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1.  Large deletions encompassing the TCOF1 and CAMK2A genes are responsible for Treacher Collins syndrome with intellectual disability 
Mandibulofacial dysostosis is part of a clinically and genetically heterogeneous group of disorders of craniofacial development, which lead to malar and mandibular hypoplasia. Treacher Collins syndrome is the major cause of mandibulofacial dysostosis and is due to mutations in the TCOF1 gene. Usually patients with Treacher Collins syndrome do not present with intellectual disability. Recently, the EFTUD2 gene was identified in patients with mandibulofacial dysostosis associated with microcephaly, intellectual disability and esophageal atresia. We report on two patients presenting with mandibulofacial dysostosis characteristic of Treacher Collins syndrome, but associated with unexpected intellectual disability, due to a large deletion encompassing several genes including the TCOF1 gene. We discuss the involvement of the other deleted genes such as CAMK2A or SLC6A7 in the cognitive development delay of the patients reported, and we propose the systematic investigation for 5q32 deletion when intellectual disability is associated with Treacher Collins syndrome.
PMCID: PMC3865420  PMID: 23695276
mandibulofacial dysostosis; Treacher Collins syndrome; TCOF1; CAMK2A; intellectual disability
2.  A diagnostic scale for Alzheimer’s disease based on cerebrospinal fluid biomarker profiles 
The relevance of the cerebrospinal fluid (CSF) biomarkers for the diagnosis of Alzheimer’s disease (AD) and related disorders is clearly established. However, the question remains on how to use these data, which are often heterogeneous (not all biomarkers being pathologic). The objective of this study is to propose to physicians in memory clinics a biologic scale of probabilities that the patient with cognitive impairments has an Alzheimer’s disease (AD) pathologic process.
For that purpose, we took advantage of the multicenter data of our Paris-North, Lille, and Montpellier (PLM) study, which has emerged through the initial sharing of information from these memory centers. Different models combining the CSF levels of amyloid-β 42, tau, and p-tau(181) were tested to generate categories of patients with very low (<10%), low (<25%), high (>75%), and very high predictive values (>90%) for positive AD. In total, 1,273 patients (646 AD and 627 non-AD) from six independent memory-clinic cohorts were included.
A prediction model based on logistic regressions achieved a very good stratification of the population but had the disadvantages of needing mathematical optimization and being difficult to use in daily clinical practice. Remarkably, a simple and intuitive model based on the number (from zero to three) of three pathologic CSF biomarkers resulted in a very efficient predictive scale for AD in patients seen in memory clinics. The scale’s overall predictive value for AD for the different categories were as follows: class 0, 9.6% (95% confidence interval (CI), 6.0% to 13.2%); class 1, 24.7% (95% CI, 18.0% to 31.3%); class 2, 77.2% (95% CI, 67.8% to 86.5%); and class 3, 94.2% (95% CI, 90.7% to 97.7%). In addition, with this scale, significantly more patients were correctly classified than with the logistic regression. Its superiority in model performance was validated by the computation of the net reclassification index (NRI). The model was also validated in an independent multicenter dataset of 408 patients (213 AD and 195 non-AD).
In conclusion, we defined a new scale that could be used to facilitate the interpretation and routine use of multivariate CSF data, as well as helping the stratification of patients in clinical research trials.
PMCID: PMC4255520  PMID: 25478015
3.  Expression of EPHRIN-A1, SCINDERIN and MHC class I molecules in head and neck cancers and relationship with the prognostic value of intratumoral CD8+ T cells 
BMC Cancer  2013;13:592.
Our group has previously shown that EPHRIN-A1 and SCINDERIN expression by tumor cells rendered them resistant to cytotoxic T lymphocyte-mediated lysis. Whereas the prognostic value of EPHRIN-A1 expression in cancer has already been studied, the role of SCINDERIN presence remains to be established. In the present work, we investigated the prognosis value of EPHRIN-A1 and SCINDERIN expression in head and neck carcinomas. In addition, we monitored the HLA-class I expression by tumor cells and the presence of tumor-infiltrating CD8+ T cells to evaluate a putative correlation between these factors and the survival prognosis by themselves or related to EPHRIN-A1 and SCINDERIN expression.
Tumor tissue sections of 83 patients with head and neck cancer were assessed by immunohistochemistry for the expression of EPHRIN-A1, SCINDERIN, HLA class I molecules and the presence of CD8+ T cells.
