Acetaminophen has been safely used for analgesia for many years. Literature suggests that a plasma acetaminophen level of 5��g/ml is necessary to maintain analgesic relief in humans. Current dosing regiments are inconvenient (every 4-6 hours) and do not maintain this minimum plasma level. Simulations were conducted to examine various doses and input rates for sustained release formulations of acetaminophen. Once parameters were selected from the simulations, sample formulations were prepared and tested using standard dissolution techniques. Investigations into dose/size relationships, hydroxypropylmethylcellulose (HPMC) percentage for erosion matrix tablets, compression force, tablet shape, tablet divisibility, and granulation methods were performed for non-disintegrating hydrophilic matrix tablets. Tablets containing 5% and 7.5% HPMC were selected for pharmacokinetic study in 10 healthy human subjects. Tylenol Extra Strength and Tylenol Extended Relief tablets were administered as control formulations. Pharmacokinetic fitting of the kinetic profiles of all four formulations were performed using Win Nonlin. The formulations were best described by a 1-compartment open model with first order input and first order elimination. The 5% HPMC sustained release acetaminophen formulation was selected for Phase II clinical trials. Patients with osteoarthritis of the knee were recruited for a double blind crossover study of 5% HPMC sustained release acetaminophen formulations and immediate release acetaminophen. Patients received two tablets of study medication, four times a day for 4 weeks. After a seven day wash-out period patients were then crossed over to the other treatment. Patients were evaluated using a twelve question questionnaire and the time to walk 50 feet was measured. Thirty patients were enrolled in the study and seventeen patients completed the study. The sustained release formulations were statistically superior to the baseline treatments in reducing pain level, decreasing disability, and improving the duration of pain relief. Additional, larger scale studies are needed to confirm these findings. / Graduation date: 2000

Extrinsic repair techniques for the treatment of acute chondral injuries continue to yield suboptimal repair. The inability of these techniques to produce hyaline cartilage underscores the limitations in our understanding of basic chondrocyte biology. Conversely, intrinsic repair tissue has not been extensively studied despite the fact that it can yield hyaline-like cartilage and is commonly observed in osteoarthritis. Attempts at extrinsic repair could therefore benefit from a better understanding of the successes and failures inherent in the intrinsic repair process. Chondrocyte culture has typically been conducted under non-physiologic conditions whereby chondrocytes readily dedifferentiate. Consequently, much of the knowledge gained about chondrocytes has been misleading thus hindering advancements in chondrocyte biology and attempts at extrinsic articular cartilage (AC) repair. Hypoxic culture conditions, which are beneficial towards the preservation of the chondrocyte phenotype, remain insufficient due to elevated collagen I gene expression. As such, an appropriate model system does not yet exist in which to study physiologically-relevant chondrocyte biology. The presence and prevalence of collagen I in both degenerate and de novo osteoartritic tissue was examined immunohistochemically. Collagen I deposition during osteoarthritic progression was compared against IHC staining for collagen II and aggrecan. A novel model system was also evaluated for chondrocytic phenotype retention. To this end, hypoxic, high-density-monolayer-chondrocyte (HDMC) cultures were compared to freshly isolated chondrocytes for their ability to maintain a chondrocytic extracellular matrix (ECM) gene expression profile. HDMC culture conditions prevented the severe loss of the phenotype typically associated with conventional monolayer culture. Moreover, prolonged HDMC culture resulted in the formation of a complex ECM and a marked suppression of collagen I expression. This study also demonstrated that collagen I deposition occurs in osteoarthritic AC at the onset of structural damage and increases in response to increasing structural damage. Collagen I deposition was also found in different types of de novo cartilage associated with osteoarthritic joints and suggests that it plays an important role in intrinsic cartilage repair. Taken together, this work demonstrates that collagen I is a common feature in the ECM of structurally immature and structurally damaged AC and hence may play a role in tissue stabilization. / Experimental Surgery

