Atrial fibrillation (AF) affects up to 50% of post-operative cardiac surgery patients. AF is rarely fatal and most cases are transient and clinically benign. AF however could occasionally lead to many serious complications such as thromboembolic strokes, ischemic bowel, hypotension, or hemorrhage secondary to the required anticoagulation therapy. In addition, hospital length of stay is often prolonged due to the need to control this arrhythmia prior to discharge. Many strategies to prevent the onset of this condition have been the subject of intense research in recent years. Many pharmacologic and non-pharmacologic agents have been studied with varying degrees of success. Amiodarone, a very effective class III anti-arrhythmic agent, has been shown to reduce the onset of this condition by half in this patient population. Most Amiodarone studies were conducted on coronary artery bypass grafting (CABG) patients and the uptake of this intervention strategy by clinicians has been poor at best. The purpose of this study was to examine the possible benefit of using Amiodarone in a select group of cardiac surgery patients who were deemed to be at a higher risk of developing post-operative AF using a randomized controlled trial model. This select group of patients included valve patients, patients with poor left ventricular function, and the elderly. In addition, the possible economic benefit of such selective prophylactic strategy was evaluated. No clear clinical or economic benefits were demonstrated at the conclusion of the trial. The required a priori sample size was not achieved at the conclusion of the trial and hence many of the results did not achieve statistical significance.

The objectives of the thesis were to determine the prevalence of functional capacity outcome measure use among physiotherapists working with post-operative cardiac surgery clients and to develop evidence-based recommendations regarding their use in clinical practice. The thesis consisted of a systematic review of the literature; a survey of outcome measure use in clinical practice; and the development of a clinical practice guideline. Thirty-one functional capacity outcome measures were included in the review. Only 2.6% of survey respondents reported almost always using outcome measures in their clinical practice. The Six Minute Walk Test, the modified Borg Rating Scale of Perceived Exertion and vital signs were recommended for routine use in clinical practice. A variety of outcome measures are available for use in clinical practice however their use in clinical practice continues to be less than optimal. There is a need for continued training in outcome measure use in clinical practice.

Incisional, chest and sternal pain is prevalent in patients after cardiac surgery. If pain is not properly managed it may prevent patients from performing activities such as deep breathing and coughing (DB & C) which are important for preventing postoperative respiratory complications. There is a scarcity of research about the nonpharmacologic modalities for treating post cardiac incisional and sternal pain. Of these modalities, cold therapy is a strategy that has been used effectively over many decades in a number of areas including orthopedic surgery. The beneficial effects of cold therapy for pain management have been widely documented and the side effects are minimal, yet its use is limited in post-surgical cardiac patients. Nurses can have an active role in relieving patients' surgical pain with cold therapy. Presently, there are no studies in the literature that specifically address cold therapy for sternotomy pain management following coronary artery bypass graft (CABG) surgery. The objectives of this study were: (1) to evaluate the effects of cold therapy on pain associated with DB & C post cardiac surgery; (2) to identify sensations from the patients' perspective when cold in the form of a gel pack is applied to the median sternotomy chest incision before DB & C; (3) to identify patients' preferences for gel or no gel pack application. A crossover research design was utilized and each patient served as their own control. Participants underwent four sessions of DB & C every two hours on postoperative day two. Two sessions were preceded by cold application and two sessions were without cold application. At the end of the four sessions of DB & C, patients were asked about their preferences for gel or no gel pack application. Pain scores associated with DB & C were significantly decreased with the application of cold therapy (F=28.69, p<.001). Most participants preferred using the gel pack before performing the DB & C exercises (n=22; 69%) and there were 2 (6%) participants who preferred DB & C without the gel pack, the other participants (n=8) had no preference. The sensations experienced were similar among all participants, most described coolness (n=9; 28%) or cold (n=23, 72%). In conclusion, this study demonstrates that cold therapy is useful for managing patients' pain associated with DB & C following CABO surgery. Cold therapy is low risk, low cost and can be easily integrated into nursing practice since cold packs are easily accessible in most hospitals. With nurses' initial supervision, cold therapy is a safe and effective pain management modality that gives patients an active role in pain management. Further research is recommended on the application of other cold modalities such as the use of ice chips as the cold source before DB & C as well as performing the intervention earlier after the surgery on postoperative day one.

