Development of New Methods Towards Actinide-Carbene Fragments

The reaction of UCl4 or ThCl4(DME)2 with 1,4,7,10-tetrazacyclodecane-1,4,7,10- tetraacetic acid (H4DOTA), and 6 equiv of trimethylamine, in DMSO results in the formation of [AnIV(k8-DOTA)(DMSO)] (An = U, Th), which can be isolated in moderate yields after work-up. Both Complexes are the first structurally characterized actinide DOTA complexes to feature the k8 binding mode for the DOTA ligand. In addition, we isolated a few crystals of [U(k4-H2DOTA)(DMSO)4][Cl]2. Crystallographic characterization of this material reveals that the [H2DOTA]2- ligand in [U(k4-H2DOTA)(DMSO)4][Cl]2 is only coordinated to U4+ by its four carboxylate arms, generating an overall k4 binding mode. Similar complexes have been previously proposed as intermediates of H4DOTA complexation pathway, but this intermediate had not been structurally characterized until now.Reaction of [Li(THF)]4[L] (L = Me8-calix[4]pyrrole]) with 0.5 equiv of [UVIO2Cl2(THF)2]2 results in formation of the oxidized calix[4]pyrrole product, [Li(THF)]2[L∆] , concomitant with formation of reduced uranium oxide by-products. [Li(THF)]2[L∆] can also be generated by reaction of [Li(THF)]4[L] with 1 equiv of I2. I hypothesize that formation of [Li(THF)]2[L∆] proceeds via formation of a highly oxidizing cis-uranyl intermediate, [Li]2[cis- UVIO2(calix[4]pyrrole)]. To test this hypothesis, I explored the reaction of [Li(THF)]2[L∆] with either 0.5 equiv of [UVIO2Cl2(THF)2]2 or 1 equiv of [UVIO2(OTf)2(THF)3], which affords the isostructural uranyl complexes, [Li(THF)][UVIO2(L∆)Cl(THF)] and [Li(THF)][UVIO2(L∆)(OTf)(THF)], respectively. In the solid state, [Li(THF)][UVIO2(L∆)Cl(THF)] and [Li(THF)][UVIO2(L∆)(OTf)(THF)] feature unprecedented uranyl-η5-pyrrole interactions, making them rare examples of uranyl organometallic complexes. In addition, [Li(THF)][UVIO2(L∆)Cl(THF)] and [Li(THF)][UVIO2(L∆)(OTf)(THF)]exhibit some of the smallest O−U−O angles reported to date (162.0(7) and 162.7(7)°; 164.5(5)°, respectively). Importantly, the O−U−O bending observed in these complexes suggests that the oxidation of [Li(THF)]4[L] does indeed occur via an unobserved cis-uranyl intermediate. The reaction of [AnCl(NR2)3] (An = U or Th; R = SiMe3) with NaCCH and tetramethylethylenediamine (TMEDA) results in the formation of [An(C≡CH)(NR2)3] (An = U, Th), which can be isolated in good yields after work-up. Similarly, reaction of 3 equiv of NaCCH and TMEDA with [AnCl(NR2)3] results in the formation of [Na(TMEDA)][An(C≡CH)2(NR2)3] (An = U, Th), which can be isolated in fair yields after work-up. Reaction of [U(C≡CH)(NR2)3] with 2 equiv of KC8 and 1 equiv of 2.2.2-cryptand in THF results in formation of the U(III) acetylide complex, [K(2.2.2- cryptand)][U(C≡CH)(NR2)3]. Thermolysis of [U(C≡CH)(NR2)3] or [Th(C≡CH)(NR2)3] results in formation of the bimetallic dicarbide complexes, [{An(NR2)3}2(μ,η1:η1-C2)] (An = U, Th), whereas reaction of [U(C≡CH)(NR2)3] with [Th{N(R)(SiMe2)CH2}(NR2)2] results in formation of [U(NR2)3(μ,η1:η1-C2)Th(NR2)3]. The 13C NMR chemical shifts of the a-acetylide carbons in [Th(C≡CH)(NR2)3], [Na(TMEDA)][Th(C≡CH)2(NR2)3], and [{Th(NR2)3}2(μ,η1:η1-C2)] exhibit a characteristic spin-orbit induced downfield shift, due to participation of the 5f orbitals in the Th-C bonds. Magnetism measurements demonstrate that [{U(NR2)3}2(μ,η1:η1-C2)] displays weak ferromagnetic coupling between the U(IV) centers (J = 1.78 cm–1). The reaction of [AnCl(NR2)3] (An = U, Th, R = SiMe3) with in situ generated lithium-3,3- diphenylcyclopropene results in the formation of [{(NR2)3}An(CH=C=CPh2)] (An = U, Th) in good yields after work-up. Deprotonation of [{(NR2)3}U(CH=C=CPh2)] or [{(NR2)3}Th(CH=C=CPh2)] with LDA/2.2.2-cryptand results in formation of the anionic allenylidenes, [Li(2.2.2-cryptand)][{(NR2)3}An(CCCPh2)] (An = U, Th). The calculated 13C NMR chemical shifts of the Cα, Cβ, and Cγ nuclei in [{(NR2)3}Th(CH=C=CPh2)] and [Li(2.2.2- cryptand)][{(NR2)3}Th(CCCPh2)] nicely reproduce the experimentally assigned order, and exhibit a characteristic spin-orbit induced downfield shift at Cα due to involvement of the 5f orbitals in Th–C bonds. Additionally, the bonding analyses for [Li(2.2.2- cryptand)][{(NR2)3}U(CCCPh2)] and [Li(2.2.2-cryptand)][{(NR2)3}An(CCCPh2)] show a delocalized multi-center character of the ligand p orbitals involving An. While a single-triple- single-bond resonance structure (e.g., An-CoC-CPh2) predominates, the An=C=C=CPh2 resonance form contributes, as well, more so for uranium analog. I also report the synthesis, characterization, and reactivity of the bis(diisopropylamino)cyclopropenylidene (BAC) adducts of [M(NR2)3] (M = Ce, U; R = SiMe3), namely, [(NR2)3M(BAC)] (M = Ce, U). Photolysis of [(NR2)3Ce(BAC)] with a 365 nm LED source results in formation of the methylenecyclopropene species, [(iPr2N)2C3C(NiPr2)(CCNiPr2)], via the formal dimerization and rearrangement of two BAC fragments. [(iPr2N)2C3C(NiPr2)(CCNiPr2)] can also be generated under catalytic conditions by performing the photolysis of BAC in the presence of 10 mol% [Ce(NR2)3]. Whereas heating [(NR2)3U(BAC)] results in the formation of [(NR2)2U{N(R)(SiMe2)(2,3-(NiPr2)- C(H)C=CC(H))}], via the formal ring opening and insertion of the BAC ligand. The reaction of [Cp3ThCl] with in situ generated lithium-3,3-diphenylcyclopropene results in the formation of [Cp3Th(3,3-diphenylcyclopropenyl)], in good yields. Thermolysis of [Cp3Th(3,3-diphenylcyclopropenyl)] results in isomerization to the ring-opened product, [Cp3Th(3-phenyl-1H-inden-1-yl)] via a hypothesized carbene intermediate. By comparison, reaction of [Cp3UCl] with in situ generated lithium-3,3-diphenylcyclopropene results in the formation of [Cp2U(h2-triphenylethylene)] via a hypothesized U(VI)-carbyne intermediate. Furthermore, reaction of [Cp3U(THF)] with 2 equiv 3,3-diphenylcyclopropene results in the formation of [Cp3U(3,3-diphenylcyclopropyl)], via formal hydrogen atom abstraction. These transformations represent several new modes of reactivity of 3,3-diphenylcyclopropene with the actinides, improving our ability to use this reagent as a carbene source. A combined DFT and 13C{1H} NMR analysis of [Cp3Th(3,3-diphenylcyclopropenyl)] shows a spin–orbit induced downfield shift at Cα due to participation of the 5f orbitals in the Th–C bond

