Rupprecht R.,Ludwig Maximilians University of Munich |
Rupprecht R.,Max Planck Institute of Psychiatry |
Papadopoulos V.,McGill University |
Rammes G.,Max Planck Institute of Psychiatry |
And 7 more authors.
Nature Reviews Drug Discovery | Year: 2010
The translocator protein (18 kDa) (TSPO) is localized primarily in the outer mitochondrial membrane of steroid-synthesizing cells, including those in the central and peripheral nervous system. One of its main functions is the transport of the substrate cholesterol into mitochondria, a prerequisite for steroid synthesis. TSPO expression may constitute a biomarker of brain inflammation and reactive gliosis that could be monitored by using TSPO ligands as neuroimaging agents. Moreover, initial clinical trials have indicated that TSPO ligands might be valuable in the treatment of neurological and psychiatric disorders. This Review focuses on the biology and pathophysiology of TSPO and the potential of currently available TSPO ligands for the diagnosis and treatment of neurological and psychiatric disorders. © 2010 Macmillan Publishers Limited. All rights reserved.
Cyteval C.,Hopital Lapeyronie |
Miquel A.,Bicetre Hospital |
Hoa D.,Hopital Lapeyronie |
Daures J.P.,Caremeau Hospital |
And 2 more authors.
Radiology | Year: 2010
Purpose: To assess a simplified scoring method (Simplified Rheumatoid Arthritis Magnetic Resonance Imaging Score [SAMIS]) developed to shorten interpretation time, while retaining both correlation with Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) and same or better intra- and interreader reliability. Materials and Methods: Ethics board approval and written patient consent were obtained. The study was HIPAA compliant. Thirty-eight patients with rheumatoid arthritis and 20 patients with no or early unclassified arthritis underwent magnetic resonance imaging of both wrists and hands. RAMRIS was used to evaluate erosions (scale, 0-10), edema (scale, 0-3), and synovitis (scale, 0-3). SAMIS assessed only one hand and was based on the radiographic Simple Erosion Narrowing Score, thus reducing the number of study areas from 116 to 36. Erosions were scored with a scale from 1 to 10. Edema and synovitis were, respectively, scored with scales from 0 to 1 and 0 to 2. SAMIS correlation with RAMRIS was tested by using the Spearman test. Last, the intra- and interobserver reproducibility of both scores were calculated. Results: SAMIS was closely correlated with RAMRIS for the entire series (r = 0.91, 0.79, and 0.94, respectively, for erosion, edema, and synovitis), as well as in patients with rheumatoid arthritis (r = 0.93, 0.81, and 0.92) and those with no or unclassified arthritis (r = 0.83, 0.73, and 0.94). The time needed to assess examination results with RAMRIS ranged from 5 to 20 minutes (13 minutes ± 3.90 [standard deviation]), whereas it ranged from 2 to 7 minutes (5 minutes ± 1.45) with SAMIS. For each of the three features (erosion, edema, and synovitis), intraobserver agreement (RAMRIS: κ = 0.67, 0.94, 0.81, respectively; SAMIS: κ = 0.66, 1.0, 0.91) and interobserver agreement (RAMRIS: κ = 0.61, 0.58, 0.74, respectively; SAMIS: κ = 0.59, 0.81, 0.81) were good to excellent. Conclusion: This simplified reproducible scoring scheme could be used to monitor joint damage in rheumatoid arthritis. © RSNA, 2010.
Champion L.,University Paris Diderot |
Durrbach A.,Bicetre Hospital |
Lang P.,Henri Mondor Hospital |
Delahousse M.,Foch Hospital |
And 4 more authors.
