Le glaucome est la deuxième cause de cécité irréversible dans le monde. La perte de vision qui se produit lors du glaucome s’explique par une dégénérescence du nerf optique et une mort progressive et sélective des cellules ganglionnaires de la rétine (CRG). L'hypertension oculaire est un facteur de risque majeur dans le glaucome, mais des défauts du champ visuel continuent à se développer chez un contingent de patients malgré l'administration de médicaments qui abaissent la pression intraoculaire (PIO). Par conséquent, bien que la PIO représente le seul facteur de risque modifiable dans le développement du glaucome, son contrôle ne suffit pas à protéger les CRGs et préserver la fonction visuelle chez de nombreux patients. Dans ce contexte, j'ai avancé l'hypothèse centrale voulant que les stratégies de traitement du glaucome visant à promouvoir la protection structurale et fonctionnelle des CRGs doivent agir sur les mécanismes moléculaires qui conduisent à la mort des ces neurones. Dans la première partie de ma thèse, j'ai caractérisé l'effet neuroprotecteur de la galantamine, un inhibiteur de l'acétylcholinestérase qui est utilisé cliniquement dans le traitement de la maladie d'Alzheimer. Cette étude s’est basée sur l'hypothèse que la galantamine, en modulant l'activité du récepteur de l'acétylcholine, puisse améliorer la survie des CRGs lors du glaucome. Nous avons utilisé un modèle expérimental bien caractérisé d'hypertension oculaire induite par l’administration d'une solution saline hypertonique dans une veine épisclérale de rats Brown Norway. Les résultats de cette étude (Almasieh et al. Cell Death and Disease, 2010) ont démontré que l'administration quotidienne de galantamine améliore de manière significative la survie des corps cellulaires et des axones CRGs. La protection structurelle des CRGs s’accompagne d’une préservation remarquable de la fonction visuelle, évaluée par l'enregistrement des potentiels évoqués visuels (PEV) dans le collicule supérieur, la cible principale des CRGs chez le rongeur. Une autre constatation intéressante de cette étude est la perte substantielle de capillaires rétiniens et la réduction du débit sanguin associé à la perte des CRGs dans le glaucome expérimental. Il est très intéressant que la galantamine ait également favorisé la protection de la microvascularisation et amélioré le débit sanguin rétinien des animaux glaucomateux (Almasieh et al. en préparation). J'ai notamment démontré que les neuro-et vasoprotections médiées par la galantamine se produisent par iv l'activation des récepteurs muscariniques de l'acétylcholine. Dans la deuxième partie de ma thèse, j'ai étudié le rôle du stress oxydatif ainsi que l'utilisation de composés réducteurs pour tester l'hypothèse que le blocage d'une augmentation de superoxyde puisse retarder la mort des CRG lors du glaucome expérimental. J'ai profité d'un composé novateur, un antioxydant à base de phosphineborane (PB1), pour tester sur son effet neuroprotecteur et examiner son mécanisme d'action dans le glaucome expérimental. Les données démontrent que l'administration intraoculaire de PB1 entraîne une protection significative des corps cellulaire et axones des CRGs. Les voies moléculaires conduisant à la survie neuronale médiée par PB1 ont été explorées en déterminant la cascade de signalisation apoptotique en cause. Les résultats démontrent que la survie des CRGs médiée par PB1 ne dépend pas d’une inhibition de signalisation de protéines kinases activées par le stress, y compris ASK1, JNK ou p38. Par contre, PB1 induit une augmentation marquée des niveaux rétiniens de BDNF et une activation en aval de la voie de survie des ERK1 / 2 (Almasieh et al. Journal of Neurochemistry, 2011). En conclusion, les résultats présentés dans cette thèse contribuent à une meilleure compréhension des mécanismes pathologiques qui conduisent à la perte de CRGs dans le glaucome et pourraient fournir des pistes pour la conception de nouvelles stratégies neuroprotectrices et vasoprotectrices pour le traitement et la gestion de cette maladie. / Glaucoma is the second cause of irreversible blindness worldwide. Loss of vision in glaucoma is accompanied by progressive optic nerve degeneration and selective loss of retinal ganglion cells (RGCs). Ocular hypertension is a major risk factor in glaucoma, but visual field defects continue to progress in a large