Search

Thèse confidentielle jusqu'au 28 septembre 2022.; Breast cancer still remains the first cause of death in women, despite the improvement in its diagnostic and treatments. Many factors may explain this high mortality, such as the lack of biomarkers for the progression of breast cancer. Preliminary data acquired by the laboratory has identified the DDB2 (DNA-Damaged Binding 2) protein as a potential candidate for the prediction of breast cancer progression. In this work, an in silico analysis of several transcriptomic databases validated the predictive value of the ddb2 gene in the metastatic progression of breast tumors, their response to adjuvant chemotherapy, and the risk of relapse post-treatment. Moreover, cases of resistance against treatment, and the severe side effects highlights the need of new therapeutic alternatives. The success of cisplatin in the treatment of different cancers, including breast cancer, drew the attention of research to the organometallic family. In that extend, the laboratory is studying cellular effects of new iron-based organometallic compounds on breast cell lines. Preliminary data have revealed the anti-proliferative effect of two iron-based organometallic compounds, named AIM2 and AIM3, on 2 breast cancer cell lines (MDA-MB231 and T47D), and on 1 normal mammary breast cell line (MCF-10A). This cytostatic effect, which extend up to 120h of treatment with only 30% of cells in the sub-G1 compartment, has been associated with the induction of senescence. Moreover, our data showed that this senescence is reversible only in the normal mammary cell line, and not in the cancer cells. Finally, our work showed that a 24h pretreatment of different cell lines with our compounds lead to a chemo-and-radiopotentialisation effect. This work suggests the possible clinical use of AIM2 and AIM3 as chemo-and-radiosensitizers, as well as senostatic agents (senescence inductors).; Le cancer du sein, malgré de nettes améliorations dans son diagnostic et sa prise en charge thérapeutique, reste la 1ère cause de décès chez les femmes. Différents paramètres permettent d’expliquer cette forte mortalité, tels que le manque actuel de biomarqueurs permettant de prédire la progression de la maladie. Des données préliminaires acquises par le laboratoire ont permis d’identifier la protéine DDB2 (Damaged-DNA binding 2) comme potentiel candidat pour la prédiction de la progression du cancer du sein. Une analyse in silico de bases de données transcriptomiques a permis de valider le rôle prédictif du gène codant DDB2 pour la progression métastatique des tumeurs mammaires, leur réponse à la chimiothérapie adjuvante, et le risque de récidive post-traitement. De plus, les cas de résistances aux thérapies, et les lourds effets secondaires soulignent le besoin actuel de nouvelles alternatives thérapeutiques. Le succès du cisplatine dans le traitement de nombreux cancers, dont celui du sein, a attiré l’attention des recherches sur les complexes organométalliques. C’est dans ce cadre que s’inscrit une autre partie des recherches du laboratoire qui étudie les effets cellulaires de complexes organométalliques à base de fer dans le modèle du cancer du sein. Des études préliminaires avaient mis en évidence la capacité de 2 complexes à base de Fer, appelés AIM2 et AIM3, à induire une inhibition de la prolifération de lignées cancéreuses mammaires (MDA-MB231 et T47D) et d’une lignée mammaire saine (MCF-10A). Cet effet cytostatique, qui s’étend jusqu’à 120h de traitement avec seulement 30% de cellules en phase sub-G1, a été associé avec une induction de la sénescence. De plus, nos résultats ont montré que cette sénescence est réversible uniquement dans la lignée mammaire saine, mais pas dans les lignées cancéreuses mammaires. Enfin, les résultats de cette thèse ont permis de mettre en évidence un effet potentialisateur des complexes face au Tamoxifène, à la Doxorubicine, au 5-Fluorouracile et à la radiothérapie dès 24h de prétraitement de différentes lignées mammaires. Ces résultats permettent d’envisager l’utilisation clinique des complexes AIM2 et AIM3 comme agent potentialisateur de la mort induite par différents traitements, mais également comme agents sénostatiques (induisant la sénescence) pour réduire le volume tumoral avant chirurgie.

Since a few decades, a new invertebrate animal model has emerged in toxicology studies: the planarian. This non-parasitic flatworm, from phylum Platyhelminthes, has an amazing regenerative capacity and has been described as "immortal under the edge of the knife" in 1814 by Dalyell. This formidable capacity is due to the abundance of stem cells called neoblasts, allowing for a tiny fragment equivalent to 1/279

Introduction Advanced pancreatic cancer (APC), one of the most aggressive tunors, was considered to be resistant to chemotherapy for decades. FOLFIRINOX (5-FU, leucovorin, iNinotecah and oxaliplatin) regimen showed an improvement of quality of life and overall sUrvival.ir APb patients with good performance status (ECOG Material and methods Seven patients diagnosed with APO, during a six-month period, received FOLFIRINOX as first line treat- ment. Tumor measurement Was assesed every two months and CA 19-9, tHe specific tumor marker of pahcteatid can6er, was assessed every two wedks at every cycle. Results Three patients ouf of seven receiving FOLFiRINOX dtpe- riented an early And transitory increase of CA 19-9 after th6 first two cybles resulting ih a considerable response with a median survival of 15 mnths and suggesting a fhdel of fdmor release syndrome. Conclusion This phenoMenon of early and transitory increase of CA 19-9 in APC could reflect the high efficacy of FOLFIRINOX and could predict better out- come in these patients.