Objectives: 1) To identify laparoscopic colorectal surgery practice patterns in Canada, 2) To systematically review the literature comparing hand assisted laparoscopic surgery to conventional laparoscopic surgery and 3) To design a randomized controlled trial protocol comparing conventional laparoscopic to hand assisted laparoscopic colorectal resections. Methods: A national cross sectional study was undertaken of Canadian General Surgeons with respect to their practice patterns specific to laparoscopic colorectal surgery. A systematic review comparing Conventional laparoscopic to Hand-Assisted Laparoscopic colorectal resections. A randomized controlled trial protocol with methodological discussions regarding issues in surgical trials was written. Results: The majority of Canadian General Surgeons are offering laparoscopic colorectal resections although the volume per surgeon appears to be low. The main barriers to adoption are operating time and lack of formal minimally invasive surgery training. There were two trials identified for inclusion in the systematic review with a total of 94 subjects with some methodological weaknesses. A potential trend towards decreased conversion to open surgery in the hand assisted group was identified. A protocol is presented for a trial comparing hand assisted to conventional laparoscopic colorectal surgery. Conclusion: A large percentage of Canadian surgeons perform laparoscopic colorectal resections although many perform less than one case per month. The limited number of trials performed and their associated methodological weaknesses and heterogeneity does not allow a reliable assessment of the relative benefits of hand-assisted and conventional laparoscopic resections for colorectal disease. Additional adequately powered and methodologically sound trials are needed to determine if there is a clinically important difference in perioperative outcomes.

Atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are cardiac-derived polypeptide hormones secreted by the heart. ANF and BNP play critical roles in maintaining fluid and electrolyte balance in both health and disease. Mechanisms of increasing ANF and BNP gene expression and secretion by mechanical or by vasoactive agonists have been thoroughly examined. However, recent experiments suggest that pro-inflammatory cytokines may also be important regulators of natriuretic peptide secretion. In this study, neonatal rat ventricular cardiocyte cultures were used to examine the effects of pro-inflammatory cytokines on natriuretic peptide gene expression and secretion. Incubation with IL-1beta or TNF-alpha elicited a dose and time dependent significant increase in BNP mRNA and secretion, whereas ANF mRNA and secretion was not affected by treatment. The increase in BNP mRNA was inhibited by pre-incubation with a transcriptional inhibitor, actinomycin D. Moreover, the IL-1beta and TNF-alpha mediated increase was not affected by pre-incubation with cycloheximide, suggesting that a translation-dependent increase in BNP mRNA stability was not involved in increasing BNP mRNA abundance. IL-1beta and TNF-alpha rapidly increased phosphorylated p38 MAP kinase and MAP kinase activity. Inhibition of p38 MAP kinase with SB203580 completely abolished IL-1beta and TNF-alpha stimulated BNP promoter activity, mRNA abundance and peptide secretion. NF-kappaB is another signaling molecule activated by IL-1beta and TNF-alpha, however, results from experiments using a peptide inhibitor to NF-kappaB signaling suggest that NF-kappaB is not important in transducing the IL-1beta and TNF-alpha-mediated increase in BNP secretion. Other pro-inflammatory and immunoregulatory cytokines like IL-6, IL-2 and IFN-gamma did not alter either BNP or ANF secretion but co-treatment with both IL-1beta and IFN-gamma maximally stimulated BNP secretion, suggesting cooperation between IL-1beta and IFN-gamma signaling. Conditioned medium from an allogenic mixed lymphocyte reaction (MLR) was used in order to circumvent the omission of individual cytokines or their combination. Serum-free MLR conditioned medium (SF-MLR-CM) in 20, 50 and 100% proportions increased BNP but not ANF secretion with respect to the basal serum-free lymphocyte medium controls. Although, this increase was sensitive to p38 MAP kinase inhibition, it appears that IL-1beta and TNF-alpha are not major active constituents in the SF-MLR-CM as neither ELISA nor soluble receptor antagonists to IL-1beta or TNF-alpha revealed the presence of these pro-inflammatory cytokines. In summary, our novel findings reveal a unique discoordinated expression of BNP and ANF induced by pro-inflammatory cytokines. Importantly it offers an opportunity to better understand the differential regulation of these two cardiac-derived endocrine hormones that share receptors as well as biological properties.

