Metabolic syndrome according to different definitions in a rapidly developing country of the African region

Rapport de synthèseLe syndrome métabolique représente un ensemble de facteurs de risque métaboliques souvent présents simultanément et il est associé à un risque accru de développer des maladies cardiovasculaires. La prevalence du syndrome métabolique est à la hausse au niveau mondial comme cela a souvent été documenté, en particulier dans les pays développés. Pourtant, les données concernant le syndrome métabolique dans les pays de la région sub-saharienne restent rares.Au cours des dernières années, plusieurs définitions du syndrome métabolique ont été formulées, dont celle du 'National Cholesterol Education Program Adult Treatment Panel III', celle de 1 Organisation Mondiale de la Santé et celle du 'International Diabetes Federation'. Parmi les controverses au sujet du syndrome métabolique persiste la question de l'utilité de rechercher la présence du syndrome métabolique chez les patients diabétiques, étant donné que la présence d'un diabète en soit suffit pour identifier un individu à haut risque de faire un événement cardiovasculaire.L'objectif de ce travail de thèse a été de déterminer la prévalence du syndrome métabolique selon les trois définitions majeures mentionnées ci-dessus, grâce à une étude de population transversale, réalisée aux Seychelles en 2004 dans un échantillon représentatif de la population âgée de 24-65 ans (n=1255, taux de participation de 80.3%). L'intérêt d'examiner cette question dans ce pays était d'obtenir des informations dans un pays en transition épidémiologique.Les résultats de ce travail montrent que la prévalence du syndrome métabolique aux Seychelles est élevée, quelque soit la définition utilisée. Selon la définition utilisée, cette prévalence était d'environ 25% chez les hommes et variant entre 25 et 35% chez les femmes.Cependant, malgré des prévalences semblables selon ces trois définitions, la concordance entre ces définitions n'était pas bonne, impliquant que ces différentes définitions classifient, à un certain degré, des individus différents comme étant porteurs du syndrome métabolique.En outre, la plupart (environ 80%) des individus diabétiques avaient un syndrome métabolique. Après exclusion des individus diabétiques, la prévalence du syndrome métabolique dans la population est réduite d'environ un tiers, à environ 20-25%.Ces résultats montrent que, d'une part, le fardeau de maladie dû au syndrome métabolique aux Seychelles, un pays en voie de développement, est considérable. Cette observation peut potentiellement s'appliquer à d'autres pays à un stade de développement semblable. Cela renforce le besoin de mettre en oeuvre des stratégies de santé publique afin de cibler les causes de ces désordres métaboliques, tels que le surpoids et la sédentarité. D'un point de vue du diagnostic, les trois définitions du syndrome métabolique semblent classifier un nombre semblable de personnes atteints du syndrome métabolique dans cette population. Par contre, la relativement mauvaise concordance entre ces définitions - certaines personnes identifiés comme porteurs du syndrome métabolique selon une définition ne le sont pas selon une autre - confirme la nécessité de clarifier la signification de ces différentes définitions et/ou éventuellement de développer une définition unifiée et fiable du syndrome métabolique.

Using transcription modules to identify expression clusters perturbed in Williams-Beuren syndrome.

The genetic dissection of the phenotypes associated with Williams-Beuren Syndrome (WBS) is advancing thanks to the study of individuals carrying typical or atypical structural rearrangements, as well as in vitro and animal studies. However, little is known about the global dysregulations caused by the WBS deletion. We profiled the transcriptomes of skin fibroblasts from WBS patients and compared them to matched controls. We identified 868 differentially expressed genes that were significantly enriched in extracellular matrix genes, major histocompatibility complex (MHC) genes, as well as genes in which the products localize to the postsynaptic membrane. We then used public expression datasets from human fibroblasts to establish transcription modules, sets of genes coexpressed in this cell type. We identified those sets in which the average gene expression was altered in WBS samples. Dysregulated modules are often interconnected and share multiple common genes, suggesting that intricate regulatory networks connected by a few central genes are disturbed in WBS. This modular approach increases the power to identify pathways dysregulated in WBS patients, thus providing a testable set of additional candidates for genes and their interactions that modulate the WBS phenotypes.

