The current study investigates the effects of vascular disease on white matter health by comparing participants with atherosclerotic vascular disease (AVD) to healthy control participants (HC). The comparison between groups will help elucidate the differences between early-stage mild vascular disease and normal aging processes in terms of their effects on white matter health as measured by diffusion tensor imaging (DTI). Relationships between white matter health and depression, attention, and processing speed are studied by the application of a variety of DTI neuroimaging techniques, which will allow investigation of these relationships at the levels of global, lobe-wise, and subregional analysis. The specific subregion of interest in the depression study is Brodmann Area 25, which has shown significant relationships with depressive symptomatology in patients with treatment refractory depression, but has not been studied in the context of aging, vascular disease, or subthreshold depressive symptoms. Results indicate that there are significant differences between AVD and HC participants in global and regional FA measures. Within the AVD group, significant relationships of FA with depressive symptoms and attentional function have been observed in the current study. Several unexpected findings emerged, most important of which was the observation that there is a significant relationship between FA in Brodmann Area 25 and depressive symptoms in AVD participants which is specific to the right hemisphere. These findings have implications for the treatment of depressive symptoms in older adults and participants with vascular disease.

Norfloxacin For Hepatopulmonary Syndrome: A Pilot Study of a Rare Disease Samir Gupta, Masters of Science, 2008 Graduate Department of Health Policy, Management and Evaluation University of Toronto Introduction: Hepatopulmonary Syndrome is a rare disease characterized by abnormal gas-exchange and a poor prognosis, with no known effective medical therapy. A rat model and preliminary human data suggest that this disease may be caused by intestinal bacterial overgrowth, systemic endotoxemia and increased nitric oxide. Methods: We conducted a pilot crossover randomized controlled trial of norfloxacin versus placebo over four weeks, in seven subjects with HPS or a milder condition called pre-HPS, with a primary outcome of alveolar-arterial oxygen gradient (AaDO2). Results: There was no trend toward improved AaDO2, this outcome and other intermediate outcomes were highly variable, and results suggested that a longer treatment course might be necessary. We identified multiple obstacles to recruitment. Conclusion: We believe that a full-scale study of norfloxacin therapy for HPS will require 1) a six-month therapeutic period, 2) more specific HPS diagnostic criteria for clinical and study populations, and 3) creative recruitment maneuvers.

Norfloxacin For Hepatopulmonary Syndrome: A Pilot Study of a Rare Disease Samir Gupta, Masters of Science, 2008 Graduate Department of Health Policy, Management and Evaluation University of Toronto Introduction: Hepatopulmonary Syndrome is a rare disease characterized by abnormal gas-exchange and a poor prognosis, with no known effective medical therapy. A rat model and preliminary human data suggest that this disease may be caused by intestinal bacterial overgrowth, systemic endotoxemia and increased nitric oxide. Methods: We conducted a pilot crossover randomized controlled trial of norfloxacin versus placebo over four weeks, in seven subjects with HPS or a milder condition called pre-HPS, with a primary outcome of alveolar-arterial oxygen gradient (AaDO2). Results: There was no trend toward improved AaDO2, this outcome and other intermediate outcomes were highly variable, and results suggested that a longer treatment course might be necessary. We identified multiple obstacles to recruitment. Conclusion: We believe that a full-scale study of norfloxacin therapy for HPS will require 1) a six-month therapeutic period, 2) more specific HPS diagnostic criteria for clinical and study populations, and 3) creative recruitment maneuvers.

