At least one in five Canadians lives with chronic pain, and the prevalence rate is rising. Chronic pain can be a result of injury, disease, surgery, and in some cases, the cause remains unknown. Due to the complexity and variability in the etiology and presentation of chronic pain, it can often be a challenge to implement an appropriate and effective treatment plan. Often, the effects of chronic pain are so debilitating that relief is only available temporarily with pain medication. However, there is the concern and possibility of addiction, health issues, and even increased risk of death with some medicinal interventions. Living with chronic pain can have widespread ramifications, affecting more than just the physical body. This includes psychological, emotional, interpersonal, and vocational challenges. In essence, all aspects of one’s quality of life can be affected by chronic pain. As chronic pain often persists over many years or even the lifetime, it is important to better understand how one might adapt to living with chronic pain. Mindfulness-Based Stress Reduction (MBSR) is a structured 8-week program that is commonly used as an intervention for people living with chronic pain, as several research studies have shown promising effects on pain outcomes and quality of life. Using hermeneutic phenomenology, the purpose of this study is to learn about the lived experiences of participating in an 8-week MBSR program from those living with chronic pain. Particularly, it explores how, if at all, an MBSR program may play a role in the participants’ adaptation to living with chronic pain. In depth semi-structured interviews were conducted with 3 participants at the end of the MBSR program. They were then analyzed, interpreted and checked by the researcher. The interpretative analysis involved the researcher explicitly detailing their own positioning in order to inform the interpretations and allow for a well-informed continued interpretation and understanding from readers. Overall, participants described several key aspects which may shed light into the benefits that MBSR can have in regards to adaptation to chronic pain as delineated by the following categories: physical pain and pain management, self-perception and identity, relationship dynamics, and emotional equilibrium. Lastly, broader themes included: being heard and understood, letting go and being here, the healing perspective, and moving from surviving to living. The results of this study speaks to the experience of living with chronic pain, and how an MBSR program offers the tools to help facilitate the adaptation process to living with chronic pain, thereby improving quality of life.

Cardiovascular complications represent the leading cause of death in chronic kidney disease (CKD) patients. Significant renal mass reduction induced by 5/6 subtotal nephrectomy (Nx) animal model leads to a chain of events that culminates in hypertension and CKD. The renin angiotensin (Ang) system (RAS) is known to be dysregulated, specifically Ang type 1 receptor (AT1R) plays a major role in development and progression of the disease. However, conflicting results have been reported on intrarenal AT1R levels, and the impact of antihypertensive drugs on RAS signaling is divergent. We hypothesize that PET imaging will be able to quantify kidney AT1R expression reliably in healthy and disease states. The broad objectives of this research project were: (i) to develop a positron emission tomography (PET) probe capable of detecting changes in the AT1R binding in the kidney; (ii) to elucidate the nature/temporal role of renal AT1R in Nx rat model of CKD; and (iii) to explore the predictive value of non-invasive PET imaging of AT1R to guide the use of antihypertensive therapy in preventing the progression of the disease. The novel selective AT1R PET radioligand [18F]FPyKYNE-losartan was successfully used with PET in detecting renal AT1Rs at early and late stages of the CKD. The PET results correlated well with in vitro [125I]-[Sar1, Ile8]Ang II autoradiography. Over the time-course of the study (10-20 weeks), the Nx rats exhibited renal impairment, proteinuria and sustained hypertension. Echocardiography indicated the development of cardiac hypertrophy most likely secondary to the hyperdynamic circulation. These abnormalities were associated with increasing plasma and kidney levels of Ang II, and compensatory downregulation of renal AT1Rs. ACEI enalapril attenuated renal impairment, hypertension and prevented progression of cardiac hypertrophy in Nx rats. This was successfully accomplished through reduction of systemic and kidney Ang II, and consequent normalization of renal AT1R as measured by PET (and autoradiography). The non-dihydropyridine CCB diltiazem also reduced blood pressure but did not normalize renal AT1R expression. Diltiazem induced elevation in Ang II levels in plasma, kidney and heart, associated with exacerbation of renal and cardiac dysfunction, and no change in AT1R renal expression. This outcome adds value to the use of [18F]FPyKYNE-losartan PET for determination of receptor abnormalities with progression of the disease and monitoring of therapy.

