L'arthrose érosive des doigts [Erosive hand osteoarthritis].

Erosive hand osteoarthritis is common and debilitating. Diagnosis is based on the presence of bone erosions which can appear late. Ultrasonography allows earlier diagnosis. The presence of apatite deposits could be of poor prognosis. Non pharmacological treatment includes the explanation of the inflammatory phenomena involved and the use of splints and physical therapy. Drug therapy includes analgesics, NSAIDs and infiltration of a steroid. Chondroitin sulfates have an analgesic and functional effect proven. DMARDs such as hydroxychloroquine and methotrexate have been used successfully. Some patients also benefited from isotope synoviortheses. New therapeutic ways, based on the pathophysiology of the disease, are new under evaluation.

Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection.

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 × 10(-10)), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10(-3); combined P = 1.00 × 10(-11)). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.

Dégénérescence maculaire liée à l'âge exsudative: efficacité et limites des différents traitements [Exudative age-related macular degeneration: efficacy and limits of the different treatments].

Ocular neovascularizations are responsible for irreversible loss of vision in various diseases, including age-related macular degeneration. Treatments have changed greatly, and photodynamic therapy with verteporfin has come into common use. However, the visual prognosis remains poor. The recent approval of new antiangiogenic molecules such as ranibizumab and pegaptanib should allow for new therapeutical possibilities. The unapproved ophthalmological use of bevacizumab requires further studies. This paper updates what is known about old and new neovascularization treatments: their mechanism of action, their efficacy, and their toxicity. It reviews the principal clinical studies, and concludes with the recognized recommendations. For the first time, ophthalmologists can hope not only to stabilize loss of vision, but also to improve visual acuity. Complementary treatments can now be tested in associations, concomitantly or not, with the hope of improving visual results.

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Common human melanoma-associated antigen(s) detected by monoclonal antibodies.

Hybridoma cells have been derived from a fusion between mouse myeloma cells (P3-NSI/1Ag4) and spleen cells from a mouse immunized with membrane-enriched fractions from the human melanoma cell line Me-43. Of the 26 hybrids obtained, seven secreted antibodies which reacted with the melanoma cell line used for immunoassay. The specificity of the antibodies produced by the seven positive hybrids was further investigated on 16 melanoma cell lines, 15 other tumors, and 14 lymphoblastoid cell lines. The antibodies from four positive hybrids showed a broad reactivity, whereas those from three hybrids reacted exclusively with melanoma cells. The antibodies from two of these three hybrids, alpha-Mel/5 and alpha-Mel/14, seem to be directed against common melanoma antigen(s) since they reacted with all (with one exception) of the 16 melanoma cell lines tested only with five of the 16 melanoma lines. Reciprocal binding inhibition tests using [3H]leeucine-labeled antibodies showed that alpha-Mel/5 and alpha-Mel/14 antibodies were directed against different antigenic determinants.

Comment tes médecins de famille prennent-ils en charge l'hypothyroïdie infraclinique [How do Swiss family physicians treat subclinical hypothyroidism?].

L'hypothyroïdie infraclinique est fréquemment rencontrée et sa prévalence augmente avec l'âge. Les recommandations relatives au dépistage et au traitement de l'hypothyroïdie infraclinique sont controversées. Une enquête internationale auprès des médecins de famille, à laquelle la Suisse a participé, a mis en évidence de fortes variations dans la prise en charge de l'hypothyroïdie infraclinique entre les pays. Ces différences de traitement traduisent avant tout le manque de données fiables quant à la prise en charge de cette condition. L'essai clinique randomisé européen TRUST devrait permettre de clarifier les indications pour le dépistage et la substitution par thyroxine. Une collaboration avec les médecins de famille et le soutien des Instituts universitaires de médecine générale à Lausanne et à Berne pour le recrutement des patients devraient permettre d'obtenir des données directement applicables à une population représentative de la médecine ambulatoire. Subclinical hypothyroidism is a common condition, and its prevalence increases with age. Currently, guidelines regarding the screening and treatment of subclinical hypothyroidism are controversial. An international survey of general practitioners (GPs), to which Swiss GPs also contributed, showed large inter-country variations in treatment strategies for subclinical hypothyroidism. These differences are mainly explained by the lack of strong evidence for the management of this condition. The European randomized-controlled clinical trial TRUST should help clarify recommendations for screening and thyroxin replacement for the elderly with subclinical hypothyroidism. Working in close collaboration with GPs in Switzerland for the recruitment of patients will ensure that the findings from this study will be applicable to primary care settings.

Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis.

Uromodulin is expressed exclusively in the thick ascending limb and is the most abundant protein excreted in normal urine. Variants in UMOD, which encodes uromodulin, are associated with renal function, and urinary uromodulin levels may be a biomarker for kidney disease. However, the genetic factors regulating uromodulin excretion are unknown. We conducted a meta-analysis of urinary uromodulin levels to identify associated common genetic variants in the general population. We included 10,884 individuals of European descent from three genetic isolates and three urban cohorts. Each study measured uromodulin indexed to creatinine and conducted linear regression analysis of approximately 2.5 million single nucleotide polymorphisms using an additive model. We also tested whether variants in genes expressed in the thick ascending limb associate with uromodulin levels. rs12917707, located near UMOD and previously associated with renal function and CKD, had the strongest association with urinary uromodulin levels (P<0.001). In all cohorts, carriers of a G allele of this variant had higher uromodulin levels than noncarriers did (geometric means 10.24, 14.05, and 17.67 μg/g creatinine for zero, one, or two copies of the G allele). rs12446492 in the adjacent gene PDILT (protein disulfide isomerase-like, testis expressed) also reached genome-wide significance (P<0.001). Regarding genes expressed in the thick ascending limb, variants in KCNJ1, SORL1, and CAB39 associated with urinary uromodulin levels. These data indicate that common variants in the UMOD promoter region may influence urinary uromodulin levels. They also provide insights into uromodulin biology and the association of UMOD variants with renal function.

Evolutionary and ecological significance of non-shivering thermogenesis in the common vole

La production endogène à long terme de chaleur, même au repos, est une adaptation que l'on retrouve chez les animaux à sang chaud (les oiseaux et les mammifères). Cette production de chaleur a comme but le maintien d'une température constante du corps indépendamment de la température extérieure. A cette fin, les mammifères ont développé une forme de tissu spécialisé nommé tissu adipeux brun (BAT). Ce tissu est responsable de la conversion de nourriture en chaleur, procédé appelé thermogenèse sans frisson (NST = non-shivering thermogenesis). Durant ce procédé la uncoupling protein 1 (UCP1) convertit, au sein des mitochondries, la nourriture en chaleur au lieu de produire de l'ATP, molécule utilisée comme énergie cellulaire. On suppose que cette inefficacité de la conversion de la nourriture en ATP dans le BAT influence l'homéostasie de l'énergie, l'allocation des ressources ainsi que la régulation de processus gourmant en énergie comme la croissance et la reproduction. Afin de maintenir une température du corps constante, les mammifères doivent ajuster leur NST en fonction de la température ambiante. La NST devrait être donc plus importante que la croissance et la reproduction durant l'hiver que lors l'été/à haute altitude qu'à basse altitude. En effet, plusieurs études ont déjà démontré la dépendance de la NST aux divers paramètres environnementaux. Par contre, l'héritabilité de la NST ainsi que sa relation avec d'autres traits de caractère, ne sont que très peu connus, ceci malgré l'importance d'une telle information afin de pouvoir comprendre son potentiel évolutif. L'étude de l'importance évolutive et écologique sur la NST chez les campagnols des champs (Microtus arvalis) fut donc le but cette thèse de doctorat. Grâce aux informations collectées sur 4 générations de campagnols (chapitre 1), une dépendance saisonnière et journalière de la NST a été démontrée: elle augmente lors des périodes froides et diminue lors de la lactation. On a démontré que bien qu'étant plastique, la variation de la NST a une composante génétique significative. Elle est corrélée avec le taux d'activité métabolique au repos indiquant des contraintes intrinsèques. A l'aide d'une expérience de jardin commune, on a pu démontrer dans le chapitre 2 que les campagnols habitant en altitude ont une capacité génétique de thermogenèse sans frisson plus haute que celles de basse altitude. Ils produisent des portées plus petites et leur descendance grandit moins vite, surtout à partir du 10ème jour ce qui coïncide avec le début de la production de chaleur endogène. En choisissant artificiellement des campagnols avec une NST faible ou grande, on a pu démontrer une relation entre la NST et la développement de la masse corporelle. Les campagnols avec une haute NST grandissent plus lentement et sont plus légères à l'âge adulte que celles ayant une basse NST. A l'aide d'un croisement interligne entre les campagnols sélectionnés (avec basse et haute NST), on a pu montrer dans le chapitre 3 des effets « parent-of-origin >> du développement massique de la descendance, indiquant une empreinte génétique parentale. Cela veut dire que l'expression d'un allele dépend de l'origine parentale. De plus, des effets « parent-of-origin » des taux de base de norépinephrine et d'irisine ont pu être trouvés. Ces hormones sont connues pour influencer non seulement la TSF mais aussi d'autres caractéristiques. Ces influences ouvrent la voie à de nouvelles études sur la relation entre la TSF et l'histoire de vie. Dans le chapitre 4 on a démontré des effets à long terme de l'allocation des ressources en manipulant la taille des portées qui ont abouti à des différences dans l'investissement dans la reproduction et de la croissance de la descendance à la fois dans le cas de la reproduction manipulé et aussi dans le non - manipulée entre les femelles avec portées agrandies et réduites. Ensemble, ces résultats mettent en évidence le rôle central de la NST dans l'allocation des ressources sur la base d'un compromis entre le maintien et la croissance et ainsi transforme l'histoire de vie des mammifères. Ces études montrent comment les mammifères peuvent répondre rapidement à court et à long terme (c'est-à-dire par des réponses génétiques ou plastiques) à un changement rapide du climat. On montre aussi qu'il y a probablement une corrélation entre l'histoire de vie et des changements du comportement. Finalement mes résultats ont montré un lien étroit entre la NST et la croissance et les dimensions du corps. Ces résultats indiquent que le tissu adipeux brun et la NST pourraient être une cible thérapeutique intéressante pour traiter l'obésité.

