L'imagerie par Résonance Magnétique permet de mesurer l'écoulement sanguin. Au niveau cardiovasculaire, elle permet d'acquérir non seulement des images anatomiques du cœur et des gros vaisseaux mais aussi des images fonctionnelles de vitesse par contraste de phase. Cette technique offre des perspectives dans l'étude de la dynamique des fluides et dans la caractérisation des artères, en particulier pour les grosses artères systémiques comme l'aorte dont le rôle est primordial dans la circulation sanguine. Par ailleurs, l'un des paramètres qui entrent en jeu dans la détermination de la fonction cardiaque et du comportement vasculaire est la pression artérielle. La méthode de référence de la mesure de pression dans l'aorte étant le cathétérisme, plusieurs méthodes combinant la modélisation à l'imagerie ont été proposées afin d'estimer un gradient de pression de façon non invasive. Ce travail de thèse propose de mesurer la pression dans un segment d'aorte grâce à un modèle 1D simplifié et en utilisant les données mesurées par IRM et un modèle 0D représentant le réseau vasculaire périphérique comme conditions aux limites. Aussi, afin d'adapter le modèle à l'aorte du patient, une loi de pression exprimant une relation entre la section aortique à la pression et basée sur la compliance a été utilisée. Cette dernière, liée à la vitesse d'onde de pouls (VOP), a été mesurée en IRM sur les ondes de vitesse.Par ailleurs, les séquences de codage de vitesse et d'accélération sont longues et ponctuées d'artéfacts dus au mouvement du patient. Une apnée est requise afin de limiter le mouvement respiratoire. Cependant, la durée de l'apnée atteint 25 à 30 secondes pour de telles séquences, ce qui est souvent impossible à tenir pour les malades. Une technique d'optimisation de séquences dynamiques par réduction du champ de vue est proposée et étudiée. La technique décrit un dépliement des régions repliées par différence complexe de deux images, l'une codée et l'autre non codée en vitesse. Cette méthode réalise une réduction de plus de 25% de la durée d'apnée. / Magnetic Resonance Imaging (MRI) is used to measure blood flow. It allows assessing not only dynamic images of the heart and the large arteries, but also functional velocity images by means of Phase Contrast. This promising technique is important for studying fluid dynamics and characterizing the arteries, especially the large systemic arteries that play a prominent role in the blood circulation. One of the parameters used for determining the cardiac function and the vascular behavior is the arterial pressure. The reference technique for measuring the aortic pressure is catheterism, but several methods combining imaging and mathematical modeling have been proposed in order to non-invasively estimate a pressure gradient. This work proposes to measure pressure in an aortic segment through a simplified 1D model using MRI measured flow and 0D model representing the peripheral vascular system as boundary conditions. To adapt the model to the aorta of a patient, a pressure law was used forming a relation between the aortic section area and pressure, based on compliance, which is linked to pulse wave velocity (PWV) estimated on MRI measured flow waves.Scan duration was optimized, as it is often a limitation during image acquisition. Velocity and acceleration sequences require a long time and may cause artifacts. Hence, they are acquired during apnea to avoid respiratory motion. However, for such acquisitions, a subject would have to hold their breath for more than 25 seconds which can pose difficulties for some patients. A technique that allows dynamic acquisition time optimization through field of view reduction was proposed and studied. The technique unfolds fold-over regions by complex difference of two images, one of which is motion encoded and the other acquired without an encoding gradient. By implementing this method, we decrease the acquisition time by more than 25%

INTRODUÇÃO: A lesão medular isquêmica continua sendo uma complicação devastadora das intervenções cirúrgicas na aorta torácica descendente e aorta toracoabdominal. Relatos das diferenças de desfechos clínicos neurológicos entre os gêneros após lesões cerebrais isquêmicas e traumáticas têm levantado o interesse nas influências hormonais, bem como gerado outros estudos buscando a comprovação dos efeitos neuroprotetores do estradiol e da progesterona. Nossa hipótese foi a de que a administração aguda de 17beta-estradiol ou de progesterona seria capaz de prevenir ou atenuar a lesão medular isquêmica causada pela oclusão transitória da aorta torácica descendente proximal. OBJETIVO: Analisar os efeitos na medula espinhal da administração aguda de 17?