Focal and segmental glomerulosclerosis (FSGS) is a common glomerular lesion and a significant cause of end-stage renal disease (ESRD). FSGS lesions result from damage to glomerular epithelial cells called podocytes, a key cell type involved in glomerular filtration. Mutations in the ACTN4 gene, encoding an actin-crosslinking protein, are causative of late-onset familial FSGS in humans. We have developed a mouse model of FSGS by expressing a high-affinity variant of alpha-actinin-4 (K256E) in a podocyte-specific manner. Transgenic mice display podocyte damage, subsequent loss of serum proteins into the urine (proteinuria), and glomerular sclerosis, similar to that observed in human patients. In cultured podocytes, alpha-actinin-4 K256E is mislocalized to stable actin-rich structures, which impairs cytoskeletal-dependent processes such as cell spreading and migration. We have also demonstrated that binding of alpha-actinin-4 to filamentous actin is regulated by calcium and phosphoinositides. Binding of calcium decreases the association of alpha-actinin-4 with actin, while binding of PIP2 and PIP3 enhances this interaction. High-affinity variants of alpha-actinin-4 are very static compared to the wildtype protein, and are insensitive to regulation by calcium or phosphoinositides. Such cytoskeletal dysfunction severely impairs the podocyte's ability to withstand mechanical stretch, a mimic of the distensive forces exerted on the podocytes in vivo. Although much insight has recently been gained into the biology of the podocyte, treatments for FSGS and other glomerular disorders remain few and ineffective. Further studies into the mechanisms involved in regulating the podocyte cytoskeleton in healthy and diseased states will surely lead to novel therapeutic interventions.

Gender differences are apparent in both the affective functioning and exercise behaviour of cardiac patients. Specifically, female cardiac patients demonstrate more anxiety and depression, and reduced exercise compared to males. Accordingly, gender appropriate screening measures and interventions are needed. In studying a diverse sample of cardiac patients over two years, the objectives of the first investigation were to (1) examine the factor structure of the HADS, and (2) test measurement invariance between genders. The aims of the second study were to (1) examine the prevalence of autonomic anxiety, negative affect and depression, and (2) determine whether gender moderated the exercise/affective relationships, and (3) evaluate whether exercise mediated the gender/affective relationships. 801 cardiac inpatients completed questionnaires including the HADS at baseline, 6 months, 12 months and 24 months post-discharge. Confirmatory factor analysis consistently supported a three-factor structure of the HADS, with the best fitting model comprised of negative affect, autonomic anxiety and depression. Structural equation modeling showed that the HADS was invariant by gender among cardiac patients. Repeated measures analysis of covariance (ANCOVA) revealed that female cardiac patients had greater autonomic anxiety, negative affect and depression and reduced exercise compared to male cardiac patients at all time points. Although exercise was significantly related to affective outcomes at various time points for both men and women, gender did not moderate any of the exercise/affective relationships, and exercise did not mediate any of the gender/affective relationships. In summary, the HADS can be appropriately used with both male and female cardiac patients to assess three domains of psychological distress. Future investigations should consider the predictive validity and relevance of the HADS subscales with respect to diagnostic distinctions and clinical outcomes among cardiac patients and other clinical populations. In addition, further research is needed to clarify the complex relationships between gender and the affective functioning of cardiac patients.

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