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A dissertation presented in partial compliance with the requirements for the Master's Degree in Technology: Chiropractic, 2001. / Hendler et al. (1995) describes low back pain as the most common, costly and disabling musculosketetal condition. Giles (1997: 28) supports this, stating that the annual incidence of low back pain in the adult population is between two and five percent, with a lifetime prevalence of well over 50%. For clinicians to choose the most appropriate therapy for managing this common condition it is essential for research to be carried out to define the most effective treatment. Shekelle (1994) explains that spinal manipulative therapy is an effective treatment for patients with low back pain, while Cherkin et al. (1995) states that there is strong evidence to support the use of nonsteroidal antiinflammatory drugs in the management of mechanical low back pain. It is therefore the purpose of this investigation to determine the relative effectiveness of spinal manipulative therapy compared to Diclofenac Sodium, in terms of subjective and objective measures, in the management of mechanical low back pain. This randomized controlled trial consisted of sixty patients between the ages of 18 and 65, complaining of mechanical low back pain. The sixty patients were randomly divided into two treatment groups of thirty each. One group received spinal manipulative therapy and the remaining thirty were administered Diclofenac Sodium. These patients were carefully screened to allow the researcher to diagnose the patient, with Lumbar Facet Syndrome, Sacroiliac Syndrome or Myofascial Pain Syndrome; or any combination of these syndromes. This is in accordance with Kirkaldy-Willis (1992: 105 - 119) classification system. The thorough examination ensured that each patient had no contra-indications to spinal manipulative therapy or Diclofenac Sodium. / M

A total of 22 non-steroidal anti-inflammatory drugs and derivatives were added to microsomes to study the denaturation of cytochrome P-450 to cytochrome P-420 in the absence of an NADPH-generating system. There was a highly significant correlation among the different compounds between the extent of denaturation of cytochrome P-450 and their surfactant potency. Endotoxin administration to rats caused a maximum decrease in hepatic microsomal enzymes after 24 hours. Significant decreases in cytochrome P-450 (40%), cytochrome b5 levels (22%), aminopyrine N-demethylase (31%) and biphenyl 4-hydroxylase (54%) activities were obtained. Concomitant intravenous injection of 16,16-DMPG F2 and 16,16-DMPG E2 prevented some of the endotoxin-induced changes in hepatic microsomal enzymes. Three days treatment with cocaine was required to obtain hepatic damage in mice. Decreases in cytochrome P-450 content (41%), aminopyrine N-demethylase (31%) and FAD-monooxygenase (35%) activities were obtained, when compared to saline treated mice. The serum enzyme activities were markedly increased (SGOT 13-fold and SOCT 44-fold). Histological changes in form of centrilobular necrosis and fatty changes were present. Repeated subcutaneous administration of iloprost or synthetic prostaglandins just before cocaine prevented some of the hepatic lesions. Iloprost was found to be a better hepatoprotective agent than synthetic prostaglandins against the cocaine mediated liver toxicity. Carbon tetrachloride administration to mice produced similar lesions to those obtained with cocaine. Administration of iloprost prevented some of the lesions caused by carbon tetrachloride, giving a partial protection to the carbon tetrachloride-induced decrease in cytochrome P-450 and the increase in SGOT. Iloprost also partially prevented the carbon tetrachloride mediated centrilobular necrosis.

Studies have demonstrated the immune system to be significantly more plastic than previously believed. Multiple external factors have been shown to influence the immune response including alterations to the host's external environment and psychological status. This thesis details an investigation of this influence; exposing male CD1 mice to a two-week environmental enrichment paradigm then subjecting them to one of a range of inflammatory disease models chosen to assess a specific aspect of their immune function. Enriched animals were found to possess significantly higher numbers of circulating innate leukocytes compared to those animals housed in a standard lab environment. This leukocytosis was found to persist when animals were subject to a model of zymosan-induced peritonitis, where enriched animals presented an enhanced neutrophil and macrophage influx into their peritoneal cavity. Similar results were observed in a model of sepsis induced by caecal ligation and puncture where enriched animals were also found possess an enhanced capacity for systemic bacterial clearance. Across both experiments no changes in inflammatory cytokine expression were observed between enriched and standard environment animals. Genomic and proteomic profiling supported these findings, revealing the increased expression of immune-modulatory genes associated with a heightened immune and moderated inflammatory response. Ex vivo analysis of leukocytes extracted from enriched animals showed they also possessed enhanced phagocytic function and an accompanying reduction in gene expression associated with heightened cytotoxic function. When subject to a model of persistent inflammation induced by sponge implantation, enriched animals again presented heightened leukocyte infiltration to the point of immune insult. This was accompanied with a reduction in the release of pro-inflammatory cytokines and the heightened expression of genes associated with a pro-resolving, wound healing phenotype. This study provides novel insights into the mechanisms by which environmental modulation may influence the immune response and of the potentially immune-protective influence of environmental enrichment.

