Therapeutic monitoring of antidepressants in the era of pharmacogenetics studies.

As for other drugs, there is a large interindividual variability of the plasma concentrations of antidepressants for a given dose. Within the last 2 decades, a very large number of pharmacogenetic studies have made it possible to understand the importance of genetic factors on the disposition of drugs in the organism, many of them at the levels of drug metabolism. Polymorphism of CYP2D6 and of other drug-metabolizing enzymes may thus lead to very large differences in drug exposure between patients and possibly also to toxicity or ineffective drug concentrations in some subjects. In consequence, dose recommendations of antidepressants based on genotypes, justified by the principle of administering bioequivalent individualized drug doses, are now proposed. However, blood (and thus possibly brain) concentrations also depend on other factors than the genetic makeup of the patients. Therapeutic drug monitoring of antidepressants allows us to take into account the influence of factors such as comedications, diet, smoking habit, impaired organ function, and compliance. Therapeutic drug monitoring and genotyping are thus complementary, and their combined use contributes to improve pharmacotherapy with antidepressants and other drugs.

Iowa Department of Transportation Major Items - Preliminary Quantity Report, May 21, 2013; With Addendums

Weekly letting report.

Light-induced racemization: artifacts in the analysis of the diastereoisomeric pairs of thioridazine 5-sulfoxide in the plasma and urine of patients treated with thioridazine.

The ring sulfoxidation of thioridazine (THD), a widely used neuroleptic agent, yields two diastereoisomeric pairs, fast- and slow-eluting (FE and SE) thioridazine 5-sulfoxide (THD 5-SO). Until now, studies in which concentrations of these metabolites were measured in THD-treated patients have revealed no significant differences in their concentrations. Preliminary experiments in our laboratory had shown that sunlight and, to a lesser extent, dim daylight led to racemization and probably also to photolysis of the diastereoisomeric pairs as measured by high-performance liquid chromatography. Similar results were also obtained with direct UV light (UV lamp). In appropriate light-protected conditions, THD, northioridazine, mesoridazine, sulforidazine, and FE and SE THD 5-SO were measured in 11 patients treated with various doses of THD for at least 1 week. Significantly higher concentrations of the FE stereoisomeric pair were found. The concentration ratios THD 5-SO (FE)/THD 5-SO (SE) ranged from 0.89 to 1.75 in plasma and from 1.15 to 2.05 in urine. Because it is known that the ring sulfoxide contributes to the cardiotoxicity of the drug even more potently than the parent compound does, these results justify further studies to determine whether there is stereoselectivity in the cardiotoxicity of THD 5-SO.

The puzzles of the prokineticin 2 pathway in human reproduction.

Prokineticin, 1 (PROK1) and prokineticin 2 (PROK2), are two closely related proteins that were identified as the mammalian homologs of their two amphibian homologs, mamba intestinal toxin (MIT-1) and Bv8. MIT-1 was initially identified as a non-toxic constituent in the venom of the black mamba snake (Dendroaspis polylepis) (Joubert and Strydom, 1980) while Bv8 was identified in the skin secretion of the toad, Bombina variegate (Mollay et al., 1999). All three homologs stimulate gastrointestinal motility thus accounting for their family name "prokineticins" (Schweitz et al., 1990, 1999). However, since its initial description, both PROK1 and PROK2 have been found to regulate a dazzling array of biological functions throughout the body. In particular, PROK1 acts as a potent angiogenic mitogen on endocrine vascular epithelium, thus earning its other name, Endocrine gland-vascular endothelial factor (EG-VEGF) (LeCouter et al., 2002). In contrast, the PROK2 signaling pathway is a critical regulator of olfactory bulb morphogenesis and sexual maturation in mammals and this function is the focus of this review.

[Priverno. Basilica cattedrale di Santa Maria Annunziata, Palazzo Comunale]

Référence bibliographique : Weigert, 346

Se former à l'entretien motivationnel pour aider ses patients à changer: Les étudiants en médecine le confirment [Learning motivational interviewing to help patients change their health-related behaviors: medical students confirm it].

