Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Le nœud auriculoventriculaire (AV) joue un rôle vital dans le cœur normal et pathologique. Il connecte les oreillettes aux ventricules et, grâce à sa conduction lente, génère un délai entre les contractions auriculaire et ventriculaire permettant d’optimiser le pompage sanguin. Sa conduction lente et sa longue période réfractaire font du nœud AV un filtre d’impulsions auriculaires lors de tachyarythmies assurant ainsi une fréquence ventriculaire plus lente favorable au débit cardiaque. L’optimisation de ce filtrage est une cible dans le traitement de ces arythmies. Malgré ce rôle vital et de nombreuses études, le nœud AV demeure l’objet de plusieurs controverses qui en rendent la compréhension laborieuse. Nos études expérimentales sur des préparations isolées de cœurs de lapin visent à apporter des solutions à certains des problèmes qui limitent la compréhension des propriétés fréquentielles du nœud AV. Le premier problème concerne la définition de la propriété de récupération nodale. On s’accorde généralement sur la dépendance du temps de conduction nodale (intervalle auriculo-Hissien, AH) du temps de récupération qui le précède mais un débat presque centenaire persiste sur la façon de mesurer ce temps de récupération. Selon que l’on utilise à cette fin la longueur du cycle auriculaire (AA) ou l’intervalle His-auriculaire précédent (HA), la même réponse nodale montre des caractéristiques différentes, un paradoxe à ce jour inexpliqué. Le temps de conduction nodale augmente aussi avec le degré et la durée d'une fréquence rapide, un phénomène appelé fatigue. Or, les caractéristiques de la fatigue mesurée varient avec l’indice de récupération utilisé (AA vs. HA). De plus, une troisième propriété appelée facilitation qui entraîne un raccourcissement du temps de conduction diffère aussi avec l’indice de récupération utilisé. Pour établir l’origine de ce problème, nous avons déterminé les différences entre les courbes de récupération (AH compilé en fonction du AA ou HA) pour 30 états fonctionnels nodaux différents. Ces conditions étaient obtenues à l’aide de protocoles permettant la variation du cycle de base (BCL) et du cycle prétest (PTCL), deux paramètres connus pour altérer la fonction nodale. Nous avons pu établir que pour chaque état fonctionnel, la forme de la courbe de récupération et le niveau de fatigue étaient les mêmes pour les deux indices de récupération. Ceci s’applique aussi aux données obtenues à des BCL et PTCL égaux comme dans les protocoles de stimulation prématurée conventionnels couramment utilisés. Nos résultats ont établi pour la première fois que les propriétés nodales de récupération et de fatigue sont indépendantes de l’indice de récupération utilisé. Nos données montrent aussi que les différences entre les courbes de récupération en fonction de l’indice utilisé proviennent d’effets associés aux variations du PTCL. Notre deuxième étude établit à partir des mêmes données pourquoi les variations du PTCL altèrent différemment les courbes de récupération selon l’indice utilisé. Nous avons démontré que ces différences augmentaient en proportion directe avec l’augmentation du temps de conduction au battement prétest. Cette augmentation cause un déplacement systématique de la courbe construite avec l’intervalle AA vers la droite et de celle construite avec l’intervalle HA vers la gauche. Ce résultat met en évidence l’importance de tenir compte des changements du temps de conduction prétest dans l’évaluation de la fonction nodale, un paramètre négligé dans la plupart des études. Ce résultat montre aussi que chacun des deux indices a des limites dans sa capacité d’évaluer le temps de récupération nodale réel lorsque le temps de conduction prétest varie. Lorsque ces limites sont ignorées, comme c’est habituellement le cas, elles entraînent un biais dans l’évaluation des effets de fatigue et de facilitation. Une autre grande difficulté dans l’évaluation des propriétés fréquentielles du nœud AV concerne son état réfractaire. Deux indices sont utilisés pour évaluer la durée de la période réfractaire nodale. Le premier est la période réfractaire efficace (ERPN) définie comme l’intervalle AA le plus long qui n’est pas conduit par le nœud. Le deuxième est la période réfractaire fonctionnelle (FRPN) qui correspond à l’intervalle minimum entre deux activations mesurées à la sortie du nœud. Paradoxalement et pour des raisons obscures, l’ERPN augmente alors que la FRPN diminue avec l’augmentation de la fréquence cardiaque. De plus, ces effets varient grandement avec les sujets, les espèces et l’âge. À partir des mêmes données que pour les deux autres études, nous avons cherché dans la troisième étude l’origine des variations fréquentielles de l’ERPN et de la FRPN. Le raccourcissement du BCL prolonge l’ERPN mais n’affecte pas la FRPN. L’allongement de l’ERPN provient principalement d’un allongement du temps de conduction prétest. Un PTCL court en comparaison avec un BCL court allonge encore plus substantiellement le temps de conduction prétest mais raccourcit en même temps l’intervalle His-auriculaire, ces deux effets opposés s’additionnent pour produire un allongement net de l’ERPN. Le raccourcissement de l’intervalle His-auriculaire par le PTCL court est aussi entièrement responsable pour le raccourcissement de la FRPN. Nous avons aussi établi que, lorsque la composante du temps de conduction prétest est retirée de l’ERPN, un lien linéaire existe entre la FRPN et l’ERPN à cause de leur dépendance commune de l’intervalle His-auriculaire. Le raccourcissement combiné du BCL et du PTCL produit des effets nets prévisibles à partir de leurs effets individuels. Ces effets reproduisent ceux obtenus lors de protocoles prématurés conventionnels. Ces observations supportent un nouveau schème fonctionnel des variations fréquentielles de l’ERPN et de la FRPN à partir des effets distincts du BCL et du PTCL. Elles établissent aussi un nouveau lien entre les variations fréquentielles de l’ERPN et de la FRPN. En conclusion, la modulation fréquentielle de la fonction du nœud AV provient de la combinaison d’effets concurrents cumulatifs liés au cycle de base et non-cumulatifs liés au cycle prétest. Ces effets peuvent être interprétés de façon consistante indépendamment de l’indice de récupération en tenant compte des changements du temps de conduction au battement prétest. Les effets fréquentiels disparates sur l’ERPN et la FRPN sont aussi grandement liés aux changements du temps de conduction prétest. Lorsque l’analyse tient compte de ce facteur, l’ERPN et la FRPN montrent des variations parallèles fortement liées à celles de l’intervalle His-auriculaire. Le nouveau schème fonctionnel des propriétés