Distribution of events of positive selection and population differentiation in a metabolic pathway: the case of asparagine N-glycosylation

Asparagine N-Glycosylation is one of the most important forms of protein post-translational modification in eukaryotes. This metabolic pathway can be subdivided into two parts: an upstream sub-pathway required for achieving proper folding for most of the proteins synthesized in the secretory pathway, and a downstream sub-pathway required to give variability to trans-membrane proteins, and involved in adaptation to the environment and innate immunity. Here we analyze the nucleotide variability of the genes of this pathway in human populations, identifying which genes show greater population differentiation and which genes show signatures of recent positive selection. We also compare how these signals are distributed between the upstream and the downstream parts of the pathway, with the aim of exploring how forces of population differentiation and positive selection vary among genes involved in the same metabolic pathway but subject to different functional constraints. Our results show that genes in the downstream part of the pathway are more likely to show a signature of population differentiation, while events of positive selection are equally distributed among the two parts of the pathway. Moreover, events of positive selection are frequent on genes that are known to be at bifurcation points, and that are identified as being in key position by a network-level analysis such as MGAT3 and GCS1. These findings indicate that the upstream part of the Asparagine N-Glycosylation pathway has lower diversity among populations, while the downstream part is freer to tolerate diversity among populations. Moreover, the distribution of signatures of population differentiation and positive selection can change between parts of a pathway, especially between parts that are exposed to different functional constraints. Our results support the hypothesis that genes involved in constitutive processes can be expected to show lower population differentiation, while genes involved in traits related to the environment should show higher variability. Taken together, this work broadens our knowledge on how events of population differentiation and of positive selection are distributed among different parts of a metabolic pathway.

Cultural events and tourist development in Catalonia (Spain)

From the point of view of local development cultural tourism events represent an opportunity since they are distributed homogeneously by the Catalan territory and are experiencing a vertiginous growth as a way to differentiate the existing supply. In our study a sample of 264 telephone surveys made to organizers of events in Catalonia has been compiled, with the purpose of characterizing the existing supply, thematic typologies, management models, commercialization inputs and economic impact. The results allow us to characterize events from the point of view of their tourist potential. Finally some recommendations are set out to develop future tourism policies based on events according to product differentiation, seasonality, competitiveness and creativity.

Cultural events as tourism supply in coastal Catalan resorts

During the last three decades, the number of tourism events has been growing in Catalan coastal resorts because of the recover of Catalan cultural traditions, festivals and folklore, and also because of tourism growth. Catalan tourism resorts use events as catalysers for new supply and as a mean to differentiate and singularize themselves from their competitors. The tourism potential of cultural events is undeniable but there are some problems that prevent a more effective impact as economic and regional development agents. This paper reflects some discussions and conclusions obtained from the analysis of 264 valid responses of a survey made to different Catalan event organizers in 2008 and 2009. We describe and characterize cultural event supply in coastal resorts in order to study the events tourism importance, their capacity to generate and spread economic development, and their managerial model. The analysis is made in a geographical basis, comparing the results of the territorial organization of events of the city of Barcelona, coastal and inland municipalities. Finally some considerations about event regional tourism policy and tourism development are discussed.

Prevention and management of potential adverse events during transapical aortic valve replacement.

BACKGROUND AND AIM OF THE STUDY: Transapical transcatheter aortic valve replacement (TAVR) is a new minimally invasive technique with a known risk of unexpected intra-procedural complications. Nevertheless, the clinical results are good and the limited amount of procedural adverse events confirms the usefulness of a synergistic surgical/anesthesiological management in case of unexpected emergencies. METHODS: A review was made of the authors' four-year database and other available literature to identify major and minor intra-procedural complications occurring during transapical TAVR procedures. All implants were performed under general anesthesia with a balloon-expandable Edwards Sapien stent-valve, and followed international guidelines on indications and techniques. RESULTS: Procedural success rates ranged between 94% and 100%. Life-threatening apical bleeding occurred very rarely (0-5%), and its incidence decreased after the first series of implants. Stent-valve embolization was also rare, with a global incidence ranging from 0-2%, with evidence of improvement after the learning curve. Rates of valve malpositioning ranged from 0% to < 3%, whereas the risk of coronary obstruction ranged from 0% to 3.5%. Aortic root rupture and dissection were dramatic events reported in 0-2% of transapical cases. Stent-valve malfunction was rarely reported (1-2%), whereas the valve-in-valve bailout procedure for malpositioning, malfunctioning or severe paravalvular leak was reported in about 1.0-3.5% of cases. Sudden hemodynamic management and bailout procedures such as valve-in-valve rescue or cannulation for cardiopulmonary bypass were more effective when planned during the preoperative phase. CONCLUSION: Despite attempts to avoid pitfalls, complications during transapical aortic valve procedures still occur. Preoperative strategic planning, including hemodynamic status management, alternative cannulation sites and bailout procedures, are highly recommended, particularly during the learning curve of this technique.

