<p>The number one cause of death in the industrialized world, atherosclerosis, can be treated through a variety of methods: angioplasty, stenting, vein graft bypass, synthetic grafts, and maybe one day tissue engineering vessels (TEBVs). The long term goal that motivated this research is the delivery of umbilical cord blood derived endothelial progenitor cells (CB-EPCs) to damaged arteries and possibly reducing the rate of re-occlusion by re-establishing a healthy, functional, intact endothelium. The proposed research tested the following hypotheses: (1) Mild trypsinization methods produces strong endothelial cell (EC) adhesion strength, (2) CB-EPCs are functionally similar to native ECs (specifically human aortic endothelial cells (HAECs)) and exhibit similar anti-thrombotic and anti-inflammatory behavior compared to HAECs, (3) CB-EPCs are capable of adhering to smooth muscle cells (SMCs) and extracellular matrix (ECM) proteins under flow conditions, (4) CB-EPCs can be used to prevent thrombosis in mice that have undergone vein bypass grafts through re-endothelialization of the vessel, and (5) CB-EPCs are capable of proliferating under flow conditions. In order to produce supraphysiological adhesion strengths of HAECs or CB-EPCs, the cells must be detached using 0.025% trypsin for 5 minutes prior to adhesion to adsorbed ECM proteins or SMCs. CB-EPCs have a high proliferation rate and express similar levels of important anti-thrombotic genes and inflammatory proteins compared to HAECs. CB-EPCs and HAECs produce similar levels of nitric oxide and alignment in the direction of flow when exposed to laminar shear stress for at least 24 hours. CB-EPCs are capable of adhering to many different substrates under flow conditions. The adhesion of CB-EPCs with response to shear stress appears to be biphasic and increases with shear stress up to 0.75 dyn/cm2 and then decreases above this value. CB-EPC adhesion is much greater than HAECs and EPCs isolated from peripheral blood (PB-EPCs) of healthy individuals, which can be related to their higher expression level of adhesion integrin &#945;5&#946;1 and their smaller size. When seeded onto FN coated plastic, CB-EPCs proliferated under flow conditions and had a much shorter doubling time than PB-EPCs and HAECs. Proliferation of CB-EPCs and HAECs on SMCs was limited. Further, Cb-EPCs formed network-like structures except when growth factors were removed and a shear stress of at least 5 dyne/cm2 was applied. To assess whether CP-EPCs could promote vessel repair in vivo, human CB-EPCs were injected into SCID mice that received a carotid interpositional vein grafts, resulting in 100% patency. In contrast, only 2 of the 8 saline injected mice had a patent vein graft 2 weeks post surgery. We found that CB-EPC injected mice had roughly 55% endothelialization compared to less than 20% for the patent saline controls, with CB-EPCs making up approximately 33% of this coverage. These results suggest that CB-EPCs could be used as a therapeutic method to prevent vessel re-occlusion in patients undergoing treatment for atherosclerosis.</p> / Dissertation

No description available.

Background. Growth-arrest specific 6 (gas6) is a novel vitamin-K dependent protein whose role in venous thromboembolism was recently characterized in murine models. Gas6 is suggested to be a prothrombotic protein capable of mediating thrombus stability. However, the association between gas6 and venous thromboembolism has yet to be elucidated in humans. The present work aims to delineate the existence of such an association in humans and propose a mechanism by which gas6 expression is related to venous thromboembolic disease. / Methods. To analyze the association between gas6 and venous thromboembolism, a highly specific ELISA method was used to measure plasma gas6 levels in 306 patients with a history of deep-vein thrombosis (DVT) and 89 control volunteers. Medication history, comorbid conditions and DVT characteristics were documented for the purposes of statistical analyses. Median gas6 levels were compared between the subgroups, and prevalence rate ratios were calculated. Human umbilical vein endothelial cells were used to measure the effect of gas6 treatment on the expression of various mediators of coagulation. Murine thrombosis models were developed to serve as in vivo models for thrombosis. / Results. The median levels of gas6 were 28.21 ng/ml in patients compared to 26.15 ng/ml in controls (p=0.01). After adjustment for age, sex, comorbidity and medications, DVT patients had a PRR of 2.5 (95% CI 1.36 to 4.61, p=0.003) compared with controls. Within the DVT subgroup, median gas6 levels were significantly higher in those with cancer-associated (vs. unprovoked or secondary) DVT (p&lt;0.001) and in those with more extensive DVT (p=0.037), while levels were significantly lower in those taking warfarin (vs. no warfarin) (p=0.03). Preliminary results with endothelial cell cultures are inconclusive with regards to the effect of gas6 on endothelium derived mediators of coagulation. / Conclusions. Elevated plasma gas6 is associated with venous thromboembolism. The etiology of the clot influences detected levels of gas6, with the highest levels seen in cancer-patients. Furthermore, increasing clot burden correlates with elevated levels of gas6. A mechanistic explanation for how gas6 modulates this association is in its preliminary stages, and is worth pursuing.