Organic and organometallic compounds represent an important potential in many fields such as optics, optoelectronics, photonics and optical data storage. In this work, we have studied the nonlinear optical properties of two types of compounds; organic molecules based on BODIPY and organometallic complexes based on ruthenium (II) and iron (II). For this, the experimental techniques used were based on SHG, THG and onZ-scan techniques. For this study, we used a pulsed picosecond laser delivering two wavelengths: 1064 nm and 532 nm. 1064 nm for SHG and THG techniques and 532 nm for Z-scantechnique were used, respectively. The results obtained are interesting and original and show that the nonlinear optical response of organic molecules based on BODIPY depends in particular on the number of electron donor groups. The same behavior has been observed in the case of organometallic complexes based on ruthenium (II) and iron (II), highlighting the modulation of the nonlinear optical response as a function of the nature of the transition metal used (Ru ( II) or Fe (II)) and the nature of the ancillary ligands around the organometallic moiety (Ru (II)).; Les composés organiques et organométalliques représentent des matériaux prometteurs pour leurs applications dans divers domaines tels que l'optique non linéaire, l'optoélectronique, la photonique et le stockage des données par voie optique. Dans ce travail,nous avons étudié les propriétés optiques non linéaires(ONL) de deux familles de composés à savoir des molécules organiques à base de BODIPY et des complexes organométalliques à base de ruthénium (II)et de fer (II). Pour cette étude nous avons utilisé un laser pulsé en régime picoseconde qui délivre deux longueurs d'ondes : 1064 nm et 532 nm. Nous avons utilisé 1064nm pour les techniques de la génération de la seconde harmonique (SHG) et la génération de la troisième harmonique (THG) et 532 nm pour celle de Zscan.Les résultats obtenus sont intéressants et originaux et montrent bien que la réponse non linéaire dépend du nombre de groupements donneurs d’électrons pour les molécules organiques à base de BODIPY. Le même comportement a été observé dans le cas des complexes organométalliques à base de ruthénium (II) et de fer (II) mettant en évidence la modulation de la réponse optique non linéaire en fonction de la nature du métal de transition utilisé(Ru(II)ou Fe(II)) et de la nature des ligands auxiliaires autour du fragment organométallique (Ru(II)).

Organic and organometallic compounds represent an important potential in many fields such as optics, optoelectronics, photonics and optical data storage. In this work, we have studied the nonlinear optical properties of two types of compounds; organic molecules based on BODIPY and organometallic complexes based on ruthenium (II) and iron (II). For this, the experimental techniques used were based on SHG, THG and onZ-scan techniques. For this study, we used a pulsed picosecond laser delivering two wavelengths: 1064 nm and 532 nm. 1064 nm for SHG and THG techniques and 532 nm for Z-scantechnique were used, respectively. The results obtained are interesting and original and show that the nonlinear optical response of organic molecules based on BODIPY depends in particular on the number of electron donor groups. The same behavior has been observed in the case of organometallic complexes based on ruthenium (II) and iron (II), highlighting the modulation of the nonlinear optical response as a function of the nature of the transition metal used (Ru ( II) or Fe (II)) and the nature of the ancillary ligands around the organometallic moiety (Ru (II)).; Les composés organiques et organométalliques représentent des matériaux prometteurs pour leurs applications dans divers domaines tels que l'optique non linéaire, l'optoélectronique, la photonique et le stockage des données par voie optique. Dans ce travail,nous avons étudié les propriétés optiques non linéaires(ONL) de deux familles de composés à savoir des molécules organiques à base de BODIPY et des complexes organométalliques à base de ruthénium (II)et de fer (II). Pour cette étude nous avons utilisé un laser pulsé en régime picoseconde qui délivre deux longueurs d'ondes : 1064 nm et 532 nm. Nous avons utilisé 1064nm pour les techniques de la génération de la seconde harmonique (SHG) et la génération de la troisième harmonique (THG) et 532 nm pour celle de Zscan.Les résultats obtenus sont intéressants et originaux et montrent bien que la réponse non linéaire dépend du nombre de groupements donneurs d’électrons pour les molécules organiques à base de BODIPY. Le même comportement a été observé dans le cas des complexes organométalliques à base de ruthénium (II) et de fer (II) mettant en évidence la modulation de la réponse optique non linéaire en fonction de la nature du métal de transition utilisé(Ru(II)ou Fe(II)) et de la nature des ligands auxiliaires autour du fragment organométallique (Ru(II)).

Kounis syndrome is an allergic acute coronary syndrome. It occurs on healthy or pathological arteries. Its complications, although often benign, can lead to cardiac arrest and death. Its triggering factors are multiple and include contrast products used in diagnostic imaging. We report the case of an 81 years old patient affected by hepatocellular carcinoma, who presented a type 2 Kounis syndrome with inferior myocardial infarction, complicated by cardiac arrest related to complete heart block following a gadoteric acid injection.