Omega-3 fatty acids (ω-3 FA, including eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]), are essential polyunsaturated fatty acids which are correlated with lower incidence of chronic diseases. DHA and EPA can be enzymatically converted to resolvins, protectins and maresins, which play important roles in resolution of inflammation. Additionally, ω-3 FA can also directly activate surface receptors, namely the long-chain free fatty acid receptors GPR40 and GPR120, two GPCRs with poorly investigated biology. Using real-time PCR analysis, GPR40 transcript in human neutrophils was detected; the protein expression was also confirmed by flow cytometry and image stream analysis. Expression of GPR40 protein was up-regulated after stimulation with platelet-activating factor (PAF, 10nM) or leukotriene B4 (LTB4, 10nM) for 10 minutes. I utilised the selective agonist GW9508 to investigate the biology of GPR40. Tested on human neutrophils, GW9508 elevated intracellular calcium when applied within the 0.1-10μM range. The up-regulation of GPR40 expression by pro-inflammatory stimuli suggested to us potential regulatory roles for this receptor during inflammation. I then showed that 1 and 10μM GW9508 increased neutrophil chemotaxis in response to the cytokine IL-8 (30ng/ml). In addition, GPR40 activation by GW9508 enhanced phagocytosis of E. coli by human neutrophils by approximately 50% when tested at 0.1 and 1μM. Moreover, GW9508-neutrophil stimulation augmented microvesicle release and delayed apoptosis after stimulation. Finally, I demonstrated that GPR40 is expressed in inflammatory cells isolated from murine arthritic joints, such as neutrophils, macrophages and inflammatory monocytes. KBN-serum induced arthritic mice developed a more severe disease when treated prophylactically with GW9508 (10mg/kg, i.p. treated from day 0, daily), characterized by a higher clinical score and increased oedema when compared to vehicle control mice. Therapeutic intervention with GW9508 at the peak of the disease (day 5) delayed the resolution of arthritis. In summary, the data suggest that activation of GPR40 by GW9508 enhances neutrophil activation, up regulating the pro-inflammatory properties of this cell type, and therefore, exacerbating experimental inflammatory arthritis.

Oxygen tension and biomechanical signals are factors that regulate inflammatory mechanisms in chondrocytes. We examined whether low oxygen tension influenced the cells response to TNFα and dynamic compression. Chondrocyte/agarose constructs were treated with varying concentrations of TNFα (0.1 to 100 ng/ml) and cultured at 5% and 21% oxygen tension for 48 hours. In separate experiments, constructs were subjected to dynamic compression (15%) and treated with TNFα (10 ng/ml) and/or L-NIO (1 mM) at 5% and 21% oxygen tension using an ex-vivo bioreactor for 48 hours. Markers for catabolic activity (NO, PGE2) and tissue remodelling (GAG, MMPs) were quantified by biochemical assay. ADAMTS-5 and MMP-13 expression were examined by real-time qPCR. 2-way ANOVA and a post hoc Bonferroni-corrected t-test were used to analyse data. TNFα dose-dependently increased NO, PGE2 and MMP activity (all p < 0.001) and induced MMP-13 (p < 0.05) and ADAMTS-5 gene expression (p < 0.01) with values greater at 5% oxygen tension than 21%. The induction of catabolic mediators by TNFα was reduced by dynamic compression and/or L-NIO (all p < 0.001), with a greater inhibition observed at 5% than 21%. The stimulation of GAG synthesis by dynamic compression was greater at 21% than 5% oxygen tension and this response was reduced with TNFα or reversed with L-NIO. The present findings revealed that TNFα has dose-dependent catabolic activities and increased production of inflammatory mediators at low oxygen tension. Dynamic compression or the NOS inhibitor downregulated the inflammatory effects induced by TNFα, linking both types of stimuli to reparative activities. Future therapeutics should develop oxygen-sensitive antagonists which are directed to interfering with the TNFα induced pathways.