Previous research has reported positive associations between anger, perceived stress and blood pressure. These associations have largely been based on cross-sectional data and a small number of longitudinal works. Using a prospective longitudinal cohort design, this study more directly tested the relationships between anger, perceived stress and blood pressure by using a psychological therapeutic intervention (mindfulness-based stress reduction) to manipulate anger and perceived stress. Anger and perceived stress were in turn evaluated for association with blood pressure. Despite improvements in psychosocial functioning and reductions in blood pressure, findings from this study failed to demonstrate an association between change in anger or perceived stress with change in daytime or 24-hour ambulatory blood pressure. A model where these variables interact indirectly via stress coping mechanisms or health behaviours may be the linking mechanism in this study. Results from this thesis have contributed evidence to a divided field dominated by cross-sectional research.

Shiga toxin-producing E. coli (STEC) comprise a group of pathogenic organisms that elaborate a family of protein exotoxins known as Shiga toxins (Stxs). Intestinal infection with these organisms may lead to hemorrhagic colitis and hemolytic uremic syndrome, a life-threatening condition characterized by thrombocytopenia, non-immune hemolytic anemia, and acute renal failure. Vascular endothelial damage is believed to be a key initiating event in Stx-mediated diseases. At the molecular level, these toxins depurinate human 28S rRNA and inhibit translation. In addition, at concentrations that only minimally affect global protein synthesis, they have been found to alter expression of specific target genes. To better understand the endothelial damage induced by Stx, we investigated the global effects of Stx on endothelial gene expression, and defined a specific group of genes whose expression was altered by the toxin. Of interest, the CXCR4/CXCR7/SDF-1 chemokine pathway, a pathway central to vascular biology, was activated by Stx. In vitro studies demonstrated that Stx enhanced both transcript levels of these molecules, as well as their association with ribosomes. To define the relevance of these findings in vivo, a mouse model was established and key changes were noted in plasma and tissue content of CXCR4/CXCR7/SDF-1 following Stx exposure. Inhibition of CXCR4/SDF-1 interaction decreased indices of endothelial activation and organ injury and improved animal survival. Importantly, in children infected with E. coli O157:H7, plasma SDF-1 levels were significantly elevated in individuals who progressed to hemolytic uremic syndrome. A second pathway critical to endothelial health and function is VEGF signaling. Of interest, our endothelial gene expression analyses revealed changes in this pathway in vitro. VEGF mRNA association with cellular polyribosomes increased following Stx treatment. Further studies in vivo demonstrated decreased cardiac function and blood pressure, and increased vascular permeability in specific tissues. VEGF, an important inducer of vascular permeability, increased in mouse plasma. Additionally, altered mRNA expression was observed in key organs, such as the kidney and heart, following Stx challenge. Inhibition of VEGF significantly improved survival of animals treated with Stx, indicating that VEGF plays a role in Stx-mediated pathogenesis. Moreover, in vitro studies demonstrated that Stx-mediated endothelial permeability was attenuated in the presence of a VEGF inhibitor. Taken together, these data indicate that E. coli-derived Stxs induce pathological changes in two pathways key to vascular biology. These pathways represent novel targets for the development of preventative and therapeutic strategies for complications associated with Shiga toxin-producing E. coli infection.

