The current study characterizes the mechanical and biodegradation properties of a polycarbonate polyurethane (PU) electrospun nanofiber scaffold intended for use in the growth of a tissue engineered annulus fibrosus (AF) intervertebral disc component. Both the tensile strength and initial modulus of aligned scaffolds were higher than those of random scaffolds and remained unaffected during a 4 week biodegradation study, suggesting a surface-mediated degradation mechanism. The resulting degradation products were non-toxic. Confined compressive mechanical force of 1kPa, was applied at 1Hz to in vitro bovine AF tissue grown on the scaffolds to investigate the influence of mechanical force on AF tissue production, which was found to decrease significantly at 72 hours relative to 24 hours, independent of any effects from mechanical forces. Overall, the consistent rate of PU degradation, along with mechanical properties comparable to those of native AF tissue, and the absence of cytotoxic effects, make this polymer suitable for further investigation for use in tissue-engineering the AF.

Background: Total hip replacement (THR) with post-operative surveillance is recommended for debilitating osteoarthritis (OA). Using self-reported pain, function or walking performance is one alternative to address increasing surveillance demands. Objective: A cross-sectional cohort study to evaluate the associations of pain, function and performance with two radiographic markers of potential THR failure. Participants: 110 patients, median 6 years after THR surgery for OA. Methods: Questionnaires assessed demographics, co-morbidity, arthritis severity, pain, pain catastrophizing, and functional status. Performance was measured using the six minute walk test. THR outcome was assessed radiographically. Results: Few patients had pain, functional impairment or radiographic markers of potential THR failure. A larger percentage of patients with some intermittent pain (10.7 versus 8.6%) and pain iii after walking performance (40.0 versus 27.6%) had higher wear, but these differences were not significant. Conclusion: Measures of pain are potentially important for larger studies aiming to develop alternative methods of post-operative surveillance.

The global burden of injury is severely underappreciated and disproportionately affects low-income countries. With timely, appropriate orthopaedic treatment disability and mortality can be prevented, yet appropriate health resources are seldom available. Without orthopaedic medical devices (OMDs), quality of orthopaedic care suffers and the burden of preventable injury is exacerbated. A qualitative case study of 45 key informant interviews was conducted in Uganda to explore accessibility of OMDs, such as plaster, external fixators and implants. Data analysis elicited four major themes as barriers preventing access to OMDs in Uganda: 1) Poor leadership in government and corruption; 2) inadequate human resources; 3) inefficient and insufficient health care infrastructure; and 4) high costs of OMDs and poverty. Potential solutions for improving access to orthopaedic care were categorized as policies prioritizing orthopaedic services, training more orthopaedic specialists and creating incentives for them to work in underserviced areas, and innovative strategies funding for orthopaedic services.

Clostridium difficile colitis (CDC) is associated with a higher risk of acute death among hospitalized ulcerative colitis (UC) patients. However, the risk of colectomy with CDC in these patients has varied across studies. No study has assessed the long-term health impact of CDC in UC patients. Therefore, the present study evaluated the impact of CDC on five-year health outcomes of hospitalized UC patients based on Ontario health administrative data. No overall association was observed between CDC and five-year risks of colectomy or death in overall cohort. However, patients who were discharged from hospital without undergoing colectomy demonstrated marginally higher five-year risks of colectomy and hospital re-admission. Mortality risk and length of stay during index hospitalization were also higher in patients with CDC. Analysis of a parallel cohort of UC patients derived using a published case definition corroborated most of these results, but demonstrated a higher five-year mortality risk with CDC.

Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by loss of renal function within days to weeks and by glomerular crescents on biopsy. The pathogenesis of this disease is unclear, but circulating factors such as antineutrophil cytoplasmic antibodies (ANCA) are believed to play a major role. In this thesis, we show that deletion of the Von Hippel-Lindau gene (Vhlh) from intrinsic glomerular cells of mice is sufficient to initiate a necrotizing crescentic glomerulonephritis and the clinical features that accompany RPGN. Loss of Vhlh leads to stabilization of hypoxia-inducible factor alpha subunits (HIFαs). Using gene expression profiling, we identified de novo expression of the HIFα target gene Cxcr4. In glomeruli from mice with RPGN, the course of RPGN is markedly improved in mice treated with a blocking antibody to Cxcr4, whereas overexpression of Cxcr4 alone in podocytes of transgenic mice is sufficient to cause glomerular disease. Despite the development of glomerular disease in mice that overexpress Cxcr4, their disease was milder and lacked features of full-blown RPGN. The Vhlh gene encodes VHL protein (pVHL, product of the Von Hippel-Lindau gene) that functions as the substrate recognition component of an E3 ubiquitin ligase. Although HIFα subunits are the best characterized substrates for pVHL, additional non-HIF mediated targets have been identified. To determine the role of HIF stabilization in this RPGN model, we generated double mutants that lack aryl hydrocarbon receptor nuclear translocator gene (Arnt, also called HIF1beta), an obligate dimerization partner for HIFα subunit function. Podocyte-selective deletion of Arnt in Vhlh mutant mice completely rescued the RPGN phenotype and mice survived longer than 8 months of age. Furthermore, stabilization of HIF2α alone led to glomerular disease characterized by crescentic transformation. Collectively, these results indicate an alternative mechanism for the pathogenesis of RPGN and glomerular disease in an animal model and suggest novel molecular pathways for intervention in this disease. In addition, we demonstrate a key role for VHL-HIF-Cxcr4 molecular pathway for the integrity of the glomerular barrier.