American Journal of Transplantation | Year: 2010
We report 10 cases of intestinal microsporidiosis due to Enterocytozoon bieneusi in renal transplant (RT) recipients who were treated with fumagillin. All patients presented with afebrile subacute diarrhea (median of 2 weeks), associated with abdominal cramps (n = 5), and weight loss (n = 6), a mean of 68 months after RT. The diagnosis was made by the identification of microsporidial spores in stools with the use of appropriate staining and confirmed by a specific polymerase chain reaction assay for E. bieneusi in 7 patients. Median CD4 cell count was 292 cells/mm3. All patients received a median of 14 days of oral fumagillin (20 mg tid), and four patients also discontinued or tapered their immunosuppressive regimen (mycophenolate mofetil in 3, and azathioprine in 2). Clinical symptoms resolved rapidly with the clearance of microsporidial spores from stools in all patients. A severe but reversible thrombocytopenia was observed in one patient during fumagillin therapy, and another patient presented with abdominal cramps. Trough levels of tacrolimus measured in seven patients dropped below 5 ng/mL in six of them after 7-14 days of fumagillin. Intestinal microsporidiosis can cause subacute diarrhea in RT recipients. Fumagillin is an effective treatment with an acceptable safety profile, but monitoring of tacrolimus levels is warranted. © 2010 The American Society of Transplantation and the American Society of Transplant Surgeons.
Gallien S.,Brigham and Women's Hospital |
Delaugerre C.,Saint Louis Hospital |
Charreau I.,French Institute of Health and Medical Research |
Braun J.,French Institute of Health and Medical Research |
And 5 more authors.
AIDS | Year: 2011
Background: The emergence of integrase strand-transfer inhibitor (INSTI) resistance-associated mutations was examined in patients with low-level viremia after switching from enfuvirtide to raltegravir in the ANRS 138-Easier trial. Methods: Integrase genes of plasma virus from raltegravir-treated patients in the Easier trial with low-level viremia (50-500 copies/ml) were sequenced to determine INSTI resistance-associated mutations. Baseline viral load, baseline and nadir CD4+ cell count, antiretroviral treatment, genotypic susceptibility score, level of viremia and degree of treatment adherence during the study period were also analyzed. Results: Forty-nine patients experienced at least one episode of low-level viremia while receiving raltegravir; integrase genotyping was successful in samples from 39 individuals (80%). Among them, three [7.7%, 95% confidence interval (CI) 1.6-20.9%] had significant INSTI resistance mutations consisting of N155H in two and P145S in one. Absence of these mutations from proviral DNA at baseline suggested selection of INSTI resistance during episodes of low-level viremia. No specific factors significantly associated with emergence of INSTI resistance mutations during low-level viremia were identified. Conclusion: Emergence of INSTI resistance mutations can occur during episodes of low-level viremia in patients receiving raltegravir-containing regimens. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Davit-Spraul A.,University Paris - Sud |
Gonzales E.,Bicetre Hospital |
Gonzales E.,University Paris - Sud |
Baussan C.,University Paris - Sud |
And 3 more authors.
Seminars in Liver Disease | Year: 2010
Class III multidrug resistance P-glycoproteins, Mdr2 in mice and MDR3 in human, are canalicular phospholipid translocators involved in biliary phospholipid (phosphatidylcholine) excretion. The role of an ABCB4 gene defect in liver disease has been initially proven in a subtype of progressive familial intrahepatic cholestasis called PFIC3, a severe pediatric liver disease that may require liver transplantation. Several ABCB4 mutations have been identified in children with PFIC3 and are associated with low level of phospholipids in bile leading to a high biliary cholesterol saturation index. ABCB4 mutations are associated with loss of canalicular MDR3 protein and /or loss of protein function. There is evidence that a biallelic or monoallelic ABCB4 defect causes or predisposes to several human liver diseases (PFIC3, low phospholipid associated cholelithiasis syndrome, intrahepatic cholestasis of pregnancy, drug-induced liver injury, transient neonatal cholestasis, adult biliary fibrosis, or cirrhosis). Most patients with MDR3 deficiency have a favorable outcome with ursodeoxycholic acid (UDCA) therapy, but some PFIC3 patients who do not respond to UDCA treatment still require liver transplantation. The latter should be good candidates for a targeted pharmacologic approach and/or to cell therapy in the future. © 2010 by Thieme Medical Publishers, Inc.
