Introdução: Estudos pré-clínicos demonstraram que impulsos de alto índice mecânico (IM) de um transdutor de ultrassom diagnóstico durante uma infusão intravenosa de microbolhas (sonotrombólise) podem restaurar o fluxo epicárdico e microvascular no infarto agudo do miocárdio com supradesnivelamento do segmento ST (IAMCSST). Objetivo: Testamos a eficácia clínica da sonotrombólise em pacientes com IAMCSST medindo a taxa de recanalização coronariana precoce, tamanho do infarto do miocárdio por ressonância magnética e ecocardiograma e a evolução do defeito de perfusão e função ventricular esquerda à chegada, após a intervenção coronária percutânea (ICP), 72h a 96h e em um e seis meses de acompanhamento. Métodos: Pacientes com seu primeiro IAMCSST foram prospectivamente randomizados para receberem impulsos de alto IM guiados por ultrassom diagnóstico (grupo terapia) durante a infusão intravenosa de um agente de ultrassom antes e após a ICP ou para um grupo controle que recebeu apenas ICP (n = 50 em cada grupo). Um grupo de referência (n = 203) que chegou fora da janela de randomização também foi analisado. Recanalização angiográfica prévia à ICP, tamanho do infarto (TI) por ressonância magnética e alteração no defeito de perfusão e função sistólica pela ecocardiografia à chegada, após-ICP, 72h a 96h, em um e seis meses foram comparados. Resultados: A média de idade dos pacientes randomizados foi de 59 anos e não houve diferença de sexo, presença de diabetes, hipertensão arterial e dislipidemia entre os grupos estudados. Os tempos porta-balão não foram diferentes entre os grupos analisados (78 ± 32 minutos para o grupo controle versus 77 ± 26 minutos para o grupo terapia, p = 0,42), mas foram mais longos no grupo de referência (96 ± 49 minutos, p < 0,001 comparado aos grupos controle e terapia). A recanalização angiográfica foi de 48% no grupo terapia versus 20% no grupo controle e 21% no grupos de referência (p < 0,001). O TI foi reduzido (29 ± 22 gramas do grupo terapia versus 40 ± 20 gramas do grupo controle, p = 0,026). Da mesma forma, as taxas de fluxo TIMI 3 pré-ICP foram maiores no grupo terapia (32% versus 14% no grupo controle e 16% no grupo de referência, p = 0,02). Após a ICP, fluxo TIMI 3 foi observado no vaso culpado em 37/50 (74%) pacientes no grupo terapia e 30/50 (60%) pacientes do grupo controle. A fração de ejeção do ventrículo esquerdo (FEVE) não foi diferente entre os grupos antes do tratamento (44 ± 11% no grupo terapia versus 43 ± 10% no grupo controle, p = 0,39), mas aumentou imediatamente após a ICP no grupo terapia (p = 0,03) e permaneceu maior aos seis meses (p = 0,015). A correlação entre as medidas do tamanho do infarto (TI) em gramas por ressonância magnética e ecocardiografia com contraste, utilizando o coeficiente de correlação intraclasses foi de 0,672 (p < 0,001). Não houve diferença significativa na % de área acometida pelo infarto pelo ecocardiograma realizado pré-ICP, pós-ICP e durante a internação com 72h a 96h de evolução, mas no seguimento de 1 mês houve consolidação de maior redução da % de área infartada no grupo terapia 20,67 ± 8,99 a 11,87 ± 7,49 quando comparado ao grupo controle 19,16 ± 10,08 a 17,02 ± 10,02 (p = 0,016), mostrando uma diferença comportamental durante as avaliações temporais, com uma maior diminuição no tamanho do infarto no grupo terapia (p < 0,001). Ao comparar a porcentagem média de áreas infartadas naqueles pacientes com artérias coronárias obstruídas na primeira angiografia, houve um menor comprometimento microvascular naqueles do grupo terapia 12,99 ± 6,53 versus 18,87 ± 9,93 do grupo controle (p = 0,015 ). Ainda assim, como consequência das melhorias observadas na % do tamanho do infarto, notamos uma melhora progressiva na fração de ejeção nos pacientes do grupo terapia: 44,0% ± 11,0% para 53,0% ± 10% versus 43 % ± 10% para 48,0% ± 11,0% no grupo controles (p = 0,048) da chegada aos 6 meses de acompanhamento. Conclusões: A sonotrombólise adicionada à ICP melhora as taxas de recanalização e reduz o tamanho do infarto, resultando em melhorias sustentadas na perfusão miocárdica e na função sistólica após o IAMCSST / Background: Pre-clinical studies have demonstrated that high mechanical index (MI) impulses from a diagnostic ultrasound transducer during an intravenous microbubble infusion (sonothrombolysis) can restore epicardial and microvascular flow in acute ST-segment elevation myocardial infarction (STEMI). Objective: We tested the clinical effectiveness of sonothrombolysis in patients with STEMI by measuring early