY IN FRENCH PhD Thesis Katrin Cabalzar 2 SUMMARY IN FRENCH Une infection persistante induit une réponse immunitaire adaptative par l'intermédiaire des lymphocytes T et B. Quand elles reconnaissent l'antigène, ces cellules sont activées et se multiplient très rapidement pour défendre efficacement l'hôte. L'activation des lymphocytes est transmise par un complexe composé de trois protéines, CARMA1, BCL10 et MALT1, qui régule la voie de signalisation NF-KB lorsque l'antigène est reconnu. L'expression ou l'activité anormalement élevée de l'une de ces trois protéines peut favoriser le développement de lymphomes, tandis que des défauts génétiques de cette voie de signalisation sont associés à l'immunodéficience. MALT1 a été identifiée comme étant une paracaspase qui partage des séquences homologues avec d'autres protéases à cystéine, comme les caspases et les métacaspases. Pour être actives, les caspases ont besoin de dimériser. Etant donné leur similarité de séquence avec MALT1, nous avons supposé que la dimérisation pouvait aussi être un mécanisme d'activation utilisé par MALT1. Pour vérifier cette hypothèse, nous avons conçu un modèle bioinformatique à partir des structures cristallographiques de plusieurs caspases. Et notre modèle a suggéré que le domaine catalytique de MALT1 était effectivement capable de former des dimères. Cette découverte a été confirmée plus tard par des publications qui montrent des structures cristallographiques dimériques de MALT1. Dans l'interface du dimère de notre modèle, nous avons remarqué la présence d'acides aminés chargés qui pouvaient former des liaisons ioniques et ainsi réunir les deux monomères. La mutation de l'un de ces résidus, E549, pour une alanine, a complètement inhibé l'activité catalytique de MALT1. De plus, nous avons mis en évidence un rôle d'E549 dans la croissance dépendante de MALT1, des cellules dérivées de lymphomes B diffus à grandes cellules (DLBCL) de sous-type cellules B actives (ABC). Dans un premier temps nous avons été surpris de constater que cette mutation révélait seulement un défaut partiel de dimérisation, ce qui indique que des acides aminés supplémentaires sont indispensables pour former un dimère stable. Les structures cristallographiques de MALT1 ont révélé un rôle primordial d'E549 dans la stabilisation du site catalytique de la protéase via son interaction avec une arginine qui se trouve à côté de la cystéine du site actif. Dans une autre étude, nous avons découvert que la monoubiquitination de MALT1 est requise pour l'activité catalytique de la protéase. A remarquer que nous avons trouvé que le mutant E549A de l'interface dimère de MALT1 n'a pas pu être monoubiquitiné. Sur la base de ces résultats, nous suggérons que la formation correcte de l'interface du dimère est une condition préalable pour la monoubiquitination. Dans un second projet, nous avons découvert une nouvelle cible de la protéase MALT1, la ribonucléase Regnase-1. Il a été décrit que l'activité RNase de Regnase-1 régulait négativement les réponses immunitaires. Nous avons pu montrer que dans les lignées cellulaires ABC DLBCL, la Regnase-1 n'était pas seulement clivée par MALT1 mais également phosphorylée, au moins en partie, par la kinase de l'inhibiteur de KB (IKK). Les deux régulations semblent supprimer la fonction RNase de Regnase-1 et permettre ainsi la stabilisation de certains ARN messagers et la production de protéines favorisant la survie. En conclusion, nos études mettent en évidence le rôle-clé de la dimérisation de MALT1 et expliquent l'importance de l'activité catalytique de MALT1 pour l'activation des lymphocytes. Ainsi, nos résultats apportent des connaissances supplémentaires pour le développement de médicaments spécifiques ciblant l'activité catalytique de MALT1, qui pourraient être utiles pour modifier les réponses immunitaires et traiter des lymphomes.

The sampling of ignitable liquids on suspects' hands

In arson cases, the collection and detection of traces of ignitable liquids on a suspect's hands can provide information to a forensic investigation. Police forces currently lack a simple, robust, efficient and reliable solution to perform this type of swabbing. In this article, we describe a study undertaken to develop a procedure for the collection of ignitable liquid residues on the hands of arson suspects. Sixteen different collection supports were considered and their applicability for the collection of gasoline traces present on hands and their subsequent analysis in a laboratory was evaluated. Background contamination, consisting of volatiles emanating from the collection supports, and collection efficiencies of the different sampling materials were assessed by passive headspace extraction with an activated charcoal strip (DFLEX device) followed by gas chromatography-mass spectrometry (GC-MS) analysis. After statistical treatment of the results, non-powdered latex gloves were retained as the most suitable method of sampling. On the basis of the obtained results, a prototype sampling kit was designed and tested. This kit is made of a three compartment multilayer bag enclosed in a sealed metal can and containing three pairs of non-powdered latex gloves: one to be worn by the sampler, one consisting of a blank sample and the last one to be worn by the person suspected to have been in contact with ignitable liquids. The design of the kit was developed to be efficient in preventing external and cross-contaminations.

One minute of grief: Emotional processing in short-term dynamic psychotherapy for adjustment disorder.

OBJECTIVE: Depth of emotional processing has shown to be related to outcome across approaches to psychotherapy. Moreover, a specific emotional sequence has been postulated and tested in several studies on experiential psychotherapy (Pascual-Leone & Greenberg, 2007). This process-outcome study aims at reproducing the sequential model of emotional processing in psychodynamic psychotherapy for adjustment disorder and linking these variables with ultimate therapeutic outcome. METHOD: In this study, 32 patients underwent short-term dynamic psychotherapy. On the basis of reliable clinical change statistics, a subgroup (n = 16) presented with good outcome and another subgroup (n = 16) had a poor outcome in the end of treatment. The strongest alliance session of each case was rated using the observer-rated system Classification of Affective Meaning States. Reliability coefficients for the measure were excellent (κ = .82). RESULTS: Using 1 min as the fine-grained unit of analysis, results showed that the experience of fundamentally adaptive grief was more common in the in-session process of patients with good outcome, compared with those with poor outcomes (χ2 = 6.56, p = .01, d = 1.23). This variable alone predicted 19% of the change in depressive symptoms as measured by the Beck Depression Inventory at the end of treatment. Moreover, sequences of the original model were supported and related to outcome. CONCLUSIONS: These results are discussed within the framework of the sequential model of emotional processing and its possible relevance for psychodynamic psychotherapy. (PsycINFO Database Record (c) 2015 APA, all rights reserved).