Impact of adjunct cytogenetic abnormalities for prognostic stratification in patients with myelodysplastic syndrome and deletion 5q.

This cooperative study assessed prognostic factors for overall survival (OS) and risk of transformation to acute myeloid leukemia (AML) in 541 patients with de novo myelodysplastic syndrome (MDS) and deletion 5q. Additional chromosomal abnormalities were strongly related to different patients' characteristics. In multivariate analysis, the most important predictors of both OS and AML transformation risk were number of chromosomal abnormalities (P<0.001 for both outcomes), platelet count (P<0.001 and P=0.001, respectively) and proportion of bone marrow blasts (P<0.001 and P=0.016, respectively). The number of chromosomal abnormalities defined three risk categories for AML transformation (del(5q), del(5q)+1 and del(5q)+ ≥ 2 abnormalities) and two for OS (one group: del(5q) and del(5q)+1; and del(5q)+ ≥ 2 abnormalities, as the other one); with a median survival time of 58.0 and 6.8 months, respectively. Platelet count (P=0.001) and age (P=0.034) predicted OS in patients with '5q-syndrome'. This study demonstrates the importance of additional chromosomal abnormalities in MDS patients with deletion 5q, challenges the current '5q-syndrome' definition and constitutes a useful reference series to properly analyze the results of clinical trials in these patients.

Sign language in Landau-Kleffner syndrome.

This article reviews the history of sign language (SL) and the rationale for its use in children with profound auditory agnosia due to Landau-Kleffner syndrome (LKS), illustrated by studies of children and adults followed for many years and rare cases from the literature. The reasons that SL was successful and brought some children out of isolation while it could not be implemented in others are discussed. The nowadays earlier recognition and treatment of LKS and better awareness of the crucial need to maintain communication have certainly improved the outcome of affected children. Alternatives to oral language, even for less severe cases, are increasingly accepted. SL can be learned at different ages with a clear benefit, but the ambivalence of the patients and their families with the world and culture of the deaf may sometimes explain its refusal or limited acceptance. There are no data to support the fear that SL learning may delay or prevent oral language recovery in children with LKS. On the contrary, SL may even facilitate this recovery by stimulating functionally connected core language networks and by helping speech therapy and auditory training.

No evidence for mutations of CTCFL/BORIS in Silver-Russell syndrome patients with IGF2/H19 imprinting control region 1 hypomethylation.

BACKGROUND: Silver-Russell syndrome (SRS) is a genetically and clinically heterogeneous disease. Although no protein coding gene defects have been reported in SRS patients, approximately 50% of SRS patients carry epimutations (hypomethylation) at the IGF2/H19 imprinting control region 1 (ICR1). Proper methylation at ICR1 is crucial for the imprinted expression of IGF2, a fetal growth factor. CTCFL, a testis-specific protein, has recently been proposed to play a role in the establishment of DNA methylation at the murine equivalent of ICR1. A screen was undertaken to assess whether CTCFL is mutated in SRS patients with hypomethylation, to explore a link between the observed epimutations and a genetic cause of the disease. METHODOLOGY/PRINCIPAL FINDINGS: DNA was obtained from 36 SRS patients with hypomethylation at ICR1. All CTCFL coding exons were sequenced and analyzed for duplications/deletions using both multiplex ligation-dependent probe amplification, with a custom CTCFL probe set, and genomic qPCR. Novel SNP alleles were analyzed for potential differential splicing in vitro utilizing a splicing assay. Neither mutations of CTCFL nor duplications/deletions were observed. Five novel SNPs were identified and have been submitted to dbSNP. In silico splice prediction suggested one novel SNP, IVS2-66A>C, activated a cryptic splice site, resulting in aberrant splicing and premature termination. In vitro splicing assays did not confirm predicted aberrant splicing. CONCLUSIONS/SIGNIFICANCE: As no mutations were detected at CTCFL in the patients examined, we conclude that genetic alterations of CTCFL are not responsible for the SRS hypomethylation. We suggest that analysis of other genes involved in the establishment of DNA methylation at imprinted genes, such as DNMT3A and DNMT3L, may provide insight into the genetic cause of hypomethylation in SRS patients.

