Yes / Coronary microvascular dysfunction (CMD) is an under-diagnosed condition characterized by functional alteration of the small coronary arterioles and the cardiac capillary bed. The vessels do not dilate appropriately in response to changes in cardiac oxygen demand, leading to chest pain and symptoms of angina. These blood vessels contain two major cell types: the endothelial cells, which line the blood vessels and detect changes in oxygen demand, and smooth muscle cells (SMC) which respond to these changes by contracting or relaxing to provide an optimal blood supply to the cardiac tissue. Many CMD studies have focused on the endothelial cells as these cells secrete vasorelaxants and vasoconstrictors. However, comparably fewer studies have examined SMC despite their functional role in contracting and relaxing. A variety of health conditions and lifestyle choices, such as diabetes, hypertension and cigarette smoking, can promote the development of both CMD and macrovascular coronary artery disease; a condition where SMC have been studied extensively. This review article will consider the influence of CMD on SMC phenotype. It will discuss the structural, cellular and molecular changes in CMD, and will summarise how co-morbidities can have differing effects on micro- and macro-vascular SMC phenotype and function, which complicates the development of new therapeutic avenues for CMD.

Dor torácica é sintoma frequente em pacientes com cardiomiopatia crônica da doença de Chagas (CCDC). Embora, em muitos casos seja atribuído empiricamente a defeitos transitórios (isquêmicos) encontrados em cintilografia de perfusão miocárdica (CPM), ainda não há evidências científicas que embasem terapêutica adequada para essa condição. Objetivos: Testar a hipótese de que ocorra redução > 50% do déficit perfusional transitório e melhora sintomática e de qualidade de vida após tratamento oral com verapamil e ácido acetilsalicílico (AAS) em pacientes com CCDC e dor torácica. Métodos: Estudo prospectivo, unicêntrico, que incluiu pacientes submetidos a cinecoronariografia por dor torácica, em que não foram identificadas lesões obstrutivas coronarianas significativas (>30%) e não apresentavam disfunção ventricular moderada ou grave. Alterações de mobilidade segmentar na ventriculografia contrastada e epidemiologia sugestiva apontaram para CCDC, que foi confirmada por dois testes sorológicos distintos. Isquemia microvascular foi comprovada por CPM com escore diferencial (Summed Difference Score (SDS) >= 1). Avaliação de dor torácica e qualidade de vida foi realizada por aplicação de Questionário de Angina de Seattle (QAS) e EQ-5D no momento da inclusão e após 3 meses de tratamento com verapamil e AAS, quando a CPM também foi repetida. As comparações pré e pós-tratamento do EQ-5D, QAS e SDS na CPM foi realizada através de teste de Wilcoxon para amostras pareadas e não normalmente distribuídas. Resultados: Vinte e seis pacientes de ambos os gêneros (58% de mulheres), idade média de 64 ±10 anos, apresentaram melhora significativa de 62,5% no SDS após o tratamento (4,5 [4-9] vs 2 [0-4.25], p<0.001). Dos 26 pacientes, 20 apresentaram melhora do SDS, dentre os quais, 10 com SDS igual a zero, ou seja, sem evidência de déficit perfusional transitório após o tratamento. Em 4 pacientes não houve mudança no SDS e apenas 2 apresentaram piora do SDS. Houve melhora significativa no valor indexado do EQ-5D após os 3 meses de tratamento (0,63±0,11 vs 0,77±0,17, p<0.001), assim como nas 5 subáreas que compõem o QAS (p<0,001).Conclusões: O uso combinado de vasodilatador microvascular e antiplaquetário (verapamil + AAS) associou-se a significativa redução dos defeitos perfusionais transitórios sugestivos de isquemia microvascular e a melhora de dor torácica e qualidade de vida em pacientes com CCDC. Este estudo pioneiro embasa investigações futuras no intuito de sedimentar evidências, comparar a placebo por exemplo, com intuito de definir terapêutica em pacientes com CCDC sintomáticos com distúrbios microvasculares. / Chest pain is a common symptom in patients with chronic Chagas disease cardiomyopathy (CCDC). Although this might be explained by myocardial perfusion scintigraphy (MPS) evidence of regional microvascular disturbances in patients with angiographically normal coronary arteries, there is no standard evidence based therapy for this condition. Purpose: Evaluate the impact of verapamil and acetylsalicylic acid (ASA) on symptoms, quality of life and myocardial perfusion defects in CDC patients with chest pain and microvascular ischemia. Methods: 26 patients were evaluated in this clinical trial. CCDC was confirmed by 2 serologic tests. All of them had chest pain and no significant epicardial coronary artery lesions by coronarography or moderate/severe ventricle systolic dysfunction by left ventriculography. Questionnaires to evaluate quality of life (EQ-5D) and chest pain symptoms (Seattle Angina Questionnaire (SAQ)) and SPECT MPS (physical stress preferably) were performed before and three months after treatment with oral verapamil and ASA. Comparison of pre and post EQ-5D/SAQ and SPECT perfusion results were performed using Wilcoxon signed rank test for paired data. Results: Mean age was 64 ± 10 years, 15 (57,7%) men. SDS was significantly reduced by 55,6% after treatment (4,5 [4-9] vs 2 [0-4.25], p<0.001). Decrease in SDS was observed in 20 (77%) participants, of those ten (38,5%) exhibited a post-treatment SDS equals zero, i.e., had no more evidence of stress induced perfusion abnormalities. Four patients (15,3%) maintained SDS values and only 2 (7,7%) increased SDS after 3 months of medications. In the evaluation of quality of life and symptoms, enhancement in EQ-5D values (index value: 0,63±0,11 vs 0,77±0,17, p<0.001) and in all dimensions of QAS post treatment were also significant (improve > 10 points each, p<0,001). Conclusions: The combined use of a microvascular vasodilator and an antiplatelet agent seems to improve quality of life and chest pain symptoms and reduce ischemic perfusion abnormalities in patients with CCDC significantly. This study paved the way for an ongoing investigation aimed at getting more definitive evidence of benefit withthese drugs as compared to placebo in CCDC and idiopathic microvascular derangements.

