Epidemiological, Clinical, and Therapeutic Profile of Uveitis in Multiple Sclerosis: A Multicenter Study.

INTRODUCTION: Uveitis may occur during approximately 1-3% of MS patients, corresponding to 10 times higher than in the general population. The development of uveitis is not currently considered as an inflammatory relapse of MS. There are no clinical guidelines for treating. MS with concomitant uveitis requiring systemic treatment. PURPOSES: To analyze clinical and therapeutic characteristics of uveitis in patients with MS and the impact of MS treatment on the progression of uveitis. MATERIALS & METHODS: We conducted a retrospective, observational, multicenter study in France about 54 patients. RESULTS: The form of MS most frequently associated with uveitis in our study was the relapsing-remitting form (85%). The mean time of onset of uveitis was 15 months before the diagnosis of MS. The most frequent form of uveitis was bilateral panuveitis (43%), non-granulomatous (61%), synechial (52%) and non-hypertonic (93%) with progressive onset (65%) and chronic course (66%). CONCLUSION: MS-associated uveitis occurs most frequently before the diagnosis of relapsing-remitting MS in the form of panuveitis or intermediate uveitis, which is mildly inflammatory and whose main complications are macular edema, cataract and venous vasculitis. Despite their chronicity, these uveitis cases have a good visual prognosis and teriflunomide appears to have a positive effect on progression.

Choroidal neovascularization and MEWDS like reaction in a child: A rare case.

PURPOSE: To report a case of choroidal neovascularization (CNV) associated with Multiple Evanescent White Dot Syndrome (MEWDS) in a child. STUDY DESIGN: Case report. RESULTS: A 13-year-old child visited us with a month-long history of blurred vision in his right eye. His right fundus showed several subretinal white dots and an atrophic macular lesion corresponding to a CNV. Angiography and optical coherence tomography (OCT) were consistent with the diagnosis of MEWDS. The patient's condition poorly improved after an intravitreal injection of anti-vascular endothelial growth factor (anti VEGF) in his right eye. CONCLUSIONS: We reported the case of CNV associated with MEWDS like reaction. The hypothesis of a triggered-MEWDS was highly suspected but no cause was found, which is often the case in paediatric inflammatory eye disorders. Long-term follow-up is needed to judge the evolution.

Localization, fate and interactions of Emilin-1 in human skin.

OBJECTIVE: Emilin-1 is a versatile protein abundant in tissues where resilience and elastic recoil are prominent and interacting with components of the extracellular matrix. Still, little is known about Emilin-1 in the skin. Therefore, we investigated Emilin-1 in the skin, its localization, its fate upon ageing, its interactions with other proteins and the effect of its knockdown. METHODS: Skin explants from young or old Caucasian women, immunofluorescently labelled by anti-Emilin-1, anti-Fibrillin-1 and anti-Elastin antibodies, were analysed using confocal microscopy. Skin explants subjected to UV-induced skin ageing were also analysed. Colocalization of Emilin-1 with Collagen IV, Fibrillin-1 and Elastin was studied by multiphoton microscopy and co-immunoprecipitation. Finally, the effect of Emilin-1 extinction was studied by producing small interfering RNA (siRNA) knockdown fibroblasts and by analysing the outcome on selected genes. RESULTS: In skin sections from young donors, Emilin-1 localizes similarly to Elastin and Fibrillin-1. In the papillary dermis, it shows clear and ramified structures, perpendicular to the dermo-epidermal junction that are reminiscent of the oxytalan fibres. In the reticular dermis, Emilin-1 signal appears identical to that of the elastic fibres network. Upon intrinsic or UV-induced ageing, the signal associated with Emilin-1 is drastically reduced and disorganized. Multiphoton microscopy study shows that, as expected, Emilin-1 colocalizes with Elastin. It also colocalizes with Collagen IV in the basement membrane and within dermal fibroblasts. Interaction of Emilin-1 with Elastin and Collagen IV was also found by co-immunoprecipitation. It also reveals interaction with Laminin-5. Finally, siRNA-mediated knockdown of EMILIN-1 show little effect on the expression level of the 61 genes we studied. The most striking change is a downregulation of fibroblast growth factor receptor 2 that show a decrease similar to that of EMILIN-1 itself and after 8 days a downregulation of COL6A1. CONCLUSION: In skin, Emilin-1 locates in the dermis, up to the basement membrane, interacting with components of the extracellular matrix but also with the anchoring complex. These interactions are important for cell adhesion, migration, proliferation and would suggest that Emilin-1 might be important for maintaining the 3D structure of the extracellular matrix.

