Transsexualisme: enjeux et spécificités liés à la prise en charge d'une demande de réassignation sexuelle [Gender identity disorder: challenges and specificity in the treatment of requests for sexual reassignment].

Gender identity disorder is defined as a permanent desire to relieve one's own sexual features to acquire the sexual features and line to life of the opposite sex. The diagnosis is based on the psychiatric evaluation and treatment on an interdisciplinary approach by endocrinologists, surgeons and psychiatrists, and can be conceptualized into distinct phases: diagnostic evaluation, real life experience, hormonal treatment and surgery. Multiples challenges have to be faced, especially by the psychiatrist who follows the patient during the whole process.

A New Look at Emotional Intelligence: A Dual-Process Framework

In this article, the author provides a framework to guide¦research in emotional intelligence. Studies conducted up¦to the present bear on a conception of emotional intelligence¦as pertaining to the domain of consciousness and¦investigate the construct with a correlational approach.¦As an alternative, the author explores processes underlying¦emotional intelligence, introducing the distinction¦between conscious and automatic processing as a potential¦source of variability in emotionally intelligent¦behavior. Empirical literature is reviewed to support the¦central hypothesis that individual differences in emotional¦intelligence may be best understood by considering¦the way individuals automatically process emotional¦stimuli. Providing directions for research, the author¦encourages the integration of experimental investigation¦of processes underlying emotional intelligence with¦correlational analysis of individual differences and¦fosters the exploration of the automaticity component¦of emotional intelligence.

Superiority of the Triple Combination of Bortezomib-Thalidomide-Dexamethasone Over the Dual Combination of Thalidomide-Dexamethasone in Patients With Multiple Myeloma Progressing or Relapsing After Autologous Transplantation: The MMVAR/IFM 2005-04 Randomized Phase III Trial From the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

PURPOSE This prospective multicenter phase III study compared the efficacy and safety of a triple combination (bortezomib-thalidomide-dexamethasone [VTD]) versus a dual combination (thalidomide-dexamethasone [TD]) in patients with multiple myeloma (MM) progressing or relapsing after autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS Overall, 269 patients were randomly assigned to receive bortezomib (1.3 mg/m(2) intravenous bolus) or no bortezomib for 1 year, in combination with thalidomide (200 mg per day orally) and dexamethasone (40 mg orally once a day on 4 days once every 3 weeks). Bortezomib was administered on days 1, 4, 8, and 11 with a 10-day rest period (day 12 to day 21) for eight cycles (6 months), and then on days 1, 8, 15, and 22 with a 20-day rest period (day 23 to day 42) for four cycles (6 months). Results Median time to progression (primary end point) was significantly longer with VTD than TD (19.5 v 13.8 months; hazard ratio, 0.59; 95% CI, 0.44 to 0.80; P = .001), the complete response plus near-complete response rate was higher (45% v 25%; P = .001), and the median duration of response was longer (17.2 v 13.4 months; P = .03). The 24-month survival rate was in favor of VTD (71% v 65%; P = .093). Grade 3 peripheral neuropathy was more frequent with VTD (29% v 12%; P = .001) as were the rates of grades 3 and 4 infection and thrombocytopenia. CONCLUSION VTD was more effective than TD in the treatment of patients with MM with progressive or relapsing disease post-ASCT but was associated with a higher incidence of grade 3 neurotoxicity.

Correcting for the bias due to expression specificity improves the estimation of constrained evolution of expression between mouse and human.

MOTIVATION: Comparative analyses of gene expression data from different species have become an important component of the study of molecular evolution. Thus methods are needed to estimate evolutionary distances between expression profiles, as well as a neutral reference to estimate selective pressure. Divergence between expression profiles of homologous genes is often calculated with Pearson's or Euclidean distance. Neutral divergence is usually inferred from randomized data. Despite being widely used, neither of these two steps has been well studied. Here, we analyze these methods formally and on real data, highlight their limitations and propose improvements. RESULTS: It has been demonstrated that Pearson's distance, in contrast to Euclidean distance, leads to underestimation of the expression similarity between homologous genes with a conserved uniform pattern of expression. Here, we first extend this study to genes with conserved, but specific pattern of expression. Surprisingly, we find that both Pearson's and Euclidean distances used as a measure of expression similarity between genes depend on the expression specificity of those genes. We also show that the Euclidean distance depends strongly on data normalization. Next, we show that the randomization procedure that is widely used to estimate the rate of neutral evolution is biased when broadly expressed genes are abundant in the data. To overcome this problem, we propose a novel randomization procedure that is unbiased with respect to expression profiles present in the datasets. Applying our method to the mouse and human gene expression data suggests significant gene expression conservation between these species. CONTACT: marc.robinson-rechavi@unil.ch; sven.bergmann@unil.ch SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The use of positional scanning synthetic combinatorial libraries (PS-SCL) to study T Lympohcyte specificity and degeneracy