La pathogénie de lostéo-arthropathie dégénérative chez le cheval est lobjet de nombreuses recherches, notamment sur le rôle des espèces activées de lazote et de loxygène (RNOS) dont les actions délétères sur larticulation sont décrites, mais dont lorigine, les raisons et la cinétique de production restent peu connues : on implique souvent les chondrocytes et des phénomènes cycliques danoxie/ré-oxygénation (A/R). Lobjectif du travail était détudier la production des RNOS par les cellules de larticulation, chondrocytes ou synoviocytes équins, cultivés séparément ou en co-culture pour imiter les interactions existantes dans larticulation où les chondrocytes matures sont nourris par diffusion à partir du liquide synovial à basse tension en O2, fourni par les synoviocytes. Pour induire leur activité oxydante, nous avions choisi de soumettre les cellules en culture à des cycles successifs dA/R. Les cellules articulaires équines sont libérées de leur matrice par digestion enzymatique. Les chondrocytes sont mis en culture en billes dalginate (culture en trois dimensions qui maintient le phénotype cellulaire) et les synoviocytes sont cultivés en monocouche. Les chondrocytes équins sont cultivés en milieu à 4,5 g/l de glucose, sous différentes conditions en O2 : 21 % (condition de culture habituelle), 5 % (condition proche de la situation in vivo) et 1 % (condition danoxie). Le nombre des chondrocytes est resté pratiquement constant partout jusquau 10e jour de culture. Mais une identification (par coloration spécifique) montre une augmentation régulière au cours du temps du nombre des cellules apoptotiques à 21% dO2 et une diminution à partir du 11e jour à 5 % et à 1% dO2. À 1 % dO2, il y a une chute du nombre de cellules vivantes jusquau 8e jour de culture, chute qui est compensée au 11e jour. 5 % dO2 sont les conditions de culture les plus favorables au maintien du nombre de cellules et les chondrocytes résistent à lanoxie pendant plus de dix jours de culture. Pour tester le rôle du glucose dans la résistance à lanoxie, les chondrocytes sont cultivés avec des concentrations variables en glucose (0, 1 et 4,5 g/l de milieu), combinées aux tensions dO2 de 1 %, 5 % et 21 %. Lexcès de glucose (4,5 g/l) a un effet défavorable après 8 jours de culture. Les chondrocytes équins sont capables de résister plusieurs jours aux conditions les plus drastiques : 1 % dO2 et absence de glucose. Les études en microscopie (optique et électronique) confirment une souffrance cellulaire à 21 % dO2, accentuée à 4,5 g/l de glucose: accumulation de gouttelettes à contenu lipidique et mitochondries dématiées. Elles montrent également la présence de lipides intracellulaires dans les chondrocytes sains, une source dénergie possible permettant leur survie en anoxie. Les synoviocytes équins en culture ont été caractérisés en microscopie (aspect, détection immmunologique de la protéine-produit du gène PGP 9,5) et par leur capacité de phagocytose. Ils se multiplient de façon exponentielle à 10 % dO2 (condition proche des conditions physiologiques) et peuvent être maintenus en culture de longue durée. À 21 % dO2, ils se multiplient plus lentement. Létude du métabolisme oxydant des chondrocytes et des synoviocytes équins, en conditions de culture normales et après A/R, est effectuée en mesurant leur consommation dO2 par oxymétrie (réponse mitochondriale), leur production globale de RNOS (estimée par la mesure de léthylène, produit par lattaque dun substrat par les RNOS) et leur production despèces radicalaires [mesurée en résonance paramagnétique électronique (RPE) avec spin trapping]. Les chondrocytes équins consomment peu dO2 (± 20 picomoles dO2/min/10 6 cellules) indépendamment des conditions de culture avant oxymétrie et malgré un complexe terminal de la chaîne mitochondriale fonctionnel. Ils sont peu influencés par les cycles dA/R et ne produisent ni de RNOS ni despèces radicalaires. Les synoviocytes équins consomment plus dO2 (± 1 nanomole dO2/min/106 cellules) et trois cycles dA/R induisent une chute de cette consommation et des signes de souffrance mitochondriale. Les synoviocytes sont capables de produire des RNOS et augmentent cette production sous leffet dune stimulation par agent pharmacologique (PMA) ou endogène (TNF-α). Cette production de RNOS est liée à lactivité denzymes à flavine comme la NOX. La RPE montre une production despèces radicalaires après A/R, identifiées aux dérivés de lanion superoxyde et dune peroxydation lipidique dont lorigine est la mitochondrie, sans pouvoir exclure une participation des enzymes oxydantes cytosoliques (NOX ou xanthine oxydase). Les synoviocytes peuvent donc répondre par une activité oxydante à lA/R. Pour la co-culture, les meilleures conditions sont un rapport synoviocytes/chondrocytes 1/3, un milieu de culture mixte, 10 % dO2, la condition dadhérence pour les synoviocytes et la culture en billes dalginate (placées en « inserts ») pour les chondrocytes. Après 48 h de co-culture dans ces conditions, 80 % des synoviocytes et 60 % des chondrocytes survivent. Les interactions entre les deux types cellulaires se traduisent par des variations importantes dans la production de certains médiateurs inflammatoires comme la PGE2. Il ressort de ce travail que les synoviocytes répondent à lA/R par une production de RNOS et en libérant des médiateurs inflammatoires et quils pourraient jouer un rôle majeur dans lOAD. Des études complémentaires sont nécessaires, surtout avec le modèle de co-culture.

