University of Macau / Institute of Chinese Medical Sciences

Atherosclerosis is a vascular degenerative disease leading to progressive thickening in the intima of large and medium sized arteries through the formation of plaque that is very rich with cholesterol. The cholesterol is carried by LDL (low density lipoprotein) particles which pass through the endothelium and accumulate in the intima. The passage of LDL is influenced by wall shear stress which activates physiological responses of the endothelium. However, the causal relationship between the physiological responses and their effect on LDL mass transport is not fully understood. To obtain blood flow patterns in human carotid arteries, a fluid structure interaction (FSI) computational approach is employed, based on the in-vivo arterial geometry constructed from black blood magnetic resonance images (BBMRI) and flow rate boundary conditions obtained from phase contrast images (PC). Wall shear stress (WSS) on the luminal surface is computed, and this variable is related to the formation of leaky junctions, which is a major transendothelial pathway for LDL. A model for the fraction of leaky junction at a surface is incorporated into the overall computational scheme for mass transport, along with pore theory. The theoretical model is applied to images from three human carotid arteries in which the degree of disease ranges from mild to moderate. Maximum mass flux is predicted to be in the downstream region of stenoses where WSS is low, and this result is consistent with the clinical observation of plaque progression downstream of the stenosis. The hypothesis that the majority of LDL enters into the intima through leaky junctions is supported by observation of similar distributions between the pattern of volume flux via leaky junctions and mass flux. These studies suggest that mass flux of LDL can be a predictor to indicate areas with potential for plaque formation and progression in human carotid artery disease.

Neovascularization, or the formation of blood vessels, is important in both normal physiological processes as well as pathophysiological processes. The main players in neovascularization, endothelial cells (EC), are highly influenced by hemodynamic shear stress and this may play an important role in neovascularization. Two typical types of shear stress found in the vascular system are a unidirectional laminar shear stress (LS) found in straight regions and a disturbed, oscillatory shear stress (OS) found at branches or curves. At the cellular level, LS is thought to promote EC quiescence whereas OS is thought to promote EC dysfunction. Oscillatory sheared EC are pro-proliferative, pro-migratory, and secrete growth factors, all functions important in neovascularization. There are several diseases that involve both disturbed shear stress and neovascularization, such as atherosclerosis, aortic valve disease, and occlusive vascular disease. In these pathophysiological scenarios fluid shear stress may provide a driving force for neovascularization. Therefore, we hypothesized that oscillatory shear stress promotes greater neovascularization compared to unidirectional laminar shear stress through the secretion of angiogenic factors, which play a physiological role in neovascularization in vivo. To test this hypothesis, we first performed tubule formation and migration assays, two important functions in neovessel formation. We found that OS promotes greater tubule formation and migration of EC as compared to LS and this was mediated through secreted factors. Using gene and protein array analysis, we identified Angiopoietin-2 (Ang2) as being upregulated by OS compared to LS in EC. We found that inhibiting Ang2 blocked OS-mediated tubule formation and migration and that LS-inhibited tubule formation could be rescued by addition of Ang2. In addition, Ang2 was found to be upregulated at sites of disturbed flow in vivo, implicating a physiological role for Ang2. To further investigate the physiological role of Ang2 in neovascularization, we examined the effects of inhibiting Ang2 in a mouse model of hindlimb ischemia, which involves both disturbed flow and neovascularization. We found that Ang2 was upregulated in the ischemic adductor muscle suggesting that it plays a role in recovery during hindlimb ischemia. In addition, we found that inhibiting Ang2 decreased blood flow recovery. Ang2 inhibition resulted in decreased smooth muscle cell coverage of vessels as well as decreased macrophage infiltration. These findings suggest that Ang2 promotes blood flow recovery through the recruitment of smooth muscle cells and formation of collaterals, as well as the recruitment of macrophages that secrete important growth factors and help degrade the extracellular matrix in order for neovascularization to occur. In conclusion, this work illustrates the shear stress regulation of neovessel formation through the expression of Ang2, and the role of Ang2 in neovascularization in vivo. By understanding how angiogenic factors are regulated and what role they play in vivo, we can better understand human disease and develop important therapeutic targets.

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Missouri--Columbia, 1999. / Typescript. Vita. Includes bibliographical references (leaves [174]-186). Also available on the Internet.

