Altered Chromosomal Positioning, Compaction, and Gene Expression with a Lamin A/C Gene Mutation

Lamins A and C, encoded by the LMNA gene, are filamentous proteins that form the core scaffold of the nuclear lamina. Dominant LMNA gene mutations cause multiple human diseases including cardiac and skeletal myopathies. The nuclear lamina is thought to regulate gene expression by its direct interaction with chromatin. LMNA gene mutations may mediate disease by disrupting normal gene expression.To investigate the hypothesis that mutant lamin A/C changes the lamina's ability to interact with chromatin, we studied gene misexpression resulting from the cardiomyopathic LMNA E161K mutation and correlated this with changes in chromosome positioning. We identified clusters of misexpressed genes and examined the nuclear positioning of two such genomic clusters, each harboring genes relevant to striated muscle disease including LMO7 and MBNL2. Both gene clusters were found to be more centrally positioned in LMNA-mutant nuclei. Additionally, these loci were less compacted. In LMNA mutant heart and fibroblasts, we found that chromosome 13 had a disproportionately high fraction of misexpressed genes. Using three-dimensional fluorescence in situ hybridization we found that the entire territory of chromosome 13 was displaced towards the center of the nucleus in LMNA mutant fibroblasts. Additional cardiomyopathic LMNA gene mutations were also shown to have abnormal positioning of chromosome 13, although in the opposite direction.These data support a model in which LMNA mutations perturb the intranuclear positioning and compaction of chromosomal domains and provide a mechanism by which gene expression may be altered

Cardiovascular health and particulate vehicular emissions: a critical evaluation of the evidence

A major public health goal is to determine linkages between specific pollution sources and adverse health outcomes. This paper provides an integrative evaluation of the database examining effects of vehicular emissions, such as black carbon (BC), carbonaceous gasses, and ultrafine PM, on cardiovascular (CV) morbidity and mortality. Less than a decade ago, few epidemiological studies had examined effects of traffic emissions specifically on these health endpoints. In 2002, the first of many studies emerged finding significantly higher risks of CV morbidity and mortality for people living in close proximity to major roadways, vs. those living further away. Abundant epidemiological studies now link exposure to vehicular emissions, characterized in many different ways, with CV health endpoints such as cardiopulmonary and ischemic heart disease and circulatory-disease-associated mortality; incidence of coronary artery disease; acute myocardial infarction; survival after heart failure; emergency CV hospital admissions; and markers of atherosclerosis. We identify numerous in vitro, in vivo, and human panel studies elucidating mechanisms which could explain many of these cardiovascular morbidity and mortality associations. These include: oxidative stress, inflammation, lipoperoxidation and atherosclerosis, change in heart rate variability (HRV), arrhythmias, ST-segment depression, and changes in vascular function (such as brachial arterial caliber and blood pressure). Panel studies with accurate exposure information, examining effects of ambient components of vehicular emissions on susceptible human subjects, appear to confirm these mechanisms. Together, this body of evidence supports biological mechanisms which can explain the various CV epidemiological findings. Based upon these studies, the research base suggests that vehicular emissions are a major environmental cause of cardiovascular mortality and morbidity in the United States. As a means to reduce the public health consequences of such emissions, it may be desirable to promulgate a black carbon (BC) PM2.5 standard under the National Ambient Air Quality Standards, which would apply to both on and off-road diesels. Two specific critical research needs are identified. One is to continue research on health effects of vehicular emissions, gaseous as well as particulate. The second is to utilize identical or nearly identical research designs in studies using accurate exposure metrics to determine whether other major PM pollutant sources and types may also underlie the specific health effects found in this evaluation for vehicular emissions

Immunohistochemistry on a Panel of Emery-Dreifuss Muscular Dystrophy Samples Reveals Nuclear Envelope Proteins as Inconsistent Markers for Pathology

Reports of aberrant distribution for some nuclear envelope proteins in cells expressing a few Emery–Dreifuss muscular dystrophy mutations raised the possibility that such protein redistribution could underlie pathology and/or be diagnostic. However, this disorder is linked to 8 different genes encoding nuclear envelope proteins, raising the question of whether a particular protein is most relevant. Therefore, myoblast/fibroblast cultures from biopsy and tissue sections from a panel of nine Emery–Dreifuss muscular dystrophy patients (4 male, 5 female) including those carrying emerin and FHL1 (X-linked) and several lamin A (autosomal dominant) mutations were stained for the proteins linked to the disorder. As tissue-specific nuclear envelope proteins have been postulated to mediate the tissue-specific pathologies of different nuclear envelopathies, patient samples were also stained for several muscle-specific nuclear membrane proteins. Although linked proteins nesprin 1 and SUN2 and muscle-specific proteins NET5/Samp1 and Tmem214 yielded aberrant distributions in individual patient cells, none exhibited defects through the larger patient panel. Muscle-specific Tmem38A normally appeared in both the nuclear envelope and sarcoplasmic reticulum, but most patient samples exhibited a moderate redistribution favouring the sarcoplasmic reticulum. The absence of striking uniform defects in nuclear envelope protein distribution indicates that such staining will be unavailing for general diagnostics, though it remains possible that specific mutations exhibiting protein distribution defects might reflect a particular clinical variant. These findings further argue that multiple pathways can lead to the generally similar pathologies of this disorder while at the same time the different cellular phenotypes observed possibly may help explain the considerable clinical variation of EDMD

