L’objectif principal de l’étude était d’identifier les principaux médicaments associés aux hépatites aiguës (HA) associé aux médicaments (HAM) en France. Trois approches méthodologiques ont été définies. L’approche méthodologique principale est l’analyse cas-population. Les autres approches sont cas-propre témoin et cas témoins.Les cas ont été identifiés parmi les patients adultes présents dans le SNIIRAM, ayant une première hospitalisation entre 01/01/2010-31/12/2014 dont le diagnostic principal est une atteinte hépatique toxique (Classification Internationale des Maladies (CIM-10) K71.1, K71.2, K71.6, K71.9) ou une insuffisance hépatique(CIM-10 K72.0). La population de référence a été définie à partir de l’EGB. La date index (DI) considérée est la date de première hospitalisation pour HA. Les délivrances de l’ensemble des traitements précédant la DI ont été étudiées en considérant une exposition variant de 7 à 60 jours avant la DI. Les produits les plus fréquemment retrouvés sont classiques: antalgiques et en premier lieu le paracétamol, puis les produits à visée digestive symptomatique (inhibiteur de la pompe à protons, prokinétique, antispasmodique). Les suivants sont l’amoxicilline seule ou associée à l’acide clavulanique, l’ibuprofène, la codéine associée et le furosémide. L’ensemble de ces résultats pourra informer les autorités sanitaires, les praticiens et les patients sur le risque associé à chacune de ces molécules tant au plan individuel (risque absolu, risque attribuable), qu’au sein d’une famille de produits(risque relatif) ainsi que plus globalement pour la population et le système de santé(nombre absolu de cas attribuables). / The main objective of EPIHAM study is to identify the main drugs associated with drug induced liver injury leading to hospital admission (DILIH) in France and the event rates associated with DILIH. Three methodological approaches were defined. Principal approach is case-population. The others are case-crossover and case control analyses. Cases were identified among adult patients present in SNIIRAM database having a first hospitalization between 01/01/2010-2010/31/12/1204, the main diagnosis of which is toxic liver disease (diagnostic codes according to the International Classification of Diseases (ICD-10) K71.1, K71.2, K71.6, K71.9) orK72.0. Reference population was defined from the EGB. Index date (ID) was considered as the date of hospital admission for DILI. The dispensations of all treatments preceding the ID were studied by considering an exposure windowvarying from 7 to 60 days before ID. The most frequently found are classical: analgesics and firstly paracetamol, followed by drugs acting on digestive system (proton pump inhibitors, prokinetics, antispasmodics). The following were amoxicillinalone or combined with clavulanic acid, ibuprofen, codeine combinations, and furosemide. These results can inform health authorities, practitioners and patients about the acute hepatitis risk leading to hospitalisation associated with each of these molecules, both individually (absolute risk, attributable risk) and within a therapeutic drug family (relative risk) as well as more generally for the population and the health system (absolute number of attributable cases).

