The Surgery Collagen Incontinence Trial (SCIT) is a randomized controlled trial evaluating the comparative efficacy of surgery versus collagen injection to treat female stress urinary incontinence (SUI). This thesis investigated two issues from SCIT: (1) the trial investigators' use of a consensus estimate that assumed collagen would be preferred as a first line treatment if it was at most 20% less efficacious than surgery; and (2) the cost-effectiveness of surgery and collagen. / A physician survey was conducted to help verify the SCIT investigators' consensus estimate. Respondents on average believed surgery was more efficacious than collagen, and they generally had stronger beliefs in the ability of surgery to meet their requirements for remaining the first line treatment for SUI. However, on average, respondents indicated a willingness to use collagen if it was at most approximately 23% less efficacious than surgery. The survey also provided baseline data for future research into how SCIT's results may or may not play a role in changing the views of clinicians. / The cost-effectiveness analysis was based on a risk-benefit model (decision-tree) that delineated the success rates, side-effects and complication rates of both surgery and collagen. Probabilities from the physician survey and the published literature were used in the model. Collagen was found to be less costly than surgery, but also less efficacious. Until more is known about collagen's long-term durability, the injection material will probably not gain coverage under Canada's provincial health insurance plans.

Angiogenesis is essential for reproduction, inflammation, development and wound repair. During these physiological processes, angiogenesis is tightly regulated. However, many pathological diseases, such as tumor growth and metastases, are driven by persistent deregulated angiogenesis. The integrin vitronectin receptor alphavbeta3 has been shown to mediate endothelial cell migration and proliferation and thus, plays a key role in angiogenesis. In the present study, the effect of alphav antisense phosphorothioate oligodeoxynucleotides (ODN) on alphavbeta3 expression, and on cellular migration and proliferation was assessed using human umbilical vein endothelial cells (HUVEC). We found that alphav antisense phosphorothioate ODN reduced alphavbeta3expression in some endothelial cell cultures and this resulted in a dose-dependent decrease in endothelial cell migration and proliferation. These results suggest that alpha v antisense phosphorothioate ODN could potentially be used as a novel class of angiogenesis inhibitors.

Objectives. (1) To measure the responsiveness of SLAM-R and SLEDAI to meaningful changes in SLE activity; (2) to determine how strongly activity in specific organ systems affects SLAM-R and SLEDAI responsiveness. / Methods. A secondary analysis was performed on blinded data of SLE patients. Sensitivity of SLAM-R and SLEDAI to change were assessed with traditional measures. Also, perceived change in disease activity was modelled as a function of change in overall instrument scores, and of change in organ system subscores. / Results. Both SLAM-R and SLEDAI were responsive to changes perceived by physicians. However, only SLAM-R was sensitive to changes reported by patients. The relevance of type of organ involvement depended on whether the assessor was the patient or the physician. / Conclusion. The differences between the type of change relevant to physicians and patients may account for SLAM-R's better ability to reflect patients' judgments.

We used decision analysis to determine the factors that influence the decision of whether or not to extubate and to evaluate the usefulness of testing with the RR/Vt ratio. A questionnaire was also distributed to experienced critical care specialists. We showed that the rate of improvement in the patient condition had the greatest influence on the decision to extubate. When the rate of improvement was high, the best decision was to continue with mechanical ventilation unless the probability of tolerating extubation was greater than 0.95. However, when there was little or no chance of further improvement with ongoing mechanical ventilation, the best decision was always to extubate. These results appeared to be counter-intuitive to experienced clinicians who were more likely to extubate when patients were improving and less likely when patients were stable. Testing with the RR/Vt ratio was of little benefit when deciding to extubate.