Les cellules CD8? T cytolytiques (CTL) sont les principaux effecteurs du système immunitaire adaptatif contre les infections et les tumeurs. La récente identification d?antigènes tumoraux humains reconnus par des cellules T cytolytiques est la base pour le, développement des vaccins antigène spécifiques contre le cancer. Le nombre d?antigènes tumoraux reconnus par des CTL que puisse être utilisé comme cible pour la vaccination des patients atteints du cancer est encore limité. Une nouvelle technique, simple et rapide, vient d?être proposée pour l?identification d?antigènes reconnus par des CTL. Elle se base sur l?utilisation de librairies combinatoriales de peptides arrangées en un format de "scanning" ou balayage par position (PS-SCL). La première partie de cette étude a consisté à valider cette nouvelle technique par une analyse détaillée de la reconnaissance des PS-SCL par différents clones de CTL spécifiques pour des antigènes associés à la tumeur (TAA) connus ainsi que par des clones de spécificité inconnue. Les résultats de ces analyses révèlent que pour tous les clones, la plupart des acides aminés qui composent la séquence du peptide antigénique naturel ont été identifiés par l?utilisation des PS-SCL. Les résultats obtenus ont permis d?identifier des peptides analogues ayant une antigènicité augmentée par rapport au peptide naturel, ainsi que des peptides comportant de multiples modifications de séquence, mais présentant la même réactivité que le peptide naturel. La deuxième partie de cette étude a consisté à effectuer des analyses biométriques des résultats complexes générés par la PS-SCL. Cette approche a permis l?identification des séquences correspondant aux épitopes naturels à partir de bases de données de peptides publiques. Parmi des milliers de peptides, les séquences naturelles se trouvent comprises dans les 30 séquences ayant les scores potentiels de stimulation les plus élevés pour chaque TAA étudié. Mais plus important encore, l?utilisation des PS-SCL avec un clone réactif contre des cellules tumorales mais de spécificité inconnue nous a permis d?identifier I?epitope reconnu par ce clone. Les données présentées ici encouragent l?utilisation des PS-SCL pour l?identification et l?optimisation d?épitopes pour des CTL réactifs anti-tumoraux, ainsi que pour l?étude de la reconnaissance dégénérée d?antigènes par les CTL.<br/><br/>CD8+ cytolytic T lymphocytes (CTL) are the main effector cells of the adaptive immune system against infection and tumors. The recent identification of moleculariy defined human tumor Ags recognized by autologous CTL has opened new opportunities for the development of Ag-specific cancer vaccines. Despite extensive work, however, the number of CTL-defined tumor Ags that are suitable targets for the vaccination of cancer patients is still limited, especially because of the laborious and time consuming nature of the procedures currentiy used for their identification. The use of combinatorial peptide libraries in positionai scanning format (Positional Scanning Synthetic Combinatorial Libraries, PS-SCL)' has recently been proposed as an alternative approach for the identification of these epitopes. To validate this approach, we analyzed in detail the recognition of PS-SCL by tumor-reactive CTL clones specific for multiple well-defined tumor-associated Ags (TAA) as well as by tumor-reactive CTL clones of unknown specificity. The results of these analyses revealed that for all the TAA-specific clones studied most of the amino acids composing the native antigenic peptide sequences could be identified through the use of PS-SCL. Based on the data obtained from the screening of PS-SCL, we could design peptide analogs of increased antigenicity as well as cross-reactive analog peptides containing multiple amino acid substitutions. In addition, the resuits of PS-SCL-screening combined with a recently developed biometric data analysis (PS-SCL-based biometric database analysis) allowed the identification of the native peptides in public protein databases among the 30 most active sequences, and this was the case for all the TAA studied. More importantiy, the screening of PS- SCL with a tumor-reactive CTL clone of unknown specificity resulted in the identification of the actual epitope. Overall, these data encourage the use of PS-SCL not oniy for the identification and optimization of tumor-associated CTL epitopes, but also for the analysis of degeneracy in T lymphocyte receptor (TCR) recognition of tumor Ags.<br/><br/>Les cellules T CD8? cytolytiques font partie des globules blancs du sang et sont les principales responsables de la lutte contre les infections et les tumeurs. Les immunologistes cherchent depuis des années à identifier des molécules exprimées et présentées à la surface des tumeurs qui puissent être reconnues par des cellules T CD8? cytolytiques capables ensuite de tuer ces tumeurs de façon spécifique. Ce type de molécules représente la base pour le développement de vaccins contre le cancer puisqu?elles pourraient être injectées aux patients afin d?induire une réponse anti- tumorale. A présent, il y a très peu de molécules capables de stimuler le système immunitaire contre les tumeurs qui sont connues parce que les techniques développées à ce jour pour leur identification sont complexes et longues. Une nouvelle technique vient d?être proposée pour l?identification de ce type de molécules qui se base sur l?utilisation de librairies de peptides. Ces librairies représentent toutes les combinaisons possibles des composants de base des molécules recherchées. La première partie de cette étude a consisté à valider cette nouvelle technique en utilisant des cellules T CD8? cytolytiques capables de tuer des cellules tumorales en reconnaissant une molécule connue présente à leur surface. On a démontré que l?utilisation des librairies permet d?identifier la plupart des composants de base de la molécule reconnue par les cellules T CD8? cytolytiques utilisées. La deuxième partie de cette étude a consisté à effectuer une recherche des molécules potentiellement actives dans des protéines présentes dans des bases des données en utilisant un programme informatique qui permet de classer les molécules sur la base de leur activité biologique. Parmi des milliers de molécules de la base de données, celles reconnues par nos cellules T CD8? cytolytiques ont été trouvées parmi les plus actives. Plus intéressant encore, la combinaison de ces deux techniques nous a permis d?identifier la molécule reconnue par une population de cellules T CD8? cytolytiques ayant une activité anti-tumorale, mais pour laquelle on ne connaissait pas la spécificité. Nos résultats encouragent l?utilisation des librairies pour trouver et optimiser des molécules reconnues spécifiquement par des cellules T CD8? cytolytiques capables de tuer des tumeurs.