Systematic surgical closure of patent foramen ovale in selected patients with cerebrovascular events due to paradoxical embolism. Early results of a preliminary study.

OBJECTIVE: To define therapeutic strategy for management of patients with ischemic stroke due to a high probability of paradoxical embolism through a Patent Foramen Ovale (PFO). METHODS: Since 1988 all consecutive patients with cerebrovascular events and PFO from the Stroke Registry of our population-based primary-care center are prospectively studied and followed. Since 1992, among 118 patients with cryptogenic embolic brain infarct or transient ischemic attack (TIA) and PFO, 32 consecutive patients younger than 60 years who presented at least two of the following criteria were admitted for surgery: history of Valsalva strain before stroke (11); multiple clinical events (13); multiple infarcts on brain Magnetic Resonance Imaging (MRI) (15); atrial septal aneurysm (ASA) (16); large right-to-left shunt (> 50 microbubbles) (12). RESULTS: Operative time 135' +/- 33'. CPB time 34' +/- 14'. Aortic crossclamping time 16' +/- 6'. Post-operative bleeding 485 +/- 170 ml. No homologous blood transfusion required. No neurological, cardiac or renal complications. All patients were followed-up corresponding to a cumulative time of 601 patient-months. This revealed no recurrent vascular events nor silent new brain lesions on brain MRI. Systematic simultaneous contrast Trans Esophageal Echocardiography (TEE)-Trans Cranial Doppler showed a small residual interatrial shunt in two patients. CONCLUSION: Surgical closure of a patent foramen ovale can be accomplished with very low morbidity and reduce efficiently the risk of stroke recurrence. It seems to be the option of choice in selected patients with a higher (> 1.5%/year) risk of stroke recurrence.

Association of electrocardiogram abnormalities and incident heart failure events.

Unless effective preventive strategies are implemented, aging of the population will result in a significant worsening of the heart failure (HF) epidemic. Few data exist on whether baseline electrocardiographic (ECG) abnormalities can refine risk prediction for HF. METHODS: We examined a prospective cohort of 2,915 participants aged 70 to 79 years without preexisting HF, enrolled between April 1997 and June 1998 in the Health, Aging, and Body Composition (Health ABC) study. Minnesota Code was used to define major and minor ECG abnormalities at baseline and at year 4 follow-up. Using Cox models, we assessed (1) the association between ECG abnormalities and incident HF and (2) the incremental value of adding ECG to the Health ABC HF Risk Score using the net reclassification index. RESULTS: At baseline, 380 participants (13.0%) had minor, and 620 (21.3%) had major ECG abnormalities. During a median follow-up of 11.4 years, 485 participants (16.6%) developed incident HF. After adjusting for the Health ABC HF Risk Score variables, the hazard ratio (HR) was 1.27 (95% CI 0.96-1.68) for minor and 1.99 (95% CI 1.61-2.44) for major ECG abnormalities. At year 4, 263 participants developed new and 549 had persistent abnormalities; both were associated with increased subsequent HF risk (HR 1.94, 95% CI 1.38-2.72 for new and HR 2.35, 95% CI 1.82-3.02 for persistent ECG abnormalities). Baseline ECG correctly reclassified 10.5% of patients with HF events, 0.8% of those without HF events, and 1.4% of the overall population. The net reclassification index across the Health ABC HF risk categories was 0.11 (95% CI 0.03-0.19). CONCLUSIONS: Among older adults, baseline and new ECG abnormalities are independently associated with increased risk of HF. The contribution of ECG screening for targeted prevention of HF should be evaluated in clinical trials.

