Exercice physique et athérosclérose : quels sont les mécanismes physiologiques et moléculaires de l'exercice qui préviennent et protègent de l'athérosclérose? : approche chez un modèle expérimental d'athérosclérose : la souris génétiquement dépourvue en apolipoprotéine E (apoE-/-)

RESUME : L'athérosclérose, pathologie inflammatoire artérielle chronique, est à l'origine de la plupart des maladies cardiovasculaires qui constituent l'une des premières causes de morbidité et mortalité en France. Les études observationnelles et expérimentales montrent que l'exercice physique prévient la mortalité cardiovasculaire. Cependant, les mécanismes précisant les bénéfices cliniques de l'exercice sur l'athérosclérose sont encore largement inconnus. Le but général de ce travail a donc été d'explorer, en utilisant un modèle expérimental d'athérosclérose, la souris hypercholestérolémique génétiquement dépourvue en apolipoprotéine E (apoE-/-), les mécanismes athéroprotecteurs de l'exercice. La dysfonction endothéliale, généralement associée aux facteurs de risque cardiovasculaire, serait l'une des étapes précoces majeures de l'athérogenèse. Elle est caractérisée par une diminution de la biodisponibilité en monoxyde d'azote (NO) avec la perte de ses propriétés vasculo-protectrices, ce qui favorise un climat pro-athérogène (stress oxydatif, adhésion et infiltration des cellules inflammatoires dans la paroi artérielle...) conduisant à la formation de la plaque athéromateuse. L'objectif de notre premier travail a donc été d'explorer les effets de l'exercice d'une part, sur le développement des plaques athéromateuses et d'autre part, sur la fonction endothéliale de la souris apoE-/-. Nos résultats montrent que l'exercice réduit significativement l'extension de l'athérosclérose et prévient la dysfonction endothéliale. L'explication pharmacologique montre que l'exercice stimule la fonction endothéliale via, notamment, une plus grande sensibilité des récepteurs endothéliaux muscariniques, ce qui active les événements signalétiques cellulaires récepteurs-dépendants à l'origine d'une bioactivité accrue de NO. Les complications cliniques graves de l'athérosclérose sont induites par la rupture de la plaque instable provoquant la formation d'un thrombus occlusif et l'ischémie du territoire tissulaire en aval. L'objectif de notre deuxième travail a été d'examiner l'effet de l'exercice sur la qualité/stabilité de la plaque. Nos résultats indiquent que l'exercice de longue durée stabilise la plaque en augmentant le nombre de cellules musculaires lisses et en diminuant le nombre de macrophages intra-plaques. Nos résultats montrent aussi que la phosphorylation de la eNOS (NO Synthase endothéliale) Akt-dépendante n'est pas le mécanisme moléculaire majeur à l'origine de ce bénéfice. Enfin, dans notre troisième travail, nous avons investigué l'effet de l'exercice sur le développement de la plaque vulnérable. Nos résultats montrent, chez un modèle murin de plaque instable (modèle d'hypertension rénovasculaire à rénine et angiotensine II élevés) que l'exercice prévient l'apparition de la plaque vulnérable indépendamment d'un effet hémodynamique. Ce bénéfice serait associé à une diminution de l'expression vasculaire des récepteurs AT1 de l'Angiotensine II. Nos résultats justifient l'importance de l'exercice comme outil préventif des maladies cardiovasculaires. ABSTRACT : Atherosclerosis, a chronic inflammatory disease, is one of the main causes of morbidity and mortality in France. Observational and experimental data indicate that regular physical exercise has a positive impact on cardiovascular mortality. However, the mechanisms by which exercise exerts clinical benefits on atherosclerosis are still unknown. The general aim of this work was to elucidate the anti-atherosclerotic effects of exercise, using a mouse model of atherosclerosis: the apolipoprotein E-deficient mice (apoE-/- mice). Endothelial dysfunction, generally associated with cardiovascular risk factors, has been recognized to be a major and early step in atherogenesis. Endothelial dysfunction is characterized by Nitric Oxide (NO) biodisponibility reduction with loss of NO-mediated vasculoprotective actions. This leads to vascular effects such as increased oxidative stress and increased adhesion of inflammatory cells into arterial wall thus playing a role in atherosclerotic plaque development. Therefore, one of the objective of our study was to explore the effects of exercise on atherosclerotic plaque extension and on endothelial function in apoE-/- mice. Results show that exercise significantly reduces plaque progression and prevents endothelial dysfunction. Pharmacological explanation indicates that exercise stimulates endothelial function by increasing muscarinic receptors sensitivity which in turn activates intracellular signalling receptor-dependent events leading to increased NO bioactivity. The clinical manifestations of atherosclerosis are the consequences of unstable plaque rupture with thrombus formation leading to tissue ischemia. The second aim of our work was to determine the effect of exercise on plaque stability. We demonstrate that long-term exercise stabilizes atherosclerotic plaques as shown by decreased macrophage and increased Smooth Muscle Cells plaque content. Our results also suggest that the Akt-dependent eNOS phosphorylation pathway is not the primary molecular mechanism mediating these beneficial effects. Finally, we assessed a putative beneficial effect of exercise on vulnerable plaque development. In a mouse model of Angiotensine II (Ang II)-mediated vulnerable atherosclerotic plaques, we provide fist evidence that exercise prevents atherosclerosis progression and plaque vulnerability. The beneficial effect of swimming was associated with decreased aortic Ang II AT1 receptor expression independently from any hemodynamic change. These findings suggest clinical benefit of exercise in terms of cardiovascular event protection.

