Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study.

BACKGROUND & AIM: Brain metastases are frequent in patients with metastatic melanoma, indicating poor prognosis. We investigated the BRAF kinase inhibitor vemurafenib in patients with advanced melanoma with symptomatic brain metastases. METHODS: This open-label trial assessed vemurafenib (960mg twice a day) in patients with BRAF(V600) mutation-positive metastatic melanoma with non-resectable, previously treated brain metastases. The primary end-point was safety. Secondary end-points included best overall response rate, and progression-free and overall survival. RESULTS: Twenty-four patients received vemurafenib for a median treatment duration of 3.8 (0.1-11.3) months. The majority of discontinuations were due to disease progression (n=22). Twenty-three of 24 patients reported at least one adverse event (AE). Grade 3 AEs were reported in four (17%; 95% confidence interval [CI], 4.7-37.4%) patients and included cutaneous squamous cell carcinoma in four patients. Median progression-free survival was 3.9 (95% CI, 3.0-5.5) months, and median survival was 5.3 (95% CI, 3.9-6.6) months. An overall partial response (PR) at both intracranial and extracranial sites was achieved in 10 of 24 (42%; 95% CI, 22.1-63.4) evaluable patients, with stable disease in nine (38%; 95% CI, 18.8-59.4) patients. Of 19 patients with measurable intracranial disease, seven (37%) achieved >30% intracranial tumour regression, and three (16%; 95% CI, 3.4-39.6%) achieved a confirmed PR. Other signs of improvement included reduced need for corticosteroids and enhanced performance status. CONCLUSIONS: Vemurafenib can be safely used in patients with advanced symptomatic melanoma that has metastasised to the brain and can result in meaningful tumour regression.

A pedicled bone graft from the acromion: an anatomical investigation regarding surgical feasibility.

OBJECTIVE: To investigate the technical feasibility of harvesting a vascularized bone graft from the acromion pedicled on the acromial branch. BACKGROUND: Complex fractures of the proximal humerus may result in partial or total avascular necrosis of the head fragment. Treatment of avascular necrosis of the humeral head is dependent upon the stage of disease as well as the dimension and location of necrosis. In general, the outcome is poor and complete restoration of the shoulder function is rarely attained. Contrary to osteonecrosis of carpal bones (where vascularized bone grafts have been routinely carried out for decades), reports of analogous procedures at the humeral head are anecdotal. METHODS: Based on selective post-mortem computer-tomographic angiography of 5 and the dissection of 30 embalmed human cadaver shoulders, we describe the anatomy of the acromial branch of the thoracoacromial trunk. The main focus was the constancy of its anatomical course, its dimensions and potential use as a nutrient vessel for a pedicled bone graft from the acromion. RESULTS: The course of the acromial branch revealed a constant topographic relationship to anatomical landmarks. Its terminal branches reliably supplied the anterior part of the acromion. The vascularized bone graft could be sufficiently mobilized to allow tension-free transfer to the humeral head as well as to the lateral two-thirds of the clavicle. CONCLUSION: We demonstrated the feasibility of vascularized bone graft harvesting from the acromion. This technique could be a joint-preserving procedure for osteonecrosis of the humeral head or may assist in the revision of a clavicular pseudoarthrosis.

Migrating concepts: Immigrant integration and the regulation of religious dress in France and Canada

Religion in general, and Islam in particular, has become one of the main focal points of policy-making and constitutional politics in many Western liberal states. This article proposes to examine the legal and political dynamics behind new regulations targeting individual religious practices of Muslims. Although one could presuppose that church-state relations or the understanding of secularism is the main factor accounting for either accommodation or prohibition of Muslim religious practices, I make the case that the policy frame used to conceptualize the integration of immigrants in each national context is a more significant influence on how a liberal state approaches the legal regulation of individual practices such as veiling. However, this influence must be assessed carefully since it may have different effects on the different institutional actors in charge of regulating religion, such as the Courts and the legislature. To assess these hypotheses I compare two countries, France and Canada, which are solid examples of two contrasting national policy frames for the integration of immigrants.