group of patients despite the use of drugs that lower intraocular pressure (IOP). Therefore, although IOP is the sole modifiable risk factor in the development of glaucoma, its regulation is not sufficient to protect RGCs and preserve visual function in many affected patients. To address this issue, I put forward the central hypothesis that effective therapeutic strategies for glaucoma must interfere with molecular mechanisms that lead to RGC death to successfully promote structural and functional protection of these neurons. In the first part of my thesis, I characterized the neuroprotective effect of galantamine, an acetylcholinesterase inhibitor that is clinically used for the treatment of Alzheimer’s disease. The specific hypothesis of this study was that galantamine, by modulating acetylcholine receptor activity, can improve the survival of injured RGCs in glaucoma. A well characterized experimental model of ocular hypertension induced by administration of a hypertonic saline into an episcleral vein of Brown Norway rats was used. The results of this study (Almasieh et al. Cell Death and Disease, 2010) demonstrated that daily administration of galantamine significantly improved the survival of RGC soma and axons in this model. Structural protection of RGCs correlated with substantial preservation of visual function, assessed by recording visual evoked potentials (VEPs) from the superior colliculus, the primary target of RGCs in the rodent brain. An interesting finding during the course of my thesis was that there is a substantial loss of retinal capillaries and a reduction in retinal blood that correlates with RGC loss in experimental glaucoma. Interestingly, galantamine also promoted the protection of the microvasculature and improved retinal blood flow in ocular hypertensive animals (Almasieh et al. in preparation). Importantly, I demonstrated that galantamine-mediated neuro- and vasoprotection occur through activation of muscarinic acetylcholine receptors. In the second part of my thesis, I investigated the role of oxidative stress and the use of reducing compounds to test the hypothesis that blockade of a superoxide burst may delay RGC death in experimental glaucoma. I took advantage of a novel phosphinevi borane based antioxidant compound available to us (PB1) to investigate its neuroprotective effect and mechanism of action in experimental glaucoma. The data demonstrate that intraocular administration of PB1 resulted in significant protection of RGC soma and axons. I also explored the molecular pathways leading to PB1-mediated neuronal survival by analyzing the components of survival and apoptotic signaling pathways involved in this response. My results show that PB1-mediated RGC survival did not correlate with inhibition of stress-activated protein kinase signaling, including ASK1, JNK or p38. Instead, PB1 led to a striking increase in retinal BDNF levels and downstream activation of the pro-survival ERK1/2 pathway (Almasieh et al. Journal of Neurochemistry, 2011). In conclusion, the findings presented in this thesis contribute to a better understanding of the pathological mechanisms underlying RGC loss in glaucoma and might provide insights into the design of novel neuroprotective and vasoprotective strategies for the treatment and management of this disease.

The mechanisms behind cardiovascular disease (CVD) initiation and progression are not fully elucidated. It is hypothesized that blood flow patterns regulate endothelial cell (EC) function to affect the progression of CVDs. A system that subjects ECs to physiologically-relevant shear stress waveforms within microfluidic devices has not yet been demonstrated, despite the advantages associated with the use of these devices. In this work, a bioreactor was designed to fulfill this need. Waveforms from regions commonly affected by CVDs including were derived. Pump motion and fluid flow profiles were validated by actuator motion tracking, particle image velocimetry, and flowmeters. While several relevant waveforms were successfully replicated, physiological waveforms could not be produced at physiological frequencies owing to actuator velocity and accuracy limitations, as well as dampening effects in the system. Overall, this work lays the foundation for designing a system that provides insight into the role of shear stress in CVD pathogenesis.