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Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A anÃlise de imagens mÃdicas por meio de tÃcnicas de visÃo computacional tornou-se bastante promissora, principalmente pelo fato de aperfeiÃoar a acurÃcia diagnÃstica de diversas patologias. Por essas razÃo, a Pneumologia à considerada atualmente uma Ãrea de concentraÃÃo de projetos que envolvem mÃtodos de Processamento Digital de Imagens. A segmentaÃÃo de vasos sanguÃneos pulmonares à de bastante auxÃlio na detecÃÃo de cardiopatias pulmonares. Esse processo à realizado atravÃs da anÃlise dos resultados obtidos por exame de diagnÃstico por imagem, os quais se destacam as radiografias torÃcicas, tomografia computadorizada (TC) do tÃrax, ressonÃncia magnÃtica, cintilografia pulmonar e angiografia. A hipertensÃo pulmonar e o cÃncer sÃo exemplos de doenÃas que podem ser diagnosticadas com menor subjetividade ao realizar a segmentaÃÃo de vasos, visualizaÃÃo em trÃs dimensÃes e extraÃÃo de seus atributos. Devido a essa importÃncia, diversos algoritmos sÃo desenvolvidos com intuito de obter uma segmentaÃÃo Ãtima destas estruturas. Dentre estes, encontram-se os mÃtodos por contornos ativos, LÃgica Fuzzy, Crescimento de RegiÃes, Filtragem Multi-escalar 3D e algoritmo Expectation Maximization (EM). Nesta dissertaÃÃo, sÃo segmentados os vasos sanguÃneos pulmonares de imagens de tomografia computadorizada do tÃrax utilizando-se trÃs mÃtodos: uma combinaÃÃo de Crescimento de RegiÃes 3D controlado por uma funÃÃo de pertinÃncia gaussiana e limiarizaÃÃo; um mÃtodo hÃbrido de segmentaÃÃo por Conectividade Fuzzy e limiarizaÃÃo; por m, a segmentaÃÃo utilizando o classicador K-mÃdias. Os resultados obtidos pelas segmentaÃÃes sÃo analisados e comparados por meio de uma anÃlise dos coecientes de similaridade e sensibilidade. Os resultados da aplicaÃÃo dos trÃs mÃtodos sÃo caracterizados aceitÃveis e compatÃveis com os observados na literatura. / Medical image analysis using computer vision techniques has become quite promising because of its improvement on the diagnostic accuracy of various pathologies. For this reason, pulmonology became an area of high concentration of projects involving methods of Digital Image Processing. The blood vessels segmentation in the lung is an important aid in the detection of pulmonary heart diseases. This process is performed by analyzing the results obtained with known diagnostic imaging exams, like chest Xrays, computed tomography (CT) scan, magnetic resonance imaging, scintigraphy and angiography. Pulmonary hypertension and cancer are examples of diseases that can be diagnosed with less subjectivity if performing vessels segmentation, three-dimensional visualization and attribute extraction of these images. Thus, several algorithms are developed with the objective of obtaining an optimal segmentation of these structures. Among those algorithms are active contours, fuzzy logic, 3D Region Growing, 3D multi-scale ltering algorithm and Expectation Maximization (EM). In this study, the blood vessels were extracted from lung CT scans of the chest using three methods. The rst is a combination of 3D Region Growing controlled by a Gaussian membership function and thresholding, the second is a hybrid segmentation by thresholding and Fuzzy Connectedness. Finally,the third refers to segmentation using the K-means classier. The results and evaluation of applying these algorithms are presented.