Significant decrease in in-hospital mortality and major adverse cardiac events in Swiss STEMI patients between 2000 and December 2007.

To evaluate the in-hospital outcome of STEMI (ST elevation myocardial infarction) patients admitted to Swiss hospitals between 2000 and December 2007, and to identify the predictors of in-hospital mortality and major cardiac events. Data from the Swiss national registry AMIS Plus (Acute Myocardial Infarction and Unstable Angina in Switzerland) were used. All patients admitted between January 2000 and December 2007 with STEMI or a new LBBB (left bundle branch block) were included in the registry. We studied 12 026 STEMI patients admitted to 68 hospitals. The mean age was 64 +/- 13 years and 73% of the patients were male. Incidence of in-hospital death was 7.6% in 2000 and 6% in 2007. Reinfarction fell from 3.7% in 2000 to 0.9% in 2007. Thrombolysis decreased from 40.2% in 2000 to 2% in 2007. Clinical predictors of mortality were: age >65 years, Killips class III or IV, diabetes, Q wave myocardial infarction (at presentation). Patients undergoing percutaneous coronary intervention (PCI) had lower mortality and reinfarction rates (3.9% versus 11.2% and 1.1% versus 3.1% respectively, p <0.001) over time, although their numbers increased from 43% in 2000 to 85% in 2007. Patients admitted to hospitals with PCI facilities had lower mortality than patients hospitalised in hospitals without it, but the demographic characteristics differ widely between the two groups. Both in-hospital mortality and reinfarction decreased significantly over the time, parallel to an increased number of PCI. PCI was also the strongest predictor of survival. In-hospital mortality and reinfarction rate have decreased significantly in Swiss STEMI patients in the last seven years, parallel to a significant increase in the number of percutaneous coronary interventions in addition to medical therapy. Outcome is not related to the site of admission but to PCI access.

Vaccines safety; effect of supervision or SMS on reporting rates of adverse events following immunization (AEFI) with meningitis vaccine (MenAfriVac?): a randomized controlled trial.

BACKGROUND: To ensure vaccines safety, given the weaknesses of the national pharmacovigilance system in Cameroon, there is a need to identify effective interventions that can contribute to improving AEFI reporting. OBJECTIVE: To assess the effect of: (i) sending weekly SMS, or (ii) weekly supervisory visits on AEFI reporting rate during a meningitis immunization campaign conducted in Cameroon in 2012 using the meningitis A conjugate vaccine (MenAfriVac?). METHODS: Health facilities that met the inclusion criteria were randomly assigned to receive: (i) a weekly standardized SMS, (ii) a weekly standardized supervisory visits or (iii) no intervention. The primary outcome was the reported AEFI incidence rate from week 5 to 8 after the immunization campaign. Poisson regression model was used to estimate the effect of interventions after adjusting for health region, type of health facility, type and position of health workers as well as the cumulative number of AEFI reported from weeks 1 to 4. RESULTS: A total of 348 (77.2%) of 451 health facility were included, and 116 assigned to each of three groups. The incidence rate of reported AEFI per 100 health facility per week was 20.0 (15.9-24.1) in the SMS group, 40.2 (34.4-46.0) in supervision group and 13.6 (10.1-16.9) in the control group. Supervision led to a significant increase of AEFI reporting rate compared to SMS [adjusted RR=2.1 (1.6-2.7); p<0.001] and control [RR=2.8(2.1-3.7); p<0.001)] groups. The effect of SMS led to some increase in AEFI reporting rate compared to the control group, but the difference was not statistically significant [RR=1.4(0.8-1.6); p=0.07)]. CONCLUSION: Supervision was more effective than SMS or routine surveillance in improving AEFI reporting rate. It should be part of any AEFI surveillance system. SMS could be useful in improving AEFI reporting rates but strategies need to be found to improve its effectiveness, and thus maximize its benefits.

Vorapaxar in the secondary prevention of atherothrombotic events.

BACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS: At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS: Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.).

Acute ischemic cerebrovascular events on antiplatelet therapy: what is the optimal prevention strategy?

