980 resultados para 1,8-NAPHTHALIMIDE DERIVATIVES


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BACKGROUND AND PURPOSE: APETx2, a toxin from the sea anemone Anthropleura elegantissima, inhibits acid-sensing ion channel 3 (ASIC3)-containing homo- and heterotrimeric channels with IC(50) values < 100 nM and 0.1-2 µM respectively. ASIC3 channels mediate acute acid-induced and inflammatory pain response and APETx2 has been used as a selective pharmacological tool in animal studies. Toxins from sea anemones also modulate voltage-gated Na(+) channel (Na(v) ) function. Here we tested the effects of APETx2 on Na(v) function in sensory neurones.¦EXPERIMENTAL APPROACH: Effects of APETx2 on Na(v) function were studied in rat dorsal root ganglion (DRG) neurones by whole-cell patch clamp.¦KEY RESULTS: APETx2 inhibited the tetrodotoxin (TTX)-resistant Na(v) 1.8 currents of DRG neurones (IC(50) , 2.6 µM). TTX-sensitive currents were less inhibited. The inhibition of Na(v) 1.8 currents was due to a rightward shift in the voltage dependence of activation and a reduction of the maximal macroscopic conductance. The inhibition of Na(v) 1.8 currents by APETx2 was confirmed with cloned channels expressed in Xenopus oocytes. In current-clamp experiments in DRG neurones, the number of action potentials induced by injection of a current ramp was reduced by APETx2.¦CONCLUSIONS AND IMPLICATIONS: APETx2 inhibited Na(v) 1.8 channels, in addition to ASIC3 channels, at concentrations used in in vivo studies. The limited specificity of this toxin should be taken into account when using APETx2 as a pharmacological tool. Its dual action will be an advantage for the use of APETx2 or its derivatives as analgesic drugs.

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PURPOSE: The macromolecule signal plays a key role in the precision and the accuracy of the metabolite quantification in short-TE (1) H MR spectroscopy. Macromolecules have been reported at 1.5 Tesla (T) to depend on the cerebral studied region and to be age specific. As metabolite concentrations vary locally, information about the profile of the macromolecule signal in different tissues may be of crucial importance. METHODS: The aim of this study was to investigate, at 7T for healthy subjects, the neurochemical profile differences provided by macromolecule signal measured in two different tissues in the occipital lobe, predominantly composed of white matter tissue or of grey matter tissue. RESULTS: White matter-rich macromolecule signal was relatively lower than the gray matter-rich macromolecule signal from 1.5 to 1.8 ppm and from 2.3 to 2.5 ppm with mean difference over these regions of 7% and 12% (relative to the reference peak at 0.9 ppm), respectively. The neurochemical profiles, when using either of the two macromolecule signals, were similar for 11 reliably quantified metabolites (CRLB < 20%) with relatively small concentration differences (< 0.3 μmol/g), except Glu (± 0.8 μmol/g). CONCLUSION: Given the small quantification differences, we conclude that a general macromolecule baseline provides a sufficiently accurate neurochemical profile in occipital lobe at 7T in healthy human brain.

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BACKGROUND: Platinum-based doublet chemotherapy is recommended to treat advanced non-small-cell lung cancer (NSCLC) in fit, non-elderly adults, but monotherapy is recommended for patients older than 70 years. We compared a carboplatin and paclitaxel doublet chemotherapy regimen with monotherapy in elderly patients with advanced NSCLC. METHODS: In this multicentre, open-label, phase 3, randomised trial we recruited patients aged 70-89 years with locally advanced or metastatic NSCLC and WHO performance status scores of 0-2. Patients received either four cycles (3 weeks on treatment, 1 week off treatment) of carboplatin (on day 1) plus paclitaxel (on days 1, 8, and 15) or five cycles (2 weeks on treatment, 1 week off treatment) of vinorelbine or gemcitabine monotherapy. Randomisation was done centrally with the minimisation method. The primary endpoint was overall survival, and analysis was done by intention to treat. This trial is registered, number NCT00298415. FINDINGS: 451 patients were enrolled. 226 were randomly assigned monotherapy and 225 doublet chemotherapy. Median age was 77 years and median follow-up was 30.3 months (range 8.6-45.2). Median overall survival was 10.3 months for doublet chemotherapy and 6.2 months for monotherapy (hazard ratio 0.64, 95% CI 0.52-0.78; p<0.0001); 1-year survival was 44.5% (95% CI 37.9-50.9) and 25.4% (19.9-31.3), respectively. Toxic effects were more frequent in the doublet chemotherapy group than in the monotherapy group (most frequent, decreased neutrophil count (108 [48.4%] vs 28 [12.4%]; asthenia 23 [10.3%] vs 13 [5.8%]). INTERPRETATION: Despite increased toxic effects, platinum-based doublet chemotherapy was associated with survival benefits compared with vinorelbine or gemcitabine monotherapy in elderly patients with NSCLC. We feel that the current treatment paradigm for these patients should be reconsidered. FUNDING: Intergroupe Francophone de Cancérologie Thoracique, Institut National du Cancer.