Objetivos: Avaliar as características do canal da artéria alveolar superior posterior (AASP) em exames de tomografia de feixe conico (TCFC) em indivíduos com fissura labiopalatina (FI) e comparar com indivíduos não fissurados (NF). Material e Métodos: Foram analisados 150 exames de TCFC de FI e 150 TCFC de NF. Os critérios de exclusão foram: exames de pacientes sindrômicos, presença de lesões intraósseas, desdentados totais, outras alterações que interferem a visivilidade do canal da AASP, presença de artefatos, idade abaixo de 20 anos e exames que não incluíam toda a maxila. As características avaliadas foram à presença/ausência, localização em relação ao seio maxilar, diâmetro, distancia em relação ao rebordo alveolar e assoalho do seio maxilar e término presença/ausência de anastomose com a artéria alveolar superior anterior (AASA).Os testes estatísticos aplicados foram Kappa, Dahlberg Fischers, test t. Resultados: O grupo de FI foi constituído de 75 homens e 75 mulheres, com idade média de 29,8 anos. O grupo de NF foi composto por 75 homens 75 mulheres com idade média de 40,3 anos. O Kappa para a concordância da presença e ausência do canal da AASP foi: intra-avaliador 0,8 substancial e inter-avaliador de 0,7 subtancial. O Dahlberg intra-avaliador foi de 0, 75 excelente e inter-avaliador de 0,7 satisfatório. No ponto de ingresso o canal AASP esteve presente em 100% em FI e em 100% em NF, em todos os casos o canal da AASP era bilateral. Os diâmetros, do canal da AASP, foram significativamente diferentes entre os dois grupos, sendo maior para os FI (Test t P < 0,0001). A localização em relação ao ponto de ingresso no seio maxilar foi estatisticamente significante entre ambos os grupos, nos FI a maior frequência foi no terço médio (Fisher\' s P <0,0001) e superior do seio maxilar (Fisher\' s P < 0,0071 lado esquerdo), e os NF apresentaram maior frequência foi no terço inferior (Fisher\' s P < 0,0001). Em relação à distância da AASP ao rebordo alveolar e ao assoalho do seio maxilar, não houve resultados estatisticamente significantes. Em relação aos tipos de términos não houve diferença estatisticamente significante entre os grupos. Conclusões: De acordo com material e métodos realizados, o canal da AASP apresentou maior diâmetro e localização mais superior no seio maxilar em FI quando comparado com NF. Esses resultados podem indicar um maior risco de sangramento durante cirurgias para os portadores de fissura labiopalatina. / Objectives: This study evaluates the characteristics of the posterior superior alveolar artery canal (AASP) in individuals with cleft lip and palate (FI) and compares with individuals without cleft lip and palate (NF). Material and Methods: 150 Cone-Beam Computed Tomography (TCFC) were evaluated from both FI and NF 150 TCFC according to the criteria outlined above. Exclusion criteria were: Sindromic patients, exams with alteration introsseous, edentulous maxilla, artifacts, people below 20 years of age, exams that did not include all maxilla. The characteristics evaluated include presence/absence, location in to maxillary sinus, diameter, distance in relation to the alveolar crest and maxillary sinus floor and presence/absence of anastomosis with the anterior superior alveolar artery canal (AASA). The statistical tests used were Kappa, Dahlberg, Fisher\'s and test t. Results: The group of FI was composed of 75 men and 75 women, with an average age of 29.8. The NF group was composed of 75 men and 75 women with average of age 40.3. In relation to the presence/absence of the AASP canal, result from an evaluation by the intra-rater was 0,8 substancial and inter-rater showed 0.7substantial. O Dahlberg intra-rater was 0.75 excelent and inter-rater 0.7 satisfactory. The prevalence of the AASP canal was100% in the FI group and NF. Regarding the diameters of the AASP canal there were significant differences between the two groups, and was considerably greater for the FI group (Test t p < 0.0001). With respect to location in relation to the point of entry in the maxillary sinus results showed significant statistical difference between both groups, with the NF group possessing higher frequency in the middle third (Fishers p <0.0001) and upper third of maxillary sinus (Fishers p < 0.0071 left side) and NF had higher frequency was in lower third (Fishers P <0.0001). There was no significant statistical difference in relation to the distance of the AASP to alveolar crest and to the floor maxillary sinus. The same was true in relation to the types of terms. Conclusion: According to the material and methods the AASP canal present larger diameter and more premium location in the maxillary sinus in individuals with FI compared with NF. The results indicate a higher risk of bleeding during surgery for patients with cleft lip and palate.