Production of the glucocorticoid hormone cortisol in response to a stressor is initiated by activation of the hypothalamic-pituitary-interrenal (HPI) axis in fish. Serotonin (5-HT) and negative feedback regulate cortisol production at the whole-animal level; the objective of the present thesis was to investigate their roles in regulating cortisol production by interrenal cells of rainbow trout (Oncorhynchus mykiss). Messenger ribonucleic acid (mRNA) for the 5-HT4 receptor was present in low abundance in interrenal cells. In addition, cortisol production was significantly increased for in vitro head kidney preparations incubated with 5-HT, and this elevated cortisol production was blocked by the 5-HT4 receptor antagonist 5-fluoro-2-methoxy-[1-[2-[(methylsulphonyl) amino] ethyl]-4-piperidinyl]-1h-indole-3-methylcarboxylate sulphamate (GR125487). Thus, 5-HT acts at the head kidney level to regulate cortisol production, probably via the 5-HT4 receptor. Chronic social stress did not appear to regulate the expression of key proteins involved in cortisol biosynthesis or corticosteroid receptors (CR). However, head kidney tissue incubated in vitro with cortisol for 2-8 h showed a reduction in adrenocorticotropic hormone-stimulated cortisol production compared to controls, suggesting the existence of an ultra-short-loop negative feedback mechanism. Thus, the high circulating levels of cortisol in trout experiencing chronic social stress may activate this ultra-short-loop negative feedback mechanism to suppress cortisol production at the head kidney level.

Objective: The increased survival rate amongst female breast cancer survivors creates a need for an understanding of chronic disability after surgery. The objective of this study is to explore the association between impairments (e.g., pain, mobility, strength) and the personality trait, fear of physical activity, and chronic daily activity limitations for women who had their surgery at least six months prior to the study. Hypothesis: The study hypothesis is that women with high levels of physical impairments and the personality trait of fear of physical activity will also have higher levels of daily activity limitations six months or more after their breast cancer surgery. Design: A cross-sectional design. Outcome Measures: Disabilities of Shoulder, Arm, and Hand (DASH), Visual Analog Scale for Pain (VAS-Pain), Fear Avoidance Belief Questionnaire – Physical Activity (FABQ-PA), and objective measures of shoulder mobility and strength. Participants: Women who had been diagnosed and undergone surgery for breast cancer, stage 1-3. They must have had their surgery at least six months previously and have completed chemotherapy or radiation therapy. Both English- and French-speaking women from the Ottawa-Gatineau region were eligible. Results: Data from twelve women were analysed with a mean age of 58.0±8.9 years and post-operative time of 4.0± 2.8 years. DASH scores mean was 12.2 ± 11.38. VAS-Pain (rs=0.819; p<.001), FABQ-Physical Activity (rs=0.746; p<.005) were significantly associated with DASH score, whereas non-significant associations were found with supraspinatus strength (rs = 0.182; p < .572) or infraspinatus strength (rs=0.553; p<.062) using the Spearman Rho test. Also, no significant relationships were observed between range of motion (hand-behind-back; p =.366; hand-behind-head; p=.390) and DASH scores using a Kruskal-Wallis test. Conclusion: The results of this exploratory study suggest that the reported daily activity limitations of women who have had breast cancer surgery may be related to the participant pain perception and/or fear of physical activity.