Research Question: This research adapted, tested, and evaluated a methodology to set priorities for systematic reviews topics within the Cochrane Collaboration that is sustainable and incorporates the social determinants of health and health equity into the analysis. Background: In 2008 a study was conducted to review, evaluate and compare the methods for prioritization used across the Cochrane Collaboration. Two key findings from that study were: 1) the methods were not sustainable and 2) health equity represented a gap in the process. To address these key findings, the objective of this research was to produce and test a method that is sustainable and incorporates the social determinants of health and health equity into the decision making process. As part of this research, the methods were evaluated to determine the level of success. Methodology: With assistance from experts in the field, a comparative analysis of existing priority setting methods was conducted. The Global Evidence Mapping (GEM) method was selected to be adapted to meet our research objectives. The adapted method was tested with assistance of the Cochrane Musculoskeletal Group in identifying priorities for Osteoarthritis. The results of the process and the outcomes were evaluated by applying the “Framework for Successful Priority Setting”. Results: This research found that the priority setting method developed is sustainable. Also, the methods succeeded in incorporating the social determinants of health and health equity into the analysis. A key strength of the study was the ability to incorporate the patients’ perspective in setting priorities for review topics. The lack of involvement of disadvantaged groups of the population was identified as a key limitation. Recommendations were put forward to incorporate the strengths of the study into future priority setting exercises within Cochrane and to address the limitations.

This thesis investigated the cost-effectiveness of a 12-month supervised aerobic walking program with or without a behavioural intervention and an educational pamphlet, compared to an unsupervised/self-directed educational pamphlet intervention, among individuals with moderate osteoarthritis (OA) of the knee. Analyses included an economic evaluation to assess the cost effectiveness of the two walking interventions from both the societal and Canadian provincial/territorial health care payer perspectives. A value of information analysis exploring the potential value of future research was also performed. Results revealed that the unsupervised/self-directed intervention was the most cost-effective approach given that it cost the least to implement and participants had higher quality-adjusted life years (QALYs). Walking, either supervised in a community setting, or unsupervised in a setting such as the home, may be a favourable non-pharmacological option for the management of OA of the knee. The thesis concludes with a policy discussion relating to the funding of non-pharmacological therapies.

Objectives: To use the means-end chain (MEC) decision-making approach to compare two groups of participants using natural health products (NHPs) with and without scientific evidence support. Methods: The laddering technique was used to interview 25 participants with osteoarthritis. Hierarchical value maps were generated to depict the decision-making processes. Semi-structured questions probed the role of scientific evidence in the decision-making process and content analysis identified thematic similarities and differences between the two groups. Results: The dominant decision-making chain between participants in the two scientific evidence categories was similar. Scientific evidence is an important decision-making factor but not as important as the advice from health care providers, friends and family. Conclusions: The MEC-approach and its associated laddering methodology helped us understand how people make decisions about NHPs. There were essentially no differences in how consumers in our two groups incorporated scientific evidence into their choice of NHPs for OA.