fréquentielles du nœud AV supporté par nos données aidera à mieux cibler les études sur les mécanismes cellulaires contrôlant la modulation fréquentielle nodale. Nos données pourraient aider à l’interprétation et au contrôle des réponses nodales diverses associées aux tachyarythmies supraventriculaires et à leur traitement pharmacologique. En bref, nos travaux supportent une compréhension factuelle améliorée du comportement fréquentiel du nœud AV, un domaine aux applications multiples en rythmologie cardiaque. / The atrioventricular (AV) node is the sole electrical connection between atria and ventricles, and is of utmost importance in both normal and perturbed cardiac function. Through slow conduction, it generates a delay between atrial and ventricular systoles, thereby optimising cardiac output. The AV node also has a long refractory period which confers it a filtering role during supraventricular tachyarrhythmias. Because of this ventricular rate watchdog role, the AV node has become a primary therapeutic target in atrial fibrillation, a frequent arrhythmia with major clinical burden. Not withstanding intense research, understanding of AV nodal function remains restrained by many controversies, some of which have persisted for almost a century. Major obstacles concern the definition of nodal recovery time and nodal refractoriness. The objective of our studies is to untangle some of these controversies regarding rate-dependent AV nodal function in an experimental model of superfused rabbit heart preparations. Our first study concerns the definition of AV nodal recovery time used to assess rate-dependent nodal function. The dependence of conduction time through the node (atrio-His interval; AH) on time elapsed since last activation i.e., recovery time (RT), is a well accepted fact but its assessment is controversial for nearly a century. This problem arises from the fact that the nodal recovery function shows different characteristics depending upon whether RT is assessed from the preceding atrial cycle length (AA) or His-atrial (HA) interval. Moreover, the rate- and time-dependent increase in AH, known as fatigue, also shows different characteristics depending on RT index used. Furthermore, the third rate-dependent AV nodal property known as facilitation and that tends to shorten AH with penultimate cycle length, is obviously present or virtually absent when studying it with HA or AA index, respectively. Our first study sought to identify the source of this paradoxical apparent dependence of nodal rate-dependent properties on selected RT index. For this purpose, we varied two known independent modulators of AV nodal function, the basic (BCL) and pretest cycle length (PTCL), in 30 different combinations and assessed how the resulting 30 nodal functional states alter the recovery and the fatigue property as assessed with both recovery indexes. We found that, for each functional state, the shape of the nodal recovery curve and the level of fatigue was identical regardless of selected recovery index. We thus documented for the first time that recovery and fatigue properties are consistent whether assessed with HA or AA. However, we also found that PTCL effects appeared different on the two recovery curve formats. In a second study, using the same data, we investigated the origin of PTCL related variations of nodal recovery curves constructed with different recovery indexes. We found that PTCL shortening induced rightward AA curve shifts and leftward HA curve shifts proportional to the increase in pretest conduction time. Moreover, these curve shifts affected all data points equally. This finding suggests that both AA and HA indexes are biased by increases in pretest conduction time. These increases appeared to delay nodal recovery for an identical AA, and to hasten nodal recovery for an identical HA. Uncontrolled changes in pretest conduction time during fast rates thus produce apparent different effects depending on nodal recovery index. Taking into account changes in pretest conduction time results in unified rate-dependent nodal conduction properties regardless of chosen recovery index. Another major problem in AV nodal physiology relates to rate-dependent changes in nodal refractoriness. Two indexes of nodal refractoriness, effective (ERPN) and functional (FRPN) refractory periods, are commonly determined. ERPN and FRPN correspond to the longest AA resulting in nodal block and shortest interval between successive His bundle activations, respectively. For unclear reasons, increasing rate typically results in ERPN prolongation but FRPN shortening, and these effects vary greatly with individuals, ages and species. In a third study, we assessed the functional origin of rate-induced changes in ERPN and FRPN. BCL shortening prolonged ERPN but did not significantly affect FRPN. This ERPN prolongation mainly arose from an increase in pretest conduction time. PTCL shortening also prolonged the pretest conduction time and hence ERPN, but this prolongation was partly counterbalanced by a decrease in the His-atrial subinterval at ERPN. Similar PTCL-induced His-atrial shortening also fully accounted for FRPN shortening. Notably, we found that when ERPN is corrected for the increase in pretest conduction time, ERPN and FRPN vary in parallel according to their respective His-atrial subintervals. Combined BCL and PTCL shortening, including those corresponding to standard commonly used protocols, result in net changes in refractory measures predictable from the sum of their individual effects. These observations not only support a new functional scheme for rate-dependent AV nodal refractoriness but also establish a relationship between ERPN and FRPN which, for a long time, were thought to reflect different nodal properties. In conclusion, rate-dependent AV nodal function reflect the net sum of concurrent yet independent cumulative and non-cumulative effects arising from BCL and PTCL changes, respectively. Nodal recovery and fatigue properties are independent of recovery index. Rate-induced non-cumulative variations in nodal recovery curves originate from changes in pretest conduction time and reflect current limitations of recovery indexes to precisely measure exact nodal recovery time. Changes in pretest conduction time also explain opposite rate-induced changes in ERPN and FRPN. When these changes are taken into account, FRPN and ERPN vary in parallel with heart rate and largely depend on His-atrial interval. These data support a new functional model of rate-dependent nodal conduction and refractoriness, which may help guide studies on underlying cellular and ionic mechanisms as well as on nodal behaviour during supraventricular tachyarrhythmias.