Background: Chronic pain is pain which has lasted for more than 3 months and is reported by 40 to 50% of adults in developed countries. The prevalence of chronic pain is consistently higher in women than in men. Chronic pain is more often reported by older adults than younger adults. As well as duration, pain can also be described in terms of its “widespreadness” by counting the number of body areas experiencing pain, or by the source of the pain e.g. musculoskeletal. Many social, psychological, physiological and behavioural factors have been found to be associated with pain. Altered sensitivity to stimuli may indicate aberrant pain processing mechanisms. Quantitative sensory testing (QST) evaluates responses to experimental, painful and non-painful stimuli. Although originally used in neurological conditions, QST data for people with musculoskeletal pain show differences from healthy controls. Aim: The aim of this study was to determine the relationship between sensitivity to stimuli (measured by QST), and both the number of body areas with pain and the prevalence of chronic widespread pain, and how these relationships vary with age and sex. Methods: A postal questionnaire which included questions about pain location and duration of pain, as well as known risk factors for pain, was returned by 2623 participants aged 34-101 years. A sub-group of 290 participants aged 34-97 years were selected on the basis of their responses to the pain questions and undertook a physical assessment which included QST. Regression models were used to quantify the relationships between QST factors and pain. Pain was classified as a continuum of “widespreadness” (0-29) and as “no pain”, “chronic widespread pain (CWP)” and “some pain” (i.e. pain other than CWP). Regression models with interaction terms were used to investigate whether these relationships varied between older (aged over 65 years) and younger (aged 65 years and younger) people, and between men and women. Results: There were very few differences in QST variables (except tender point count) across the two pain classifications, however, differences in several QST variables were found between the age and sex groups (Chapter 6). Three of the QST measures, tender point count, cool detection threshold at the foot and thermal sensory limen at the foot, were statistically significantly related to number of painful areas, and tender point count and cool detection threshold at the foot were also significantly different among participants with “no pain” and those with CWP (Chapter 7). None of these relationships were significantly moderated by age or sex (Chapter 8). Sleep quality and beliefs about pain duration were found to be statistically significantly related to number of pain areas and to the presence of CWP in all the analyses (Chapter 7). Conclusion: The findings from this study indicate that some QST variables are related to pain, but none of the relationships are moderated by age or sex. The importance of sleep quality and pain beliefs as risk factors for pain has been further confirmed. Further research may allow treatments for pain to be tailored to the individual in the light of these facts.

Introduction: Venous disease impairs the quality of life, necessitates time off work and causes venous ulcers. The focus of this thesis is to explore strategies to prevent chronic venous insufficiency (CVI) and venous ulceration. Aims 1. To identify a population at risk of developing venous ulcers 2. To study the pressure profile required by elastic stockings to halve transit venous time 3. To explore the role of compression following ankle fracture Methods: Data was collected from 231 patients with venous ulcers and age and sex matched 210 controls to identify risk factors for venous ulceration. Univariate and multivariate analysis of potential risk factors was undertaken to identify those that independently predict this risk. After identifying the population at risk, prophylactic strategies were developed. The effect of Engineered Compression Stockings (ECS) delivering 15mmHg, 25mmHg and 35mmHg pressure at the ankle on the calf venous transit time and volume was measured to determine the ideal pressure profile required to halve transit venous time, which should be appropriate for DVT prophylaxis. A dorsal foot vein was cannulated in 15 healthy volunteers with no venous disease. The transit time (secs) for ultrasound contrast from a foot vein to the popliteal vein was measured using duplex ultrasound. Calf volumes were recorded by water displacement. ECS delivering 25mmHg of pressure around the ankle were compared with no compression in a randomized controlled trial (RCT) in 90 patients within 72 hours of ankle fracture. Patients were randomised to either i) ECS and air-cast boot or ii) a liner and air-cast boot and were followed at 2, 4, 8, 12 weeks and 6 months. The primary outcome was functional recovery measured using the Olerud Molander Ankle Score (OMAS). Secondary outcomes were i) The American Orthopaedic Foot and Ankle Score (AOFAS), ii) SF12v2 Quality of Life score (QoL), iii) pain, and iv) frequency of DVT. Results The risk factors significantly associated with venous ulceration on multivariate analysis included a history of Deep Vein Thrombosis (DVT), phlebitis, hip replacement, poor mobility, weight/kg>100Kg, varicose veins (VV), family history of VV and weight (kg) between 75-100kg. A simple diagnostic scoring system was derived from this regression analysis with scores of . 3 predicting a 6.7% annual risk and of < 1 a 0.6% risk. Mean transit time without compression was 35, 32 and 33 secs while standing, sitting and lying. Transit time was consistently halved by ECS delivering 25mmHg to 14, 13 and 14 secs respectively (p<0.001). Mean leg volume whilst standing was reduced significantly from 3447ml with no ECS to 3259ml, 3161ml and 3067ml with ECS applying 15, 25 and 35mmHg respectively (p<0.001). ECS in ankle fracture patients reduced ankle swelling at all time points and significantly improved mean OMAS score at six months to 98 compared with 67 for the liner (p<0.001). AOFAS and SF12v2 scores were also significantly improved (p<0.001, p= 0.016). Of 86 patients with duplex imaging at four weeks, only five (12%) of the 43 ECS patients had a DVT compared with 10 (23%) of the 43 controls (p= 0.26). Conclusions: The risk score for venous ulcers will allow us to undertake RCTs on the prevention of leg ulceration. The pressure profile required to halve transit venous time is 25mmHg. The frequency of asymptomatic DVT following ankle fracture is sufficient to justify prophylaxis. Compression has a potential role in the management of ankle fractures by improving functional outcome and QoL. These studies facilitate research into the prevention of venous disease.

