Corticobasal Syndrome (CBS) is a rare movement and cognitive disorder. There is significant heterogeneity observed in it clinical presentation, neuroimaging, pathology and genetics. Understanding this heterogeneity is a priority and may help to shed light on underlying pathogenic mechanisms. We first demonstrated that truncating mutations in the progranulin gene (PGRN) can cause familial CBS associated with frontotemporal lobar degeneration (FTLD)-ubiquitin pathology. This study identified a mutation in PGRN (Intervening Sequence 7+1 guanine > adenine [IVS7+1G>A]) that segregated with CBS in a family. The mutation was predicted to result in a shortened messenger RNA (mRNA) sequence and the absence of the mutant PGRN allele was confirmed in the reverse transcriptase-polymerase chain reaction (RT-PCR) product, which supported the model of haploinsufficiency for PGRN-linked disease. In a second familial study, clinical, radiological, genetic, and pathological studies were performed to contrast clinical features of the affected members. Sequencing PGRN revealed a novel, heterozygous cytosine-adenine dinucleotide deletion in exon 11 (g.2988_2989delCA, P439_R440fsX6). The proband`s clinical diagnosis was frontotemporal dementia and parkinsonism (FTDP). The proband’s brother with the same mutation presented initially as a progressive non-fluent aphasia (PNFA), and later evolved into a CBS. Pathological analysis revealed Frontotemporal Lobar Degeneration-Ubiquitin (FTLD-U)/ TAR DNA-binding protein 43 (TDP43) positive pathology. The next studies shift away from pathogenic mechanisms to focus on brain-behavioural correlations and phenotypic heterogeneity in a prospective sample of 31 CBS cases. We provide the first direct correlative analysis between the severity of ideomotor apraxia, a common sign in CBS, and cerebral SPECT perfusion imaging. Reductions in perfusion within the left inferior parietal lobule (t=5.7, p=0.03, Family-Wise Error [FWE] corrected), including the left angular gyrus (t=5.7, p=0.02, FWE corrected), were associated with more severe ideomotor apraxia. We stratified the sample into CBS presenting with early motor features (CBS-M; n=9) or early dementia (CBS-D; n=22), which identified that CBS-M were more likely to have cortical sensory loss than CBS-D (p=0.005). In contrast, the presence of aphasia was found to be more common and severe in CBS-D compared to CBS-M (p=0.02). CBS-M patients had significantly reduced perfusion in the right supplementary and premotor areas compared to CBS-D (p<0.05).

Gabapentin is an anticonvulsant that has become a treatment option for several indications that are not approved by Health Canada. Commonly, gabapentin is prescribed for neuropathic pain and anxiety disorders. The objective of this dissertation was to evaluate the efficacy of gabapentin for reducing pre-operative anxiety, post-operative pain and opioid consumption. The initial study examined regimens of pre-operative and post-operative gabapentin given to patients undergoing total knee arthroplasty. Patients that received gabapentin postoperatively used significantly less morphine at 24 hrs, 36 hrs and 48 hrs (p<0.05). Furthermore these patients had significantly better active-assisted knee flexion on postoperative day (POD) 2, POD 3, with a trend toward better flexion on POD 4. Next, we examined whether: 1) gabapentin administration reduces pain and opioid use after total hip arthroplasty using a multimodal analgesic regimen that included spinal anesthesia; and whether 2) preoperative administration of gabapentin is more effective than postoperative administration. Our results demonstrated that whether a 600 mg dose of gabapentin was given preoperatively or postoperatively, patients’ postoperative morphine consumption or pain scores were not reduced in hospital nor was there a reduction in pain 6 months after hip arthroplasty. The third study found that a single dose of 600 mg of gabapentin was not sufficient to reduce preoperative anxiety in patients prior to hip arthroplasty. In contrast, the final study demonstrated that 1200mg of gabapentin reduced pre-operative anxiety and pain catastrophizing in female patients with moderate to high levels of preoperative anxiety prior to major surgery, but also increased preoperative and early postoperative sedation. Our findings demonstrate the efficacy of perioperative gabapentin with respect to preoperative anxiety reduction and decreasing morphine consumption after surgery. Future studies that focus on the optimal dose and duration of perioperative gabapentin, with the aim of improving functional outcomes and decreasing the incidence and severity chronic post-surgical pain are warranted.

The implementation of Electronic Medical Records (EMRs) may lead to improved quality of primary health care. To investigate this, we conducted a mixed methods study of eighteen Toronto family physicians who implemented EMRs in 2006 and nine comparison family physicians who continued to use paper records. We used a controlled before-after design and two focus groups. We examined five preventive services with Pay for Performance incentives: Pap smears, screening mammograms, fecal occult blood testing, influenza vaccinations and childhood vaccinations. There was no difference between the two groups: after adjustment, combined preventive services for the EMR group increased by 0.7% less than for the non-EMR group (p=0.55, 95% CI -2.8, 3.9). Physicians felt that EMR implementation was challenging.