Estimar a região de estabilidade de um ponto de equilíbrio assintoticamente estável é importante em aplicações tais como sistemas de potência, economia e ecologia. A compreensão da estrutura qualitativa da fronteira da região de estabilidade é fundamental para estimar com eficiência a região de estabilidade. Caracterizações topológicas e dinâmicas da fronteira da região de estabilidade foram desenvolvidas ao longo das últimas décadas. Estas caracterizações foram desenvolvidas sob hipóteses de hiperbolicidade dos pontos de equilíbrio na fronteira e transversalidade. Para sistemas que dependem de parâmetros, a condição de hiperbolicidade pode ser violada em pontos de bifurcações. Estaremos interessados em estimar a região de estabilidade, para sistemas sujeitos a variações de parâmetros, onde ocorre a violação da condição de hiperbolicidade dos pontos de equilíbrio na fronteira da região de estabilidade devido ao aparecimento de uma bifurcação sela-nó do tipo zero nesta fronteira. Apresentaremos neste trabalho uma caracterização completa da fronteira da região de estabilidade na presença de um ponto de equilíbrio não hiperbólico sela-nó do tipo zero. Motivados também em oferecer um algoritmo conceitual para obter estimativas da região de estabilidade perturbada via conjunto de nível de uma dada função energia na vizinhança de um parâmetro de bifurcação sela-nó do tipo zero, buscaremos exibir resultados que permitam compreender o comportamento da região de estabilidade e de sua fronteira sob a influência das variações do parâmetro, incluindo variações do parâmetro próximo a um parâmetro de bifurcação sela-nó do tipo zero. / Estimating the stability region of an asymptotically stable equilibrium point is fundamental in applications such as power systems, economy and ecology. The knowledge of the qualitative structure of the stability boundary is essential to estimate with efficiency the stability region. Topological and dynamical characterizations of the stability boundary have been developed over the past decades. These characterizations were developed under assumptions of hyperbolicity of equilibrium points on the stability boundary and transversality. For systems that depend on parameters, the condition of hyperbolicity can be violated at points of bifurcations. We will be primarily interested in estimating the stability region, for systems subjected to parameter variations, when the condition of hyperbolicity of equilibrium points on the stability boundary is violated due to the appearance of a type-zero saddle-node bifurcation on the stability boundary. We will develop in this work, a complete characterization of the stability boundary in the presence of a type-zero saddle-node non-hyperbolic equilibrium point. Also, motivated to providing a conceptual algorithm to obtain estimates of the perturbed stability region via level sets of a given energy function in the neighborhood of a type-zero saddle-node bifurcation parameter, we offer results that explain the behavior of the stability region and its boundary under the influence of parameter variations, including variations of the parameter close to a type-zero saddle-node bifurcation parameter.