No significant prognosis value could be attributed to these factors independently, despite a tendency of association between EPHRIN-A1 and a worse clinical outcome. No prognostic value could be observed when CD8+ T cell tumor infiltration was analyzed combined with EPHRIN-A1, SCINDERIN or HLA class I expression.
These results highlight that molecules involved in cancer cell resistance to cytotoxic T lymphocytes by themselves are not a sufficient criteria for prognosis determination in cancer patients. Other intrinsic or tumor microenvironmental features should be considered in prognostic evaluation.
PMCID: PMC3867221  PMID: 24330498
4.  An essential role for decorin in bladder cancer invasiveness 
EMBO Molecular Medicine  2013;5(12):1835-1851.
Muscle-invasive forms of urothelial carcinomas are responsible for most mortality in bladder cancer. Finding new treatments for invasive bladder tumours requires adequate animal models to decipher the mechanisms of progression, in particular the way tumours interact with their microenvironment. Herein, using the murine bladder tumour cell line MB49 and its more aggressive variant MB49-I, we demonstrate that the adaptive immune system efficiently limits progression of MB49, whereas MB49-I has lost tumour antigens and is insensitive to adaptive immune responses. Furthermore, we unravel a parallel mechanism developed by MB49-I to subvert its environment: de novo secretion of the proteoglycan decorin. We show that decorin overexpression in the MB49/MB49-I model is required for efficient progression, by promoting angiogenesis and tumour cell invasiveness. Finally, we show that these results are relevant to muscle-invasive human bladder carcinomas, which overexpress decorin together with angiogenesis- and adhesion/migration-related genes, and that decorin overexpression in the human bladder carcinoma cell line TCCSUP is required for efficient invasiveness in vitro. We thus propose decorin as a new therapeutic target for these aggressive tumours.
PMCID: PMC3914526  PMID: 24142880
angiogenesis; bladder carcinoma; decorin; tumour immunity; tumour microenvironment
6.  Glycoform-Selective Prion Formation in Sporadic and Familial Forms of Prion Disease 
PLoS ONE  2013;8(3):e58786.
The four glycoforms of the cellular prion protein (PrPC) variably glycosylated at the two N-linked glycosylation sites are converted into their pathological forms (PrPSc) in most cases of sporadic prion diseases. However, a prominent molecular characteristic of PrPSc in the recently identified variably protease-sensitive prionopathy (VPSPr) is the absence of a diglycosylated form, also notable in familial Creutzfeldt-Jakob disease (fCJD), which is linked to mutations in PrP either from Val to Ile at residue 180 (fCJDV180I) or from Thr to Ala at residue 183 (fCJDT183A). Here we report that fCJDV180I, but not fCJDT183A, exhibits a proteinase K (PK)-resistant PrP (PrPres) that is markedly similar to that observed in VPSPr, which exhibits a five-step ladder-like electrophoretic profile, a molecular hallmark of VPSPr. Remarkably, the absence of the diglycosylated PrPres species in both fCJDV180I and VPSPr is likewise attributable to the absence of PrPres glycosylated at the first N-linked glycosylation site at residue 181, as in fCJDT183A. In contrast to fCJDT183A, both VPSPr and fCJDV180I exhibit glycosylation at residue 181 on di- and monoglycosylated (mono181) PrP prior to PK-treatment. Furthermore, PrPV180I with a typical glycoform profile from cultured cells generates detectable PrPres that also contains the diglycosylated PrP in addition to mono- and unglycosylated forms upon PK-treatment. Taken together, our current in vivo and in vitro studies indicate that sporadic VPSPr and familial CJDV180I share a unique glycoform-selective prion formation pathway in which the conversion of diglycosylated and mono181 PrPC to PrPSc is inhibited, probably by a dominant-negative effect, or by other co-factors.
PMCID: PMC3602448  PMID: 23527023
7.  Cerebrospinal Fluid PKR Level Predicts Cognitive Decline in Alzheimer’s Disease 
PLoS ONE  2013;8(1):e53587.