The purpose of this study was to explore the relationship between the formalization of inter-organizational partnerships and collaboration among staff members working together across primary care, mental health and addition organizations to provide services to adults with complex mental health and addiction needs. Phase I of the study provided an environmental scan of existing partnerships among Family Health Teams (FHTs) and Community Health Centres (CHCs), and the Mental Health and/or Addiction (MHA) organizations they partner with, in the province of Ontario (Canada). Phase II explored the relationship between formalization and a) administrative collaboration and b) and service delivery collaboration. The hypotheses proposed that staff members who are part of formalized partnerships would report higher levels of collaboration. Phase III explored how formal and informal partnerships and collaboration are experienced by the administrative and service provider staff members who work across FHTs, CHCs and MHAs organizations. Using a mixed methods approach, data were collected using electronic surveys and telephone interviews. The results of Phase I indicated that FHTs and CHCs in Ontario have between 1-3 partnerships with MHA organizations. Most are informal partnerships, have existed for less than 5 years, and most staff members (partners) interact on a monthly basis. The quantitative results of Phase II showed no significant relationship between formalization and either form of collaboration. The qualitative findings from Phase III provide two key contributions. First, the results of the interviews may help explain why collaboration was not higher in formalized partnerships, as demonstrated by the range of advantages and disadvantages experienced by administrators and service providers in both formal and informal partnerships. Second, the findings illuminate factors related to the process of creating and/or formalizing partnerships, suggesting that there may be other factors that mediate or have a direct impact on the relationship between formalization and collaboration. By bringing together the study findings, the study addresses a gap in the literature by proposing a pathway through which formalization may be associated with collaboration. The results of the study provide opportunities for future research to help improve the quality and accessibility of services to adults with complex mental health and addiction needs.

An acute demyelinating syndrome (ADS) in a child may be a monophasic illness or may represent the incident attack of multiple sclerosis (MS) – an inflammatory demyelinating neurodegenerative disorder affecting the brain, spinal cord and optic nerves. The central objective of this dissertation was to identify MRI parameters present at ADS that predict MS diagnosis. A scoring tool was first created containing 14 parameters identified from the literature and demonstrating substantial inter-rater agreement (Cohen’s kappa values ≥0.6). Children aged <16 years were enrolled at incident ADS and are currently followed for five years at 23 Canadian centers. Standardized MRI scans were acquired at onset and serially. MS was defined based on the occurrence of a second demyelinating attack or MRI evidence of new lesions in accordance with McDonald criteria for dissemination in time. Multivariable Cox proportional hazards regression models were used to identify MRI parameters that predicted MS diagnosis. Over 1100 MRI scans in 284 children with ADS were evaluated. To date, 57(20%) children have been diagnosed with MS. For those that developed MS, the median (IQR) time from incident attack to diagnosis was 6.2 (4.7-11.1) months. The presence of ≥1 T1-hypointense lesion (HR 20.6, 95% CI 5.5-78.0) and ≥1 T2 periventricular lesion (3.3, 1.3-8.8) were associated with an increased likelihood for MS diagnosis (sensitivity 84%, specificity 93%, PPV 76%, NPV 96%). The predictive parameters were validated in an independent Dutch cohort of 45 children with ADS (n=15, 33% MS): sensitivity 93%, specificity 87%, PPV 78%, NPV 96%. Finally, it was determined that the 2010 McDonald criteria are applicable for diagnosis of pediatric-onset MS diagnosis in older children with non-ADEM presentations. The work embodied herein emphasizes the value of MRI in predicting MS diagnosis in children with incident ADS. Early identification of children with MS is important for planning clinical care and will be valuable in future pediatric MS treatment trials.

This study characterized the effects of two anti-diabetic drugs, a thiazolidinedione (TZD) and a Dipeptidyl Peptidase-4 (DPP-4) inhibitor on bone quality in a glucose intolerant mouse model. Bone quality in a DPP-4 -/- mouse model was also examined. Bone quality was evaluated through densitometry, mechanical testing and techniques to assess remodeling, structural and mineral properties. TZD treatment negatively affected trabecular mechanical properties in male, female and ovariectomized female (OVX) mice. Male mice exhibited the greatest effect due to TZD treatment with reduced vertebral vBMD, trabecular structure and bone formation. DPP-4 inhibitor treatment improved vertebral vBMD and trabecular architecture in female mice but improvements were lost in females following OVX. Male, female and OVX mice experienced increased trabecular mineralization due to DPP-4 inhibitor treatment. Genetic inactivation of DPP-4 did not produce a major bone phenotype in male and female mice but lead to reduced femoral geometry and mechanics in OVX mice.