La biopsie du ganglion sentinelle (GS) est actuellement la technique de référence pour le diagnostic des métastases ganglionnaires du cancer du sein. Cependant, les traceurs utilisés pour la cartographie du GS (colorant bleu et radiocolloïde) ne sont pas idéaux et peuvent occasionner des réactions allergiques et engendrer des coûts importants. Une alternative à l'utilisation de ces traceurs repose sur le repérage du GS par imagerie de fluorescence proche infrarouge à l'aide de nanoparticules. Deux types de nanoparticules ont été étudiés : les Quantum Dots (QDs) à base d'indium et les nanoparticules de silice (NPSi) renfermant de la cyanine 7. Dans un modèle murin de carcinome mammaire, tous les GS envahis par les métastases ont pu être visualisés grâce à la fluorescence des QDs-indium. L'étude de biodistribution a mis en évidence une capture majeure des QDs au point d'injection et dans les ganglions associée à une faible concentration dans le foie et la rate. La toxicité des QDs a été évaluée in vitro et a démontré une toxicité fortement réduite des QDs-indium par rapport aux QDs-cadmium. Les NPSi présentent les avantages suivants : biocompatibilité, amélioration de la rétention dans le ganglion et des propriétés photophysiques par rapport au fluorophore libre. Le GS est rapidement visualisable par fluorescence suite à l'injection de NPSi. Le suivi des souris, pendant 3 mois post-injection, n'a révélé aucun signe de toxicité générale ou hépatique. Ces deux types de nanoparticules fluorescentes sont particulièrement bien adaptés à la cartographie du GS et pourraient avantageusement remplacer les traceurs employés actuellement / Sentinel lymph node (SLN) biopsy is a reliable technique for the diagnosis of metastases in breast cancer. However, the tracers used (blue dye and radiocolloid) are not optimal because they can cause allergic reactions and major costs in waste processing. Our strategy was to use near-infrared emitting nanoparticles for the mapping of SLN: indium-based Quantum Dots (QDs) and cyanine 7 embedded in silica nanoparticles (SiNP). In a murine model of mammary carcinoma, all SLN containing lymphatic metastases could be visualized with fluorescent indium-based QDs. The biodistribution study concluded that the major organs of retention were the injection point and lymph nodes whereas liver and spleen accumulated fewer QDs. The cytotoxicity tests demonstrated a weak in vitro toxicity of indium- compared to cadmium-based QDs. SiNP show several advantages over free fluorophore such as biocompatibility, better retention in the SLN and greatest photophysical properties. SLN could be mapped as soon as 5 minutes after SiNP injection. The in vivo toxicity in mice was followed during 3 months after injection and did not reveal any signs of general or hepatic toxicity. Both fluorescent nanoparticles are thus well adapted for the mapping of the SLN and could be a favourable substitute to the actually tracers

Au cours du développement tumoral, le système immunitaire est constamment exposé aux antigènes tumoraux, mais le plus souvent dans un contexte non-inflammatoire qui favorise l'induction d'une tolérance envers ces antigènes. La tolérance peut être médiée par des mécanismes passifs (ignorance, anergie ou délétion des clones spécifiques de la tumeur) ou actifs, pour lesquels les lymphocytes T régulateurs (Tregs) jouent un rôle prépondérant. Les lymphocytes T (LT) CD4+ sont la source principale des Tregs mais présentent également des fonctions antitumorales directes et indirectes. Les connaissances actuelles sur le rôle des LT CD4+ au cours du développement tumoral proviennent en grande partie d'études de modèles murins de tumeurs transplantées. Cependant, l'inflammation initiée lors de l'inoculation de ces tumeurs due à une mort cellulaire importante favorise la présentation persistante par le MHC-II des antigènes tumoraux dans un environnement inflammatoire artificiel. Nous tentons ici de contourner ce problème en utilisant deux modèles murins différents: le premier est un modèle de tumeur transplantée dans lequel un néoantigène de classe II (DBY) est induit à distance du moment de l'inoculation de la tumeur. Le deuxième est un modèle d'adénocarcinome pulmonaire induit génétiquement exprimant l’epitope DBY, dans lequel la tumorigenèse est initiée par l'expression d’un oncogène associée à la délétion d’un gène suppresseur de tumeurs. La réponse antitumorale des LT CD4+ est suivie par le transfert de LT CD4+ spécifiques de DBY "Marilyn". Dans le modèle de tumeur transplantée, nous montrons que l'apparition d'un néoantigène dans une tumeur bien établie n'est pas ignorée par le système immunitaire. Bien au contraire, le néoantigène arrive au ganglion drainant la tumeur et induit une activation efficace des cellules Marilyn, qui prolifèrent, produisent de l'IFN-γ et recirculent jusqu'à la tumeur. En revanche, malgré une activation efficace des LT CD4+, les tumeurs ne sont pas rejetées. Dans le modèle génétiquement induit, nous montrons que des néoantigènes exprimés dès le début du développement tumoral, arrivent jusqu'au ganglion drainant la tumeur en quantité suffisante pour induire l'activation et la prolifération des LT CD4+, mais que cette activation est non-optimale et ne permet qu'une faible migration vers le site de la tumeur. En revanche, une partie des cellules Marilyn acquièrent l'expression de FOXP3 ainsi qu'une signature transcriptomique de Tregs et ce dès les stades précoces du développement tumoral, tandis que le reste des cellules Marilyn présentent un phénotype anergique (CD44hiCD73hiFR4hi). L'administration de CpG n'empêche pas la conversion en Treg des cellules Marilyn, malgré l'augmentation de la maturation des cellules dendritiques dans le poumon et le ganglion drainant la tumeur. La déplétion des Tregs de l'hôte en revanche inhibe cette conversion et favorise l'activation des cellules Marilyn en cellules effectrices compétentes, capables de migrer jusqu'au site tumoral. Enfin, les cellules Marilyn, lorsqu'elles sont activées hors du ganglion drainant la tumeur échappent à l'inhibition induite par la tumeur et deviennent des cellules effectrices compétentes. Ainsi, dans un modèle tumoral reproduisant le développement naturel progressif des tumeurs humaines, un état de tolérance est induit par la tumeur. Cette tolérance est dépendante des Tregs présents dans le ganglion drainant la tumeur, qui confèrent une tolérance aux LT CD4+ naïfs arrivant dans le ganglion. / During tumor development, the immune system is persistently exposed to tumor-associated antigens, frequently in a non-inflammatory context, favoring the establishment of tolerance. Passive (ignorance, anergy or deletion of tumor-specific T cells) or active mechanisms mediated by regulatory T cells (Tregs) may be involved in tolerance. CD4+ T cells are the main source of Tregs but