Even though patients who develop ischemic stroke despite taking antiplatelet drugs represent a considerable proportion of stroke hospital admissions, there is a paucity of data from investigational studies regarding the most suitable therapeutic intervention. There have been no clinical trials to test whether increasing the dose or switching antiplatelet agents reduces the risk for subsequent events. Certain issues have to be considered in patients managed for a first or recurrent stroke while receiving antiplatelet agents. Therapeutic failure may be due to either poor adherence to treatment, associated co-morbid conditions and diminished antiplatelet effects (resistance to treatment). A diagnostic work up is warranted to identify the etiology and underlying mechanism of stroke, thereby guiding further management. Risk factors (including hypertension, dyslipidemia and diabetes) should be treated according to current guidelines. Aspirin or aspirin plus clopidogrel may be used in the acute and early phase of ischemic stroke, whereas in the long-term, antiplatelet treatment should be continued with aspirin, aspirin/extended release dipyridamole or clopidogrel monotherapy taking into account tolerance, safety, adherence and cost issues. Secondary measures to educate patients about stroke, the importance of adherence to medication, behavioral modification relating to tobacco use, physical activity, alcohol consumption and diet to control excess weight should also be implemented.

Epigenetic alterations and constitutive Wnt signaling are early events in the progression from Barrett's esophagus to esophageal adenocarcinoma

SUMMARY Barrett's esophagus (BE) is an acquired condition in which the normal squamous epithelium in the distal esophagus is replaced by a metaplastic columnar epithelium, as a complication of chronic gastroesophageal reflux. The clinical significance of this disease is its associated predisposition to esophageal adenocarcinoma (EAC). EAC is a highly lethal disease. Better understanding of the pathogenesis of columnar metaplasia and its progression to cancer might allow the identification of biomarkers that can be used for early diagnosis, which will improve the patient survival. In this study, an improved protocol for methylation-sensitive single-strand conformation analysis, which is used to analyze promoter methylation, is proposed and a methylation-sensitive dot blot assay is described, which allows a rapid, easy, and sensitive detection of promoter methylation. Both methods were applied to study the methylation pattern of the APC promoter in histologically normal appearing gastric mucosa. The APC promoter showed monoallelic methylation, and because the methylated allele differed between the different gastric cell types, this corresponded to allelic exclusion. The APC methylation pattern was frequently altered in noimal gastric mucosa associated with neoplastic lesions, indicating that changes in the pattern of promoter methylation might precede the development of neoplasia, without accompanying histological manifestations. An epigenetic profile of 10 genes important in EAC was obtained in this study; 5 promoter genes (APC, TIMP3, TERT, CDKN2A and SFRP1) were found to be hypermethylated in the tumors. Furthermore, the promoter of APC, TIMP3 and TERT was frequently methylated in BE samples from EAC patients, but rarely in BE samples that did not progress to EAC. These three biomarkers might therefore be considered as potential predictive markers for increased EAC risk. Analysis of Wnt pathway alterations indicated that WNT2 ligand is overexpressed as early as the low-grade dysplastic stage and downregulation by promoter methylation of the SFRP1 gene occurrs already in the metaplastic lesions. Moreover, loss of APC expression is not the only factor involved in the activation of the Wnt pathway. These results indicate that a variety of biologic, mostly epigenetic events occurs very early in the carcinogenesis of BE. This new information might lead to improved early diagnosis of EAC and thus open the way to a possible application of these biomarkers in the prediction of increased EAC risk progression. RESUME L'oesophage de Barrett est une lésion métaplasique définie par le remplacement de la muqueuse malpighienne du bas oesophage par une muqueuse cylindrique glandulaire, suite à une agression chronique par du reflux gastro-esophagien. La plus importante signification clinique de cette maladie est sa prédisposition au développement d'un adénocarcinome. Le pronostic de l'adénocarcinome sur oesophage de Barrett est sombre. Seule une meilleure compréhension de la pathogenèse de l'épithélium métaplasique et de sa progression néoplasique permettrait l'identification de biomarqueurs pouvant être utilisés pour un diagnostic précoce ; la survie du patient serait ainsi augmentée. Dans cette étude, un protocole amélioré pour l'analyse de la méthylation par conformation simple brin est proposé. De plus, une technique d'analyse par dot blot permettant une détection rapide, facile et sensible de la méthylation d'un promoteur est décrite. Les deux méthodes ont été appliquées à l'étude de la méthylation du promoteur du gène APC dans des muqueuses gastriques histologiquement normales. Le promoteur APC a montré une méthylation monoallélique et, parce que les allèles méthylés différaient entre les différents types de cellules gastriques, celle-ci correspondait à une méthylation allélique exclusive. La méthylation d'APC a été trouvée fréquemment altérée dans la muqueuse gastrique normale associée à des lésions néoplasiques. Ceci indique que des changements dans la méthylation d'un promoteur peuvent précéder le développement d'une tumeur, et cela sans modification histologique. Un profil épigénétique des adénocarcinomes sur oesophage de Barrett a été obtenu dans cette étude. Cinq promoteurs (APC, TIMP3, TERT, CDKN2A et SFRP1) ont été trouvés hyperméthylés dans les tumeurs. Les promoteurs d'APC, TIMP3 et TERT étaient fréquemment méthylés dans l'épithélium métaplasique proche d'un adénocarcinome et rarement dans l'épithélium sans évolution néoplasique. Ces trois biomarkers pourraient par conséquent être considérés comme marqueur prédicatif d'un risque accru de développer une tumeur. L'analyse des altérations de la voie Wnt a montré que WNT2 est surexprimé déjà dans des dysplasies de bas-grade et que la dérégulation de SFRP1 par méthylation de son promoteur intervenait dans les lésions métaplasiques. Une perte d'expression d'APC n'est pas le seul facteur impliqué dans l'activation de cette voie. Ces résultats montrent qu'une grande diversité d'événements biologiques, principalement épigénétiques, surviennent très tôt lors de la carcinogenèse de l'oesophage de Barrett. Ces nouveaux éléments pourraient améliorer le diagnostic précoce et rendre possible l'application de ces biomarqueurs dans la prédiction d'un risque accru de développer un adénocarcinome sur un oesophage de Barrett.

Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons.

BACKGROUND: Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. METHODS: In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. RESULTS: A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9 × 10(-4)). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05-2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06-1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16-1.96), diabetes (OR = 1.66; 95% CI, 1.10-2.49), ≥ 1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06-1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17-2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. CONCLUSIONS: In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.

BoBo mixing meseasurement at Belle using dilepton events tagged with a soft pion

L'expérience Belle, située dans le centre de recherche du KEK, au Japon, est consacrée principalement à l'étude de la violation de CP dans le système des mésons B. Elle est placée sur le collisionneur KEKB, qui produit des paires Banti-B. KEKB, l'une des deux « usines à B » actuellement en fonction, détient le record du nombre d'événements produits avec plus de 150 millions de paires. Cet échantillon permet des mesures d'une grande précision dans le domaine de la physique du méson B. C'est dans le cadre de ces mesures de précision que s'inscrit cette analyse. L'un des phénomènes remarquables de la physique des hautes énergies est la faculté qu'a l'interaction faible de coupler un méson neutre avec son anti-méson. Dans le présent travail, nous nous intéressons au méson B neutre couplé à l'anti-méson B neutre, avec une fréquence d'oscillation _md mesurable précisément. Outre la beauté de ce phénomène lui-même, une telle mesure trouve sa place dans la quête de l'origine de la violation de CP. Cette dernière n'est incluse que d'une façon peu satisfaisante dans le modèle standard des interactions électro-faibles. C'est donc la recherche de phénomènes physiques encore inexpliqués qui motive en premier lieu la collaboration Belle. Il existe déjà de nombreuses mesures de _md antérieures. Celle que nous présentons ici est cependant d'une précision encore jamais atteinte grâce, d'une part, à l'excellente performance de KEKB et, d'autre part, à une approche originale qui permet de réduire considérablement la contamination de la mesure par des événements indésirés. Cette approche fut déjà mise à profit par d'autres expériences, dans des conditions quelque peu différentes de celles de Belle. La méthode utilisée consiste à reconstruire partiellement l'un des mésons dans le canal ___D*(D0_)l_l, en n'utilisant que les informations relatives au lepton l et au pion _. L'information concernant l'autre méson de la paire Banti-B initiale n'est tirée que d'un seul lepton de haute énergie. Ainsi, l'échantillon à disposition ne souffre pas de grandes réductions dues à une reconstruction complète, tandis que la contamination due aux mésons B chargés, produits par KEKB en quantité égale aux B0, est fortement diminuée en comparaison d'une analyse inclusive. Nous obtenons finalement le résultat suivant : _md = 0.513±0.006±0.008 ps^-1, la première erreur étant l'erreur statistique et la deuxième, l'erreur systématique.<br/><br/>The Belle experiment is located in the KEK research centre (Japan) and is primarily devoted to the study of CP violation in the B meson sector. Belle is placed on the KEKB collider, one of the two currently running "B-meson factories", which produce Banti-B pairs. KEKB has created more than 150 million pairs in total, a world record for this kind of colliders. This large sample allows very precise measurements in the physics of beauty mesons. The present analysis falls within the framework of these precise measurements. One of the most remarkable phenomena in high-energy physics is the ability of weak interactions to couple a neutral meson to its anti-meson. In this work, we study the coupling of neutral B with neutral anti-B meson, which