The mechanisms behind cardiovascular disease (CVD) initiation and progression are not fully elucidated. It is hypothesized that blood flow patterns regulate endothelial cell (EC) function to affect the progression of CVDs. A system that subjects ECs to physiologically-relevant shear stress waveforms within microfluidic devices has not yet been demonstrated, despite the advantages associated with the use of these devices. In this work, a bioreactor was designed to fulfill this need. Waveforms from regions commonly affected by CVDs including were derived. Pump motion and fluid flow profiles were validated by actuator motion tracking, particle image velocimetry, and flowmeters. While several relevant waveforms were successfully replicated, physiological waveforms could not be produced at physiological frequencies owing to actuator velocity and accuracy limitations, as well as dampening effects in the system. Overall, this work lays the foundation for designing a system that provides insight into the role of shear stress in CVD pathogenesis.

Positron emission tomography (PET) is a functional imaging method that allows studying physiological, biochemical or pharmacological processes in vivo. PET is being used in both research and clinical practice. In the brain, it has been used to investigate metabolism, receptor binding, and alterations in regional blood flow. This thesis involves both preclinical and clinical dual-tracer PET imaging studies of different neurological disorders. In this way, different radiotracers were used along the projects. The first project focused on the implementation and in vivo validation of the simultaneous dual-tracer PET imaging technique on the rat brain and its applications in the study of cerebral ischemia. In particular, in this project two biological processes were studied at the same time: cerebral blood flow and cerebral glucose metabolism. The second project consisted in a clinical correlation study of the GABAergic and serotonin systems in a population with Essential Tremor (ET), the most commonly movement disorders. / La tomografia per emissió de positrons (PET) és un mètode d'imatge funcional que permet l'estudi in vivo de processos fisiològics, bioquímics i farmacològics. La PET s'utilitza tant en la pràctica clínica com en la recerca. Al cervell, s'ha utilitzat per investigar el metabolisme, la neurotransmissió, i les alteracions en el flux sanguini regional. Aquesta tesi implica estudis preclínics i clínics de la tècnica PET en diversos trastorns neurològics. D'aquesta manera, es van utilitzar diferents radiotraçadors al llarg dels projectes. El primer projecte es va centrar en la implementació i validació in vivo de la tècnica PET del doble-marcador simultani en el cervell de rata i les seves aplicacions en l'estudi de la isquèmia cerebral. En particular, en aquest projecte es van estudiar en el mateix moment dos processos biològics: el flux sanguini cerebral i el metabolisme cerebral de la glucosa. El segon projecte va consistir en un estudi clínic de correlació dels sistemes GABAèrgic i serotoninèrgic en una població amb tremolor essencial (TE), el trastorn del moviment més comú

Cette thèse est consacrée à la modélisation mathématique de la coagulation sanguine et de la formation de thrombus dans des conditions normales et pathologiques. La coagulation sanguine est un mécanisme défensif qui empêche la perte de sang suite à la rupture des tissus endothéliaux. C'est un processus complexe qui est règlementé par différents mécanismes mécaniques et biochimiques. La formation du caillot sanguin a lieu dans l'écoulement sanguin. Dans ce contexte, l'écoulement à faible taux de cisaillement stimule la croissance du caillot tandis que la circulation sanguine à fort taux de cisaillement la limite. Les désordres qui affectent le système de coagulation du sang peuvent provoquer différentes anomalies telles que la thrombose (coagulation exagérée) ou les saignements (insuffisance de coagulation). Dans la première partie de la thèse, nous présentons un modèle mathématique de coagulation sanguine. Le modèle capture la dynamique