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PURPOSE: To evaluate the prognostic and predictive value of Ki-67 labeling index (LI) in a trial comparing letrozole (Let) with tamoxifen (Tam) as adjuvant therapy in postmenopausal women with early breast cancer. PATIENTS AND METHODS: Breast International Group (BIG) trial 1-98 randomly assigned 8,010 patients to four treatment arms comparing Let and Tam with sequences of each agent. Of 4,922 patients randomly assigned to receive 5 years of monotherapy with either agent, 2,685 had primary tumor material available for central pathology assessment of Ki-67 LI by immunohistochemistry and had tumors confirmed to express estrogen receptors after central review. The prognostic and predictive value of centrally measured Ki-67 LI on disease-free survival (DFS) were assessed among these patients using proportional hazards modeling, with Ki-67 LI values dichotomized at the median value of 11%. RESULTS: Higher values of Ki-67 LI were associated with adverse prognostic factors and with worse DFS (hazard ratio [HR; high:low] = 1.8; 95% CI, 1.4 to 2.3). The magnitude of the treatment benefit for Let versus Tam was greater among patients with high tumor Ki-67 LI (HR [Let:Tam] = 0.53; 95% CI, 0.39 to 0.72) than among patients with low tumor Ki-67 LI (HR [Let:Tam] = 0.81; 95% CI, 0.57 to 1.15; interaction P = .09). CONCLUSION: Ki-67 LI is confirmed as a prognostic factor in this study. High Ki-67 LI levels may identify a patient group that particularly benefits from initial Let adjuvant therapy.

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A straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino- and guanidinoglycosides, as potential RNA-targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(η6-p-cym)RuCl(PPh3)2]+, allowing the assembly of the target conjugates. The guanidinylated analogue was easily prepared from the neomycin-ruthenium conjugate by reaction with N,N′-di-Boc-N″-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semipreparative high-performance liquid chromatography (HPLC) and characterized by electrospray ionization (ESI) and matrix-assisted laser desorptionionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and NMR spectroscopy. The cytotoxicity of the compounds was tested in MCF-7 (breast) and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, the neomycinruthenium conjugate (2) displayed moderate antiproliferative activity in both cancer cell lines (IC50 ≈ 80 μM), whereas the neamine conjugate (4) was inactive (IC50 ≈ 200 μM). However, the guanidinylated analogue of the neomycinruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC50 = 7.17 μM in DU-145 and IC50 = 11.33 μM in MCF-7). Although the same ranking in antiproliferative activity was found in the nontumorigenic cell line (3 2 > 4), IC50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g., IC50 = 49.4 μM for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC50 = 12.75 μM for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher antiproliferative activity of 3. Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycinruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycinruthenium conjugate (2). Such differences in cytotoxic activity and cellular accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides.