At the Lausanne University, 5th year medical students were trained in Motivational interviewing (MI). Eight hours of training improved their competence in the use of this approach. This experience supports the implementation of MI training in medical schools. Motivational interviewing allows the health professional to actively involve the patient in this behavior change process (drinking, smoking, diet, exercise, medication adherence, etc.), by encouraging reflection and reinforcing personal motivation and resources.

Horae secundum usum romanum.

F. A-B. Bifolium contenant la fin de l’office du Saint Esprit ; cf. le même texte aux ff. 156-156v. XVe siècle. Copie inachevée dont les initialesont été laissées en blanc. Le f. B réglé est blanc. La justification est la même que celle du corps du manuscrit.F. 1-12v. Calendrier écrit à l’encre rouge et bleue et à l’or: nombreux saints méridionaux, en particulier de la vallée du Rhône et du Languedoc : « Fulcrani ep. [Lodevensis] » (13 févr.) ; « translatio s. Pauli » (20 février) ; « translatio s.Augustini » (28 février) ; « Pauli archi. Narbo[nensis] » (22 mars) ; « translatio b. Ferreoli [ ?] (1er avril) ; « Baudilii mart. [Nemausiensis] (20 mai) ; « Quiterie (21 mai) ; « Eutropii [ep. Arausicani] (27 mai) ; « translatio s. Saturnini » (22 juin) ; « Petri de Lucemburgo » (5 juillet) ; « Roqui mart. [Montispessulani] » (16 août) ; « Ludovici regis fratris [ep. Toletani]» (19 août) ; « Privati conf. [ep. Gabalitanus (Gévaudan)] » (21 août) ; « Fereoli mart. [Viennae] (18 sept.) ; « Apolinaris ep. [Valentinensis] » (10 oct.) ; « Firmini ep. [Ucetensis] » (11 oct.] ; « Florencii ep. [Arausicani] » (17 oct.] ; « Amancii ep. [Ruthenensis] » (5 nov.) ; « Restituti ep. [Tricastini] » (8 nov.) ; « Rufi ep. [Avenionensis] » (14 nov.) ; « Pauli ep. [Narbonensis] » (11 déc.) ; « Dominici conf. [de Silos] » (20 déc.). Mentions zodiacales et de comput, parmi lesquelles on note une « renovatio indicionum », le 24 septembre. F. 13-17. Extraits des quatre Evangiles : Io (13-14) ; Lc (14-15) ; Mt (15-16v) ; Mc (16v-17).F. 17v-71. [Horae beatae Mariae virginis secundum usum romanum]. [Ad matutinas], psaumes répartis selon les jours de la semaine (18-32v) ; — « In laudibus » (32v-42v) ; — « Ad primam » (43-46v) ; — « Ad tertiam » (46v-49) ; — « Ad sextam » (49v-52) ; « Ad IXa » (52-55) ; — « Ad vesperas » (55-60) ; — « Ad comple[c]torium » (60-64) ; — Antiennes, psaumes, leçons et répons pour les différents temps de l’année (64v-71) .F. 71-77v. Messe votive. « Missa beate Marie virginis ». « Salve sancta parens... » F. 78-85. Prières et hymnes. [Septem gaudia spiritualia b. Mariae virginis], incomplet des quatre premiers vers par lacune matérielle. « [Gaude flore virginali...] et sanctorum decoratum//...-... per eterna secula » (AH, XXXI, n° 198) ; « O sponsa Dei electa// Esto nobis via recta... » ; « ...Oratio. Domine Jhesu Christe qui beatissimam gloriosam virginem...-... pervenire mereamur » ; « Gaudia. Gaude virgo mater Christi// Que per aurem concepisti// ...-... perhemni gaudio. » (AH, XXIV, n° 57) ; cf. Leroquais, Livres d’heures, I, XXVI-XXVII ; « ... Oratio. Deus qui beatissimam virginem Mariam in consceptu... pervenire. Per... » ; « Gaudia beate Marie spiritualia. Gaude stirpe regis nata// Ab angelo saluta[ta]...