The cerebrospinal fluid (CSF) levels of the proapoptotic kinase R (PKR) and its phosphorylated PKR (pPKR) are increased in Alzheimer’s disease (AD), but whether CSF PKR concentrations are associated with cognitive decline in AD patients remain unknown. In this study, 41 consecutive patients with AD and 11 patients with amnestic mild cognitive impairment (aMCI) from our Memory Clinic were included. A lumbar puncture was performed during the following month of the clinical diagnosis and Mini-Mental State Examination (MMSE) evaluations were repeated every 6 months during a mean follow-up of 2 years. In AD patients, linear mixed models adjusted for age and sex were used to assess the cross-sectional and longitudinal associations between MMSE scores and baseline CSF levels of Aβ peptide (Aβ 1-42), Tau, phosphorylated Tau (p-Tau 181), PKR and pPKR. The mean (SD) MMSE at baseline was 20.5 (6.1) and MMSE scores declined over the follow-up (-0.12 point/month, standard error [SE] = 0.03). A lower MMSE at baseline was associated with lower levels of CSF Aβ 1–42 and p-Tau 181/Tau ratio. pPKR level was associated with longitudinal MMSE changes over the follow-up, higher pPKR levels being related with an exacerbated cognitive deterioration. Other CSF biomarkers were not associated with MMSE changes over time. In aMCI patients, mean CSF biomarker levels were not different in patients who converted to AD from those who did not convert.These results suggest that at the time of AD diagnosis, a higher level of CSF pPKR can predict a faster rate of cognitive decline.
PMCID: PMC3539966  PMID: 23320095
8.  A Meta-Analysis of the Relationship between FGFR3 and TP53 Mutations in Bladder Cancer 
PLoS ONE  2012;7(12):e48993.
TP53 and FGFR3 mutations are the most common mutations in bladder cancers. FGFR3 mutations are most frequent in low-grade low-stage tumours, whereas TP53 mutations are most frequent in high-grade high-stage tumours. Several studies have reported FGFR3 and TP53 mutations to be mutually exclusive events, whereas others have reported them to be independent. We carried out a meta-analysis of published findings for FGFR3 and TP53 mutations in bladder cancer (535 tumours, 6 publications) and additional unpublished data for 382 tumours. TP53 and FGFR3 mutations were not independent events for all tumours considered together (OR = 0.25 [0.18–0.37], p = 0.0001) or for pT1 tumours alone (OR = 0.47 [0.28–0.79], p = 0.0009). However, if the analysis was restricted to pTa tumours or to muscle-invasive tumours alone, FGFR3 and TP53 mutations were independent events (OR = 0.56 [0.23–1.36] (p = 0.12) and OR = 0.99 [0.37–2.7] (p = 0.35), respectively). After stratification of the tumours by stage and grade, no dependence was detected in the five tumour groups considered (pTaG1 and pTaG2 together, pTaG3, pT1G2, pT1G3, pT2-4). These differences in findings can be attributed to the putative existence of two different pathways of tumour progression in bladder cancer: the CIS pathway, in which FGFR3 mutations are rare, and the Ta pathway, in which FGFR3 mutations are frequent. TP53 mutations occur at the earliest stage of the CIS pathway, whereas they occur would much later in the Ta pathway, at the T1G3 or muscle-invasive stage.
PMCID: PMC3521761  PMID: 23272046
9.  Cerebrospinal fluid biomarker supported diagnosis of Creutzfeldt–Jakob disease and rapid dementias: a longitudinal multicentre study over 10 years 
Brain  2012;135(10):3051-3061.