Bicaval dual-lumen cannula for venovenous extracorporeal membrane oxygenation: Avalon© cannula in childhood disease.

Severe acute refractory respiratory failure is considered a life-threatening situation, with a high mortality of 40 to 60%. When conservative oxygenation methods fail, a lifesaving measure is the introduction of extracorporeal membrane oxygenation (ECMO). Venovenous ECMO (VV-ECMO) is a preferred modality of support for patients with refractory acute respiratory failure. Specifically, bicaval VV-ECMO is a well-recognized and validated therapy, where single or double periphery venous access is used for the insertion of two differently sized cannulas in order to achieve adequate blood oxygenation. Compared to venoarterial ECMO, in VV-ECMO, the rate of complications, such as thrombosis, bleeding, infection and ischemic events, is lower. On the other hand, the size and insertion location is an obstacle to patient mobilization. This is a considerable problem for patients where the time interval for lung recovery and the bridge to the transplantation is prolonged. To address this issue, a dual-lumen, single venovenous cannula was introduced. Here, by insertion of one single catheter in one target vessel, in a majority of cases in the right internal jugular vein, satisfactory oxygenation of the patient is achieved. In this form, the instituted VV-ECMO enables patient mobility, better physical rehabilitation and facilitates pulmonary extubation and toilet. However, relatively early, after the first short-term reports were published, a relatively high complication rate became evident. In the recent literature, the complication rate using actual commercially available double-lumen venovenous cannula ranges between 5 and 30%. These cases were mostly conjoined to the implantation phase or the early postoperative phase and vary between right heart perforation to migration of the cannula. This review focuses on complications allied to commercially available dual-lumen, single, venovenous cannula implantation, pointing out the critical segments of the implantation process and analyzing the structure of the device.

Reproducibility of Vertebral Fracture Assessment Readings From Dual-energy X-ray Absorptiometry in Both a Population-based and Clinical Cohort: Cohen's and Uniform Kappa.