-... et celorum mansio » (AH, XXXI, n° 182) ; « Oratio. Consolator mitissime Deus... sempiternis perfrui. Per... » ; « Alia oratio. Deus qui Gabrielem archangelum... mereamur habere. Qui... » ; « Devota oratio ad beatam virginem Mariam. Obsecro te domina... et michi famulo tuo pauperrimo N. ... » (Leroquais, Livres d’heures, II, 346-347).F. 85v blanc.F.86-91v. [Horae Trinitatis].F.91v-93v. Messe votive. « Missa de Trinitate ».F. 93v-97. « Devota oratio. Deus omnipotens propicius esto michi peccatori, custos mei omnibus diebus et horis vite mee, Deus Abraham... Omnes sancti angeli et archangeli Dei succurrite et subvenite michi peccatori... horis vite mee » ; cf. Leroquais, Livres d’heures, II, 396 ; — « O bone Jhesu illumina oculos meos ne unquam obdormiam... impietatem peccati mei » ; cf. Leroquais, Livres d’heures, I, XXX-XXXI ; — « Omnipotens, sempiterne et clementissime Deus qui Ezechie regi ... merear et optinere. Per... », à la forme masculine ; cf. Leroquais, Livres d’heures, II, 438 ; — « Oratio. Omnipotens sempiterne Deus te supplices exoramus ut celesti... consequantur. Per... » (Corpus orationum, VI, n° 4076).F. 97v blanc.F. 98-108. [Psaumes de la pénitence]. F. 108-117v. « Letania ». A noter parmi les confesseurs, la séquence inattendue de trois évêques de Toul honorés en Lorraine : « ... s. Mansuete, s. Gerarde, s. Aper ». Parmi les saintes : « ... s. Martha, s. Eulalia... s. Radegundis... ». — Oraisons diverses : « Propicius esto, parce nobis Domine... ut michi indigno famulo tuo N... exaudire digneris » ; — ... « Omnipotens sempiterne Deus miserere michi indigno famulo tuo N.... perficiat. Per... » ; — « Pie et exaudibilis domine Jhesu Christe Deus noster clementiam tuam... digneris eternam » ; cf. Leroquais, Psautiers, I, 25 ; — « Pietate tua quesumus Domine nostrorum solve vincula delictorum et intercedente pro nobis... virgine Dei genitrice Maria cum beatis apostolis tuis Petro et Paulo atque Andrea... eternam concede. Per... » (Corpus orationum, VI, n° 4227)...F. 118-145. [Officium mortuorum secundum usum romanum]F. 145-147v. Messe votive. « Missa pro omnibus fidelibus defunctis ». F. 148-151. [Horae sancti Spiritus].F. 151-153v. Messe votive. « Missa de sancto Spiritu », incomplet de la fin par lacune matérielle.F. 154-156v. [Horae omnium sanctorum], incomplet du premier feuillet.F. 156v-159v. Messe votive. « Missa de omnibus sanctis. F. 160-162v. [Horae sancti Sacramentis], incomplet du début par lacune matérielle. F. 162v-164v. Messe votive. « Missa de corpore Christi ».F. 164v-169v. Prières et hymnes. « ... salutatio sacratissimi corporis domini nostri Jhesu Christi. Ave Jhesu Christe verbum Patris filius [Virginis] agnus Dei...-... requies nostra vita perhemnis » ; cf. ms NAL 3211, 342 ; — « Alia oratio. Salve sancta caro Dei per quam salvi...-... da michi sedem justorum. Qui... » (ed. Leroquais, Livres d’heures, II, 348) ; — In elevatione corporis Christi. Anima Christi sanctifica me // Corpus Christi salva me... secula seculorum. Amen » ; (ed. Leroquais, Livres d’heures, II, 340 variantes) ; — « Alia. Ave verum corpus natum... o pia... ora pro nobis » (AH, LIV, n° 257) ; — « Alia devota oratio. Domine Jhesu Christe qui hanc sacratissimam carnem tuam... et periculis et in eternum » ; cf.ms NAL 3203, 26v ; — « Dum volueris communicare dic orationem. Omnipotens et misericors Deus ecce accedo ad sacratissimum accedo inquam infirmus ad medicum...-... tutela finalis in morte. Qui... » ; — « Alia oratio ante communionem. Domine sancte Pater, omnipotens eterne Deus, da mihi corpus et sanguinem... in infinita secula... » ; cf. Leroquais, Livres d’heures, II, 108 ; — « Post communionem. Gratias tibi ago Domine sancte pater omnipotens eterne Deus qui me peccatorem indignum famulum tuum saciare... et gaudium sempiternum... » ; cf. Leroquais, Livres d’heures, I, 51 ; — « Post communionem ad beatam Virginem. Serenissima Virgo et inclita mater nostri Jhesu Christi, sancta Maria regina celi et terre que eundem creatorem... hodie veracis [incomplet de la fin par lacune matérielle] ; cf. Leroquais, Livres d’heures, I, 156, 299.F. 170-173. [Horae sanctae Crucis], incomplet du début.F. 173-178. Messe votive. « Missa in honore sancte Crucis ». « Crucem tuam adoramus et veneramur domine Jhesu Christe, et per ipsam tuam sanctissimam recolimus passionem...