To date, cerebrospinal fluid analysis, particularly protein 14-3-3 testing, presents an important approach in the identification of Creutzfeldt–Jakob disease cases. However, one special point of criticism of 14-3-3 testing is the specificity in the differential diagnosis of rapid dementia. The constant observation of increased cerebrospinal fluid referrals in the national surveillance centres over the last years raises the concern of declining specificity due to higher number of cerebrospinal fluid tests performed in various neurological conditions. Within the framework of a European Community supported longitudinal multicentre study (‘cerebrospinal fluid markers’) we analysed the spectrum of rapid progressive dementia diagnoses, their potential influence on 14-3-3 specificity as well as results of other dementia markers (tau, phosphorylated tau and amyloid-β1–42) and evaluated the specificity of 14-3-3 in Creutzfeldt–Jakob disease diagnosis for the years 1998–2008. A total of 29 022 cerebrospinal fluid samples were analysed for 14-3-3 protein and other cerebrospinal fluid dementia markers in patients with rapid dementia and suspected Creutzfeldt–Jakob disease in the participating centres. In 10 731 patients a definite diagnosis could be obtained. Protein 14-3-3 specificity was analysed for Creutzfeldt–Jakob disease with respect to increasing cerebrospinal fluid tests per year and spectrum of differential diagnosis. Ring trials were performed to ensure the comparability between centres during the reported time period. Protein 14-3-3 test specificity remained high and stable in the diagnosis of Creutzfeldt–Jakob disease during the observed time period across centres (total specificity 92%; when compared with patients with definite diagnoses only: specificity 90%). However, test specificity varied with respect to differential diagnosis. A high 14-3-3 specificity was obtained in differentiation to other neurodegenerative diseases (95–97%) and non-neurological conditions (91–97%). We observed lower specificity in the differential diagnoses of acute neurological diseases (82–87%). A marked and constant increase in cerebrospinal fluid test referrals per year in all centres did not influence 14-3-3 test specificity and no change in spectrum of differential diagnosis was observed. Cerebrospinal fluid protein 14-3-3 detection remains an important test in the diagnosis of Creutzfeldt–Jakob disease. Due to a loss in specificity in acute neurological events, the interpretation of positive 14-3-3 results needs to be performed in the clinical context. The spectrum of differential diagnosis of rapid progressive dementia varied from neurodegenerative dementias to dementia due to acute neurological conditions such as inflammatory diseases and non-neurological origin.
PMCID: PMC3470713  PMID: 23012332
rapid dementia; Creutzfeldt–Jakob disease; cerebrospinal fluid; 14-3-3; specificity; neurodegeneration; differential diagnosis in dementia
10.  A direct comparison of CellSearch and ISET for circulating tumour-cell detection in patients with metastatic carcinomas 
British Journal of Cancer  2011;105(6):847-853.
Circulating tumour cells (CTCs) can provide information on patient prognosis and treatment efficacy. However, there is no universal method to detect CTC currently available. Here, we compared the performance of two CTC detection systems based on the expression of the EpCAM antigen (CellSearch assay) or on cell size (ISET assay).
Circulating tumour cells were enumerated in 60 patients with metastatic carcinomas of breast, prostate and lung origins using CellSearch according to the manufacturer's protocol and ISET by studying cytomorphology and immunolabelling with anti-cytokeratin or lineage-specific antibodies.
Concordant results were obtained in 55% (11 out of 20) of the patients with breast cancer, in 60% (12 out of 20) of the patients with prostate cancer and in only 20% (4 out of 20) of lung cancer patients.
Our results highlight important discrepancies between the numbers of CTC enumerated by both techniques. These differences depend mostly on the tumour type. These results suggest that technologies limiting CTC capture to EpCAM-positive cells, may present important limitations, especially in patients with metastatic lung carcinoma.
PMCID: PMC3171010  PMID: 21829190
circulating tumour cell; breast cancer; prostate cancer; lung cancer; CellSearch; ISET
11.  A case of Gerstmann-Sträussler-Scheinker disease with a novel six octapeptide repeat insertion 
PMCID: PMC3135713  PMID: 21426368
Amyloid; Gerstmann-Sträussler-Scheinker (GSS) disease; Neuropathology; Octapeptide repeat insertion (OPRI); Prion protein
12.  New highly sensitive rodent and human tests for soluble amyloid precursor protein alpha quantification: preclinical and clinical applications in Alzheimer’s disease 
BMC Neuroscience  2012;13:84.
Amyloid precursor protein (APP), a key molecule in Alzheimer’s disease (AD), is metabolized in two alternative cleavages, generating either the amyloidogenic peptides involved in AD pathology or the soluble form of APP (sAPPα). The level of amyloidogenic peptides in human cerebrospinal fluid (CSF) is considered to be a biomarker of AD, whereas the level of sAPPα in CSF as a biomarker has not been clearly established. sAPPα has neurotrophic and neuroprotective properties. Stimulating its formation and secretion is a promising therapeutic target in AD research. To this end, very sensitive tests for preclinical and clinical research are required.
The tests are based on homogenous time-resolved fluorescence and require no washing steps.
We describe two new rapid and sensitive tests for quantifying mouse and human sAPPα. These 20 μl-volume tests quantify the levels of: i) endogenous mouse sAPPα in the conditioned medium of mouse neuron primary cultures, as well as in the CSF of wild-type mice, ii) human sAPPα in the CSF of AD mouse models, and iii) human sAPPα in the CSF of AD and non-AD patients. These tests require only 5 μl of conditioned medium from 5 × 104 mouse primary neurons, 1 μl of CSF from wild-type and transgenic mice, and 0.5 μl of human CSF.