coronary recanalization rate, size of myocardial infarction by MRI and echocardiography and the evolution of the perfusion defect and left ventricular function at arrival, after PCI, 72h to 96h and at one- and six-months follow-up. Methods: Patients with their first STEMI were prospectively randomized to either diagnostic ultrasound-guided high MI impulses (therapy group) during an intravenous ultrasound agent infusion prior to, and following emergent percutaneous coronary intervention (PCI), or to a control group that received PCI only (n = 50 in each group). A reference group (n = 203) who arrived outside the randomization window was also analyzed. Angiographic recanalization prior to PCI, infarct size (IS) by magnetic resonance imaging, and change in perfusion defect and systolic function by echocardiography at arrival, post PCI, 72h to 96h, one and six months were compared. Results: The mean age of the randomized patients was 59 years and there was no difference in gender, presence of diabetes, arterial hypertension and dyslipidemia between the groups studied. Door to balloon times were not different between groups (78 ± 32 minutes for control versus 77 ± 26 minutes for therapy groups, p = 0.42), but were longer in the reference group (96 ± 49 minutes, p < 0.001 compared to control and therapy groups). Angiographic recanalization was 48% in therapy group versus 20% in control group and 21% in the reference group (p < 0.001). IS was reduced (29 ± 22 grams in therapy group versus 40 ± 20 grams in control group, p = 0.026). Likewise, pre-PCI TIMI 3 flow rates were higher in the therapy group (32% versus 14% in control group and 16% in the reference group, p = 0.02). After PCI, the TIMI 3 flow was observed in the culprit vessel in 37/50 (74%) patients in therapy group and 30/50 (60%) in patients in the control group. Left ventricular ejection fraction (LVEF) was not different between groups before treatment (44 ± 11% in therapy group versus 43 ± 10% in control group, p = 0.39), but increased immediately after PCI in the therapy group (p = 0.03) and remained higher at six months (p = 0.015). The correlation between the measurements of infarct size (IS) in grams by magnetic resonance and contrast echocardiography, using the intra-class correlation coefficient was 0.672 (p < 0.001). There was no significant difference in the % area affected by the infarction on echocardiography performed pre-PCI, post-PCI and during hospital stay with 72h to 96h of evolution, but in the follow-up of 1 month there was a consolidation of greater reduction of the % infarcted area in the therapy group 20.67 ± 8.99 to 11.87 ± 7.49 when compared to control group 19.16 ± 10.08 to 17.02 ± 10.02 (p = 0.016), showing a behavioral difference during the temporal evaluations, with a greater decrease in infarct size in the therapy group (p < 0.001). When comparing the mean % of infarcted areas in those patients with occluded coronary arteries at the first angiography, there was a lower microvascular impairment in those in the therapy group 12.99 ± 6.53 versus 18.87 ± 9,93 in control group (p = 0.015). Still, as a consequence of the improvements observed in the % of infarct size, we noticed a progressive improvement in the ejection fraction in patients in the therapy group 44.0% ± 11.0% to 53.0% ± 10% versus 43% ± 10% to 48.0% ± 11,0% in the control group (p = 0.048) from arrival to 6-month follow-up. Conclusions: Sonothrombolysis added to PCI improves recanalization rates and reduces infarct size, resulting in sustained improvements in myocardial perfusion and systolic function after STEMI

La circulation sanguine joue un rôle vital en microcirculation, et ce pour le transport de l'oxygène, le dioxide de carbone et d'autres nutriments. Les globules rouges (GR) constituent la majorité des cellules du sang, c'est pourquoi par "écoulement sanguin", nous entendrons "écoulement d'une suspension de GR". Pendant longtemps l'écoulement sanguin était vu comme un phénomène passif où les GR sont considérés comme des cargos d'oxygène. La vision moderne est tout autre: l'écoulement sanguin est bel et bien un phénomène actif. Les GR ainsi que les cellules endothéliales (qui tapissent les faces internes des vaisseaux sanguins) sont impliquées dans un grand nombre de signalisations biochimiques induites par les contraintes hydrodynamiques, la route vers des régulations vasomotrices sans l'intervention du système nerveux. Par exemple, les GR ne transportent pas que l'oxygène, mais également de l'ATP (adenosine triphosphate), qui