Vertebral fracture assessments (VFAs) using dual-energy X-ray absorptiometry increase vertebral fracture detection in clinical practice and are highly reproducible. Measures of reproducibility are dependent on the frequency and distribution of the event. The aim of this study was to compare 2 reproducibility measures, reliability and agreement, in VFA readings in both a population-based and a clinical cohort. We measured agreement and reliability by uniform kappa and Cohen's kappa for vertebral reading and fracture identification: 360 VFAs from a population-based cohort and 85 from a clinical cohort. In the population-based cohort, 12% of vertebrae were unreadable. Vertebral fracture prevalence ranged from 3% to 4%. Inter-reader and intrareader reliability with Cohen's kappa was fair to good (0.35-0.71 and 0.36-0.74, respectively), with good inter-reader and intrareader agreement by uniform kappa (0.74-0.98 and 0.76-0.99, respectively). In the clinical cohort, 15% of vertebrae were unreadable, and vertebral fracture prevalence ranged from 7.6% to 8.1%. Inter-reader reliability was moderate to good (0.43-0.71), and the agreement was good (0.68-0.91). In clinical situations, the levels of reproducibility measured by the 2 kappa statistics are concordant, so that either could be used to measure agreement and reliability. However, if events are rare, as in a population-based cohort, we recommend evaluating reproducibility using the uniform kappa, as Cohen's kappa may be less accurate.

RasGAP Shields Akt from Deactivating Phosphatases in Fibroblast Growth Factor Signaling but Loses This Ability Once Cleaved by Caspase-3.

Fibroblast growth factor receptors (FGFRs) are involved in proliferative and differentiation physiological responses. Deregulation of FGFR-mediated signaling involving the Ras/PI3K/Akt and the Ras/Raf/ERK MAPK pathways is causally involved in the development of several cancers. The caspase-3/p120 RasGAP module is a stress sensor switch. Under mild stress conditions, RasGAP is cleaved by caspase-3 at position 455. The resulting N-terminal fragment, called fragment N, stimulates anti-death signaling. When caspase-3 activity further increases, fragment N is cleaved at position 157. This generates a fragment, called N2, that no longer protects cells. Here, we investigated in Xenopus oocytes the impact of RasGAP and its fragments on FGF1-mediated signaling during G2/M cell cycle transition. RasGAP used its N-terminal Src homology 2 domain to bind FGFR once stimulated by FGF1, and this was necessary for the recruitment of Akt to the FGFR complex. Fragment N, which did not associate with the FGFR complex, favored FGF1-induced ERK stimulation, leading to accelerated G2/M transition. In contrast, fragment N2 bound the FGFR, and this inhibited mTORC2-dependent Akt Ser-473 phosphorylation and ERK2 phosphorylation but not phosphorylation of Akt on Thr-308. This also blocked cell cycle progression. Inhibition of Akt Ser-473 phosphorylation and entry into G2/M was relieved by PHLPP phosphatase inhibition. Hence, full-length RasGAP favors Akt activity by shielding it from deactivating phosphatases. This shielding was abrogated by fragment N2. These results highlight the role played by RasGAP in FGFR signaling and how graded stress intensities, by generating different RasGAP fragments, can positively or negatively impact this signaling.

A probable dual mode of action for both L- and D-lactate neuroprotection in cerebral ischemia.

Lactate has been shown to offer neuroprotection in several pathologic conditions. This beneficial effect has been attributed to its use as an alternative energy substrate. However, recent description of the expression of the HCA1 receptor for lactate in the central nervous system calls for reassessment of the mechanism by which lactate exerts its neuroprotective effects. Here, we show that HCA1 receptor expression is enhanced 24 hours after reperfusion in an middle cerebral artery occlusion stroke model, in the ischemic cortex. Interestingly, intravenous injection of L-lactate at reperfusion led to further enhancement of HCA1 receptor expression in the cortex and striatum. Using an in vitro oxygen-glucose deprivation model, we show that the HCA1 receptor agonist 3,5-dihydroxybenzoic acid reduces cell death. We also observed that D-lactate, a reputedly non-metabolizable substrate but partial HCA1 receptor agonist, also provided neuroprotection in both in vitro and in vivo ischemia models. Quite unexpectedly, we show D-lactate to be partly extracted and oxidized by the rodent brain. Finally, pyruvate offered neuroprotection in vitro whereas acetate was ineffective. Our data suggest that L- and D-lactate offer neuroprotection in ischemia most likely by acting as both an HCA1 receptor agonist for non-astrocytic (most likely neuronal) cells as well as an energy substrate.