The high sensitivity of the mouse sAPPα test will allow high-throughput investigations of molecules capable of increasing the secretion of endogenous sAPPα in primary neurons, as well as the in vivo validation of molecules of interest through the quantification of sAPPα in the CSF of treated wild-type mice. Active molecules could then be tested in the AD mouse models by quantifying human sAPPα in the CSF through the progression of the disease. Finally, the human sAPPα test could strengthen the biological diagnosis of AD in large clinical investigations. Taken together, these new tests have a wide field of applications in preclinical and clinical studies.
PMCID: PMC3418197  PMID: 22824057
Alzheimer’s disease; Soluble amyloid precursor protein alpha; Homogeneous time-resolved fluorescence; Rodent; Human; Cerebrospinal fluid; Primary neurons; Sensitivity
13.  Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in the intergroup phase III trial (PCI99-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01) 
Annals of Oncology  2010;22(5):1154-1163.
Background: We recently published the results of the PCI99 randomised trial comparing the effect of a prophylactic cranial irradiation (PCI) at 25 or 36 Gy on the incidence of brain metastases (BM) in 720 patients with limited small-cell lung cancer (SCLC). As concerns about neurotoxicity were a major issue surrounding PCI, we report here midterm and long-term repeated evaluation of neurocognitive functions and quality of life (QoL).
Patients and methods: At predetermined intervals, the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and brain module were used for self-reported patient data, whereas the EORTC–Radiation Therapy Oncology Group Late Effects Normal Tissue–Subjective, Objective, Management, Analytic scale was used for clinicians’ assessment. For each scale, the unfavourable status was analysed with a logistic model including age, grade at baseline, time and PCI dose.
Results: Over the 3 years studied, there was no significant difference between the two groups in any of the 17 selected items assessing QoL and neurological and cognitive functions. We observed in both groups a mild deterioration across time of communication deficit, weakness of legs, intellectual deficit and memory (all P < 0.005).
Conclusion: Patients should be informed of these potential adverse effects, as well as the benefit of PCI on survival and BM. PCI with a total dose of 25 Gy remains the standard of care in limited-stage SCLC.
PMCID: PMC3082159  PMID: 21139020
limited disease; neurocognitive evaluation; phase III clinical trial; prophylactic cranial irradiation; quality of life; small-cell lung cancer
14.  Metastatic Medulloblastoma in Childhood: Chang's Classification Revisited 
Purpose. To correlate the radiological aspects of metastases, the response to chemotherapy, and patient outcome in disseminated childhood medulloblastoma. Patients and Methods. This population-based study concerned 117 newly diagnosed children with disseminated medulloblastoma treated at the Institute Gustave Roussy between 1988 and 2008. Metastatic disease was assessed using the Chang staging system, their form (positive cerebrospinal fluid (CSF), nodular or laminar), and their extension (positive cerebrospinal fluid, local, extensive). All patients received preirradiation chemotherapy. Results. The overall survival did not differ according to Chang M-stage. The 5-year overall survival was 59% in patients with nodular metastases compared to 35% in those with laminar metastases. The 5-year overall survival was 76% in patients without disease at the end of pre-irradiation chemotherapy compared to 34% in those without a complete response (P = 0.0008). Conclusions. Radiological characteristics of metastases correlated with survival in patients with medulloblastoma. Complete response to sandwich chemotherapy was a strong predictor of survival.
PMCID: PMC3265270  PMID: 22312539
15.  A Novel Epigenetic Phenotype Associated With the Most Aggressive Pathway of Bladder Tumor Progression 
Epigenetic silencing can extend to whole chromosomal regions in cancer. There have been few genome-wide studies exploring its involvement in tumorigenesis.
We searched for chromosomal regions affected by epigenetic silencing in cancer by using Affymetrix microarrays and real-time quantitative polymerase chain reaction to analyze RNA from 57 bladder tumors compared with normal urothelium. Epigenetic silencing was verified by gene re-expression following treatment of bladder cell lines with 5-aza-deoxycytidine, a DNA demethylating agent, and trichostatin A, a histone deacetylase inhibitor. DNA methylation was studied by bisulfite sequencing and histone methylation and acetylation by chromatin immunoprecipitation. Clustering was used to distinguish tumors with multiple regional epigenetic silencing (MRES) from those without and to analyze the association of this phenotype with histopathologic and molecular types of bladder cancer. The results were confirmed with a second panel of 40 tumor samples and extended in vitro with seven bladder cancer cell lines. All statistical tests were two-sided.