they also display indirect and direct antitumor activity. So far, the contribution of CD4+ T cells during tumor development has been mainly addressed in murine transplanted tumor models. However, in these models the artificial inflammation associated with the presence of dying tumor cells at the time of tumor inoculation favors a long-lasting MHC-II-restricted tumor antigen presentation in an artificial inflammatory context. Here, we addressed this issue using two different models: a transplanted one in which the MHC-II neoantigen (DBY) is induced long after tumor implantation and a genetically engineered mouse (GEM) model of lung adenocarcinoma also expressing the DBY epitope, in which malignant transformation results from both the expression of an oncogene and the deletion of a tumor suppressor gene. Tumor-specific CD4+ T cell response was followed by transfer of naive DBY-specific Marilyn CD4+ T cells. In the transplanted tumor model, we found that the appearance of a neoantigen in established tumors was not ignored by the immune system. On the contrary, the neoantigen reached the tumor-draining lymph node (TdLN) and induced efficient priming of Marilyn cells that proliferated, produced IFN-γ, and recirculated to the tumor site. However, despite efficient induction of a tumor-specific CD4+ T cell response, tumors were not rejected. In the GEM model, we found that starting at the early tumor stages, neoantigens were expressed and reached the TdLN in sufficient amount to induce activation and proliferation of naive Marilyn T cells. However, this priming was suboptimal and resulted in a weak migration to the tumor site. Instead, some of the activated Marilyn cells acquired the expression of FOXP3 and a Treg gene signature while the remaining FOXP3- cells displayed a CD44hiCD73hiFR4hi anergic phenotype. CpG administration did not revert the Marilyn Treg conversion despite reinforcing dendritic cell maturation in the lung and the TdLN. Depletion of the host Treg compartment however, inhibited this conversion and favored Marilyn cell activation into full-blown effector cells able to migrate to the tumor site. Finally, Marilyn cells that were primed at distance of the TdLN, escaped tumor induced inhibition and became full effectors. Thus, in a tumor model reproducing the natural development of slowly growing human tumors, a tumor-associated dominant tolerance is established in the lymph node draining the tumor. This state of unresponsiveness is highly dependent on the presence of Treg cells in the TdLN, conferring tolerance to incoming tumor-specific naive CD4+ T cells.

A elaboração de planos de restabelecimento de energia (PRE) de forma rápida, para re-energização de sistemas de distribuição radiais (SDR), faz-se necessária para lidar com situações que deixam regiões dos SDR sem energia. Tais situações podem ser causadas por faltas permanentes ou pela necessidade de isolar zonas dos SDR para serviços de manutenção. Dentre os objetivos de um PRE, destacam-se: (i) reduzir o número de consumidores interrompidos (ou nenhum), e (ii) minimizar o número de manobras; que devem ser atendidos sem desrespeitar os limites operacionais dos equipamentos. Conseqüentemente, a obtenção de PRE em SDR é um problema com múltiplos objetivos, alguns conflitantes. As principais técnicas desenvolvidas para obtenção de PRE em SDR baseiam-se em algoritmos evolutivos (AE). A limitação da maioria dessas técnicas é a necessidade de simplificações na rede, para lidar com SDR de grande porte, que limitam consideravelmente a possibilidade de obtenção de um PRE adequado. Propõe-se, neste trabalho, o desenvolvimento e implantação computacional de um algoritmo para obtenção de PRE em SDR, que consiga lidar com sistemas de grande porte sem a necessidade de simplificações, isto é, considerando uma grande parte (ou a totalidade) de linhas, barras, cargas e chaves do sistema. O algoritmo proposto baseia-se em um AE multi-objetivo e na estrutura de dados, para armazenamento de grafos, denominada representação nó-profundidade (RNP), bem como em dois operadores genéticos que foram desenvolvidos para manipular de forma eficiente os dados armazenados na RNP. Em razão de se basear em um AE multi-objetivo, o algoritmo proposto possibilita uma investigação mais ampla do espaço de busca. Por outro lado, fazendo uso da RNP, para representar computacionalmente os SDR, e de seus operadores genéticos, o algoritmo proposto aumenta significativamente a eficiência da busca por adequados PRE. Isto porque aqueles operadores geram apenas configurações radiais, nas quais todos os consumidores são atendidos. Para comprovar a eficiência do algoritmo proposto, várias simulações computacionais foram realizadas, utilizando o sistema de distribuição real, de uma companhia brasileira, que possui 3.860 barras, 635 chaves, 3 subestações e 23 alimentadores. / An elaborated and fast energy restoration plan (ERP) is required to deal with steady faults in radial distribution systems (RDS). That is, after a faulted zone has been identified and isolated by the relays, it is desired to elaborate a proper ERP to restore energy on that zone. Moreover, during the normal system operation, it is frequently necessary to elaborate ERP to isolate zones to execute routine tasks of network maintenance. Some of the objectives of an ERP are: (i) very few interrupted customers (or none), and (ii) operating a minimal number of switches, while at the same time respecting security constraints. As a consequence, the service restoration is a multiple objective problem, with some degree of conflict. The main methods developed for elaboration of ERP are based on evolutionary algorithms (EA). The limitation of the majority of these methods is the necessity of network simplifications to work with large-scale RDS. In general, these simplifications restrict the achievement of an adequate ERP. This work proposes the development and implementation of an algorithm for elaboration of ERP, which can deal with large-scale RDS without requiring network simplifications, that is, considering a large number (or all) of lines, buses, loads and switches of the system. The proposed algorithm is based on a multi-objective EA, on a new graph tree encoding called node-depth encoding (NDE), as well as on two genetic operators developed to efficiently manipulate a graph trees stored in NDEs. Using a multi-objective EA, the proposed algorithm enables a better exploration of the search space. On the other hand, using NDE and its operators, the efficiency of the search is increased when the proposed algorithm is used generating proper ERP, because those operators generate only radial configurations where all consumers are attended. The efficiency of the proposed algorithm is shown using a Brazilian distribution system with 3,860 buses, 635 switches, 3 substations and 23 feeders.