est libérée suite à des changements de conformation de protéines membranaires induite par les contraintes hydrodynamiques. Cette thèse est dédiée à la circulation sanguine et son couplage avec la signalisation biochimique ayant lieu en microcirculation. Plus précisément, les questions traités dans cette thèse sont i) la dynamique des GR, ii) le problème de la diffiusion-advection d'espèces chimiques au sein des écoulements sanguins, et iii) le rôle de la géométrie des réseaux vasculaires dans le processus de la signalisation biochimique mentionnés plus haut. Dans un premier temps nous analysons la dynamique de GR dans un écoulement de Poiseuille en présence de valeurs réalistes de contraste de viscosité. Dans un deuxième temps nous développons un modèle de diffusion-advection et le couplons aux écoulements sanguins en adoptant la méthode de Boltzmann sur réseaux; nous exploitons ensuite formulation en l'appliquant au problème de la libération de l'ATP par les GR sous écoulement. Enfin nous présentons des résultats préliminaires pour la problématique générale de l'écoulement sanguin mettant en jeu l'ATP libéré par les GR et la signalisation de calcium par les cellules endothéliales. Cette étude constitue un premier pas vers le problème général et ambitieux de la régulation locale mechano-biochimique impliquée dans la microcirculation. / Blood flow in microcirculation is vital for oxygen, carbon dioxide and nutrients transport. Most of blood cells are red blood cells (RBCs), so that by blood flow we mean flow of a suspension of RBCs. For long time blood flow has been mainly considered as a passive phenomenon, in which RBCs are viewed as passive carriers of oxygen. The modern view is completely different: blood flow is more active than we thought. The RBCs as well as vascular endothelial cells covering the internal walls of blood vessels are involved in a number of biochemical signaling processes that are triggered by shear stress eliciting a number of biochemical events, and ultimately resulting into vasomotor regulation without participation of the nerve system. For example, RBCs do not only carry oxygen but also ATP (adenosine triphosphate) , the release of which occurs thanks to changes of RBC membrane protein conformations caused by shear stress. Released ATP reacts with some endothelial membrane receptors leading to vasodilation. This thesis is devoted to blood flow and its coupling to biochemical signaling. More precisely, we investigate i) the dynamics of RBCs, ii) the advection diffusion of chemicals in blood flow and the role of iii) the geometry of vessel networks, in the mentioned signaling processes in microcirculations. Firstly, we study the RBC dynamics in a pipe flow with realistic viscosity contrast values, where a link between shape dynamics and rheology is established. Secondly, we develop an advection-diffusion solver that can handle general moving curved boundaries based on lattice-Boltzmann method (LBM); we then implement it for the study of the problem of ATP release from RBCs under shear flow. Membrane tension and deformation induced by shear stress together with vessel network geometry contribute to ATP release. Finally we demonstrate the capability of applying our model and our numerical tool to the complete problem of blood under flow involving ATP release from RBCs and endothelial calcium signaling as a preliminary step to the ambitious task of mechano-involved local regulation events in microcirculation.

Introdução: este estudo avaliou o efeito do laser vermelho de baixa potência na viabilidade de retalhos cutâneos randômicos em ratos. Métodos: 40 ratos Wistar foram divididos em 4 grupos, aleatoriamente, onde 1 grupo foi utilizado como controle (G1) e os demais foram irradiados com laser de 670 nm, com 2,14 (G2), 5,36 (G3) e 20,36 J/cm2 (G4), respectivamente. Resultados: o G1 apresentou 49,35% da área do retalho necrosada, G2 39,14%, G3 47,01% e G4 29,17%. À análise estatística obtivemos diferença significativa apenas quando comparamos G4 com o G1 (p < 0,001). Conclusão: o LBP vermelho (20,36 J/cm2) é capaz de incrementar a viabilidade dos retalhos cutâneos randômicos em ratos / Introduction: This study assessed the effects of different LLLT doses on randomic skin flap rats. Methodology: 40 wistar rats were divided in four groups. The control group (CG) was not irradiated. The experimental groups were irradiated with different fluency: group 2 (G2) with 2,14 J/cm²; group 3 (G3) 5,36 J/cm² and group 4 (G4) 20,36 J/cm². The necrosis area was evaluated in the seventh postoperative day. Results: The CG shows 49,35% of necrosis area in the skin flap; G2, 39,14%; G3, 47,01% and G4, 29,17% respectively. There was a significantly difference when G4 was compared with CG`s skin flap necrosis area. Conclusion: Red LLLT with increases the survival in randomic skin flap rats