Objectives: To use the means-end chain (MEC) decision-making approach to compare two groups of participants using natural health products (NHPs) with and without scientific evidence support. Methods: The laddering technique was used to interview 25 participants with osteoarthritis. Hierarchical value maps were generated to depict the decision-making processes. Semi-structured questions probed the role of scientific evidence in the decision-making process and content analysis identified thematic similarities and differences between the two groups. Results: The dominant decision-making chain between participants in the two scientific evidence categories was similar. Scientific evidence is an important decision-making factor but not as important as the advice from health care providers, friends and family. Conclusions: The MEC-approach and its associated laddering methodology helped us understand how people make decisions about NHPs. There were essentially no differences in how consumers in our two groups incorporated scientific evidence into their choice of NHPs for OA.

Background: Osteoarthritis (OA) is a debilitating joint disease marked by cartilage and bone changes. Morphological and mechanical changes to bone, which are thought to increase overall bone stiffness, result in distorted joint mechanics and accelerated cartilage degeneration. Using a parametric finite element (FE) model of the proximal tibia, the primary objective of this study was to determine the relative and combined effects of OA-related osteophyte formation, and morphological and mechanical alterations to subchondral and epiphyseal bone on overall bone stiffness. The secondary objective was to assess how simulated bone changes affect load transmission in the OA joint. Methods: The overall geometry of the model was based on a segmented CT image of a cadaveric proximal tibia used to develop a 2D, symmetric, plane-strain, FE model. Simulated bone changes included osteophyte formation and varied thickness and stiffness (elastic modulus) in subchondral and epiphyseal bone layers. Normal and OA related values for these bone properties were based on the literature. “Effective Stiffness (K)” was defined as the overall stiffness of the proximal tibia, calculated using nodal displacement of the loaded area on the subchondral cortical bone surface and the load magnitude. Findings: Osteophyte formation and thickness or stiffness of the subchondral bone had little effect on overall bone stiffness. Epiphyseal bone stiffness had the most marked effect on overall bone stiffness. Load transmission did not differ between OA and normal bone. Interpretation: Results suggest that epiphyseal (trabecular) bone is a key site of interest in future analyses of OA and normal bone. Results also suggest that observed OA-related alterations in epiphyseal bone may result in OA bone being more flexible than normal bone.

Research Question: This research adapted, tested, and evaluated a methodology to set priorities for systematic reviews topics within the Cochrane Collaboration that is sustainable and incorporates the social determinants of health and health equity into the analysis. Background: In 2008 a study was conducted to review, evaluate and compare the methods for prioritization used across the Cochrane Collaboration. Two key findings from that study were: 1) the methods were not sustainable and 2) health equity represented a gap in the process. To address these key findings, the objective of this research was to produce and test a method that is sustainable and incorporates the social determinants of health and health equity into the decision making process. As part of this research, the methods were evaluated to determine the level of success. Methodology: With assistance from experts in the field, a comparative analysis of existing priority setting methods was conducted. The Global Evidence Mapping (GEM) method was selected to be adapted to meet our research objectives. The adapted method was tested with assistance of the Cochrane Musculoskeletal Group in identifying priorities for Osteoarthritis. The results of the process and the outcomes were evaluated by applying the “Framework for Successful Priority Setting”. Results: This research found that the priority setting method developed is sustainable. Also, the methods succeeded in incorporating the social determinants of health and health equity into the analysis. A key strength of the study was the ability to incorporate the patients’ perspective in setting priorities for review topics. The lack of involvement of disadvantaged groups of the population was identified as a key limitation. Recommendations were put forward to incorporate the strengths of the study into future priority setting exercises within Cochrane and to address the limitations.

This Bachelor paper deals with skeletal diseases like osteoporosis and osteoarthritis. 24 medieval individuals from the block Banken 1 in Visby, Gotland were chosen for an osteological analysis. Osteoporosis affects the bone with low bone mineral density and can lead to possible fractures and Osteoarthritis is a degenerative joint disease. A DEXA reading was done at Dr. Roland Alvarssons Doctorial practice in Visby and the results from the DEXA reading showed that none of the individuals suffered from osteoporosis, but one suffered from osteopenia. Some individuals were x-rayed at Visby hospital and the x-rays were interpreted by Dr. Staffan Jennerholm. The x-ray showed that two individuals suffered from osteoarthritis. You can get a glint into the past and daily life of medieval people with a little help of modern technology like x-ray and DEXA reading.