Niobium (Nb) and Rare Earth Elements (REE’s) have in recent years received considerable attention because of their importance to the modern technical industry, and more specifically the enhanced sustainability that comes with them. The main source for Nb and REE’s on Earth are carbonatites and associated alkaline silicate rocks. This report examines the magnetic properties of rocks from the Oldoinyo Dili carbonatite complex in northern Tanzania. Previous workers have suggested a link between the Fe-bearing mineralogy and the formation of Nb-mineralizations at Oldoinyo Dili. This hypothesis is further examined in this report by combining detailed petrographic observations and withnew measurements of magnetic susceptibility. The aim is to see if any correlation exists between occurrence of Nb-mineralizations and the types of Fe-minerals present at Oldoinyo Dili. Based on the magnetic susceptibility measurements, at least two different species of Fe-minerals arefound in the examined samples. These are characterized by different magnetic trends during heating/cooling and also by their separate Curie temperatures (Tc). In combination with the petrographic observations these minerals are interpreted to be magnetite (Fe2O4) with Tc ~580°C, and a mineral that most likely represents a solid solution between ilmenite (FeTiO3) and hematite (Fe2O3) with Tc ~300°C. Here, no clear link between the type of opaque mineral(s) present and the total Nb content of the carbonatites can be conclusively determined based on the petrography and the magnetic measurements alone. Although the results of this report provide an important first step towards understanding the relationship between Nb-mineralizations and the magnetic mineralogy at Oldoinyo Dili, more detailed analyses of the mineral chemistry is a necessity to fully understand their complex relations and the specific conditions under which they formed. / Niob (Nb) och sällsynta jordartsmetaller (REE’s) har på senare år fått stor uppmärksamhet för sin betydelse för den moderna tekniska industrin, och specifikt för den förhöjda hållbarhet som de bidrar med. Den huvudsakliga källan till Nb och REE’s på jorden är karbonatiter och associerade alkalisilikater. Denna rapport undersöker de magnetiska egenskaperna för karbonatit-komplexet Oldoinyo Dili i norra Tanzania. Forskare har tidigare anat att det finns en koppling mellan Fe-bärande mineralogi och bildandet av Nb-mineraliseringar vid Oldoinyo Dili. Denna hypotes undersöks vidare i denna rapport genom att kombinera detaljerade petrografiska observationer med nya mätningar av magnetisk susceptibilitet. Syftet är att undersöka om det finns någon korrelation mellan förekomst av Nb-mineraliseringar och de typer av järnmineral som finns vid Oldoinyo Dili. Baserat på de genomförda magnetiska susceptibilitets-mätningarna så finns det åtminstone två olika sorters järnmineral i de undersökta proverna. De karaktäriseras av olika magnetiska trender vid upphettning/nedkylning och även av sina olika Curietemperaturer (Tc). Kombinerat med petrografiska observationer uttolkas att dessa mineral är magnetit (Fe2O4) med Tc ~580°C, samt en mineral som troligen är en solid solution av ilmenit (FeTiO3) och hematit (Fe2O3) med Tc ~300°C. Det går inte att senågon tydlig koppling mellan förekommande opaka mineral och det totala Nb-innehållet i karbonatiterna med säkerhet enbart utifrån petrografin och de genomförda magnetiska mätningarna. Resultaten av denna rapport utgör ett bra första steg mot att förstå relationen mellan Nb-mineraliseringar och den magnetiska mineralogin för Oldoinyo Dili, men mer detaljerade analyser av mineralkemin är nödvändigt för att till fullo förstå de komplexa förhållanden som råder vid bildning av dessa.

Tez (Yüksek Lisans) - Süleyman Demirel Üniversitesi, Sosyal Bilimler Enstitüsü, Sosyoloji Anabilim Dalı, 2008. / Bibliyografya var.