We present a Nuclear Magnetic Resonance (NMR) study of the NiCl2-4SC(NH2)2 compound, called DTN, consisting of spin-1 chains that are weakly coupled along the transverse directions. At low temperatures and for magnetic field values between the two critical fields Hc1 and Hc2, this system enters an ordered phase of the Bose-Einstein Condensate (BEC) type. Within this phase, we first describe the experimental determination of the order parameter (transverse magnetization), the amplitude of which is found to be well described by theory while its phase (orientation) seems to be fixed by an anisotropy term. Second, by NMR relaxation rate 1/T1 we have studied the low-energy fluctuations of the electronic spins and found that they obey the power law 1/T1 ~ T 5. Such a behaviour points to a 2nd order process involving linearly dispersing excitations, such as Bogoliubov quasiparticles, but its nature is not yet well understood. Outside the BEC phase, we report a study of the spin fluctuations in the quantum critical regime (H ~ Hc2), demonstrating a scaling law on 1/T1 similar to the one that has already been observed in another equivalent compound, BPCB spin-ladder, thus proving the universality of this regime [S. Mukhopadhyay et al., Phys. Rev. Lett. 109, 177206 (2012)]. We have also studied the effect of disorder induced by the Br-Cl substitution in the compound Ni(Cl1-xBrx)2-4SC(NH2)2 (doped DTN), for which measurements using macroscopic techniques have suggested the existence of a "Bose glass" phase [R. Yu et al., Nature 489, 379 (2012)]. This phase is characterized, for all studied doping concentrations x = 4%, 9%, 13%, by a peak in the NMR relaxation rate 1/T1 at the field value Hp ~ 13.5 T, evidencing an upsurge of the longitudinal spin fluctuations, and presenting strong inhomogeneity of the 1/T1 values – probably reflecting the glassy character of the system. The observed doping-independence of Hp demonstrates that the corresponding physics is dominated by local effects due to the dopants.; Nous présentons l'étude par Résonance Magnétique Nucléaire (RMN) du composé NiCl2-4SC(NH2)2, dit DTN, constitué de chaînes de spins 1 faiblement couplées suivant les directions transverses aux chaînes. A basse température et dans un champ magnétique compris entre les deux valeurs critiques Hc1 et Hc2, ce système s'ordonne dans un état de type Condensat de Bose-Einstein (CBE). Dans cette phase, nous décrivons d'une part la détermination expérimentale du paramètre d'ordre (aimantation transverse), dont l'amplitude est bien décrite par la théorie mais dont la phase (orientation) semble fixée par un terme d'anisotropie. D'autre part nous avons étudié les fluctuations des spins électroniques à basse énergie, par la mesure du taux de relaxation RMN 1/T1, et montré que celui-ci obéit à la loi de puissance 1/T1 propto T^5. Ce comportement peut être associé au processus de 2ème ordre lié à des excitations ayant une dispersion linéaire, tels que les quasiparticules de Bogoliubov, mais sa nature n'est pas encore bien comprise. En dehors de la phase CBE, nous décrivons l'étude des fluctuations de spin dans le régime critique quantique (H ~ Hc2), dans lequel nous établissons une loi d'échelle sur 1/T1, identique à celle que l'on a observé dans un autre composé de description équivalente (échelle de spins BPCB), prouvant ainsi l'universalité de ce régime [S. Mukhopadhyay et al., Phys. Rev. Lett. 109, 177206 (2012)]. Nous avons aussi étudié les effets du désordre induit par la substitution Br-Cl dans le composé Ni(Cl1−xBrx)2-4SC(NH2)2, pour lequel des mesures par des techniques macroscopiques ont suggéré l'existence d'une phase "verre de Bose" [R. Yu et al., Nature 489, 379 (2012)]. Cette phase est caractérisée, pour différentes concentrations du dopage x = 4%, 9%, 13%, par un pic de relaxation RMN 1/T1 au champ Hp = 13.5 T, marquant un regain des fluctuations longitudinales et présentant une forte distribution des valeurs de 1/T1 - probablement due à l'aspect vitreux du système. L'indépendance du Hp en fonction de x démontre que la physique y est dominée par les effets locaux liés aux dopants.

Les auteurs rapportent les caractéristiques épidémiologiques et cliniques de la forme érysipéloïde de leishmaniose cutanée ainsi que ses difficultés diagnostiques et thérapeutiques. Chez une patiente âgée de 44 ans, sans antécédents, a consulté pour une tuméfaction nasale inflammatoire évoluant depuis 4 mois. L'examen clinique a révélé un placard érythémateux, infiltré centrofaciale. Une antibiothérapie avec des soins locaux quotidiens n'ont pas entraîné une amélioration, voire l'extension de lésions sous anti-inflammatoire non stéroïdiens. Le diagnostic de leishmaniose cutanée a été confirmé par le frottis cutané. Un traitement par l'antimoniate de méglumine par voie intramusculaire a été instauré à la dose de 20 mg/kg par jour avec évolution favorable. La forme érysipéloïde de leishmaniose cutanée constitue une entité rare et inhabituelle entraînant souvent un retard diagnostique. Le diagnostic repose sur l'examen parasitologique direct, la recherche de l'ADN des leishmanies par PCR et sur l'examen histologique. Et il existe plusieurs options thérapeutiques. L’évolution est généralement favorable.