Dor torácica é sintoma frequente em pacientes com cardiomiopatia crônica da doença de Chagas (CCDC). Embora, em muitos casos seja atribuído empiricamente a defeitos transitórios (isquêmicos) encontrados em cintilografia de perfusão miocárdica (CPM), ainda não há evidências científicas que embasem terapêutica adequada para essa condição. Objetivos: Testar a hipótese de que ocorra redução > 50% do déficit perfusional transitório e melhora sintomática e de qualidade de vida após tratamento oral com verapamil e ácido acetilsalicílico (AAS) em pacientes com CCDC e dor torácica. Métodos: Estudo prospectivo, unicêntrico, que incluiu pacientes submetidos a cinecoronariografia por dor torácica, em que não foram identificadas lesões obstrutivas coronarianas significativas (>30%) e não apresentavam disfunção ventricular moderada ou grave. Alterações de mobilidade segmentar na ventriculografia contrastada e epidemiologia sugestiva apontaram para CCDC, que foi confirmada por dois testes sorológicos distintos. Isquemia microvascular foi comprovada por CPM com escore diferencial (Summed Difference Score (SDS) >= 1). Avaliação de dor torácica e qualidade de vida foi realizada por aplicação de Questionário de Angina de Seattle (QAS) e EQ-5D no momento da inclusão e após 3 meses de tratamento com verapamil e AAS, quando a CPM também foi repetida. As comparações pré e pós-tratamento do EQ-5D, QAS e SDS na CPM foi realizada através de teste de Wilcoxon para amostras pareadas e não normalmente distribuídas. Resultados: Vinte e seis pacientes de ambos os gêneros (58% de mulheres), idade média de 64 ±10 anos, apresentaram melhora significativa de 62,5% no SDS após o tratamento (4,5 [4-9] vs 2 [0-4.25], p<0.001). Dos 26 pacientes, 20 apresentaram melhora do SDS, dentre os quais, 10 com SDS igual a zero, ou seja, sem evidência de déficit perfusional transitório após o tratamento. Em 4 pacientes não houve mudança no SDS e apenas 2 apresentaram piora do SDS. Houve melhora significativa no valor indexado do EQ-5D após os 3 meses de tratamento (0,63±0,11 vs 0,77±0,17, p<0.001), assim como nas 5 subáreas que compõem o QAS (p<0,001).Conclusões: O uso combinado de vasodilatador microvascular e antiplaquetário (verapamil + AAS) associou-se a significativa redução dos defeitos perfusionais transitórios sugestivos de isquemia microvascular e a melhora de dor torácica e qualidade de vida em pacientes com CCDC. Este estudo pioneiro embasa investigações futuras no intuito de sedimentar evidências, comparar a placebo por exemplo, com intuito de definir terapêutica em pacientes com CCDC sintomáticos com distúrbios microvasculares. / Chest pain is a common symptom in patients with chronic Chagas disease cardiomyopathy (CCDC). Although this might be explained by myocardial perfusion scintigraphy (MPS) evidence of regional microvascular disturbances in patients with angiographically normal coronary arteries, there is no standard evidence based therapy for this condition. Purpose: Evaluate the impact of verapamil and acetylsalicylic acid (ASA) on symptoms, quality of life and myocardial perfusion defects in CDC patients with chest pain and microvascular ischemia. Methods: 26 patients were evaluated in this clinical trial. CCDC was confirmed by 2 serologic tests. All of them had chest pain and no significant epicardial coronary artery lesions by coronarography or moderate/severe ventricle systolic dysfunction by left ventriculography. Questionnaires to evaluate quality of life (EQ-5D) and chest pain symptoms (Seattle Angina Questionnaire (SAQ)) and SPECT MPS (physical stress preferably) were performed before and three months after treatment with oral verapamil and ASA. Comparison of pre and post EQ-5D/SAQ and SPECT perfusion results were performed using Wilcoxon signed rank test for paired data. Results: Mean age was 64 ± 10 years, 15 (57,7%) men. SDS was significantly reduced by 55,6% after treatment (4,5 [4-9] vs 2 [0-4.25], p<0.001). Decrease in SDS was observed in 20 (77%) participants, of those ten (38,5%) exhibited a post-treatment SDS equals zero, i.e., had no more evidence of stress induced perfusion abnormalities. Four patients (15,3%) maintained SDS values and only 2 (7,7%) increased SDS after 3 months of medications. In the evaluation of quality of life and symptoms, enhancement in EQ-5D values (index value: 0,63±0,11 vs 0,77±0,17, p<0.001) and in all dimensions of QAS post treatment were also significant (improve > 10 points each, p<0,001). Conclusions: The combined use of a microvascular vasodilator and an antiplatelet agent seems to improve quality of life and chest pain symptoms and reduce ischemic perfusion abnormalities in patients with CCDC significantly. This study paved the way for an ongoing investigation aimed at getting more definitive evidence of benefit withthese drugs as compared to placebo in CCDC and idiopathic microvascular derangements.

