Showing papers by "Paris Descartes University published in 2003"

Pyogenic Bacterial Infections in Humans with MyD88 Deficiency

Abstract: MyD88 is a key downstream adapter for most Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). MyD88 deficiency in mice leads to susceptibility to a broad range of pathogens in experimental settings of infection. We describe a distinct situation in a natural setting of human infection. Nine children with autosomal recessive MyD88 deficiency suffered from life-threatening, often recurrent pyogenic bacterial infections, including invasive pneumococcal disease. However, these patients were otherwise healthy, with normal resistance to other microbes. Their clinical status improved with age, but not due to any cellular leakiness in MyD88 deficiency. The MyD88-dependent TLRs and IL-1Rs are therefore essential for protective immunity to a small number of pyogenic bacteria, but redundant for host defense to most natural infections.

Octogenarians Reaching End-Stage Renal Disease: Cohort Study of Decision-Making and Clinical Outcomes

Abstract: The fate of octogenarians reaching end-stage renal disease (ESRD) is poorly defined, and implicit dialysis rationing may be practiced in this age group. The main objectives of this study were to analyze the characteristics of pre-ESRD octogenarians offered dialysis or not and to identify factors influencing mortality while on dialysis, to improve prognosis assessment and decision-making. In this single-center cohort, 146 consecutive pre-ESRD octogenarians were referred to a nephrology unit over a 12-yr period (1989 to 2000). Main outcome measures were baseline characteristics of patients offered dialysis and conservative therapy and overall and 1-yr survival according to effective treatment. A therapeutic decision was made for 144 patients. Octogenarians who were not proposed dialysis (n = 37) differed from those who were proposed dialysis (n = 107) mainly in terms of social isolation (43.3% versus 14.7%; P = 0.03), late nephrologic referral (51.4% versus 28.9%; P = 0.01), Karnofsky score (55 +/- 18 versus 63 +/- 20; P = 0.03), and diabetic status (22.2% versus 6.5%, P = 0.008). Six patients refused the dialysis proposal. During the 12-yr observation period, 99 patients died (68.7%). Median survival was 28.9 mo (95% CI, 24 to 38) in patients undergoing dialysis, compared with 8.9 mo (95% CI, 4 to 10) in patients treated conservatively (P < 0.0001). In multivariable piecewise Cox analysis, independent predictors of death within 1 yr on dialysis were poor nutritional status, late referral, and functional dependence. Included in a survivor function, these covariates predict groups with low and high 1-yr mortality risk. Beyond 1 yr on dialysis, the only independent predictor of death was the presence of peripheral vascular disease. It is concluded that beside a patient's individual refusal, late referral, social isolation, low functional capacity, and diabetes may have oriented medical decision toward withholding dialysis in a significant proportion of pre-ESRD octogenarians. Although most patients on dialysis experienced a substantial prolongation of life, identification of mortality predictors in this age group should improve the process of decision-making regarding the expected benefit of renal replacement therapy.

Therapeutic dendritic-cell vaccine for simian AIDS

Abstract: An effective immune response against human immunodeficiency virus or simian immunodeficiency virus (SIV) is critical in achieving control of viral replication. Here, we show in SIV-infected rhesus monkeys that an effective and durable SIV-specific cellular and humoral immunity is elicited by a vaccination with chemically inactivated SIV-pulsed dendritic cells. After three immunizations made at two-week intervals, the animals exhibited a 50-fold decrease of SIV DNA and a 1,000-fold decrease of SIV RNA in peripheral blood. Such reduced viral load levels were maintained over the remaining 34 weeks of the study. Molecular and cellular analyses of axillary and inguinal node lymphocytes of vaccinated monkeys revealed a correlation between decreased SIV DNA and RNA levels and increased SIV-specific T-cell responses. Neutralizing antibody responses were augmented and remained elevated. Inactivated whole virus-pulsed dendritic cell vaccines are promising means to control diseases caused by immuno- deficiency viruses.

