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Bonne G.,French Institute of Health and Medical Research | Bonne G.,University Pierre and Marie Curie | Bonne G.,French National Center for Scientific Research | Bonne G.,Institute Of Myologie And Ap Hp Uf Cardiogenetique Et Myogenetique | And 3 more authors.
Handbook of Clinical Neurology | Year: 2013

The nuclear envelopathies, more frequently known as laminopathies are a rapidly expanding group of human hereditary diseases caused by mutations of genes that encode proteins of the nuclear envelope. The most frequent and best known form is Emery-Dreifuss muscular dystrophy (EDMD), a skeletal myopathy characterized by progressive muscular weakness, joint contractures, and cardiac disease. EMD gene, encoding emerin, causes the X-linked form of EDMD, while LMNA gene encoding lamins A and C, is responsible for autosomal forms, usually with a dominant transmission. In the last years, the spectrum of conditions has been extraordinarily enlarged, from a congenital muscular dystrophy with severe paralytic or rapidly progressive picture due to de novo mutations in LMNA (L-CMD) to a limb-girdle muscular dystrophy with adult onset and much milder weakness (LGMD1B). LMNA has also been involved in a form of isolated cardiomyopathy associated with cardiac conduction disease and in an axonal form of hereditary neuropathy. Identification of this gene has been reported also in a number of non-neuromuscular disorders including lipodystrophy syndromes and a wide spectrum of premature aging syndromes ranging from mandibuloacral dysplasia to restrictive dermopathy. Mutations in other genes implicated in the processing or maturation of nuclear lamins have also been found. The extraordinary complexity of the molecular and pathophysiological mechanisms of these diseases is still not well known and the occurrence of modifying factors or genes is highly suspected. Identification of new genes and investigation of new therapeutic approaches are in progress. © 2013 Elsevier B.V. Source


Dervaux B.,University of Monastir | Szwarcensztein K.,Johnson and Johnson Produits de Sante | Josseran A.,SNITEM | Barna A.,CEDIT | And 13 more authors.
Therapie | Year: 2015

Medical devices (MDs) cover a wide variety of products. They accompany changes in medical practice in step with technology innovations. Innovations in the field of MDs can improve the conditions of use of health technology and/or modify the organisation of care beyond the strict diagnostic or therapeutic benefit for the patients. However, these non purely clinical criteria seem to be only rarely documented or taken into account in the assessment of MDs during reimbursement decisions at national level or for formulary listing by hospitals even though multidimensional models for the assessment of health technologies have been developed that take into account the views of all stakeholders in the healthcare system In this article, after summarising the background concerning the assessment of health technologies in France, a definition of non-clinical criteria for the assessment of MDs is proposed and a decision tree for the assessment of MDs is described. Future lines of approach are proposed as a conclusion. © 2015 Société Franc¸aise de Pharmacologie et de Thérapeutique. Source


Saleh-Mghir A.,Hopital University Raymond Poincare | Saleh-Mghir A.,University of Versailles | Dumitrescu O.,University of Lyon | Dinh A.,Hopital University Raymond Poincare | And 10 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2012

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) can cause osteomyelitis with severe sepsis and/or local complications in which a Panton-Valentine leukocidin (PVL) role is suspected. In vitro sub-MIC antibiotic effects on growth and PVL production by 11 PVL+ MRSA strains, including the major CA-MRSA clones (USA300, including the LAC strain; USA400; and USA1000), and 11 PVL+ methicillin-susceptible S. aureus (MSSA) strains were tested in microplate culture. Time-kill analyses with ceftobiprole at its MIC were also run with LAC. Efficacies of ceftobiprole (40 mg/kg of body weight subcutaneously [s.c.] four times a day [q.i.d.]) or vancomycin (60 mg/kg intramuscularly [i.m.] twice a day [b.i.d.]) alone or combined with rifampin (10 mg/kg b.i.d.) against rabbit CA-MRSA osteomyelitis, induced by tibial injection of 3.4 × 107 CFU of LAC, were compared. Treatment, started 14 days postinoculation, lasted 14 days. In vitro, 6/11 strains cultured with sub-MICs of ceftobiprole produced 1.6- to 4.8-fold more PVL than did the controls, with no link to specific clones. Rifampin decreased PVL production by all tested strains. In time-kill analyses at the LAC MIC (0.75 mg/liter), PVL production rose transiently at 6 and 8 h and then declined 2-fold at 16 h, concomitant with a 2-log10-CFU-count decrease. In vivo, the mean log10 CFU/g of bone for ceftobiprole (1.44 ± 0.40) was significantly lower than that for vancomycin (2.37 ± 1.22) (P = 0.034), with 7/10 versus 5/11 bones sterilized, respectively. Combination with rifampin enhanced ceftobiprole (1.16 ± 0.04 CFU/g of bone [P = 0.056], 11/11 sterile bones) and vancomycin (1.23 ± 0.06 CFU/g [P = 0.011], 11/11 sterile bones) efficacies. Ceftobiprole bactericidal activity and the rifampin anti-PVL effect could play a role in these findings, which should be of interest for treating CA-MRSA osteomyelitis. Copyright © 2012, American Society for Microbiology. All Rights Reserved. Source


