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Azathioprine keeps an important place in the treatment of inflammatory bowel disease and autoimmune hepatitis. This molecule has a narrow therapeutic margin, associated with a risk of toxicity, particularly hematological and hepatic. Its complex metabolism is subject to genetic polymorphisms that are reflected in the inter-individual variability observed in the response to treatment and its tolerance profile. Hence, its use requires a good knowledge of this molecule. Treatment is initiated after a preliminary workup, followed by a progressive titration of the dosage while closely monitoring possible toxicities. Monitoring of blood levels of metabolites (including active ones) helps guide personalized dose adjustment.L’azathioprine garde actuellement une place importante dans le traitement des maladies inflammatoires chroniques de l’intestin et de l’hépatite autoimmune. Il s’agit d’une molécule à marge thérapeutique étroite, associée à un risque de toxicité, notamment hématologique et hépatique. Son métabolisme complexe est influencé par des polymorphismes génétiques qui sont reflétés dans la variabilité interindividuelle observée dans la réponse au traitement et le profil de tolérance. Son utilisation nécessite donc une bonne connaissance de cette molécule. L’instauration du traitement se fait après un bilan préalable, puis une titration progressive des posologies, tout en surveillant étroitement les éventuelles toxicités. Le monitoring des concentrations sanguines des métabolites (notamment actifs) permet de guider l’adaptation personnalisée des posologies.

Azathioprine keeps an important place in the treatment of inflammatory bowel disease and autoimmune hepatitis. This molecule has a narrow therapeutic margin, associated with a risk of toxicity, particularly hematological and hepatic. Its complex metabolism is subject to genetic polymorphisms that are reflected in the inter-individual variability observed in the response to treatment and its tolerance profile. Hence, its use requires a good knowledge of this molecule. Treatment is initiated after a preliminary workup, followed by a progressive titration of the dosage while closely monitoring possible toxicities. Monitoring of blood levels of metabolites (including active ones) helps guide personalized dose adjustment.

Seed quality acquisition is an environmental moduled process that is finely controlled by the expression of many interconnected molecular and metabolic actors. Current climate projections predict that crops will be exposed to an increase of multiple and combined environmental constraints, leading to complex and generally non-deductible impacts. A better knowledge of these impacts on seed development, still poorly studied, appears thus as a relevant lever to enhance environmental resilience of agricultural productions. This thesis work is part of this scientific theme and sought to answer the following question: what are the impacts of a combination of biotic and abiotic stress on the yield elaboration and seed quality acquisition of the rapeseed?To answer this question, two rapeseed genotypes were grown in a large experimental device and subjected to a combination of stresses that are major for this crop, the water deficit and clubroot, caused by the pathogen Plasmodiophora brassicae. Signature impacts of water deficit on plants and mature seed quality have been identified using physiological and metabolic data, as well as germination kinetics. Subsequently, RNAseq, metabolic and physiological data, were used for the characterization of the rapeseed transcritional developing seed gene transcrotions and quality acquisition. The correlations between these modulations and their agronomic perspectives are discussed.; L’acquisition de la qualité de la graine est un processus contrôlé par l’expression de nombreux acteurs moléculaires et métaboliques interconnectés et modulés par l’environnement. Les modélisations climatiques actuelles prévoient l’augmentation des contraintes environnementales multiples et combinées sur les cultures, dont les effets complexes s’avèrent généralement peu prédictibles. Une meilleure compréhension de ces impacts sur le développement des graines représente un levier pertinent pour l’augmentation de la résilience environnementale des productions agricoles. Le travail de thèse s’est inscrit dans cette thématique scientifique et a cherché à répondre à la question suivante : quels sont les impacts d’une combinaison de stress biotique et abiotique sur l’élaboration du rendement et l’acquisition de la qualité de la graine de colza ?Pour y répondre, deux génotypes de colza ont été cultivés au sein d’un large dispositif expérimental et exposés à une combinaison de stress majeurs pour cette culture que sont le déficit hydrique et la hernie des crucifères, causée par le pathogène Plasmodiophora brassicae. Des impacts du déficit hydrique sur les plantes et la qualité des graines matures ont été identifiés. Par la suite, des données RNAseq, métaboliques et physiologiques ont permis de caractériser le programme transcriptionnel développemental des graines de colza et d’identifier des modulations spécifiques d’un stress ou de leur combinaison sur la transcription des gènes et l’acquisition de la qualité de graine en développement. Les corrélations entre ces modulations et leurs perspectives agronomiques sont discutées.

