Interactions of Lipoprotein(a) with the Plasminogen System: Mechanisms and Pathophysiological Consequences

Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are associated with increased risk of atherothrombotic disease. Lp(a) is a unique lipoprotein consisting of a low density lipoprotein-like moiety covalently linked to apolipoprotein(a) (apo(a)), a homologue of the fibrinolytic proenzyme plasminogen. Apo(a) is extremely heterogeneous in size with small isoforms being independently associated with increased cardiovascular risk. Several in vitro and in vivo studies have shown that Lp(a)/apo(a) can inhibit tissue-type plasminogen activator (tPA)-mediated plasminogen activation on fibrin surfaces, although the mechanism of inhibition by apo(a) remains controversial. Essential to fibrin clot lysis are a number of plasmin-dependent positive feedback reactions that enhance the efficiency of plasminogen activation, including the plasmin-mediated conversion of Glu1-plasminogen to Lys78-plasminogen. Additionally, abnormal fibrin clot structures have been associated with both an increased risk of cardiovascular disease and elevated Lp(a) levels. Similarly, oxidized phospholipids have been implicated in the development of cardiovascular disease, and are not only preferentially carried by Lp(a) in the plasma but have also been shown to covalently-modify both apo(a) and plasminogen. In this thesis, we built upon the understanding of the role of apo(a) in plasminogen activation on the fibrin/degraded fibrin surface by determining that: (i) apo(a) inhibits plasmin-mediated Glu1-plasminogen to Lys78-plasminogen conversion and identifying the critical domains in apo(a) responsible for this effect, (ii) apo(a) isoform size does not affect either the inhibition of tPA-mediated plasminogen activation or the inhibition of plasmin-mediated Glu1-plasminogen to Lys78-plasminogen conversion, (iii) apo(a) modifies fibrin clot structure to form more dense clots with thinner fibers and reduced permeability, modifications that enhance the ability of apo(a) to inhibit tPA-mediated plasminogen activation and (iv) the phosphorus content of apo(a) affects its ability to inhibit tPA-mediated plasminogen activation and the phosphorus content of plasminogen affects its ability to be activated by tPA. By understanding these individual reactions, each of which has the potential to affect the broader fibrin clot lysis process, we have expanded our understanding of the overall effect of Lp(a)/apo(a) in the inhibition of plasminogen activation on the fibrin/degraded fibrin surface and thus broadened our understanding of how Lp(a)/apo(a) may mediate the inhibition of thrombolysis in vivo.

Self-Management of Chronic Pain: Interventions, Strategies, Barriers, and Facilitators

Background & Purpose: Chronic pain is a prevalent chronic condition for which the best management options rarely provide complete relief. Individuals with chronic pain with neuropathic characteristics (NC) report more severe pain and experience less relief from interventions. Little is known about current self-management practices. The purpose of this dissertation was to inform self-management of chronic pain with and without NC at the individual, health system, and policy levels using the Innovative Care for Chronic Conditions Framework. Methods: The study included a systematic search and review and cross-sectional survey. The review evaluated the evidence for chronic pain self-management interventions and explored the role of health care providers in supporting self-management. The survey was mailed to 8,000 randomly selected Canadians in November 2011, and non-respondents were followed-up in May 2012. Screening questions were included for both chronic pain and NC. The questionnaire captured pain descriptions, self-management strategies, and self-management barriers, and facilitators. Results: Findings of the review suggested that self-management interventions are effective in improving pain and health outcomes. Health care professionals provided self-management advice and referred individuals to self-management interventions. The questionnaire was completed by 1,520 Canadians. Those with chronic pain (n=710) identified primary care physicians as the most helpful pain management professional. Overall, use of non-pharmaceutical medical self-management strategies was low. While use positive emotional self-management strategies was high, individuals with NC were more likely to use negative emotional self-management strategies compared to those without NC. Multiple self-management barriers and facilitators were identified, however those with NC were more likely than those without NC to experience low self-efficacy, depression and severe pain which may impair the ability to self-management. Conclusions: Health care professionals have the opportunity to improve chronic pain outcomes by providing self-management advice, referring to self-management interventions, and addressing self-management barriers and facilitators. Individuals with NC may require additional health services to address their greater self-management challenges, and further research is needed to identify non-pharmaceutical interventions effective in relieving chronic pain with NC. Public policy is needed to facilitate health systems in providing long-term self-management support for individuals with chronic pain.

A Study of the Development of the Ability of the Archives Department of the Hudson's Bay Company to Carry Out Document Repairs

The objective of this thesis was to determine whether the establishment and operation of an archives services by the Hudson's Bay Company had an effect on the company's ability to carry out document repairs. Data collection methods included reviews of published material, archival records of the Hudson's Bay Company, and semi-structured interviews. The study found that the Hudson's Bay Company's commitment to operating a modern archives service in accordance with accepted archive administration practices had a substantial effect on its ability to carry out document repairs. The principled approach to repair, as practiced by the Public Record Office, was a major influence. A review of secondary sources placed this development squarely within the context of archival developments in 20th century England. Overall, the thesis findings add to the growing conversation about conservation history in England, in particular, archive conservation history as it occurred outside of the Public Record Office in the 20th century, by discussing how some methods of repair that were devised, adopted and extended by the Public Record Office in the 19th and 20th centuries were adopted and applied in the 20th century by a well-established business corporation.