A disfunção microvascular, envolvendo células endoteliais, plaquetas e leucócitos, está presente na hipertensão arterial pulmonar (HAP), associando-se a risco aumentado de trombose e menor sobrevida. Estudos sobre disfunção microvascular são escassos em outras formas da doença que não a idiopática. Os objetivos do estudo foram: caracterizar a disfunção microvascular em diferentes formas de HAP através da dosagem de marcadores bioquímicos, avaliando possíveis correlações com índices de gravidade; investigar os efeitos da administração de rosuvastatina em níveis circulantes de marcadores de disfunção microvascular nesses pacientes; e investigar possível associação entre o nível plasmático dos marcadores e prognóstico. Foram incluídos sessenta pacientes: 14 com HAP idiopática ou hereditária, e 46 com HAP associada a cardiopatia congênita (HAPCCg) sem hipoxemia (N=18) ou com hipoxemia (N=28), com idades entre 13 e 60 anos. Foram dosados os níveis plasmáticos circulantes do antígeno do fator de von Willebrand (vWF:Ag), ativador tecidual do plasminogênio (t-PA); inibidor do ativador do plasminogênio (PAI-1), fator de necrose tumoral (TNF-), proteína C reativa (PCR), selectina-P; interleucina-6 (IL-6); e interleucina-10 (IL -10), na condição basal e após 30, 60 e 180 dias de tratamento, por método imunoenzimático. Após randomização, administrouse placebo (N=30) ou dose única oral diária (10mg) de rosuvastatina (N=30), por seis meses. Dados demográficos e funcionais como idade, distância caminhada em seis minutos, saturação periférica de oxigênio em repouso e após esforço, bem como hematócrito, também foram registrados. Pacientes com HAPCCg foram acompanhados por um período de 0,7 a 4,0 anos (mediana de 3,6 anos). Na condição basal, excetuando-se TNF- e PCR, todas as proteínas apresentaram-se significantemente elevadas em relação aos controles (p<0,001), havendo correlação com índices de gravidade clínica. No estudo com rosuvastatina, houve redução significante nos níveis de selectina-P em relação ao placebo (p=0,037), ao longo do tratamento. Houve melhora na saturação periférica de oxigênio após seis minutos de caminhada, no grupo estatina, em pacientes com HAPCCg com hipoxemia, em relação ao placebo. Considerando-se o período de acompanhamento, em portadores de HAPCCg, níveis plasmáticos persistentemente elevados do vWF:Ag (média de quatro determinações), acima do nível correspondente ao percentil 95 dos controles (139 U/d/L) associaram-se maior risco de morte (razão de risco 6,56, IC 95% 1,46 a 29,4, p=0.014), sem alteração após ajustamento para variáveis demográficas, funcionais e de tratamento, à análise multivariada. Assim, a disfunção microvascular está presente em indivíduos com HAP idiopática, hereditária ou associada a cardiopatias congênitas. Na HAP, o uso crônico de rosuvastatina em dose baixa associase à redução do nível circulante de selectina-P, e propicia aumento na saturação periférica de oxigênio ao final do exercício, em indivíduos com HAPCCg e hipoxemia. Em indivíduos portadores de HAPCCg, níveis plasmáticos persistentemente elevados do vWF:Ag são indicativo de pior prognóstico / Microvascular dysfunction, involving endothelial cells, platelets and leukocytes, is present in pulmonary arterial hypertension (PAH), and is associated to higher risk to thrombotic complications and mortality. Most data about microvascular dysfunction in PAH do not include other forms of the disease beyond idiopathic PAH. The present study was planned to measure plasma levels microvascular dysfunction markers in two different forms of PAH, and investigate possible correlations with indices of severity of the disease; to investigate the effects of chronic rosuvastatin administration versus placebo on the circulating levels of these markers; and to investigate possible associations between levels of these parameters and prognosis. Sixty patients (aged 13 to 60 years) were included, 14 with idiopathic or hereditary PAH, and 46 with congenital heart disease-associated PAH (CHDPAH), in the absence (N=18) or presence (N=28) of hypoxemia. Plasma levels of von Willebrand factor antigen (vWF:Ag), tissue-plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor alpha (TNF-), reactive C protein (RCP), P-selectin, interleukin-6 (IL- 6), and interleukin-10 (IL-10) were measured before treatment and 30, 90, and 180 days on treatment using high-sensitivity enzyme-linked immunosorbent assay kits. Patients were randomly assigned to placebo (N=30) or a single oral dose of rosuvastatin (N=30), 10mg/day, for six months. Demographic and functional data such as age, six-minute walk distance, peripheral oxygen saturation at rest and at the end of the six-minute walk, as well as the hematocrit, were recorded. Patients with CHDPAH were followed-up for 0.7 to 4.0 years (median 3.6 years). At baseline, levels of all proteins (except TNF- and RCP) were significantly increased in patients versus controls (p<0,001), and correlated significantly with indices of severity of the disease. P-selectin level was lower in the rosuvastatin group compared with placebo throughout the treatment (p = 0.037). In hypoxemic CHDPAH patients, the peripheral oxygen saturation, at the end of the six-minute walk, was higher in the rosuvastatin group, compared with placebo. During the follow-up of patients with CHDPAH, an average vWF:Ag (mean of four determinations) above the level corresponding to the 95th percentile of controls (139 U/dL) was associated with a high risk of death (hazard ratio 6.56, 95% CI 1.46 to 29.4, p=0.014). This was not modified after adjustment for demographic, functional and treatment-related variables in multivariate analysis. In conclusion, microvascular dysfunction is present in individuals with idiopathic, hereditary and the congenital heart disease-associated PAH. The chronic use of low-dose rosuvastatin is associated to reduction of circulating levels of P-selectin. In patients with CHDPAH with hypoxemia, rosuvastatin also increases peripheral oxygen saturation during exercise. In CHDPAH patients, a sustained increase in plasma vWF:Ag is indicative of poor prognosis