Hipertensos têm rarefação capilar e disfunção endotelial microcirculatória, tornando-se mais vulneráveis a lesões em órgãos-alvo. O estudo buscou avaliar o efeito de seis meses de tratamento farmacológico sobre densidade capilar e reatividade microvascular a estímulos fisiológicos e farmacológicos em hipertensos de baixo risco cardiovascular. Secundariamente testou-se a existência de diversidade nas respostas a diferentes estratégias anti-hipertensivas. Foram recrutados 44 pacientes, com 46,71,3 anos e 20 normotensos com 48,01,6 anos. Avaliaram-se dados antropométricos e laboratoriais e dosaram-se no soro o fator de crescimento vascular endotelial (VEGF), receptor Flt-1 para VEGF e óxido nítrico (NO). A contagem capilar foi por microscopia intravital, captando-se imagens da microcirculação no dorso da falange do dedo médio e contando os capilares com programa específico. Repetia-se o procedimento após hiperemia reativa pós-oclusiva (HRPO) para avaliar o recrutamento capilar. A reatividade vascular foi testada por fluxometria Laser Doppler, iontoforese de acetilcolina (Ach), HRPO e hiperemia térmica local (HTL). Os pacientes foram distribuídos aleatoriamente para dois grupos de tratamento: succinato de metoprolol titulado a 100 mg diários ou olmesartana medoxomila titulada a 40 mg diários, empregando-se, se necessário, a hidroclorotiazida. Os controles seguiram o mesmo protocolo inicial e após seis meses todos os testes foram repetidos nos hipertensos. As variáveis clínicas e laboratoriais basais eram semelhantes em comparação aos controles e entre os dois grupos de tratamento. Após seis meses, havia pequenas diferenças entre os grupos na relação cintura-quadril e HDL. A densidade capilar antes do tratamento era significativamente menor que no grupo controle (71,31,5 vs 80,61,8 cap/mm2 p<0,001 e HRPO 71,71,5 vs 79,52,6 cap/mm2 p<0,05) e, com o tratamento, aumentou para 75,41,1 cap/mm2 (p<0,01) no estado basal e para 76,81,1 cap/mm2 à HRPO (p<0,05). À reatividade vascular, a condutância vascular cutânea (CVC) em unidades de perfusão (UP)/mmHg era similar à HTL nos controles e hipertensos e aumentou com o tratamento nos dois subgrupos (metoprolol:1,730,2 a 1,900,2 p<0,001 e olmesartana:1,490,1 a 1,870,1 p<0,001). A CVC máxima à HRPO era menor nos hipertensos: 0,30(0,22-0,39) que nos controles: 0,39(0,31-0,49) com p<0,001. Após tratamento, aumentou para 0,41(0,29-0,51) com p<0,001. O aumento foi significativo apenas no grupo olmesartana (0,290,02 a 0,420,04 p<0,001). A diferença entre o tempo para atingir o fluxo máximo à HRPO aumentou no grupo metoprolol após tratamento 3,0 (-0,3 a 8,8) segundos versus olmesartana 0,4 (-2,1 a 2,4) segundos p<0,001. À iontoforese, a área sob a curva de fluxo (AUC) era similar nos grupos e aumentou com o tratamento, de 6087(3857-9137) para 7296(5577-10921) UP/s p=0,04. O VEGF e receptor não diferiam dos controles nem sofreram variações. A concentração de NO era maior nos hipertensos que nos controles: 64,9 (46,8-117,6) vs 50,7 (42-57,5) M/dl p=0,02 e não variou com tratamento. Em conclusão, hipertensos de baixo risco têm menor densidade e menor recrutamento capilar e ambos aumentam com tratamento. Apresentam também disfunção endotelial microcirculatória que melhora com a terapia. / Capillary rarefaction and microcirculatory endothelial dysfunction are hallmarks of hypertension, rendering patients vulnerable to target organ lesions. The study aimed at assessing the effect of a six-month treatment period upon capillary density and microvascular reactivity to physiological and pharmacological stimuli. In addition, two different treatment strategies were tested for possible differences between effects upon those variables. A total of 44 patients were recruited, mean age 46.71.3 years and 20 normotensive individuals served as controls, mean age 48.01.6 years. Anthropometrical and laboratory data were collected, as well as plasma levels of vascular endothelial growth factor (VEGF), its receptor Flt-1 and nitric oxide (NO). Capillary density was obtained by intra-vital microscopy of the dorsum of the middle phalanx before and after post-occlusive reactive hyperemia (PORH). Capillary loops were counted by a semi-automated software. Microvascular