Inflammatory and neuropathic pains arise in part from sensitization at nociceptive synapses in the spinal cord. Activity-dependent signaling cascades converge onto the tyrosine kinase Src, which participates in augmenting the function of N-methyl-D-aspartate receptors (NMDARs) and thus potentiates the nociceptive system. Src is capable of these effects because it is anchored to the NMDAR complex via an adaptor protein called NADH dehydrogenase subunit 2 (ND2). There is evidence that this interaction occurs between amino acids 40-49 of Src and amino acids 310-321 of ND2. I have determined that a peptide consisting of amino acids 310-321 of ND2, and affixed to the HIV Tat domain for cell permeability, is capable of alleviating tactile allodynia induced by Complete Freund's Adjuvant (CFA) in rats. Src40-49Tat was not effective in two models of inflammatory pain. This work further implicates the Src-ND2 interaction in pain hypersensitivity and suggests that Tat ND2 310-321 may alleviate it.

The objective of this project was to evaluate the effects of local endothelial progenitor cell (EPC) therapy on bone regeneration in a segmental defect in the rat femur. Animals from the EPC-treated (N=28) and control (N=28) groups were sacrificed at 1, 2, 3, and 10 weeks post-operatively. Bone healing was evaluated with radiographic, histological, and micro computed tomography (micro-CT) scans. Radiographically; mean scores of the EPC group at 1, 2, and 3 weeks were significantly higher compared to control group. At 10 weeks, all the animals in the EPC group had complete union (7/7), but in the control group none achieved union (0/7). Histologically, specimens from EPC-treated animals had abundant new bone formation compared to controls. Micro-CT assessment showed significantly improved parameters of bone healing for the EPC group compared to control group. In conclusion, local EPC therapy significantly enhanced bone regeneration in a segmental bone defect in rat femur.

Background: The neurological examination in critically ill patients is limited due to decreased level of consciousness and sedating medications. Electroencephalography (EEG) can be used to monitor brain injury; however, availability is limited. Methods: To determine the perceived need for EEG monitoring in the ICU and its current availability, we used rigorous methodology to develop and disseminate a survey to 199 Canadian critical care physicians. Results: Of 103 (52%) respondents (77% academic practice; 83% adult focus), 75% stated EEG monitoring should be a standard of care; yet, 75.5% were unable to obtain an EEG in an optimal timeframe. Technology under-use was exacerbated during non-standard working hours and greater in adult institutions. Perceived barriers to optimal care were lack of EEG technicians, physicians to interpret EEG and finances. Conclusion: Sub-optimal availability of EEG represents an important gap in the care of neurologically injured patients. Specific barriers represent targets for quality improvement.

Background: The neurological examination in critically ill patients is limited due to decreased level of consciousness and sedating medications. Electroencephalography (EEG) can be used to monitor brain injury; however, availability is limited. Methods: To determine the perceived need for EEG monitoring in the ICU and its current availability, we used rigorous methodology to develop and disseminate a survey to 199 Canadian critical care physicians. Results: Of 103 (52%) respondents (77% academic practice; 83% adult focus), 75% stated EEG monitoring should be a standard of care; yet, 75.5% were unable to obtain an EEG in an optimal timeframe. Technology under-use was exacerbated during non-standard working hours and greater in adult institutions. Perceived barriers to optimal care were lack of EEG technicians, physicians to interpret EEG and finances. Conclusion: Sub-optimal availability of EEG represents an important gap in the care of neurologically injured patients. Specific barriers represent targets for quality improvement.

Background: Nosocomial pneumonia (NP) is a significant cause of morbidity and mortality in hospitalized patients. Objective: The objectives of this study were to describe the epidemiology of NP in adult patients hospitalized in Canadian acute care facilities and identify prognostic indicators for death. Methods: A retrospective cohort study was conducted in 114 patients with NP admitted to hospitals that participated in a 2002 Canadian point prevalence survey. Results: A high proportion of NP patients had a rapidly or ultimately fatal underlying illness. NP in non-intensive care unit (ICU) patients accounted for the larger proportion of these infections.There was no mortality difference between patients with and without ventilator-associated NP, or with and without ICU-acquired NP. Delayed initiation of appropriate antimicrobial therapy was associated with a poorer outcome. Discussion: Strategies that result in the timely administration of appropriate antimicrobial therapy should be investigated in an effort to reduce NP-associated mortality.