A disfunção microvascular, envolvendo células endoteliais, plaquetas e leucócitos, está presente na hipertensão arterial pulmonar (HAP), associando-se a risco aumentado de trombose e menor sobrevida. Estudos sobre disfunção microvascular são escassos em outras formas da doença que não a idiopática. Os objetivos do estudo foram: caracterizar a disfunção microvascular em diferentes formas de HAP através da dosagem de marcadores bioquímicos, avaliando possíveis correlações com índices de gravidade; investigar os efeitos da administração de rosuvastatina em níveis circulantes de marcadores de disfunção microvascular nesses pacientes; e investigar possível associação entre o nível plasmático dos marcadores e prognóstico. Foram incluídos sessenta pacientes: 14 com HAP idiopática ou hereditária, e 46 com HAP associada a cardiopatia congênita (HAPCCg) sem hipoxemia (N=18) ou com hipoxemia (N=28), com idades entre 13 e 60 anos. Foram dosados os níveis plasmáticos circulantes do antígeno do fator de von Willebrand (vWF:Ag), ativador tecidual do plasminogênio (t-PA); inibidor do ativador do plasminogênio (PAI-1), fator de necrose tumoral (TNF-), proteína C reativa (PCR), selectina-P; interleucina-6 (IL-6); e interleucina-10 (IL -10), na condição basal e após 30, 60 e 180 dias de tratamento, por método imunoenzimático. Após randomização, administrouse placebo (N=30) ou dose única oral diária (10mg) de rosuvastatina (N=30), por seis meses. Dados demográficos e funcionais como idade, distância caminhada em seis minutos, saturação periférica de oxigênio em repouso e após esforço, bem como hematócrito, também foram registrados. Pacientes com HAPCCg foram acompanhados por um período de 0,7 a 4,0 anos (mediana de 3,6 anos). Na condição basal, excetuando-se TNF- e PCR, todas as proteínas apresentaram-se significantemente elevadas em relação aos controles (p<0,001), havendo correlação com índices de gravidade clínica. No estudo com rosuvastatina, houve redução significante nos níveis de selectina-P em relação ao placebo (p=0,037), ao longo do tratamento. Houve melhora na saturação periférica de oxigênio após seis minutos de caminhada, no grupo estatina, em pacientes com HAPCCg com hipoxemia, em relação ao placebo. Considerando-se o período de acompanhamento, em portadores de HAPCCg, níveis plasmáticos persistentemente elevados do vWF:Ag (média de quatro determinações), acima do nível correspondente ao percentil 95 dos controles (139 U/d/L) associaram-se maior risco de morte (razão de risco 6,56, IC 95% 1,46 a 29,4, p=0.014), sem alteração após ajustamento para variáveis demográficas, funcionais e de tratamento, à análise multivariada. Assim, a disfunção microvascular está presente em indivíduos com HAP idiopática, hereditária ou associada a cardiopatias congênitas. Na HAP, o uso crônico de rosuvastatina em dose baixa associase à redução do nível circulante de selectina-P, e propicia aumento na saturação periférica de oxigênio ao final do exercício, em indivíduos com HAPCCg e hipoxemia. Em indivíduos portadores de HAPCCg, níveis plasmáticos persistentemente elevados do vWF:Ag são indicativo de pior prognóstico / Microvascular dysfunction, involving endothelial cells, platelets and leukocytes, is present in pulmonary arterial hypertension (PAH), and is associated to higher risk to thrombotic complications and mortality. Most data about microvascular dysfunction in PAH do not include other forms of the disease beyond idiopathic PAH. The present study was planned to measure plasma levels microvascular dysfunction markers in two different forms of PAH, and investigate possible correlations with indices of severity of the disease; to investigate the effects of chronic rosuvastatin administration versus placebo on the circulating levels of these markers; and to investigate possible associations between levels of these parameters and prognosis. Sixty patients (aged 13 to 60 years) were included, 14 with idiopathic or hereditary PAH, and 46 with congenital heart disease-associated PAH (CHDPAH), in the absence (N=18) or presence (N=28) of hypoxemia. Plasma levels of von Willebrand factor antigen (vWF:Ag), tissue-plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor alpha (TNF-), reactive C protein (RCP), P-selectin, interleukin-6 (IL- 6), and interleukin-10 (IL-10) were measured before treatment and 30, 90, and 180 days on treatment using high-sensitivity enzyme-linked immunosorbent assay kits. Patients were randomly assigned to placebo (N=30) or a single oral dose of rosuvastatin (N=30), 10mg/day, for six months. Demographic and functional data such as age, six-minute walk distance, peripheral oxygen saturation at rest and at the end of the six-minute walk, as well as