The administration of a radionuclide in unsealed source whose radiation will destroy cells that have selectively accumulated product is called radiometabolic therapy. The management of bone pain is a major problem, particularly in cases of breast or prostate where the presence of metastases can remain compatible with long-term survival of cancer patients. In this context, the radiometabolic therapy reduces the pain secondary to bone metastases, in association or not with analgesics. This technique is rarely prescribed as first-line. It can also be combined with external beam radiotherapy or chemotherapy, if clinical conditions permit (due to the increased risk of hematologic toxicity). In this setting, the currently used substances are Metastron® and Quadramet®. Recently, a new product, radium chloride (or Alpharadin®) has shown efficacy in bone metastases from prostate cancer, particularly in terms of bone pain palliation, but also of increased overall survival. In addition, this product has virtually no hematologic toxicity.

To describe drugs used in the non-hormonal treatment of metastatic prostate cancer.Bibliographical search was performed from the database Medline (National Library of Medicine, PubMed) and websites of the HAS and the ANSM. The search was focused on the characteristics, the mode of action, the efficiency and the side effects of the various drugs concerned.The metabolic radiotherapy although under-used for this indication, kept a place at the beginning of the disease. Radium-223 chloride seems to have to occupy an important place in the coming years. The chemotherapy, the only recourse until very recently in the castration-resistant prostate cancer, must redefine its place partially. The denosumab provide an interesting alternative to bisphosphonates.The non-hormonal treatment of the metastatic disease of the prostate cancer is changing rapidly with the emergence of new molecules. Urologist must know perfectly these new drugs.

In France, cutaneous leishmaniasis is frequently seen in patients returning from North Africa or South America. Autochthonous leishmaniasis due to Leishmania infantum causes rather visceral forms. Nevertheless, cutaneous leishmaniasis caused by this parasite is occasionally seen in immunocompetent patients who have never been outside France.An 8-year-old girl living in the Haute-Savoie region and who had never travelled overseas presented with chronic ulceration of the right cheekbone that failed to regress under topical therapy. Laboratory tests demonstrated the presence of L. infantum. Following cryotherapy and intralesional injections of meglumine antimonite, the lesion resolved within a month. The patient's medical history revealed repeated journeys to the Pyrénées-Orientales region of southern France.For chronic ulceration on an uncovered area that does not resolve with topical therapy, cutaneous leishmaniasis should be considered in the differential diagnosis even if the patient has never left France. Trips to the South of France (an endemic region) should be sought in the history. In addition to direct examination of the product from curettage of the lesion and histopathology, non-invasive methods such as Western blotting with PCR run on filter paper impressions allow accurate diagnosis.

We report the case of a 3-year-old boy admitted to the pediatric emergency department for ethylene glycol poisoning. During hospitalization, he presented dysuria associated with crystalluria. Blood tests showed metabolic acidosis with an elevated anion gap. A renal ultrasound performed a few weeks later revealed bilateral medullary hyperechogenicity. Urine microscopic analysis showed the presence of weddellite crystals. Secondary nephrocalcinosis due to ethylene glycol intoxication was diagnosed. Hyperhydration and crystallization inhibition by magnesium citrate were initiated. Despite this treatment, persistent weddellite crystals and nephrocalcinosis were seen more than 2years after the intoxication. Ethylene glycol is metabolized in the liver by successive oxidations leading to its final metabolite, oxalic acid. Therefore, metabolic acidosis with an elevated anion gap is usually found following ethylene glycol intoxication. Calcium oxalate crystal deposition may occur in several organs, including the kidneys. The precipitation of calcium oxalate in renal tubules can lead to nephrocalcinosis and acute kidney injury. The long-term renal prognosis is related to chronic tubulointerstitial injury caused by nephrocalcinosis. Treatment of ethylene glycol intoxication is based on specific inhibitors of alcohol dehydrogenase and hemodialysis in the most severe forms, and should be started promptly.

Study of side effects (SE) associated with strontium ranelate required by the French Drug agency (Afssaps).SE associated with strontium ranelate and spontaneously reported until March 2009 to the manufacturer or to the French Regional Pharmacovigilance Centers and the periodic safety reports have been analyzed. Utilisation and sales data have been obtained from the manufacturer.During the 3 years of the study, 844 SE have been reported in France in patients treated with strontium ranelate. The 199 severe SE are cardiovascular (52%), cutaneous (26%), hepatodigestive (6%), neurological (5%), haematological (3%), osteomuscular (3%) and various (3%). Venous thromboembolic events (VTEE) are the most frequent cardiovascular SE (93/104) with an incidence of 1/31,052 months of treatment. At least one VTEE risk factor is present in 26 (28%) patients. DRESS syndrome which median delay of advent is 35 days is the most frequent cutaneous SE (19/51 SE) with an incidence of 1/13,725 months of treatment. The 14 severe hepatodigestive SE are hepatitis (n=5), pancreatitis (n=2) and various others SE (n=7). The 10 severe neurological SE are confusion/amnesia (n=5), convulsions (n=4) and parenthesis (n=1). The seven severe haematological SE are pancytopenia (n=5), erythroblastopenia (n=1) and thrombocytopenic purpura (n=1). Among the seven deaths, only three (two pulmonary embolisms, one DRESS syndrome) are attributable to strontium ranelate. Apart from the severe SE, 685 SE have also been reported because strontium ranelate was the only drug with an imputability "suspect".Anti-fractural effect of strontium ranelate is at least as equal as those of bisphosphonates. Its usual SE are benign but two severe risks of strontium ranelate i.e. VTEE and DRESS syndrome are confirmed. The profile of tolerability, different from the one of bisphosphonates makes strontium ranelate as an alternative when bisphosphonates are not recommended or contraindicated (renal insufficiency for example).If DRESS syndrome is unpredictable, the one of VTEE could be reduced by a strontium ranelate contraindication for patients with a history of VTEE and by stopping the drug if a new VTEE risk situation happens.