Background: Whilst the experience of chronic physical conditions is well documented and has been recognised as relevant for health policy and practice little is known about notions of recovery and prognosis from the point of view of those with long-term physical health conditions. The extent to which people consider the future outcomes of their conditions is relevant to health policy which seeks to engage people in shared decision making, care plans, and self-management. This gap in knowledge about lay perceptions of recovery and prognosis becomes more pronounced when compared with literature from the mental health field in which recovery is one of the dominant foci, is comparatively well researched and in recent years has fed into policy and management approaches.Aims: The aim of the thesis is to explore perceptions of recovery and prognosis with people with long-term physical health conditions and to compare these with perspectives on recovery and prognosis apparent in the mental health field.Methodology: Using qualitative methods, a two phased approach to data collection and analysis was undertaken. Phase 1 used secondary data analysis with two existing datasets to examine whether notions of recovery and prognosis were implicit in narratives about the experience of illness. Phase 2 built on the findings from phase 1 and utilised longitudinal, primary data collection in the form of narrative interviews undertaken at two time points (baseline and 12 month follow-up). The analysis in both phases involved a cross case thematic analysis to look for commonalities and differences across individuals. Data from phase 2 were also subject to a narrative emplotment of individual stories which were used to capture the longitudinal changes in patient perspectives over time.Results: There were similarities with findings from the mental health field (recovery as a complex, nonlinear journey, the input from friends and family, notions of burden and the impact of condition on sense of self). However, there were nuanced differences in relation to physical health conditions which related to expectations about mortality, the experience of time, the extent to which narratives were future oriented and the experience of stigma. The dual focus on mental and physical health recovery proved useful for understanding those experiences of multiple morbidities. The results were used to develop a model of recovery narratives based on two dimensions (expectations and responsibility) which gave rise to four typologies of narratives. The aim of this model was to further highlight and summarise the themes arising from the data analysis.Discussion: The results of this study highlight the importance of understanding notions of recovery and prognosis in order to better understand the experience of illness and self-management. The thesis challenges the blanket use of health promotion strategies for those with and without chronic health conditions and supports a shift in policy focus from improved choice and autonomy to what Mol (2009) refers to as ‘enhanced care’.

The psychosocial adjustment of nine adolescents with end-stage renal disease (ESRD) was described by two standard psychologic tests; Piers-Harris Self-Concept Scale and Nowicki-Strickland Locus of Control. Life Events were recorded to evaluate the effect of stress at the time of testing. The mean self-concept scores were higher (p = .009) for the ESRD adolescents than the normative sample. However, the individual's scores did not differ significantly. The Life Events were comparable to the healthy population for age. The family members were assessd on the Family Assessment Measure (FAM) to assess the influence of family functioning on adolescent psychosocial adjustment. The standardized FAM scores were comparable to a normative sample. Cluster analysis of the ESRD adolescents revealed three groups differing significantly on: self-concept, locus of control, FAM self-rating and number of years from diagnosis to dialysis. Significant differences were maintained across the family members on FAM General Scale and FAM Self-Rating Scale. The adequate psychosocial adjustment of the adolescents with ESRD is consistent with recent studies suggesting that chronically ill children and adolescents do not differ from healthy children. However, the results also suggest that within the study group, a number of individuals may be experiencing problems of adjustment. / Education, Faculty of / Educational and Counselling Psychology, and Special Education (ECPS), Department of / Graduate