Background: Modulation of ischemia-dependent pathways alters electrophysiological evolution of ventricular fibrillation(VF). Hypothesis: 1)There is regional disease-related expression of KATP-channels in human cardiomyopathic hearts. 2)KATP-channel blockade promotes spontaneous VF termination by attenuating spatiotemporal dispersion of refractoriness(ΔERP). Methods and Results: Electric mapping of control(n=6) and treatment(n=9) (10 μmol/L glibenclamide) isolated human cardiomyopathic hearts was performed. Spontaneous defibrillation and KATP-subunit gene expression were studied. Spontaneous VF termination occurred in 1/6 control and 7/8 treated hearts (P=0.026). After 180 seconds of ischemia, LV transmural dispersion in VF cycle length was observed(p=0.001), which was attenuated by glibenclamide. There was greater gene expression of all KATP-subunit on the endocardium compared with the epicardium(P<0.02). In ischemic rat heart model, ΔERP was verified with pacing protocols (36±5ms vs 4.9±4ms, p=0.019). Conclusions: KATP channel subunit gene expression is heterogeneously altered in the cardiomyopathic human heart. Blockade of KATP channels promotes spontaneous defibrillation by attenuating ischemia-dependent ΔERP during VF.

This study determined the sensitivity and specificity of questionnaires and administrative databases compared to a clinical reference standard for asthma. 208 schoolchildren from a population-based sample participated. They underwent a physician assessment, spirometry, methacholine challenge, exhaled nitric oxide and skin testing. Data was linked to the Ontario Asthma Surveillance Information System. “Questionnaire diagnosis” was an affirmative response to physician-diagnosed asthma. “Database diagnosis” was 2 outpatient visits or 1 hospitalization within 2 years. “Clinical diagnosis” required a physician assessment and objective findings of asthma. “Questionnaire diagnosis” of asthma was specific (92.1%) but not sensitive (75.3%) compared to the “clinical diagnosis”. “Database diagnosis” was sensitive (87.5%) but not specific (64.8%). Both sources had an excellent negative predictive value (97-98%) but poor positive predictive value (24-55%). Epidemiologic methods accurately identify those without asthma but are poor at identifying those with asthma, leading to an overestimation of asthma prevalence and dilution of risk estimates.

Post-stroke fatigue (PSF) is a common yet under-diagnosed and undertreated phenomenon. The unresolved debate over what is PSF has hampered the ability of clinicians to study and develop treatments for this condition. Patients with stroke (n=70) seeking neurorehabilitation at Toronto Rehabilitation Institute completed self-report ratings of fatigue, depressive and anxiety symptoms, and sleepiness. Data were collected from objective measures of stroke topography, sleep disorders, physical fatigability and comorbid medical conditions. A Principal-Components Analysis was performed. Factor 1, the “Distress” factor, was comprised of the all of the self-reported scales i.e. depression, anxiety, fatigue and sleepiness. Factor 2, the “Physical State” factor, was comprised of a diagnosis of Obstructive Sleep Apnea, stroke territory and total medical burden. Factor 3, the “Performance” factor, was comprised by the 6 Minute Walk Test. An orthogonal rotation was the most parsimonious fit to the data, suggesting that the three factors are uncorrelated to each other.

Background: No spine-specific educational tool has been developed using input from all relevant stakeholders, including patients. Purpose: The objective of this study was to determine the information needs of lumbar microdiscectomy patients. Methods: Qualitative methods with thematic analysis was used. Focus groups were conducted with: 1) preoperative microdiscectomy patients; 2) postoperative microdiscectomy patients; 3) spine surgeons; 4) spine fellows; 5) orthopaedic surgery residents; 6) anesthesiologists; 7) surgeons’ administrative assistants; and, 8) preoperative assessment team. Results: Major information needs were related to: anesthesia, surgical procedure details and postoperative course. Patients desire information on postoperative course much more than surgeons perceive. Desired attributes of information tools as well as patient factors that influence the extent of information shared by surgeons were determined. Information resources should be given to patients as soon as they are deemed surgical candidates. Conclusions: Microdiscectomy patients desire more information than currently provided to them – in particular postoperative-related information.

Inflammatory and neuropathic pains arise in part from sensitization at nociceptive synapses in the spinal cord. Activity-dependent signaling cascades converge onto the tyrosine kinase Src, which participates in augmenting the function of N-methyl-D-aspartate receptors (NMDARs) and thus potentiates the nociceptive system. Src is capable of these effects because it is anchored to the NMDAR complex via an adaptor protein called NADH dehydrogenase subunit 2 (ND2). There is evidence that this interaction occurs between amino acids 40-49 of Src and amino acids 310-321 of ND2. I have determined that a peptide consisting of amino acids 310-321 of ND2, and affixed to the HIV Tat domain for cell permeability, is capable of alleviating tactile allodynia induced by Complete Freund's Adjuvant (CFA) in rats. Src40-49Tat was not effective in two models of inflammatory pain. This work further implicates the Src-ND2 interaction in pain hypersensitivity and suggests that Tat ND2 310-321 may alleviate it.