Computational fluid dynamics of the right ventricular outflow tract and of the pulmonary artery: a bench model of flow dynamics.

OBJECTIVES: The reconstruction of the right ventricular outflow tract (RVOT) with valved conduits remains a challenge. The reoperation rate at 5 years can be as high as 25% and depends on age, type of conduit, conduit diameter and principal heart malformation. The aim of this study is to provide a bench model with computer fluid dynamics to analyse the haemodynamics of the RVOT, pulmonary artery, its bifurcation, and left and right pulmonary arteries that in the future may serve as a tool for analysis and prediction of outcome following RVOT reconstruction. METHODS: Pressure, flow and diameter at the RVOT, pulmonary artery, bifurcation of the pulmonary artery, and left and right pulmonary arteries were measured in five normal pigs with a mean weight of 24.6 ± 0.89 kg. Data obtained were used for a 3D computer fluid-dynamics simulation of flow conditions, focusing on the pressure, flow and shear stress profile of the pulmonary trunk to the level of the left and right pulmonary arteries. RESULTS: Three inlet steady flow profiles were obtained at 0.2, 0.29 and 0.36 m/s that correspond to the flow rates of 1.5, 2.0 and 2.5 l/min flow at the RVOT. The flow velocity profile was constant at the RVOT down to the bifurcation and decreased at the left and right pulmonary arteries. In all three inlet velocity profiles, low sheer stress and low-velocity areas were detected along the left wall of the pulmonary artery, at the pulmonary artery bifurcation and at the ostia of both pulmonary arteries. CONCLUSIONS: This computed fluid real-time model provides us with a realistic picture of fluid dynamics in the pulmonary tract area. Deep shear stress areas correspond to a turbulent flow profile that is a predictive factor for the development of vessel wall arteriosclerosis. We believe that this bench model may be a useful tool for further evaluation of RVOT pathology following surgical reconstructions.

Profound impact of uncomplicated pregnancy on diastolic, but not systolic pulse contour of aortic pressure

RESUME: L'objectif de cette étude était de déterminer l'impact de la grossesse non compliquée sur l'onde de pouls de la pression aortique centrale. Méthode 66 femmes au total avec une grossesse simple ont été réparties en trois groupes selon le stade de leur gestation: premier trimestre (T1, n=22), deuxième trimestre (T2, n=20) et troisième trimestre (T3, n=24). Le groupe contrôle (C, n=21) était constitué de femmes non enceintes, en bonne santé habituelle, prenant une contraception oestroprogestative. La tonométrie d'aplanation a été utilisée pour l'acquisition des ondes de pouls centrale un appareil disponible dans le commerce (SphygmoCor) permet l'enregistrement de l'onde de pouls périphérique avec un tonomètre d'aplanation de l'artère radiale au niveau du poignet, puis effectue sa transformation en sa forme centrale, grâce à une analyse de Fourrier et une fonction de transfert. L'influence des ondes réfléchies sur l'onde de pouls a été déterminée non seulement pendant la systole (augmentation systolique), comme on procède habituellement dans l'analyse de l'onde de pouls, mais aussi pendant la diastole (augmentation diastolique). Résultats Au cours de la grossesse, les pressions centrales systolique et diastolique sont restées inchangées et comparables aux valeurs mesurées chez les femmes qui ne sont pas enceintes. Dans le groupe contrôle, l'augmentation systolique s'élevait à 8.1±7.5% de la pression de pouls ; il n'y avait pas de différence statistiquement significative avec les valeurs obtenues chez les femmes enceintes, et ce, à n'importe quel stade de la grossesse (T1 : 4.6±11.4%, T2: 5.0±9.3%, T3 : 4.7±8.1%). Par contre, l'amplitude de l'augmentation diastolique diminuait avec la progression de la grossesse (C 6.5±2.4%, T1 : 5.2±3.1%, T2 : 3.8±2.6%; P=0.002 versus C; T3 : 2.3±2.0%; P<0.0001 versus C et P=0.004 versus T 1). Conclusion La grossesse ne modifie pas la forme de l'onde de pouls systolique centrale, ce qui implique de la part du système cardiovasculaire une adaptation fine à la demande croissante de flux sanguin, et ce, à tous les stades de la grossesse. Par contre, l'amplitude de l'onde de réflexion atteignant l'aorte pendant la diastole diminue progressivement au cours de la grossesse. Perspectives De récentes études montrent qu'une valeur anormalement haute de l'augmentation systolique de la pression centrale, comme on peut la déterminer avec la tonométrie d'aplanation, pourrait être un indice de trouble hypertensif de la grossesse débutant. Cette technique simple pourrait être d'autant plus facile à mettre en oeuvre si les valeurs normales pour l'augmentation systolique étaient indépendantes du stade de la grossesse, comme le suggèrent nos résultats, du moins pour les mesures prises en position assise.

ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting.

INTRODUCTION: The 2004 version of the World Health Organization classification subdivides thymic epithelial tumors into A, AB, B1, B2, and B3 (and rare other) thymomas and thymic carcinomas (TC). Due to a morphological continuum between some thymoma subtypes and some morphological overlap between thymomas and TC, a variable proportion of cases may pose problems in classification, contributing to the poor interobserver reproducibility in some studies. METHODS: To overcome this problem, hematoxylin-eosin-stained and immunohistochemically processed sections of prototypic, "borderland," and "combined" thymomas and TC (n = 72) were studied by 18 pathologists at an international consensus slide workshop supported by the International Thymic Malignancy Interest Group. RESULTS: Consensus was achieved on refined criteria for decision making at the A/AB borderland, the distinction between B1, B2, and B3 thymomas and the separation of B3 thymomas from TCs. "Atypical type A thymoma" is tentatively proposed as a new type A thymoma variant. New reporting strategies for tumors with more than one histological pattern are proposed. CONCLUSION: These guidelines can set the stage for reproducibility studies and the design of a clinically meaningful grading system for thymic epithelial tumors.

Depressive disorder moderates the effect of the FTO gene on body mass index.

There is evidence that obesity-related disorders are increased among people with depression. Variation in the FTO (fat mass and obesity associated) gene has been shown to contribute to common forms of human obesity. This study aimed to investigate the genetic influence of polymorphisms in FTO in relation to body mass index (BMI) in two independent samples of major depressive disorder (MDD) cases and controls. We analysed 88 polymorphisms in the FTO gene in a clinically ascertained sample of 2442 MDD cases and 809 controls (Radiant Study). In all, 8 of the top 10 single-nucleotide polymorphisms (SNPs) showing the strongest associations with BMI were followed-up in a population-based cohort (PsyCoLaus Study) consisting of 1292 depression cases and 1690 controls. Linear regression analyses of the FTO variants and BMI yielded 10 SNPs significantly associated with increased BMI in the depressive group but not the control group in the Radiant sample. The same pattern was found in the PsyCoLaus sample. We found a significant interaction between genotype and affected status in relation to BMI for seven SNPs in Radiant (P<0.0057), with PsyCoLaus giving supportive evidence for five SNPs (P-values between 0.03 and 0.06), which increased in significance when the data were combined in a meta-analysis. This is the first study investigating FTO and BMI within the context of MDD, and the results indicate that having a history of depression moderates the effect of FTO on BMI. This finding suggests that FTO is involved in the mechanism underlying the association between mood disorders and obesity.

Viral inhibitor of apoptosis vFLIP/K13 protects endothelial cells against superoxide-induced cell death.

Human herpesvirus 8 (HHV-8) is the etiological agent of Kaposi's sarcoma (KS). HHV-8 encodes an antiapoptotic viral Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (vFLIP/K13). The antiapoptotic activity of vFLIP/K13 has been attributed to an inhibition of caspase 8 activation and more recently to its capability to induce the expression of antiapoptotic proteins via activation of NF-kappaB. Our study provides the first proteome-wide analysis of the effect of vFLIP/K13 on cellular-protein expression. Using comparative proteome analysis, we identified manganese superoxide dismutase (MnSOD), a mitochondrial antioxidant and an important antiapoptotic enzyme, as the protein most strongly upregulated by vFLIP/K13 in endothelial cells. MnSOD expression was also upregulated in endothelial cells upon infection with HHV-8. Microarray analysis confirmed that MnSOD is also upregulated at the RNA level, though the differential expression at the RNA level was much lower (5.6-fold) than at the protein level (25.1-fold). The induction of MnSOD expression was dependent on vFLIP/K13-mediated activation of NF-kappaB, occurred in a cell-intrinsic manner, and was correlated with decreased intracellular superoxide accumulation and increased resistance of endothelial cells to superoxide-induced death. The upregulation of MnSOD expression by vFLIP/K13 may support the survival of HHV-8-infected cells in the inflammatory microenvironment in KS.

