Statement of the Problem: Unfractionated heparin (UFH) is an anticoagulant with anti-inflammatory properties. The efficacy and safety of UFH in severe sepsis or septic shock has yet to be evaluated in clinical trials. Methods of Investigation: We performed a systematic review to evaluate the current evidence regarding the use of heparin in patients with sepsis. We then conducted a cross-sectional survey to evaluate the perceived utility and current use of anticoagulants in sepsis, to assess the degree of certainty regarding clinical benefits and harms of heparin, and to assess the willingness of physicians to consider future clinical trials of heparin. Results: The pooled OR for mortality in 7 trials comparing heparin to any other intervention was 0.88 (95%CI 0.74 to 1.05, I2 0%, n=2473). A large observational cohort study also showed a similar reduction in death associated with heparin (HR 0.85, 95%CI 0.73 to 1.00, n=1390). Data from the national survey indicate that 89% (n=279) of critical care physicians believe that anticoagulant therapies used to modulate host inflammation in patients with severe sepsis or septic shock are clinically important, but not routinely used. Respondents were uncertain if UFH or LWMH are beneficial (67%, n=211), or harmful (61%, n=189) when used in this context, and 90%I(n=281) believe that further clinical trials or UFH or LMWH are warranted. Conclusion: Limited evidence to date suggests UFH may be beneficial when administered to patients with severe sepsis or septic shock. Future clinical trials are warranted and supported by a medical community that believes this avenue of research is clinically important and who is genuinely uncertain regarding the potential therapeutic benefits or harms of heparin in this patient population.

The Ste20-like kinase (SLK) is a conserved serine/threonine kinase that induces the dissociation of actin stress fibers in a Rac1-dependent manner. Recently, our laboratory has shown that SLK is a microtubule-associated protein regulating migratory components at the cell periphery in membrane ruffles and lamellipodia (Storbeck et al.; Wagner et al. unpublished data). To investigate the role of SLK during cell adhesion and migration, we used the Polyomavirus Enhancer Activator 3-null (PEA3(-/-/)) cell line, known to exhibit migration deficiencies. We observed that SLK redistribution to the cell periphery is altered in the PEA3(-/-) cells and that this phenotype could be rescued by the re-expression of PEA3 cDNA into PEA3(-/-) cells. Further analysis revealed that the PEA3(-/-) cells exhibit impaired c-src activation highlighted by decreased focal adhesion kinase (FAK) cleavage and reduced p130Cas tyrosine phosphorylation following fibronectin stimulation, suggesting that c-src activity and proper adhesion signaling may be required for SLK recruitment to the cell periphery. To further investigate FAK and c-src involvement in SLK redistribution to the cell periphery, we used FAK- or src, yes and fyn (SYF)-deficient cells. We have shown that SLK redistribution to the cell periphery is also altered in SYF deficient cells but not in FAK-deficient cells, suggesting that c-src mediates SLK redistribution to the cell periphery independently of FAK. SLK in vitro kinase assays performed on PEA3(-/-), FAK- and SYF-deficient cells revealed that SLK kinase activity is unaffected. However, v-src and c-srcY527F transformed cells displayed a 2- to 3-fold decrease in SLK kinase activity. Biochemical analysis revealed that SLK is hyperphosphorylated on serine residues in these cells with the kinase domain being the main target. Further analysis revealed that casein kinase II (CK2) phosphorylates the SLK kinase domain on serine 347/348 to downregulate SLK kinase activity. In addition, we also showed that CK2 kinase activity is dramatically increased in v-src-transformed cells and that the inhibition of CK2 restores SLK kinase activity. Overall, we showed that SLK redistribution to the cell periphery requires c-src, which can also regulate SLK kinase activity via CK2 to allow the turnover of adhesion sites and cytoskeletal rearrangements.