Health system restructuring combined with the preferences of palliative care recipients to be cared for at home has lead to a shift in the delivery of care from the hospital to the home setting. An analysis was conducted on five main home-based palliative care health service components: home-based nurse visits, home personal support worker visits, home-based physician visits, ambulatory physician visits, and other ambulatory and home-based visits. First, we assessed the proportion of total cost associated with the main services at different time points over the palliative care trajectory. Second we examined the socio-demographic and clinical factors that predict the propensity and intensity of service use, using a two-part model. The results suggest that the greatest contributor to the total cost of home-based palliative care was personal support worker visits, followed by nurse visits. The regression analysis revealed that patient age as well as functional status most often predicted health service use.

Background: Variation exists in quality of life (i.e., utility) estimates depending on the utility elicitation method utilized. Using the EQ-5D, VAS, and HUI-III, the aim of this thesis was to determine whether these measures adequately capture HRQOL in a CRC population and assess the relationship between utility estimates generated. Methods: A mixed methods study design was employed to collect health status scores and interview data from a sample of 50 CRC patients in Toronto, Ontario. Results: Mean utility scores between the EQ-5D and HUI-III were identical at 0.76 (95% CI), with an overall VAS score of 0.72 (95% CI). Conclusion: The fact that the EQ-5D and HUI-III resulted in identical mean utility scores provides assurance for future studies using these tools in CRC. However, many factors that CRC patients identify as important to their HRQOL are not captured by these instruments. These findings have implications for informing economic evaluations.

Previous research has reported positive associations between anger, perceived stress and blood pressure. These associations have largely been based on cross-sectional data and a small number of longitudinal works. Using a prospective longitudinal cohort design, this study more directly tested the relationships between anger, perceived stress and blood pressure by using a psychological therapeutic intervention (mindfulness-based stress reduction) to manipulate anger and perceived stress. Anger and perceived stress were in turn evaluated for association with blood pressure. Despite improvements in psychosocial functioning and reductions in blood pressure, findings from this study failed to demonstrate an association between change in anger or perceived stress with change in daytime or 24-hour ambulatory blood pressure. A model where these variables interact indirectly via stress coping mechanisms or health behaviours may be the linking mechanism in this study. Results from this thesis have contributed evidence to a divided field dominated by cross-sectional research.

The family of human kallikrein-related peptidases (KLKs) numbers 15 serine proteinases implicated in tumour progression. Despite the wide tissue distribution of KLKs and the numerous reports of their differential expression in pathological settings, the signalling mechanism(s) whereby these enzymes regulate tissue function are not yet known. Further, knowledge of the levels of their activity, as well as of their potential endogenous targets, has only been extracted from in vitro studies and cell culture systems. We hypothesized that KLKs can trigger tumour signalling via proteinase-activated receptors (PARs), a family of G-protein-coupled receptors. To test our hypothesis, we evaluated the ability of KLKs 5, 6, and 14: to activate or prevent signalling via PARs 1, 2, and 4 in cells and tissues expressing these receptors. Further, we used a novel activity-based probe approach, coupled with conventional immunoassay (ELISA), to determine the abundance of active KLK6 relative to total immunoreactive KLK6 in cancer-related biological fluids. We concluded that KLKs can regulate multiple signalling pathways triggered by PARs 1, 2, and 4, resulting in calcium release, platelet aggregation and vascular relaxation, and they can cause murine inflammation. Further, our activity-based ELISA demonstrated the presence of active KLK6 in ovarian cancer ascites fluids and cancer cell supernatants. We, therefore, suggest that tumours can produce active KLKs, which can potentially control tumour behaviour by regulating PAR activity.

The prevalence of neurodegenerative disease in India is rising. Regenerative medicine (RM) is being developed to treat these conditions. However, despite advances in RM application for neurological disorders (NeuroRM), there is a lack of research on clinical translation of NeuroRM technologies in developing countries. Given that India is one of the first nations to translate in this field, much can be learned on challenges and solutions arising during translation. This study identifies stakeholders involved in such translation and outlines roles of each; it describes India’s regulatory environment concerning NeuroRM translation; and discusses the impact of collaboration in clinical translation. Twenty-three face-to-face interviews with clinicians, researchers and policy-makers within India were undertaken and transcripts subjected to thematic analysis. The study demonstrates that clinical translation of NeuroRM within India is taking place robustly, it identifies barriers and good practices being adopted, and provides recommendations based on participants’ experiences.