reactivity was tested by laser Doppler flowmetry (LDF), and the challenges consisted of acetylcholine iontophoresis, local thermal hyperemia (LTH) and PORH. Patients were randomly allocated to either one of two treatment arms: metoprolol succinate uptitrated to 100 mg daily or olmesartan medoxomil uptitrated to 40 mg daily, with addition of hydrochlorothiazide if necessary. Controls underwent the same initial protocol and all tests were repeated in patients after six months. Baseline clinical and laboratory parameters were similar between patients and controls and between the two treatment groups. After six months there were slight, although significant, differences between the two groups in waist/hip ratio and HDL-cholesterol. In the whole cohort, pretreatment capillary density was significantly reduced compared to controls (71.31.5 vs 80.61.8 cap/mm2 p<0.001 and PORH 71.71.5 vs 79.52.6 cap/mm2 p<0.05). After treatment it increased to 75.41.1 cap/mm2 (p<0.01) at rest and 76.81,1 cap/mm2 during PORH. During LTH, cutaneous vascular conductance (CVC) in perfusion units (PU)/ mmHg was similar in patients and controls and increased significantly in both subgroups (metoprolol: from 1.730.2 to 1.900.2 p<0,001 and olmesartan: from 1.490.1 to 1.870.1 p<0.001). Maximal CVC during PORH was reduced in hypertensive patients: 0.30 (0.22-0.39) compared to controls: 0.39(0.31-0.49) with p<0.001. After therapy it increased to 0.41(0.29-0.51) with p<0.001. The change was significant only for the olmesartan subgroup (from 0.290.02 to 0.420.04 p<0.001). After treatment, the difference in time spent to reach peak flow during PORH inreased significantly in patients taking metoprolol but not in those taking olmesartan: -3.0 (-8.8 to 0.2) and 0.4 (-2.1 to 2.4) seconds after vs before, respectively p<0,001. Area under the Ach iontophoresis flow curve (AUC) was similar in controls and hypertensive patients, and increased after treatment, from 6087 (3857-9137) to 7296 (5577-10921) PU/s p=0.04. VEGF and Flt-1 receptor were similar among all groups and did not change with treatment. NO levels were higher in hypertensive individuals than in controls: 64.9 (46.8-117.6) vs 50.7 (42.0-57.5) M/dl p=0.02 and did not change with treatment. In conclusion, low-risk hypertensive patients show reduced capillary density/recruitment, and endothelial microvascular dysfunction. Both improve with treatment

Conselho Nacional de Desenvolvimento Científico e Tecnológico / A síndrome dos ovários policísticos é uma desordem frequente e complexa, com grande variabilidade fenotípica, predominando os sinais de disfunção ovariana. Alterações metabólicas, inflamatórias e vasculares vinculadas à resistência à insulina são muito prevalentes nessa desordem podendo manifestar-se precocemente. O objetivo principal deste estudo foi investigar a presença de alterações microvasculares em mulheres jovens e não obesas portadoras da síndrome dos ovários policísticos, através de videocapilaroscopia periungueal e dosagem dos níveis séricos de endotelina-1. O objetivo secundário foi verificar a existência de associações entre os achados vasculares, níveis séricos de androgênios, parâmetros clínicos, bioquímicos, metabólicos e inflamatórios relacionados ao risco cardiovascular. Em estudo observacional, transverso e controlado avaliamos 12 mulheres com diagnóstico de síndrome dos ovários policísticos, segundo os critérios estabelecidos pelo consenso de Rotterdam e nove voluntárias saudáveis. A idade (22,82,3 X 24,62,7), o índice de massa corporal (22,53,4 X 23,73,1) e a circunferência da cintura (7510,1 X 77,38,1) foram semelhantes nos dois grupos. As portadoras da síndrome apresentavam hiperandrogenismo clínico. Não foram observadas diferenças significativas entre os grupos quando analisados os níveis séricos de estradiol, testosterona total, androstenediona ou o índice de testosterona livre, entretanto a SHBG mostrou-se significativamente mais baixa no grupo de estudo (p=0,011). A glicemia de jejum, insulina, HOMA-IR e o perfil lipídico foram normais e sem diferença entre os grupos. A amostra com síndrome dos ovários policísticos não apresentava intolerância à glicose ou Diabetes Mellitus pelo teste oral de tolerância à glicose. Os níveis séricos dos marcadores inflamatórios (leucócitos, ácido úrico, adiponectina, leptina e proteína c reativa) e do marcador de função endotelial avaliado também foram similares nos dois grupos. A velocidade de deslocamento das hemácias no basal e após oclusão foram significativamente menores nas pacientes