-estradiol ou de progesterona em modelo experimental de isquemia-reperfusão medular por oclusão transitória da aorta torácica descente proximal de ratos machos. MÉTODOS: Ratos machos, da linhagem wistar, foram divididos aleatoriamente em 3 grupos para a administração de 280ug/Kg de 17beta-estradiol (n=12) ou de 4mg/Kg de progesterona (n=8) ou do veículo de infusão (grupo controle) (n=12), 30 minutos antes da oclusão transitória da aorta torácica descendente por 12 minutos. A confirmação da oclusão efetiva aórtica deu-se por meio da monitorização contínua da pressão arterial média distal com o uso de cateter colocado na artéria caudal dos animais (mantida em 10mmHg). A oclusão da aorta torácica descendente deu-se por meio do posicionamento de um cateter de Fogarty no. 2, passado no sentido caudal, via dissecção da artéria carótida comum esquerda do animal. A função locomotora dos animais foi avaliada no 1o, 3o, 5o, 7o, e 14o dia pós-operatório. No 14o dia pós-operatório, os animais, após anestesia profunda, foram sacrificados e tiveram suas medulas espinhais retiradas para análise histológica e imunohistoquímica. RESULTADOS: Houve comprometimento significativo da função locomotora inicialmente nos 3 grupos de estudo, com recuperação parcial da mesma ao longo do período de observação, não havendo diferença entre os grupos durante o período de observação. A análise histológica da substância cinzenta evidenciou escassos neurônios viáveis e importante vacuolização celular nos 3 grupos de estudo no 14o dia. A análise imunohistoquímica da substância cinzenta medular com anticorpos anti-Bcl2 e anti-anexina V foi similar nos 3 grupos. Houve marcação positiva de necrose celular com o iodeto de propídio, sendo a mesma semelhante nos 3 grupos estudados. CONCLUSÃO: A administração aguda de estradiol ou de progesterona, 30 minutos antes da oclusão transitória da aorta descendente proximal de ratos machos não foi capaz de prevenir ou atenuar a lesão medular isquêmica, até o 14o dia de observação, do ponto vista funcional ou histológico / BACKGROUND: Spinal cord ischemic injury remains a dreadful complication following thoracic and thoracoabdominal aortic interventions. Reports on gender-related neurological outcomes after ischemic and traumatic brain injuries have raised interest in hormonal influences, and have generated studies into neuroprotective effects of estrogen and progesterone. We hypothesized that the acute pre-operative administration of estradiol or of progesterone would prevent or attenuate spinal cord ischemic injury induced by transitory occlusion of the proximal descending thoracic aorta. OBJECTIVE: Evaluate the spinal cord effects of the acute administration of 17beta-estradiol or of progesterone in a spinal cord ischemia-reperfusion model. METHODS: Male rats were divided to receive 280ug/Kg of 17beta-estradiol (n=12) or 4mg/Kg of progesterone (n=8) or vehicle (control group) (n=12) 30 minutes before transitory occlusion of the proximal descending thoracic aorta, mean distal arterial blood pressure was maintained at 10mmHg during 12 minutes. Hind limb motor function was assessed at 1, 3, 5, 7 and 14 days after reperfusion. At the 14th day, a segment of the thoracolumbar spinal cord was harvested and prepared to histological and imunohistochemical analyses. RESULTS: There was an important hind limb motor function impairment initially in the 3 study groups, with partial improvement along time, but no difference was detected between groups during de observational period. Gray matter analysis showed scarce viable neurons and a marked cellular vacuolation in all three groups, but the number of viable neurons per section areas was not different between study groups at day 14th. Immunostaining of the spinal cord gray matter with antibodies anti-Bcl2 and anti-annexin V was similar among the 3 study groups. There was positive staining for the necrotic marker propidium iodide, with all groups presenting a similar staining pattern. CONCLUSION: We found that a single-dose administration of estradiol or of progesterone, 30 minutes before transitory occlusion of the proximal descending thoracic aorta of male rats, was not able to prevent spinal cord ischemic injury through analysis of functional and histological outcomes at 14 days of observation

INTRODUÇÃO: A dopplervelocimetria foi incorporada à propedêutica obstétrica por ser um método rotineiro e não-invasivo, que possibilita a avaliação da função placentária e da resposta fetal à hipoxia em gestações de alto risco. Várias curvas de valores de referência dos índices dopplervelocimétricos dos vasos de interesse na especialidade já foram publicados, porém os mais antigos utilizaram tecnologia ultra-sonográfica inferior à disponível atualmente; outros apresentaram falhas na execução do estudo (por ex. tamanho e seleção da amostra, número de exames; método estatística na análise dos dados). OBJETIVO: Este estudo tem como finalidade a confecção de curvas de normalidade dos índices dopplervelocimétricos das circulações uteroplacentária (artérias uterinas direita e esquerda maternas - AUT), fetoplacentária (artérias umbilicais - AU) e fetal (artéria cerebral média - ACM, aorta torácica descendente - ATD e ducto venoso - DV), da 14ª à 42ª semana de gestação, confeccionadas a partir