Reação Adversa ao Medicamento (RAM) é definida como a reação a um medicamento que é nociva e não-intencional. O dano hepático induzido por medicamento (DILI) é um exemplo de RAM que pode ser muito severa e provocar casos de transplante hepático e morte. A falta de marcadores específicos ou testes para o diagnóstico de DILI conduziu ao desenvolvimento de escalas para avaliar a imputabilidade do medicamento na ocorrência do dano hepático. O presente estudo teve como objetivo caracterizar os tipos de danos hepáticos induzidos por medicamentos e investigar a concordância de três escalas utilizadas na sua identificação: RUCAM, Maria & Victorino (M&V) e Naranjo. Trata-se de um estudo seccional realizado em um hospital universitário no Rio de Janeiro em que a população fonte foi composta por 230 pacientes internados no período de junho de 2006 a novembro de 2007, que apresentaram dano hepático segundo os critérios do CIOMS (Council for Internacional Organizations of Medical Science), que consideram os resultados dos exames hepáticos e os níveis enzimáticos. Com a aplicação dos critérios CIOMS e após a exclusão das causas alternativas de dano hepático, foram identificados 41 indivíduos com suspeita de serem portadores de dano hepático induzido por medicamento. A imputabilidade do medicamento foi investigada mediante aplicação de escalas específicas para estudo da hepatotoxicidade, RUCAM e Maria & Victorino, e pela aplicação da escala Naranjo utilizada para qualquer tipo de RAM. O estimador kappa foi utilizado para interpretação da concordância entre as escalas. Foram avaliados 23 homens e 18 mulheres e a grande maioria dos pacientes (87,8%) apresentava dano hepático do tipo colestático. Todos os homens apresentavam este tipo de dano, enquanto que entre as mulheres, a distribuição foi: 72,2% para danos colestáticos, 22,2% para danos hepatocelulares e 5,6% para danos mistos. Para cada medicamento suspeito utilizado pelos pacientes foram aplicadas as escalas RUCAM, M&V e Naranjo, o que resultou em 166 avaliações. O cálculo para avaliar a concordância entre as escalas RUCAM e M&V resultou em Кw = 0, 2492, IC 95% (0,1293- 0,3617), valor superior ao encontrado na comparação entre RUCAM e Naranjo, Кw = 0,0006. A avaliação entre as escalas M&V e Naranjo com valor de Кw= 0,013 também apontou baixa concordância. Os resultados mostraram que a concordância no diagnóstico de DILI entre as escalas utilizadas é baixa, sendo, como esperado, um pouco maior quando da avaliação das escalas específicas para hepatotoxicidade (RUCAM e M&V), quando comparada às concordâncias entre estas e a escala global de Naranjo, que foi desenhada para a avaliação de todos os tipos de RAM. A aplicação de escalas para avaliação da hepatotoxicidade representa uma alternativa ao diagnóstico baseado apenas no julgamento clínico. Entretanto, a baixa concordância entre as escalas demonstra que existem limitações das definições e dos escores adotados pelos métodos que devem ser reavaliados. Espera-se que um consenso sobre definições em comum, critérios diagnósticos e terminologias oriente a construção de um novo instrumento para avaliar causalidade. / ADR (Adverse Drug Reaction) is defined as a response to a drug that is noxious and unintended. Drug induced liver injury (DILI) is a type of ADR that can be very severe and result in liver failure and death. The lack of specific biomarkers or diagnostic tests for DILI led to the development of numeric scales to assess the imputability of drug in DILI cases. The aim of this present work was to describe the types of DILI and assess the agreement of three scales used for its identification: RUCAM, Maria & Victorino and Naranjo. It is a sectional study was conducted at a university hospital in Rio de Janeiro. The target population was composed of 230 inpatients between June 2006 and November 2007, who had liver injury classified according to the criteria of CIOMS (Council for Internacional Organizations of Medical Science) that consider the results of liver tests and the enzyme levels. With the use of CIOMS criteria and after the exclusion of alternative causes of liver injury, 41 inpatients were identified as suspected DILI cases. Drug causality was assessed through the use of specific scales to study cases of hepatotoxicity, RUCAM and Maria & Victorino, and with Naranjo scale, used in the evaluation of any type of ADR. Kappa statistical test was used to assess the agreement between the scales. Twenty-three men and 18 were women were evaluated. The great majority of patients (87.8%) had cholestatic liver injury. All men had cholestatic liver injury, while for women, 72.2% of the cases were cholestatic, 22.2% were hepatocelular and 5.6% were mixed cases. For each suspected drug taken by the patients, the three scales were used, with a total of 166 ratings generated for each scale. The agreement between RUCAM and M & V was Кw = 0. 2492, CI 95% (0.1293 0.3617), as compared to RUCAM and Naranjo (Кw = 0.0006). The comparison between M&V and Naranjo (Кw= 0.013) showed low agreement. Results showed low agreement between the scales used for the diagnostic of DILI. As expected, the results were a little bit higher when assessment was made with specific scales for hepatotoxicity (RUCAM and M&V), as compared to the agreement made with these scales and the global scale Naranjo, which was designed to assess all types of RAM. The use of scales to assess hepatotoxicity are an alternative to diagnosis based only on clinical judgment. However, the low agreement between the scales shows that there are limitations in definitions and methods adopted by the scores that should be reconsidered. It is hoped that a consensus on common definitions, diagnostic criteria and terminology guide the construction of a new instrument to assess causality.