the hematocrit, were recorded. Patients with CHDPAH were followed-up for 0.7 to 4.0 years (median 3.6 years). At baseline, levels of all proteins (except TNF- and RCP) were significantly increased in patients versus controls (p<0,001), and correlated significantly with indices of severity of the disease. P-selectin level was lower in the rosuvastatin group compared with placebo throughout the treatment (p = 0.037). In hypoxemic CHDPAH patients, the peripheral oxygen saturation, at the end of the six-minute walk, was higher in the rosuvastatin group, compared with placebo. During the follow-up of patients with CHDPAH, an average vWF:Ag (mean of four determinations) above the level corresponding to the 95th percentile of controls (139 U/dL) was associated with a high risk of death (hazard ratio 6.56, 95% CI 1.46 to 29.4, p=0.014). This was not modified after adjustment for demographic, functional and treatment-related variables in multivariate analysis. In conclusion, microvascular dysfunction is present in individuals with idiopathic, hereditary and the congenital heart disease-associated PAH. The chronic use of low-dose rosuvastatin is associated to reduction of circulating levels of P-selectin. In patients with CHDPAH with hypoxemia, rosuvastatin also increases peripheral oxygen saturation during exercise. In CHDPAH patients, a sustained increase in plasma vWF:Ag is indicative of poor prognosis

Submitted by Ubirajara Cruz (ubirajara.cruz@gmail.com) on 2016-09-21T16:39:07Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) dissertacao_daniela_silva.pdf: 1064609 bytes, checksum: 8a6b89b15f9df72c182d7fe50c38554f (MD5) / Approved for entry into archive by Aline Batista (alinehb.ufpel@gmail.com) on 2016-09-21T16:49:28Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) dissertacao_daniela_silva.pdf: 1064609 bytes, checksum: 8a6b89b15f9df72c182d7fe50c38554f (MD5) / Made available in DSpace on 2016-09-21T16:49:28Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) dissertacao_daniela_silva.pdf: 1064609 bytes, checksum: 8a6b89b15f9df72c182d7fe50c38554f (MD5) Previous issue date: 2014-02-28 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / O presente trabalho é constituído por estudos que visam avaliar potenciais marcadores prognósticos para tumores mamários caninos. Realizou-se um levantamento retrospectivo dos dados do Laboratório Regional de Diagnóstico da Faculdade de Veterinária da Universidade Federal de Pelotas (UFPel) acerca da casuística de dados clínico-patológicos de paciente com tumores mamários em diferentes períodos entre 2000-2012. A dissertação está apresentada na forma de dois artigos científicos. O primeiro artigo consiste da avalição do valor prognóstico do método de graduação de Elston e Ellis (1991). Foram avaliados 218 tumores. Verificou-se que a relação entre o tipo de tumor e tempo de sobrevida dos pacientes foi significativo (p<0,0001); que a maioria dos tumores pertenciam ao grau II (77/144-53.52%) e o grau tumoral influencia no tempo de sobrevida (p<0,0447). No segundo artigo estudou-se a possibilidade do uso da mensuração da densidade microvascular como fator prognóstico em tumores mamários caninos. Inicialmente dois métodos diferentes de mensuração de densidade vascular (campos aleatórios e hot-spot) foram avaliados e demonstrou-se que são equivalentes. Verificou-se que tanto a contagem de campos aleatórios ou contagem em áreas de intensa proliferação vascular apresentam resultados similares. Nos 218 neoplasmas avaliados não houve relação significativa entre o tipo histológico e o grau em relação a mensuração densidade microvascular, avaliadas pelos 2 métodos. Tumores de grau I apresentaram mais vasos que os de grau II e III. Conclui-se que no presente trabalho os carcinossarcomas foram os tumores mais prevalentes na casuística avaliada; que a associação do tipo e grau histológico tem valor prognóstico, enquanto que densidade microvascular não é um bom fator prognóstico para tumores mamários caninos. / This manuscript aims evaluate potential morphological prognostic factors to canine mammary tumors. Retrospective chart reviews of data from the Regional Diagnostic Laboratory were carried out to obtain the clinical and pathological features of the patients and mammary tumors in different periods from 2000 to 2012. The dissertation will be presented as two scientific manuscripts. The first manuscript aims the evaluation of the prognostic graduation method of Elston e Ellis (1991). A total of 218 tumors were evaluated. The relationship between tumor type and survival time were significant (p<0.0001). It was observed a preponderance of grade II (77/144-53.52%) tumors and also that the tumor grade can influence survival time (p<0.0447). The second manuscript evaluates the microvascular density as a prognostic factor in canine mammary tumors. Initially, two methods of mensuration (aleatory fields and hot spot) were evaluated and proved to be equivalent. In the 218 tumors evaluated no significant results were obtained in the comparison of histologic type or tumor grade with microvascular density evaluated by both methods. Grade I tumors presented more vessels than grade II or III tumors. It was possible to conclude that carcinosarcomas are the prevalent tumor type; association between tumor type and histologic grade could be used as prognostic factor. Microvascular density not consists in a good prognostic factor.