The occurrence of intra-operative hypotension varies between hospitals: observational analysis of more than 147,000 anaesthesia.

BACKGROUND: Hypotension, a common intra-operative incident, bears an important potential for morbidity. It is most often manageable and sometimes preventable, which renders its study important. Therefore, we aimed at examining hospital variations in the occurrence of intra-operative hypotension and its predictors. As secondary endpoints, we determined to what extent hypotension relates to the risk of post-operative incidents and death. METHODS: We used the Anaesthesia Databank Switzerland, built on routinely and prospectively collected data on all anaesthesias in 21 hospitals. The three outcomes were assessed using multi-level logistic regression models. RESULTS: Among 147,573 anaesthesias, hypotension ranged from 0.6% to 5.2% in participating hospitals, and from 0.3% up to 12% in different surgical specialties. Most (73.4%) were minor single events. Age, ASA status, combined general and regional anaesthesia techniques, duration of surgery and hospitalization were significantly associated with hypotension. Although significantly associated, the emergency status of the surgery had a weaker effect. Hospitals' odds ratios for hypotension varied between 0.12 and 2.50 (P < or = 0.001), even after adjusting for patient and anaesthesia factors, and for type of surgery. At least one post-operative incident occurred in 9.7% of the procedures, including 0.03% deaths. Intra-operative hypotension was associated with a higher risk of post-operative incidents and death. CONCLUSION: Wide variations remain in the occurrence of hypotension among hospitals after adjustment for risk factors. Although differential reporting from hospitals may exist, variations in anaesthesia techniques and blood pressure maintenance may also have contributed. Intra-operative hypotension is associated with morbidities and sometimes death, and constant vigilance must thus be advocated.

The role of thymic accessory cells in cytokine production and in the intra-thymic T cell differentiation pathway

Intrathymic T lymphocyte differentiation proceeds from complex interactions between prothymocytes of bone marrow origin and cells of the thymic stroma, epithelial cells and "acessory" cells (macrophages and/or interdigitating cells). The present paper describes the role of the accessoty cell compartment in this intrathymic process. Acessory cells produce factors which are involved in thymocyte proliferation (interleukin 1, prostaglandins, deoxynucleosides). Cell-cell interaction between "accessory" cells and thymocytes is required for the regulation of interleukin production. Prothymocytes, the precursors of all thymocyte subsets, need the accessory cell compartment for their IL2 dependent proliferation and their differentiation. Accessory cells of the thymic stroma may be involved in the intrathymic selection process at the prothymocyte level.

Chimiothérapie intra-artérielle super-sélective dans l'artère ophtalmique en cas de rétinoblastome avancé chez l'enfant.

Objectifs: Etude prospective sur l'efficacité de la chimio-perfusion super-sélective avec Melphalan dans l'artère ophtalmique en tant qu'agent tumoricide chez l'enfantatteint de rétinoblastome avancé, pour éviter l'énucléation chirurgicale et/ou la radiothérapie externe. Matériels et méthodes: 19 enfants (âge moyen 25 mois) atteints de rétinoblastome de groupe D ont reçu 1 à 3 séances d'administration intra-artérielle de Melphalan (0,35 mg/kg) dans l'artère ophtalmique sous anesthésie générale. Au total 48 procédures ont été réalisées. Chaque séance était associée à une injection intra-vitréenne deMelphalan, ainsi qu'à une thermothérapie et/ou une cryothérapie. Résultats: Le traitement a été effectué avec succès chez 17/19 enfants avec une régression importante du volume tumoral. L'énucléation ainsi que la radiothérapie externeont pu être évitées dans 15/17 enfants, sur un suivi moyen d'une année. Aucune complication systémique ou thromboembolique n'a été observée. Lescomplications locales ont comporté 2 décollements de la rétine, 5 oedèmes conjonctivaux et palpébraux, 1 cas de pigmentation cutanée locale, 1 vasospasmetransitoire de l'artère carotide interne et 2 cas d'artériopathie occlusive choroïdienne sectorielle . Conclusion: L'administration intra-artérielle de Melphalan s'avère être très efficace dans les cas avancés de rétinoblastome chez l'enfant, aussi bien comme techniquecurative que pour éviter l'énucléation et/ou la radiothérapie externe.