We identified seven chromosomal regions of contiguous genes that were silenced by an epigenetic mechanism. Epigenetic silencing was not associated with DNA methylation but was associated with histone H3K9 and H3K27 methylation and histone H3K9 hypoacetylation. All seven regions were concordantly silenced in a subgroup of 26 tumors, defining an MRES phenotype. MRES tumors exhibited a carcinoma in situ–associated gene expression signature (25 of 26 MRES tumors vs 0 of 31 non-MRES tumors, P < 10−14), rarely carried FGFR3 mutations (one of 26 vs 22 of 31 non-MRES tumors, P < 10−6), and contained 25 of 33 (76%) of the muscle-invasive tumors. Cell lines derived from aggressive bladder tumors presented epigenetic silencing of the same regions.
We have identified an MRES phenotype characterized by the concomitant epigenetic silencing of several chromosomal regions, which, in bladder cancer, is specifically associated with the carcinoma in situ gene expression signature.
PMCID: PMC3014990  PMID: 21173382
17.  Carcinoma of an unknown primary: are EGF receptor, Her-2/neu, and c-Kit tyrosine kinases potential targets for therapy? 
British Journal of Cancer  2007;97(7):857-861.
Carcinomas of an unknown primary site (CUP) are heterogeneous tumours with a median survival of only 8 months. Tyrosine kinase inhibitors are promising new drugs. The aim of this study was to determine the expression of EGF-receptor, Her-2/neu, and c-Kit tyrosine kinases in CUP. Paraffin-embedded specimens were obtained from 54 patients with a CUP who were included in the GEFCAPI 01 randomised phase II trial. Immunohistochemistry was performed using the Dako autostainer with antibodies directed against HER-2/neu protein, EGFR protein, and c-Kit protein (CD117). EGFR expression was found in 36 out of 54 samples (66%). In contrast, Her-2/neu overexpression and c-Kit positivity were only detected in 4 and 10% of patients, respectively. No significant association was found between the expression of the tyrosine kinase receptors and prognosis. EGFR expression was significantly associated with response to cisplatin-based chemotherapy: the response rates were 50 and 22% in patients with EGFR-positive tumours and EGFR-negative tumours, respectively (P<0.05). This study shows that EGFR is frequently expressed in CUP. This finding may prompt clinical trials investigating EGFR inhibitors in this setting. In contrast, c-Kit expression and Her-2/neu overexpression occur infrequently in CUP. EGFR expression was correlated to tumour chemosensitivity.
PMCID: PMC2360401  PMID: 17876336
carcinoma of an unknown primitive; tyrosine kinase receptor; EGFR; c-Kit; Her-2/neu overexpression
18.  Serotonin transporter gene polymorphisms and hyperserotonemia in autistic disorder 
Molecular Psychiatry  2002;7(1):67-71.
Previous studies have provided conflicting evidence regarding the association of the serotonin transporter (5-HTT) gene with autism. Two polymorphisms have been identified in the human 5-HTT gene, a VNTR in intron 21 and a functional deletion/insertion in the promoter region (5-HTTLPR) with short and long variants.2 Positive associations of the 5-HTTLPR polymorphism with autism have been reported by two family-based studies, but one found preferential transmission of the short allele3 and the other of the long allele.4 Two subsequent studies failed to find evidence of transmission disequilibrium at the 5-HTTLPR locus.5,6 These conflicting results could be due to heterogeneity of clinical samples with regard to serotonin (5-HT) blood levels, which have been found to be elevated in some autistic subjects.7–9 Thus, we examined the association of the 5-HTTLPR and VNTR polymorphisms of the 5-HTT gene with autism, and we investigated the relationship between 5-HTT variants and whole-blood 5-HT. The transmission/disequilibrium test (TDT) revealed no linkage disequilibrium at either loci in a sample of 96 families comprising 43 trios and 53 sib pairs. Furthermore, no significant relationship between 5-HT blood levels and 5-HTT gene polymorphisms was found. Our results suggest that the 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism.