Proopiomelanocortin, a polypeptide precursor with multiple functions: from physiology to pathological conditions

Abstract: Proopiomelanocortin (POMC) is the polypeptide precursor of ACTH. First discovered in anterior pituitary corticotroph cells, it has more recently been revealed to have many other physiological aspects. The fine molecular mechanisms of ACTH biosynthesis show that ACTH is but one piece of a puzzle which contains many other peptides. Present in various tissues, among which are pituitary, hypothalamus, central nervous system and skin, POMC undergoes extensive post-translational processing. This processing is tissue-specific and generates, depending on the case, various sets of peptides involved in completely diverse biological functions. POMC expressed in corticotroph cells of the pituitary is necessary for adrenal function. Recent developments have shown that POMC-expressing neurons in the brain play a major role in the control of pain and energy homeostasis. Local production of POMC-derived peptides in skin may influence melanogenesis. A still unknown function in the placenta is likely. POMC has become a paradigmatic polypeptide precursor model illustrating the variable roles of a single gene and its various products in different localities.

Prognostic value of ERBB family mRNA expression in breast carcinomas

Abstract: The ErbB-driven autocrine growth pathway has been implicated in the development and progression of most common human epithelial malignancies; its blockade is therefore a promising therapeutic strategy, and several candidate drugs are currently undergoing clinical trials Paradoxically, little is known of the expression pattern of these 4 genes in human tumors, and the clinical significance of the 2 most recently discovered ERBB genes, ERBB3 and ERBB4, is unclear We used a real-time quantitative RT-PCR assay to quantify ERBB family mRNA copy numbers in a large series of breast tumors from patients with known long-term outcome ERBB gene expression varied widely, by more than 2 orders of magnitude for ERBB1 and ERBB3, more than 3 orders for ERBB2 and more than 4 orders for ERBB4 We found a positive correlation between ERBB3 and ERBB4 mRNA levels, and a negative correlation between the expression of these 2 latter genes and that of ERBB1 Compared to normal breast tissue, ERBB1 was underexpressed (823% of tumors), ERBB2 (169%) and ERBB3 (462%) were overexpressed and ERBB4 was both underexpressed (246%) and overexpressed (292%) Links were also found between ERBB status on the one hand and Scarff-Bloom-Richardson (SBR) histopathological grade and estrogen receptor alpha (ERa) status on the other hand Relapse-free survival (RFS) was shorter among patients with ERBB3-overexpressing tumors (p=00092) and longer among those with ERBB4-underexpressing tumors (p=00085) relative to patients with normal expression of the respective genes; in contrast, RFS was not significantly influenced by ERBB1 or ERBB2 mRNA status Only ERBB4 status retained prognostic significance in Cox multivariate regression analysis (p=0015) Our results point to the involvement of several ErbB-specific ligands (amphiregulin and neuregulin 1) and enzymes or adaptor molecules (PI3K, Src, Shc and Grb7) in the ErbB pathway dysregulation associated with breast cancer These findings reveal a complex expression pattern of ERBB gene family members in breast tumors and suggest that it is this pattern of expression, rather than the expression of individual family members, that should be taken into account when evaluating antitumoral drugs designed to target these receptors

Expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in healthy and diseased human gingiva.

Abstract: Background: The purpose of this study was to quantify the amount of matrix metalloproteinases such as MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, and MMP-13 and tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 expressed by human gingival explants in culture media and the area fraction (AA%) of gingival collagen fibers according to the degree of inflammation, to investigate a possible correlation between these enzymes and collagen loss. Methods: Gingival tissue specimens from 6 healthy controls (group 1), 17 patients with mild gingival inflammation (group 2), 10 patients with moderate gingival inflammation (group 3), and 9 patients with severe gingival inflammation (group 4) were placed in organ culture for 3 days. The MMPs and TIMPs in the culture media were quantified using zymography, dot blotting, and Western blotting. Paraffin gingival sections were stained with sirius red F3Ba for visualization of collagen fibers, then the area fraction (AA%) occupied by the gingival fibers was determined by automate...

