Concern exists that individuals with systemic lupus erythematosus (SLE) have increased susceptibility to cancer compared with the general population. My thesis contains five chapters, each presenting a different perspective on the issue of cancer in SLE. / Although past literature has suggested an increased risk of cancer in SLE, conclusions from earlier studies were not uniform. I review this earlier data in the first chapter of my thesis. / The absence of adequate data regarding malignancy risk in SLE meant that a large, multicentre effort was needed. We have recently completed this multi-centre cohort study, comparing cancer risk in SLE relative to the general population. In the second chapter I present my analyses of these data, which confirm an increased risk of cancer in SLE. The risk is particularly evident for non-Hodgkin's lymphoma (NHL), where an almost four-fold increased risk is estimated. / A potential bias which has been invoked as a possible explanation for the associations between cancer and other chronic disease exposures has been variously called "misclassification", "detection" or "surveillance" bias. If this bias, related to a potential for greater scrutiny for cancer in SLE patients, does exist, one could expect that cancers in SLE patients are diagnosed at earlier stages than in the general population. I examine this in the third chapter, presenting my work that does not support the presence of "surveillance" bias in the results from the multi-centre SLE cohort study. / In the fourth chapter, I describe the demographic factors, subtypes, and survival of the NHL cases that arose in the multicentre SLE cohort sample. The data suggest that aggressive NHL subtypes and poor outcome are common in SLE. / Though the pathogenesis of cancer in SLE is unknown, one theory is that exposure to immunosuppressive medications is a factor. Although definitive evidence is not available, I present, in the final chapter, my findings within the Montreal General Hospital SLE cohort, where immunosuppressive exposure was associated with abnormalities on cervical cancer screening (Pap) tests. / In summary, our work demonstrates an increased risk of cancer in SLE; this is not likely due to surveillance bias. Immunosuppressive exposure may be associated with abnormal Pap tests; further work will determine whether immunosuppressives confer risk for other neoplastic events in SLE, particularly NHL.

Graft copolymers using biodegradable and biocompatible bacterial poly([ R]-3-hydroxybutyrate) blocks were synthesized and tested as biomaterial candidates for orthopaedic surgery applications. Low molecular weight poly([ R]-3-hydroxyalkanoates), namely poly([R]-3-hydroxybutyrate), poly([R]-3-hydroxyvalerate), and their copolymers poly([ R]-3-hydroxybutyrate-co-[R]-3-hydroxyvalerate), were prepared by thermal degradation in the melt at 190°C. The chemical composition of the oligomers was well-defined, featuring the same repeat unit as their high molecular weight analogues, a carboxylic acid end, and an alkenyl end mostly in the trans configuration (crotonate-type). Increase in the reaction temperature, time, or [R]-3-hydroxyvalerate content decreased the molecular weight of the products. Methacrylic macromonomers of PHB were obtained by functionalization of the oligomers at the carboxyl end, and copolymerized with methyl methacrylate. Two free radical polymerization methods were employed: conventional free radical and a controlled free radical polymerization, Atom Transfer Radical Polymerization. Kinetics of the copolymerizations were studied, and the copolymerization behavior of the comonomers was shown to change with the comonomer feed composition. This would have resulted in variable graft copolymer microstructures. Graft copolymers produced by conventional free radical copolymerization were incorporated in commercial acrylic (poly(methyl methacrylate)-based) bone cement formulations. Cements with formulations containing 6.6-6.7, and 13.5 wt.-% of PMMA-graft-PHB were prepared. The morphology of the graft copolymer particles was suggested to influence the processability of the modified cement. The cements were found rather porous, with average porosities of 13.5 to 16.9%. Nevertheless compression strengths were quite similar to those found for the reference material, pure Antibiotic SimplexRTM, and met the ASTM requirements on acrylic b

Objective. This study was designed to assess the association between cardiovascular disease and the use of antihypertensive drugs in a diabetic population. / Design and setting. We conducted a case-control study nested within a cohort of 2499 subjects over 45 years old with diabetes and hypertension in Saskatchewan. / Outcomes. The main outcome measure was first hospitalization for cardiovascular disease. / Exposure definition. The main exposure of interest was current use of antihypertensive drugs, defined as drug dispensing within 90 days of the index date. / Statistical analysis. Relative risks were calculated with 95% confidence intervals using conditional logistic regression models. Full multivariate models, adjusting for all potential confounding covariates, were performed. / Results. Compared with diuretics, current use of calcium antagonists was associated with a 1.90-fold increase in risk of cardiovascular disease (RR 1.90; 95% Cl = 1.25--2.91). The current use of beta-blockers was not associated with an increase in morbidity. The risk of cardiovascular disease for angiotensin-converting enzyme inhibitors (ACE-I) relative to diuretics was found to be increased only in the subgroup of patients currently exposed to other antihypertensive drugs, including peripheral vasodilators, centrally-acting alpha 2 agonists, and a-blockers (RR 1.6; 95% Cl = 1.19--2.18). / Conclusion. Results of this research agree with the findings from several observational studies and clinical trials. However, factors influencing selective prescribing practices could not be completely accounted for and may partially explain our results.