Background. Septic patients produce increased nitric oxide (NO). We postulated increased exhaled nitric oxide (exNO) in SIRS after cardiopulmonary bypass surgery (CPB). / Methods. Forty-two intubated patients were studied postoperatively and at two-hour intervals for eight hours or until extubated. Hemodynamic indices, including indexed systemic vascular resistance (SVRi) and cardiac index (CI) were measured. ExNO was analyzed by ozone chemiluminescence. / Results. Six patients (14%) Manifested SIRS, defined as SVRI <1800 dynes&middot;sec/cm5/m2. ExNO indexed by expired volume of minute ventilation and body surface area (exNO&middot; V&dot;Ei) was less in SIRS patients at each interval. Overall, normal exNO&middot;V&dot;Ei was 4.3 +/- 0.4 nL/min/m2 with a Cl of 2.56 +/- 0.05 L/min/m 2 and an SVRI of 2488 +/- 62 dynes&middot;sec/cm5/m 2, whereas in SIRS exNO&middot;V&dot;Ei was 0.7 +/- 0.3 (p < 0.001) with a Cl of 2.97 +/- 0.09 (p < 0.001) and an SVRi of 1826 +/- 86 (p < 0.001). / Conclusions. Pulmonary production of NO in post-CPB SIRS differs from sepsis and may not be reflective of systemic levels. Increased pulmonary blood flow may scavenge lung production of NO thereby decreasing exhaled levels.

No description available.

The purpose of this study was to directly compare bone growth into identical porous coated titanium and cobalt-chromium canine implants. A transcortical screw was chosen as the cortical implant model. A straight cylindrical implant was used in cancellous bone. Quantitative analysis was performed using backscattered electron microscopy (BSEM) and computerized digital analysis. Cortical specimens were analyzed after six and twelve week periods of implantation. Bone ingrowth at six weeks for the cobalt-chromium implants averaged 50.4% $ pm$ 10.4% and for the titanium implants averaged 54.1% $ pm$ 5.1%. At twelve weeks, ingrowth for cobalt-chromium was 55.1% $ pm$ 9.2% and for titanium was 57.3% $ pm$ 9.3%. There was no statistically significant difference between the six and twelve week specimens or between cobalt-chromium and titanium for either time period. Cancellous implants were analyzed after twelve weeks and no difference in bone ingrowth between the two materials was observed.

Breast cancer kills through the process of metastasis. In order to improve the prognosis of patients with breast cancer, a better understanding of the underlying factors driving the metastatic process in patients is required. One theory that helps explain the metastatic process suggests that chemokines, such as stromal cell-derived factor (SDF)-1, are overexpressed in specific distant metastatic organs, such as lung, liver, and bone, and serve to home in cancer cells that express their receptors, like CXCR4. The hypothesis of this thesis is that the SDF-1/CXCR4 axis plays an important role in the process of metastasis in breast cancer, and that this ligand/receptor axis can be exploited in the diagnostics and therapy of breast cancer. The first objective of this thesis was to determine if circulating levels of SDF-1 could predict breast cancer metastasis. We found low levels of plasma SDF-1 to be a strong independent prognostic marker, suggesting that the concentration gradient of low plasma SDF-1 and high SDF-1 expressed in the metastatic organ may be critical in driving cancer cells from the circulation to the target organ. We further determined that the levels of plasma SDF-1 were tumor-independent, identifying the first host-derived blood marker predictive of distant metastasis. The second objective was to determine if tumor expression of CXCR4 could modulate the prognostic effect of plasma SDF-1 levels. We found that patients with tumors that highly expressed the activated form of the receptor, phosphorylated-CXCR4, and low plasma SDF-1 levels had a much poorer prognosis than those patients with either risk factor alone. These results highlighted the importance of the dysfunctional relationship between the tumor and the host in the metastatic process. The third objective assessed the therapeutic potential of targeting CXCR4 with a peptide antagonist in a transgenic mouse model. In combination with a / Le cancer du sein tue par le processus des métastases. Dans le but d'améliorer le pronostic des patients atteints du cancer du sein, une meilleure compréhension des facteurs sous-jacents qui conduisent à la transformation métastatique est nécessaire. Une théorie qui explique la transformation métastatique propose que les chimiokines, telles que le stromal cell-derived factor (SDF)-1, sont surexprimées dans des organes métastatiques distants spécifiques, tels que le poumon, le foie, et les os et servent à attirer les cellules cancéreuses qui expriment leurs récepteurs, tels CXCR4. L'hypothèse de cette t hèse est donc que l'axe SDF-1/CXCR4 joue un rôle important dans la transformation métastatique dans le cancer du sein, et que cet axe ligand/récepteur peut être exploité dans le diagnostic et la thérapie du cancer du sein. Le premier objectif de cette thèse était de déterminer si les niveaux circulants de SDF-1 peuvent prédire la présence de métastases du cancer du sein. Nous avons découvert que des niveaux peu élevés de SDF-1 dans le plasma représentent un bon déterminant pronostique indépendant, suggérant que le gradient de concentration de faible niveaux de SDF-1 dans le plasma et de niveaux élevés de SDF-1 dans l'organe métastasé peut être un événement critique dans le transfert des cellules cancéreuses de la circulation sanguine jusqu'à l'organe-cible. Nous avons de plus déterminé que les niveaux plasmatiques de SDF-1 sont indépendants des tumeurs, identifiant le premier marqueur sanguin, dérivé de l'hôte, de prédiction de métastases éloignées. Le second objectif était de déterminer si l'expression tumorale de CXCR4 pourrait moduler l'effet pronostique des niveaux plasmatiques de SDF-1. Nous avons découvert que les patients dont les tumeurs expriment de façon élevée la forme activée du récepteur, CXCR4 phosphorylé, et des niveaux plasmatiq

