Médication neuroleptique et risque de dyskinésie tardive : une enquête auprès de psychiatres et d’omnipraticiens du Québec

Chez les patients schizophrènes adultes, l'incidence des dyskinésies tardives (DT) durant les premiers cinq ans de traitement aux neuroleptiques peut atteindre 35 %. La prévention de cet effet iatrogénique reste pourtant un objectif secondaire pour les cliniciens. Cette étude explore l'influence de variables relatives aux patients et aux médecins sur les décisions de prescription de neuroleptiques et sur la prévention des DT. En réponse à 12 vignettes cliniques décrivant un patient schizophrène traité depuis cinq ans au moyen de 20 mg par jour d'halopéridol, 352 psychiatres et 279 omnipraticiens ont pris des décisions de prescription simulées. L'âge du patient, la présence des symptomes psychotiques, la présence de DT ainsi que l'efficacité du traitement médicamenteux variaient systématiquement dans les vignettes. Résultats : Seul l'âge du patient n'a pas d'effet sur les décisions. La plupart des médecins réduisent les doses pour les patients en rémission. Dans les cas de psychose active, les décisions sont affectées par la présence de DT et l'efficacité du traitement. Les psychiatres ont tendance à augmenter ou à réduire les doses, les omnipraticiens à changer la médication. Très peu de médecins choisissent de cesser la médication. Les psychiatres plus jeunes ont tendance à prescrire plus prudemment. Conclusions : les prescriptions similaires pour patients jeunes et âgés sont inquiétantes, ces derniers étant plus à risque de développer des DT irréversibles. Il faudrait comprendre pourquoi les médecins jugent que les patients âgés méritent des stratégies médicamenteuses aussi agressives que les plus jeunes. Psychiatres et omnipraticiens prescrivent de manière similaire mais leurs décisions ne reflètent pas nécessairement les recommandations émanant des recherches sur le traitement neuroleptique prolongé.The incidence of tardive dyskinesia (TD) during the first five years of neuroleptic treatment of adult schizophrenic patients, may rise to 35 %. Yet, the prevention of this iatrogenic effect remains a secondary objective for clinicians. This study explored how medication decisions might vary depending on patient characteristics and medical specialty, and to identify correlates of prescribing aimed at the prevention of TD. Method: Simulated medication decisions were elicited from 352 psychiatrists and 279 general practitioners in response to 12 brief written descriptions of a male schizophrenic outpatient treated for 5 years with 20 mg/day of haloperidol. Patient age, psychotic symptoms, signs of dyskinesia, and effectiveness of past treatment varied systematically in the descriptions. Results: Every variable except patient age affected decisions. Most physicians reduced doses for stable patients. In cases of active psychosis, decisions were affected by presence of dyskinesia and treatment effectiveness. Psychiatrists were more likely to increase or reduce doses, general practitioners to change medication. Very few physicians opted to cease medication. Younger psychiatrists made the most prudent decisions. Conclusions: From a tardive dyskinesia prevention perspective, similar prescriptions to older and younger patients are worrying. We need to understand why physicians might believe that older patients require just as aggressive medication regimen as younger patients. Respondents within and between specialties tend make similar simulated decisions, but these do not necessarily reflect recommendations from controlled research on chronic neuroleptic treatment

Hedgehog Signalling in Androgen Independent Prostate Cancer

Objectives: Androgen-deprivation therapy effectively shrinks hormone-naïve prostate cancer, both in the prostate and at sites of distant metastasis. However prolonged androgen deprivation generally results in relapse and androgen-independent tumour growth, which is inevitably fatal. The molecular events that enable prostate cancer cells to proliferate in reduced androgen conditions are poorly understood. Here we investigate the role of Hedgehog signalling in androgen-independent prostate cancer (AIPC). Methods: Activity of the Hedgehog signalling pathway was analysed in cultured prostate cancer cells, and circulating prostate tumour cells were isolated from blood samples of patients with AIPC. Results: AIPC cells were derived through prolonged culture in reduced androgen conditions, modelling hormone therapy in patients, and expressed increased levels of Hedgehog signalling proteins. Exposure of cultured AIPC cells to cyclopamine, which inhibits Hedgehog signalling, resulted in inhibition of cancer cell growth. The expression of the Hedgehog receptor PTCH and the highly prostate cancer-specific gene DD3PCA3 was significantly higher in circulating prostate cancer cells isolated from patients with AIPC compared with samples prepared from normal individuals. There was an association between PTCH and DD3PCA3 expression and the length of androgen-ablation therapy. Conclusions: Our data are consistent with reports implicating overactivity of Hedgehog signalling in prostate cancer and suggest that Hedgehog signalling contributes to the androgen-independent growth of prostate cancer cells. As systemic anti-Hedgehog medicines are developed, the Hedgehog pathway will become a potential new therapeutic target in advanced prostate cancer.Peer reviewedFinal Accepted Versio