Approche diagnostique de l'hyponatrémie [Hyponatremia: diagnostic approach].

Hyponatremia is the most common electrolyte disorder in hospitalized patients and may be associated with non negligible morbidity and mortality. Here we summerize its diagnostic approach based on the physiopathology. Assessment of volume status, measurement of plasma and urinary osmolality remain key steps in the management of this electrolyte disorder.

Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression.

Hypertension and chronic kidney disease (CKD) are complex traits representing major global health problems. Multiple genome-wide association studies have identified common variants in the promoter of the UMOD gene, which encodes uromodulin, the major protein secreted in normal urine, that cause independent susceptibility to CKD and hypertension. Despite compelling genetic evidence for the association between UMOD risk variants and disease susceptibility in the general population, the underlying biological mechanism is not understood. Here, we demonstrate that UMOD risk variants increased UMOD expression in vitro and in vivo. Uromodulin overexpression in transgenic mice led to salt-sensitive hypertension and to the presence of age-dependent renal lesions similar to those observed in elderly individuals homozygous for UMOD promoter risk variants. The link between uromodulin and hypertension is due to activation of the renal sodium cotransporter NKCC2. We demonstrated the relevance of this mechanism in humans by showing that pharmacological inhibition of NKCC2 was more effective in lowering blood pressure in hypertensive patients who are homozygous for UMOD promoter risk variants than in other hypertensive patients. Our findings link genetic susceptibility to hypertension and CKD to the level of uromodulin expression and uromodulin's effect on salt reabsorption in the kidney. These findings point to uromodulin as a therapeutic target for lowering blood pressure and preserving renal function.

A taxonomical re-evaluation of the Valais chromosome race of the common shrew Sorex araneus (Insectivora: Soricidae)

The common shrew Sorex araneus Linnaeus, 1758 is subject to intense chromosomal polymorphism. About 65 chromosome races are presently known. One of these chromosome races (the Valais race) is karyologically, morphologically, biochemically, and genetically clearly distinct from all other chromosome races of the species. Recent studies of hybrid zones between the Valais race and other chromosome races in the Swiss and French Alps add further strong evidence for the specific taxonomic status of the Valais race. Chromosomes and diagnostic protein markers reveal sharp frequency clines and strong heterozygote deficits. In one hybrid zone, the maintenance of the strong genetic differentiation of the hybridizing taxa was confirmed by a study with autosomal microsatellites indicating minimal gene flow. A microsatellite marker on the Y-chromosome showed complete absence of male mediated gene flow suggesting hybrid male sterility. To clarify the taxonomic status of this taxon, additional analyses were conducted. A morphometric analysis of the mandible indicated the Valais race is morphologically as distinct from neighbouring chromosome races of S. araneus as from other related Sorex species. In a phylogeny based on complete mitochondrial DNA cytochrome b gene sequences, the Valais race clearly appears as the sister taxon to all other races of S. araneus. Therefore, the chromosome race Valais of S. araneus herein is elevated to specific status and the name Sorex antinorii Bonaparte, 1840 is applied.