de dados obtidos prospectivamente e longitudinalmente, de gestações normais cujos resultados de parto e neonatal não foram adversos. MÉTODOS: As gestantes foram recrutadas e avaliadas nas unidades de atendimento pré-natal de baixo risco da Clínica Obstétrica no Setor de Avaliação da Vitalidade Fetal do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil; no período de abril de 2000 a maio de 2004. Das 294 pacientes que foram recrutadas, somente 154 foram selecionadas para fazer parte da amostra analisada. As 908 avaliações dopplervelocimétricas foram realizadas somente por um operador, com taxa de sucesso de exame maior que 94% para cada vaso estudado. Foram utilizados aparelhos de ultra-sonografia com Doppler pulsátil e imagem em tempo real com dispositivo de mapeamento colorido de fluxo. Na análise estatística, adotou-se método de efeitos aleatórios ou modelo de múltiplos níveis descrito por Royston (1995). A distribuição dos valores dos índices para cada idade gestacional (IG em semanas) foi estudada. Quando verificada distribuição não-normal dos valores, aplicou-se modelos de transformação, sendo escolhido o modelo mais simples. Os valores originais dos índices foram mantidos quando a transformação não surtiu melhora da distribuição dos dados. A variável tempo (IG em semanas) foi testada por modelos de transformação polinomial (polinômios fracionários), sendo escolhido aquele que apresentou melhor desempenho. RESULTADOS: Foram determinados os intervalos de referência condicional e não-condicional dos valores dos índices dopplervelocimétricos de cada vaso, utilizando-se intervalo de confiança de 90% (alfa = 0,10). Após comparação, por sobreposição das curvas obtidas, considerando-se os intervalos de referência condicional e não-condicional, optou-se pelo uso dos valores calculados a partir de intervalos de referência não-condicionais por apresentarem curvas mais suaves e os valores serem muito semelhantes. CONCLUSÃO: foram obtidas as curvas de normalidade dos índices dopplervelocimétricos das AUT, das AU, das ACM e ATD fetais (relação S/D, IP e IR); e do DV (relação S/a, IPV e IDV), da 14ª à 42ª semana de gestação, a partir de dados coletados longitudinalmente de população brasileira, apresentando os percentis 5, 50 e 95. / INTRODUCTION: The Doppler velocimetry is a non-invasive method that allows the evaluation of the placental function and the fetal response to hypoxia in high-risk pregnancies. Many publications have presented the Doppler velocimetric indices reference ranges of the vessels. However, the oldest ones used inferior Doppler ultrasound technology when compared to what is currently available. Others have shown flaws in the methods size and selection of the samples, number of exams performed, the use of inappropriate statistical method to analyze the obtained data. OBJECTIVE: The purpose of this study is to construct the normal Doppler velocimetric indices reference ranges of the uteroplacental (maternal right and left uterine arteries - UAT), fetoplacental (umbilical arteries - UA) and fetal (middle cerebral artery - MCA, descendent thoracic aorta - DTA, ductus venosus - DV) circulations. Prospective and longitudinal data was obtained from normal pregnancies from 14 to 42 gestational weeks with normal delivery and neonatal outcomes. METHODS: Pregnant women were recruited from low-risk prenatal care units, and examined in the Fetal Surveillance Unit at the Obstetric Clinic (Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, SP, Brazil), between April 2000 and May 2004. Two-hundred ninety-four patients were recruited and 154 qualified to be part of the sample. A total of 908 Doppler velocimetric evaluations were performed by the same operator with a success rate of greater than 94% for each vessel studied, using ultrasound equipment with pulsatile Doppler and real-time color flow mapping technology. Random effects or multilevel models described by Royston (1995) were used in the analysis of the data obtained. The indices and the gestational age (in weeks) were tested for normal distribution by using fitted models and fractional polynomials transformation, respectively. When the transformed data did not show improvement in the normal distribution, the original values were used. RESULTS: The conditional and unconditional reference intervals for the 90% confidence interval were obtained for the indices of each vessel. Since the comparison between the unconditional and conditional reference intervals curves were very similar, the curves of the unconditional reference intervals were presented as they showed smoothed lines. CONCLUSION: The normal reference ranges of the Doppler velocimetric indices S/D ration, pulsatility index (PI) and resistance index (RI) of the UAT, UA, fetal MCA and DTA; and the S/a ratio, pulsatility index for veins (IPV) and DV index (IDV) of the DV were obtained from normal pregnancies between 14 and 42 weeks\' gestation, in a prospective and longitudinal study of the Brazilian population.