Objective: The primary aim of this study was to assess patients’ preferences between radiofrequency ablation (RFA) versus hepatic resection (HR) for the treatment of small hepatocellular carcinomas (HCC). Methods: Decision analysis was performed by using probability trade-off (PTO) technique to elicit patients’ preferences and the strength of their decisions. Results: The vast majority of the study population preferred RFA over HR (70% vs. 30%, p=0.001). Their initial choice changed if 5-year survival benefit after surgery was at least 14% superior to RFA and if the 3-year disease-free survival advantage was at least 13% better than ablation. Conclusions: The results of this study suggest that fully informed cirrhotic patients would prefer RFA if diagnosed with early stage HCC even if able to undergo surgery.

No description available.

Master of Science / Department of Kinesiology / Timothy I. Musch / Aged rats exhibit a decreased muscle microvascular O[subscript]2 partial pressure (PO[subcript]2mv) at rest as well as during contractions compared to young rats and this may contribute to their reduced exercise tolerance. Age-related reductions in nitric oxide (NO) bioavailability due, in part, to elevated reactive O[subscript]2 species (ROS) constrain muscle blood flow (Qm). Therefore, antioxidants may restore NO bioavailability, Qm and ameliorate the reduction in PO[subscript]2mv and hence the decrease in exercise tolerance seen in aged rats. PURPOSE: To test the hypothesis that antioxidants would elevate Qm at rest and during contractions and therefore PO[subscript]2mv in aged muscle. METHODS: PO[subscript]2mv and Qm were measured in the spinotrapezius while muscle oxygen consumption (VO[subscript]2m) was estimated in 20 anesthetized male Fisher 344 x Brown Norway hybrid (F344xBN) rats at rest and during 1 Hz contractions before and after antioxidant intravenous infusion (76mg/kg vitamin C and 52mg/kg tempol). Moreover, muscle force production was measured in a subset of animals. RESULTS: Before infusion, contractions invoked a biphasic PO[subscript]2mv that fell from 30.6 [plus or minus] 0.9 mmHg to a nadir of 16.8 [plus or minus] 1.2 mmHg with an 'undershoot' of 2.8 [plus or minus] 0.7 mmHg below the subsequent steady-state (19.7 [plus or minus] 1.2 mmHg). Antioxidants elevated baseline PO[subscript]2mv to 35.7 [plus or minus] 0.8 mmHg (P<0.05) and reduced or abolished the 'undershoot' (P<0.05) without changing the steady-state contracting PO[plus or minus]2mv. Antioxidants did not change Qm at rest but during contractions Qm was reduced from 157 [plus or minus] 28 to 91 [plus or minus] 15 ml min[superscript]-1 100g[superscript]-1 (P<0.05). Antioxidants produced no significant effect on VO[subscript]2m. However, antioxidant supplementation produced a 16.5% decrease (P<0.05) in muscle force production that occurred within the first contraction and remained throughout the duration of stimulation. In addition, the ratio of muscle force production to VO[subscript]2m (F/VO[subscript]2m) actually increased from 0.92 [plus or minus] 0.03 to 1.06 [plus or minus] 0.6 (P<0.05) following infusion of antioxidants. CONCLUSION: Antioxidant supplementation significantly alters the balance between muscle O[subscript]2 delivery and VO[subscript]2 at rest and during contractions, which modifies the microvascular PO[subscript]2mv profile. Specifically, antioxidants elevate PO[subscript]2mv, which improves the potential for diffusive blood-myocyte flux. This effect arises, in part, from the unanticipated fall in muscle force production consequent to antioxidant supplementation.

No description available.

No description available.