<p> <b>Background:</b> Implementation of evidence-based knowledge in healthcare is challenging with success rates less than optimal at times. This is particularly true in the area of pressure ulcer prevention. Attention to use of the affective domain in educational interventions to implement best practices may be part of the solution. </p><p> <b>Purpose:</b> The ultimate purpose of this study was to compare the use of two different educational interventions on medical-surgical nurses' behavioral intent to use evidence-based practice in preventing pressure ulcers. </p><p> <b>Theoretical Framework:</b> The theoretical framework for this study was the theory of planned behavior. </p><p> <b>Methods:</b> This study proceeded in three phases and collected both qualitative and quantitative data for instrument development and instrument testing. The resultant instrument was used to collect data for hypothesis testing in a cluster randomized experiment. </p><p> <b>Results:</b> The theory of planned behavior was not fully supported in this study. Attitudes toward pressure ulcers were predictive of behavioral intent. Nurses who experienced the affective domain educational intervention showed significant improvements over the control group on attitude and perceived behavioral control. Behavioral intent and subjective norm were not impacted. </p><p> <b>Conclusions:</b> A reliable and valid theory of planned behavior derived instrument was created. The theory of planned behavior was partially supported. An affective domain intervention has the potential to favorably impact nurses in valuing pressure ulcer prevention, despite any barriers.</p>

<p> Paracrine signals, essential for the proper survival and functioning of tissues, can be mimicked by delivery of therapeutic proteins within engineered tissue constructs. Conventional delivery methods are of limited duration and are unresponsive to the local environment. I developed a system for sustained and regulated delivery of paracrine signals by encapsulating living cells of one type in alginate beads and co-suspending these cell-loaded particles along with unencapsulated cells of a second type within a 3D protein gel. By using cells as particulate protein delivery sources in a 3D gel, an array of soluble factors are delivered in an adaptable manner throughout the gel material for as long as the cells are alive and healthy.</p><p> This system was applied to vascular tissue engineering by placing human placental microvascular pericytes (PCs) in the particulate alginate phase and human umbilical vein endothelial cells (HUVECs) in the protein gel phase. Particle characteristics were optimized to keep the encapsulated PCs viable for at least two weeks. Encapsulated PCs were bioactive <i>in vitro</i>, secreting multiple angiogenic proteins for up to 7 days, including hepatocyte growth factor and vascular endothelial growth factor, and responding to externally applied HUVEC-derived signals. Medium conditioned by encapsulated PCs stimulated the formation of longer cumulative sprout lengths (1.4x) in an HUVEC sprouting assay.</p><p> Encapsulated PCs were biologically active in the complete dual-cell system described. These encapsulated PCs influenced HUVEC behavior in the surrounding gel by enhancing the formation of vessel-like structures, when compared to empty alginate bead controls. Significantly more multi-cell cords (3.1x) and tubes (2.6x) were formed by HUVEC in the presence of encapsulated PC. Additionally, multi-cell cords were significantly longer (1.4x) and lumen diameter was significantly smaller (1.5x) than in control gels containing empty alginate particles.</p><p> Encapsulated PCs appear to lead to important functional consequences in the developing vascular network: paracrine signals from the entrapped PCs lead to smaller lumen diameters in vessels formed by HUVEC that were suspended in protein gels and subcutaneously implanted in the abdominal wall of immunodeficient mice. In native <i>in vivo</i> microvessels, PCs reside in the basement membrane and directly contact EC tubes. Previous studies, in which EC-PC contact was permitted, showed that the presence of PCs lead to smaller vessel diameter. These earlier studies hypothesize that this limitation of lumen diameter requires EC-PC contact, and was due to a physical restriction. Our studies, on the other hand, suggest that paracrine signals contribute to this control of vessel diameter.</p><p> I conclude that alginate-encapsulated cells can provide functional paracrine signals within engineered tissues. The dual-cell system described in this dissertation can be used both as an engineering therapy to adaptably deliver an array of paracrine signals and as a platform for studying the purely paracrine interactions between two cell types in the absence of cell-cell contact.</p>