L'électrocardiogramme systématique (variations chez les patientes asymptomatiques)

[Résumé en français]Actuellement, l'électrocardiogramme systématique préopératoire n'est pas recommandé chez les sujets de moins de 40 ans, sans facteur de risque, en l'absence de symptomatologie. Cependant, de nouveaux syndromes sont mieux connus ou nouvellement décrits. Il s'agit principalement du syndrome de Wolff Parkinson White, la dysplasie arythmogène du ventricule droit ou le syndrome de Brugada qui sont responsables pour une part de la mort subite d'effort chez le sujet jeune. Certaines études ont montré des variations selon l'origine ethnique. Il s'agit d'une étude rétrospective de 1241 dossiers portants sur les électrocardiogrammes de patientes jeunes asymptomatiques hospitalisées dans le service d'orthogénie de l'hôpital Avicenne, pour évaluer la proportion d'anomalies. D'après les résultats de notre étude, il semblerait que le risque de survenue d'un syndrome de Wolff Parkinson White et d'un syndrome de Brugada soit plus fort dans la population asiatique et noirePARIS13-BU Serge Lebovici (930082101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

INTERETS DE LA RECHERCHE D'UNE HTA SECONDAIRE EN PRESENCE D'UNE POPULATION D'HYPERTENDUS RESISTANT A UN TRAITEMENT MEDICAL BIEN CONDUIT

PARIS13-BU Serge Lebovici (930082101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Peptide natriurétique de type B et dépistage des dysfonctions ventriculaires gauches dans une population diabétique de rtype 2 asymptomatique

REIMS-BU Santé (514542104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Myopathie familiale du quadriceps avec atteintes cardiaques (études phénotypique, génotypique et biochimique)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Prise en charge cardiologique des patients diabétiques de type II (étude rétrospective de 50 patients consécutifs hospitalisés dans le service de cardiologie)

Le diabète est un problème de santé publique en raison des complications. La prévalence du diabète de type 11 est en constante augmentation. Si la rétinopathie est la complication la plus fréquente, les coronaropathies, aggravées par leur caractère asymptomatique, constituent la cause majeure de décès. Cette étude évalue : les caractéristiques et la prise en charge cardiologique d une population de diabétiques de type II ; la différence selon l existence ou non de symptômes. Population et méthodes : Ont été inclus tous les patients consécutifs, diabétiques de type II , adressés en 1999-2000 pour bilan cardiaque. Les patients avaient un examen clinique complet, un ECG, une échographie ainsi qu une épreuve d effort. En cas de doute (n=6) ou d épreuve d effort non interprétable (n= 12), une scintigraphie myocardique était pratiquée. En présence d une ischémie, une coronarographie était réalisée (n = 20).Lorsqu une cardiopathie était découverte lors du bilan initial, la coronarographie était réalisée d emblée (n= 14).Résultats:Cette étude a inclus 50 patients (âge moyen: 60+/-8,2 ans; 66% d hommes); 34% des patients sont asymptomatiques sur le plan coronaire. Tous les patients ont au moins deux autres facteurs de risque (hypertension artérielle: 76% ; dvslipidémie: 70% ; surpoids : 50% ; tabac : 48%).La durée moyenne du diabète chez les patients asymptomatiques est de 17,3 +/- 5,1 ans et de 10, 1 +1-3,6 ans chez les patients symptomatiques.L ECG est anormal chez 40% des patients. Les échographies retrouvent des troubles de la cinétique segmentaire chez 27,6 % des patients ; une cardiopathie est découverte chez 13 patients: ardiopathie hypertrophique (n=8) ou dilatée (n=5). L épreuve d effort est pathologique chez 38 % des patients et ininterprétable chez 38,2 % . Les scintigraphies myocardiques sont positives chez 51,2 % des patients. Une coronarographie est confirmée chez 72,4 % de la population : atteinte monotronculaire (30,8%), bitronculaire (26,9%), tritronculaire (42,3%).Conclusion : Dans notre population, une cardiopathie ischémique est retrouvée chez 52% des diabétiques de type II. Près de 60 % des patients asymptomatiques sont coronariens, en rapport avec une durée plus longue du diabète responsable de neuropathie autonome cardiaque.PARIS13-BU Serge Lebovici (930082101) / SudocSudocFranceF