Dual and Opposite Effects of hRAD51 Chemical Modulation on HIV-1 Integration.

The cellular DNA repair hRAD51 protein has been shown to restrict HIV-1 integration both in vitro and in vivo. To investigate its regulatory functions, we performed a pharmacological analysis of the retroviral integration modulation by hRAD51. We found that, in vitro, chemical activation of hRAD51 stimulates its integration inhibitory properties, whereas inhibition of hRAD51 decreases the integration restriction, indicating that the modulation of HIV-1 integration depends on the hRAD51 recombinase activity. Cellular analyses demonstrated that cells exhibiting high hRAD51 levels prior to de novo infection are more resistant to integration. On the other hand, when hRAD51 was activated during integration, cells were more permissive. Altogether, these data establish the functional link between hRAD51 activity and HIV-1 integration. Our results highlight the multiple and opposite effects of the recombinase during integration and provide new insights into the cellular regulation of HIV-1 replication.

Interleukin-1- and type I interferon-dependent enhanced immunogenicity of an NYVAC-HIV-1 Env-Gag-Pol-Nef vaccine vector with dual deletions of type I and type II interferon-binding proteins.

UNLABELLED: NYVAC, a highly attenuated, replication-restricted poxvirus, is a safe and immunogenic vaccine vector. Deletion of immune evasion genes from the poxvirus genome is an attractive strategy for improving the immunogenic properties of poxviruses. Using systems biology approaches, we describe herein the enhanced immunological profile of NYVAC vectors expressing the HIV-1 clade C env, gag, pol, and nef genes (NYVAC-C) with single or double deletions of genes encoding type I (ΔB19R) or type II (ΔB8R) interferon (IFN)-binding proteins. Transcriptomic analyses of human monocytes infected with NYVAC-C, NYVAC-C with the B19R deletion (NYVAC-C-ΔB19R), or NYVAC-C with B8R and B19R deletions (NYVAC-C-ΔB8RB19R) revealed a concerted upregulation of innate immune pathways (IFN-stimulated genes [ISGs]) of increasing magnitude with NYVAC-C-ΔB19R and NYVAC-C-ΔB8RB19R than with NYVAC-C. Deletion of B8R and B19R resulted in an enhanced activation of IRF3, IRF7, and STAT1 and the robust production of type I IFNs and of ISGs, whose expression was inhibited by anti-type I IFN antibodies. Interestingly, NYVAC-C-ΔB8RB19R induced the production of much higher levels of proinflammatory cytokines (tumor necrosis factor [TNF], interleukin-6 [IL-6], and IL-8) than NYVAC-C or NYVAC-C-ΔB19R as well as a strong inflammasome response (caspase-1 and IL-1β) in infected monocytes. Top network analyses showed that this broad response mediated by the deletion of B8R and B19R was organized around two upregulated gene expression nodes (TNF and IRF7). Consistent with these findings, monocytes infected with NYVAC-C-ΔB8RB19R induced a stronger type I IFN-dependent and IL-1-dependent allogeneic CD4(+) T cell response than monocytes infected with NYVAC-C or NYVAC-C-ΔB19R. Dual deletion of type I and type II IFN immune evasion genes in NYVAC markedly enhanced its immunogenic properties via its induction of the increased expression of type I IFNs and IL-1β and make it an attractive candidate HIV vaccine vector. IMPORTANCE: NYVAC is a replication-deficient poxvirus developed as a vaccine vector against HIV. NYVAC expresses several genes known to impair the host immune defenses by interfering with innate immune receptors, cytokines, or interferons. Given the crucial role played by interferons against viruses, we postulated that targeting the type I and type II decoy receptors used by poxvirus to subvert the host innate immune response would be an attractive approach to improve the immunogenicity of NYVAC vectors. Using systems biology approaches, we report that deletion of type I and type II IFN immune evasion genes in NYVAC poxvirus resulted in the robust expression of type I IFNs and interferon-stimulated genes (ISGs), a strong activation of the inflammasome, and upregulated expression of IL-1β and proinflammatory cytokines. Dual deletion of type I and type II IFN immune evasion genes in NYVAC poxvirus improves its immunogenic profile and makes it an attractive candidate HIV vaccine vector.