Tissue engineering is limited by inability to create early and adequate blood supply. In-vivo DCE-MRI has imaged angiogenesis in soft tissues, yet has not been considered in hard tissues. Bilateral critical defects created in parietal bones of eighteen adult rabbits were left void, treated with haluronic acid acellular matrix (HA-ACM), or HA-ACM impregnated with vascular endothelial growth factor (VegF). DCE- MRI was acquired at weeks 1,2,3,6, and 12. Histologic analysis of HA-ACM treated defects demonstrated quantitatively greater immature bone formation, increased quantity and larger blood vessels compared to void. Statistically significant greater angiogenesis evidenced by quantitative perfusion on MRI supported histologic findings. DCE MRI is a novel means of imaging angiogenesis in grafted bone defects. DCE-MRI discerns physiologically important phases of angiogenesis: Initial vasoactive response, vessel network initiation, establishment, and pruning. DCE-MRI is adaptable to non-invasive study of candidate tissue engineered constructs and in evaluating scaffolds and treatments on angiogenesis.

Background: Parameters of carotid atherosclerosis dynamic contrast-enhanced MRI (DCE-MRI) are associated with stroke risk indices, but studies have only evaluated symptomatic arteries. I hypothesized that DCE-MRI parameters are different between carotid atherosclerotic plaques at high and low risk for precipitating ischemic stroke. Methods: High and low risk carotid plaques undergoing nonmodel-based DCE-MRI (n=18) were compared using two independent schema: 1) clinical standard (high risk defined as ipsilateral stroke/TIA <1 week old or stenosis >70%); 2) MRI standard (high risk defined as presence of intraplaque hemorrhage [IPH]). Results: IPH-positive plaques (n=9) exhibited greater area under the curve, early and late enhancement rate, and peak enhancement than IPH-negative plaques (n=9) (p<0.05 for all). High (n=8) and low (n=7) risk plaques defined by clinical criteria were not differentiated by any DCE-MRI parameters. Conclusions: Nonmodel-based DCE-MRI discriminates high versus low risk carotid plaque based on the presence of IPH, but not by clinical criteria.

Breast cancer is a growing international health epidemic, and patients in low and middle income countries (LMCs) have worse outcomes than those in high income countries. High quality, well-implemented guidelines help improve patient outcomes, but are often not resource-sensitive, and support therapies that may not be feasible in LMCs. A systematic review to address the content, quality, and resource-sensitivity of international breast cancer guidelines was completed. Also, a survey of global physicians evaluated the impact of resource setting on practice patterns and guideline use. Guideline use did not appear to be directed by quality (which was variable across guidelines) or resource-sensitivity (found in few guidelines). However, practice patterns were found to vary by resource setting and by continent, often due to the cost of certain therapies. In order for guidelines to better impact global breast cancer outcomes, they need to be of higher quality, more resource-sensitive, and better implemented.

Acute Respiratory Distress Syndrome (ARDS) following hemorrhagic shock/resuscitation (S/R) is an important contributor to late morbidity and mortality in trauma patients. S/R promotes ARDS by inducing oxidative stress that primes cells of the innate immune system for excessive responsiveness to small inflammatory stimuli, termed the “twohit” hypothesis. Activated alveolar macrophages (AM) play a central role and when recovered from S/R animals exhibit an exaggerated responsiveness to lipopolysaccharide (LPS) with increased activation of the proinflammatory transcription factor NF-κB, and augmented expression of cytokines. LPS triggers AM signalling through Toll like receptor 4 (TLR4), which resides in plasma membrane lipid rafts. The objective of this work is to define cellular mechanisms of macrophage priming by oxidative stress following shock resuscitation. The main hypothesis investigated is that altered cellular distribution of TLR4 can lead to macrophage priming and antioxidant resuscitation strategies can diminish these effects. AM of rodents, exposed in vivo to oxidant stress following S/R, increase their surface levels of TLR4, which in turn results in augmented NF-κB translocation in response to small doses of LPS. Furthermore, in vitro H2O2 treatment of RAW 264.7 macrophages results in similar TLR4 surface translocation. Depletion of intracellular calcium, disruption of the cytoskeleton or inhibition of the Src kinases prevents the H2O2-induced TLR4 translocation, suggesting the involvement of receptor exocytosis. Further, fluorescent resonance energy iii transfer between TLR4 and lipid rafts as well as biochemical raft analysis demonstrated that oxidative stress redistributes TLR4 to surface lipid rafts. Preventing the oxidant-induced movement of TLR4 to lipid rafts using methyl-ß-cyclodextrin precluded the increased responsiveness of cells to LPS after H2O2 treatment. Further, AM priming by oxidative stress can be diminished by early exposure to resuscitation regimens with direct or indirect systemic antioxidant effects, such as 25% albumin, N-acetylcysteine and hypertonic saline. Hyperosmolarity was found to modulate AM TLR4 gene and protein expression. Collectively, these studies suggest a novel mechanism whereby oxidative stress might prime the responsiveness of cells of the innate immune system. Targeting the TLR4 signalling pathway early during shock resuscitation may represent an anti-inflammatory strategy able to ameliorate late morbidity and mortality following S/R.