essentielle de la croissance du caillot dans le plasma et le flux sanguin quiescent. Ce modèle peut être réduit à un modèle qui consiste en une équation de génération de thrombine et qui donne approximativement les mêmes résultats. Nous avons utilisé des simulations numériques en plus de l'analyse mathématique pour montrer l'existence de différents régimes de coagulation sanguine. Nous spécifions les conditions pour ces régimes sur différents paramètres pathophysiologiques du modèle. Ensuite, nous quantifions les effets de divers mécanismes sur la croissance du caillot comme le flux sanguin et l'agrégation plaquettaire. La partie suivante de la thèse étudie certaines des anomalies du système de coagulation sanguine. Nous commençons par étudier le développement de la thrombose chez les patients présentant une carence en antihrombine ou l'une des maladies inflammatoires. Nous déterminons le seuil de l'antithrombine qui provoque la thrombose et nous quantifions l'effet des cytokines inflammatoires sur le processus de coagulation. Puis, nous étudions la compensation de la perte du sang après un saignement en utilisant un modèle multi-échelles qui décrit en particulier l'érythropoïèse et la production de l'hémoglobine. Ensuite, nous évaluons le risque de thrombose chez les patients atteints de cancer (le myélome multiple en particulier) et le VIH en combinant les résultats du modèle de coagulation sanguine avec les produits des modèles hybrides (discret-continues) multi-échelles des systèmes physiologiques correspondants. Finalement, quelques applications cliniques possibles de la modélisation de la coagulation sanguine sont présentées. En combinant le modèle de formation du caillot avec les modèles pharmacocinétiques pharmacodynamiques (PK-PD) des médicaments anticoagulants, nous quantifions l'action de ces traitements et nous prédisons leur effet sur des patients individuels / This thesis is devoted to the mathematical modelling of blood coagulation and clot formation under flow in normal and pathological conditions. Blood coagulation is a defensive mechanism that prevents the loss of blood upon the rupture of endothelial tissues. It is a complex process that is regulated by different mechanical and biochemical mechanisms. The formation of the blood clot takes place in blood flow. In this context, low-shear flow stimulates clot growth while high-shear blood circulation limits it. The disorders that affect the blood clotting system can provoke different abnormalities such thrombosis (exaggerated clotting) or bleeding (insufficient clotting). In the first part of the thesis, we introduce a mathematical model of blood coagulation. The model captures the essential dynamics of clot growth in quiescent plasma and blood flow. The model can be reduced to a one equation model of thrombin generation that gives approximately the same results. We used both numerical simulations and mathematical investigation to show the existence of different regimes of blood coagulation. We specify the conditions of these regimes on various pathophysiological parameters of the model. Then, we quantify the effects of various mechanisms on clot growth such as blood flow and platelet aggregation. The next part of the thesis studies some of the abnormalities of the blood clotting system. We begin by investigating the development of thrombosis in patients with antihrombin deficiency and inflammatory diseases. We determine the thrombosis threshold on antithrombin and quantify the effect of inflammatory cytokines on the coagulation process. Next, we study the recovery from blood loss following bleeding using a multiscale model which focuses on erythropoiesis and hemoglobin production. Then, we evaluate the risk of thrombosis in patients with cancer (multiple myeloma in particular) and HIV by combining the blood coagulation model results with the output of hybrid multiscale models of the corresponding physiological system. Finally, possible clinical applications of the blood coagulation modelling are provided. By combining clot formation model with pharmacokinetics-pharmacodynamics (PK-PD) models of anticoagulant drugs, we quantify the action of these treatments and predict their effect on individual patients