Okulicz J.F.,San Antonio Military Medical Center |
Lambotte O.,French Institute of Health and Medical Research |
Lambotte O.,Bicetre Hospital |
Lambotte O.,University Paris - Sud
Current Opinion in HIV and AIDS | Year: 2011
Purpose of review: Recent studies have been published characterizing the epidemiology of elite controllers. The demographic features, clinical characteristics, and HIV disease outcomes of elite controllers are summarized. Recent findings: Elite controllers are defined by the ability to spontaneously suppress plasma viremia. Despite differing definitions in the literature, studies have shown that elite control of HIV infection is established soon after seroconversion and occurs in less than 1% of HIV-infected individuals. Elite controllers are demographically heterogeneous with diverse racial backgrounds and modes of HIV transmission, though genetic studies demonstrate an overrepresentation of protective HLA alleles. Elite controllers typically have elevated CD4 cell counts, stable CD4 trajectories, and more favorable clinical outcomes compared with viremic patients. A proportion of elite controllers, however, may experience HIV disease progression with loss of virologic control, CD4 cell declines, and rarely AIDS-defining events. Summary: Elite controllers are a subgroup of HIV-infected individuals characterized by the ability to spontaneously maintain virologic control. The mechanisms underlying elite control are aggressively being sought to guide vaccine development and novel therapeutic strategies. As elite control may be a temporary state, the ability to distinguish and further characterize elite controllers with long-term clinical success from those with HIV disease progression is of major importance. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Jacquemin E.,Bicetre Hospital |
Jacquemin E.,University Paris - Sud
Clinics and Research in Hepatology and Gastroenterology | Year: 2012
Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal-recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The exact prevalence remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births. Three types of PFIC have been identified and associated with mutations in hepatocellular transport-system genes involved in bile formation. PFIC1 and PFIC2 usually appear in the first months of life, whereas onset of PFIC3 may arise later in infancy, in childhood or even during young adulthood. The main clinical manifestations include cholestasis, pruritus and jaundice. PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. Both PFIC1 and PFIC2 are caused by impaired bile salt secretion due to defects in . ATP8B1 encoding the FIC1 protein and in . ABCB11 encoding bile salt export pump (BSEP) protein, respectively. Defects in . ABCB4, encoding multidrug resistance 3 protein (MDR3), impair biliary phospholipid secretion, resulting in PFIC3. Diagnosis is based on clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests to exclude other causes of childhood cholestasis. MDR3 and BSEP liver immunostaining, and analysis of biliary lipid composition should help to select PFIC candidates for whom genotyping could be proposed to confirm the diagnosis. Antenatal diagnosis may be proposed for affected families in which a mutation has been identified. Ursodeoxycholic acid (UDCA) therapy should be initiated in all patients to prevent liver damage. In some PFIC1 and PFIC2 patients, biliary diversion may also relieve pruritus and slow disease progression. However, most PFIC patients are ultimately candidates for liver transplantation. Monitoring of liver tumors, especially in PFIC2 patients, should be offered from the first year of life. Hepatocyte transplantation, gene therapy and specific targeted pharmacotherapy may represent alternative treatments in the future. © 2012 Elsevier Masson SAS.
Bonnet M.,Epicentre |
Bhatt N.,Instituto Nacional Of Saude |
Baudin E.,Epicentre |
Silva C.,Epicentre |
And 9 more authors.