PMCID: PMC1896269  PMID: 11803447
Adolescent; Adult; Alleles; Autistic Disorder; blood; genetics; Blood Platelets; metabolism; Carrier Proteins; genetics; physiology; Child; Child, Preschool; Female; Genetic Heterogeneity; Genetic Predisposition to Disease; Haplotypes; genetics; Humans; Introns; genetics; Linkage Disequilibrium; Male; Membrane Glycoproteins; genetics; physiology; Membrane Transport Proteins; Minisatellite Repeats; Mutagenesis, Insertional; Nerve Tissue Proteins; Polymorphism, Genetic; Risk Factors; Sequence Deletion; Serotonin; blood; Serotonin Plasma Membrane Transport Proteins; Autistic disorder; serotonin; serotonin transporter; endophenotype; association; linkage disequilibrium
19.  Platelet serotonergic markers as endophenotypes for obsessive-compulsive disorder 
Neuropsychopharmacology   2005;30(8):1539-1547.
Although compelling evidence has shown that obsessive-compulsive disorder (OCD) has a strong genetic component, its genetic basis remains to be elucidated. Identifying biological abnormalities in non-affected relatives is one of the strategies advocated to isolate genetic vulnerability factors in complex disorders. Because peripheral serotonergic disturbances are frequently observed in OCD patients, the aim of this study was to investigate if they could represent endophenotypes, by searching for similar abnormalities in the unaffected parents of OCD patients.
We assessed whole blood serotonin (5-HT) concentration, platelet 5-HT transporter (5-HTT) and 5-HT2A receptor binding characteristics, and platelet inositol trisphosphate (IP3) content in a sample of OCD probands (n = 48) and their unaffected parents (n = 65), and compared them with sex- and age-matched controls (n = 113).
Lower whole blood 5-HT concentration, fewer platelet 5-HTT binding sites, and higher platelet IP3 content were found in OCD probands and their unaffected parents compared to controls. Whole blood 5-HT concentration showed a strong correlation within families (p<0.001). The only parameter that appeared to discriminate affected and unaffected subjects was 5-HT2A receptor binding characteristics, with increased receptor number and affinity in parents and no change in OCD probands.
The presence of peripheral serotonergic abnormalities in OCD patients and their unaffected parents supports a familial origin of these disturbances. These alterations may serve as endophenotypic markers in OCD, and could contribute to the study of the biological mechanisms and genetic underpinnings of the disorder.
PMCID: PMC1885456  PMID: 15886722
Adolescent; Adrenergic Uptake Inhibitors; pharmacokinetics; Adult; Biological Markers; Blood Platelets; drug effects; metabolism; Case-Control Studies; Child; Female; Genotype; Humans; Imipramine; pharmacokinetics; Inositol 1,4,5-Trisphosphate; blood; Iodine Isotopes; pharmacokinetics; Lysergic Acid Diethylamide; pharmacokinetics; Male; Middle Aged; Minisatellite Repeats; genetics; Obsessive-Compulsive Disorder; blood; genetics; Paroxetine; pharmacokinetics; Radioimmunoassay; methods; Receptor, Serotonin, 5-HT2A; metabolism; Serotonin; blood; Serotonin Agents; pharmacokinetics; Serotonin Uptake Inhibitors; pharmacokinetics; Statistics; Statistics, Nonparametric; Tritium; pharmacokinetics; serotonin; serotonin transporter; 5-HT2A receptor; binding; inositol triphosphate; intrafamilial correlation
20.  The risk of thrombo-embolic events is increased in patients with germ-cell tumours and can be predicted by serum lactate dehydrogenase and body surface area 
British Journal of Cancer  2005;93(8):909-914.
The aim of this study was to evaluate the risk of thrombo-embolic events (TEE) in patients with germ-cell tumours (GCT) who receive cisplatin-based chemotherapy, to compare this risk to that of a matched control group of non-GCT cancer patients, and to identify risk factors of TEE. The rate of TEE during the 6 months following the initiation of chemotherapy was assessed in 100 consecutive patients with GCT and in 100 controls with various neoplasms who were matched on sex and age, and who received first-line cisplatin-based chemotherapy during the same period of time at Institut Gustave Roussy, Villejuif, France. Data were subsequently tested on a validation group of 77 GCT patients treated in Lyon, France. A total of 19 patients (19%) (95% confidence interval (CI): 13–28) and six patients (6%) (95% CI: 3–13) had a TEE in the GCT group and the non-GCT control group, respectively (relative risk (RR): 3.4; P<0.01). Three patients from the GCT group died of pulmonary embolism. In multivariate analysis, two factors had independent predictive value for TEE: a high body surface area (>1.9 m2) (RR: 5 (1.8–13.9)) and an elevated serum lactate dehydrogenase (LDH) (RR: 6.4 (2.3–18.2)). Patients with no risk factor (n=26) and those with at least one risk factor (n=71) had a probability of having a TEE of 4% (95% CI: 1–19) and 26% (95% CI: 17–37), respectively. In the GCT validation set, 10 (13%) patients had a TEE; patients with no risk factor and those with at least one risk factor had a probability of having a TEE of 0 and 17% (95% CI: 10–29), respectively. Patients with GCT are at a higher risk for TEE than patients with non-GCT cancer while on cisplatin-based chemotherapy. This risk can be accurately predicted by serum LDH and body surface area. This predictive index may help to study prospectively the impact of thromboprophylaxis in GCT patients.