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2 février : Lui adresse son poème "Hommage à Auber" composé plusieurs strophes avec hendécasyllabes et lui explique qu'il a voulu "louer toutes les qualités distinctives du génie français : la clarté , la précision, le respect de la forme, l'inspiration mélodique, le goût sans lequel il n'y a pas de proportion. Et qui osera dire que c'est là une attaque contre Halévy, Thomas, Gounod, Massé, reyer et tant d'autres de mes illustres et chers collaborateurs, sans parler des musiciens étrangers qui, comme Meyerbeer, ont conquis leurs lettres de naturalisation en faisant de la musique vraiment française"?. - 3 février : Lui demande de publier "ne varietur" son poème à Auber accompagné de sa lettre "profession de foi" du 2 février. - 12 février : lui demande une avance et un premier paiement de "Françoise de Rimini" sans attendre la première représentation. - 8 avril : Au sujet de "Françoise de Rimini". Débat avec Heugel sur certaines modifications du texte : "c'est ingénieux, mais cela détruirait certainement l'équilibre du second acte qui marche admirablement dans sa forme actuelle". - 20 avril : Au sujet de "Françoise de Rimini" et du refus de Lassalle de chanter son grand air : "On croit gagner beaucoup à avoir de pareils interprètes et l'on ne s'aperçoit que trop tard quel préjudice énorme portent à un ouvrage ces personnalités encombrantes." Défend son travail de librettiste : "Est-ce que le livret n'a pas été aussi longuement médité, fouillé, retourné que la partition même?". - 24 avril 1882 : Au sujet de "Françoise de Rimini" dont le succès n'a pas été au rendez-vous le soir de la première. Ne voit pas l'opportunité de modifier le livret : "Vous avez pu voir depuis quelques mois combien je suis accessible à toutes les idées et avec quelle sincérité je cherche à les mettre en œuvre, tant qu'on est dans la période de la gestation, mais après que l'enfant est venu au monde, j'éprouve comme une immense lassitude qui me rend incapable de le recommencer sur [de] nouveaux frais. Aussi bien ne le trouvè-je ni tordu ni bossu, et ce ne sont pas les critiques inconsistantes ou de mauvaises foi qui me feront changer d'avis". - 13 septembre 1882 : Réagit à la mort du compositeur Edmond Membrée : "Quel coup affreux et imprévu! J'en suis plus frappé que je ne puis vous dire. Il y avait tant d'énergie et d'espérances dans ce pauvre grand artiste atteint par la mort avant de l'être par la vieillesse". - 26 octobre : Au sujet de la question des droits d'auteur : souhaite obtenir 250 francs par représentation. Lettre cosignée d'Ambroise Thomas.

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13 avril : au sujet de ses droits d'auteur. - 13 mai : remerciements. - 12 juillet : L'informe s'être rendu chez lui pour procéder aux remises d'argent. Déclare être "à la veille de conclure une affaire qui [lui] permettra de faire honneur à tous ses engagements". - 17 juillet : Au sujet du "Timbre d'argent" qui ne trouve pas d'éditeur : "Je regrette pour Saint-Saëns et pour moi que ce pauvre "Timbre" ne soit pas entre les mains d'un croyant qui l'aurait certainement fait vibrer.". - 28 août : Lui adresse un article pour le "Ménestrel". - 15 septembre : Lui recommande une artiste du chant, Mademoiselle Maindron. - 12 novembre : "Je viens d'entendre le duo de Boussy chanté par Madame de Lanchâtre et sa fille. C'est tout simplement adorable". - 1er décembre : remerciements

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9 mai 1891. Le prie d'envoyer 300 francs à son fils Pierre. - 30 juin 1891. Le prie de donner 200 francs à sa fille. - 29 juillet 1891. Lui demande 300 francs d'avance. - 16 août 1891. Au sujet de "Néron" qui pourrait être repris sur la scène du théâtre de Nice. Evoque la distribution qui paraît la plus adéquate et ses relations avec le compositeur Antoine Rubinstein. Barbier voit dans cette reprise un avantage, celui de "mettre enfin la pièce au point, ce qu'[il n'a] pu encore faire, avec la diable de collaboration fantaisiste et vagabonde de Rubinstein.". - 20 août 1891. Au sujet de "Néron" et de la distribution la plus convenable : "Ce qui me séduit le plus, c'est la possibilité de parfaire l'ouvrage et d'en donner enfin une version définitive et dont je sois content". - 23 août 1891. Au sujet de "Néron". S'incline devant les choix de son éditeur et le met en garde sur le compositeur : "Avec son génie (car il en a), c'est un homme à rater tous les succès du monde! Son art l'aveugle et lui masque les nécessités du théâtre". - 12 septembre 1891. Au sujet de "Néron" et des hésitations d'Eugène Bertrand à monter la pièce. Le directeur de théâtre préfèrerait monter "Paul et Virginie". - 15 septembre 1891. Lui renvoie son "traité" signé de "Paul et Virginie" et lui demande une avance