Intérêt du rituximab dans les myasthénies réfractaires

NICE-BU Médecine Odontologie (060882102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Intérêt du rituximab dans les cytopénies auto-immunes réfractaires (thèse)

NICE-BU Médecine Odontologie (060882102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Sclérites et épisclérites (aspects cliniques, étiologiques et thérapeutiques)

Les sclérites et les épisclérites désignent des maladies inflammatoires rares de la sclère, pour la moitié d entre elles associées à des maladies de système dont elles peuvent être le symptôme révélateur. Elles peuvent constituer une urgence diagnostique et thérapeutique du fait du pronostic visuel mis en jeu. Du fait de leur faible incidence, peu de données sont disponibles concernant la démarche diagnostique à mettre en place afin d optimiser la prise en charge thérapeutique. L objectif de ce travail était d évaluer la proportion de maladies secondaires associées aux sclérites et/ou épisclérite après un bilan étiologique standardisé et d évaluer l intérêt de l hydroxychloroquine dans la prise en charge de l inflammation sclérale idiopathique. Nous avons colligé de façon rétrospective une série de patients atteints de sclérites et /ou épisclérites pris en charge conjointement en Médecine Interne et en Ophtalmologie entre 1997 et 2012 dans le CHU de Nice. 19 patients ont été inclus : 7 patients présentaient une épisclérite et 14 patients une sclérite. Deux patients souffraient de l association des deux maladies. Le bilan clinico-biologique a révélé une maladie secondaire associée aux épisclérites et aux sclérites respectivement dans 57% et 82% des cas. Les explorations ont mis en évidence une maladie de système chez deux patients avec épisclérite : gougerot Sjögren (n=1), granulomatose avec polyangéite (n=1), et chez 9 patients atteints de sclérites : granulomatose avec polyangéite (n=6), polyarthrite rhumatoïde (n=1), syndrome d hyper IgG4 (n=1), Gougerot Sjögren (n=1).Six patients atteints de pathologies sclérales idiopathiques (3 épisclérites et 3 sclérites) se sont vu proposer de l hydroxychloroquine. 100 % des patients dès trois mois étaient en rémission et le sont restés, avec un suivi moyen de 50,33 mois. L introduction des antipaludéens de synthèse a permis chez deux patients l arrêt des traitements systémiques. Seul un patient a présenté des effets secondaires digestifs ayant nécessité l arrêt du traitement. Un traitement par chloroquine en relais a permis la poursuite de la rémission. Notre étude retrouve un diagnostic positif dans 82 % des cas, en rapport avec des maladies associées aux pathologies sclérales. Il s agit le plus souvent de maladies de systèmes. Une gestion rapide pluridisciplinaire, un bilan étiologique exhaustif, une absence de corticothérapie avant exploration semblerait améliorer la prise en charge des patients. L utilisation de l hydroxychloroquine (aux propriétés immunomodulatrices et anti-inflammatoires) dans les sclérites et/ou épisclérites idiopathiques semblerait efficace et permettrait une épargne voire un sevrage en cortisone ainsi que l éviction d escalade thérapeutique. Des études avec prospectives avec des effectifs plus importants devront être menées afin de confirmer ces données.NICE-BU Médecine Odontologie (060882102) / SudocSudocFranceF

Caractéristiques cliniques, radiologiques, anatomopathologiques, thérapeutiques et évolutives de l’amylose périoculaire et/ou intraorbitaire : à propos de 6 cas et revue de la littérature [Clinical, radiological, pathological features, treatment and follow-up of periocular and/or orbital amyloidosis: Report of 6 cases and literature review]