Malignancies and opportunistic infections are frequently observed after solid-organ transplantation. Their occurrence strongly affects recipient survival. We report the case of a 29-year-old Tunisian kidney-recipient who was diagnosed simultaneously with post-transplant lymphoproliferative disease (PTLD) and visceral leishmaniasis (VL). Withdrawal of immunosuppressive therapy together with antiparasitic treatment using liposomal amphotericin B, and anti-CD20 antibodies medication resulted in cure of leishmaniasis and remission from PTLD. This case is of clinical interest because of the uncommon association of VL with PTLD after solid organ transplantation. It is also original by the favourable outcome of VL and PTLD, both known as life-threatening diseases. Also, it illustrates the predisposing role of immunosuppressive therapy in occurrence of opportunistic infections and malignancies after solid organ transplantation.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe form of adverse drug reaction. Strontium ranelate has recently been authorised for postmenopausal osteoporosis. We report a case of strontium ranelate-induced DRESS complicated by linear Ig A dermatosis due to vancomycin.A 77-year-old woman with osteoporosis had been treated by strontium ranelate for 4 weeks when she developed a febrile generalized skin rash. Blood tests showed eosinophilia (12.74 × 10(9)/L) and liver damage. A diagnosis of DRESS was made, leading to discontinuation of strontium ranelate and prescription of systemic corticosteroids. Two days later, methicillin-resistant Staphylococcus aureus bacteraemia occurred and treatment with vancomycin was started. The liver dysfunction resolved. After two weeks of antibiotherapy, bullous lesions were noted on the thighs. Skin biopsy results suggested a diagnosis of linear IgA bullous dermatosis. Vancomycin was stopped. Two weeks later, the eruption resolved. The eosinophil count gradually returned to normal after four months of corticosteroid therapy.More than 15 cases of DRESS syndrome have been reported in Europe, including 2 deaths related to ranelate strontium, prompting European health authorities to publish a warning concerning the risk of strontium ranelate-induced DRESS. A particular feature of our patient was complication with linear IgA bullous dermatosis caused by vancomycin. In conclusion, it is essential to be aware of the risk of severe cutaneous reaction to strontium ranelate, a new drug used to treat osteoporosis.

Leishmaniasis is wide spread parasitic disease considered to be endemic in 88 countries in both old and new world. The standard treatment remains Meglumine antimoniate.We study the side effects of systemic meglumine antimoniate in cutaneous leishmaniasis.We conduct a retrospective study covering 3-year period (2002- 2005). All medical reports of cutaneous leishmaniasis treated by systemic Meglumine antimoniate are reviewed.The study comprise 63 patients all treated by systemic meglumine antimoniate at the dose of 60 mg/kg/day for 10-15 days. Side effects were noted in 15 cases (12 females and 3 males). The subject's age range from 11 to 78 years. Stibio-intolerance (fever, rash, arthralgia, abdominal pain) was observed in 12 cases and stibiotoxicity in 3 cases: precordialgies 1 case, hyperamylasemia and increase liver enzyme: 1 case, pancytopenia, renal and hepatic failure leading to death: 1 case, skin eruption: 7 cases, pruritus and erythema in the site of injection: 5 cases, urticaria: 1 case. Meglumine antimoniate was stopped in 13 cases.Meglumine antimoniate is the generally recommended treatment of cutaneous leishmaniasis. In spite of the rarity of Glucantime's side effects, we recommend a careful survey especially in older patients.