Data from daily diaries were used to examine the relationships between daily pain appraisals (Catastrophizing, Self-Efficacy, and perceived control over pain) and coping strategy use (Distraction, Ignoring Pain, Praying and Hoping, and Reinterpreting Pain Sensation) and nighttime negative mood and pain intensity for 88 women (mean age 46.83 years, SD 11.90) with chronic low back pain who were not attending a specialized pain treatment program. These relationships were examined at two levels using the Hierarchical Linear Modeling program (Bryk & Raudenbush, 1992). The first level of analyses examined whether pain appraisals and coping strategy use during the day predicted levels of nighttime depressed and anxious mood, and pain. This analysis was based on 30 days of monitoring for each participant. The second level of analyses examined whether these daily processes could be predicted by psychosocial and functional variables important to the experience of chronic pain. This analysis was based on the Mutidimensional Pain Inventory (Kerns, Turk, & Rudy, 1985) completed prior to participants beginning the daily monitoring. There were four major findings in this study. First, pain appraisals were more predictive of negative mood and pain intensity than coping strategy use, with Catastrophizing the strongest predictor of depressed and anxious mood, and control the strongest predictor of pain intensity. Second, general affective distress predicted higher levels of negative mood on a daily basis. Third, women who perceived their pain to be interfering a great deal in their lives were more anxious on a daily basis. Fourth, punishing spousal responses predicted nightly negative mood and pain more than solicitous or distracting spousal responses. These results are similar to findings based on patients attending pain treatment programs. This suggests that some of the same processes identified in clinical pain patients may apply to low back pain sufferers in the community who are comparable to study participants. The implications of these findings for pain research and treatment are discussed. / Education, Faculty of / Educational and Counselling Psychology, and Special Education (ECPS), Department of / Graduate

Injury-induced sensitization of nociceptors contributes to pain states and the development of chronic pain. Inhibiting activity-dependent mRNA translation through mechanistic target of rapamycin and mitogen-activated protein kinase (MAPK) pathways blocks the development of nociceptor sensitization. These pathways convergently signal to the eukaryotic translation initiation factor (eIF) 4F complex to regulate the sensitization of nociceptors, but the details of this process are ill defined. Here we investigated the hypothesis that phosphorylation of the 5' cap-binding protein eIF4E by its specific kinase MAPK interacting kinases (MNKs) 1/2 is a key factor in nociceptor sensitization and the development of chronic pain. Phosphorylation of ser209 on eIF4E regulates the translation of a subset of mRNAs. We show that pronociceptive and inflammatory factors, such as nerve growth factor (NGF), interleukin-6 (IL-6), and carrageenan, produce decreased mechanical and thermal hypersensitivity, decreased affective pain behaviors, and strongly reduced hyperalgesic priming in mice lacking eIF4E phosphorylation (eIF4E(S209A)). Tests were done in both sexes, and no sex differences were found. Moreover, in patch-clamp electrophysiology and Ca2+ imaging experiments on dorsal root ganglion neurons, NGF-and IL-6-induced increases in excitability were attenuated in neurons from eIF4ES209A mice. These effects were recapitulated in Mnk1/2(-/-) mice and with the MNK1/2 inhibitor cercosporamide. We also find that cold hypersensitivity induced by peripheral nerve injury is reduced in eIF4ES209A and Mnk1/2 (-/-) mice and following cercosporamide treatment. Our findings demonstrate that the MNK1/2-eIF4E signaling axis is an important contributing factor to mechanisms of nociceptor plasticity and the development of chronic pain.