Heterogeneity of atherosclerotic plaque phenotypes and composition in four different arterial beds: an intravascular ultrasound virtual histology study

Purpose: The purpose of this study was to compare the plaque morphology between coronary and peripheral arteries using intravascular ultrasound (IVUS). Methods: IVUS was performed in 68 patients with coronary and 93 with peripheral artery lesions (29 carotid, 50 renal, and 14 iliac). Plaques were classified as fibroatheroma (VH-FA) (further subclassified as thin-capped [VH-TCFA] and thick-capped [VH-ThCFA]), fibrocalcific plaque (VH-FC) and pathological intimal thickening (VH-PIT). Results: Plaque rupture (13% of coronary, 7% of carotid, 6% of renal, and 7% of iliac arteries; P=NS) and VH-TCFA (37% of coronary, 24% of carotid, 16% of renal, and 7% of iliac arteries; P=0.02) was observed in all arteries. Compared to coronary arteries, VH-FA was less frequently observed in renal (P<0.001) and iliac arteries (P<0.006), while VH-PIT and VH-FC were prevalent in both of these peripheral arteries. Lesions with positive remodeling demonstrated more characteristics of VH-FA in coronary, carotid, and renal arteries compared to those with intermediate/negative remodeling (all P<0.01). There was positive relationship between RI and percent necrotic core area in all four arteries. Conclusions: Atherosclerotic plaque phenotypes were heterogeneous among four different arteries. In contrast, the associations of remodeling mode with plaque phenotype and composition were similar among the various arterial beds.

Thrombolysis in ischemic stroke without arterial occlusion at presentation.

BACKGROUND AND PURPOSE: None of the randomized trials of intravenous tissue-type plasminogen activator reported vascular imaging acquired before thrombolysis. Efficacy of tissue-type plasminogen activator in stroke without arterial occlusion on vascular imaging remains unknown and speculative. METHODS: We performed a retrospective, multicenter study to collect data of patients who presented to participating centers during a 5-year period with ischemic stroke diagnosed by clinical examination and MRI and with imaging evidence of no vascular occlusion. These patients were divided into 2 groups: those who received thrombolytic therapy and those who did not. Primary outcome measure of the study was excellent clinical outcome defined as modified Rankin Scale of 0 to 1 at 90 days from stroke onset. Secondary outcome measures were good clinical outcome (modified Rankin Scale, 0-2) and perfect outcome (modified Rankin Scale, 0). Safety outcome measures were incidence of symptomatic intracerebral hemorrhage and poor outcome (modified Rankin Scale, 4-6). RESULTS: A total of 256 patients met study criteria, 103 with thrombolysis and 153 without. Logistic regression analysis showed that patients who received thrombolysis had more frequent excellent outcomes with odds ratio of 3.79 (P<0.01). Symptomatic intracerebral hemorrhage was more frequent in thrombolysis group (4.9 versus 0.7%; P=0.04). Thrombolysis led to more frequent excellent outcome in nonlacunar group with odds ratio 4.90 (P<0.01) and more frequent perfect outcome in lacunar group with odds ratio 8.25 (P<0.01). CONCLUSIONS: This study provides crucial data that patients with ischemic stroke who do not have visible arterial occlusion at presentation may benefit from thrombolysis.

Expérimentation et étude de la validité de nouvelles échelles de personnalité spécifiques à la relation intra-couple

Résumé : La présente étude vise à déterminer quels sont les facteurs permettant de valider de nouvelles échelles de personnalité spécifiques à la relation intra-couple construites sur la base de profils de personnalité en auto- et hétéro-évaluation. Pour ce faire, nous avons défini des critères sociologiques (par exemple âge, niveau socioprofessionnel, nombre de relations passées), des critères psychologiques (satisfaction conjugale) et des critères biologiques (distance génétique et préférence d'odeurs) afin de vérifier s'ils sont susceptibles de valider les six échelles de personnalité intra-couples inédites que nous avons construites dans le cadre de cette recherche de doctorat. Notre échantillon se compose de 106 couples mariés et de 60 jeunes couples non mariés, qui ont chacun complété le test de personnalité L.A. B. E. L. (F Gendre & R. Capel), l'Échelle d'Ajustement Dyadique (Spanier, 1976) ainsi qu'un test génétique pour une partie d'entre eux.