Σκοπός της πρόδρομης αυτής τυχαιοποιημένης μελέτης ήταν να εκτιμήσουμε την αποτελεσματικότητα της εξωτερικής ακτινοβόλησης και την προφυλακτική της δράση στην μείωση της επαναστένωσης του αυλού της επιπολής μηριαίας αρτηρίας μετά από αγγειοπλαστική και τοποθέτηση μεταλλικής ενδοπρόθεσης (stent). Στην μελέτη συμπεριελήφθησαν ασθενείς με σοβαρού βαθμού στένωση ή απόφραξη της επιπολής μηριαίας αρτηρίας, οι οποίοι υποβλήθηκαν σε διαδερμική αγγειοπλαστική με μπαλόνι και τοποθέτηση stent για την αποκατάσταση του προβλήματός τους, και τυχαιοποιήθηκαν σε δυο ομάδες. Οι ασθενείς της πρώτης ομάδας υποβλήθηκαν σε αγγειοπλαστική με μπαλόνι και τοποθέτηση stent στην περιοχή της στένωσης ή της απόφραξης χωρίς να υποβληθούν σε εξωτερική ακτινοβόληση της περιοχής. Οι ασθενείς της δεύτερης ομάδας, 24 ώρες μετά την αγγειοπλαστική με μπαλόνι και τοποθέτηση stent στην περιοχή της στένωσης ή της απόφραξης, υποβλήθηκαν σε εξωτερική ακτινοβόληση στην περιοχή, με συνολικά χορηγούμενη δόση 24Gy που δόθηκαν σε 6 συνεδρίες ανά 48 ώρες. Μετά το τέλος της ακτινοβόλησης οι ασθενείς παρακολουθούνταν ανά τακτά χρονικά διαστήματα. Η συνολική διάρκεια παρακολούθησης ήταν 1 έτος, με τελικό σημείο αξιολόγησης το 1 έτος. / Purpose: To evaluate the long-term results of external beam irradiation (EBI), for the prevention of neointimal hyperplasia, after percutaneous transluminal angioplasty (PTA) and stenting of the superficial femoral artery. Materials and methods: A prospective randomised study was conducted from November 2000 to February 2002. A total of 60 patients who suffered from superficial femoral artery stenoses or short occlusions included in this study. Following successful post-angioplasty stenting, patients were randomly assigned in two groups and thirty of them received external beam irradiation (6 MV photons, total dose of 24 Gy in 6 fractions,during a 2 week period) at the stented area (EBI group) while the rest thirty received no radiation therapy (Control group).All patients were advised to receive anti-platelet therapy. Results and conclusions: Radiation therapy was technically feasible in all patients, without radiation related side effects. Statistically significant differences (p<0,05) observed at the 1- year follow-up concerning the primary patency (66% for the irradiated patients vs 33% for the control patients) and re-intervention rates (40% for the irradiated patients vs 70% for the control patients) between the two groups. Irradiated patients revealed re-stenotic lesions mainly at the stent ends, while control group patients suffered extensive re-stenotic lesions within the stent lumen and the stent ends.Our study suggests that EBI is feasible, safe and effective method for the prevention of neointimal hyperplasia at the superficial femoral artery. Further studies are deemed necessary to optimize the radiation dose and the number of fractions.

This thesis presents the first work, to our knowledge, to evaluate the potential of Optical Coherence Tomography (OCT) as an intravascular imaging modality to characterize and guide interventions on chronic total occlusions (CTOs) in arteries. An ex vivo imaging study using OCT is presented that characterizes various pathologies associated with peripheral CTOs and illustrates the ability to differentiate between the vessel wall and the occluded lumen. We also found that, while OCT could image approximately 1mm through tissue, it was effective for imaging deeper through clarified microchannels seen within the occluded lumen. While others had reported observing such microchannels within the lumen before, little was known about the global architecture of these channels. This motivated a study of the global morphology of microchannels in occlusions using micro computed tomography (microCT). In this microCT study, we found that microchannels within the occluded lumen of the artery appeared to be continuous over several millimeters. However, these channels also exited the artery frequently, suggesting the need for some form of imaging guidance. As a potential intravascular imaging set-up, a forward-viewing OCT catheter was built. This catheter uses a novel scanning mechanism that combines high voltage and a dissipative polymer to achieve fast compact actuation. Doppler OCT results are presented using this catheter to image flow in the forward direction. Doppler OCT imaging of microchannels in vivo is also shown in a surgically exposed occluded artery in situ.

