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.

Parkinson’s disease (PD) and dystonia are movement disorders related to dysfunctions of basal ganglia (BG). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal globus pallidus (GPi) are treatments for PD and dystonia. Previous research indicated that abnormally elevated oscillatory activities at the theta (3-10 Hz) beta frequency bands (11-30 Hz) may be related to parkinsonian and dystonic motor symptoms but their precise roles are not well understood. Recently, DBS of the pedunculopontine nucleus region (PPNR) has been used to treat PD patients with postural and gait dysfunctions, but movement-related PPNR activities had not been explored. We aimed to investigate movement-related local field potentials (LFP) recorded from the BG and PPNR in PD and dystonia patients. We recorded STN LFP from PD patients and subsequently applied the intrinsic STN theta, beta, and gamma (31-100 Hz) frequencies through DBS to study their effects on PD motor signs. We also recorded movement-related PPNR LFP in PD patients and movement-related GPi activities in patients with primary dystonia. Finally, we simultaneously recorded movement-related activities from the GPi and the motor thalamus in a patient with secondary dystonia. We found that DBS at the dopamine-dependent and movement-related intrinsic STN gamma frequencies, were as effective as traditionally used high frequencies (130-185 Hz) in reducing PD motor signs, but theta and beta frequencies did not worsen motor symptoms. Voluntary movements modulated two discrete movement-related frequencies in the theta and beta bands in the PPNR and these two frequencies interacted with the sensorimotor and frontal cortices during movements. We showed that voluntary movements modulated beta and gamma frequencies in the GPi. A resting ~5-18 Hz coherence between the GPi bilaterally was attenuated during movements in patients, which may be related to dystonia because this 5-18Hz coherence was also present between the GPi and motor thalamus in the patient with secondary dystonia. Our findings indicated that intrinsic STN gamma frequency oscillations were likely prokinetic rhythms but theta and beta frequencies may not contribute to PD motor symptoms. Voluntary movements modulated theta and beta frequencies in the PPNR, which may explain why PPNR DBS uses lower frequencies than those of the BG. The 5-18 Hz oscillatory activities in the BG-thalamic circuit may be a feature of dystonia.

Objectives: 1) Evaluate the risk of atherosclerosis in rheumatic disease compared to healthy controls; 2) Assess the lipid profile of children with systemic lupus erythematosus (SLE) at presentation before treatment with corticosteroids; 3) Compare the lipid profiles of children with juvenile dermatomyositis (JDM), systemic juvenile idiopathic arthritis (SJIA), and SLE; 4) Evaluate the extent of early atherosclerosis in children with JDM, SJIA, and SLE; 5) Investigate the progression of early markers of atherosclerosis in children with SLE. Methods. The methods include a systematic review, a cross sectional study of serum lipid levels of a cohort of children with SLE, an analysis of the first time point of a prospective study of cardiovascular disease risk factors and vascular function measures of a cohort of children with JDM, and SJIA, and SLE and a longitudinal study of vascular function measures of a prospective study of a cohort of children with SLE. Results. Our systematic review demonstrated that carotid intima media thickness (CIMT), a surrogate marker of early atherosclerosis, was significantly increased in rheumatic disease populations. We found that newly diagnosed children with SLE before corticosteroid treatment exhibited a pattern of dyslipoproteinemia of increased triglycerides and depressed HDL-cholesterol. When we measured the lipid profiles in children with the rheumatic diseases of JDM, SJIA, and SLE, one third of children had at least one abnormal lipid value. The most common abnormalities were found for total cholesterol and triglyceride levels and most often in children with JDM. One quarter of all patients were found to have insulin resistance. Lastly, when we considered the effects of treatment in children with SLE, we found that improvement in CIMT was possible and it correlated with a higher cumulative dose of prednisone over the study period. Conclusions. Early markers of atherosclerosis in pediatric rheumatic disease are important for determining the risk of these children in developing heart disease as young adults. Chronic inflammation plays a significant role and should be considered an important predictor of premature atherosclerosis.

Similarities between the peripheral auditory and vestibular systems suggest that children with sensorineural hearing loss (SNHL) may demonstrate vestibular and balance impairments. This hypothesis was studied in 40 children with severe to profound SNHL and unilateral cochlear implants (CI). Vestibular function was assessed with caloric, rotational, and vestibular evoked myogenic potential (VEMP) testing; balance was assessed with standardized static and dynamic tests. Horizontal semicircular canal function was abnormal in 53% (17/32) with caloric, and 39% (14/36) with rotational stimulation. Saccular function was absent bilaterally in 5/26 (19%) and unilaterally in 5/26 (19%) with VEMP. Balance abilities were significantly poorer (μ=12.9±5(SD)) than normal hearing controls (μ=17±5(SD); p=0.0006) and correlated best with horizontal canal function from rotational stimulation (p=0.004;R2=0.24). SNHL from meningitis was associated with worse balance function than other etiologies. Vestibular and balance dysfunction occurred in >1/3 of children with SNHL and CI, and is highly dependent on etiology.

The main objective of my dissertation was to evaluate the biomedical and psychosocial factors associated with pain and disability in patients following traumatic upper extremity nerve injuries. This was approached by conducting 3 studies. The first study surveyed peripheral nerve surgeons regarding the assessment of pain in patients with nerve injury. The results showed that only 52% of surgeons always evaluate pain in patients referred for motor/sensory dysfunction. Pain assessment frequently includes verbal response and assessment of psychosocial factors is infrequent. The second study was a retrospective review to assess disability, as measured by the Disabilities of the Arm, Shoulder and Hand (DASH), in patients with chronic nerve injury. Results showed substantial disability (mean DASH 52 + 22) and a significantly lower health status (p < 0.001) compared with well-established norms. In the regression model, the factors associated with the DASH (R2 = 44.5%) were pain, older age and nerve injured. The third study was a cross-sectional evaluation of the biomedical and psychosocial factors associated with pain and disability after upper extremity nerve injury in 158 patients. DASH scores were significantly higher in patients with workers’ compensation or litigation (p = 0.03), brachial plexus injuries (p < 0.001) and unemployed patients (p < 0.001). In the multivariable regression analysis, the final model explained 52.7% of the variance with these predictors; pain intensity (Beta = .230, p = 0.006), nerve injured (Beta = -.220, p = 0.000), time since injury (Beta = -.198, p = 0.002), pain catastrophizing (Beta = .192, p = 0.025), age (Beta = .187, p = 0.002), work status (Beta = .179, p = 0.008), cold sensitivity (Beta = .171, p = 0.015), depression score (Beta = .133, p = 0.066), workers’ compensation/litigation (Beta = .116, p = 0.049) and gender (Beta = -.104, p = 0.09). Future investigation regarding treatments of the factors that are associated with disability and chronic pain will assist to improve health related quality of life in patients with traumatic nerve injury.