To assess demographic, clinical, radiological, pathological features, treatment and follow-up of periocular or/and orbital amyloidosis. We conducted an observational retrospective monocentric study from January 2004 to April 2017 in patients diagnosed with histologically proven periocular or/and orbital amyloidosis. Six patients were included (2 females, 4 males). Mean age was 76.8 years (range 66-88 years). Mean time between first ophthalmological symptoms and diagnosis was 27 months (range 11-36 months). The main symptoms were subconjunctival infiltration (6 patients; 100%), periocular pain or discomfort (4 patients; 66.6%) and subconjunctival hemorrhage (1 patient; 16.6%). Clinical findings included ptosis (4 patients; 66.6%), keratitis (3 patients; 50%) leading to corneal perforation in one patient, and proptosis (3 patients; 50%). One-half of the patients showed bilateral involvement. AL amyloidosis was identified on immunohistochemistry in 5 patients (83.3%). One case of B cell marginal zone orbital lymphoma was diagnosed. Systemic work-up was negative for all patients. Treatment consisted of simple monitoring (1 patient; 16.6%), surgical debulking (3 patients; 50%), ptosis surgery (1 patient; 16.6%), eyelid or eyelash malposition surgery (2 patients; 33.3%) and orbital radiation beam therapy (2 patients; 33.3%). Mean follow-up was 14.6 months (range 6-36 months), and no progression nor recurrence were noted. Periocular or/and orbital amyloidosis is rarely encountered. Diagnosis is based on pathological examination, and immunohistochemistry analysis should always be performed to guide systemic work-up. Orbital lymphoma and multiple myeloma should be ruled out if AL amyloidosis is diagnosed. Progression is slow, and surgery is the mainstay of treatment in symptomatic patients. Long-term multidisciplinary follow-up is advocated

Influence of human osteoblasts on hematopoietic stem cells: Analysis in coculture on a synthetic biphasic calcium phosphate ceramic.

24th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research, SAN ANTONIO, TEXAS, SEP 20-24, 200

The HELLP syndrome in the antiphospholipid syndrome: retrospective study of 16 cases in 15 women

Objective: To study the characteristics of the haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome in the antiphospholipid syndrome (APS) and its influence on the subsequent pregnancies. Methods: This was a retrospective analysis of 16 episodes of HELLP complicating APS in 15 women. Results: HELLP was complete in 10 cases and partial in six. It occurred during the second trimester in seven cases (the earliest at 18 weeks' gestation), the third trimester in seven cases, and the day following delivery in two cases. Pre-eclampsia was present in six cases and eclampsia in five. Outcome of pregnancies was: live birth (n = 8), stillbirth (n = 2) and fetal death (n = 6). APS was primary in nine women and secondary to systemic lupus erythematosus (SLE) in six. HELLP revealed primary APS in six cases. Seven women were not treated. Low dose aspirin was empirically prescribed in one woman whose APS had been undiagnosed despite a history of two fetal deaths. In the other women, therapy consisted of aspirin (n = 8), low molecular weight heparin with a dose varying between 3000 and 12 000 U daily (n = 5), and high dose immunoglobulin every 4 weeks (n = 2), hydroxychloroquine (n = 4), and prednisone (n = 6). Six women had seven subsequent pregnancies, 3–6 years after the complicated pregnancy. HELLP recurred at 33 weeks' gestation in one woman with SLE treated with prednisone, hydroxychloroquine, aspirin, and enoxaparin, and pregnancy ended in live birth. One woman became pregnant after in vitro fertilisation and embryo transfer, but pregnancy ended in fetal death despite prednisone, hydroxychloroquine, and enoxaparin. Four women had five uneventful pregnancies with 100 mg daily aspirin and heparin. Conclusions: APS may be revealed by HELLP. In APS, HELLP is associated with pre-eclampsia/eclampsia in most cases and seems to occur earlier than in the general population. Heparin plus aspirin may prevent obstetric complications in the subsequent pregnancies

Influence of human osteoblasts on hematopoietic stem cells: Analysis in coculture on a synthetic biphasic calcium phosphate ceramic.

24th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research, SAN ANTONIO, TEXAS, SEP 20-24, 200