Multicomponent reactions are processes in which at least three starting materials react together to form a final compound containing most of the starting atoms. They constitute one of the most efficient processes in synthetic organic chemistry. They are also more economical and environmentally friendly than classic organic reactions. Moreover, since they allow a straightforward access to large libraries of compounds containing the same core units, they represent a valuable tool for pharmaceutical industries, especially for high-throughput screening. In 2006, the laboratory developed a Mannich-type multicomponent reaction between aromatic organozinc compounds, aldehydes and secondary amines allowing the efficient preparation of diarylmethylamines. These structures, and more generally the α,α-disubstituted amine core unit, are found in a large range of compounds displaying diverse pharmacological properties. The main purpose of this PhD project was to extend the multicomponent process to other types of α,α-disubstituted amines. In the first part of this work, a range of β-arylethylamines, and in particular those bearing a carboxyethyl group at the position α to the nitrogen, have been prepared starting from in situ-generated benzylic organozinc compounds (Barbier-like conditions), carbonyl compounds and primary or secondary amines. These conditions present the advantage to avoid the pre-formation of the organometallic compound. Due to their broad potential applications, the synthesis of α-aminoesters has also been undertaken starting from functionalized aromatic organozinc species. It could be noticed that in this case, due to possible side-reactions, the formation of the organometallic reagent had to be undergone prior to the three-component coupling. In a second part of this work, diastereoselective versions of the reaction have been developed starting from chiral amines. Interesting results, regarding both chemical yields and diastereoselectivity, have been obtained, especially with (R)-phenylethylamine. Concomitantly, the mechanism was evaluated via the monitoring of the reaction by in-situ infrared spectroscopy (ReactIR apparatus). Data obtained should help to develop strategies for the further development of enantioselective versions of the reaction, Les réactions multicomposant sont des réactions faisant intervenir au minimum trois composés pour la préparation d'un produit contenant la majeure partie des atomes de départ. Elles constituent l'un des procédés les plus performants en synthèse organique. En diminuant les coûts et les rejets par rapports aux réactions classiques de chimie organique, elles sont également plus économes et plus respectueuses de l'environnement. De plus, en permettant la formation rapide et efficace d'une large librairie de molécules complexes à partir de substrats simples, elles représentent un outil à forte valeur ajoutée dans le domaine pharmaceutique pour l'élaboration de chimiothèques. Face à ces enjeux, le laboratoire a développé en 2006 une réaction multicomposant de type Mannich entre des organozinciques aromatiques, des amines secondaires et des aldéhydes. Cette réaction permet la synthèse en une étape d'une variété de diarylméthylamines, dont la structure amine α,α-disubstituée est rencontrée dans de nombreux composés d'intérêt pharmacologique. A partir de ces travaux, le premier objectif du projet de thèse a été d'étendre la réaction multicomposant à d'autres types d'amines α,α-disubstituées. Tout d'abord, la préparation de nombreuses β-aryléthylamines, et notamment d'α-aminoesters, a été mise au point de manière rapide et efficace à l'aide d'organozinciques benzyliques formés in situ dans des conditions de type Barbier. Ces conditions opératoires présentent l'avantage d'éviter l'étape préliminaire de formation de l'organozincique. En raison de l'intérêt de ces composés, la synthèse d'α-aminoesters à partir d'organozinciques aromatiques a ensuite été réalisée, en préformant l'organométallique à partir du dérivé bromé correspondant par une catalyse au cobalt. Au delà de l'extension de cette réaction, le deuxième objectif du projet de thèse a été de développer des versions diastéréosélectives de la réaction multicomposant à partir d'amines chirales. Des résultats corrects en termes de diastéréosélectivité ont été obtenus, notamment à l'aide de (R)-phényléthylamine. Dans un dernier temps, le mécanisme réactionnel a été étudié par suivi de la réaction par infrarouge à l'aide d'un appareillage ReactIR. Les données receuillies sur les intermédiaires réactionnels potentiels serviront de base pour l'élaboration de stratégies énantiosélectives

Three clinical forms of cutaneous leishmaniasis can be found in Tunisia, i.e. the sporadic form due to Leishmania infantum in the North, the zoonotic epidemic form due to Leishmania major in the center and Southwest, and the chronic cutaneous form due to Leishmania tropica in the South. Unlike cutaneous forms, mucosal involvement is uncommon. The purpose of this report is to describe another case of mucosal leishmaniasis due to contiguity with a skin lesion in a 54-years-old woman. The patient responded well to treatment with meglumine antimoniate.

The association of hemophagocytic syndrome (HS) and visceral leishmaniasis is a frequent disorder during infancy in endemic areas such as Tunisia. The range of severity of HS secondary to visceral leishmaniasis includes both pure biological forms that resolve with antimicrobial therapy and life-threatening emergencies that require specific treatment. We describe 2 cases of severe HS secondary to visceral leishmaniasis. The diagnosis of HS was based on the HLH-2004 diagnostic criteria. Therapy involved pentavalent antimonial (Glucantime) in both cases. The combination of corticosteroids with immunoglobulins, used in the 1st case, but introduced late, led to an unfavorable course and death. In the 2nd case, the specific treatment of HS was based on immunochemotherapy including etoposide and corticosteroids. Progression was favorable with a follow-up of 24 months. Etoposide containing therapeutic regimens can be proposed in severe forms of HS associated with visceral leishmaniasis.

To use diffusion weighted MR imaging (DWI), a technique routinely used in patients with stroke, for diagnosis of myocardial infarction (MI).A breath hold ECG gated DWI sequence (b = 300 sec/mm2) was developped and applied to 7 patients with recent MI (3-15 days), 3 patients with chronic MI (6 months) and 4 patients with valvular heart disease without MI (control cases). DWI data were correlated to T2W, first pass perfusion and delayed enhancement data.In all patients with recent MI, DWI showed an area of increased signal with reduction of ADC relative to normal myocardium. Hyperintense lesion on DWI corresponded to areas of delayed enhancement. The diffusion images were normal in patients with chronic MI or no MI.Even though no animal model or other reference method is available, these preliminary results indicate that DWI could assist clinicians in detecting recent MI.