Objetivos: Este trabalho objetivou avaliar e comparar a incidência de linfedema, dor, restrição na amplitude de movimento e déficit sensorial 1 dia, 15 dias, 3 meses, 6 meses e 18 meses no membro superior homolateral, após linfadenectomia axilar total (LAT) e biópsia de linfonodo sentinela (BLS) para tratamento do câncer de mama. MÉTODOS: Neste estudo incluiu-se pacientes que realizaram ressecção segmentar de mama e LAT ou BLS. As pacientes foram avaliadas entre Dezembro de 2003 e Dezembro de 2004 e foram constituídos por dois grupos, o grupo A (n=100) foi formado por casos submetidos à LAT e o Grupo B, por casos submetidos à BLS (n=50). As pacientes foram analisadas através de questionário com respostas afirmativas e negativas, onde foram incluídas questões avaliando os sintomas de linfedema, dor, restrição da amplitude de movimento e déficit sensorial 1 dia (n=30), 15 dias (n=30), 6 meses (n=30) e 18 meses (n=30), após o procedimento cirúrgico. Além disto efetuou-se avaliação fisioterapêutica na qual foi realizada perimetria de membros superiores, mensuração da amplitude de movimento através da goniometria, os testes de sensibilidade cutânea através dos monofilamentos de Semmes-Weinstein e teste eletrodiagnóstico, utilizando-se gerador universal de correntes. RESULTADOS: No grupo A houve diferenças significantes (p < 0,05) em todos os sintomas subjetivamente avaliados, existindo maior queixa de edema (31%), dor (58%), restrição do movimento (52%) e dormência (57%). No grupo B houve menor prevalência da sensação de edema (2%), dor (26%), restrição do movimento (24%) e dormência (20%), em todos os tempos estudados. No exame clínico, o exame sensorial com monofilamentos apresentou 82% de diminuição da sensibilidade tátil na região axilar e 73% na região braquial proximal no grupo de mulheres submetidas à LAT e no grupo de mulheres submetidas à BLS houve diminuição da sensibilidade tátil nas duas regiões avaliadas em 40% (p<0.05). Nas provas cronaximétricas, a sensibilidade estava diminuída no grupo de mulheres submetidas à LAT em 56% na região axilar e 48% na região braquial proximal medial e no grupo BLS a sensibilidade estava diminuída em 39% e 14% respectivamente. CONCLUSÕES: A morbidade é maior a e funcionalidade do braço é menor em mulheres submetidas à LAT, quando comparadas à BLS, em mulheres operadas por câncer de mama / OBJECTIVES: The aim of this study was to evaluate and compare occurrence of lymphedema, pain, motion restriction and sensory deficit in the upper homolateral limb at 1 day, 15 days, 3 months, 6 months and 18 months after axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB) after breast cancer surgery. METHODS: A controlled study was designed to include patients who underwent breast conservative surgery and ALND or SLNB. Patients were evaluated between December 2003 and December 2004, and they were divided into two groups, group A (n=100) consisted who had ALND and group B, with patients after only SLNB (n=50). All of them subjectively answer a \"yes\" or \"no\" questionnaire in which were included questions about incidence of lymphedema, pain, motion restriction and arm numbness at 1day (n=30), 15 days (n=30), 3 months (n=30), 6 months (n=30) and 18 months (n=30) after surgery. Besides this a physiotherapy examination was performed measuring circunference, shoulder adbuction range by a goniometer, sensibility tests by pressure Semmes-Weinsten monofilaments and by eletrodiagnostic tests using an universal stimulator. RESULTS: In the group A significant differences (p < 0,05) were seen in subjectively sensations, with significantly higher incidence of subjective swelling (31%), pain (58%), motion restriction (52%), arm numbness (57%). In group B there were less symptoms of subjective swelling (2%), pain (58%), motion restriction (24%), arm numbness (20%). In clinical examination sensory deficit using monofilaments the occurrence of numbness was 82% on axillary fold and 73% on medial part of upper arm after ALND and in 40% on axillary fold and medial part of upper arm after SLNB, with significantly different between the groups (p < 0.05). At cronaximetric proofs the sensibility was decreased in 56% in the axillary fold and 48% in the medial part of upper arm for ALND and 39% in the axillary fold and 14% at medial part of upper arm on patients who underwent SLNB. CONCLUSIONS: Arm morbidity is higher and function is lower after ALND compared to SLNB, in women submitted to breast cancer surgery

Cette thèse explore les caractéristiques uniques offertes par le mélangeur Josephson dans le domaine émergeant de l’optique quantique micro-onde. Nous avons démontré que le mixeur Josephson pouvait jouer trois rôles majeurs pour le traitement de l’information quantique. Nous avons conçu et fabriqué un amplificateur à la limite quantique avec la meilleure efficacité quantique démontrée à cette date. Cet outil crucial peut être utilisé pour la mesure microonde de systèmes mésoscopiques dont les circuits supraconducteurs. En particulier, cela nous a permis de réaliser avec succès la stabilisation de trajectoires d’un bit quantique supraconducteur par rétroaction basée sur la mesure. Ensuite, nous avons montré comment ce circuit peut générer et distribuer des radiations micro-ondes intriquées par conversion paramétrique spontanée sur des lignes de transmissions séparées dans l’espace et à des fréquences différentes. En utilisant deux