Das Ziel dieser Studie liegt darin, die Vor- und Nachteile der Heparinapplikation nach mikrovaskulär-anastomosierten Transplantaten in der Mund-, Kiefer- und Gesichtschirurgie zu verifizieren und damit einen Nutzen für den klinischen Alltag abzuleiten. In der Zeit von Anfang Februar 2012 bis Ende Februar 2015 erfolgten in der Abteilung für Mund- Kiefer- und Gesichtschirurgie und Plastische Operationen im Klinikum Bremen Mitte 100 mikrovaskulär-anastomosierte Transplan-tationen. Bei 95 % der Fälle wurde die aPTT durch Heparin im Sinne einer Antikoagulation verlängert. Bei 79 % der 100 Fälle konnte ein Verbleiben des Lappens verzeichnet werden. Eine antikoagulative Therapie galt bei mikrovaskulären Transplantaten bisher als ein etabliertes Verfahren zur Vermeidung einer venösen Thrombose des Gefäßstieles. Aufgrund der Kontrollierbarkeit und Steuerbarkeit von hochmolekularem Heparin ist Heparin zur Zeit als das Mittel der Wahl anzusehen in der postoperativen antikoagulativen Therapie bei der mikrovaskulären Lappenchirurgie. Eine antikoagulative Therapie mit Heparin erfordert Aufmerksamkeit und eine intensive Betreuung. Durch die Applikation von Heparin wird das Risiko von Komplikationen erhöht, z.B. eine Heparin-induzierte Thrombozytopenie oder die Gefahr von Blutungen. Inwieweit eine hämostasehemmende / antikoagulative Therapie sinnvoll ist, ist fraglich. Ein signifikanter Unterschied wurde in der eigenen Untersuchung und auch in der neusten Literatur nicht verzeichnet. Die Einflussfaktoren auf das Lappenüberleben scheinen multifaktoriell zu sein. Die Indikationsstellung zur Operation muss gut überlegt sein, um den Erfolg der Operation und das Überleben der Patienten nicht zu gefährden. Patienten, bei denen eine Endothelalteration zu vermuten ist, die zum Beispiel eine vorausgegangene Kombinationsbehandlung mit Strahlentherapie und Chemobehandlung erhalten haben, zeigen ein deutlich höheres Risiko für den Erfolg der Operation im Hinblick auf das Lappenüberleben. Weitere prospektive randomisierte Studien sind erforderlich, um zu beweisen, dass und inwieweit eine hämostasehemmende Therapie einen Einfluss auf das Überleben der Transplantate hat.