Refractory coeliac sprue is a diffuse gastrointestinal disease

Abstract: Background: Refractory coeliac sprue (RCS) with an immunophenotypically aberrant clonal intraepithelial lymphocyte (IEL) population is considered a cryptic form of intestinal T cell lymphoma. Aims: To investigate the distribution of the abnormal and monoclonal IEL population in the digestive tract of RCS patients. Patients and methods: We compared the frequency of lymphocytic gastritis (LG) and lymphocytic colitis (LC), together with IEL phenotype and T cell clonality, in gastric and colonic samples from 15 adults with RCS (all with aberrant CD3 intracytoplasmic+ surface− CD8− clonal IELs on duodenojejunal biopsies), 18 patients with active coeliac disease (ACD), and 10 patients with coeliac disease (CD) on a gluten free diet (GFD-CD) by means of immunohistochemistry and multiplex polymerase chain reaction amplification of the T cell receptor γ gene (TCR-γ) rearrangement. Blood samples of nine RCS patients were also tested for clonality. Results: LG was found in 9/14 (64%), 11/18 (61%), and 3/10 (30%) patients with RCS, ACD, and GFD-CD, respectively, while LC was found in 6/11 (55%), 3/4 (75%), and 2/3 (66%) patients. Contrary to CD, all samples from patients with LG and LC showed an aberrant IEL phenotype. Monoclonal TCR-γ rearrangements were detected in 8/13 (62%), 8/10 (80%), and 4/9 (44%) of gastric, colonic, and blood samples, respectively, from RCS patients, while in CD patients such rearrangements were only found in 2/25 (8%) gastric samples. Conclusion: The immunophenotypically aberrant monoclonal IEL population present in the small intestine of patients with RCS frequently disseminates to the blood and the entire gastrointestinal epithelium, suggesting that this is a diffuse gastrointestinal disease.

Increase in bone mineral density of patients with spondyloarthropathy treated with anti-tumour necrosis factor α

Abstract: Patients and methods: 29 patients (six women; 23 men) aged 22–68 years, with persistently active SpA despite a high dose of non-steroidal anti-inflammatory drug and/or treatment with methotrexate or sulfasalazine, were studied. Median duration of disease was 13 years (range 3–30). Twenty five patients were treated with 5 mg/kg and four with 3 mg/kg of infliximab at weeks 0, 2, 6 and then received either no infusion (n=3), or additional infusion of infliximab every other month (n=6), and the remainder received one infusion only in the case of a relapse. Lumbar and femoral BMD was measured by dual energy x ray absorptiometry at baseline and six months later. Serum osteocalcin and urinary deoxypyridinoline were measured in 19 patients at weeks 0, 2, 24, and in 13 patients at all visits. Results: In six months there was a significant increase in BMD at the spine (3.6%, p=0.001), total hip (2.2%, p=0.0012), and trochanter (2.3%, p=0.0012). A trend for increase (1.1%) was observed at the femoral neck. There was an increase in osteocalcin between baseline and week 6 (third infusion)—median 1.45 µg/l (p=0.013). No change in marker of bone resorption was observed at the same time. There was no change in biochemical markers between baseline and final visits. There was a trend for a correlation between the decrease at six months in erythrocyte sedimentation rate, and lumbar spine BMD change (rs=-0.35, p=0.06). Conclusion: These data suggest that a benefit of anti-tumour necrosis factor α therapy on BMD in patients with SpA may be through an uncoupling effect on bone cells.

Questioning some paradigms of signal processing via concrete examples

Abstract: This paper was presented in November 2003 in Mexico City. It gives an overview of recent on-line and non-asymptotic estimation techniques in signal processing, which do not necessitate any precise statistical knowledge of the noises. Several concrete examples with their computer simulations are discussed.