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OBJECTIVE: Interleukin-1 (IL-1) mediates ischemia-reperfusion injury and graft inflammation after heart transplantation. IL-1 affects target cells through two distinct types of transmembrane receptors, type-1 receptor (IL-1R1), which transduces the signal, and the non-signaling type-2 receptor (IL-1R2), which acts as a ligand sink that subtracts IL-1beta from IL-1R1. We analyzed the efficacy of adenovirus (Ad)-mediated gene transfer of a soluble IL-1R2-Ig fusion protein in delaying cardiac allograft rejection and the mechanisms underlying the protective effect. METHODS: IL-1 inhibition by IL-1R2-Ig was tested using an in vitro functional assay whereby endothelial cells preincubated with AdIL-1R2-Ig or control virus were stimulated with recombinant IL-1beta or tumor necrosis factor-alpha (TNF-alpha), and urokinase-type plasminogen activator (u-PA) induction was measured by zymography. AdIL-1R2-Ig was delivered to F344 rat donor hearts ex vivo, which were placed in the abdominal position in LEW hosts. Intragraft inflammatory cell infiltrates and proinflammatory cytokine expression were analyzed by immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. RESULTS: IL-1R2-Ig specifically inhibited IL-1beta-induced u-PA responses in vitro. IL-1R2-Ig gene transfer reduced intragraft monocytes/macrophages and CD4(+) cell infiltrates (p<0.05), TNF-alpha and transforming growth factor-beta (TGF-beta) expression (p<0.05), and prolonged graft survival (15.6+/-5.7 vs 10.3+/-2.5 days with control vector and 10.1+/-2.1 days with buffer alone; p<0.01). AdIL-1R2-Ig combined with a subtherapeutic regimen of cyclosporin A (CsA) was superior to CsA alone (19.4+/-3.0 vs 15.9+/-1.8 days; p<0.05). CONCLUSIONS: Soluble IL-1 type-2 receptor gene transfer attenuates cardiac allograft rejection in a rat model. IL-1 inhibition may be useful as an adjuvant therapy in heart transplantation.

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Maçãs 'Royal Gala', colhidas em dois estádios de maturação, foram tratadas com 1-MCP (1-metilciclopropeno) nas concentrações de 0; 625 e 1250 nL.L-1, durante 48 horas, à temperatura de 20 ± 2 ºC. Após este tratamento, foram armazenadas em dois diferentes sistemas: em atmosfera controlada à temperatura de 0 ± 0,5 ºC, 2,1 a 2,3 kPa de CO2 , 1,8 a 2,0 kPa de O2 e umidade relativa de 95 ± 5 %, durante 9 meses. Em ar refrigerado a 0,5 ± 0,5 ºC e 95 ± 5 % de umidade relativa, durante 8 meses. As análises realizadas demonstraram a eficiência do 1-MCP em controlar a maturação das frutas durante o armazenamento em ambas as condições e pontos de colheita. A aplicação do 1-MCP reduziu drasticamente a produção de etileno, diminuiu a perda de firmeza, além de preservar a acidez total titulável.

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PURPOSE: Rechallenge with temozolomide (TMZ) at first progression of glioblastoma after temozolomide chemoradiotherapy (TMZ/RT→TMZ) has been studied in retrospective and single-arm prospective studies, applying temozolomide continuously or using 7/14 or 21/28 days schedules. The DIRECTOR trial sought to show superiority of the 7/14 regimen. EXPERIMENTAL DESIGN: Patients with glioblastoma at first progression after TMZ/RT→TMZ and at least two maintenance temozolomide cycles were randomized to Arm A [one week on (120 mg/m(2) per day)/one week off] or Arm B [3 weeks on (80 mg/m(2) per day)/one week off]. The primary endpoint was median time-to-treatment failure (TTF) defined as progression, premature temozolomide discontinuation for toxicity, or death from any cause. O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation was prospectively assessed by methylation-specific PCR. RESULTS: Because of withdrawal of support, the trial was prematurely closed to accrual after 105 patients. There was a similar outcome in both arms for median TTF [A: 1.8 months; 95% confidence intervals (CI), 1.8-3.2 vs. B: 2.0 months; 95% CI, 1.8-3.5] and overall survival [A: 9.8 months (95% CI, 6.7-13.0) vs. B: 10.6 months (95% CI, 8.1-11.6)]. Median TTF in patients with MGMT-methylated tumors was 3.2 months (95% CI, 1.8-7.4) versus 1.8 months (95% CI, 1.8-2) in MGMT-unmethylated glioblastoma. Progression-free survival rates at 6 months (PFS-6) were 39.7% with versus 6.9% without MGMT promoter methylation. CONCLUSIONS: Temozolomide rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation.

