Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2004. / Bibliography: leaves 109-125.

Thesis (M.A.)--Boston University

The motivation for this research into flow in pipes with non-uniform geometry comes from physiological flows. It is now widely believed that haemodynamics plays an important role in the initiation and development of atherosclerosis. Experiments have shown that the preferred sites for atherogenesis are regions of low wall shear stress. The build-up of atherosclerotic plaques in the coronary arteries can lead to arterial blockage and coronary failure. Previous studies have examined uniformly curved pipes and, more recently, uniformly curved and twisted pipes. However, it is well known that the arterial system displays non-uniform, time-dependent geometry. The main objective of this thesis is to describe flow in various pipes with weakly non-uniform curvature and torsion, with a view to understanding the resulting wall shear stress distribution and velocity profiles. The work herein models the flow of an incompressible Newtonian fluid through a pipe whose curvature and torsion vary along the pipe. The governing equations are first derived, then solved for both steady and oscillatory pressure gradients. The solution of these equations involves asymptotic and numerical techniques. The effects due to the non-uniform geometry and possible applications to physiology are discussed. Finally, the effects of torsion upon fluid motion are studied from the Lagrangian viewpoint, using numerical particle tracking.

In the last three decades, autohaemotherapy with blood treated with oxygen containing low concentrations of ozone, either alone or in combination with an elevated temperature and ultraviolet irradiation (HOU), has been used in Europe for the treatment of peripheral vascular diseases. Many apparently widely differing beneficial claims have been made for this therapeutic approach. This study has provided an objective rationale as to how HOU-treated blood administered as autohaemotherapy may work as a therapeutic agent. This study has investigated the effect of the treatment of blood in vitro with HOU on the blood platelets. The results indicate that either in healthy volunteers or in patients with PVD and/or diabetes, HOU-treated blood causes a dose-dependent, reversible inhibition of blood platelet aggregation in response to ADP and collagen, calcium ionophore A23187 and thrombin. The treatment of whole blood with HOU did not result in the destruction of platelets, as indicated by a lack of increase in release of the alpha-granule component platelet-derived growth factor into the plasma, and a increase in total platelet count. The concentrations of endothelium-derived relaxing factor (EDRF, known to be closely related to or identical with nitric oxide) and prostacyclin (PGI[2]) released from immune cells in the HOU-treated blood are increased by this treatment in vitro. EDRF and PGI[2] are both well known inhibitors of platelets aggregation and vasodilators. Evidence that the observed inhibition of platelet aggregation in treated blood is at least in part caused by EDRF production is provided by the reversal of the inhibition in the presence of oxy-haemoglobin, an EDRF inhibitor. An In vivo clinical study was performed on normal healthy volunteers using autohaemotherapy with blood exposed to UV light and ozone in medical oxygen (15 mug/mL) at a temperature of 42.5 °C. These volunteers were monitored by measurement of standard haematological parameters, a clinical chemistry profile and clinical symptoms and signs. These was no evidence of harmful effects of the treatment. In vivo HOU-autohaemotherapy enhanced the expression of the activation markers IL-2R, Ber-Mac3 and HLA-DR on peripheral blood mononuclear cells demonstrating for the first time objectively -measurable systemic changes in treated individuals. There was also significant increase in plasma prostacyclin concentrations measured as its stable metabolite 6-keto-PGF[1alpha] after HOU-autohaemotherapy. Endothelial dysfunction, with a reduction in the synthesis of vasodilators, particularly nitric oxide and perhaps also prostacyclin, plays a critical role in many vascular diseases. If autohaemotherapy with HOU-treated blood can restore endothelial function, as suggested by the evidence of an increase in prostacyclin levels in treated individuals, then this therapy could represent a major advance in the treatment of a number of vascular diseases.

Submitted by Edileide Reis (leyde-landy@hotmail.com) on 2015-04-14T02:26:45Z No. of bitstreams: 1 GLAUCO MONIZ DE ARAGÃO DORIA.pdf: 389847 bytes, checksum: 2db42741df4e78cf56b5fa498d43cc57 (MD5) / Made available in DSpace on 2015-04-14T02:26:45Z (GMT). No. of bitstreams: 1 GLAUCO MONIZ DE ARAGÃO DORIA.pdf: 389847 bytes, checksum: 2db42741df4e78cf56b5fa498d43cc57 (MD5) Previous issue date: 2014 / HTLV-1 infection induces a systemic inflammation and occasionally is associated with co infections. Atherosclerosis is closely related to the inflammatory process and its progression lasts for decades. Objectives: 1) To study the risk factors for cardiovascular diseases and atherosclerosis in patients infected by HTLV-1 . 2) To identify the thickening of the intimal-medial layer. 3) To evaluate the association between intimal thickening of the intima , the presence of HAM / TSP , ultrasensitive C-reactive protein and cardiovascular risk factors (age, sex, hypertension , hypercholesterolemia , diabetes mellitus and smoking).Study Design: Cross-sectional observational study. Methods: this study was carried out at the Center for HTLV / EBMSP, Salvador, Brazil, in the period between April, 2012 to September, 2013 The outcome of interest was the presence of atherosclerosis. Sociodemographic and cardiovascular risk factors were evaluated. Results 54 patients were enrolled, with a mean age (SD) of 57.06 (12.33) years, median (p25 - p75) to 57 (46.8 to 65.0) years and predominantly composed of women (72.2%), 41% of women and 3% of men had atherosclerosis. Conclusions: No association was observed between HTLV-1 and clinical or subclinical atherosclerosis as well as with the risk for cardiovascular diseases. A positive association between atherosclerosis and age was observed.