PMCID: PMC2361657  PMID: 16205699
cancer of the testis; chemotherapy; cisplatin; germ-cell tumour; thrombosis
21.  Bilateral germ-cell tumours: 22-year experience at the Institut Gustave Roussy 
British Journal of Cancer  2004;90(1):55-59.
PMCID: PMC2395303  PMID: 14710206
incidence; bilateral testicular germ-cell tumours; seminoma; nonseminomatous germ-cell tumour
22.  Trends in mortality from sporadic Creutzfeldt-Jakob disease in France 1992-7 
This study examined trends in mortality from sporadic Creutzfeldt-Jakob disease in France for 1992-7 by age, genotype at the codon 129 of the prion protein gene, and geographical area. Case ascertainment was based on notifications by neurologists, neuropathologists, and laboratories; 324 deaths from definite or probable Creutzfeldt-Jakob disease were registered during the study period. The yearly number of deaths increased significantly between 1992 and 1997. The rise was higher for older age groups. It was also higher in those who were homozygous for valine compared with other genotypes. Eighteen departments (geographical administrative areas) out of 95 showed a significant increase in the number of deaths from sporadic Creutzfeldt-Jakob disease. Intensive epidemiological surveillance is a likely explanation for the apparent increase in the number of sporadic cases of Creutzfeldt-Jakob disease over the 1992-7 period, particularly in older age groups and in departments with low mortality rate at the beginning of the study period. Intensive surveillance may also have led to a better identification of atypical valine homozygous cases.

PMCID: PMC1736947  PMID: 10811709
24.  Earlier Positivity of Central-Venous- versus Peripheral-Blood Cultures Is Highly Predictive of Catheter-Related Sepsis 
Journal of Clinical Microbiology  1998;36(1):105-109.
To diagnose catheter-related sepsis without removing the catheter, we evaluated the differential positivity times of cultures of blood drawn simultaneously from central venous catheter and peripheral sites. In a 450-bed cancer reference center, simultaneous central- and peripheral-blood cultures were prospectively performed for patients with suspicion of catheter-related sepsis over an 18-month period. Data for 64 patients for whom the same microorganisms were found when central- and peripheral-blood samples were cultured were retrospectively reviewed by two independent physicians blinded to the differential positivity time values in order to establish or refute the diagnosis of catheter-related sepsis. The diagnosis was established in 28 cases, refuted in 14, and indeterminate in the remaining 22. The differential positivity time was significantly greater for patients with catheter-related sepsis (P < 10−4). A cutoff limit of +120 min had 100% specificity and 96.4% sensitivity for the diagnosis of catheter-related sepsis. These results strongly suggest that measurement of the differential positivity time might be a reliable tool facilitating the diagnosis of catheter-related sepsis in patients with an indwelling catheter.
PMCID: PMC124817  PMID: 9431930
25.  Leukaemia mortality around French nuclear sites. 
British Journal of Cancer  1995;71(3):651-653.
This study was designed to investigate leukaemia mortality in the population under the age of 25 residing around the 13 French nuclear sites operating in 1985. In four geographical zones defined according to the distance from the site, 503 exposed communes were identified and followed up between 1968 and 1989. A total of 4,132,000 person-years of observation were accumulated. The number of leukaemia deaths observed (69) did not differ from the expected number (86.15) estimated according to national mortality statistics. There was no difference in the risks of leukaemia mortality according to sex, age, type of installation and no trend with an increasing distance from installations.
PMCID: PMC2033652  PMID: 7880754

Results 1-25 (32)