Reação Adversa ao Medicamento (RAM) é definida como a reação a um medicamento que é nociva e não-intencional. O dano hepático induzido por medicamento (DILI) é um exemplo de RAM que pode ser muito severa e provocar casos de transplante hepático e morte. A falta de marcadores específicos ou testes para o diagnóstico de DILI conduziu ao desenvolvimento de escalas para avaliar a imputabilidade do medicamento na ocorrência do dano hepático. O presente estudo teve como objetivo caracterizar os tipos de danos hepáticos induzidos por medicamentos e investigar a concordância de três escalas utilizadas na sua identificação: RUCAM, Maria & Victorino (M&V) e Naranjo. Trata-se de um estudo seccional realizado em um hospital universitário no Rio de Janeiro em que a população fonte foi composta por 230 pacientes internados no período de junho de 2006 a novembro de 2007, que apresentaram dano hepático segundo os critérios do CIOMS (Council for Internacional Organizations of Medical Science), que consideram os resultados dos exames hepáticos e os níveis enzimáticos. Com a aplicação dos critérios CIOMS e após a exclusão das causas alternativas de dano hepático, foram identificados 41 indivíduos com suspeita de serem portadores de dano hepático induzido por medicamento. A imputabilidade do medicamento foi investigada mediante aplicação de escalas específicas para estudo da hepatotoxicidade, RUCAM e Maria & Victorino, e pela aplicação da escala Naranjo utilizada para qualquer tipo de RAM. O estimador kappa foi utilizado para interpretação da concordância entre as escalas. Foram avaliados 23 homens e 18 mulheres e a grande maioria dos pacientes (87,8%) apresentava dano hepático do tipo colestático. Todos os homens apresentavam este tipo de dano, enquanto que entre as mulheres, a distribuição foi: 72,2% para danos colestáticos, 22,2% para danos hepatocelulares e 5,6% para danos mistos. Para cada medicamento suspeito utilizado pelos pacientes foram aplicadas as escalas RUCAM, M&V e Naranjo, o que resultou em 166 avaliações. O cálculo para avaliar a concordância entre as escalas RUCAM e M&V resultou em Кw = 0, 2492, IC 95% (0,1293- 0,3617), valor superior ao encontrado na comparação entre RUCAM e Naranjo, Кw = 0,0006. A avaliação entre as escalas M&V e Naranjo com valor de Кw= 0,013 também apontou baixa concordância. Os resultados mostraram que a concordância no diagnóstico de DILI entre as escalas utilizadas é baixa, sendo, como esperado, um pouco maior quando da avaliação das escalas específicas para hepatotoxicidade (RUCAM e M&V), quando comparada às concordâncias entre estas e a escala global de Naranjo, que foi desenhada para a avaliação de todos os tipos de RAM. A aplicação de escalas para avaliação da hepatotoxicidade representa uma alternativa ao diagnóstico baseado apenas no julgamento clínico. Entretanto, a baixa concordância entre as escalas demonstra que existem limitações das definições e dos escores adotados pelos métodos que devem ser reavaliados. Espera-se que um consenso sobre definições em comum, critérios diagnósticos e terminologias oriente a construção de um novo instrumento para avaliar causalidade. / ADR (Adverse Drug Reaction) is defined as a response to a drug that is noxious and unintended. Drug induced liver injury (DILI) is a type of ADR that can be very severe and result in liver failure and death. The lack of specific biomarkers or diagnostic tests for DILI led to the development of numeric scales to assess the imputability of drug in DILI cases. The aim of this present work was to describe the types of DILI and assess the agreement of three scales used for its identification: RUCAM, Maria & Victorino and Naranjo. It is a sectional study was conducted at a university hospital in Rio de Janeiro. The target population was composed of 230 inpatients between June 2006 and November 2007, who had liver injury classified according to the criteria of CIOMS (Council for Internacional Organizations of Medical Science) that consider the results of