Involvement of connexin 43 in human trophoblast cell fusion and differentiation.

Abstract: The syncytiotrophoblast is the principal component of the human placenta involved in feto-maternal exchanges and hormone secretion. The syncytiotrophoblast arises from the fusion of villous cytotrophoblasts. We recently showed that functional gap junctional intercellular communication (GJIC) is an important prerequisite for syncytiotrophoblast formation and that connexin 43 (Cx43) is present in cytotrophoblasts and in the syncytiotrophoblast. To determine whether Cx43 is directly involved in trophoblast fusion, we used an antisense strategy in primary cultures of human villous cytotrophoblasts that spontaneously differentiate into the syncytiotrophoblast by cell fusion. We assessed the morphological and functional differentiation of trophoblasts by desmoplakin immunostaining, by quantifying hCG (human chorionic gonadotropin) production and by measuring the expression of specific trophoblast genes (hCG and HERV-W). Furthermore, we used the gap-FRAP (fluorescence recovery after photobleaching) method to investigate functional GJIC. Cytotrophoblasts treated with Cx43 antisense aggregated and fused poorly. Furthermore, less HERV-W env mRNA, hCGbeta mRNA and hCG secretion were detected in Cx43 antisense-treated cytotrophoblasts than in cells treated with scrambled antisense. Treatment with Cx43 antisense dramatically reduced the percentage of coupled trophoblast cells. Taken together, these results suggest that Cx43 is directly involved in human trophoblast cell-cell communication, fusion and differentiation.

Qualitative analysis of verbal fluency in depression

Abstract: The aim of this study was to analyze qualitative aspects of verbal fluency in depression. Phonemic and semantic output was scored for word clustering and switching between clusters in depressed patients and normal control subjects. Depressed patients (n=25) and normal control subjects (n=19) were administered both phonemic and semantic fluency tasks. All patients were also evaluated with executive card sorting tests. Patients with depression produced fewer words on the semantic fluency task than controls and showed normal performance on the phonemic fluency tasks. The deficit on semantic fluency of depressed patients was related to a reduced number of switches with normal cluster sizes. The number of switches in depression was associated with a reduced ability to shift mental set on card sorting tests, suggesting that verbal fluency impairment reflects general executive problems in depression.

Are cytokines linked to collagen breakdown during periodontal disease progression

Abstract: Background: Evidence of the role of cytokines produced by resident and inflammatory cells during inflammation is well established. The aim of this study was to quantify in healthy and diseased human gingiva the area fraction (AA%) occupied by collagen fibers and the amount of cytokines such as interleukin (IL)-1β, IL-4, IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and epidermal growth factor (EGF) to investigate a possible correlation between such cytokines, collagen degradation, and the gingival index. Methods: Gingival tissue specimens from 6 healthy controls (group 1), 6 patients with mild gingival inflammation (group 2), 6 patients with moderate gingival inflammation (group 3), and 6 patients with severe gingival inflammation (group 4) were cultured for 72 hours, and the cytokines present in the culture media were quantified using an enzyme-linked immunosorbent assay (ELISA). Paraffin gingival sections from the 24 subjects were stained with sirius red F3Ba for visualization...

Placenta-Specific INSL4 Expression Is Mediated by a Human Endogenous Retrovirus Element