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A straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino- and guanidinoglycosides, as potential RNA-targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(η6-p-cym)RuCl(PPh3)2]+, allowing the assembly of the target conjugates. The guanidinylated analogue was easily prepared from the neomycin-ruthenium conjugate by reaction with N,N′-di-Boc-N″-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semipreparative high-performance liquid chromatography (HPLC) and characterized by electrospray ionization (ESI) and matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and NMR spectroscopy. The cytotoxicity of the compounds was tested in MCF-7 (breast) and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, the neomycin-ruthenium conjugate (2) displayed moderate antiproliferative activity in both cancer cell lines (IC50 ≈ 80 μM), whereas the neamine conjugate (4) was inactive (IC50 ≈ 200 μM). However, the guanidinylated analogue of the neomycin-ruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC50 = 7.17 μM in DU-145 and IC50 = 11.33 μM in MCF-7). Although the same ranking in antiproliferative activity was found in the nontumorigenic cell line (3 2 > 4), IC50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g., IC50 = 49.4 μM for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC50 = 12.75 μM for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher antiproliferative activity of 3. Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycin-ruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycin-ruthenium conjugate (2). Such differences in cytotoxic activity and cellular accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides.

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La fracture périprothétique du fémur (FPF) représente une complication sérieuse des arthroplasties de hanche. Différents matériels d'ostéosynthèse ont été utilisés pour l'ostéosynthèse des FPFs. Toutefois, aucune étude n'a rapporté les résultats obtenus avec une plaque anatomique non-verrouillée avec des trous excentrés. Les buts de ce travail étaient de présenter 1) le taux de consolidation des FPF traitées par cet implant, 2) les caractéristiques péri-opératoires 3) le taux de complications, et 4) les résultats en terme d'autonomie obtenus après le traitement des FPF du groupe B selon Vancouver avec une plaque anatomique à trous excentrés. Hypothèse L'utilisation de cette plaque permet d'obtenir un taux élevé de consolidation avec un minimum de complications mécaniques. Matériels et Méthodes Quarante-trois patients, d'âge moyen 79 ans ± 13 (41 - 98), qui ont été traités pour une ostéosynthèse d'une FPF de type B selon Vancouver avec cette plaque entre 2002 et 2007 ont été inclus. Les patients ont été classifiées selon les scores ASA et de Charnley. Le temps opératoire, les pertes sanguines chirurgicales, le nombre de transfusion, la durée d'hospitalisation, le délai de consolidation, le lieu de vie ainsi que l'autonomie (score de Parker) ont été évalués. Le taux de survie sans révision a été calculé par la méthode de Kaplan-Meier. Le recul moyen est de 42 mois ± 20 (min - max : 16 - 90). Résultats La consolidation a été obtenue chez tous les patients avec un délai moyen de 2,4 mois ± 0,6 (2-4). 1 patient avec un cal vicieux en varus était à déplorer. Le score de Parker a diminué de 5,93 ± 1,94 (2-9) à 4,93 ± 1,8 (1- 9) (p = 0.01). 2 révisions chirurgicales ont été nécessaires sur la série. Le taux de survie à 5 ans des prothèses après ostéosynthèse de la FPF était de 83,3 % ± 12,6 %. Conclusion Cette plaque anatomique avec trous excentrés permet le traitement des FPF du type B et garantit une consolidation de la fracture avec un faible taux de complications liés à l'ostéosynthèse. Toutefois, les FPF représentent une complication sérieuse des arthroplasties de hanche assortie d'un fort taux de morbidités et de mortalité.

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Digitoitu 1. 8. 2008.

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Digitoitu 1. 8. 2008.