Glucantime is the firstline treatment for cutaneous leishmaniasis in Tunisia. Adverse effects related to systemic administration of Glucantime are frequent. The purpose of this retrospective study was to review the files of 53 patients who were treated for cutaneous leishmaniasis using meglumine antimoniate at a dose of 60 mg/kg/day for 15 days during the period between 1998 and 2007. Adverse effects were observed in 5 men and 4 women with an average age of 40.8 years. Antimony intolerance occurred in 8 patients and stibio-intoxication occurred in 4. Glucantime was considered as the most likely cause of adverse effects in 6 patients and as the plausible cause in 3 patients. Fever was the most frequent complication of antimony intolerance followed by cough, myalgia, and cutaneous lesions. Hepatic cytolysis was the most frequent sign of stibio-intoxication. Asymptomatic elevation of amylase level to 108 UI/l was observed in one case. The most serious complication was acute toxic kidney failure on the 15th day of treatment. The incidence of adverse events to Glucantime ranges from 16% to 59%. The most severe complication is acute renal failure on the 15th day of treatment, as observed in one patient in this series. Patient status must be monitored by performing laboratory tests at the beginning and end of the treatment. Since cutaneous leishmaniasis observed in Tunisia is a self-healing dermatosis that never results in sequels, treatment with Glucantime should be discontinued in any patient who develops suspicious symptoms.

Marginal kidneys must be reanimated before their transplantation. Reanimation is conducted with hypothermic pulsatile perfusion. The tests used generally to demonstrate the viability is the vascular resistance which is not convenient for everybody. We have developed a magnetic resonance compatible perfusional technology allowing us to test the organs during the perfusion by Gd-perfusion MRI.We have used pigs' kidneys with no warm ischemic time to establish the basis in a normal kidney. After an eight-hour hypothermic pulsatile perfusion, kidneys are submitted to a Gd perfusion. First, we measure the anatomy of the vessels, then the distribution of Gd in the kidney. We obtain simultaneously a dynamic study of the organs where T0 represents the Gd bolus arrival in the cortex and TP the maximum saturation time of Gd.We have observed that a normal T0 is inferior to 30s and TP is inferior to one minute. We have compared these values with ATP resynthesis in these organs and found that they correlate. We hope for the future through that predictive use of Gd-MRI to avoid the clinical use of "too" marginal kidneys or the discard of good kidneys but not corresponding with the vascular resistance theory.

Leishmaniases are parasitic diseases frequent in the Mediterranean Basin. In Algeria they occupy the first place among parasitic diseases and represent 35% of diseases with compulsory notification. This is an alarming situation because the extension of the disease can also deteriorate the epidemiological situation of the tuberculosis and the HIV/AIDS because of coinfection. The authors report a series of 213 cases of Aden ulcers listed in the wilaya of Tizi-Ouzou within nine years, region known for endemia of infantile visceral leishmaniases.

Cutaneous leishmaniasis is a protozoal infection. Its prevalence is increasing, especially in immunocompromised subjects.We report four patients with rheumatoid arthritis, treated with methotrexate and prednisone who developed cutaneous leishmaniasis. Clinical outcome was favorable after institution of antimony therapy in three cases despite the continuation of methotrexate and prednisone. One patient failed to respond to therapy.The frequency of cutaneous leishmaniasis is increasing especially in immunocompromised subjects. In our patients, rheumatoid arthritis, corticosteroid therapy and methotrexate were predisposing factors of cutaneous leishmaniasis.

Strontium ranelate, with its unique mode of action combining inhibition of bone resorption and stimulation of bone formation is characterized by a wide scatter of activity, both in terms of skeletal sites positively affected and of patients experiencing benefits of its administration. It is currently reimbursed, in Belgium, in osteoporotic patients aged 80 years and older. In this group, it is the only drug which has shown an extensive range of anti-fracture efficacy.

THE OBJECTIVE of this work is to evaluate a new therapy, the metabolic radiotherapy to the 153Samarium-EDTMP, of recent introduction in Tunisia, in the painful bony metastasis treatment observed at the patients affected of cancer of the prostate.It is about a retrospective survey with a receding of 40 months, achieved through 45 files of patients having benefited all of this new treatment for painful bony metastases in relation with a prostatic adenocarcinoma and collected by three centers of Nuclear Medicine of the capital: the institute Salah Azaiez (state-controlled), the Center CERU (deprives) and the Military hospital (HMPIT).We tried to appreciate essentially four parameters: the therapeutic efficiency, the factors influencing the answer in the treatment, the toxicity of the treatment and the sources of failure. We observed a positive answer in 92,1% of the cases, this answer was complete in 36,5% of the cases. The results gotten after multiple administrations show that the cures could be repeated with results comparable to those of the first cure. The therapeutic efficiency is at least equivalent to those of the other therapeutic means, with nearly non-existent secondary effects. The only toxicity is of hematological order; it is the most often moderate and reversible with a complete recuperation at the end of 8 weeks. Besides, the effect on the pain came with an improvement of the quality of life of the patients treaties.Its precocious introduction in the taken in charge of the metastatic patients, would allow them to benefit better from its efficiency, simplicity and weak toxicity and therefore to enjoy a better quality of life.