Made available in DSpace on 2015-07-22T20:50:43Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-11-24. Added 1 bitstream(s) on 2015-08-11T03:26:10Z : No. of bitstreams: 1 Publico-12685a.pdf: 1258050 bytes, checksum: 53b17db1fdfbd3e4583d4358e7515aed (MD5). Added 1 bitstream(s) on 2015-08-11T03:26:10Z : No. of bitstreams: 2 Publico-12685a.pdf: 1258050 bytes, checksum: 53b17db1fdfbd3e4583d4358e7515aed (MD5) Publico-12685b.pdf: 2009901 bytes, checksum: 92f9b67aa48fc3b5890595ab949a78a4 (MD5). Added 1 bitstream(s) on 2015-08-11T03:26:10Z : No. of bitstreams: 3 Publico-12685a.pdf: 1258050 bytes, checksum: 53b17db1fdfbd3e4583d4358e7515aed (MD5) Publico-12685b.pdf: 2009901 bytes, checksum: 92f9b67aa48fc3b5890595ab949a78a4 (MD5) Publico-12685c.pdf: 2013198 bytes, checksum: 64df6a7e1d8d760785004ef7cb8107b9 (MD5) / Na insuficiencia cardiaca (IC) o comprometimento do fluxo sanguineo muscular na transicao do exercicio leve para o intenso pode reduzir temporariamente a pressao microvascular de O2 e diminuir a oferta de O2 do capilar para a mitocondria. No entanto, os avancos no tratamento medicamentoso da IC (por exemplo, os inibidores da enzima conversora de angiotensina e ƒÀ-bloqueadores de terceira geracao) poderiam ter melhorado a oferta microvascular de O2 a um ponto em que a lentidao da maquinaria metabolica intramuscular passaria a ser o fator limitante da resposta cinetica do consumo de oxigenio ( O2). O objetivo do presente estudo foi investigar a relacao dinamica entre oferta e utilizacao microvascular de O2 na transicao do exercicio leve (sem carga) para o intenso, em portadores de IC com tratamento otimizado e nao treinados, comparado a um grupo controle de individuos saudaveis. Foram incluidos 10 pacientes com IC com tratamento clinico otimizado (fracao de ejecao = 29 } 8%) e 11 controles pareados por idade. Avaliou-se as respostas cineticas da captacao pulmonar de O2 ( O2p), da extracao tissular de O2 no musculo vasto lateral, como estimada pela variacao na concentracao relativa de deoxihemoglobina + mioglobina (~ƒ¢[deoxi-Hb+Mb]), mensurada pelo metodo de espectroscopia de raios quasi-infravermelhos (NIRS) e do debito cardiaco (DC), durante exercicio de alta intensidade ate o limite de tolerancia (Tlim). A cinetica da O2p e do DC foram mais lentas nos pacientes com IC em comparacao aos controles e correlacionaram-se significativamente com menores valores de Tlim (P = 0,05). A cinetica total da ƒ¢[deoxi-Hb+Mb] foi mais rapida nos pacientes do que nos controles (tempo medio de resposta (MRT) = 15,9 } 2,0 s vs. 19,0 } 2,9 s; P = 0,05), com uma resposta de "overshoot" presente apenas nos pacientes (7/10). Alem disso, a razao t O2p/MRT-ƒ¢[deoxi-Hb+Mb] foi maior nos pacientes (4,69 } 1,42 s vs. 2,25 } 0,77 s; P < 0,05) e correlacionou-se com a cinetica do DC e o Tlim (R = 0,89 e 0,78, respectivamente; P = 0,01). Conclui-se que apesar dos avancos no tratamento medicamentoso da IC, os disturbios nos ajustes circulatorios "centrais" e "perifericos" continuam a desempenhar um papel proeminente na limitacao da cinetica da O2p e tolerancia a exercicio de alta intensidade em pacientes nao treinados com IC. / Impaired muscle blood flow at the onset of heavy-intensity exercise may transiently reduce microvascular O2 pressure and decrease the rate of O2 transfer from capillary to mitochondria in chronic heart failure (CHF). However, advances in the pharmacological treatment of CHF (e.g., angiotensin-converting enzyme inhibitors and third generation of â-blockers) may have improved microvascular O2 delivery to an extent that intramyocyte metabolic inertia might become the main locus of limitation of O2 uptake ( O2) kinetics. We included 10 optimally treated sedentary patients (ejection fraction = 29 ± 8%) and 11 age-matched controls. We assessed the rate of change of pulmonary O2 ( O2p), tissue O2 extraction in the vastus lateralis estimated by concentration of deoxy-hemoglobin+myoglobin (~Ä[deoxy-Hb+Mb]) measured by near-infrared spectroscopy (NIRS), and cardiac output ( T) during highintensity exercise performed to the limit of tolerance (Tlim). Sluggish O2p and T kinetics in patients were significantly related to lower Tlim values (P = 0.05). The dynamics of Ä[deoxy-Hb+Mb] were faster in patients than controls (mean response time (MRT) = 15.9 ± 2.0 s vs. 19.0 ± 2.9 s; P = 0.05) with a subsequent response “overshoot” being found only in patients (7/10). Moreover, t O2p/MRT-Ä[deoxy- Hb+Mb] ratio was greater in patients (4.69 ± 1.42 s vs. 2.25 ± 0.77 s; P = 0.05) and related to T kinetics and Tlim (R = 0.89 and 0.78, respectively; P = 0.01). We conclude that despite the advances in the pharmacological treatment of CHF, disturbances in “central” and “peripheral” circulatory adjustments still play a prominent role in limiting O2p kinetics and tolerance to heavy-intensity exercise in nontrained patients. / TEDE / BV UNIFESP: Teses e dissertações

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Cette thèse est consacrée à la modélisation mathématique et simulations numériques des écoulements sanguins dans des artères en présence d’une endoprothèse vasculaire de type stent. La présence de stent peut être considérée comme une perturbation locale d’un bord lisse d’écoulement, plus précisément les parois de l’artère sont assimilées à une surface fortement rugueuse. Nous nous sommes principalement intéressés au contrôle de la régularité H² sur un modèle simplifié permettant de prendre en compte l’effet de ces stents lorsque le flux sanguin est gouverné par une équation de Laplace (en lien avec la composante axiale de la vitesse d’écoulement) avec une condition aux limites de type Dirichlet, dans un domaine à bord rugueux (en fonction d’un petit paramètre ε). Dans une première partie, nous soulevons la question d’existence et d’unicité de la solution de ce modèle d’écoulement sanguin et nous traitons la régularité H² par des techniques d’analyse variationnelle. Une étude minutieuse permet de contrôler la régularité H² en O(ε−1). Le deuxième axe est dédié à l’étude de la régularité H² par des analyse asymptotiques multiéchelles. Nous montrons que la norme H² de la solution de ce modèle d’écoulement sanguin est singulière en O(ε−½ ). D’autre part, nous améliorons les ordres de convergence des résultats existants concernant la construction des approximations multiéchelles. Dans un troisième temps, nous présentons des estimations d’erreur et des résultats numériques. Ces résultats illustrent le bien fondé des estimations d’erreur sur le plan pratique. Nous montrons bien l’importance des méthodes asymptotiques qui se révèlent plus efficaces qu’un calcul direct. / This thesis is devoted to mathematical modeling and numerical simulations of the blood-flows in arteries in the presence of a vascular prosthesis of type stent. The presence of stent can be considered as a local perturbation of a smooth edge of flow, more precisely the walls artery can be seen as a strongly rough surface.Weare mainly interested in controlling the H² regularity of a simplified model which takes into account the impact of these stents when the blood flow is controlled by a Laplace equation (in link with the axial component rateof flow) with a Dirichlet boundary condition, in a domain with a rough board (according to a small parameter ε). First, we raise the question of existence and unicity of the solution of this model of blood-flow and we study the H² regularity using variational analysis methods. By a detailed study, we control the H² regularity of order O(ε−1). The second part is devoted to the study of the regularity H² regularity using multi-scale analysis.We prove that the H² norm of the solution of this model is singular of order O(ε−½). Moreover, we improve the convergence rate of the existing results on the construction of the multi-scale approximation. Finally, we present an error estimation and numerical results. These numerical results illustrate the well-founded of the error estimates on a practical level. We show the importance of the asymptotic methods that seem to be more effective than a direct computation.