liver tests and the enzyme levels. With the use of CIOMS criteria and after the exclusion of alternative causes of liver injury, 41 inpatients were identified as suspected DILI cases. Drug causality was assessed through the use of specific scales to study cases of hepatotoxicity, RUCAM and Maria & Victorino, and with Naranjo scale, used in the evaluation of any type of ADR. Kappa statistical test was used to assess the agreement between the scales. Twenty-three men and 18 were women were evaluated. The great majority of patients (87.8%) had cholestatic liver injury. All men had cholestatic liver injury, while for women, 72.2% of the cases were cholestatic, 22.2% were hepatocelular and 5.6% were mixed cases. For each suspected drug taken by the patients, the three scales were used, with a total of 166 ratings generated for each scale. The agreement between RUCAM and M & V was Кw = 0. 2492, CI 95% (0.1293 0.3617), as compared to RUCAM and Naranjo (Кw = 0.0006). The comparison between M&V and Naranjo (Кw= 0.013) showed low agreement. Results showed low agreement between the scales used for the diagnostic of DILI. As expected, the results were a little bit higher when assessment was made with specific scales for hepatotoxicity (RUCAM and M&V), as compared to the agreement made with these scales and the global scale Naranjo, which was designed to assess all types of RAM. The use of scales to assess hepatotoxicity are an alternative to diagnosis based only on clinical judgment. However, the low agreement between the scales shows that there are limitations in definitions and methods adopted by the scores that should be reconsidered. It is hoped that a consensus on common definitions, diagnostic criteria and terminology guide the construction of a new instrument to assess causality.

No description available.

Après avoir analysé l'influence de la culture éducative turque sur l'enseignement du français en Turquie (2012, J.-C. Beacco), nous en avons conclu que les pratiques éducatives y sont fondées davantage sur la grammaire, ce qui peut s’expliquer par le rattachement à la culture éducative turque. Nous poursuivons nos recherches sur les contextualisations de la description du français dans des grammaires pédagogiques qui sont élaborées par et pour des turcophones (Grammaire et contextualisations- GRAC). Ces grammaires présentant des « contextualisations », s’écartent de celles dites de référence du français pour s’adapter aux cultures éducatives et métalinguistiques des apprenants turcophones. Il est intéressant d’étudier le discours grammatical à partir de plusieurs entrées : les articles avec les changements terminologiques dont ils sont l’objet, le genre avec la création d’une catégorie inexistante en turc et les cas grammaticaux avec la production de règles d’équivalence. Une démarche complémentaire par une cyber-enquête est engagée pour identifier les contextualisations des erreurs de français les plus fréquentes en milieu scolaire et universitaire turcophone. Les données obtenues ont permis de montrer que les discours sont modelés par les cultures éducatives et métalinguistiques. Il serait opportun de faire contribuer ces grammaires « extérieures » du français à une grammaire plus « centrale » du français. / After having studied the impact of educational culture on French teaching (2012, J.-C. Beacco), we concluded that teaching methods applied in Turkey are mostly based on grammar. This tendency reflects the educational culture of this country. The present research focuses on the contextualization of French grammar in reference books which were written by and for Turkish-speaking people (Project of GRAC).French reference books written in Turkey contain a number of “contextualization”, resulting from educational and metalinguistic culture of Turkish students learning French. Therefore, they differed from the French edition of French grammar. For this purpose, the French grammatical discourse was analyzed in many aspects: the articles which cause the