The purpose of this study was to evaluate in a retrospective analysis, cases of Mediterranean visceral leishmaniasis (VL) diagnosed in adults during a 20-year period in a department of infectious diseases. Demographic data, clinical and laboratory features and therapeutic findings were considered. During the study period, 22 cases of VL were diagnosed, and 6 (27%) were associated with HIV infection. Fever and splenomegaly were observed in all cases. Anaemia was constant. The anti-leishmanial IF titer was positive among 21 patients (95%). Smears from bone marrow aspiration were positive at microscopy in 95% of cases. Zymodeme analysis was carried out in nine isolates. L. infantum zymodeme MON-1 was characterized in all cases. Seventeen patients (77%) received meglumine antimoniate (MA) (20 mg SbV/kg per day) and 5 (23%) patients amphotericin B (AB) (0.5-1 mg/kg per day) for an average period of 25 days (10-49 days). Adverse events occurred in 7 patients (32%), among them 4 received AB. Clinical cure was achieved with success in 21 patients (95%). After a successful MA treatment of the initial episode, VL relapse was observed in one HIV-positive patient. Only one HIV-positive patient died from neurological disorders. VL is rare in adults. However, its incidence is increasing everywhere in the world, because of HIV-related cases. Its prognosis depends on the precocity of diagnosis and treatment.

Economic evaluations are increasingly being used by decision-makers to estimate the cost-effectiveness of interventions. Major changes have recently occurred in the treatment of osteoporosis. The development of a valid economic model (Markov) in the field of osteoporosis is discussed, as well as these limitations. Intervention, such hip protectors, calcium and vitamin D, bisphosphonates, hormonal replacement therapy, SERMs, strontium ranélate, analogue of parathyroid hormone are analysed in the light of cost-effectiveness analyses.

To determine the influence of 4 independent parameters on signal intensity and density measurements after injection of an arthrography-specific form of gadoterate meglumine and an iodinated contrast material for combined MR and CT arthrography. The parameters included: 1) variations of gadolinium and iodinated contrast agents within the mixture, 2) variations of concentration of the iodinated contrast agent, 3) variation of temperature of the mixture, 4) the type of MR pulse sequence acquired.The study was performed on a CT using a phantom containing 47 different syringes. Ten separate mixtures of gadolinium and iodinated contrast agents were obtained, each with a 10% change in the respective proportion of each contrast agent. This was repeated 4 times for 4 iodinated contrast agents of different iodine concentration. Two control syringes, 4 mixtures containing 50% normal saline and 50% iodinated contrast material (one for each of the 4 concentrations of iodinated contrast material) and one with a mixture of 50% of normal saline and gadolinium contrast agent. For the MR acquisition, the syringes were separated into 4 groups for 4 phantoms. On a 1.5 T MR unit, SE T1W, FSE T2W, PD and 3D FIESTA sequences were acquired. All acquisitions were repeated 2 times, and a 3 different temperatures.The progressive increase in the proportion of gadolinium contrast in the solution was associated with a non-linear increase of signal on T1W, 3D FIESTA, and PD images. The signal intensity reached a plateau at concentrations between 40-60%. Signal variations on the 3D FIESTA sequence were significant. On T2W images, there was an increase of measured signal intensity at low gadolinium concentrations. On CT, there was a linear relationship between density measurements and dilution of gadolinium. The progressive increase of the concentration of the iodinated contrast was associated with increased signal loss on MR and progressive increase of density values on CT. Temperature variations were associated with signal intensity changes on T2W and FIESTA images, but not on T1W images.At 1.5 T, a mixture of 50% iodinated contrast and 50% gadolinium contrast corresponded to an acceptable compromise for combined acquisition of MR and CT arthrography.

Auguste Cahours succeeded Dumas, as professor to Ecole centrale, and Chevreul, as examiner to Ecole polytechnique. He was connected with many french and foreign chemists. His works relating to vapour densities, radicals and organometallic compounds were conclusive for acceptance of the Avogadro's law and setting up valency by chemists about 1860.

Visceral Leishmania infantum leishmaniasis is endemic in the south of France. For many years the mainstay for treatment of infected children was pentavalent antimony: meglumine antimoniate (Glucantime) or sodium stibogluconate (Pentostam). However these drugs are poorly tolerated and resistance similar to that observed in the treatment of Indian visceral Leishmania donovani leishmaniasis has been reported. Currently liposomal amphotericin B is being used instead of antimony for treatment of visceral leishmaniasis in children in France. In addition to being well tolerated, liposomal amphotericin B is almost 100% effective. It can be administered in six intravenous injections of 3-4 mg/kg each (days 1 to 5 then day 10). A two-day protocol (10 mg/kg/d) that would reduce overall cost by shortening the duration of hospitalization is now being studied. Another oral drug, i.e., miltefosine, has been successfully used for treatment of visceral leishmaniasis in India. However it has not been evaluated for treatment of Mediterranean visceral leishmaniasis.

Osteoporosis is a frequent disease among the elderly and has major consequences in terms of mortality, morbidity and cost. Guidelines for diagnostic procedures are often difficult to apply in frail, elderly patients with multiple comorbidities. Bisphosphonates are the reference treatment for the elderly, combined with vitamin D and calcium supplementation. Vitamin D deficiency must also be treated to prevent falls and fractures. Strontium ranelate is a promising treatment in this population. Fall prevention is a major part of osteoporosis management. The potential benefit of hip protectors is questionable, even in institutionalized patients.