Elle peut être estimée par deux indices : la distensibilité de la paroi aortique et la vitessede propagation de l'onde de pouls (VOP) le long de l'artère. Ces marqueurs peuvent êtreobtenus dans l'aorte proximale grâce à l'imagerie de résonance magnétique (IRM) et sontreliés entre eux par le modèle de Bramwell-Hill. L'objectif de cette thèse est, d'une part, deproposer et de valider cliniquement des méthodes d'estimation de la distensibilité et de laVOP aortique, et, d'autre part, d'étudier le modèle théorique de Bramwell-Hill, au regarddes données cliniques. Nous avons dans un premier temps comparé différentes méthodesd'estimation de la distensibilité de l'aorte. Cette étude a permis d'identifier l'approche quifournit la meilleure description physiologique de l'aorte ascendante et descendante. Ensuite,nous avons proposé une nouvelle méthode de mesure de la VOP proximale. Celle-cia été validée par comparaison avec les méthodes proposées dans la littérature en termesde reproductibilité et de corrélations des mesures avec : 1) l'âge : facteur de risque "naturel " de la rigidité aortique chez des sujets sains, et 2) la VOP carotido-fémoralemesurée par tonométrie, méthode de référence utilisée en routine clinique pour estimer larigidité globale de l'aorte. Enfin, nous avons validé le modèle théorique de Bramwell-Hillau niveau des sections de l'aorte ascendante et descendante. En conclusion, nous avonsproposé des approches locale et régionale d'évaluation de la rigidité de l'aorte proximaleet nous en avons validé la robustesse, notamment dans le cadre du vieillissement artériel. / The aortic stiffness is recognized as a major factor of cardiovascular risk, and is characterizedby distensibility and pulse wave velocity (PWV) measurements. These aorticindices are related according to the Bramwell-Hill model and can be assessed in the proximalaorta with magnetic resonance imaging (MRI). The aims of this thesis were : 1) topropose and validate clinical methods for estimating the distensibility and aortic PWVfrom MRI data, and 2) to study the theoretical model of Bramwell-Hill in the light ofclinical data. First, we compared different methods for estimating the distensibility ofthe aorta. This study permitted to identify the approach which provides the best physiologicaldescription of the ascending and descending aorta. Then we proposed a newmethod for estimating the PWV in the proximal aorta, which was validated by comparisonwith previously described methods in terms of reproducibility and correlation ofaortic PWV with : 1) age : major risk factor of aortic stiffness in healthy subjects, and 2)carotid-femoral PWV measured by tonometry, gold standard method in clinical routinefor estimating the overall stiffness of the aorta. Finally, we validated the theoretical modelof Bramwell-Hill at the sections of the ascending and descending aorta. In conclusion, weproposed local and regional approaches to assess the stiffness of the proximal aorta, andwe validated its robustness, particularly in the context of aging.

Introdução: O presente estudo visa elucidar a apresentação anatômica da vasculatura medular em exame angiotomográfico e suas diferenças entre pacientes aortopatas e não aortopatas na população brasileira. Objetivos: Determinar as características da artéria de Adamkiewicz (AKA) e artéria espinhal anterior (ASA) por método não invasivo. Secundariamente, determinaremos a distribuição anatômica da AKA na população brasileira e a influência de determinadas aortopatias e comorbidades na identificação da AKA. Casuística: Cento e quinze angiotomografias elegíveis realizadas no Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo foram avaliadas e separadas entre pacientes aortopatas e não aortopatas. Trinta e dois (52,5%) homens e 29 mulheres constituíram o grupo não aortopata e 30 (56,6%) homens e 23 mulheres constituíram o grupo de aortopatas. Método: Análise prospectiva de angiotomografias realizadas em aparelho de 320 detectores através de software open-source OsiriX e identificação da AKA e ASA por reconstrução multiplanar tridimensional. Dados clínicos e sociodemográficos foram estratificados. Resultados: A AKA foi identificada em 78,7% dos integrantes do grupo não aortopata e em 40,7% dos pacientes aortopatas (p =< 0,0001). A ASA foi identificada em 80,3% dos integrantes do grupo não aortopata e em 46,3% dos pacientes aortopatas (p=0,0001). Em 53 (73,6%) casos a AKA originou-se do lado esquerdo. Discussão: A angiotomografia é exame de rotina no pré-operatório de doenças aórticas. O presente trabalho apresentou detecção da AKA em grupo não aortopata equiparável com a literatura, apesar do aumento de detectores no aparelho de tomografia e a identificação da AKA em grupo aortopata pouco abaixo da literatura, mas significativamente diferente do grupo não aortopata: maior proporção de identificação da AKA e ASA em pacientes não aortopatas. Houve diferença na distribuição da AKA em comparação com a literatura. Conclusão: A detecção da AKA e ASA pelo método proposto é factível, porém não ocorre na totalidade dos pacientes. A AKA e ASA são mais identificáveis em pacientes não aortopatas e sua distribuição na população estudada não se assemelha à literatura. A origem da AKA é mais frequente entre T10 e T12 à esquerda / Introduction: This study investigated differences in spinal vasculature between healthy and