change of terms; the gender of nouns which does not exist in Turkish introduces a new grammatical classification and the grammatical cases which result in the creation of equivalent rules. A cyber-survey was prepared to find out the contextualization of the frequent errors in French in high school and university area in Turkey. All the research, showed that these discourses were modulated by the educational and metalinguistic culture. Moreover, we demonstrated that the “off-center” Turkish edition of French grammar books need to be standardized to the “central norm” of the French edition. / Türk eğitim anlayışının Fransızca öğretimine etkisi incelenmiş olup (2012, J.-C. Beacco), Türkiye’de daha çok dil bilgisine dayalı bir öğretim şekli uygulandığı ve bunun da geleneksel eğitim anlayışına bağlı kalmanın bir sonucu olduğu belirlenmiştir. Fransızca dil bilgisinin Türkiye bağlamına uyarlanmış ve Türk yazarlar tarafından Türk okuyucular için kaleme alınan kaynak kitaplar üzerine çalışılmıştır (GRAC Projesi).Türkiye’de yayımlanan Fransızca kaynak kitapları bu “bağlama göre uyarlanmakta”, dolayısıyla bir Fransız yayını Fransızca dil bilgisinden uzaklaşmaktadır: bu kitaplar, Türk öğrencilerin eğitim anlayışları gereği ve dil ötesi nedenlerle farklı algıladıkları “o yabancı dile” uygun olabilmesi için uyarlanmıştır. Bu varsayımdan yola çıkarak, Fransızca dilbilgisel söylem birçok açıdan ele alınmıştır: terim değişikliğine neden olan « article », Türkçede karşılığı olmadığı için yeni bir sınıflandırmaya yol açan isimlerde cinsiyet ve iki dil arası kural denkliğine neden olan ismin halleri. İnternet ortamında yayımlanan bir anket ile Türkiye’de lise ve üniversite düzeyinde sıklıkla yapılan Fransızca yanlışların bu bağlama uyarlanması araştırılmıştır. Tüm bu veriler, bu söylemlerin Türklerin eğitim anlayışı ve dil ötesi algıları ile şekillendiğini göstermiştir. Elde edilen sonuçlar doğrultusunda ise, “merkez dışı” bu kaynak kitapların daha “merkezi” bir Fransız yayın ölçütüne kazandırılması gerekmektedir.

Membrane transport proteins are known to influence the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. At the onset of this thesis work, only a few structure-activity models, in general describing P-glycoprotein (Pgp/ABCB1) interactions, were developed using small datasets with little structural diversity. In this thesis, drug-transport protein interactions were explored using large, diverse datasets representing the chemical space of orally administered registered drugs. Focus was set on the ATP-binding cassette (ABC) transport proteins expressed in the canalicular membrane of human hepatocytes. The inhibition of the ABC transport proteins multidrug-resistance associated protein 2 (MRP2/ABCC2) and bile salt export pump (BSEP/ABCB11) was experimentally investigated using membrane vesicles from cells overexpressing the investigated proteins and sandwich cultured human hepatocytes (SCHH). Several previously unknown inhibitors were identified for both of the proteins and predictive in silico models were developed. Furthermore, a clear association between BSEP inhibition and clinically reported drug induced liver injuries (DILI) was identified. For the first time, an in silico model that described combined inhibition of Pgp, MRP2 and breast cancer resistance protein (BCRP/ABCG2) was developed using a large, structurally diverse dataset. Lipophilic weak bases were more often found to be general ABC inhibitors in comparison to other drugs. In early drug discovery, in silico models can be used as predictive filters in the drug candidate selection process and membrane vesicles as a first experimental screening tool to investigate protein interactions. In summary, the present work has led to an increased understanding of molecular properties important in ABC inhibition as well as the potential influence of ABC proteins in adverse drug reactions. A number of previously unknown ABC inhibitors were identified and predictive computational models were developed.