Bustamante J.,French Institute of Health and Medical Research |
Bustamante J.,University of Paris Descartes |
Arias A.A.,Indiana University |
Vogt G.,Rockefeller University |
And 48 more authors.
Nature Immunology | Year: 2011
Germline mutations in CYBB, the human gene encoding the gp91phox subunit of the phagocyte NADPH oxidase, impair the respiratory burst of all types of phagocytes and result in X-linked chronic granulomatous disease (CGD). We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes. These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase. This 'experiment of nature' indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria. © 2011 Nature America, Inc. All rights reserved.
Royer M.,Toulouse 1 University Capitole |
Bodemer C.,Service de Dermatologie |
Barbarot S.,Nantes Hospital |
Paul C.,Toulouse 1 University Capitole |
Mazereeuw J.,Toulouse 1 University Capitole
British Journal of Dermatology | Year: 2011
Background Alopecia areata (AA) occurring in childhood is associated with a poorer prognosis than adult AA and may severely affect quality of life. The efficacy of methotrexate (MTX) was reported in adults with AA but there is little information about its use in children. Objectives We aimed to assess the efficacy and safety of MTX in severe childhood AA. Methods We conducted a retrospective study including children with severe AA treated with MTX in the Departments of Paediatric Dermatology in France between November 2005 and December 2009. Results Fourteen children (eight girls and six boys) aged between 8 and 18 years (mean 14·7) were included. AA was present for a mean duration of 5·7 years (range 2 months-11 years 8 months). The treatment was administered once weekly, the mean maximal dose was 18·9 mg weekly (range 15-25) and the mean duration of treatment was 14·2 months (range 1-31). Thirteen children were assessable. Of these 13 children, MTX was considered as successful (regrowth > 50% of hair) for five of them. The remaining eight children were considered treatment failures. No serious side-effects were reported. Conclusions The efficacy of MTX in children with severe AA is variable. MTX may be considered for severe childhood AA in the absence of alternative effective treatments. © 2011 British Association of Dermatologists.
PubMed | Nantes Hospital, Rockefeller University, Montpellier Hospital, University of Paris Pantheon Sorbonne and 14 more.
Type: Journal Article | Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America | Year: 2014
About 10% of pediatric patients with invasive pneumococcal disease (IPD) die from the disease. Some primary immunodeficiencies (PIDs) are known to confer predisposition to IPD. However, a systematic search for these PIDs has never been carried out in children presenting with IPD.We prospectively identified pediatric cases of IPD requiring hospitalization between 2005 and 2011 in 28 pediatric wards throughout France. IPD was defined as a positive pneumococcal culture, polymerase chain reaction result, and/or soluble antigen detection at a normally sterile site. The immunological assessment included abdominal ultrasound, whole-blood counts and smears, determinations of plasma immunoglobulin and complement levels, and the evaluation of proinflammatory cytokines.We included 163 children with IPD (male-to-female ratio, 1.3; median age, 13 months). Seventeen children had recurrent IPD. Meningitis was the most frequent type of infection (87%); other infections included pleuropneumonitis, isolated bloodstream infection, osteomyelitis, endocarditis, and mastoiditis. One patient with recurrent meningitis had a congenital cerebrospinal fluid fistula. The results of immunological explorations were abnormal in 26 children (16%), and a PID was identified in 17 patients (10%), including 1 case of MyD88 deficiency, 3 of complement fraction C2 or C3 deficiencies, 1 of isolated congenital asplenia, and 2 of Bruton disease (X-linked agammaglobulinemia). The proportion of PIDs was much higher in children aged >2 years than in younger children (26% vs 3%; P < .001).Children with IPD should undergo immunological investigations, particularly those aged >2 years, as PIDs may be discovered in up to 26% of cases.
Beauval J.-B.,Toulouse University Hospital Center |
Ploussard G.,Henri Mondor Hospital |
Soulie M.,Toulouse University Hospital Center |
Pfister C.,Charles Nicolle Hospital |
And 13 more authors.
Urology | Year: 2012
To evaluate the pathologic features of surgical specimens after radical prostatectomy in patients with low-risk prostate cancer fulfilling the strictest pathologic selection criteria for active surveillance. Retrospective analysis of 10 785 consecutive radical prostatectomy performed in 10 university hospitals (January 2003 through December 2008). A total of 919 patients fulfilled the following unique and very stringent criteria: T1c, prostate-specific antigen (PSA) <10 ng/mL, a single positive biopsy, tumor length <3 mm, and Gleason score <7. Clinico-biologic and pathologic data at diagnosis and after radical prostatectomy, prostatic and tumor volume, pathologic Gleason score and stage, positive surgical margins, insignificant prostate cancer, and PSA outcomes were recorded. Median age was 63 years. Mean prebiopsy PSA level was 6.2 ng/mL. At radical prostatectomy, Gleason score was upgraded in 34% of patients, including 1.2% Gleason score 8-9. Pathologic stages were pT2 in 87.3%, pT3 in 11.1%, and pT4 in 1.4% of cases. Extraprostatic extension was found in 12.5%. Only 26% of patients had "insignificant" tumors. Biochemical recurrence-free survival at 5 years was 92.3%. There was no significant difference in survival between patients with "significant" and "insignificant" tumors (90.1% vs 93.4%; P = .06). Despite of a stringent selection of patients with low-risk prostate cancer, active surveillance definition included a significant proportion of patients with upstaged (about 12%) and upgraded (about one-third) disease at diagnosis. Only a quarter of active surveillance patients have a pathologically confirmed "insignificant" cancer. © 2012 Elsevier Inc. All Rights Reserved.