diseased aortas among Brazilian population. Objective: The study aimed to identify and describe the spinal vascular anatomy, evaluate Anterior Spinal Artery (ASA) and Adamkiewicz artery (AKA) characteristics using non-invasive multidetector computed tomography (CT), as well as examine differences between groups with and without aortic disease. The secondary aim was to evaluate anatomic distribution of AKA level and side and the influence of clinical factors in its detection. Methods: CT scans of 115 patients from Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo were evaluated in terms of detection rate and AKA level and side. The results were also compared with data compiled from a review of the English language literature on this topic. We analysed 320-detector CT scans using OsiriX open source software. Furthermore, we identified the AKA and ASA using tridimensional multiplannar reconstruction. Clinical and demographics data were retrieved. Results: AKA identification showed higher detection rate in patients with healthy aortas (78.7%) compared to diseased aortas (40.7%) p < 0.0001. ASA was identified in 80.3% of the healthy aortas patients and 46.3% of the diseased aortas patients (p=0.0001). In 53 (76.6%) cases, the AKA originated from a left intercostal artery. Discussion: CT scan is a routine preoperative exam for aorta diseases. We observed a detection rate similar to that reported in previous literature on healthy aortas, in spite of the CT having more detectors. Furthermore, AKA identification in aorta diseased group was below literature, but statistically different from the healthy aorta group, higher AKA and ASA identification was found in healthy aorta group. The results indicated significant difference between previous literatures and our study in AKA detection. Conclusions: AKA detection using proposed method is feasible but is not detected in all patients. AKA and ASA have a higher detection rate in patients with a healthy aorta. The proposed method and data compiled from the literature did not show similar AKA level distribution. AKA originated more frequently from the left side between T10 and T12

INTRODUÇÃO: A dopplervelocimetria foi incorporada à propedêutica obstétrica por ser um método rotineiro e não-invasivo, que possibilita a avaliação da função placentária e da resposta fetal à hipoxia em gestações de alto risco. Várias curvas de valores de referência dos índices dopplervelocimétricos dos vasos de interesse na especialidade já foram publicados, porém os mais antigos utilizaram tecnologia ultra-sonográfica inferior à disponível atualmente; outros apresentaram falhas na execução do estudo (por ex. tamanho e seleção da amostra, número de exames; método estatística na análise dos dados). OBJETIVO: Este estudo tem como finalidade a confecção de curvas de normalidade dos índices dopplervelocimétricos das circulações uteroplacentária (artérias uterinas direita e esquerda maternas - AUT), fetoplacentária (artérias umbilicais - AU) e fetal (artéria cerebral média - ACM, aorta torácica descendente - ATD e ducto venoso - DV), da 14ª à 42ª semana de gestação, confeccionadas a partir de dados obtidos prospectivamente e longitudinalmente, de gestações normais cujos resultados de parto e neonatal não foram adversos. MÉTODOS: As gestantes foram recrutadas e avaliadas nas unidades de atendimento pré-natal de baixo risco da Clínica Obstétrica no Setor de Avaliação da Vitalidade Fetal do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil; no período de abril de 2000 a maio de 2004. Das 294 pacientes que foram recrutadas, somente 154 foram selecionadas para fazer parte da amostra analisada. As 908 avaliações dopplervelocimétricas foram realizadas somente por um operador, com taxa de sucesso de exame maior que 94% para cada vaso estudado. Foram utilizados aparelhos de ultra-sonografia com Doppler pulsátil e imagem em tempo real com dispositivo de mapeamento colorido de fluxo. Na análise estatística, adotou-se método de efeitos aleatórios ou modelo de múltiplos níveis descrito por Royston (1995). A distribuição dos valores dos índices para cada idade gestacional (IG em semanas) foi estudada. Quando verificada distribuição não-normal dos valores, aplicou-se modelos de transformação, sendo escolhido o modelo mais simples. Os valores originais dos índices foram mantidos quando a transformação não surtiu melhora da distribuição dos dados. A variável tempo (IG em semanas) foi testada por modelos de transformação polinomial (polinômios fracionários), sendo escolhido aquele que apresentou melhor desempenho. RESULTADOS: Foram determinados os intervalos de referência condicional e não-condicional dos valores dos índices dopplervelocimétricos de cada vaso, utilizando-se intervalo de confiança de 90% (alfa = 0,10). Após comparação, por sobreposição das curvas obtidas, considerando-se os intervalos de referência condicional e não-condicional, optou-se pelo uso dos valores calculados a partir de intervalos de referência não-condicionais por apresentarem curvas mais suaves e os valores serem muito semelhantes. CONCLUSÃO: foram obtidas as curvas de normalidade dos índices dopplervelocimétricos das AUT, das AU, das ACM e ATD fetais (relação S/D, IP e IR); e do DV (relação S/a, IPV e IDV), da 14ª à 42ª semana de gestação, a partir de dados coletados longitudinalmente de população brasileira, apresentando