Abstract: The human insulin-family genes regulate cell growth, metabolism, and tissue-specific functions. Among these different members, only INSL4 gene shows a predominant placenta-specific expression. Here, we show that the human INSL4 gene is tightly clustered with three other members of the human insulin superfamily (RLN1, RLN2, and INSL6) within a 176-kilobase genomic segment on chromosome region 9p23.3‐p24.1. We also report evidence that INSL4 is probably the only insulin-like growth factor gene to be primate-specific. We identified an unexpected human endogenous retrovirus (HERV) element inserted into the human INSL4 promoter with a sequence similar to that of env gene, flanked by two long terminal repeats(LTRs). The emergence of INSL4 gene and genomic insertion of HERV appear to have occurred after the divergence of New World and Old World monkeys (;45 million years ago). Transient transfection experiments showed that the placenta-specific expression of INSL4 is mediated by the 39 LTR of the HERV element, and that the latter may have a major role in INSL4 up-regulation during human cytotrophoblast differentiation into syncytiotrophoblast. Finally, we identified an INSL4 alternatively spliced mRNA species that encodes putative novel INSL4-like peptides. These data support the view that ancient retroviral infection may have been a major event in primate evolution, especially in the functional evolution of the human placenta. gene regulation, insulin, placenta, pregnancy, relaxin

Assessment of fatigue in the management of patients with ankylosing spondylitis

Abstract: Background. Pain, stiffness, functional impairment, range of motion and quality of life are the main conventional domains used in studies evaluating ankylosing spondylitis (AS). However, fatigue has been reported as the major complaint of AS patients. Objectives. To evaluate fatigue as a potential independent domain in comparison with the ‘conventional’ ones and to evaluate the sensitivity to change after nonsteroidal anti-inflammatory drug (NSAID) therapy. Methods. Patients were classified as having painful AS (modified New York criteria). The following variables were recorded at baseline and after 6 weeks of therapy (either placebo or NSAIDs): pain (VAS), function (Bath Ankylosing Spondylitis Functional Index), patient’s global assessment (VAS), inflammation (night pain), morning stiffness, metrology (Schober test, finger-to-floor) and fatigue using 0–100 VAS scale. Analysis consisted of (i) the prevalence of fatigue (VAS value of at least 50 mm), (ii) the independence of the information evaluated using a regression model, and (iii) the sensitivity to change, by calculating the standardized response mean (mean change/S.D. change) (SRM) between placebo and NSAID group. Results. Fatigue was considered important in 401 patients (out of 639: 63%). The information provided by the variables ‘pain’, ‘function’ and ‘global assessment’ explained only 44% of the variability of the variable ‘fatigue’ (similar analyses considering ‘pain’ on the one hand and ‘function’ on the other hand as the dependent variables showed an R 2 value of 34 and 60%, respectively). The NSAID treatment effect (SRM) was higher for the variables ‘pain’ and ‘function’ (0.76 and 0.71, respectively) than for the variable ‘fatigue’ (0.34). Conclusion. This study strongly suggests that fatigue should be considered as an independent domain to be systematically evaluated in AS patients and that conventional therapy such as NSAIDs have a lower effect on this domain than on pain or functional impairment.

CFTR genotypes in patients with normal or borderline sweat chloride levels.

Abstract: In recent years, some patients bearing "atypical" forms of cystic fibrosis (CF) with normal sweat chloride concentrations have been described. To identify the spectrum of mutant combinations causing such atypical CF, we collected the results of CFTR (ABCC7) mutation analysis from 15 laboratories. Thirty patients with one or more typical symptoms of the disease associated with normal or borderline sweat chloride levels and bearing two CFTR mutations were selected. Phenotypes and genotypes of these 30 patients are described. A total of 18 different CFTR mutations were observed in the 60 chromosomes analysed. F508del was present in 31.6 % of the mutated chromosomes and 3849+10kbC>T in 13.3 %. R117H, D1152H, L206W, 3272-26A>G, S1235R, G149R, R1070W, S945L, and the poly-T tract variation commonly called IVS8-5T were also observed. The relative frequency of CFTR mutations clearly differed from that observed in typical CF patients or in CBAVD patients with the same ethnic origin. A mild genotype with one or two mild or variable mutations was observed in all the patients. These findings improve our understanding of the distribution of CFTR alleles in CF with normal or borderline sweat chloride concentrations and will facilitate the development of more sensitive CFTR mutation screening.

Human invasive trophoblasts transformed with simian virus 40 provide a new tool to study the role of PPARγ in cell invasion process.