The Lancet Infectious Diseases | Year: 2013
Background: In countries with a high incidence of HIV and tuberculosis co-infection, nevirapine and efavirenz are widely used as antiretroviral therapy but both interact with antituberculosis drugs. We aimed to compare efficacy and safety of a nevirapine-based antiretroviral therapy (started at full dose) with an efavirenz-based regimen in co-infected patients. Methods: We did a multicentre, open-label, randomised, non-inferiority trial at three health centres in Maputo, Mozambique. We enrolled adults (≥18 years) with tuberculosis and previously untreated HIV infection (CD4 cell counts <250 cells per μL) and alanine aminotransferase and total bilirubin concentrations of less than five times the upper limit of normal. 4-6 weeks after the start of tuberculosis treatment, we randomly allocated patients (1:1) with central randomisation, block sizes of two to six, and stratified by site and CD4 cell count to nevirapine (200 mg twice daily) or efavirenz (600 mg once daily), plus lamivudine and stavudine. The primary endpoint was virological suppression at 48 weeks (HIV-1 RNA <50 copies per mL) in all patients who received at least one dose of study drug (intention-to-treat population); death and loss to follow-up were recorded as treatment failure. The non-inferiority margin for the difference of efficacy was 10%. We assessed efficacy in intention-to-treat and per-protocol populations and safety in all patients who received study drug. This study is registered with ClinicalTrials.gov, number NCT00495326. Findings: Between October, 2007, and March, 2010, we enrolled 285 patients into each group. 242 (85%) patients in the nevirapine group and 233 (82%) patients in the efavirenz group completed follow-up. In the intention-to-treat population, 184 patients (64·6%, 95% CI 58·7-70·1) allocated nevirapine achieved virological suppression at week 48, as did 199 patients (69·8%, 64·1-75·1) allocated efavirenz (one-sided 95% CI of the difference of efficacy 11·7%). In the per-protocol population, 170 (70·0%, 63·8-75·7) of 243 patients allocated nevirapine achieved virological suppression at week 48, as did 194 (78·9%, 73·2-83·8) of 246 patients allocated efavirenz (one-sided 95% CI 15·4%). The median CD4 cell count at randomisation was 89 cells per μL. 15 patients substituted nevirapine with efavirenz and six patients substituted efavirenz with nevirapine. 20 patients allocated nevirapine (7%) had grade 3-4 increase of alanine aminotransferase compared with 17 patients allocated efavirenz (6%). Three patients had severe rash after receipt of nevirapine (1%) but no patients did after receipt of efavirenz. 18 patients in the nevirapine group died, as did 17 patients in the efavirenz group. Interpretation: Although non-inferiority of the nevirapine-regimen was not shown, nevirapine at full dose could be a safe, acceptable alternative for patients unable to tolerate efavirenz. Funding: French Research Agency for HIV/AIDS and hepatitis (ANRS). © 2013 Elsevier Ltd.
Rossi-Semerano L.,Bicetre Hospital |
Kone-Paut I.,Bicetre Hospital
International Journal of Inflammation | Year: 2012
Systemic juvenile idiopathic arthritis (sJIA), formerly called Still's disease, is officially classified as a subset of juvenile idiopathic arthritis (JIA). Beside arthritis, it is characterized by prominent systemic features and a marked inflammatory response. Even if it is still included in the group of juvenile arthritides, sJIA is set apart from all the other forms of JIA. This disorder has markedly distinct clinical and laboratory features suggesting a different pathogenesis. sJIA does not show any association with HLA genes or with autoantibodies and is characterised by an uncontrolled activation of phagocytes with hypersecretion of IL-1 and IL-6. Based on clinical and laboratory features, as well as on new acquisitions on the pathogenesis, it seems evident that sJIA is an autoinflammatory disease related to abnormality in innate immune system. The new insights on the pathogenesis of sJIA have therefore dramatically changed the approach to treatment, with the development of targeted treatments (anti-IL-1 and anti-IL-6 agents) more effective and safer than earlier medications. © 2012 Linda Rossi-Semerano and Isabelle Koné-Paut.
Nordmann P.,Bicetre Hospital |
Naas T.,Bicetre Hospital |
Poirel L.,Bicetre Hospital
Emerging Infectious Diseases | Year: 2011
Carbapenemases increasingly have been reported in Enterobacteriaceae in the past 10 years. Klebsiella pneumoniae carbapenemases have been reported in the United States and then worldwide, with a marked endemicity at least in the United States and Greece. Metalloenzymes (Verona integron-encoded metallo-β-lactamase, IMP) also have been reported worldwide, with a higher prevalence in southern Europe and Asia. Carbapenemases of the oxacillinase-48 type have been identified mostly in Mediterranean and European countries and in India. Recent identification of New Delhi metallo-β-lactamase-1 producers, originally in the United Kingdom, India, and Pakistan and now worldwide, is worrisome. Detection of infected patients and carriers with carbapenemase producers is necessary for prevention of their spread. Identification of the carbapenemase genes relies mostly on molecular techniques, whereas detection of carriers is possible by using screening culture media. This strategy may help prevent development of nosocomial outbreaks caused by carbapenemase producers, particularly K. pneumonia.