Receptores ativados por protease (PARs) pertencem à família de GPCRs. Desses, PAR-1, PAR-3 e PAR-4 são ativados por trombina, e PAR-2 por tripsina. Como as proteases, peptídeos sintéticos (PARs-AP) também ativam esses receptores. Estudamos o papel dos PARs na reatividade vascular de Wistar e SHR. In vitro, PAR-1 AP, promoveu maior vasoconstrição em aorta com endotélio (E+) de SHR vs Wistar. PAR-2 AP promoveu vasodilatação similar em aorta E+ de SHR e Wistar, enquanto PAR-4 AP e peptídeos reversos não causaram efeito. In vivo/in situ PAR-1 e PAR-2 AP mostraram intensa vasomotilidade em arteríolas mesentéricas. A expressão gênica de PAR-1 está aumentada em aorta e arteríolas de SHR, mas a expressão protéica está aumentada apenas em arteríolas. Demonstramos ainda que a vasoconstrição induzida por PAR-1 AP, é dependente de Ca++ e da liberação de Ang II, ET-1 e O2- pelo endotélio. Assim, sugerimos que PAR-1 pode ser um alvo terapêutico para novos antihipertensivos com efeito antitrombótico, já que este receptor também tem sido envolvido em eventos romboembólicos. / Protease activated receptors are a new GPCRs family. The PAR-1, PAR-3 and PAR-4 are activated by thrombin and PAR-2 by tripsin. Like proteases, synthetic peptides (PARs-AP) can also activate those receptors. We studied the role of PARs in vascular reactivity of Wistar and SHR. In vitro, PAR-1 promoted higher vasoconstriction to PAR-1 AP in SHR aorta with endothelium (E+) than the Wistar ones. PAR-2 AP produced similar vasodilation in Wistar and SHR aorta E+, while neither PAR-4 nor reverse peptides presented any effect. In vivo/in situ PAR-1 and PAR-2 showed an intensive vasomotion in mesenteric vessels. PAR-1 gene expression was increased in SHR aorta and arterioles, while the protein expression was increased only in the arterioles. We have also shown that the vasoconstriction induced by PAR-1 AP, is Ca++-dependent and Ang II, ET-1 and O2- release from endothelium. Thus, we suggest that PAR-1 might represent a therapeutic target to new antihypertensive drugs with antithrombotic effect, since this receptor has been involved in thromboembolics events.

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No. of bitstreams: 1 paulakrempser.pdf: 3199319 bytes, checksum: 0c2d5739e26106f9b0a2def014ce4092 (MD5) Previous issue date: 2014-08-08 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Pesquisa quantitativa que objetivou criar e aplicar na prática clínica um “bundle de prevenção de trauma vascular periférico” para abordagem do processo de punção vascular periférica em serviço de urgência e emergência nas situações em que o vaso foi utilizado para fins de infusão de volumes e fármacos intravasculares e analisar sua efetividade na prática clínica comparando a incidência de trauma vascular antes e após intervenção educativa. O cenário da investigação foi um serviço de urgência e emergência com participação de pessoas de ambos os gêneros e maiores de 18 anos de uma cidade mineira. Foram utilizados multimétodos e técnicas para identificar a ocorrência de manifestações de traumas vasculares decorrentes de punções periféricas (técnicas semiológicas, mensurações e registros fotográficos) a partir da construção de duas coortes intercaladas por intervenção educativa. Dados analisados por estatística descritiva, inferencial e correlacional. Atendidos todos os requisitos éticos e legais de pesquisa envolvendo seres humanos. Avaliadas 244 e 191 sítios de punções observados no setor de urgência e emergência com a rotina da instituição e após sua modificação, respectivamente. Na primeira etapa foram observadas em 143 casos (58,6%) de trauma vasculares periféricos distribuídos em: dor (49,6%); alteração da cor da pele (17,6%) dos tipos, equimose (8,6%), hematoma (1,2%) e eritema (13,5%); diminuição da capacidade funcional do membro puncionado ou parte dele (7%), alteração da integridade da pele dos tipos: edema (23%); endurado (15,2%); visualização da solução de continuidade (12,7%); visualização de secreção no sítio de inserção do cateter (0,8%) e alteração da temperatura local (10,2%). O bundle de “prevenção de traumas vasculares periféricos” foi criado baseado em evidências científicas e adaptáveis ao perfil de pessoas que tiveram seus vasos puncionados abrangendo as etapas de fixação, manutenção e remoção do cateter do interior do vaso sanguíneo. Ele foi apresentado à equipe de enfermagem por meio de processo educativo cuja abordagem contemplou: motivação inicial a partir dos índices de incidências de traumas vasculares periféricos, estratégias para preveni-los e ações para diminuir as iatrogenias. Posteriormente o bundle foi incorporado à rotina institucional nos setores investigados, sendo avaliados 191 sítios de punções nos quais ele foi utilizado. Foram observados 60 casos (31,4%) de trauma vasculares periféricos com