-...defunctis vitam et gloriam sempiternam... » ; — « Alia oratio. Domine Jhesu Christe plasmator tocius creature, rex glorie obsecro miserere mei quia locutus sum... semper benedictus... » ; — « Alia oratio. Domine Jhesu Christe qui voluisti pro redemptione mundi nasci et circumcidi... ego miserrimus, vilissimus, nequissimus atque indignissimus peccator...-... latronem crucifixum. Qui... » ; — « Alia oratio. Precor te, piissime domine Jhesu Christe, per illam eximiam caritatem qua tu rex celestis... mihi tribuere digneris. Qui... » ; — « Alia oratio. Deus propicius esto michi peccatori. Quid est Jhesus nisi salvator ergo Jhesus per te ipsum redemptus sum... miserere michi Deus » ; — « Dic totum deinde dic oracionem. Tribulacionem nobis [sic], quesumus, Domine propicius respice... clementer averte. Per... ». F. 178-200. « ... suffragia sanctorum ». « ... de Trinitate » ; — « De sancto Michaele archangelo » ; — « De sancto Johanne Baptista » ; — « De sancto Petro et Paulo » ; — « De sancto Andrea apostolo » ; — « De sancto Johanne evangelista » ; — « De sancto Jacobo minori » ; — « Sanctorum Philippi et Jacobi » ; — « De innocentibus » ; — « De apostolis et evvangelistis » ; — « De sancto Stephano » ; — « De sancto Laurencio » ; — « De sancto Eutropio... Eutropium martyrem tuum (f. 183v)... » ; — « De sancto Georgio » ; — « De sancto Blasio » ; — « De sancto Dyonisio » ; — « De sancto Yppolito » ; — « De sancto Christophoro » ; — « De sancto Sebastiano. Omnipotens sempiterne Deus qui meritis beati Sebastiani martyris gloriosissimi quemdam pestem epydimie generalem hominibus mortiferam revocasti, presta supplicibus tuis ut qui hanc orationem super se portavit aut in domibus vel mansionibus scriptam aut alias de ea in tuo nomine memoriam habuerint sive in die aut in nocte legerint a simili a peste et morbo epydimie sub ejus confidencia ad te confugerint ipsius meritis et precibus ab ipsis peste et morbo epydimie et ab omnibus nocumentis venenosis necnon ab omnibus periculis corporis et anime atque a subitanea et improvisa morte et ab omnibus inimicis visibilibus et invisibilibus singulis diebus et noctibus horis atque momentis liberemur. Per Dominum. Pater noster. Ave Maria. Credo. Salva regina. Ave stella matutina, rosa sine spinis, cum reliquis ». — « Unius martyris communis » ; — « De martyribus communis » ; — « De sancto Martino » ; — « De sancto Nicholao » ; — « De sancto Anthonio » ; — « De sancto Lazaro » ; — « De sancto Restituto... Deus qui per merita beati Restituti confessoris atque pontificis a multorum oculis dolorem sanas, labem removes et visum clarificas... (189v-190) » ; — « Unius confessoris » ; — « De confessoribus communis » ; — « De beata Maria Magdalena prosa. Gaude pia Magdalena // Spes salutis // Vite vena // Lapsorum fiducia // Gaude dulcis advocata // ... » ; — « De beata Catherina. Gaude virgo Catherina /// Quam refecit lux divina // Ter quaternis noctibus //... » ; — « De beata Lucia » ; — « De beata Apollonia » ; — « De beata Agatha » ; — « De virginibus » ; — « De omnibus sanctis » ; — « De pace » ; — « De sancto Petro de Lucemburgo » ; le suffrage commence par la prière attribuée à s. Pierre de Luxembourg : « Deus pater qui creasti // Mundum et illuminasti // Suscipe...-... requiescant in pace. Amen » ; cf.ms NAL 3196, 152.F. 200v-204, feuillets réglés blancs.