Evolution can help to provide valuable information to understand protein sequence, structure and function relationship. In a first project, I used molecular phylogeny to show the coevolution of “Testis expressed 19” (Tex19) and “Secreted and Transmembrane 1” (Sectm1) genes. Although Tex19 and Sectm1 are involved in different biological pathways, i.e. transposon regulation and immunity respectively, coevolution supports a strong functional relationship between both genes.Since Tex19 is expressed only in adult healthy testis and cancer cells, this result may be useful for cancer immunotherapy. In a second project, I used molecular modelling and sequence evolution analysis to question the validity of the glucocorticoïd receptor ɑ (GR ɑ ) ligand binding domain (LBD) homodimeric assembly [Bledsoe R.K. et al, 2002]. First, this complex is likely a crystallization artefact. Second, I have identified an alternative assembly that presents the molecular characteristics of a biological interface., Intégrer l’évolution peut aider à comprendre la relation séquence, structure, fonction des protéines. Dans un 1er projet, j’ai utilisé la phylogénèse moléculaire pour montrer que les gènes Testis expressed 19 » (Tex19) et « Secreted and transmembrane 1 » (Sectm1) coévoluent. Bien que Tex19 et Sectm1 interviennent dans des processus biologiques différents, régulation des transposons et immunité respectivement, la coévolution établit entre eux un lien fonctionnel très fort. Comme Tex19 ne s’exprime que dans le testicule de l’adulte sain et en cellule cancéreuse, ce résultat pourrait présenter un intérêt en immunothérapie du cancer. Dans un 2nd projet, je me suis appuyé sur des calculs de modélisation moléculaire et sur l’analyse d'évolution de séquence pour interroger la validité de la structure de l’homodimère du domaine de liaison au ligand (LBD) du récepteur ɑ aux glucocorticoïdes (GR ɑ) [Bledsoe R.K. et al, 2002]. Premièrement, ce complexe serait vraisemblablement un artefact de contact cristallin. Deuxièmement, j’ai identifié un assemblage alternatif présentant les caractéristiques moléculaires d’une interface de contact biologique.

Notre projet consiste à étudier la possibilité de bloquer les variations dimensionnelles du bois apparaissant lorsqu'il est soumis à des conditions climatiques changeantes. La société SFS Intec, à l'origine de ce projet, est un fabricant français de systèmes d'assemblages qui s'interroge sur la possibilité de concevoir des quincailleries assurant un maintien dimensionnel des éléments mis en oeuvre dans les ouvrages d'art. Suite à nos recherches bibliographiques, nous avons décidé d'organiser notre projet selon deux axes d'étude, l'un consistant à évaluer les efforts mis en jeu pour bloquer le gonflement du bois et l'autre permettant de tester différentes solutions de blocage des variations. La première expérience nous a ainsi amenés à concevoir entièrement un montage d'essai à l'aide de différents types de capteurs, dans l'optique de quantifier précisément le phénomène de gonflement. Puis, lors d'une réunion avec l'industriel, nous avons déterminé quels systèmes de maintien mécanique allaient être testés au cours de la seconde expérience. L'analyse des résultats est faite sur la base de critères visuels, géométriques et mécaniques, ce qui donnera à l'industriel une idée de la viabilité de tels systèmes.