de estudo (p=0,02), mas o tempo para atingir a VDHmax e os parâmetros relativos à morfologia e densidade capilar foram semelhantes. Não observamos correlação entre a velocidade de deslocamento das hemácias e níveis plasmáticos de endotelina-1, androgênios ou parâmetros de resistência insulínica. A velocidade de deslocamento das hemácias associou-se positivamente aos níveis plasmáticos de estradiol (r= 0,45, p<0,05) e negativamente aos de colesterol total e LDL colesterol (r= -0,52, p<0,05; r=-0,47, p<0,05, respectivamente). Em conclusão nossos resultados fornecem evidência adicional de dano precoce à função microvascular em mulheres portadoras de síndrome dos ovários policísticos. Através da capilaroscopia periungueal dinâmica, demonstramos que mulheres jovens com moderado hiperandrogenismo, sem obesidade, RI, hipertensão ou dislipidemia, já apresentam disfunção microvascular nutritiva, caracterizada por redução na velocidade de fluxo das hemácias no basal e após oclusão. Estes achados micro-circulatórios não foram acompanhados de elevações nos níveis plasmáticos de endotelina-1. / Polycystic ovary syndrome is a frequent and complex disorder, showing a great phenotypic variability, with predominance of signs of ovarian dysfunction and, more particularly, of hyperandrogenism and oligo-anovulatory cycles. This disorder shows a high prevalence of insulin resistance -related metabolic, inflammatory and vascular alterations, which may present at early stages. The main purpose of this study was to investigate the presence of microvascular alterations in young and non-obese women with polycystic ovary syndrome through periungueal videolaparoscopy and dosage of endothelin-1 serum levels. The secondary purpose was to verify further associations between vascular findings, serum androgen levels, and clinical, biochemical, metabolic and inflammatory parameters related to cardiovascular risk. We conducted an observational, transversal and controlled study to evaluate 12 women who, according to Rotterdam criteria, were diagnosed with polycystic ovary syndrome, and also nine healthy volunteers. Our selective process excluded from both groups women with smoking habits, as well as those who had made use of oral contraceptive, metformin or antilipemic drugs within three months prior to the beginning of the study. The age range (22,82,3 X 24,62,7), body mass index (22,53,4 X 23,73,1), and waist circumference (7510,1 X 77,38,1) were similar in both groups. Our patients with polycystic ovary syndrome presented clinical hyperandrogenism. Analysis of serum estradiol, total testosterone, androstenedione levels or testosterone free index disclosed no significant differences between the groups, although SHBG appeared to be expressively lower in the studied group (p=0.003). Fasting blood glucose test, insulin level, HOMA-IR and lipid profile showed normal results, and without difference between the groups. As disclosed by the oral glucose tolerance test, the group with PCOS did not present tolerance to either glucose or diabetes mellitus. When evaluated, the serum levels of inflammatory markers (leukocytes, uric acid, adinopectin, leptin and c-reactive protein) and of endothelial function marker (endothelin-1) were also similar in both groups. The red blood cell velocity at baseline and peak were significantly lower in patients with PCOS (p=0.02), although the timeframe to reach blood cell velocity at baseline and peak and the parameters referring to morphology and capillary density were similar between the groups. No association was observed between the speed of movement of red blood cells and plasma levels of endothelin-1, androgens or insulin resistance parameters. The velocity of movement of red blood cells was positively related to estradiol plasma levels (rho= 0.45, p<0.05) and negatively to the levels of total cholesterol and LDL cholesterol (rho= -0.52, p<0.05; rho=-0.47, p<0.05 respectively). Taken together, our results provide an additional evidence of early lesion to microvascular function in women with polycystic ovary syndrome. By using a simple procedure, namely the dynamic nailfoldvideocapillaroscopy, we demonstrated that young women with mild hyperandrogenism, who do not present obesity, insulin resistance, high blood pressure or dyslipidemia, already show a nutritional microvascular dysfunction, characterized by a reduced speed of red blood cells flow at basal level and after occlusion. Such microcirculatory findings were not accompanied by an increase of endothelin-1 plasma levels.