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.

Some 70,000 people in New Zealand may have undiagnosed diabetes. This study aims to develop ‘systematic opportunistic screening’ for diabetes, testing people attending a general practitioner (GP) for some other reason, and to trial this process with Auckland GPs. The literature on how to change doctor behaviour is reviewed for both theoretical perspectives and empirical evidence. Two of the most promising strategies are computer reminders within a medical consultation and having patients influence doctors. Literature reviews cover GP attitudes to diabetes, guidelines and preventive care and the role of a computer in a GP consultation. The Mail Survey (response rate 154/212, 72.6%) reports GP attitudes to guidelines and preventive care. Factor analysis showed five ‘guidelines’ factors and two ‘preventive care’ factors that might indicate differential motivations to screening for diabetes. The Focus Group Study, of 35 GPs in 5 groups, discussed guidelines, diabetes and computer reminders in a consultation. The analysis suggested that GPs would respond to a patient reminder and may respond to a computer reminder to screen for diabetes. The Screening Reminder Trial involved 107 GPs randomly allocated across four interventions: Computer reminders, Patient reminders, Both and Usual care. The main outcome measures were whether a patient who was eligible for diabetes screening and who visited a GP during the trial had a glucose test done within the trial. The trial ran for two months. Analysis was by intention-to-treat and allowed for clustering by GP. Compared with the Usual care group (screening rate 15.5%), the Odds Ratio of eligible patients being screened were; Computer group OR 2.55 (1.68-3.88), Patient group OR 1.72 (1.21-2.43) and Both group OR 1.69 (1.11-2.59). The Computer reminders were more acceptable to GPs than were the Patient intervention. The findings suggest that a simple computer reminder can implement systematic opportunistic screening for diabetes in New Zealand. If all GPs in New Zealand used the computer reminders for one year, some 8000 patients might benefit from having their diabetes treated for five years longer than they would have under ‘usual care’. / Subscription resource available via Digital Dissertations only.

Some 70,000 people in New Zealand may have undiagnosed diabetes. This study aims to develop ‘systematic opportunistic screening’ for diabetes, testing people attending a general practitioner (GP) for some other reason, and to trial this process with Auckland GPs. The literature on how to change doctor behaviour is reviewed for both theoretical perspectives and empirical evidence. Two of the most promising strategies are computer reminders within a medical consultation and having patients influence doctors. Literature reviews cover GP attitudes to diabetes, guidelines and preventive care and the role of a computer in a GP consultation. The Mail Survey (response rate 154/212, 72.6%) reports GP attitudes to guidelines and preventive care. Factor analysis showed five ‘guidelines’ factors and two ‘preventive care’ factors that might indicate differential motivations to screening for diabetes. The Focus Group Study, of 35 GPs in 5 groups, discussed guidelines, diabetes and computer reminders in a consultation. The analysis suggested that GPs would respond to a patient reminder and may respond to a computer reminder to screen for diabetes. The Screening Reminder Trial involved 107 GPs randomly allocated across four interventions: Computer reminders, Patient reminders, Both and Usual care. The main outcome measures were whether a patient who was eligible for diabetes screening and who visited a GP during the trial had a glucose test done within the trial. The trial ran for two months. Analysis was by intention-to-treat and allowed for clustering by GP. Compared with the Usual care group (screening rate 15.5%), the Odds Ratio of eligible patients being screened were; Computer group OR 2.55 (1.68-3.88), Patient group OR 1.72 (1.21-2.43) and Both group OR 1.69 (1.11-2.59). The Computer reminders were more acceptable to GPs than were the Patient intervention. The findings suggest that a simple computer reminder can implement systematic opportunistic screening for diabetes in New Zealand. If all GPs in New Zealand used the computer reminders for one year, some 8000 patients might benefit from having their diabetes treated for five years longer than they would have under ‘usual care’. / Subscription resource available via Digital Dissertations only.