mixeurs Josephson, nous avons fourni la première démonstration d’intrication non- locale entre deux champs propageants dans le domaine micro-onde, les états dits EPR. Finalement, nous avons utilisé le mixeur Josephson dans le mode de conversion de fréquence. Il se comporte alors comme un interrupteur, permettant d’ouvrir ou fermer dynamiquement l’accès à une cavité de haut facteur de qualité. L’ensemble constitue une mémoire quantique. En combinant cela avec la génération d’intrication, nous avons mesuré la distribution, le stockage et la libération sur demande d’un état intriqué. Ceci est un pré-requis pour jouer le rôle de nœud au sein d’un réseau quantique. / This thesis work explores unique features offered by the Josephson mixer in the upcoming field of microwave quantum optics. We have demonstrated three major roles the Josephson mixer could play in emerging quantum information architectures. First, we have designed and fabricated a state-of-the-art practical quantum limited amplifier with the best quantum efficiency achieved to date. This tool is crucial for probing mesoscopic systems with microwaves, and in particular superconducting circuits. Hence, it has enabled us to realize successfully the stabilization of quantum trajectories of a superconducting qubit by measurement-based feedback. Second, we have shown how this circuit can generate and distribute entangled microwave radiations on separated transmission lines at different frequencies. Using two Josephson mixers, we have provided the first demonstration of entanglement between spatially separated propagating fields in the microwave domain, the so-called Einstein-Podolsky-Rosen states. Finally, we have used the Josephson mixer as a frequency converter. Acting as a switch, it is able to dynamically turn on and off the coupling to a low loss cavity. This feature allowed us to realize a quantum memory for microwaves. In combination with the ability to generate entanglement, we have measured the time-controlled generation, storage and on-demand release of an entangled state, which is a prerequisite for nodes of a quantum network.

Objetivos: Este trabalho objetivou avaliar e comparar a incidência de linfedema, dor, restrição na amplitude de movimento e déficit sensorial 1 dia, 15 dias, 3 meses, 6 meses e 18 meses no membro superior homolateral, após linfadenectomia axilar total (LAT) e biópsia de linfonodo sentinela (BLS) para tratamento do câncer de mama. MÉTODOS: Neste estudo incluiu-se pacientes que realizaram ressecção segmentar de mama e LAT ou BLS. As pacientes foram avaliadas entre Dezembro de 2003 e Dezembro de 2004 e foram constituídos por dois grupos, o grupo A (n=100) foi formado por casos submetidos à LAT e o Grupo B, por casos submetidos à BLS (n=50). As pacientes foram analisadas através de questionário com respostas afirmativas e negativas, onde foram incluídas questões avaliando os sintomas de linfedema, dor, restrição da amplitude de movimento e déficit sensorial 1 dia (n=30), 15 dias (n=30), 6 meses (n=30) e 18 meses (n=30), após o procedimento cirúrgico. Além disto efetuou-se avaliação fisioterapêutica na qual foi realizada perimetria de membros superiores, mensuração da amplitude de movimento através da goniometria, os testes de sensibilidade cutânea através dos monofilamentos de Semmes-Weinstein e teste eletrodiagnóstico, utilizando-se gerador universal de correntes. RESULTADOS: No grupo A houve diferenças significantes (p < 0,05) em todos os sintomas subjetivamente avaliados, existindo maior queixa de edema (31%), dor (58%), restrição do movimento (52%) e dormência (57%). No grupo B houve menor prevalência da sensação de edema (2%), dor (26%), restrição do movimento (24%) e dormência (20%), em todos os tempos estudados. No exame clínico, o exame sensorial com monofilamentos apresentou 82% de diminuição da sensibilidade tátil na região axilar e 73% na região braquial proximal no grupo de mulheres submetidas à LAT e no grupo de mulheres submetidas à BLS houve diminuição da sensibilidade tátil nas duas regiões avaliadas em 40% (p<0.05). Nas provas cronaximétricas, a sensibilidade estava diminuída no grupo de mulheres submetidas à LAT em 56% na região axilar e 48% na região braquial proximal medial e no grupo BLS a sensibilidade estava diminuída em 39% e 14% respectivamente. CONCLUSÕES: A morbidade é maior a e funcionalidade do braço é menor em mulheres submetidas à LAT, quando comparadas à BLS, em mulheres operadas por câncer de mama / OBJECTIVES: The aim of this study was to evaluate and compare occurrence of lymphedema, pain, motion restriction and sensory deficit in the upper homolateral limb at 1 day, 15 days, 3 months, 6 months and 18 months after axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB) after breast cancer surgery. METHODS: A controlled study was designed to include patients who underwent breast conservative surgery and ALND or SLNB. Patients were evaluated between December 2003 and December 2004, and they were divided into two groups, group A (n=100) consisted who had ALND and group B, with patients after only SLNB (n=50). All of them subjectively answer a \"yes\" or \"no\" questionnaire in which were included questions about incidence of lymphedema, pain, motion restriction and arm numbness at 1day (n=30), 15 days (n=30), 3 months (n=30), 6 months (n=30) and 18 months (n=30) after surgery. Besides this a physiotherapy examination was performed measuring