This thesis presents the first work, to our knowledge, to evaluate the potential of Optical Coherence Tomography (OCT) as an intravascular imaging modality to characterize and guide interventions on chronic total occlusions (CTOs) in arteries. An ex vivo imaging study using OCT is presented that characterizes various pathologies associated with peripheral CTOs and illustrates the ability to differentiate between the vessel wall and the occluded lumen. We also found that, while OCT could image approximately 1mm through tissue, it was effective for imaging deeper through clarified microchannels seen within the occluded lumen. While others had reported observing such microchannels within the lumen before, little was known about the global architecture of these channels. This motivated a study of the global morphology of microchannels in occlusions using micro computed tomography (microCT). In this microCT study, we found that microchannels within the occluded lumen of the artery appeared to be continuous over several millimeters. However, these channels also exited the artery frequently, suggesting the need for some form of imaging guidance. As a potential intravascular imaging set-up, a forward-viewing OCT catheter was built. This catheter uses a novel scanning mechanism that combines high voltage and a dissipative polymer to achieve fast compact actuation. Doppler OCT results are presented using this catheter to image flow in the forward direction. Doppler OCT imaging of microchannels in vivo is also shown in a surgically exposed occluded artery in situ.

The aims of this study were to determine the effects of smoking on the incidence and prognosis of erectile dysfunction (ED) and that of ED on smoking behavior, and to find out whether smoking either directly or through vascular diseases causes ED. The target population comprised of all men born in 1924, 1934 or 1944 and residing in the city of Tampere or 11 adjacent municipalities in Finland. Questionnaires were mailed to 3,143 men in 1994, to 2,864 in 1999 and to 2,510 men in 2004. The response rates were 70%, 75% and 75% respectively. ED was assessed using two questions on subjects’ erectile capacity. Logistic and Poisson regression models were used in the multivariable analyses. Current smoking was associated with ED (Adjusted prevalence odds ratio (POR) = 1.7, 95% CI 1.2-2.4), but not with ex smoking. The incidence of ED non-significantly increased (incidence density ratio (IDR)=1.4) and that of ED recovery reduced (IDR=0.7) with current smoking. A dose-response relationship was found between smoking and ED. Although the relative risks estimates were not statistically significant, probably due to small numbers. Only heavy smokers were significantly at higher risk of ED. Compared with non-smokers, confounder-adjusted IDR was 1.6 (95% CI 1.0-2.6) for men who smoked 21 cigarettes or more daily. Both quitting (IDR=1.7) and starting smoking (IDR=1.9) were rare and higher in men with ED. However, the IDRs estimates were not statistically significant. Current smokers at baseline (1994) who developed vascular disease during 1994-1999 were three times (Confounder-adjusted IDR=3.1, 95% CI 1.3-7.5) at higher risk of ED during 1999-2004 compared with never or ex smokers who did not develop vascular diseases. On the other hand, current smokers who did not develop vascular diseases were not at higher risk of ED (IDR=1.0). There were two bi-directional relations between smoking and ED. Smoking caused ED though vascular diseases and ED caused smoking. The recovery from ED was less in smokers than in non-smokers, and current smokers with ED were more likely to stop smoking compared with men free from ED. / <p>ISBN 91-7997-124-5</p>

The physiological role of the plasma contact system still remains a partial enigma. The aim of the presented work was to expand our understanding of the plasma contact system, focusing on its physiological activation and function, principally from a hemostatic perspective. It also explored contact system activation under pathological conditions. We found that when human platelets become activated in blood, plasma proteins of the contact system bind to platelets and initiate contact activation. The platelet-triggered contact activation contributed to clot formation by shortening the clotting time and enhancing clot stability. We demonstrated that the regulation of contact activation elicited by activated platelets differed from the previously described contact activation elicited by negatively charged material surfaces. Platelet-triggered contact activation and activation propelled by clotting blood were found to be regulated by antithrombin, whereas material-induced activation was regulated by C1 inhibitor. We also showed that the fibrin fibers that are formed during the clot process further enhance and propagate the contact activation initially induced by activated platelets. Fibrin not only activated factor XII but also seemed to increase the affinity of antithrombin for the proteases of the contact system, leading to the generation of contact enzyme-antithrombin complexes during clot formation. To determine whether the contact system might be involved in the inflammation and vascular disease associated with systemic lupus erythematosus (SLE), we analyzed plasma samples from SLE patients. These patients were found to have altered levels of contact enzyme-serpin complexes, supporting the concept that the contact system may be involved in the pathophysiology of SLE. The contact enzyme-antithrombin complexes were clearly linked to platelet activation in vivo. Altered levels of both FXIIa-antithrombin and FXIIa-C1 inhibitor were found to be correlated with previous vascular disease and may therefore be potential biomarkers for assessing the risk of thrombotic events in SLE patients. These findings add to our knowledge of how the plasma contact system is activated and functions in vivo and will help us to understand the role of the contact system, not only in hemostasis but also in vascular disease and thrombotic conditions.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