A administração intravenosa de solução salina hipertônica (HSS) induz alterações sistêmicas circulatórias como o aumento da pressão arterial e do volume circulante efetivo, além de ter efeitos locais sobre a microcirculação. No presente estudo foram analisados os efeitos produzidos pela administração de solução salina hipertônica 7,5% sobre a hemodinâmica do tumor através de estudos de imagem funcional e posteriormente, foi avaliado o seu potencial de otimizar a entrega de moléculas no tumor. A velocidade do sangue nos vasos tumorais estimada por Ultrassom Color Doppler foi aumentada após a injeção da HSS em comparação ao controle PBS em tumores de melanoma (B16F10 (p=0,019), SK-MEL-147 (p =0,028)) e de mama (4T1 (p=0,015)). Este mesmo efeito não foi observado nas artérias segmentarias do rim (p=0,476). Ultrassonografia com contraste por microbolhas (CEUS) foi realizada em xenoenxertos de tumor de melanoma (B16F10), carcinoma de cólon (HCT-116) e mama (MDA-MB-231), e como controle foi realizada imagem no rim e no músculo nos animais portadores destes tipos tumorais (n=3 por grupo). Após a injeção da HSS, o volume relativo de sangue foi aumentado nos tumores B16F10 (p=0,022) e HCT-116 (P = 0,039), mas o mesmo não foi observado com o tumor MDA-MB-231 (p=0,186). Além disso, não houve alterações nos tecidos normais (rim p = 0,957; músculo p = 0,104). Todos os testes estatísticos foram bicaudais. Quando a HSS foi utilizada como veículo para entrega de moléculas de baixo peso molecular como cisplatina e doxorrubicina no tratamento de tumores B16F10 e 4T1 respectivamente, não houve aumento da eficácia terapêutica, avaliada através do crescimento tumoral e peso dos tumores. O efeito da HSS sobre a retenção de macromoléculas nos tumores SK-Mel- 147 e 4T1, avaliado através de imagem por epifluorescência do contraste ótico IR-783, não foi suficientemente notório para rejeitar a hipótese nula. Assim, a HSS induz um aumento transitório na velocidade do sangue e do volume sanguíneo, de maneira relativamente seletiva para os tumores avaliados, com exceção do MDA-MB-231. Portanto, esta pode ser uma estratégia útil para aumentar a entrega de moléculas e otimizar tanto o efeito terapêutico, quanto o diagnóstico por imagem / Intravenous administration of Hypertonic saline solution (HSS) induces systemic circulatory changes including blood pressure rising, effective circulating volume increase as well as local effects on microvasculature. We analyzed the effects produced by Hypertonic Saline 7,5% administration on tumor hemodynamics through functional imaging studies as well as whether it enhances molecular delivery in tumor tissue when used as a vehicle. Blood velocity assessed by Color Doppler Ultrasound was increased after HSS injection compared to PBS in the following tumors: B16F10 (p=0,019), SKMEL- 147 (p=0,028) and 4T1 (p=0,015). No statistical difference was observed on the segmental kidney arteries (p=0,476). Dynamic Contrast enhanced ultrasound (CEUS) was done in B16F10, HCT-116 and MDA-MB-231 tumor xenografts, kidney and muscle tissues (n=3 per group). After HSS injection, relative blood volume was increased in B16F10 (p=0,022) and HCT-116 (p=0,039) but not on MDA-MB-231 (p=0,186). Changes on normal tissues were not statistically different (kidney p=0,957; muscle p=0,104). All statistical tests were two-sided. Administration of HSS as a vehicle for low molecular weight molecules cisplatin and doxorubicin in the treatment of B16F10 and 4T1 tumors respectively had no significant improvement of therapeutic efficacy, estimated by tumor growth and tumor weight measurements. Effect of HSS over retention of macromolecules in tumors SK-Mel-147 and 4T1, evaluated by epifluorescence imaging of the optical contrast IR- 783 was not large enough to reject the null hypothesis. HSS induces a transient increase in velocity of the blood as well as the blood volume that is relatively selective for the evaluated tumors with exception of MDA-MB-231. Data suggest that HSS administration might be a useful strategy to increase the delivery of molecules and optimize both therapy and diagnostic imaging