International audience; Fifteen START domain-containing proteins exist in mammals. On the basis of their structural homology, this family is divided into several sub-families consisting mainly of non-vesicular intracellular lipid carriers. With the exception of the Thioesterase-START subfamily, the other subfamilies are represented among invertebrates. The START domain is always located in the C-terminus of the protein. It is a module of about 210 residues that binds lipids, including sterols. Cholesterol, 25-hydroxycholesterol, phosphatidylcholine, phosphatidylethanolamine and ceramides are ligands for STARD1/STARD3-6, STARD5, STARD2/STARD10, STARD10 and STARD11, respectively. The lipids or sterols bound by the remaining 7 START proteins are unknown. The START domain can be regarded as a lipid-exchange and/or a lipid-sensing domain. The START domain consists in a deep lipid-binding pocket--that shields the hydrophic ligand from the external aqueous environment--covered by a lid formed by a C-terminal alpha helix. Within the same subgroup, such as the sterols-carriers subgroup, different START domains have similar biochemical properties; however, their expression profile and their subcellular localization distinguish them and are critical for their different biological functions. START proteins act in a variety of distinct physiological processes, such as lipid transfer between intracellular compartments, lipid metabolism and modulation of signaling events. Mutation or misexpression of START proteins is linked to pathological processes, including genetic disorders, autoimmune diseases and cancers.

Ten crucible fragments collected at a single location on the surface of Altyn-Depe, most probably datable to the second half of the 3rd millennium BC, have been studied and analysed by the means of different techniques. The research provides new information on Middle Bronze Age (Namazga V) copper-based metallurgy at this important southern Turkmenian early urban site., Résumé: À Altyn Tepe, dix fragments de creusets datant très probablement de la seconde moitié du IIIe millénaire BC ont été trouvés en surface du site, groupés en un seul endroit. Leur analyse, par différentes techniques d’observation, apporte des informations nouvelles sur la métallurgie à base de cuivre et de bronze de ce site proto-urbain du Turkménistan (Bronze Moyen, Namazga V)., Masioli Elisa, Artioli Domenico, Bianchetti Pierluigi, Di Pilato Sergio, Guida Giuseppe, Salvatori Sandro, Sidoti Giancarlo, Vidale Massimo. Copper-melting crucibles from the surface of Altyn-Depe, Turkmenistan ( ca 2500-2000 BC). In: Paléorient, 2006, vol. 32, n°2. pp. 157-174.

Pediatricians currently have improved understanding of how to best manage childhood hypertension. The goal of antihypertensive drug therapy in children with secondary hypertension is currently to reduce the blood pressure below the 90th centile. Most authors currently favor therapy with a blocker of the renin-angiotensin system (a converting enzyme inhibitor or an angiotensin II antagonist) or a calcium channel blocker. In patients with kidney disease and diabetes mellitus we generally advise therapy of hypertension with a blocker of the renin-angiotensin system especially in the presence of pathological proteinuria.

Fifty years after the first report by Gasser and Gautier, hemolytic, uremic syndrome is rather rare but severe childhood disease. A recent survey demonstrates that more than 90% of the cases occurring in Switzerland are caused either by Escherichia coli that produces shigatoxin or by Streptococcus pneumoniae.

Instituted by the law of 23 August 1947, the missions of the Order of Veterinarians include monitoring compliance by all of its members (private veterinarians) with their professional obligations and with the rules laid down bythe Code of Practice of the profession. This code provides a national guide to good practice with which private veterinarians must comply, both in their personal behaviour and in their relations with their colleagues, the administration and their partners. Any violation of the provisions of the Code may result in disciplinary procedures being invoked by the administrative and judiciary authorities, or by any other interested person. This procedure leads to sanctions ranging from a warning to ten years suspension. In order to carry out its monitoring task, the Order needs to know the precise number and quality of its members and must then assess the quality of the service provided by these professionals in terms of respect for the Code of Practice. The Order must audit the competence of veterinarians, throughout their lives, by means of a continuing quality assurance mechanism for ongoing assessment of their knowledge; this mechanism has yet to be created. Finally, the Order must constantly listen to users of the profession, who must be provided with the best service at the lowest cost.