Davido B.,Hopital University Raymond Poincare | Davido B.,University of Versailles | Saleh-Mghir A.,Hopital University Raymond Poincare | Saleh-Mghir A.,University of Versailles | And 9 more authors.
PLoS ONE | Year: 2016

Introduction: In bone and joint infections (BJIs), bacterial toxins are major virulence factors: Panton - Valentine leukocidin (PVL) expression leads to severe local damage, including bone distortion and abscesses, while α-hemolysin (Hla) production is associated with severe sepsis-related mortality. Recently, other toxins, namely phenol-soluble modulins (PSMs) expressed by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strain USA300 (LAC WT) were shown to have ex vivo intracellular cytotoxic activity after S. aureus invasion of osteoblasts, but their in vivo contribution in a relatively PVL-sensitive osteomyelitis model remains poorly elucidated. Materials and Methods: We compared the outcomes of experimental rabbit osteomyelitises induced with pvl+hla+- psms+ LAC WT and its isogenic Δpsm derivatives (LAC Δpsmα and LAC Δpsmαβhld) using an inoculum of 3 × 108 CFUs. Mortality, hematogenous spread (blood culture, spleen and kidney), lung and bone involvements were assessed in two groups (non-survivors of severe sepsis and survivors sacrificed on day (D) 14). Results: Severe sepsis-related mortality tended to be lower for Δpsm derivatives (Kaplan - Meier curves, P = .06). Non-survivors' bone LAC-Δpsmα (6.9 log10 CFUs/g of bone, P = .04) or -Δpsmαβhld (6.86 log10 CFUs/g of bone, P = .014) densities were significantly higher than LAC WT (6.43 log10 CFUs/g of bone). Conversely, lung Δpsmαβhld CFUs were significantly lower than LAC WT (P = .04). LAC Δpsmα, Δpsmαβhld and WT induced similar bone damage in D14 survivors, with comparable bacterial densities (respectively: 5.89, 5.91, and 6.15 log10 CFUs/g of bone). Meanwhile, pulmonary histological scores of inflammation were significantly higher for LAC Δpsmα- and Δpsmαβhld-infected rabbits compared to LAC WT (P = .04 and .01, respectively) but with comparable lung bacterial densities. Conclusion: Our experimental results showed that deactivating PSM peptides significantly limited bacterial dissemination from bone during the early phase of infection, but did not affect local severity of USA300 rabbit osteomyelitis. © 2016 Davido et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source


Cremieux A.-C.,Hopital University Raymond Poincare | Cremieux A.-C.,University of Versailles | Saleh-Mghir A.,University of Versailles | Danel C.,University Paris Diderot | And 23 more authors.
Journal of Infectious Diseases | Year: 2014

Background. Severe sepsis, combining acute osteomyelitis and lung involvement, has been described increasingly in healthy children with the spread of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA).Methods. Outcomes (mortality, hematogenous spread, lung and bone involvements) of rabbit osteomyelitis caused by CA-MRSA LACWT USA300 and its Panton-Valentine leukocidin (PVL)- and α-hemolysin (Hla)-negative isogenic derivatives (LACΔpvl and LACΔhla, respectively) were compared. Results. Three days after inoculation (D3), all LACWT- and LACΔpvl-, and 72% of LACΔhla-infected rabbits had no hematogenous spread and similar lung and bone bacterial densities. LACΔpvl and LACΔhla caused less severe histological lung lesions than LACWT (P ≤. 01). Between D3 and D9, 10 (53%) LACWT-, 11 (55%) LACΔpvl-, but no LACΔhla-infected rabbits (P <. 005) died of severe sepsis with disseminated infection. Unlike deceased animals, most LACWT, LACΔpvl, and LACΔhla D14 survivors had no hematogenous spread (P <. 001). LACWT (88%) caused more bone abscesses than LACΔpvl (0, P =. 001) or LACΔhla (30%, P =. 01).Conclusion. In this model, both PVL and Hla seemed to be required for early lung involvement via hematogenous spread. Hla, but not PVL, significantly impacted severe sepsis-related mortality. PVL was the predominant factor determining late-stage bone abscesses. © 2013 The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. Source

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