Prostate cancer (PCa) is among most prevalent causes of cancer death in North American men. Hence mechanisms of progression are poorly understood. The host laboratory reported on the up-regulated FER tyrosine kinase in PCa, comparatively to the benign prostate, and on its nuclear accumulation in higher grade tumors. In vitro, FER also contributed to cell survival and growth. In searching for FER partners, the tyrosine phosphorylated (pY)-actin was discovered for the first time in mammalian cells. In this study, pY-actin levels were correlated to aggressive phenotypes of PCa cell lines. FER was shown to phosphorylate actin directly and to bind actin via its SH2 domain. Furthermore, levels of complexes increased in response to stress, once targeting cytoskeletal actin in a process accentuating levels of predominantly nuclear, globular and tyrosine phosphorylated actin. Considering data in amoeba, it is proposed that FER and pY-actin provide tumors with cell survival advantages to resist stress, thereby contributing to PCa progression. / Le cancer de la prostate (CaP) est une cause majeure de décès en Amérique duNord. Or, les mécanismes de progression demeurent obscurs. Le laboratoire d'accueil arapporté la surexpression de la tyrosine kinase FER dans le CaP comparativement à laprostate bénigne, et son accumulation dans le noyau des cellules tumorales de haut grade.In vitro, FER contribue à la survie et la croissance des cellules du CaP. La recherche despartenaires de FER a conduit à la découverte de l'actine et de sa phosphorylation surtyrosine (pY), une première chez les cellules de mammifères. Dans cette étude, nousdémontrons que les niveaux de pY-actine corrèlent avec le phénotype agressif des lignéescellulaires de CaP. FER phosphoryle l'actine directement et s'y lie via son domaine SH2.De plus, les niveaux de complexes augmentent en réponse à un stress qui cible l'actine ducytosquelette, en un processus qui accentue les niveaux nucléaires d'actine globulairephosphorylée sur tyrosine. Considérant les données chez l'amibe, il est proposé que FERet la pY-actine confèrent aux tumeurs, des avantages de survie et de résistance au stress quicontribuent à la progression du CaP.

Studies into the calmodulin content and activity of tissues from hypertensive and normotensive rats and mice have shown the existence of a factor which potentiates calmodulin's capability to stimulate Ca$ sp{2+}/$CaM-dependent phosphodiesterase (CaM-PDE) and which is detected more in hypertensive animals. This CaM-PDE activator is present in the heart, kidney, erythrocytes, and aortic smooth muscle cells. The augmentation of the CaM-PDE activator is found, as well, in human hypertensives. CaM-PDE activator content is modulated by dietary calcium and sodium. Physicochemical and biochemical characterization of the activator reveal it to be a heat-stable, hydrophobic, protease-sensitive factor with a molecular mass of 4 kDa. Subcellular fractionation studies have revealed that the CaM-PDE activator resides principally in the cytosol although there is a small difference in its subcellular distribution between normotensives and hypertensives. Partial purification of the activator to the step of isocratic, reversed-phase HPLC shows the samples from hypertensive mice to partition into three activity peaks while the normotensives partition into two.