induces an oscillation of frequency _md we can measure accurately. Besides the interest of this phenomenon itself, this measurement plays an important role in the quest for the origin of CP violation. The standard model of electro-weak interactions does not include CP violation in a fully satisfactory way. The search for yet unexplained physical phenomena is, therefore, the main motivation of the Belle collaboration. Many measurements of _md have previously been performed. The present work, however, leads to a precision on _md that was never reached before. This is the result of the excellent performance of KEKB, and of an original approach that allows to considerably reduce background contamination of pertinent events. This approach was already successfully used by other collaborations, in slightly different conditions as here. The method we employed consists in the partial reconstruction of one of the B mesons through the decay channel ___D*(D0_)l_l, where only the information on the lepton l and the pion _ are used. The information on the other B meson of the initial Banti-B pair is extracted from a single high-energy lepton. The available sample of Banti-B pairs thus does not suffer from large reductions due to complete reconstruction, nor does it suffer of high charged B meson background, as in inclusive analyses. We finally obtain the following result: _md = 0.513±0.006±0.008 ps^-1, where the first error is statistical, and the second, systematical.<br/><br/>De quoi la matière est-elle constituée ? Comment tient-elle ensemble ? Ce sont là les questions auxquelles la recherche en physique des hautes énergies tente de répondre. Cette recherche est conduite à deux niveaux en constante interaction. D?une part, des modèles théoriques sont élaborés pour tenter de comprendre et de décrire les observations. Ces dernières, d?autre part, sont réalisées au moyen de collisions à haute énergie de particules élémentaires. C?est ainsi que l?on a pu mettre en évidence l?existence de quatre forces fondamentales et de 24 constituants élémentaires, classés en « quarks » et « leptons ». Il s?agit là de l?une des plus belles réussites du modèle en usage aujourd?hui, appelé « Modèle Standard ». Il est une observation fondamentale que le Modèle Standard peine cependant à expliquer, c?est la disparition quasi complète de l?anti-matière (le « négatif » de la matière). Au niveau fondamental, cela doit correspondre à une asymétrie entre particules (constituants de la matière) et antiparticules (constituants de l?anti-matière). On l?appelle l?asymétrie (ou violation) CP. Bien qu?incluse dans le Modèle Standard, cette asymétrie n?est que partiellement prise en compte, semble-t-il. En outre, son origine est inconnue. D?intenses recherches sont donc aujourd?hui entreprises pour mettre en lumière cette asymétrie. L?expérience Belle, au Japon, en est une des pionnières. Belle étudie en effet les phénomènes physiques liés à une famille de particules appelées les « mésons B », dont on sait qu?elles sont liées de près à l?asymétrie CP. C?est dans le cadre de cette recherche que se place cette thèse. Nous avons étudié une propriété remarquable du méson B neutre : l?oscillation de ce méson avec son anti-méson. Cette particule est de se désintégrer pour donner l?antiparticule associée. Il est clair que cette oscillation est rattachée à l?asymétrie CP. Nous avons ici déterminé avec une précision encore inégalée la fréquence de cette oscillation. La méthode utilisée consiste à caractériser une paire de mésons B à l?aide de leur désintégration comprenant un lepton chacun. Une plus grande précision est obtenue en recherchant également une particule appelée le pion, et qui provient de la désintégration d?un des mésons. Outre l?intérêt de ce phénomène oscillatoire en lui-même, cette mesure permet d?affiner, directement ou indirectement, le Modèle Standard. Elle pourra aussi, à terme, aider à élucider le mystère de l?asymétrie entre matière et anti-matière.