INTRODUÇÃO: A utilização de enxertos arteriais na revascularização cirúrgica do miocárdio já está bem estabelecida atualmente pelos cirurgiões cardiovasculares, e sua esqueletização tem apresentado algumas vantagens, a princípio com a artéria torácica interna esquerda. OBJETIVO: Com o objetivo de analisar esse método de dissecção na artéria radial, foram avaliados os desempenhos funcional e hemodinâmico bem como as características morfoanatômicas e histológicas dos enxertos aortocoronários de artéria radial, esqueletizados ou com tecidos adjacentes, na revascularização cirúrgica do miocárdio. MÉTODOS: Foram comparados 40 pacientes, distribuídos randomicamente em dois grupos. No grupo I foi utilizada artéria radial esqueletizada (20 pacientes) e no grupo II, artéria radial com tecidos adjacentes (20 pacientes), para os ramos marginais da artéria coronária esquerda. No total, 39 pacientes foram submetidos a cinecoronariografia e fluxometria com cateter-guia Doppler de 12 MHz (0,014 polegada, Flowire, Jometrics Inc.), no pós-operatório imediato. RESULTADOS: Os dois grupos apresentaram características demográficas semelhantes. As variáveis intra-operatórias principais da artéria radial também foram semelhantes, com comprimento de 17,1 cm no grupo I e de 16,3 cm no grupo II, e débito livre de 80,3 ml/min no grupo I e de 95,5 ml/min no grupo II. Não foram observadas diferenças morfoanatômicas e histológicas nos grupos comparados. Os diâmetros dos enxertos de artéria radial, calculados por meio de angiografia quantitativa no pós-operatório, foram semelhantes (2,66 mm no grupo I e 2,53 mm no grupo II), assim como as variáveis fluxométricas (fluxo sanguíneo de 54,9 ml/min no grupo I e de 44,28 ml/min no grupo II, e reserva de fluxo de 2,12 no grupo I e de 2 no grupo II). Por outro lado, a cinecoronariografia revelou presença de oclusão em um enxerto e estenose em cinco enxertos no grupo II, enquanto o grupo I apresentou estenose em apenas um enxerto de artéria radial (p = 0,091). CONCLUSÕES: Os enxertos aortocoronários de artéria radial tiveram bom desempenho funcional e hemodinâmico precoce. Não houve diferença entre os grupos quanto ao desempenho funcional e hemodinâmico precoce, e quanto às características morfoanatômicas e histológicas. / BACKGROUND: The use of artery grafts in the surgical revascularization of the myocardium is currently a well-established procedure by cardiovascular surgeons, and its skeletonization has posed some advantages, in principle, with the left internal thoracic artery. OBJECTIVE: With the purpose of analyzing this radial artery harvest method, the study evaluated the functional and hemodynamic early performance, as well as the morphological anatomic and histological features of the aortic coronary grafts of the radial artery, skeletonized or with surrounding tissues, in the surgical revascularization of the myocardium. METHODS: The study compared 40 patients, randomly distributed in two groups. In Group I, we employed a skeletonized radial artery (20 patients), and in Group II, the radial artery with surrounding tissues (20 patients), for the marginal branches of the left coronary artery. In total, 39 patients underwent cinecoronariography and fluxometry with a 12-MHz Doppler guide catheter (0.014 in., Flowire, Jometrics Inc.), in the immediate postoperative period. RESULTS: Both groups presented similar demographic features. The main intra-surgical variables of the radial artery were also similar, with an extension of 17.1 cm in Group I, and 16.3 cm in Group II, and the free flow was of 80.3 ml/min in Group I, and of 95.5 ml/min in Group II. No morphological anatomic and histological differences were observed in the compared groups. The diameters of the radial artery grafts, which were calculated by quantitative angiography in the postoperative period, were similar (2.66 mm in Group I, and 2.53 mm in Group II), as well as the flow variables (blood flow of 54.9 ml/min in Group I, and of 44.28 ml/min in Group II, and a flow reserve of 2.12 in Group I, and of 2 in Group II). On the other hand, the cinecoronariography revealed the presence of an occlusion in one graft, and of stenosis in five grafts of Group II, while Group I presented stenosis in only one radial artery graft (p = 0.091). CONCLUSIONS: The aortic coronary grafts of the radial artery displayed good functional and hemodynamic early performance. There was no difference between the groups regarding functional and hemodynamic early performance, and the morphological anatomical and histological features.