OBJECTIF: Emilin-1 est une protéine polyvalente, abondante dans les tissus où résilience et élasticité sont importantes et qui interagit avec la matrice extracellulaire. Pourtant, la protéine Emilin-1 a été peu étudiée dans la peau. Nous avons donc étudié sa localisation, son devenir lors du vieillissement, ses interactions avec d'autres protéines et l'effet de son inhibition dans la peau. MÉTHODES: Des explants de peau de femmes caucasiennes jeunes ou âgées, marqués par immunofluorescence avec des anticorps anti-Emilin-1, anti-Fibrilline-1 et anti-Élastine, ont été analysés par microscopie confocale. Des explants cutanés soumis au soumis aux UV pour mimer un photo-vieillissement ont également été analysés. La co-localisation de l'Emilin-1 avec le collagène IV, la fribrilline-1 et l'élastine a été étudiée par microscopie multiphotonique et par co-immunoprécipitation. Enfin, l'effet de l'inhibition de l'expression de la protéine Emilin-1 par interférence ARN a été étudié sur 61 gènes. RÉSULTATS: Dans les coupes de peau de jeunes donneurs, Emilin-1 est localisée comme l'élastine et la fibrilline-1. Dans le derme papillaire, elle présente des structures claires et ramifiées, perpendiculaires à la jonction dermo-épidermique, qui font penser aux fibres d'oxytalane. Dans le derme réticulaire, le signal de l'Emilin-1 apparaît identique à celui du réseau de fibres élastiques. Lors du vieillissement intrinsèque ou induit par les UV, le signal associé à Emilin-1 est considérablement réduit et désorganisé. Une étude en microscopie multiphotonique montre que l'Emilin-1 est co-localisée avec de l'élastine. Elle est aussi co-localisée avec le collagène IV dans la membrane basale et dans les fibroblastes du derme. La co-immunoprécipitation montre l'existence d'interactions entre l'Emilin-1 et l'Elastine ou le collagène IV. Une interaction avec la laminine-5 a aussi été mise en évidence. Enfin, l'inhibition de l'expression de l'EMILIN-1 n'a que peu d'effet sur l'expression des 61 gènes étudiés. Le changement le plus frappant est une diminution de l'expression de FGFR2 (récepteur 2 du facteur de croissance des fibroblastes), diminution similaire à celle d'EMILIN-1, et, après 8 jours, une diminution de l'expression de COL6A1. CONCLUSION: Dans la peau, Emilin-1 se localise dans le derme, jusqu'à la membrane basale, et interagit avec les composants de la matrice extracellulaire mais aussi avec les complexes d'ancrage. Ces interactions sont importantes pour l'adhésion, la migration, la prolifération cellulaire et suggéreraient qu'Emilin-1 pourrait être important pour le maintien de la structure de la matrice extracellulaire.

Exposure to acute electromagnetic radiation of mobile phone exposure range alters transiently skin homeostasis of a model of pigmented reconstructed epidermis.

Exposure to electromagnetic radiations (EMR) produced by mobile phone concerns half the world's population and raises the problem of their impact on human health. In this study, we looked at the effects of mobile phone exposure (GSM basic, 900 MHz, SAR 2 mW g(-1) , 6 h) on a model of pigmented skin. We have analysed the expression and localization of various markers of keratinocyte and melanocyte differentiation 2, 6, 18 and 24 h after EMR exposure of reconstructed epidermis containing either only keratinocytes or a combination of keratinocytes and melanocytes grown on dead de-epidermized dermis, using histology, immunohistochemistry and Western blot. No changes were found in epidermal architecture, localization of epidermal markers, presence of apoptotic cells and the induction of p53 in both types of epidermis (with or without melanocytes) after exposure to EMR. In pigmented reconstructs, no change in the location and dendricity of melanocytes and in melanin transfer to neighbouring keratinocytes was detected after EMR exposure. Loricrin, cytokeratin 14 were significantly decreased at 6 h. The level of all markers increased at 24 h as compared to 6 h post-EMR exposure, associated with a significant decrease of the 20S proteasome activity. Our data indicate that exposure to 900 MHz frequency induces a transient alteration of epidermal homoeostasis, which may alter the protective capacity of the skin against external factors. Presence or absence of melanocytes did not modify the behaviour of reconstructs after EMR exposure.

Ultrastructural assessments of the melanosome distribution patterns and pigmentation features in human epidermal cells after UV irradiation and kojic acid treatment.

It is well-known that skin pigmentation depends, among others, on number, aggregation and distribution of melanosomes in the epidermis. Here we describe a correlative microscopy-based ultrastructural approach that investigates the spatial distribution and pigmentation features of the melanosomes within melanocytes and keratinocytes. Data obtained from control skin, ultraviolet (UV)-stimulated tissue and kojic acid-treated UV-irradiated explants are compared. We introduce original parameters for the evaluation of the aggregation and pigmentation features of the melanosomes: the aggregation and pigmentation indexes. The aggregation index evaluates the presence of clustered melanosomes when the pigmentation index expresses the electron-density level of the pigment granules. The present study demonstrates that the last parameters clearly express histological effects induced by UVB irradiation. Results indicate that UV light did not change the number of melanosomes within either melanocytes or keratinocytes, but it definitely modified the distribution patterns of the pigment granules in both cell types. It also enhanced the pigmentation state of the epidermal cells. Moreover, statistical analysis concerning keratinocytes discloses a significant decrease in the mean pigmentation index when explants exposed to UV light were treated with kojic acid. Obviously, the present numerical findings point out the relevance of the introduced parameters to characterize the pigmentation state of skin.