<p> Objective: This study was designed to evaluate the use of low dose vaginal estriol and low dose vaginal estradiol creams for the treatment of vulvovaginal atrophy. Methods: We designed a 12-week randomized double blinded pilot study. Participants applied the study cream daily (estriol 10mcg, estradiol 10mcg, or placebo) for 2 weeks and then twice weekly for a further 10 weeks. Results: Sixty three women were accrued, of whom 56 completed the study. There was no statistical difference between the three groups in improvement in the symptoms of vulvovaginal atrophy. There was a within group improvement for vaginal dryness and itch in all 3 arms. The within group improvement for vaginal dryness was greatest in the estriol group. Estriol levels remained &lt;25ng/ml at baseline, week 2 and week 12 for all participants except 1 (in the placebo group at week 2 when it rose to 29.8ng/ml). Estradiol levels at week 2 in the estradiol group were significantly higher than week 2 levels in the estriol or placebo group. Conclusions: Low dose vaginal estriol cream is a feasible alternative to low dose vaginal estradiol cream for the treatment of vulvovaginal atrophy. Further research should include a larger volume of base cream and an adequately powered clinical trial.</p>

<p> The purpose of the study was to document how individuals' experiences and understanding of genetics concepts affects their medical experiences. Recently pregnant women were interviewed because they represent a population that needs to comprehend biological and genetic information to understand their health. Three women were designated as science experts (SE) defined as having extensive university level science education and three women were designated as science non-experts (SNE). In general, SEs described a more positive pregnancy experience. Both SEs and SNEs demonstrated a basic understanding of genetic concepts but varied in the application of concepts to personal medical issues. Participants' views and experiences of pre and postnatal tests were linked to their understanding of nature of science components such as recognition that tests have limitations. Results from this study indicate an incomplete understanding of the nature of science among participants may have led to unsatisfactory medical experiences.</p>

<p> Endometriosis, defined by ectopic growths of uterine tissue, is considered an enigma because it is unknown how or even if these abnormal growths contribute to the painful conditions including dysmenorrhea, dyspareunia, and chronic pelvic pain that often accompany the disease. Many clinicians and biomedical scientists assume that the amount of ectopic growth (cysts) predicts the presence or severity of pain symptoms, even though considerable evidence suggests that this assumption is unwarranted. Studies from our laboratory using a rat model of surgically-induced endometriosis (ENDO) demonstrated for the first time that the cysts develop a sensory and sympathetic nerve supply. This discovery gave rise to the hypothesis that this <i><b>newly-sprouted innervation of the cysts is a significant contributor to the <u>development</u> (i.e., generation) and <u>maintenance</u> of painful symptoms. One of these common symptoms, studied here, is vaginal hyperalgesia</b></i> (often called dyspareunia in women). The purpose of this dissertation was to use a combination of immunohistochemical, physiological, and behavioral methods to test various aspects of this hypothesis.</p><p> In the first study, the developmental time course of cyst innervation (sensory and sympathetic) and ENDO-induced vaginal hyperalgesia was examined over a 10 week period post-ENDO. It was found that rudimentary innervation <b> appears</b> within the cysts at 2 weeks post-ENDO, and becomes <b>active </b> at 3 weeks post-ENDO. Between 4 and 5 weeks post-ENDO, vaginal hyperalgesia becomes significant, but is highly variable as the innervation increases and approaches maturity. By 8 to 10 weeks post-ENDO the cyst innervation and hyperalgesia have both matured completely, plateaued and stabilized. Based on these findings, the developmental timeline was divided into three phases: <i>INITIAL </i> (1-2 weeks post-ENDO), <i>TRANSITIONAL</i> (4-6 weeks post-ENDO), and <i>ESTABLISHED</i> (8-10 weeks post-ENDO). In each phase, characteristics of the cyst innervation and vaginal hyperalgesia were found to be as follows: <i>INITIAL,</i> no innervation and no vaginal hyperalgesia; <i>TRANSITIONAL,</i> <b>immature</b> but <b> active</b> innervation and significant but highly variable hyperalgesia; <i> ESTABLISHED,</i> <b>mature</b> innervation and stabilized hyperalgesia both of which varied with the estrous cycle.</p><p> Then, in each of the three phases, the contribution of the cysts (and their innervation) to ENDO-induced vaginal hyperalgesia was tested, by removing the cysts and assessing the effect on the <u>development</u> and <u>maintenance</u> of the vaginal hyperalgesia. In the <i> TRANSITIONAL</i> phase, the relationship between the severity of ENDO-induced vaginal hyperalgesia and the innervation of the cysts, eutopic uterus, and vaginal canal was also assessed.</p><p> The effect of cyst removal on ENDO-induced vaginal hyperalgesia in the <i> INITIAL</i> phase <b>prevented</b> the <u>development</u> of vaginal hyperalgesia. In the <i>TRANSITIONAL</i> phase, cyst removal did not significantly <b>alleviate</b> the vaginal hyperalgesia <u> developed</u> prior to cyst-removal, but, <b>prevented</b> its future <u>development</u>. In the <i>ESTABLISHED</i> phase, cyst removal completely <b>alleviated</b> the vaginal hyperalgesia. Further, in the <i>TRANSITIONAL</i> phase, innervation of the cysts (sensory and sympathetic) and innervation of the vaginal canal (sympathetic only) significantly correlated with severity of ENDO-induced vaginal hyperalgesia. </p><p> Overall, results from these studies strongly support the general hypothesis that the innervation of the cysts contributes to ENDO-induced vaginal hyperalgesia. Specifically, the cyst innervation likely contributes to the <u>development </u>, severity, and <u>maintenance</u> of ENDO-vaginal hyperalgesia. Importantly however, the varying effects of cyst removal suggest that mechanisms by which the innervation operates to contribute to the vaginal hyperalgesia change during its progression through the three phases from peripheral sensitization to peripherally-independent then peripherally-dependent, hormonally-modulated central sensitization. Thus changes, which emerge most clearly in the <i> TRANSITIONAL</i> phase, could help explain the poorly-understood, clinically-challenging issue on how pain transitions from an acute to a chronic problem, not only in endometriosis but also in other chronic pain conditions. </p>