os percentis 5, 50 e 95. / INTRODUCTION: The Doppler velocimetry is a non-invasive method that allows the evaluation of the placental function and the fetal response to hypoxia in high-risk pregnancies. Many publications have presented the Doppler velocimetric indices reference ranges of the vessels. However, the oldest ones used inferior Doppler ultrasound technology when compared to what is currently available. Others have shown flaws in the methods size and selection of the samples, number of exams performed, the use of inappropriate statistical method to analyze the obtained data. OBJECTIVE: The purpose of this study is to construct the normal Doppler velocimetric indices reference ranges of the uteroplacental (maternal right and left uterine arteries - UAT), fetoplacental (umbilical arteries - UA) and fetal (middle cerebral artery - MCA, descendent thoracic aorta - DTA, ductus venosus - DV) circulations. Prospective and longitudinal data was obtained from normal pregnancies from 14 to 42 gestational weeks with normal delivery and neonatal outcomes. METHODS: Pregnant women were recruited from low-risk prenatal care units, and examined in the Fetal Surveillance Unit at the Obstetric Clinic (Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, SP, Brazil), between April 2000 and May 2004. Two-hundred ninety-four patients were recruited and 154 qualified to be part of the sample. A total of 908 Doppler velocimetric evaluations were performed by the same operator with a success rate of greater than 94% for each vessel studied, using ultrasound equipment with pulsatile Doppler and real-time color flow mapping technology. Random effects or multilevel models described by Royston (1995) were used in the analysis of the data obtained. The indices and the gestational age (in weeks) were tested for normal distribution by using fitted models and fractional polynomials transformation, respectively. When the transformed data did not show improvement in the normal distribution, the original values were used. RESULTS: The conditional and unconditional reference intervals for the 90% confidence interval were obtained for the indices of each vessel. Since the comparison between the unconditional and conditional reference intervals curves were very similar, the curves of the unconditional reference intervals were presented as they showed smoothed lines. CONCLUSION: The normal reference ranges of the Doppler velocimetric indices S/D ration, pulsatility index (PI) and resistance index (RI) of the UAT, UA, fetal MCA and DTA; and the S/a ratio, pulsatility index for veins (IPV) and DV index (IDV) of the DV were obtained from normal pregnancies between 14 and 42 weeks\' gestation, in a prospective and longitudinal study of the Brazilian population.

INTRODUCCIÓN. Las enfermedades cardiovasculares constituyen la principal causa de muerte en el mundo. La mayoría de las miocardiopatías y canalopatías son de origen genético y se caracterizan por el riesgo de muerte súbita y morbilidad crónica. La detección de mutaciones en los pacientes, permite establecer el diagnóstico molecular y en algunos casos definir su pronóstico o medidas terapéuticas o preventivas, así como asesorar a las familias del afecto. Sin embargo, el gran número de genes implicados, hace que sea difícil su análisis utilizando técnicas convencionales de secuenciación. OBJETIVOS. Con este trabajo se pretende caracterizar, desde el punto de vista molecular, a un grupo de pacientes afectos de patología cardiovascular de origen heterogéneo, mediante la utilización de paneles de resecuenciación dirigida de 72 genes. Los objetivos propuestos fueron: 1. Diseñar y validar un panel de resecuenciación dirigida a enfermedades cardiovasculares genéticas heterogéneas con riesgo de muerte súbita. 2. Desarrollar una estrategia de estudio de alta sensibilidad y especificidad para aplicar al diagnóstico de enfermedades cardiogenéticas con riesgo de muerte súbita mediante secuenciación masiva. 3. Trasladar a la práctica clínica las nuevas técnicas de secuenciación masiva. Para ello se va a utilizar un modelo de enfermedades con gran heterogeneidad genética y un panel de genes asociado al desarrollo de diferentes patologías cardiovasculares para confirmar su diagnóstico. PACIENTES Y MÉTODOS. El diseño del panel para enfermedades cardiovasculares con riesgo de muerte súbita fue de 72 genes y se realizó mediante la búsqueda de información clínica y genética en las diferentes fuentes de información biomédica. Este diseño incluyó genes asociados a miocardiopatías, trastornos del ritmo cardíaco y aneurismas de aorta de tipo genético, monogénico y heterogéneo. El diseño bioinformático se realizó en la Unidad de Bioinformática de Sistemas Genómicos e incluyó 1.4 Mb de exones de los que 100 nucleótidos/gen correspondían a las zonas de splicing. Las regiones no traducidas 5’ y 3’ de los 72 genes se diseñaron con 1000 y 200 nucleótidos, respectivamente, mediante la herramienta eArray, proporcionado por Agilent. La validación bioinformática se llevó a cabo con la línea celular HapMap12144 y la validación clínica se realizó con 10 muestras de pacientes previamente diagnosticados de enfermedades cardiovasculares con riesgo de muerte súbita. El desarrollo de un pipeline de diagnóstico incluyó la aplicación de un sistema de filtrados para categorizar a las diferentes variantes