Differences in low-grade chronic inflammation and insulin resistance in women with previous gestational diabetes mellitus and women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) and gestational diabetes mellitus (GDM) are both characterized by an increase in insulin resistance. Our goal in the present study was to measure insulin resistance (as estimated by homeostasis model assessment, sex hormone-binding globulin (SHBG) and adiponectin concentrations) and parameters of low-grade inflammation in non-diabetic, non-hyperandrogenic ovulatory women with previous GDM (pGDM) and in non-diabetic women with classic PCOS, characterized by hyperandrogenism and oligo/anovulation. PATIENTS AND DESIGN: We evaluated 20 women with PCOS, 18 women with pGDM and 19 controls, all matched according to body mass index (BMI). Fasting blood samples were drawn in all women 3-6 days after spontaneous or dydrogesterone-induced withdrawal bleeding. Body fat distribution was assessed using dual-energy X-ray absorptiometry in all women. RESULTS: After adjusting for age and percent body fat, measures of insulin resistance such as SHBG and adiponectin concentrations were decreased and central obesity was increased in women with PCOS and pGDM compared with controls (all p < 0.05). Parameters of low-grade inflammation such as serum tumor necrosis factor-alpha and highly sensitive C-reactive protein concentrations, white blood cell and neutrophil count were increased only in women with PCOS compared with BMI-matched controls (all p < 0.05). CONCLUSIONS: Certain markers of insulin resistance are increased in both women with PCOS and women with pGDM, while low-grade inflammation is increased only in PCOS. PCOS and GDM might represent specific phenotypes of one disease entity with an increased risk of cardiovascular disease, whereby women with PCOS demonstrate an augmented cardiovascular risk profile.

Human epidermal Langerhans cells express the tight junction protein claudin-1 and are present in human genetic claudin-1 deficiency (NISCH syndrome).

Claudin-1 (CLDN1) is a structural tight junction (TJ) protein and is expressed in differentiating keratinocytes and Langerhans cells in the epidermis. Our objective was to identify immunoreactive CLDN1 in human epidermal Langerhans cells and to examine the pattern of epidermal Langerhans cells in genetic human CLDN1 deficiency [neonatal ichthyosis, sclerosing cholangitis (NISCH) syndrome]. Epidermal cells from healthy human skin labelled with CLDN1-specific antibodies were analysed by confocal laser immunofluorescence microscopy and flow cytometry. Skin biopsy sections of two patients with NISCH syndrome were stained with an antibody to CD1a expressed on epidermal Langerhans cells. Epidermal Langerhans cells and a subpopulation of keratinocytes from healthy skin were positive for CLDN1. The gross number and distribution of epidermal Langerhans cells of two patients with molecularly confirmed NISCH syndrome, however, was not grossly altered. Therefore, CLDN1 is unlikely to play a critical role in migration of Langerhans cells (or their precursors) to the epidermis or their positioning within the epidermis. Our findings do not exclude a role of this TJ molecule once Langerhans cells have left the epidermis for draining lymph nodes.

Primary Sjögren's syndrome (SS) and malignant lymphoma. A retrospective cohort study of 55 patients with SS.

The aim of this study was to assess the prevalence of malignant lymphomas in patients with long-standing primary Sjögren's syndrome (pSS). We retrospectively studied a cohort of 55 patients with pSS over a mean follow-up period of 12 years. Five patients (9%) developed malignant lymphoma. The interval between the diagnoses of SS and lymphoma ranged from four to 12 years (mean = 6.5 years). The lymphoma arose in the lymph nodes in two cases, the parotid gland in one case, the lacrimal gland in one case, and the lung in one case. All five cases were B-cell low-grade lymphomas. Among our SS patients, those with extraglandular manifestations and/or a mixed cryoglobulin were at increased risk for lymphoma development. Secondary lymphoma carried a poor prognosis in our study. Three of the six SS patients who died during the follow-up period had lymphoma.

C19orf12 mutation leads to a pallido-pyramidal syndrome.

Pallido-pyramidal syndromes combine dystonia with or without parkinsonism and spasticity as part of a mixed neurodegenerative disorder. Several causative genes have been shown to lead to pallido-pyramidal syndromes, including FBXO7, ATP13A2, PLA2G6, PRKN and SPG11. Among these, ATP13A2 and PLA2G6 are inconsistently associated with brain iron deposition. Using homozygosity mapping and direct sequencing in a multiplex consanguineous Saudi Arabian family with a pallido-pyramidal syndrome, iron deposition and cerebellar atrophy, we identified a homozygous p.G53R mutation in C19orf12. Our findings add to the phenotypic spectrum associated with C19orf12 mutations.