Huber C.,University of Paris Descartes |
Fradin M.,University of Paris Descartes |
Edouard T.,Hospital Purpan |
Le Merrer M.,University of Paris Descartes |
And 15 more authors.
Human Mutation | Year: 2010
3-M syndrome is an autosomal recessive disorder characterized by severe pre- and postnatal growth retardation and minor skeletal changes. We have previously identified CUL7 as a disease-causing gene but we have also provided evidence of genetic heterogeneity in the 3-M syndrome. By homozygosity mapping in two inbred families, we found a second disease locus on chromosome 2q35-36.1 in a 5.2-Mb interval that encompasses 60 genes. To select candidate genes, we performed microarray analysis of cultured skin fibroblast RNA from one patient, looking for genes with altered expression; we found decreased expression of IGFBP2 and increased expression of IGFBP5. However, direct sequencing of these two genes failed to detect any anomaly. We then considered other candidate genes by their function/location and found nine distinct mutations in the OBSL1 gene in 13 families including eight nonsense and one missense mutations. To further understand the links between OBSL1, CUL7, and insulin-like growth factor binding proteins (IGFBPs), we performed real-time quantitative PCR (RT-PCR) analysis for OBSL1, CUL7, IGFBP2, and IGFBP5, using cultured fibroblast RNAs from two patients with distinct OBSL1 mutations (p.F697G; p.H814RfsX15). We found normal CUL7 mRNA levels but abnormal IGFBP2 and IGFBP5 mRNA levels in the two patients, suggesting that OBSL1 modulates the expression of IGFBP proteins. © 2009 Wiley-Liss, Inc.
PubMed | Paul Brousse Hospital, Nantes Hospital, Saint Andre Hospital, Paris-Sorbonne University and 6 more.
Type: | Journal: Annals of surgical oncology | Year: 2015
In view of increased response rates and survivals in patients with metastatic pancreatic adenocarcinoma (PAC) with FOLFIRINOX, many centers proposed this regimen as induction chemotherapy for borderline (BR) or locally advanced (LA) PAC. The aim of this study was to assess surgical and oncological outcomes of patients who underwent resection after induction FOLFIRINOX therapy.We prospectively identified surgical consecutive BR or LA PAC patients after induction FOLFIRINOX in 20 observational French centers between November 2010 and December 2013. Two independent experts retrospectively evaluated initial CT scan for central review.Eighty patients were included, 47 had BR and 33 had LA PAC. Median number of FOLFIRINOX cycles was 6 (range 1-30) and 65 % of patients received chemoradiation. The 30-day-mortality, major complications, and symptomatic pancreatic fistula rates were 2.5, 22.5, and 4 %, respectively. R0 resection was achieved in 84 %. After a median follow-up of 38.2 months since diagnosis, disease-free survival (DFS) was 17.16 months. The overall survival rates at 12 and 24 months were 92 and 81 %, respectively. A 26 % (n = 21) pathologic major response (pMR) rate was reached. In univariate and multivariate analysis, pMR was a prognostic factor for DFS (hazard ratio 0.33; P = 0.01 and hazard ratio 0.38; P = 0.035).Resection after induction FOLFIRINOX is safe and associated with similar or better outcomes as upfront surgery in patients with PAC. A pMR was observed in 26 % of cases and was prognostic of DFS. This therapeutic design should be investigated in prospective studies.
Teletchea S.,University of Nantes |
Stresing V.,University of Nantes |
Hervouet S.,University of Nantes |
Baud'Huin M.,University of Nantes |
And 8 more authors.
Journal of Bone and Mineral Research | Year: 2014
Receptor activator of nuclear factor-κB (RANK) and RANK ligand (RANKL) play a pivotal role in bone metabolism, and selective targeting of RANK signaling has become a promising therapeutic strategy in the management of resorptive bone diseases. Existing antibody-based therapies and novel inhibitors currently in development were designed to target the ligand, rather than the membrane receptor expressed on osteoclast precursors. We describe here an alternative approach to designing small peptides able to specifically bind to the hinge region of membrane RANK responsible for the conformational change upon RANKL association. A nonapeptide generated by this method was validated for its biological activity in vitro and in vivo and served as a lead compound for the generation of a series of peptide RANK antagonists derived from the original sequence. Our study presents a structure- and knowledge-based strategy for the design of novel effective and affordable small peptide inhibitors specifically targeting the receptor RANK and opens a new therapeutic opportunity for the treatment of resorptive bone disease. © 2014 American Society for Bone and Mineral Research. © 2014 American Society for Bone and Mineral Research.
Salou M.,French Institute of Health and Medical Research |
Salou M.,University of Nantes |
Nicol B.,French Institute of Health and Medical Research |
Nicol B.,University of Nantes |
And 4 more authors.
Frontiers in Immunology | Year: 2015
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by focal demyelination patches associated with inflammatory infiltrates containing T lymphocytes. For decades, CD4+ T cells have been recognized as playing a major role in the disease, especially in animal models, which has led to the development of several therapies. However, interest has recently developed in the involvement of CD8+ T cells in MS following the analysis of infiltrating T cells in human brain lesions. A broad range of evidence now suggests that the pathological role of this T cell subset in MS may have been underestimated. In this review, we summarize the literature implicating CD8+ T cells in the pathophysiology of MS. We present data from studies in the fields of genetics, anatomopathology and immunology, mainly in humans but also in animal models of MS. Altogether, this strongly suggests that CD8+ T cells may be major effectors in the disease process, and that the development of treatments specifically targeting this subset would be germane. © 2015 Salou, Nicol, Garcia and Laplaud.