En simulant l’écoulement du sang dans un réseau de capillaires (en l’absence de contrôle biologique), il est possible d’observer la présence d’oscillations de certains paramètres comme le débit volumique, la pression et l’hématocrite (volume des globules rouges par rapport au volume du sang total). Ce comportement semble être en concordance avec certaines expériences in vivo. Malgré cet accord, il faut se demander si les fluctuations observées lors des simulations de l’écoulement sont physiques, numériques ou un artefact de modèles irréalistes puisqu’il existe toujours des différences entre des modélisations et des expériences in vivo. Pour répondre à cette question de façon satisfaisante, nous étudierons et analyserons l’écoulement du sang ainsi que la nature des oscillations observées dans quelques réseaux de capillaires utilisant un modèle convectif et un modèle moyenné pour décrire les équations de conservation de masse des globules rouges. Ces modèles tiennent compte de deux effets rhéologiques importants : l’effet Fåhraeus-Lindqvist décrivant la viscosité apparente dans un vaisseau et l’effet de séparation de phase schématisant la distribution des globules rouges aux points de bifurcation. Pour décrire ce dernier effet, deux lois de séparation de phase (les lois de Pries et al. et de Fenton et al.) seront étudiées et comparées. Dans ce mémoire, nous présenterons une description du problème physiologique (rhéologie du sang). Nous montrerons les modèles mathématiques employés (moyenné et convectif) ainsi que les lois de séparation de phase (Pries et al. et Fenton et al.) accompagnés d’une analyse des schémas numériques implémentés. Pour le modèle moyenné, nous employons le schéma numérique explicite traditionnel d’Euler ainsi qu’un nouveau schéma implicite qui permet de résoudre ce problème d’une manière efficace. Ceci est fait en utilisant une méthode de Newton- Krylov avec gradient conjugué préconditionné et la méthode de GMRES pour les itérations intérieures ainsi qu’une méthode quasi-Newton (la méthode de Broyden). Cette méthode inclura le schéma implicite d’Euler et la méthode des trapèzes. Pour le schéma convectif, la méthode explicite de Kiani et al. sera implémentée ainsi qu’une nouvelle approche implicite. La stabilité des deux modèles sera également explorée. À l’aide de trois différentes topologies, nous comparerons les résultats de ces deux modèles mathématiques ainsi que les lois de séparation de phase afin de déterminer dans quelle mesure les oscillations observées peuvent être attribuables au choix des modèles mathématiques ou au choix des méthodes numériques. / While simulating blood flow in a microvascular network (in the absence of biological control), it is possible to observe the presence of oscillations in certain parameters such as blood flow, nodal pressure and hematocrit (red blood cell concentration in blood). This behaviour seems consistent with certain in vivo experiments. Despite this agreement, one has to wonder if the fluctuations observed in simulations are physical in nature, numerical or an artefact of unrealistic models since there are always differences between modelling and in vivo experiments. To settle this question satisfactorily, we will study and analyze blood flow and the nature of the fluctuations in different microvascular networks using a convective model and a well-mixed model to depict the governing equations for conservation of red blood cell mass. These models take into account two important rheological effects : the Fåhraeus-Lindqvist effect describing the apparent viscosity of blood flow in a vessel and the plasma skimming effect which describes the separation of red blood cells at diverging nodes. To describe the latter effect, we will implement two plasma skimming models (Pries et al. and Fenton et al.). In this thesis, we will present a description of the physiological problem (blood rheology). We will introduce the mathematical models used (well-mixed and convective) as well as the plasma skimming models (Pries et al. and Fenton et al.) accompanied by a detailed analysis of the numerical methods implemented. For the well-mixed model, we use the traditional explicit Euler method as well as a new implicit scheme that allows us to solve the problem in an efficient manner. This is done using a Newton-Krylov method with a preconditioned conjugate gradient and GMRES method for the inner iterations as well as a quasi- Newton method (Broyden’s method). The implicit method will include the vi backward Euler and trapezoidal methods. For the convective model, the explicit method of Kiani et al. will be implemented as well as a new numerical implicit approach. The stability of these numerical schemes will be explored. Using three different topologies, we will compare the results of the two mathematical models as well as the two plasma skimming models and the various numerical methods in order to ascertain to what extent the oscillations that have been observed using the traditional schemes may be attributable to the choice of the mathematical models or the choice of the numerical methods.

En simulant l’écoulement du sang dans un réseau de capillaires (en l’absence de contrôle biologique), il est possible d’observer la présence d’oscillations de certains paramètres comme le débit volumique, la pression et l’hématocrite (volume des globules rouges par rapport au volume du sang total). Ce comportement semble être en concordance avec certaines expériences in vivo. Malgré cet accord, il faut se demander si les fluctuations observées lors des simulations de l’écoulement sont physiques, numériques ou un artefact de modèles irréalistes puisqu’il existe toujours des différences entre des modélisations et des expériences in vivo. Pour répondre à cette question de façon satisfaisante, nous étudierons et analyserons l’écoulement du sang ainsi que la nature des oscillations observées dans quelques réseaux de capillaires utilisant un modèle convectif et un modèle moyenné pour décrire les équations de conservation de masse des globules rouges. Ces modèles tiennent compte de deux effets rhéologiques importants : l’effet Fåhraeus-Lindqvist décrivant la viscosité apparente dans un vaisseau et l’effet de séparation de phase schématisant la distribution des globules rouges aux points de bifurcation. Pour décrire ce dernier effet, deux lois de séparation de phase (les lois de Pries et al. et de Fenton et al.) seront étudiées et comparées. Dans ce mémoire, nous présenterons