Role of CYP2D6 in the stereoselective disposition of venlafaxine in humans.

CYP2D6 is involved in the O-demethylation metabolic pathway of venlafaxine in humans. In this study, we investigated whether this isozyme is stereoselective. Plasma samples from seven CYP2D6 extensive metabolizers (EMs) and five CYP2D6 poor metabolizers (PMs), collected during a period without and with coadministration of quinidine, were analysed. Subjects were administered venlafaxine hydrochloride 18.75 mg orally every 12 h for 48 h on two occasions (1 week apart); once alone and once during the concomitant administration of quinidine sulphate every 12 h. Blood and urine samples were collected under steady-state conditions over one dosing interval (12 h). The present results show that, although CYP2D6 catalyses the O-demethylation of both enantiomers of venlafaxine, it displays a marked stereoselectivity towards the (R)-enantiomer. The oral clearance of (R)-venlafaxine was found to be nine-fold higher in EMs compared to PMs [median (range) 173 (29-611) l/h versus 20 (16-24) l/h, P < 0.005], while it was two-fold higher for (S)-venlafaxine [73 (32-130) l/h versus 37 (21-44) l/h, P < 0.05]. In EMs, quinidine decreased (R)- and (S)-venlafaxine oral clearance by 12-fold ( 0.05) and four-fold ( 0.05), respectively. In contrast, quinidine did not have any effects on renal clearance of (R)-venlafaxine [4 (2-10) l/h for venlafaxine alone versus 5 (0.6-7) l/h for venlafaxine + quinidine] and of (S)-venlafaxine [4 (1-7) l/h for venlafaxine alone versus 3 (0.4-6) l/h for venlafaxine + quinidine]. The coadministration of quinidine to EMs resulted in an almost complete inhibition of the partial metabolic clearance of (R)-venlafaxine to O-demethylated metabolites [127 (10-493) l/h down to 1 (0.1-3) l/h, 0.05], while a seven-fold reduction was measured for (S)-venlafaxine [47 (14-94) l/h versus 7 (1-19) l/h, 0.05]. In PMs, coadministration of quinidine did not significantly change oral clearance and partial metabolic clearance of (R)- and (S)-venlafaxine to its various metabolites. In contrast, data obtained on the partial metabolic clearance of (R)- and (S)-venlafaxine to N-demethylated metabolites, a reaction which is mediated by CYP3A4, suggest a lack of stereoselectivity of this enzyme.

Stimulation of thermogenesis in men after combined glucose-long-chain triglyceride infusion.

The effect of combined long-chain triglyceride infusion (Intralipid 20%) with graded doses of insulin/glucose on energy expenditure was examined in 17 healthy young male volunteers by using the euglycemic insulin clamp technique in combination with indirect calorimetry. Intralipid was infused for 90 min at a constant rate of 0.23 g/min; plasma free fatty acids increased from base-line values of 380 +/- 8 mumol/l to steady state levels of 650 +/- 12 mumol/l. After 90 min the Intralipid was continued and insulin was infused at three rates (0.5, 2, and 4 mU/kg . min) to achieve steady state hyperinsulinemic plateaus of 63 +/- 4, 167 +/- 10, and 410 +/- 15 microU/ml. Plasma glucose concentration was maintained constant at basal euglycemic levels (insulin clamp technique) by infusing glucose at 0.24, 0.48, and 0.59 g/min, respectively. Glucose storage during the insulin clamp (ie, glucose uptake minus glucose oxidation) was 0.13, 0.33, and 0.40 g/min for each group and exogenous lipid storage was 0.17, 0.18, and 0.19 g/min, respectively. The net increment in energy expenditure was 0.15, 0.24, and 0.26 kcal/min, respectively, which represents 8.5% of the energy content of the total amount of glucose and lipid stored. The experimentally determined value (approximately 9%) for the cost of storing both glucose and lipid was found to be significantly greater than predicted by stoichiometric calculations. However, the experimental value for the combined infusion was less than that observed for glucose storage alone (12%). This finding provides support for the use of combined glucose/fat infusions in parenteral nutrition as it is used more economically than when glucose is infused alone.