Abstract: Invasive cytotrophoblasts play a key role in the development of human placenta and is therefore essential for subsequent development of the embryo. Human implantation is characterized by a major trophoblastic invasion that offers a unique model of a controlled and oriented tumor-like process. The ligand-activated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) modulates cell growth and differentiation and might be therefore considered as a tumor suppressor. We have recently reported that PPARgamma, in synergy with its dimerization partner retinoid X receptor (RXR)alpha, controls the invasion of human primary cytotrophoblasts. Because these cells are unable to replicate in culture, we have, in the present study, transformed these primary cells with the simian virus 40 large T antigen for studying the role of PPARgamma in cell invasion process. Our results show that the cell line human invasive proliferative extravillous cytotrophoblast (HIPEC) 65 expressed markers of human invasive primary cytotrophoblast as determined by immunocytochemistry, immunobloting and real-time RT-PCR, and were highly invasive in vitro. We have next studied the role of PPARgamma/RXRalpha heterodimers in cell proliferation and invasion. Our results show that PPARgamma and RXRalpha are co-expressed by HIPEC 65 and that, as commonly observed, activation of PPARgamma/RXRalpha heterodimers with the specific PPARgamma agonist rosiglitazone induced lipid droplet accumulation as revealed by oil red O staining. Treatment with rosiglitazone or with the natural PPARgamma agonist 15-deoxy-delta-(12,14) PGJ2 did not modify cell growth, but interestingly, activation of PPARgamma by this synthetic (rosiglitazone) or natural (15d-PGJ2) ligand markedly inhibited cell invasion in a concentration-dependent manner. Finally, we showed that other potential natural PPARgamma ligand such as oxidized-but not native-low-density lipoprotein inhibited cell invasion. This proliferative and invasive human cytotrophoblast cell line from extravillous origin provides a new tool for studying specifically the role of PPARgamma in the control of cell invasion.

Genes involved in β-oxidation, energy metabolism and glyoxylate cycle are induced by Candida albicans during macrophage infection

Abstract: The ability of intracellular pathogens to cause infection is related to their capacity to survive and grow inside macrophages or in other cell types. Candida albicans latent virulence is likely to be related to a similar mechanism of avoiding killing by specialized cells and to the resulting ability to grow in such hostile environments. Using a differential display reverse transcription polymerase chain reaction technique, we have identified seven genes induced in C. albicans during macrophage phagocytosis. Sequence analyses and database searches revealed that these cDNAs coded for proteins homologous to yeast metabolic proteins. Interestingly, four of them are putative peroxisomal proteins, and two are involved in environmental signal sensing and transduction. Among the seven genes induced by C. albicans, six represent new information that were not described in other infection models.

[Cannabis and schizophrenia: demographic and clinical correlates].