Psychosocial care for persons affected by emergencies and major incidents: a Delphi study to determine the needs of professional first responders for education, training and support

Background The role of ambulance clinicians in providing psychosocial care in major incidents and emergencies is recognised in recent Department of Health guidance. The study described in this paper identified NHS professional first responders’ needs for education about survivors’ psychosocial responses, training in psychosocial skills, and continuing support. Method Ambulance staff participated in an online Delphi questionnaire, comprising 74 items (Round 1) on 7-point Likert scales. Second-round and third-round participants each received feedback based on the previous round, and responded to modified versions of the original items and to new items for clarification. Results One hundred and two participants took part in Round 1; 47 statements (64%) achieved consensus. In Round 2, 72 people from Round 1 participated; 15 out of 39 statements (38%) achieved consensus. In Round 3, 49 people from Round 2 participated; 15 out of 27 statements (59%) achieved consensus. Overall, there was consensus in the following areas: ‘psychosocial needs of patients’ (consensus in 34/37 items); ‘possible sources of stress in your work’ (8/9); ‘impacts of distress in your work’ (7/10); ‘meeting your own emotional needs’ (4/5); ‘support within your organisation’ (2/5); ‘needs for training in psychosocial skills for patients’ (15/15); ‘my needs for psychosocial training and support’ (5/6). Conclusions Ambulance clinicians recognise their own education needs and the importance of their being offered psychosocial training and support. The authors recommend that, in order to meet patients’ psychosocial needs effectively, ambulance clinicians are provided with education and training in a number of skills and their own psychosocial support should be enhanced

Determination of the standard deviation for proficiency assessment from past participant’s performances

The “uncertainty function” introduced by Thompson et al. estimates the reproducibility standard deviation (SR) as a function of concentration. This model was successfully applied to a data set derived from three proficiency testing schemes aiming at the quantification of three toxic elements (cadmium, lead and mercury) in blood and urine. A threshold concentration was determined for each element. Below this concentration SR is found to be constant, while above it the reproducibility relative standard deviation is constant. This model allows the a priori estimation of standard deviation for performance assessment for proficiency testing rounds.JRC.D.5-Standards for Food Bioscienc

Estrogen-Like Activity of Perfluoroalkyl Acids In Vivo and Interaction with Human and Rainbow Trout Estrogen Receptors In Vitro

The objectives of this study were to determine the structural characteristics of perfluoroalkyl acids (PFAAs) that confer estrogen-like activity in vivo using juvenile rainbow trout (Oncorhynchus mykiss) as an animal model and to determine whether these chemicals interact directly with the estrogen receptor (ER) using in vitro and in silico species comparison approaches. Perfluorooctanoic (PFOA), perfluorononanoic (PFNA), perfluorodecanoic (PFDA), and perfluoroundecanoic (PFUnDA) acids were all potent inducers of the estrogen-responsive biomarker protein vitellogenin (Vtg) in vivo, although at fairly high dietary exposures. A structure-activity relationship for PFAAs was observed, where eight to ten fluorinated carbons and a carboxylic acid end group were optimal for maximal Vtg induction. These in vivo findings were corroborated by in vitro mechanistic assays for trout and human ER. All PFAAs tested weakly bound to trout liver ER with half maximal inhibitory concentration (IC50) values of 15.2-289μM. Additionally, PFOA, PFNA, PFDA, PFUnDA, and perlfuorooctane sulfonate (PFOS) significantly enhanced human ERα-dependent transcriptional activation at concentrations ranging from 10-1000nM. Finally, we employed an in silico computational model based upon the crystal structure for the human ERα ligand-binding domain complexed with E2 to structurally investigate binding of these putative ligands to human, mouse, and trout ERα. PFOA, PFNA, PFDA, and PFOS all efficiently docked with ERα from different species and formed a hydrogen bond at residue Arg394/398/407 (human/mouse/trout) in a manner similar to the environmental estrogens bisphenol A and nonylphenol. Overall, these data support the contention that several PFAAs are weak environmental xenoestrogens of potential concer