Records of all neurosurgical inpatients admitted to Royal North Shore Hospital since 1976 have been prospectively kept in a relational database. Demographic details, diagnoses, operations and complications have been entered continuously since 1982 by the author of this study. Complications are monitored at monthly review meetings attended by medical staff. The recurrence of deep vein thrombosis (DVT) and pulmonary embolism (PE) at these meetings, despite continual improvements in patient care, prompted this study. It aims to use the database to study changes in the incidence of DVT and PE over the previous twenty years; to find what database variables predict these complications; and whether use of mechanical and pharmacological agents has had an impact on DVT and PE rate. Univariate analysis of the incidence of DVT and PE by age, sex, length of stay (LOS), admission month, diagnosis, operation and surgeon over time was run. Any significant variables were then analysed by multivariate logistic regression. The DVT rate was low by world standards, but rose from 0.6% in 1979-83 to 1.2% in 1984-88, then rose exponentially to 3.60% in 1994-98 with a significantly increasing trend over the twenty years (c2 MH =114.20, with IDF, P<0.001). PE rate doubled significantly over the twenty years from 0.6% to 1.2% (c2 MH =17.94 with 1DF, P<0.001). Age, LOS, diagnosis, operation and surgeon were significant predictors of DVT and PE. After adjustment for LOS, time period and age, vascular surgery was found to be the strongest predictor of DVT (OR=2.82, 95% CI: 2.08-3.82, c2 =43.91, P<0.01). Vascular diagnosis was the strongest diagnosis predictor. No effect of sex or month of admission was shown. After adjustment for LOS, time period and age, spinal fusion was the strongest predictor of PE (OR=4.04, 95% CI: 1.81-9.03). Anterior communicating artery aneurysm was the diagnosis most highly associated with PE. The rise in DVT rate may be due to increased complexity of surgical and nursing management, and some screening of patients with the introduction of duplex scanning. The doubling of PE rate is unexplained. The risk of brain or spinal cord haemorrhage makes prophylactic anticoagulation a difficult choice. This study reveals groupings which can be used to determine appropriate prophylaxis. Use of mechanical and pharmaceutical agents is not recorded consistently in the database, but it is known approximately when they were introduced. No impact on the rate of DVT and PE can be demonstrated by these agents. More vigilant and widespread use of mechanical prophylaxis might be just as effective in controlling DVT and PE.

Diss. (sammanfattning) Uppsala : Univ., 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 4 uppsatser.

Thesis (Ph.D.)--University of Tennessee Health Science Center, 2008. / Title from title page screen (viewed on February 2, 2009). Research advisor: Lisa K. Jennings, Ph.D. Document formatted into pages (xv, 126 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 104-126).

Thesis (M.S.)--Oregon State University, 2009. / Printout. Includes bibliographical references (leaves 45-49). Also available on the World Wide Web.

Thesis (doctoral)--Utrecht, 1981.

Thesis (doctoral)--Katholieke Universiteit te Leuven. / Includes bibliographical references (p. 141-152).