Coronary artery disease (CAD) is the leading cause of death worldwide caused by a complex array of environmental and genetic factors. In recent years, the CARDIoGRAM Consortium has identified dozens of novel CAD-associated loci, including COL4A1/COL4A2 and SMAD3. The goals of this project were two-fold. First, to identify functional CAD-associated SNPs (single nucleotide polymorphisms) at these loci and investigate how these common polymorphisms alter CAD risk. Second, to determine if the COL4A1/COL4A2 and SMAD3 loci display both biological interaction and statistical interaction in the context of atherosclerosis. COL4A1 and COL4A2 are critical components of vascular basement membranes and have many additional roles in the vessel wall. SMAD3 is a transcription factor that is a key mediator in the canonical TGFβ signaling pathway. In the first section of this thesis, I show that COL4A1/COL4A2 and SMAD3 display biological interaction in that the TGFβ-mediated upregulation of COL4A1 and COL4A2 is dependent on SMAD3. Furthermore, we were able to identify a COL4A2-SMAD3 SNP pair that displayed a highly significant statistical interaction for CAD association, highlighting that perturbations of the SMAD3/type IV collagen signaling axis contribute to the pathogenesis of atherosclerosis. The second section details the characterization of a novel functional CAD-associated SNP at the SMAD3 locus. The rs17293632 SNP, highly linked to the rs56062135 index SNP reported by CARDIoGRAM, disrupts a conserved AP-1 binding site in intron 1 of the SMAD3 gene. rs17293632 lies within a strong enhancer in many cell types, including arterial smooth muscle cells. The minor, protective allele (T) at rs17293632 disrupts binding of AP-1 proteins, lowers the activity of this enhancer and lowers SMAD3 mRNA levels in humans in both whole blood and carotid plaque tissue. Altogether, AP-1 regulation of SMAD3 enhancer activity suggests a novel regulatory mechanism relevant to the pathogenesis of CAD. The third section summarizes efforts to characterize the mechanisms whereby the independent rs4773144 and rs9515203 SNPs at the COL4A1/COL4A2 locus associate highly with CAD. We were unable to identify causal SNPs at the COL4A1/COL4A2 locus, highlighting the challenges of post-GWAS characterization of some CAD-associated loci. The experiments with SNPs at COL4A1/COL4A2 demonstrate the challenges in defining mechanisms whereby noncoding DNA variants can lead to common disease.

Atherosclerosis is a chronic inflammatory condition of larger arteries characterized by build-up of plaques in the vessel wall. Disruption of plaques results in superimposed thrombus formation, or atherothrombosis, leading to the occlusion of the blood vessels. Atherosclerosis is the primary cause of heart attacks and strokes. Recent studies show that various fibrinolytic factors influence atherosclerosis progression. A healthy fibrinolytic system is fundamental to mitigating the worsening of the lesion and atherosclerosis progression by rapidly removing unwanted microthrombi that is otherwise incorporated into the plaque. In this regard, the activated thrombin-activable fibrinolysis inhibitor (TAFIa), a potent antifibrinolytic metallocarboxypeptidase that attenuates clot dissolution, could influence atherosclerosis progression. Aside from its antifibrinolytic property, TAFIa also affects inflammation by inactivating anaphylatoxins and kinins. Therefore, TAFIa possesses the potential to influence atherosclerosis via antifibrinolytic and anti-inflammatory facets. We utilized mice deficient in apolipoprotein E (ApoE-/-) as a model of atherosclerosis. Characterization of murine TAFIa determined that the functional half-lives at 37 and 25 ˚C were about 4.0 and 12.7 minutes, respectively. TAFIa was stable indefinitely at 0 ˚C. In vitro clot lysis assays were performed on the plasmas of C57BL/6J (wild-type) and ApoE-/- mice, aged 5, 10, 15 and 30+ weeks. No differences in clot lysis times were observed between the two genotypic classifications. TAFIa was directly quantified using our in-house assay, which showed decreased TAFIa levels in the ApoE-/- mice. Closer examination revealed that the plasma from the ApoE-/- mice was negatively influencing the TAFIa assay. Total TAFI zymogen levels in these samples appeared to increase with age. Other biomarkers of inflammation were quantified using ELISAs; however, only IL-10 levels were measurable with slight elevation in the ApoE-/- mice across age, while IL-1beta, TNF-alpha, and IL-6 was unquantifiable. Overall, TAFIa does not appear to influence atherosclerosis progression in ApoE-/- mice. / Thesis / Master of Science (MSc) / Atherosclerosis is an inflammatory disease of large blood vessels that leads to unwanted clot formation on these weakened/compromised vessel walls. Eventually, the blood flow is hindered by these clots and the supply of oxygen and nutrients to vital organs are disrupted, leading to irreparable damage and death of these organs. As such, it, is the primary cause of heart attacks and strokes depending on the location of vessel occlusion. Thrombin activable fibrinolysis inhibitor (TAFI), when activated to TAFIa, contains both anti-inflammatory and antifibrinolytic properties. Therefore, it is likely that TAFI(a) would be involved in atherosclerosis development and/or progression, especially since other fibrinolytic factors have shown to be involved. Despite promising preliminary data, we found that TAFI(a) alone may minimally be involved in the overall atherosclerosis progression and development using a mouse model of atherosclerosis. We further investigate whether TAFI(a) can be used as a biomarker for early diagnosis of atherosclerosis.