Parental monitoring: a way to decrease substance use among Swiss adolescents?

The objective of this research was to determine whether the level of parental monitoring is associated with substance use among adolescents in Switzerland, and to assess whether this effect remains when these adolescents have consuming peers. For this purpose, we used a nationally representative sample from the Swiss participation in the 2007 European School Project on Alcohol and Other Drugs survey, which included 7,611 adolescents in public schools (8th-10th grades). Four levels of parental control were created and four substances (tobacco, alcohol, cannabis, and ecstasy) were analyzed. All significant variables at the bivariate level were included in the multivariate analysis. Most adolescents had a high level of parental monitoring and that was associated with younger age, females, high socioeconomic status, intact family structure, and satisfactory relationships with mother, father, and peers. Overall, substance use decreased as parental monitoring increased and high parental monitoring decreased as having consuming peers increased. Results remained essentially the same when the variable "having consuming peers" was added to the analysis. Conclusion: parental monitoring is associated to positive effects on adolescent substance use with a reduction of consumption and a lower probability of having consuming peers, which seems to protect adolescents against potentially negative peer influence. Encouraging parents to monitor their adolescents' activities and friendships by establishing rules about what is allowed or not is a way to limit the negative influence of consuming peers on adolescent substance use.

FAM111A Mutations Result in Hypoparathyroidism and Impaired Skeletal Development.

Kenny-Caffey syndrome (KCS) and the similar but more severe osteocraniostenosis (OCS) are genetic conditions characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. We studied five individuals with KCS and five with OCS and found that all of them had heterozygous mutations in FAM111A. One mutation was identified in four unrelated individuals with KCS, and another one was identified in two unrelated individuals with OCS; all occurred de novo. Thus, OCS and KCS are allelic disorders of different severity. FAM111A codes for a 611 amino acid protein with homology to trypsin-like peptidases. Although FAM111A has been found to bind to the large T-antigen of SV40 and restrict viral replication, its native function is unknown. Molecular modeling of FAM111A shows that residues affected by KCS and OCS mutations do not map close to the active site but are clustered on a segment of the protein and are at, or close to, its outer surface, suggesting that the pathogenesis involves the interaction with as yet unidentified partner proteins rather than impaired catalysis. FAM111A appears to be crucial to a pathway that governs parathyroid hormone production, calcium homeostasis, and skeletal development and growth.

Dépression post-partum maternelle et développement de l'enfant: revue de littérature et arguments en faveur d'une approche familiale

De nombreuses recherches ont montré que la dépression post-partum maternelle a un impact négatif sur le développement de l'enfant. Les difficultés affectives de la mère peuvent entraver sa capacité à interagir avec son enfant de manière ajustée, perturbant précocement la relation mère/enfant. Cependant, d'autres études ont souligné l'importance d'autres facteurs susceptibles de modérer cet impact, dans un sens positif ou négatif. Parmi ces facteurs, les recherches s'intéressant au rôle du père ont souligné que celui-ci pourrait compenser cet effet négatif, soit en offrant à l'enfant l'expérience d'interactions ajustées, soit en soutenant la mère dans ses difficultés. Mais il pourrait au contraire l'aggraver, dans le cas d'une relation conjugale conflictuelle par exemple. L'objectif de cette revue de littérature est de porter l'attention du lecteur sur l'intérêt que représente une approche familiale de ces questions, tant au point de vue de la recherche que du travail clinique.