o uso do bundle: dor (21,5%); alteração da cor da pele (7,3%) dos tipos, equimose (1,6%), hematoma (2,1%) e eritema (6,3%); a diminuição da capacidade funcional do membro puncionado ou parte dele (0,5%), alteração da integridade da pele dos tipos: edema (4,7%); endurado (6,8%); visualização da solução de continuidade (3,7%); visualização de secreção no sítio de inserção do cateter (1%) e alteração da temperatura local (1%). A criação e aplicação de um “bundle de prevenção de trauma vascular periférico” para abordagem do processo de punção vascular periférica em serviço de urgência e emergência mostrou-se eficiente a ponto de reduzir a incidência de trauma vascular quando comparada no período antes (58,6%) e após intervenção educativa do conteúdo do bundle (31,4%). Os tipos de manifestações de trauma identificados nos dois momentos retrataram problemas de enfermagem presentes na prática clínica de enfermeiros para os quais a presente investigação traz como contribuição sua identificação e condutas cuja efetividade foi comprovada a partir da padronização de condutas simples, de baixo custo operacional e que permitiram obter resultados capazes de qualificar o cuidado de enfermagem na medida em que são passíveis de serem abordados com condutas de enfermagem. / Quantitative research aimed to create and apply in clinical practice a 'bundle of peripheral vascular trauma prevention "approach to the process of peripheral vascular puncture in urgent and emergency situations in the service in which the vessel was used for infusion volumes and intravascular drugs and analyze their effectiveness in clinical practice by comparing the incidence of vascular trauma before and after educational intervention. The setting of the research was an emergency service and emergency participation of people of both genders, sexes and over 18 years of a mining town. Multimethod and techniques were used to identify the occurrence of manifestations of peripheral vascular injuries from punctures (semiotic techniques, measurements and photographic records) from the construction of two cohorts interspersed with educational intervention. Data analyzed using descriptive, inferential and correlational statistics. Met all legal and ethical requirements for research involving humans. Evaluated 244 and 191 sites of punctures observed in the emergency care industry with the routine of the institution and after modification, respectively. In the first stage were observed in 143 cases (58.6%) of peripheral vascular trauma distributed as follows: pain (49.6%); the change of skin color (17.6%) types, ecchymosis (8.6%), hematoma (1.2%) and erythema (13.5%); decreased functional capacity of limb or punctured it (7%), the change of skin integrity types of edema (23%); induration (15.2%); visualization of interruption (12.7%); viewing secretion at the site of catheter insertion (0.8%) and the change in local temperature (10.2%). The bundle of "prevention of peripheral vascular trauma" was created based on scientific and adaptable to people who had their punctured vessels comprising the steps of fixing, maintenance and removal of the catheter into the blood vessel profile evidence. He was presented to the nursing staff through educational process whose approach included: initial motivation from the indices of incidence of peripheral vascular trauma, strategies to prevent them, and actions to reduce iatrogenic complications. The bundle was subsequently incorporated into the routine of institutional sectors investigated and evaluated 191 sites of punctures in which it was used. 60 cases (31.4%) of peripheral vascular trauma using the bundle were observed: pain (21.5%); changing the color of the skin (7.3%) types, ecchymosis (1.6%), hematoma (2.1%) and erythema (6.3%); decreased functional capacity of limb or punctured it (0.5%), the change of skin integrity types of edema (4.7%); induration (6.8%); visualization of a discontinuity (3.7%); viewing secretion at the site of catheter insertion (1%) and the change in local temperature (1%). The creation and implementation of a "bundle of peripheral vascular trauma prevention" approach to the punching process in peripheral vascular and emergency rescue service was efficient to the point of reducing the incidence of vascular trauma when compared with the period before (58, 6%) and after educational intervention bundle content (31.4%). The types of manifestations of trauma identified in two moments portrayed nursing problems present in clinical nursing practice for which the present investigation has as its contribution identification and ducts whose effectiveness has been proven through the standardization of simple pipelines, low operating cost and which achieved results that qualify the nursing care to the extent that they are capable of being dealt with nursing behaviors.