Linkage analysis of candidate myelin genes in familial multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. A complex genetic etiology is thought to underlie susceptibility to this disease. The present study was designed to analyze whether differences in genes that encode myelin proteins influence susceptibility to MS. We performed linkage analysis of MS to markers in chromosomal regions that include the genes encoding myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), oligodendrocyte myelin glycoprotein (OMGP), and myelin oligodendrocyte glycoprotein (MOG) in a well-characterized population of 65 multiplex MS families consisting of 399 total individuals, 169 affected with MS and 102 affected sibpairs. Physical mapping data permitted placement of MAG and PLP genes on the Genethon genetic map; all other genes were mapped on the Genethon genetic map by linkage analysis. For each gene, at least one marker within the gene and/or two tightly linked flanking markers were analyzed. Marker data analysis employed a combination of genetic trait model-dependent (parametric) and model-independent linkage methods. Results indicate that MAG, MBP, OMGP, and PLP genes do not have a significant genetic effect on susceptibility to MS in this population. As MOG resides within the MHC, a potential role of the MOG gene could not be excluded.

Vocal cord and pharyngeal weakness with autosomal dominant distal myopathy: clinical description and gene localization to 5q31.

Distal myopathy refers to a heterogeneous group of disorders in which the initial manifestations are weakness and atrophy of the hands and feet. We report a family segregating an autosomal dominant distal myopathy, with multiple affected individuals in whom vocal cord and pharyngeal weakness may accompany the distal myopathy, without involvement of the ocular muscles. To our knowledge, this pedigree displays a distinct distal myopathy with the added features of pharyngeal and vocal cord dysfunction (VCPDM) that has not been previously reported. We mapped the MPD2 gene for VCPDM to chromosome 5q within a 12-cM linkage interval between markers D5S458 and D5S1972 in a large pedigree (a maximum LOD score of 12.94 at a recombination fraction of 0 for D5S393) and combined genome screening and DNA pooling successfully adapted to fluorescent markers. This technique provides for the possibility of fully automated genome scans.

A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex. The Multiple Sclerosis Genetics Group.

Multiple sclerosis (MS), an inflammatory autoimmune demyelinating disorder of the central nervous system, is the most common cause of acquired neurological dysfunction arising in the second to fourth decades of life. A genetic component to MS is indicated by an increased relative risk of 20-40 to siblings compared to the general population (lambda s), and an increased concordance rate in monozygotic compared to dizygotic twins. Association and/or linkage studies to candidate genes have produced many reports of significant genetic effects including those for the major histocompatability complex (MHC; particularly the HLA-DR2 allele), immunoglobulin heavy chain (IgH), T-cell receptor (TCR) and myelin basic protein (MBP) loci. With the exception of the MHC, however, these results have been difficult to replicate and/or apply beyond isolated populations. We have therefore conducted a two-stage, multi-analytical genomic screen to identify genomic regions potentially harbouring MS susceptibility genes. We genotyped 443 markers and 19 such regions were identified. These included the MHC region on 6p, the only region with a consistently reported genetic effect. However, no single locus generated overwhelming evidence of linkage. Our results suggest that a multifactorial aetiology, including both environmental and multiple genetic factors of moderate effect, is more likely than an aetiology consisting of simple mendelian disease gene(s).

[Surgical treatment of Graves' disease (author's transl)]. / Traitement chirugical de la maladie de Basedow.

135 patients with goiter treated for Graves' disease have been followed during 10 years (12) 5 to 1 years (64) 1 to 5 years (59) after surgical treatment. The incidence of hypothyroidism increases with the delay (23 % after 1 year, 32,6 % after 5 years, 37,8 % after 10 years). The incidence of relapses is similar (7,4 % after 1 year, 15,5 % after 5 years, 22,2 % after 10 years). There is no predictive value of clinical and biological data. Only the limits of thyroidectomy and the pathological findings can inform on the post operative evolution : relapses are more frequent after subtotal bilateral thyroidectomy, hypothyroidism is more frequent after one total lobectomy + subtotal lobectomy on the other side and in the case of large lymphocytic infiltration.

Sex differences in the adrenergic response to hypoglycemic stress in human.

We have found different patterns of adrenergic response to insulin-induced hypoglycemia in men and women. The differences involve the readiness of adrenergic reactivity, the magnitude of the responses, and the nature of secreted amines. In men, a strong and transient discharge of epinephrine (E) is observed in plasma, corresponding to a great increase in the urinary level of this amine in the 2 h period following insulin. In women, the adrenergic response is delayed and consists of moderately increased amounts of E and norepinephrine (NE) which persist in plasma for a longer period. From the correlations observed between urinary amount and the increase of plasmatic catecholamines after 30, 45, and 60 min, it may be assumed that urinary data may reflect the cumulative plasma levels of catecholamines in the corresponding period, but not the precise pattern of plasmatic changes. Our findings show that the differences in adrenergic behavior previously observed in men and women under the effect of psychological stress, may also be induced by a metabolic stimulus such a insulin hypoglycemia; however, women, but not men, exhibit a mild release of NE under this metabolic stress.