The investigation of the effects of fluid status and fluid therapy on the dying illustrates some of the obstacles to doing palliative care clinical research. Fluid status and fluid therapy. Objectives. Investigate the effects of fluid status and fluid therapy on the dying. Setting. Two inpatient palliative care units (PCUs), one in Ottawa (Ott) and one in Edmonton (Edm). 123 patients were approached for participation and 94 consented. These were followed in Phase I until 70 were at clinical risk of developing a fluid deficit and started the main phase of the study. (Phase II). Hypodermoclysis was given to all patients in Edm to maintain optimal fluid balance. No parenteral fluids were administered to Ott patients. Patients remained in Phase II until their risk of fluid deficit resolved for 10 days. The groups showed differences in indicators of fluid status, with poorer fluid status, the Ott group. The groups displayed differences at the start of Phase II in several symptom-related outcomes. Median survival in Ott from the start of Phase II was four days, and in Edm was 31.5 days. Both groups showed deterioration in cognitive status close to death. Myoclonus was more prevalent in Ott as were pressure ulcers, but there were no differences in level of consciousness or prevalence of edema. Drugs with sedating effects and with anticholinergic effects were used more often in Ott, while corticosteroids and oxygen were used more in Edm. Clinical research obstacles which are particularly relevant to palliative care and strategies for dealing with them were identified. Sixty-nine studies were identified. Eight included comparison groups and six of these were randomized trials. Obstacles were classified into four main categories: problems caused by the patients' poor and unstable conditions; ethical concerns; population heterogeneity; and lack of relevant outcome measures. (Abstract shortened by UMI.)

The aim of this thesis was to provide feasibility and statistical information that could be used to develop a grant proposal for a multidisciplinary study of the reliability and accuracy of the bedside diagnosis of aspiration and dysphagia in acute stroke patients. The objectives of this pilot study were: (1) To determine the feasibility of doing simple bedside tests for dysphagia and aspiration and determining intra-observer and inter-observer reliability. (2) To determine the required sample sizes to measure the inter-observer reliability of each of the video-recorded bedside tests with the Kappa statistic within a desired confidence interval based on estimates of the observed and expected agreements. (3) To determine the rate of admission of acute stroke patients at one hospital center and the approximate proportion of acute stroke patients who are eligible for enrollment and give consent. (4) To determine the approximate proportion of recruited acute stroke patients with the clinical outcomes of pneumonia and disruption of oral feeding. The pilot study used a prospective design to determine the agreement between two blinded observers for each of the various bedside tests recorded on videotape. It was conducted at Etobicoke General, a suburban community hospital. (Abstract shortened by UMI.)

Statement of the problem. Cardiac arrest is the leading cause of death in Canada, yet it remains a problem with extremely poor prognosis. The prehospital response to cardiac arrest is critical since the majority of these events occur in the community, prior to the patient being transported to hospital. Cardiac arrests that occur after the arrival of trained emergency medical services (EMS) personnel (either ambulance or firefighters) may be a particularly homogeneous subgroup in which to assess not only mechanisms of cardiac arrest, but also the effectiveness of prehospital systems, and thereby contribute to our current understanding of the cardiac arrest condition. Objectives. The objectives of this study are threefold: (1) to elucidate the epidemiology of EMS-witnessed cardiac arrest in Ontario in terms of demographics, EMS-system and clinical characteristics, and rates of incidence and survival; (2) to determine predictors of survival to hospital discharge in this group; and (3) to compare outcomes among EMS-witnessed and bystander-witnessed cardiac arrest. (Abstract shortened by UMI.)

The study objective was to develop and evaluate the psychometric properties of preference-based measures in osteoporosis. Preference scenarios were constructed for marker health states associated with osteoporosis using the feeling thermometer. The reliability, validity and sensitivity to change of these measures and the standard gamble were evaluated in 42 women from four different patient subgroups. The four subgroups of women included women commencing hormone replacement, and women with recent wrist, vertebral or hip fractures. The reason for looking at different groups of women was to establish the feasibility of eliciting preferences in women with varying degrees of osteoporosis. Also, for cost-effectiveness analyses in osteoporosis, estimates of quality of life are required for the four different subgroups. The validity and sensitivity to change of the feeling thermometer and standard gamble were compared with the Health Utilities Index (HUI) and SF-36. All subgroups were reassessed 2-3 months following their first interview. (Abstract shortened by UMI.)

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