ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment.

BACKGROUND AND OBJECTIVE: The in vivo implication of various cytochrome P450 (CYP) isoforms and of P-glycoprotein on methadone kinetics is unclear. We aimed to thoroughly examine the genetic factors influencing methadone kinetics and response to treatment. METHODS: Genotyping for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, ABCB1, and UGT2B7 polymorphisms was performed in 245 patients undergoing methadone maintenance treatment. To assess CYP3A activity, the patients were phenotyped with midazolam. RESULTS: The patients with lower CYP3A activity presented higher steady-state trough (R,S)-methadone plasma levels (4.3, 3.0, and 2.3 ng/mL x mg for low, medium, and high activity, respectively; P = .0002). As previously reported, CYP2B6*6/*6 carriers had significantly higher trough (S)-methadone plasma levels (P = .0001) and a trend toward higher (R)-methadone plasma levels (P = .07). CYP2D6 ultrarapid metabolizers presented lower trough (R,S)-methadone plasma levels compared with the extensive or intermediate metabolizers (2.4 and 3.3 ng/mL x mg, respectively; P = .04), whereas CYP2D6 poor metabolizer status showed no influence. ABCB1 3435TT carriers presented lower trough (R,S)-methadone plasma levels (2.7 and 3.4 ng/mL . mg for 3435TT and 3435CC carriers, respectively; P = .01). The CYP1A2, CYP2C9, CYP2C19, CYP3A5, and UGT2B7 genotypes did not influence methadone plasma levels. Only CYP2B6 displayed a stereoselectivity in its activity. CONCLUSION: In vivo, CYP3A4 and CYP2B6 are the major CYP isoforms involved in methadone metabolism, with CYP2D6 contributing to a minor extent. ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics. The genetic polymorphisms of these 4 proteins had no influence on the response to treatment and only a small influence on the dose requirement of methadone.

Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease.

BACKGROUND: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD. OBJECTIVE: We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD. DESIGN: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P < 10(-8)) were tested for association with CAD in 31,400 cases and 92,927 controls. RESULTS: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 Ã- 10(-9)), SLC17A3 (1.0 Ã- 10(-8)), GTPB10 (1.7 Ã- 10(-8)), CUBN (7.5 Ã- 10(-10)), HNF1A (1.2 Ã- 10(-12)), and FUT2 (6.6 Ã- 10(-9)), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-μmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 Ã- 10(-36)). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49). CONCLUSIONS: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD.

Inauguration du monument élevé aux soldats français morts à Arlon [Belgique] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 55661

Le roi Georges V en costume de higlander passe en revue la garde d'honneur à son arrivée à Ballater/ derrière le roi et lord Aberdeen : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 55671

M. Deschanel à Dinant [cérémonie en souvenir du sac de Dinant le 23 août 1914] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 55706

[Cérémonie militaire aux Invalides] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 55716

Habitatges "Els Químics" de Girona

Conjunt residencial Edificis A i C, Fase I, de 150 habitatges, locals comercials i aparcament, 15.668,62 m2 superfície edificable i una sèrie d’espais públics en el solar de l’antiga fàbrica anomenada “Els Químics”, a la ciutat de Girona.

Identification of a Poor-Prognosis BRAF-Mutant-Like Population of Patients With Colon Cancer.

PURPOSE Our purpose was development and assessment of a BRAF-mutant gene expression signature for colon cancer (CC) and the study of its prognostic implications. Materials and METHODS A set of 668 stage II and III CC samples from the PETACC-3 (Pan-European Trails in Alimentary Tract Cancers) clinical trial were used to assess differential gene expression between c.1799T>A (p.V600E) BRAF mutant and non-BRAF, non-KRAS mutant cancers (double wild type) and to construct a gene expression-based classifier for detecting BRAF mutant samples with high sensitivity. The classifier was validated in independent data sets, and survival rates were compared between classifier positive and negative tumors. Results A 64 gene-based classifier was developed with 96% sensitivity and 86% specificity for detecting BRAF mutant tumors in PETACC-3 and independent samples. A subpopulation of BRAF wild-type patients (30% of KRAS mutants, 13% of double wild type) showed a gene expression pattern and had poor overall survival and survival after relapse, similar to those observed in BRAF-mutant patients. Thus they form a distinct prognostic subgroup within their mutation class. CONCLUSION A characteristic pattern of gene expression is associated with and accurately predicts BRAF mutation status and, in addition, identifies a population of BRAF mutated-like KRAS mutants and double wild-type patients with similarly poor prognosis. This suggests a common biology between these tumors and provides a novel classification tool for cancers, adding prognostic and biologic information that is not captured by the mutation status alone. These results may guide therapeutic strategies for this patient segment and may help in population stratification for clinical trials.

Disseny de les instal·lacions de climatització, gas, electricitat i aigua calenta sanitària d'un edifici de 12 habitatges amb pàrquing

El projecte defineix les instal·lacions bàsiques en un edifici de 12 habitatges, incloent el disseny de la instal·lació d'ACS amb aportació per energies renovables. S'avaluen els sistemes més adequats per a cada instal·lació i es defineixen els materials i els elements constructius de l'edifici. Del pàrquing situat al soterrani s'estudiarà la ventilació que més s'escaigui i les proteccions contra incendis necessàries.

Complications liées aux piercings [Complications of body piercing].

Au sein de la population générale, de plus en plus de personnes arborent des piercings, en particulier parmi les jeunes adultes. Hormis les réactions inflammatoires et les infections locales, les complications liées à ces piercings sont méconnues. Les personnes ne sont en général pas informées des risques avant de réaliser un piercing et leurs antécédents, traitements médicamenteux ou comorbidités éventuelles, sont largement négligés par les personnes qui réalisent le geste. Les complications sont le plus souvent locales et bénignes, mais des complications sérieuses et parfois mortelles ont été décrites dans la littérature. Cet article propose une revue des problématiques possibles auxquelles pourrait être confronté un médecin de premier recours, face à un patient qui souhaiterait réaliser un piercing ou présenterait des complications suite à la mise en place d'un tel dispositif. The trend of body piercing has grown in popularity in the past decade within the general population and especially among young adults. Complications of body piercing include local inflammation and infections, but severe complications are also possible and largely underestimated. People are usually not aware of the risks before making a piercing, and their medical history, medication and comorbidities are largely neglected by the people who realise the piercing. This article presents a review of the complications that a primary care physician may observe, for a patient who wishes to make a piercing, or presents complications due to the implementation of such a device.