Formulae for estimating glomerular filtration rate with the use of body size, circulating creatinine, and an empirically derived constant are widely used. The aim of the present study was to determine whether these formulae enable accurate prediction of glomerular filtration measured from the labeled ethylenediaminetetraacetic acid in 843 pediatric patients. Bland-Altman analysis was performed on the measured glomerular filtration rate and that estimated using the constant developed in our laboratory. Age and sex of the 843 patients failed to consistently influence the empirically derived constant. Measured and estimated glomerular filtration rate were on the average identical. However, the 95% limits of agreement of the measured glomerular filtration rate with that estimated were wide (measured over estimated glomerular filtration from 0.53 to 2.04). Use of height to creatinine formulae to estimate glomerular filtration is therefore frequently insufficiently accurate.

On the basis of one case, the authors give the highlights on the various clinicopathological features of malignant gastric perforations. While medical imaging does not seem to contribute much in the positive diagnosis of such complications, it does remain essential to establish the local extension of the tumour process and thus to allow a better therapeutic management.

On the basis of one personal case, the various clinicopathological features of primary malignant fibrous histiocytoma of the lung are summed up. This tumor, which has a nonspecific radiological appearance, most often appears as a large peripheral pulmonary opacity, for which the prognosis is guarded and the positive diagnosis based on surgical exeresis or biopsy.

On the basis of one personal case of leiomyosarcoma, the various anatomicoclinical features of sarcomas of the pulmonary artery are summed up. They most often produce a picture of severe pulmonary embolism that is resistant to all treatments; the lesion most often is a hilar mass without any associated bronchoscopic abnormality. Angiograms are not always easily interpreted, and the modern imaging techniques (ultrasound, computed tomography, and above all MRI) can best lead to the preoperative diagnosis, although this lesion is unfrequent.

A 17-year-old female patient had a road traffic accident. She suffered from a minor head injury, and a right pneumothorax which had to be drained. However, when admitted, an unusual picture was found on the chest film. It was a left para-mediastinal shadow with a fluid level, its greater axis being vertical. She underwent a computerised tomographic chest scan. This picture was seen to be in the left costo-vertebral gutter, and in contact with an area of pulmonary contusion in the left posterior basal segment. Another smaller similar picture was discovered on the right side. These were interpreted as being infrapleural pneumatoceles on the mediastinal surface of the lower pulmonary lobes. The patient recovered spontaneously. In fact, these effusions of air and blood can be seen in other areas in the chest (mediastinum, pleura, lung); these are discussed.

The authors report three cases of diltiazem overdose with hypotension and atrio-ventricular conduction disturbances. Hemodynamic study in 2 cases showed a hyperkinetic state with a decrease of systemic vascular resistances. Diltiazem kinetics studied in 2 cases showed a plasma half life of 5.4 and 8.3 hours, a prolonged absorption until the 28th hours in one case. Treatment included gastric lavage, oral activated charcoal (2 cases), plasma expanders and in 2 cases vasopressors with alpha effects. All three patients recovered.

Over a 4-year period, 63 premature babies presenting with patent ductus arteriosus were treated with indomethacin at two different dosage levels (0.1 and 0.2 mg/kg). For all infants the permanent closure rate was 68% (56% with 0.1 mg/kg and 75% with 0.2 mg/kg - n.s.) and the positive response rate (i.e. permanent and transient closure) 84%. There was no difference between the two dosages in the incidence of side-effects, particularly on diuresis, and in mortality and morbidity rates; the overall mortality rate was 31%. Pharmacokinetic studies performed in 51 cases did not show any difference related to indomethacin dosage. The changes observed after 2 or 3 doses resulted from improvement in haemodynamics. This study confirms the effectiveness of indomethacin in the treatment of patent ductus arteriosus and suggests an advantage for the 0.2 mg/kg dose.