encontradas, consulta de bases de datos, estudios de predicción in silico, clasificación de las variantes, validación por secuenciación Sanger de todas las variantes potencialmente patogénicas y de las variantes de significado desconocido y elaboración del informe clínico biológico. Este modelo de trabajo se aplicó sobre un grupo de 163 pacientes afectados de diferentes patologías cardiovasculares de tipo monogénico, analizados durante dos años en la Unidad de Genética Médica de Sistemas Genómicos. RESULTADOS. Los resultados obtenidos en 163 pacientes con diferentes enfermedades cardiovasculares y riesgo de muerte súbita, mediante el análisis de 4795 genes, fueron: detección de 45 mutaciones, 26 de ellas previamente descritas, 14 nuevas mutaciones y 178 variantes de significado desconocido que fueron evaluadas a través de predicciones in silico y validadas por secuenciación Sanger. En resumen, un 27.6% de los pacientes afectados de diferentes patologías susceptibles de producir muerte súbita, pudieron ser genéticamente diagnosticados y establecer el diagnóstico precoz y medidas preventivas en los familiares en riesgo. La sensibilidad bioinformática del panel de 72 genes fue de 96.68% para SNPs y 70.85% para Indels en la plataforma SOLID v.4, mientras que la validación diagnóstica fue del 100% para SNPs y del 90% para Indels. CONCLUSIÓN. La resecuenciación dirigida del panel de 72 genes asociado a patología cardiovascular de origen genético heterogéneo permite un análisis rápido, eficiente, de alto rendimiento y coste efectivo para la detección de mutaciones en todos los genes descritos, implicados en una patología, mejorando los registros de mutaciones. Estos resultados son importantes para establecer el diagnóstico molecular del paciente, explicar la variabilidad fenotípica de la enfermedad cardíaca y asesorar a la familia del afecto sobre la necesidad de políticas preventivas si son portadores de mutaciones.

<p>Postmenopausal estrogen therapy, initiated early in the menopause, seems to protect against development of atherosclerosis and cardiovascular diseases. This thesis concerns studies of artery wall thickness and arterial stiffness estimated by noninvasive ultrasound techniques in long-term estrogen treated postmenopausal women who initiated therapy at the time of the menopause.</p><p>A noninvasive 25 MHz high-frequency ultrasound technique was validated in the imaging of superficial arteries by using an animal model. Ultrasound estimates of the artery wall layers obtained <i>in vivo</i> in the pig were compared to <i>ex-vivo</i> histomorphometry. Valid estimates of total artery wall and media thickness were found for the most superficial arteries. Adventitia thickness was underestimated and intima thickness overestimated in this animal model when non-atherosclerotic vessels were imaged.</p><p>To validate the clinical usefulness of separately estimating the artery wall layers in the human, the carotid artery wall was imaged in elderly subjects. Separate estimates of intima thickness, media thickness and intima/media ratio differed significantly between subjects with and without atherosclerosis and CVD, indicating that this noninvasive high-frequency ultrasound method might be a strong tool in monitoring changes in artery wall morphology associated with aging and development of atherosclerosis.</p><p>The investigation of intima thickness, media thickness and intima/media ratio of the carotid and femoral arteries in long-term estrogen treated postmenopausal women showed a maintenance of a thin intima and a preservation of media thickness and intima/media ratio at values similar to those obtained in women of fertile age. By comparing estrogen-users with age-matched postmenopausal nonusers, long-term estrogen therapy initiated at the time of the menopause seemed to counteract the increase in intima and decrease in media thickness associated with aging and development of atherosclerosis. The preservation of the artery wall morphology into older age might be a mechanism for the well-documented cardioprotective effects of estrogen when therapy is initiated early after menopause. However, long-term estrogen therapy showed no substantial effects on the age-related changes in arterial stiffness estimated at the aorta, carotid and femoral arteries, suggesting that any long-term cardioprotective effect that estrogen therapy may have is unlikely to be mediated by an impact on arterial stiffness. </p>

Postmenopausal estrogen therapy, initiated early in the menopause, seems to protect against development of atherosclerosis and cardiovascular diseases. This thesis concerns studies of artery wall thickness and arterial stiffness estimated by noninvasive ultrasound techniques in long-term estrogen treated postmenopausal women who initiated therapy at the time of the menopause. A noninvasive 25 MHz high-frequency ultrasound technique was validated in the imaging of superficial arteries by using an animal model. Ultrasound estimates of the artery wall layers obtained in vivo in the pig were compared to ex-vivo histomorphometry. Valid estimates of total artery wall and media thickness were found for the most superficial arteries. Adventitia thickness was underestimated and intima thickness overestimated in this animal model when non-atherosclerotic vessels were imaged. To validate the clinical usefulness