The intra-industry trade for a high-income country: new empirical evidence for Italy

This paper examines the determinants of Italian intra-industry trade in horizontally and vertically differentiated products, using a dataset which eliminates the effects linked to the hypothesis of homogeneity both between countries - when specific industry characteristics are analysed - and between sectors - within the same country. In this way, within limits, we have tried to address an issue raised by Greenaway et al. in 1999 which, in the light of the current state of the literature on intra-industry trade, does not seem to have been explicitly dealt with. Our paper highlights how strong the impact of this hypothesis could be in the analyses of the determinants of intraindustry trade in the case of Italy.

Intra-Group Competition and Inter-Group Conflict: An Application to Northern Ireland

This paper reviews four economic theories of leadership selection in conflictual settings. The first of these by Cukierman and Tomassi (1998) labeled the ‘information rationale’, argues that hawks may actually be necessary to initiate peace agreements. The second labeled the ‘bargaining rationale’ borrowing from Hamlin and Jennings (2007) agrees with the conventional wisdom that doves are more likely to secure peace, but post-conflict there are good reasons for hawks to be rationally selected. The third found in Jennings and Roelfsema (2008) is labeled the social psychological rationale. This captures the idea of a competition over which group can form the strongest identity, so can apply to group choices which do not impinge upon bargaining power. As in the bargaining rationale, dove selection can be predicted during conflict, but hawk selection post-conflict. Finally, the expressive rationale is discussed which predicts that regardless of the underlying structure of the game (informational, bargaining, psychological) the large group nature of decision-making by making individual decision makers non-decisive in determining the outcome of elections may cause them to make choices based primarily on emotions which may be invariant with the mode of group interaction, be it conflictual or peaceful. Finally, the paper analyses the extent to which the theories can throw light on Northern Ireland electoral history over the last 25 years.

Bionomia de mosquitos (Diptera: Culicidae) em áreas da Mata Atlântica no município de Itaguaí, estado do Rio de janeiro, Brasil: I. Frequência intra, peri e extradomiciliar

Along 24 consecutive months, from January 1984 to December 1986, mosquito captures were performed in a rural area of said municipality. Aiming to evaluate the comparative frequency of the mosquito species inside houses and in the immediate vicinity and far from houses, the captures were made in two types of domiciles - one permanently and the other only sporadically inhabited - as well as in surrounding woods. Variations in temperature, relative humidity and rainfall were locally recorded. A tendency for domiciliation became evident by the presence of Aedes scapularis in the human domiciles, mainly in those permantely inhabited. Culex quinquefasciatus showed to be adapted to live with humans also in rural areas, in which, in some instances, insecticides had to be used to keep in under control. Such observations, mainly in terms of Ae. scapularis, reinforce the possibility of those mosquitoes, under favourable conditions, becoming carries of arboviroses to humans in rural environments.

Adjonction d'un anesthésique local intra-articulaire lors d'arthro-TDM/IRM : utilité et avantages de la Bupivacaïne.

Objectifs: Une phase hyperalgique dans les 4 heures post-examen arthrographique est maintenant reconnue dans la littérature. Comment s'en amender ? Nous comparonsl'absence d'anesthésique à l'adjonction de deux différents anesthésiques locaux intra-articulaires(rapidocaïne/bupivacaïne) lors d'arthro-TDM/IRM. Matériels et méthodes: Après approbation du comité d'éthique, étude prospective chez 150 patients répartis aléatoirement en trois groupes : 1) sans anesthésique intra-articulaire, 2)rapidocaïne 1%, 3) bupivacaïne 0,25%. Recueil du score EVA (0-10) aux 5 temps suivants : avant injection (score de base), puis 20 minutes, 4 heures, 24 heureset 7 jours après la procédure. Résultats: Le pic douloureux maximal se trouve à 4h après la procédure (idem littérature). La douleur augmente en moyenne de 1,60 unités 4h après la procédure pour legroupe 1, de 1,22 unités pour le groupe 2 et de 0,29 unités pour le groupe 3. La différence entre les groupes 1 et 3 est statistiquement significative (p=0,002 -Tests ANOVA et de Sidak). Elle n'est pas significative entre les groupes 1 et 2 (p=0,536). La comparaison rapidocaïne et bupivacaïne est moins concluante(p=0,065). Conclusion: L'adjonction de bupivacaïne intra-articulaire devrait être réalisée lors d'examens arthrographiques, surtout afin d'améliorer le confort du patient mais aussi pourfavoriser son immobilité lors de l'acquisition des images TDM ou IRM .