Nos travaux de recherche menés dans l'ischémie cérébrale néonatale ont évalué l'effet de la Ciclosporine A sur la réduction du volume lésionnel, mais aussi sur le fonctionnement du métabolisme mitochondrial. Nous avons également étudié l'effet du postconditionnement ischémique et les conséquences hémodynamiques de la reperfusion. Le pore de perméabilité membranaire mPTP s'ouvre au cours de l'ischémie néonatale. La CsA, inhibiteur de la Cyclophiline D freine l'ouverture du pore mPTP, améliore la capacité de recapture du calcium par la mitochondrie, la respiration mitochondriale, et limite les effets inflammatoires de l'ischémie. Néanmoins, la CsA ne réduit pas le volume des lésions cérébrales. Nous avons pu montrer que la Cyclophiline D et le pore mPTP étaient bien deux acteurs majeurs dans la constitution des lésions induites par la reperfusion dans l'ischémie cérébrale focale néonatale. Le postconditionnement ischémique ne permet pas de réduire les volumes des lésions. Nous avons montré que la reperfusion chez le jeune était progressive et lente, sans hyperhémie comme chez l'adulte. Cette cinétique de reperfusion est identique dans les deux hémisphères, tant pour la perfusion tissulaire corticale que pour la perfusion des régions cérébrales profondes. La vasoconstriction cérébrale chez le jeune traduit le recrutement précoce de la circulation collatérale mais aussi les dysfonctionnements de la microcirculation cérébrale. Au final, ces résultats ouvrent la voie à de nouvelles stratégies thérapeutiques spécifiques au profil particulier de la reperfusion dans le cerveau immature

Les modèles actuels de prédiction de la sensation thermique et du confort thermique ainsi que les solutions visant à améliorer l'état de bien-être thermique des occupants d'un bâtiment sont insuffisants. Ils ne prennent pas assez en compte les différences interindividuelles de jugement thermosensoriel. Pourtant, ces différences, souvent associées à la sensibilité thermique de chaque individu, existent mais restent inexpliquées sur le plan physiologique. Ces travaux de thèse, qui se sont déroulés en deux étapes, ont pour objectif d'identifier les causes physiologiques potentielles des différences interindividuelles du ressenti thermique, à travers des expérimentations multiparamétriques basées sur des mesurées cutanées. Toutes les mesures ont été réalisées après 30 minutes d'acclimatation en environnement thermique contrôlé. La première étape, exploratoire, a permis d'analyser à la fois l'activité neurosensorielle, les propriétés thermo-vasculaires et les propriétés du film hydrolipidique cutané de deux groupes présentant des sensibilités au froid distinctes (selon leur sensation thermique déclarée). Ainsi, les expérimentations ont montré qu'il était plus pertinent d'analyser davantage les propriétés cutanées thermiques et hydriques (reliées aux mécanismes de thermorégulation) plutôt que l'activité neurosensorielle des volontaires pour caractériser les différences interindividuelles de jugement thermosensoriel. Elles ont également mis en évidence la nécessité de contrôler les facteurs non thermiques des environnements et de sélectionner rigoureusement les sujets. La deuxième étape s'est focalisée sur l'analyse des propriétés thermo-vasculaires et des propriétés du film hydrolipidique de deux groupes de sensibilité au froid. Pour cela, 13 femmes ont été confrontées à 6 environnements de températures modérées comprises entre 17°C et 30°C (avec 2 transitions chaudes et 2 transitions froides) et les groupes ont été construits à partir du degré de frilosité déclaré par les sujets. Des différences sur les paramètres cutanées ont alors pu être relevées entre les deux groupes. Le résultat le plus significatif est que les individus dits " frileux " présentent une activité microcirculatoire plus intense sur les joues avec une vasoconstriction plus forte au froid et une vasodilatation plus forte au chaud que l'autre groupe " non sensible au froid " (p=0,002 d'après le test de l'ANCOVA pour l'effet des groupes). De plus, il a été montré que l'approche multiparamétrique (introduction de variables non thermiques comme variables prédictives) ainsi que la prise en compte des sensibilités thermiques individuelles améliorent la prédiction du confort thermique surtout pour le groupe " frileux " (+ 6,4 %).