circunference, shoulder adbuction range by a goniometer, sensibility tests by pressure Semmes-Weinsten monofilaments and by eletrodiagnostic tests using an universal stimulator. RESULTS: In the group A significant differences (p < 0,05) were seen in subjectively sensations, with significantly higher incidence of subjective swelling (31%), pain (58%), motion restriction (52%), arm numbness (57%). In group B there were less symptoms of subjective swelling (2%), pain (58%), motion restriction (24%), arm numbness (20%). In clinical examination sensory deficit using monofilaments the occurrence of numbness was 82% on axillary fold and 73% on medial part of upper arm after ALND and in 40% on axillary fold and medial part of upper arm after SLNB, with significantly different between the groups (p < 0.05). At cronaximetric proofs the sensibility was decreased in 56% in the axillary fold and 48% in the medial part of upper arm for ALND and 39% in the axillary fold and 14% at medial part of upper arm on patients who underwent SLNB. CONCLUSIONS: Arm morbidity is higher and function is lower after ALND compared to SLNB, in women submitted to breast cancer surgery

A elaboração de planos de restabelecimento de energia (PRE) de forma rápida, para re-energização de sistemas de distribuição radiais (SDR), faz-se necessária para lidar com situações que deixam regiões dos SDR sem energia. Tais situações podem ser causadas por faltas permanentes ou pela necessidade de isolar zonas dos SDR para serviços de manutenção. Dentre os objetivos de um PRE, destacam-se: (i) reduzir o número de consumidores interrompidos (ou nenhum), e (ii) minimizar o número de manobras; que devem ser atendidos sem desrespeitar os limites operacionais dos equipamentos. Conseqüentemente, a obtenção de PRE em SDR é um problema com múltiplos objetivos, alguns conflitantes. As principais técnicas desenvolvidas para obtenção de PRE em SDR baseiam-se em algoritmos evolutivos (AE). A limitação da maioria dessas técnicas é a necessidade de simplificações na rede, para lidar com SDR de grande porte, que limitam consideravelmente a possibilidade de obtenção de um PRE adequado. Propõe-se, neste trabalho, o desenvolvimento e implantação computacional de um algoritmo para obtenção de PRE em SDR, que consiga lidar com sistemas de grande porte sem a necessidade de simplificações, isto é, considerando uma grande parte (ou a totalidade) de linhas, barras, cargas e chaves do sistema. O algoritmo proposto baseia-se em um AE multi-objetivo e na estrutura de dados, para armazenamento de grafos, denominada representação nó-profundidade (RNP), bem como em dois operadores genéticos que foram desenvolvidos para manipular de forma eficiente os dados armazenados na RNP. Em razão de se basear em um AE multi-objetivo, o algoritmo proposto possibilita uma investigação mais ampla do espaço de busca. Por outro lado, fazendo uso da RNP, para representar computacionalmente os SDR, e de seus operadores genéticos, o algoritmo proposto aumenta significativamente a eficiência da busca por adequados PRE. Isto porque aqueles operadores geram apenas configurações radiais, nas quais todos os consumidores são atendidos. Para comprovar a eficiência do algoritmo proposto, várias simulações computacionais foram realizadas, utilizando o sistema de distribuição real, de uma companhia brasileira, que possui 3.860 barras, 635 chaves, 3 subestações e 23 alimentadores. / An elaborated and fast energy restoration plan (ERP) is required to deal with steady faults in radial distribution systems (RDS). That is, after a faulted zone has been identified and isolated by the relays, it is desired to elaborate a proper ERP to restore energy on that zone. Moreover, during the normal system operation, it is frequently necessary to elaborate ERP to isolate zones to execute routine tasks of network maintenance. Some of the objectives of an ERP are: (i) very few interrupted customers (or none), and (ii) operating a minimal number of switches, while at the same time respecting security constraints. As a consequence, the service restoration is a multiple objective problem, with some degree of conflict. The main methods developed for elaboration of ERP are based on evolutionary algorithms (EA). The limitation of the majority of these methods is the necessity of network simplifications to work with large-scale RDS. In general, these simplifications restrict the achievement of an adequate ERP. This work proposes the development and implementation of an algorithm for elaboration of ERP, which can deal with large-scale RDS without requiring network simplifications, that is, considering a large number (or all) of lines, buses, loads and switches of the system. The proposed algorithm is based on a multi-objective EA, on a new graph tree encoding called node-depth encoding (NDE), as well as on two genetic operators developed to efficiently manipulate a graph trees stored in NDEs. Using a multi-objective EA, the proposed algorithm enables a better exploration of the search space. On the other hand, using NDE and its operators, the efficiency of the search is increased when the proposed algorithm is used generating proper ERP, because those operators generate only radial configurations where all consumers are attended. The efficiency of the proposed algorithm is shown using a Brazilian distribution system with 3,860 buses, 635 switches, 3 substations and 23 feeders.