Non-linear susceptibilities of spherical models

The static and dynamic susceptibilities for a general class of mean field random orthogonal spherical spin glass models are studied. We show how the static and dynamical properties of the linear and nonlinear susceptibilities depend on the behaviour of the density of states of the two body interaction matrix in the neighbourhood of the largest eigenvalue. Our results are compared with experimental results and also with those of the droplet theory of spin glasses.Comment: 20 pages, 2 fig

Elucidating the structural basis for differing enzyme inhibitor potency by cryo-EM

Histidine biosynthesis is an essential process in plants and microorganisms, making it an attractive target for the development of herbicides and antibacterial agents. Imidazoleglycerol-phosphate dehydratase (IGPD), a key enzyme within this pathway, has been biochemically characterized in both Saccharomyces cerevisiae (Sc_IGPD) and Arabidopsis thaliana (At_IGPD). The plant enzyme, having been the focus of in-depth structural analysis as part of an inhibitor development program, has revealed details about the reaction mechanism of IGPD, whereas the yeast enzyme has proven intractable to crystallography studies. The structure–activity relationship of potent triazole-phosphonate inhibitors of IGPD has been determined in both homologs, revealing that the lead inhibitor (C348) is an order of magnitude more potent against Sc_IGPD than At_IGPD; however, the molecular basis of this difference has not been established. Here we have used single-particle electron microscopy (EM) to study structural differences between the At and Sc_IGPD homologs, which could influence the difference in inhibitor potency. The resulting EM maps at ∼3 Å are sufficient to de novo build the protein structure and identify the inhibitor binding site, which has been validated against the crystal structure of the At_IGPD/C348 complex. The structure of Sc_IGPD reveals that a 24-amino acid insertion forms an extended loop region on the enzyme surface that lies adjacent to the active site, forming interactions with the substrate/inhibitor binding loop that may influence inhibitor potency. Overall, this study provides insights into the IGPD family and demonstrates the power of using an EM approach to study inhibitor binding

Soufisme et Tradition

René Guénon, s’il n’a pas laissé de textes conséquents sur le soufisme, s’en est toujours recommandé, comme l’un des prolongements possibles de son exposé doctrinal. Chez lui, le soufisme d’abord, et l’islam ensuite ne se comprennent qu’au regard de la Tradition primordiale, mère de toutes les traditions religieuses. Certains de ses disciples, dont le roumain Michel Vâlsan, vont creuser le même sillon pour donner au soufisme une teinte particulière. Ressourcé à la pensée du mystique Ibn Arabî, passé au crible de la doctrine traditionnelle, le soufisme guénonien se présente comme la dernière possibilité initiatique en Occident. De son côté, le cheikh Pallavicini développe une conception similaire pour installer sa confrérie dans le paysage religieux italien. Il favorise ainsi l’émergence d’un soufisme d’Occident, chrétien dans son univers culturel, européen dans son espace géographique et guénonien dans ses projections métapolitiques.If René Guénon hasn’t left any sizeable texts about sufism, it has always been a reference as a possible extension of his doctrinal work. According to him, sufism first and then Islam can only be understood from the primordial Tradition viewpoint, the origin of all the religions traditions. Some of his followers, like Michel Vâlsan, a Rumanian man will pave the same way to give sufism a certain tone. Enriched by mystic Ibn Arabî, closely examined by the traditional doctrine, guenonian sufism is presented as the last initiatory possibility in the West. As for Shaykh Pallavicini, he develops a similar conception to impose his brotherhood in the Italian religious scene. He then favours the emergence of a western sufism, which is christian for its culture, european for its geographical place and Guenonian for its metapolitical projections.René Guénon, si bien no dejó textos consecuentes sobre el sufismo, siempre lo mencionó como una de las posibles ramificaciones de su desarrollo doctrinal. En su trabajo, el sufismo primero y el Islam luego no se comprenden si no es en relación con la Tradición primordial, madre de todas las tradiciones religiosas. Algunos de sus discípulos, entre ellos el rumano Michel Vâlsan, van a recorrer el mismo camino para dar al sufismo un rasgo particular. Abrevado en el pensamiento del místico Ibn Arabî, pasado por el filtro de la doctrina tradicional, el sufismo gueoniano se presenta como la última posibilidad iniciática en Occidente. Por su parte, el sheik Pallavicini desarrolla una concepción similar para instalar su cofradía en el paisaje religioso italiano. Favorece así la emergencia de un sufismo de Occidente, cristiano en su universo cultural, europeo en su espacio geográfico y gueoniano en sus proyecciones metapolíticas