Unusual association of diseases/symptoms: Encephalitis with herpes simplex-2 in the cerebrospinal fluid and anti-RI (ANNA-2) antibodies: an infectious or a paraneoplastic syndrome?

We report on a 70-year-old woman with partial complex status epilepticus who was initially diagnosed with herpes simplex-2 (HSV-2) encephalitis, based on brain magnetic resonance imaging (MRI) findings, cerebrospinal fluid (CSF) lymphocytic pleocytosis and HSV-2 DNA detection by polymerase chain reaction (PCR) in the CSF, but without improvement on intravenous acyclovir. Anti-Ri antibodies were positive and computed tomography (CT) investigations revealed a small cell carcinoma at biopsy suggesting paraneoplastic encephalitis. The outcome was unfavourable and the autopsy showed typical features of paraneoplastic encephalitis but no evidence of viral inclusions. This case report is interesting because: (1) it is the first report of an autopsy proven paraneoplastic widespread encephalitis with anti-Ri antibodies; (2) despite a positive HSV-2 PCR in the CSF, there was no sign of herpetic infections of the nervous system; and (3) it illustrates the fact that if paraneoplastic antibodies are usually good markers of the underlying tumour, they are not always predictive of neurological deficits.

Brugada syndrome unmasked by accidental inhalation of gasoline vapors.

Loss-of-function mutations in the gene SCN5A can cause Brugada syndrome (BrS), which is an inherited form of idiopathic ventricular fibrillation. We report the case of a 46-year-old patient, with no previous medical history, who had ventricular fibrillation after accidental inhalation of gasoline vapors. His electrocardiogram (ECG) showed a typical type-1 BrS pattern that persisted after the acute event. Genetic investigations allowed the identification of a novel SCN5A mutation leading to a frame-shift and early termination of the channel protein. Biochemical and cellular electrophysiology experiments confirmed the loss-of-function of the mutant allele. The patient was implanted with a cardioverter/defibrillator.

Lymphomes des annexes de l'oeil au cours du syndrome de Gougerot-Sjögren [Lymphomas of the ocular adnexa in Gougerot-Sjögren syndrome. Apropos of 4 cases].

The risk of malignant B cell lymphoma is increased in Sjögren's syndrome (SS). Orbital localization seems infrequent. We report 4 cases of malignant lymphoma (ML) occurring in 4 women aged 47 to 77 years, with primary SS in 3 cases, located to the conjunctiva in 2 cases, the lacrymal gland in 1 case and the eyelid in 1 case. The interval between the diagnosis of SS and orbital ML varied from 6 months to 15 years. All 4 lymphomas were of the B cell type, low histopathologic grade, with monoclonal gammopathy in 1 case. Extraocular lymphoma was initially present in 1 case. ML remained localized in 2 cases with a follow-up of 4 and 6 years. Two patients treated by excisional biopsy alone are in complete remission 3 and 6 years later. The 2 other patients treated with orbital radiotherapy and chemotherapy died rapidly (transformation into a high grade malignancy in 1 case). We conclude that clinical, immunopathologic features, as well as prognosis and treatment of ocular adnexa ML in SS are similar to those of primary ML without SS.

Williams-Beuren syndrome TRIM50 encodes an E3 ubiquitin ligase.

Williams-Beuren syndrome (WBS) is a neurodevelopmental and multisystemic disease that results from hemizygosity of approximately 25 genes mapping to chromosomal region 7q11.23. We report here the preliminary description of eight novel genes mapping within the WBS critical region and/or its syntenic mouse region. Three of these genes, TRIM50, TRIM73 and TRIM74, belong to the TRIpartite motif gene family, members of which were shown to be associated to several human genetic diseases. We describe the preliminary functional characterization of these genes and show that Trim50 encodes an E3 ubiquitin ligase, opening the interesting hypothesis that the ubiquitin-mediated proteasome pathway might be involved in the WBS phenotype.