Current practice in neuropsychological outcome reporting after aneurysmal subarachnoid haemorrhage.

BACKGROUND: Neuropsychological deficits (NPD) are common in patients with aneurysmal subarachnoid haemorrhage (aSAH). NPD are one of the major limiting factors for patients with an otherwise acceptable prognosis for sustained quality of life. There are only a few studies reporting outcome after aSAH, which used a standardized neuropsychological test battery as a primary or secondary outcome measure. Aim of this study was to determine the current practice of reporting NPD following aSAH in clinical studies. METHODS: A MEDLINE analysis was performed using the search term "subarachnoid haemorrhage outcome". The latest 1,000 articles were screened. We recorded study design, number of patients, and the presence of neuropsychological outcome report. Additionally, the time of testing after aSAH, the neuropsychological tests administered, as well as the percentage of patients with NPD were analyzed. RESULTS: A total of 324 publications between 2009 and 2012 were selected for further review. Of those, 21 studies (6.5%) reported neuropsychological outcome, in 2,001 of 346,666 patients (0.6%). The assessment of NPD differed broadly using both subjective and objective cognitive evaluation, and a large variety of tests were used. CONCLUSION: Neuropsychological outcome is underreported, and there is great variety in assessment in currently published clinical articles on aSAH. Prospective randomized trials treating aSAH may benefit from implementing more comprehensive and standardized neuropsychological outcome measures. This approach might identify otherwise unnoticed treatment effects in future interventional studies of aSAH patients.

Tumeurs fibroblastiques et myofibroblastiques de la tête et du cou [Fibroblastic and myofibroblastic tumors of the head and neck.]

Fibroblastic and myofibroblastic tumors of the head and neck are numerous and may develop either in adults or in childhood. They can be benign and nonrecurring, benign but locally recurring, of low-grade of malignancy or fully malignant. The diagnosis and treatment of these lesions can be difficult. This review focuses on several (myo)fibroblastic lesions of the head and neck, including nodular fasciitis and related neoplasms, hemangiopericytoma-like tumor (glomangiopericytoma) of sinonasal passages, nasopharyngeal angiofibroma, desmoid fibromatosis, Gardner-associated fibroma, extrapleural solitary fibrous tumor, inflammatory myofibroblastic tumor, low-grade myofibroblastic sarcoma, and adult-type fibrosarcoma.

Etudiants en médecine et centres médico-sociaux: préparer l'avenir [Medical students and community health care centers: preparing the future].