Made available in DSpace on 2014-06-11T19:32:53Z (GMT). No. of bitstreams: 0 Previous issue date: 2001Bitstream added on 2014-06-13T20:24:16Z : No. of bitstreams: 1 dores_smc_dr_botfm.pdf: 759684 bytes, checksum: 063f07ede97ac9753c4a3553a1919597 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A vitamina K, descoberta em 1929, tem reconhecida função na coagulação sangüínea. Esta vitamina age como co-fator na reação de carboxilação para biossíntese, após tradução, de resíduos de ácido gama carboxi-glutâmico (Gla) em limitado número de proteínas. A reação de carboxilação é passo necessário para a formação de fatores e proteínas da coagulação (fatores II, VII, IX, X, proteínas C e S) e proteínas envolvidas no metabolismo ósseo, como osteocalcina e proteína Gla da matriz. As drogas anticoagulantes orais são usadas na prevenção primária e secundária de fenômenos tromboembólicos e funcionam reduzindo a atividade plasmática das proteínas de coagulação vitamina K-dependentes. As causas da instabilidade da terapia anticoagulante são múltiplas e incluem: baixa adesão ao tratamento, interação droga-droga, resistência herdada à varfarina e alterações dietéticas. O presente trabalho versa sobre a influência do estado nutricional relacionado à vitamina K sobre a terapia de anticoagulação oral, em pacientes portadores de doença vascular. Levantou-se a hipótese de que o consumo de dieta com teor inadequado de vitamina K (elevado ou reduzido), assim como as concentrações plasmáticas da vitamina, podem estar associados a dificuldades na promoção da anticoagulação ou favorecer o estado de hipocoagulabilidade. Objetivou-se ainda a realização de avaliação do estado nutricional relacionado à vitamina K do grupo estudado, identificar as principais fontes dietéticas de vitamina K e investigar o efeito de diversas variáveis (chamadas variáveis descritivas) sobre a ingestão e concentrações plasmáticas de vitamina K. Para atender aos objetivos propostos, o trabalho incluiu dois estudos: transversal e longitudinal. Do estudo transversal, constam a aplicação de protocolo, que contém: os dados... / Vitamin K, which was discovered in the decade of 1930, has a recognized function in blood coagulation. The vitamin acts as a cofactor in posttranslational conversion of specific glutamyl residues to gammacarboxyglutamic acid (GLA) residues in limited numbers of proteins. The carboxylation reaction is a necessary step to synthesis of factors and anticoagulant proteins (factors II , VII, IX, X, proteins C and S) and proteins involved in bone metabolism, such as osteocalcin and matrix GLA-protein. The oral anticoagulant drugs have been used in the primary and secondary prevention of thromboembolic disorders and act reducing the plasmatic activity of blood coagulation proteins. Causes of the unstable anticoagulant therapy are multiple and include poor compliance, drug-drug interaction, inherited warfarin resistance and dietary changes. The present study examined the influence of vitamin K nutritional status on the warfarin anticoagulation therapy in vascular disease patients. We tested the hypothesis that inadequate diet intake of vitamin K (high or low), and the vitamin plasmatic concentrations are related to a disturbances of the coagulation leading to hypercoagulability or favoring hypocoagulability condition. The aim of the study was to assess the vitamin K nutritional status of the group, identify important food sources and investigate the effect of some variables on the dietary vitamin K intake and the vitamin plasmatic concentration. The work included a crosssectional and longitudinal study. The cross-sectional study consisted of clinical history and examination, a 24-hour recall method for assessment of recent food intake of vitamin K and laboratory methods for biochemical assessment, including coagulation test and body composition techniques. For the longitudinal study, a food frequency questionnaire was applied in order to... (Complete abstract click electronic access below)