Abstract: UNLABELLED: The high prevalence of psychoactive substance abuse or dependence among schizophrenic patients has now been well established. Mueser et al. stressed the need to assess the abuse of specific classes of substances and analyse the data accordingly. The objective of this study was to compare the socio-demographic correlates and the clinical features in a group of schizophrenic patients with a lifetime cannabis abuse or dependence according to the DSM III-R with a group of schizophrenic patients who had never presented any abuse or dependence. SUBJECTS AND METHODS: The study included 124 subjects with diagnoses of schizophrenia or schizoaffective disorders according to the DSM III-R. Inclusion criteria for participation in the study were age 18 years or older and willingness to provide consent to participate in the study. The inpatients were evaluated when their condition was stabilised. Assessment tools were the psychoactive substance use disorder section of the Composite International Diagnostic Interview (CIDI), the Positive and Negative Syndrome Scale (PANSS), the Global Assessment of Functioning Scale (GAF). Subjects with cannabis abuse or dependence during their lifetime were compared with subjects without abuse or dependence, using chi(2) test for categorical variables and analyses of covariance (ANCOVA) for quantitative variables. RESULTS: Forty-nine subjects (42,6%) presented lifetime abuse or dependence on one or more substances. Since 19 patients with alcohol, stimulant, sedative or opiate abuse or dependence were excluded, the study finally included 96 subjects including a first group of schizophrenic patients with cannabis abuse (n=6) or dependence (n=24) and a second group without any psychoactive substance abuse (n=66). Thirteen (11.3%) patients presented cannabis abuse or dependence within the 6 months prior to the assessment. The mean SD age of onset of cannabis abuse or dependence was 19.6 +/- 3.0 years. Cannabis abuse/dependence preceded the first psychiatric treatment in 70% of the subjects (n=21). 83.3% of the schizophrenic patients with cannabis abuse or dependence were male (n=25) compared to 62.1% in the group without substance abuse (n=41) (chi(2)=4.32, df=1, p=0.04). Schizophrenic patients with cannabis abuse were significantly younger (mean age: 28.9 +/- 6.3 vs 37.0 +/- 12.7, ANCOVA, F=7.2, df=1,96 p=0.009). There was no significant difference between the two groups for marital status, (chi(2)=5.34, df=2, p=0.07), level of education, (chi(2)=0.93, df=2, p=0.62) professional status, (chi(2)=8.7, df=5, p=0.11), on PANSS total score (ANCOVA, F=0.42, df=1,93, p=0.52), GAF score (ANCOVA, F=0.06, df=1,92, p=0.80), mean number of hospitalizations (ANCOVA, F=3.25, df=1,85, p=0.08), mean age of first psychiatric contact (ANCOVA, F=0.74, df=1,93, p=0.39), and neuroleptic dosages (ANCOVA, F=0.03, df=1,90, p=0.87). In contrast, the total duration of hospitalization was significantly longer for the group with cannabis abuse. Patients with cannabis abuse were more likely to have an history of suicide attempts than subjects without substance abuse (chi(2)=11.52, df=1, p=0.0007). DISCUSSION: The prevalence rates for substance abuse and the socio-demographic characteristics of the population of our study are consistent with findings of previous studies. Male gender and age were significantly related to history of cannabis abuse or dependence. Cannabis abuse frequently preceded the onset of psychiatric treatment. However, both schizophrenia and substance abuse tend to develop gradually, with no clear demarcation for the onset of schizophrenia. The absence of any link between the scores for the subscales of the PANSS and cannabis abuse, both in our study and in some retrospective previous studies, is not suggestive of cannabis abuse as a self-medication of positive or negative symptoms of schizophrenia. Self-medication could concern other symptoms, such as cognitive deficits. In addition, the hypothesis of self-medication has especially been suggested in cocaine abuse or dependence. Some limitations to this study can be discussed. First, although the recruitment was systematic and done in a public mental health service, the patients of our study are not necessarily representative of all schizophrenic patients. Secondly, as in any retrospective study, the prevalence of lifetime substance abuse may have been under-estimated. Urinary toxicology tests may have been able to improve the sensitivity of the diagnosis of recent substance abuse, but structured interviews are more appropriate for the diagnosis of lifetime substance abuse in schizophrenic patients than urinary toxicology tests. CONCLUSION: The socio-demographic characteristics of cannabis abuse or dependence in schizophrenia are similar to those found in general population. Cannabis using schizophrenic patients were more likely to be younger and male than non users. The duration of hospitalization was significantly longer for the group with cannabis abuse. Prevalence of suicide attempts in schizophrenia is closely correlated to cannabis abuse. Language: fr

NMR Studies of the Phosphorylation Motif of the HIV-1 Protein Vpu Bound to the F-Box Protein β-TrCP†