It has been hypothesized that the pathophysiology of chronic heart failure (CHF) may be due to a relative deficiency of atrial natriuretic factor (ANF) and/or blunted responsiveness to ANF in this state. The work presented in this thesis evaluates the role of ANF in rats with chronic moderate high-output heart failure by (1) characterizing plasma and tissue ANF levels, hemodynamics and renal function at different stages of the development of heart failure; (2) assessing the contribution of the atria and ventricles to plasma ANF levels; and (3) investigating the role of ANF and renin-angiotensin systems (RAS) in rats with aorto-caval (A-C) shunts. / Chronically increased cardiac filling pressure stimulated not only ANF release but also ANF synthesis in each cardiac chamber. This in turn contributed to elevated plasma ANF levels in A-C shunt rats. An attenuated renal response to endogenous ANF and sodium and water retention were apparent in A-C shunt rats. Under inhibition of RAS, plasma ANF may exert its actions more effectively. Thus, chronic ACE inhibition and ANG II receptor antagonism improved hemodynamic conditions, diminished water retention, reversed cardiac hypertrophy, and restored plasma and tissue ANF to more "normal" levels in rats with moderate high-output heart failure. / Taken together, elevated plasma ANF levels may play an important role in maintaining hemodynamic and body fluid homeostasis by opposing the neurohormonal vasoconstrictor systems in A-C shunt rats. However, a relative deficiency of plasma ANF and/or an attenuated response to endogenous ANF, mediated by activated neurohormonal vasoconstrictor systems, may contribute to the pathophysiology and development of heart failure at different stages. (Abstract shortened by UMI.)

Temporal lobe epilepsy (TLE) is among the most common chronic seizure disorders, accounting for approximately one-fourth of all cases of epilepsy. Although hippocampal sclerosis is the most common pattern of damage in TLE, there is electrophysiological and neuropathological evidence in both humans and animal models of this condition for the involvement of the parahippocampal region. / In clinical practice, the investigation and treatment of patients with epilepsy has been revolutionized by the advent of MRI, which has been demonstrated to be a reliable and accurate indicator of pathologic findings underlying epilepsy. Advances in image acquisition and processing techniques combined with detailed descriptions of anatomy and cytoarchitectonic borders of parahippocampal structures on histologic sections have created the basis for precise determination of the boundaries of these cortical areas on MRI. This dissertation presents a series of MRI studies aimed at assessing volume changes in vivo of the parahippocampal region, and further elucidating its role in the pathogenesis of TLE. / To accomplish this we developed a standardized MRI protocol to measure the volume of the parahippocampal region structures in vivo. In agreement with previous neuropathological studies (Meencke and Veith, 1991), our results showed that damage to the mesial temporal lobe involves not only the hippocampus and the amygdala, but also the parahippocampal region structures in patients with intractable TLE. Within the parahippocampal region, the entorhinal cortex was the most affected structure. We observed that the atrophy was more severe in the anterior portion of the mesial temporal lobe involving mostly the hippocampal head and body as well as the EC. This pattern of atrophy, characterized by an antero-posterior gradient of pathology, may be explained by a disruption of entorhinal-hippocampal connections. / To evaluate the clinical role of entorhinal cortex volumetry we studied groups of TLE patients with hippocampal atrophy and those with normal hippocampal volumes as well as patients with extra-temporal lobe epilepsy. / Entorhinal cortex volumetry could provide correct lateralization of the seizure focus in 73% of TLE patients with hippocampal atrophy. Entorhinal cortex atrophy seems to be specific to TLE, since we found no atrophy in other forms of epilepsy, including frontal lobe and primary generalized epilepsy. We subsequently demonstrated that entorhinal cortex atrophy ipsilateral to the seizure focus can be the only MRI sign of mesial temporal damage in 64% of patients with normal hippocampal volumes.