De nombreuses craintes sont aujourd'hui formulées quant à la nocivité des champs de radiofréquences émis par les téléphones portables sur la santé. Etant donné que la tête et la peau sont les organes les plus exposés, la circulation sanguine cérébrale, la microcirculation cutanée au niveau du visage et l'activité électrique du cerveau sont spécifiquement concernées. A cet effet, nous avons mené deux études chez des volontaires adultes sains pour évaluer la vitesse du débit sanguin cérébral dans les artères cérébrales moyennes par Doppler transcrânien et le micro-débit sanguin cutané du visage par laser Doppler fluxmétrique dans la première étude ; et pour détecter d'éventuelles modifications dans l'activité électrique du cerveau par électroencéphalographie dans la deuxième. L'exposition aux radiofréquences était réalisée par deux téléphones issus du commerce, un 'réel' qui émettait des radiofréquences et chauffait en même temps et l'autre 'sham' qui chauffait seulement sans émission. La première étude n'a pas montré d'effet des radiofréquences sur la vitesse du débit sanguin cérébral au niveau des artères cérébrales moyennes, pourtant une augmentation significative du micro-débit sanguin cutané pendant l'exposition 'réelle' par rapport à l'exposition 'sham' a été observée alors que l'augmentation de la température de la peau était identique dans les deux sessions d'exposition 'sham' et 'réelle'. L'activité électrique du cerveau a présenté une diminution dans la puissance spectrale de la bande de fréquence alpha (8-12 Hz) pendant et après l'exposition 'réelle' par rapport à l'exposition 'sham'.

Background: To assess acute effects of bevacizumab (anti-VEGF therapy) on cerebral microvessels and systemic cardiovascular regulation. Design and subjects: 20 consecutive patients with colorectal cancer (median age: 60.4 years, range 45.5-73.9 years) received bevacizumab intravenously (5 mg/kg) uncoupled of chemotherapy. Prior to and within the first 24 hours after bevacizumab infusion, patients were investigated for retinal endothelial function. A series of a triple 24-hour ambulatory blood pressure measurement was conducted. Retinal endothelial function was determined as flicker light-induced vasodilation. The integrity of baroreflex arc and autonomic cardiovascular control was examined by stimulatory manoeuvres. Results: Bevacizumab therapy significantly reduced the vasodilatory capacity of retinal arterioles in response to flicker light. A slight decrease in diastolic pressure and heart rate was observed after bevacizumab infusion but this was unrelated to changes in retinal function. The pressure response upon nitroglycerin was largely preserved after bevacizumab infusion. The proportion of patients with abnormal nocturnal blood pressure regulation increased under anti-angiogenic therapy. Autonomic blood pressure control was not affected by bevacizumab treatment. Conclusions: Bevacizumab acutely impairs microvascular function independent of blood pressure changes. Imaging of the retinal microcirculation seems a valuable tool for monitoring pharmacodynamic effects of bevacizumab.

Introduction : L'angiogenèse tumorale conduit au développement de nouveaux vaisseaux destinés à permettre la croissance de la tumeur. Les vaisseaux tumoraux sont caractérisés notamment par des anomalies des cellules murales (cellules musculaires périvasculaires), responsables d'anomalies de la fonctionnalité et de la maturation. Dans ce travail de thèse, nous avons étudié un modèle tumoral de thérapie cellulaire par injection de cellules murales en IRM et vidéomicroscopie de fluorescence. Matériels et méthodes : Notre étude a porté sur un modèle sous cutané de carcinome épidermoïde chez la souris nude. Les animaux étaient divisés en trois groupes : contrôle (n=17), contrôle négatif (n=16) et " traité " avec injection locale de cellules murales humaines (n=17). Les animaux bénéficiaient d'une IRM et d'une exploration par vidéomicroscopie avant (J7) et après traitement (J14). Les paramètres mesurés étaient la taille tumorale (pied-à-coulisse et IRM), la densité microvasculaire (DMV par IRM, vidéomicroscopie et histologie), l'ADC, f, Dr et D* (IRM de diffusion), les variations de R2* sous air, oxygène et carbogène (IRM par effet BOLD) et " l'index leakage " (reflétant la perméabilité capillaire, en vidéomicroscopie). Résultats : Lors de la croissance tumorale, le groupe contrôle a montré une diminution des vaisseaux circulants (ou fonctionnels) qui se reflétait par une diminution du D* et du R2* sous air, une perte de la capacité à répondre au carbogène qui se reflétait par une augmentation du delta R2* sous carbogène, et une augmentation de la perméabilité capillaire qui se traduisait par un " index leakage " plus élevé. Dans le groupe traité par injection de cellules murales, nous avons observé un ralentissement de la croissance tumorale et une stabilisation de ces paramètres de microcirculation et maturation vasculaire. Conclusion : Nous avons montré un effet biologique de notre thérapie cellulaire par injection locale de cellules murales qui se traduisait par un ralentissement de la croissance tumorale, une stabilisation de l'hémodynamique microcirculatoire et de la maturation, et une perméabilité capillaire diminuée, concordants avec l'effet présumé stabilisateur et normalisateur des cellules murales sur les microvaisseaux.