une description du problème physiologique (rhéologie du sang). Nous montrerons les modèles mathématiques employés (moyenné et convectif) ainsi que les lois de séparation de phase (Pries et al. et Fenton et al.) accompagnés d’une analyse des schémas numériques implémentés. Pour le modèle moyenné, nous employons le schéma numérique explicite traditionnel d’Euler ainsi qu’un nouveau schéma implicite qui permet de résoudre ce problème d’une manière efficace. Ceci est fait en utilisant une méthode de Newton- Krylov avec gradient conjugué préconditionné et la méthode de GMRES pour les itérations intérieures ainsi qu’une méthode quasi-Newton (la méthode de Broyden). Cette méthode inclura le schéma implicite d’Euler et la méthode des trapèzes. Pour le schéma convectif, la méthode explicite de Kiani et al. sera implémentée ainsi qu’une nouvelle approche implicite. La stabilité des deux modèles sera également explorée. À l’aide de trois différentes topologies, nous comparerons les résultats de ces deux modèles mathématiques ainsi que les lois de séparation de phase afin de déterminer dans quelle mesure les oscillations observées peuvent être attribuables au choix des modèles mathématiques ou au choix des méthodes numériques. / While simulating blood flow in a microvascular network (in the absence of biological control), it is possible to observe the presence of oscillations in certain parameters such as blood flow, nodal pressure and hematocrit (red blood cell concentration in blood). This behaviour seems consistent with certain in vivo experiments. Despite this agreement, one has to wonder if the fluctuations observed in simulations are physical in nature, numerical or an artefact of unrealistic models since there are always differences between modelling and in vivo experiments. To settle this question satisfactorily, we will study and analyze blood flow and the nature of the fluctuations in different microvascular networks using a convective model and a well-mixed model to depict the governing equations for conservation of red blood cell mass. These models take into account two important rheological effects : the Fåhraeus-Lindqvist effect describing the apparent viscosity of blood flow in a vessel and the plasma skimming effect which describes the separation of red blood cells at diverging nodes. To describe the latter effect, we will implement two plasma skimming models (Pries et al. and Fenton et al.). In this thesis, we will present a description of the physiological problem (blood rheology). We will introduce the mathematical models used (well-mixed and convective) as well as the plasma skimming models (Pries et al. and Fenton et al.) accompanied by a detailed analysis of the numerical methods implemented. For the well-mixed model, we use the traditional explicit Euler method as well as a new implicit scheme that allows us to solve the problem in an efficient manner. This is done using a Newton-Krylov method with a preconditioned conjugate gradient and GMRES method for the inner iterations as well as a quasi- Newton method (Broyden’s method). The implicit method will include the vi backward Euler and trapezoidal methods. For the convective model, the explicit method of Kiani et al. will be implemented as well as a new numerical implicit approach. The stability of these numerical schemes will be explored. Using three different topologies, we will compare the results of the two mathematical models as well as the two plasma skimming models and the various numerical methods in order to ascertain to what extent the oscillations that have been observed using the traditional schemes may be attributable to the choice of the mathematical models or the choice of the numerical methods.

Master of Science / Department of Kinesiology / Timothy I. Musch / Aged rats exhibit a decreased muscle microvascular O[subscript]2 partial pressure (PO[subcript]2mv) at rest as well as during contractions compared to young rats and this may contribute to their reduced exercise tolerance. Age-related reductions in nitric oxide (NO) bioavailability due, in part, to elevated reactive O[subscript]2 species (ROS) constrain muscle blood flow (Qm). Therefore, antioxidants may restore NO bioavailability, Qm and ameliorate the reduction in PO[subscript]2mv and hence the decrease in exercise tolerance seen in aged rats. PURPOSE: To test the hypothesis that antioxidants would elevate Qm at rest and during contractions and therefore PO[subscript]2mv in aged muscle. METHODS: PO[subscript]2mv and Qm were measured in the spinotrapezius while muscle oxygen consumption (VO[subscript]2m) was estimated in 20 anesthetized male Fisher 344 x Brown Norway hybrid (F344xBN) rats at rest and during 1 Hz contractions before and after antioxidant intravenous infusion (76mg/kg vitamin C and 52mg/kg tempol). Moreover, muscle force production was measured in a subset of animals. RESULTS: Before infusion, contractions invoked a biphasic PO[subscript]2mv that fell from 30.6 [plus or minus] 0.9 mmHg to a nadir of 16.8 [plus or minus] 1.2 mmHg with an 'undershoot' of 2.8 [plus or minus] 0.7 mmHg below the subsequent steady-state (19.7 [plus or minus] 1.2 mmHg). Antioxidants elevated baseline PO[subscript]2mv to 35.7 [plus or minus] 0.8 mmHg (P<0.05) and reduced or abolished the 'undershoot' (P<0.05) without changing the steady-state contracting PO[plus or minus]2mv. Antioxidants did not change Qm at rest but during contractions Qm was reduced from 157 [plus or minus] 28 to 91 [plus or minus] 15 ml min[superscript]-1 100g[superscript]-1 (P<0.05). Antioxidants produced no significant effect on VO[subscript]2m. However, antioxidant supplementation produced a 16.5% decrease (P<0.05) in muscle force production that occurred within the first contraction and remained throughout the duration of stimulation. In addition, the ratio of muscle force production to VO[subscript]2m (F/VO[subscript]2m) actually increased from 0.92 [plus or minus] 0.03 to 1.06 [plus or minus] 0.6 (P<0.05) following infusion of antioxidants. CONCLUSION: Antioxidant supplementation significantly alters the balance between muscle O[subscript]2 delivery and VO[subscript]2 at rest and during contractions, which modifies the microvascular PO[subscript]2mv profile. Specifically, antioxidants elevate PO[subscript]2mv, which improves the potential for diffusive blood-myocyte flux. This effect arises, in part, from the unanticipated fall in muscle force production consequent to antioxidant supplementation.