The pharmacokinetic and pharmacodynamic effects of indomethacin were studied in 18 prematures with patent ductus arteriosus, treated either enterally (group I, n = 7), or intravenously (group II, n = 11). A definitive closure assessed by echocardiography was observed in 13 cases (72%), and it was only transient in 4 cases (21%). Assisted ventilation was discontinued between 1 and 6 days following therapy in 14 cases. In most cases, indomethacin induced a significant reduction of diuresis but the plasma creatinine level increased above 15 mg/l in 3 cases only. The elimination half life of indomethacin (t 1/2 beta), of 40.3 +/- 12.2 hours in group I and 33.9 +/- 11.7 hours in group II, is increased as compared with adults. The difference of the surface under the curve (AUC O leads to 24 h, ng.ml-1.h-1) between the infants who presented complete or transient closure, suggests a relationship between the biodisponibility of the drug and the effect on patent ductus arteriosus. Treatment with indomethacin is an interesting alternative to surgical ligation in prematures with patent ductus arteriosus. Because of its side effects, especially on the kidneys, it is recommended to use this treatment only in intensive care units. The intravenous route seems to be better than the enteral route.

The efficacy and the safety of betaxolol (BTX), a cardio-selective adrenoceptor blocking agent with a long half life, was tested in 22 hypertensive pregnant women. BTX doses varied from 10 to 40 mg/day. BTX given as monotherapy (n = 19) or associated to dihydralazine (n = 3) led to a satisfactory control of arterial blood pressure (ABP). In the mother, the drug was very well tolerated. (table; see text) The fetal safety, evaluated by mean of cardiotocography and echography was also satisfactory. Fetal heart rythm was significantly slowed following first intake of BTX and remained stable until delivery; there was only one case of intra-uterine growth retardation pre-existing to the pharmacological treatment. Nine deliveries were ceasarian [fetal distress (n = 1); poor control ABPI (n = 1); obstetrical reasons (n = 7)]. Seventeen neonates were full-term and six were premature (twins included). The state of neonates at birth was very satisfactory (Apgar at 5 minutes greater than 9 in 21/23). Glycemia less than 1.66 mmoles/1 in two neonates, was normal within 24 to 48 hours. In conclusion, BTX was very efficacious in controlling increased blood pressure in pregnant women and its safety in the mother, the fetus and the newborn was very good.

Monitoring of haloperidol plasma levels during long-term treatment is not commonly practised in adults and even less in children. In this study, haloperidol plasma levels were measured in children and teenagers with psychotic episodes or abnormal movements. Steady state concentrations ranged from 0.7 to 19 ng/ml. They were apparently unrelated to the doses administered (15-285 micrograms/kg/day), and variations of up to 15-fold were observed with the same dosage. In contrast, a significant correlation (p less than 0.02) was determined between age and dose-concentration ratio. Side-effects also seemed to be significantly related to plasma levels (p less than 0.01); they occurred at concentration higher than 6 ng/ml. Therapeutic response was observed with plasma concentrations of 1 to 4 ng/ml in cases with abnormal movements, but no dose-effect relationship was found in patients with psychotic episodes.

The effect of high doses of haloperidol on the clinical status, plasma neuroleptic and prolactin concentrations as well as on CSF HVA and GABA levels was investigated in 3 paranoid schizophrenic patients over a 6 weeks period. When the study was initiated patients had been on haloperidol (10 mg a day) for 4-10 weeks. Oral doses were increased at weekly intervals from 10 (day 0) to 100 (day 7) and 200 (days 14 to 28) mg a day and then reduced to 100 (day 35) and 10 (day 42) mg/day. A linear relationship was observed between plasmatic levels and daily doses of haloperidol. In neither patient, the increase in haloperidol dosage affected paranoid symptoms. Neurological side effects were slightly increased in 2 cases and moderately reduced in one case. Prolactin plasma levels, already high at the onset of the study rose when increasing the dose to 100 mg a day but did not increase further despite increment in the haloperidol dosage. CSF levels of HVA and GABA rose from day 0 to day 7 but were back to the initial values on day 28 in 2 patients and were decreased from day 0 to day 28 in one patient. For the 3 patients a close correlation was observed between changes in CSF HVA and GABA levels. It is concluded that high doses of haloperidol, although causing biochemical changes compatible with the occurrence of dopamine target cell supersensitivity, do not lead to any clinical improvement in the 3 studied schizophrenic patients.