Abstract: A protein-protein association regulated by phosphorylation of serine is examined by NMR studies. Degradation of the HIV receptor CD4 by the proteasome, mediated by the HIV-1 protein Vpu, is crucial for the release of fully infectious virions. Phosphorylation of Vpu at two sites, Ser52 and Ser56, on the motif DSGXXS is required for the interaction of Vpu with the ubiquitin ligase SCF-betaTrCP which triggers CD4 degradation by the proteasome. This motif is conserved in several signaling proteins known to be degraded by the proteasome. To elucidate the basis of beta-TrCP recognition, the bound conformation of the P-Vpu(41-62) peptide was determined by using NMR and MD. The TRNOE intensities provided distance constraints which were used in simulated annealing. The beta-TrCP-bound structure of P-Vpu was found to be similar to the structure of the free peptide in solution and to the structure recognized by its antibody. Residues 50-57 formed a bend while the phosphate groups are pointing away. The binding fragment was studied by STD-NMR spectroscopy. The phosphorylated motif DpS(52)GNEpS(56) was found to make intimate contact with beta-TrCP, and pSer52 displays the strongest binding effect. It is suggested that Ser phosphorylation allows protein-protein association by electrostatic stabilization: an obvious negative binding region of Vpu was recognizable by positive residues (Arg and Lys) of the WD domain of beta-TrCP. The Ile46 residue was also found essential for interaction with the beta-TrCP protein. Leu45 and Ile46 side chains lie in close proximity to a hydrophobic pocket of the WD domain.

Skewed X-chromosome inactivation pattern in SRY positive XX maleness: a case report and review of literature.

Abstract: XX maleness is the most common condition in which testes develop in the absence of a cytogenetically detectable Y chromosome. Using fluorescence in situ hybridization (FISH) or PCR, it was possible to detect the transfer of Yp fragments including SRY gene to the terminal part of X chromosome in the majority of XX males. We report a 32-year-old-male in whom a seminal analysis showed azoospermia, an X chromatin analysis showed 44% of Barr body positive nuclei and a chromosomal analysis revealed a 46,XX karyotype. Physical examination showed a normal sexual development and bilateral small testes. Hormonal studies revealed hypergonadotropic hypogonadism. Testis histological examination showed a profile of Sertoli Only Cell Syndrome. FISH study ruled out the presence of a Y-bearing cell line, and confirmed translocation of SRY to Xp terminal part. In order to confirm that the complete masculinized phenotype was related to a preferential inactivation of the no rearranged X chromosome, X-chromosome inactivation patterns (XCIP) were studied by analysis of methylation status of the androgen receptor gene. Highly skewed XCIP was observed by greater than 90% preferential inactivation involving one of the two X chromosomes, suggesting that the SRY-bearing X chromosome was the preferentially active X allowing for sufficient SRY expression for complete masculinization.

Influence of concurrent antiepileptic medication on the pharmacokinetics of lamotrigine as add‐on therapy in epileptic children

Abstract: 1. Lamotrigine is a new antiepileptic drug, chemically unrelated to currently used antiepileptic medication. Its pharmacokinetics can be influenced by concomitant antiepileptic medication. 2. This study was performed to assess the pharmacokinetic profile of lamotrigine in three groups of children treated with different types of comedication: drugs known to induce, to inhibit or to have no clinically significant influence on drug metabolism, respectively. 3. Thirty-one children aged 6 months to 5 years were included and received a 2 mg kg-1 single oral dose. Lamotrigine plasma profiles were different between the three comedication groups. The half-lives (mean +/- s.d.) were: 7.7 +/- 1.8 h, 21.9 +/- 6.8 h, 44.7 +/- 10.2 h in the "inducer', "other' and "inhibitor' groups respectively. 4. Patients were then dosed to steady state, with the dosage adjusted on the basis of the single dose pharmacokinetics to achieve a minimum plasma concentration between 1.5 and 3 mg l-1. The mean minimum plasma concentration for the three groups was 2.54 +/- 1.28 mg l-1 at steady state. 5. Dosage of lamotrigine can be optimised with knowledge of the metabolic effects of antiepileptic comedication.