Common variants near MC4R are associated with fat mass, weight and risk of obesity.

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.

Fermeture percutanée de l'auricule gauche: un nouvel espoir pour le patient en fibrillation auriculaire [Percutaneous closure of left atrial appendage: a new hope for patients with atrial fibrillation?].

Atrial fibrillation (AF) is the most common cardiac arrhythmia. The risk of thromboembolic events is important, and at that time, there is no definite treatment for AF. Oral anticoagulation also represents a hemorrhagic risk factor. Ninety percent of atrial thrombi are located within the left atrial appendage. The percutaneous closure of this left atrial appendage with a device has been shown to decrease thromboembolic events even after interruption of oral anticoagulation as compared to warfarin in a recent randomized study. Recent data support this innovative technique as a reasonable alternative to long term anticoagulation in patients at high risk of bleeding.

Linking supply to demand: the neuronal monocarboxylate transporter MCT2 and the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid receptor GluR2/3 subunit are associated in a common trafficking process.

MCT2 is the major neuronal monocarboxylate transporter (MCT) that allows the supply of alternative energy substrates such as lactate to neurons. Recent evidence obtained by electron microscopy has demonstrated that MCT2, like alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA) receptors, is localized in dendritic spines of glutamatergic synapses. Using immunofluorescence, we show in this study that MCT2 colocalizes extensively with GluR2/3 subunits of AMPA receptors in neurons from various mouse brain regions as well as in cultured neurons. It also colocalizes with GluR2/3-interacting proteins, such as C-kinase-interacting protein 1, glutamate receptor-interacting protein 1 and clathrin adaptor protein. Coimmunoprecipitation of MCT2 with GluR2/3 and C-kinase-interacting protein 1 suggests their close interaction within spines. Parallel changes in the localization of both MCT2 and GluR2/3 subunits at and beneath the plasma membrane upon various stimulation paradigms were unraveled using an original immunocytochemical and transfection approach combined with three-dimensional image reconstruction. Cell culture incubation with AMPA or insulin triggered a marked intracellular accumulation of both MCT2 and GluR2/3, whereas both tumor necrosis factor alpha and glycine (with glutamate) increased their cell surface immunolabeling. Similar results were obtained using Western blots performed on membrane or cytoplasm-enriched cell fractions. Finally, an enhanced lactate flux into neurons was demonstrated after MCT2 translocation on the cell surface. These observations provide unequivocal evidence that MCT2 is linked to AMPA receptor GluR2/3 subunits and undergoes a similar translocation process in neurons upon activation. MCT2 emerges as a novel component of the synaptic machinery putatively linking neuroenergetics to synaptic transmission.

Absence of association between specific common variants of the obesity-related FTO gene and psychological and behavioral eating disorder phenotypes.

Extensive population-based genome-wide association studies have identified an association between the FTO gene and BMI; however, the mechanism of action is still unknown. To determine whether FTO may influence weight regulation through psychological and behavioral factors, seven single-nucleotide polymorphisms (SNPs) of the FTO gene were genotyped in 1,085 individuals with anorexia nervosa (AN) and 677 healthy weight controls from the international Price Foundation Genetic Studies of Eating Disorders. Each SNP was tested in association with eating disorder phenotypes and measures that have previously been associated with eating behavior pathology: trait anxiety, harm-avoidance, novelty seeking, impulsivity, obsessionality, compulsivity, and concern over mistakes. After appropriate correction for multiple comparisons, no significant associations between individual FTO gene SNPs and eating disorder phenotypes or related eating behavior pathology were identified in cases or controls. Thus, this study found no evidence that FTO gene variants associated with weight regulation in the general population are associated with eating disorder phenotypes in AN participants or matched controls. © 2011 Wiley-Liss, Inc.