Since 2011, second year medical students from Lausanne University follow a single day course in the community health care centers of the Canton of Vaud. They discover the medico-social network and attend to patients' visits at home. They experience the importance of the information transmission and the partnership between informal caregivers, professional caregivers, general practitioner and hospital units. The goal of this course is to help the future physicians to collaborate with the community health care centers teams. This will be particularly important in the future with an aging and more dependant population.

Diversity and structure of AMF communities as affected by tillage in a temperate soil.

Arbuscular mycorrhizal fungi (AMF) were studied in differently tilled soils from a long-term field experiment in Switzerland. Diversity and structure of AMF communities were surveyed either directly on spores isolated from the field soil or on spores isolated from trap cultures, planted with different host plants. Single-spore cultures were established from the AMF spores obtained from trap cultures. Identification of the AMF was made by observation of spore morphology and confirmed by sequencing of ITS rDNA. At least 17 recognised AMF species were identified in samples from field and/or trap cultures, belonging to five genera of AMF--Glomus, Gigaspora, Scutellospora, Acaulospora, and Entrophospora. Tillage had a significant influence on the sporulation of some species and non- Glomus AMF tended to be more abundant in the no-tilled soil. The community structure of AMF in the field soil was significantly affected by tillage treatment. However, no significant differences in AMF diversity were detected among different soil tillage treatments. AMF community composition in trap cultures was affected much more by the species of the trap plant than by the original tillage treatment of the field soil. The use of trap cultures for fungal diversity estimation in comparison with direct observation of field samples is discussed.

Improvement of therapeutic drug monitoring of imatinib by Bayesian prediction of trough levels. Personalized drug dosage

Aims: Plasma concentrations of imatinib differ largely between patients despite same dosage, owing to large inter-individual variability in pharmacokinetic (PK) parameters. As the drug concentration at the end of the dosage interval (Cmin) correlates with treatment response and tolerability, monitoring of Cmin is suggested for therapeutic drug monitoring (TDM) of imatinib. Due to logistic difficulties, random sampling during the dosage interval is however often performed in clinical practice, thus rendering the respective results not informative regarding Cmin values.Objectives: (I) To extrapolate randomly measured imatinib concentrations to more informative Cmin using classical Bayesian forecasting. (II) To extend the classical Bayesian method to account for correlation between PK parameters. (III) To evaluate the predictive performance of both methods.Methods: 31 paired blood samples (random and trough levels) were obtained from 19 cancer patients under imatinib. Two Bayesian maximum a posteriori (MAP) methods were implemented: (A) a classical method ignoring correlation between PK parameters, and (B) an extended one accounting for correlation. Both methods were applied to estimate individual PK parameters, conditional on random observations and covariate-adjusted priors from a population PK model. The PK parameter estimates were used to calculate trough levels. Relative prediction errors (PE) were analyzed to evaluate accuracy (one-sample t-test) and to compare precision between the methods (F-test to compare variances).Results: Both Bayesian MAP methods allowed non-biased predictions of individual Cmin compared to observations: (A) - 7% mean PE (CI95% - 18 to 4 %, p = 0.15) and (B) - 4% mean PE (CI95% - 18 to 10 %, p = 0.69). Relative standard deviations of actual observations from predictions were 22% (A) and 30% (B), i.e. comparable to the intraindividual variability reported. Precision was not improved by taking into account correlation between PK parameters (p = 0.22).Conclusion: Clinical interpretation of randomly measured imatinib concentrations can be assisted by Bayesian extrapolation to maximum likelihood Cmin. Classical Bayesian estimation can be applied for TDM without the need to include correlation between PK parameters. Both methods could be adapted in the future to evaluate other individual pharmacokinetic measures correlated to clinical outcomes, such as area under the curve(AUC).

Rikosoikeuden harmonisointi Euroopan unionissa : harmonisointiteoreettisia näkökulmia

English summary: Harmonisation of criminal law in the EU: A theoretical approach to harmonisation models (s. 346.)