of separately estimating the artery wall layers in the human, the carotid artery wall was imaged in elderly subjects. Separate estimates of intima thickness, media thickness and intima/media ratio differed significantly between subjects with and without atherosclerosis and CVD, indicating that this noninvasive high-frequency ultrasound method might be a strong tool in monitoring changes in artery wall morphology associated with aging and development of atherosclerosis. The investigation of intima thickness, media thickness and intima/media ratio of the carotid and femoral arteries in long-term estrogen treated postmenopausal women showed a maintenance of a thin intima and a preservation of media thickness and intima/media ratio at values similar to those obtained in women of fertile age. By comparing estrogen-users with age-matched postmenopausal nonusers, long-term estrogen therapy initiated at the time of the menopause seemed to counteract the increase in intima and decrease in media thickness associated with aging and development of atherosclerosis. The preservation of the artery wall morphology into older age might be a mechanism for the well-documented cardioprotective effects of estrogen when therapy is initiated early after menopause. However, long-term estrogen therapy showed no substantial effects on the age-related changes in arterial stiffness estimated at the aorta, carotid and femoral arteries, suggesting that any long-term cardioprotective effect that estrogen therapy may have is unlikely to be mediated by an impact on arterial stiffness.

In the first part of this dissertation, the phenomenon of self-sustained pressure os-cillations due to the flow past a circular, axisymmetric cavity, associated with inline gate valves, was investigated. In many engineering applications, such as flows through open gate valves, there exists potential for coupling between the vortex shedding from the up-stream edge of the cavity and a diametral mode of the acoustic pressure fluctuations. The effects of the internal pipe geometry immediately upstream and downstream of the shal-low cavity on the characteristics of partially trapped diametral acoustic modes were in-vestigated numerically and experimentally on a scaled model of a gate valve mounted in a pipeline that contained convergence-divergence sections in the vicinity of the valve. The resonant response of the system corresponded to the second acoustic diametral mode of the cavity. Excitation of the dominant acoustic mode was accompanied by pressure oscillations, and, in addition to that, as the angle of the converging-diverging section of the main pipeline in the vicinity of the cavity increased, the trapped behavior of the acoustic diametral modes diminished, and additional antinodes of the acoustic pressure wave were observed in the main pipeline. In addition to that, the effect of shallow chamfers, introduced at the upstream and/or downstream cavity edges, was investigated in the experimental system that con-tained a deep, circular, axisymmetric cavity. Through the measurements of unsteady pressure and associated acoustic mode shapes, which were calculated numerically for several representative cases of the internal cavity geometry, it was possible to identify the configuration that corresponded to the most efficient noise suppression. This arrangement also allowed calculation of the azimuthal orientation of the acoustic modes, which were classified as stationary, partially spinning or spinning. Introduction of shallow chamfers at the upstream and the downstream edges of the cavity resulted in changes of azimuthal orientation and spinning behaviour of the acoustic modes. In addition, introduction of splitter plates in the cavity led to pronounced change in the spatial orientation and the spinning behaviour of the acoustic modes. The short splitter plates changed the behaviour of the dominant acoustic modes from partially spinning to stationary, while the long split-ter plates enforced the stationary behaviour across all resonant acoustic modes. Finally, the evolution of fully turbulent, acoustically coupled shear layers that form across deep, axisymmetric cavities and the effects of geometric modifications of the cavity edges on the separated flow structure were investigated using digital particle image velocimetry (PIV). Instantaneous, time- and phase-averaged patterns of vorticity pro-vided insight into the flow physics during flow tone generation and noise suppression by the geometric modifications. In particular, the first mode of the shear layer oscillations was significantly affected by shallow chamfers located at the upstream and, to a lesser degree, the downstream edges of the cavity. In the second part of the dissertation, the performance of aortic heart valve pros-thesis was assessed in geometries of the aortic root associated with certain types of valve diseases, such as aortic valve stenosis and aortic valve insufficiency. The control case that corresponds to the aortic root of a patient without valve disease was used as a reference. By varying the aortic root geometry, it was possible to investigate corresponding changes in the levels of Reynolds shear stress and establish the possibility of platelet activation and, as a result of that, the formation of blood clots. / Graduate / 0541 / 0546 / 0548 / 0986 / alexbn024@gmail.com