A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy, to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Johannesburg 2018 / Knee osteoarthritis (OA) is the most prevalent form of OA and it is present in over 33% of adults aged 50 years and above. Patients with end-stage knee OA have poor health outcomes including severe knee pain, functional limitations and poor quality of life (QoL) with decreased physical activity (PA) and increased sedentary behaviour (SB). In spite of the cost-effectiveness of total knee arthroplasty (TKA) in improving patients’ health outcomes (as measured using patient-reported outcome measures (PROMs)), the objectively measured PA shows little or no change after surgery and SB has received very little attention following TKA. However, published studies have only been conducted in populations from high-income countries and no studies have assessed PA and SB in knee OA patients from low-middle income countries including South Africa. Furthermore, the detailed patterns by which patients with knee OA accumulate PA and SB before and after TKA have not been described. Studies have mainly focused on measuring overall PA or moderate to vigorous PA (MVPA) and/or patients’ adherence to the PA guidelines with very little attention to low intensity activities of the movement continuum (SB and light activity- LPA). Furthermore, different activity monitors have been used with very few of them capable of measuring low intensity activities. Assessing activity behaviours incidental in activities of daily living (ADL) (such as sitting, standing and walking) before and after TKA may be clinically useful as activities of older adults undergoing TKA mainly constitute these low intensity activities. With no previously published systematic review on changes in SB following TKA, the objective of the first study of this thesis was to integrate available evidence on changes in SB in patients with knee OA after a primary TKA. A systematic literature search from January 2002 to 31 October 2017 was performed across seven electronic databases, for longitudinal and cross-sectional studies published in English on objectively (through accelerometry) and/or subjectively measured changes in SB following TKA. Ten studies reporting on SB with a total of 1,028 participants were included in the review. Three studies reported changes in SB with two showing a reduction in SB and one, with high risk of bias, showing an increase in SB after TKA. Seven studies showed no change in SB following TKA. The second study of this thesis was a longitudinal design comprising of two parts (Study 2A and B). Participants wore two activity monitors (ActiGraph GT3X+ and ActivPAL) to measure PA and SB for seven consecutive days (24 hours/day) at baseline (preoperative), six weeks and six months after TKA. Therefore, the second objective (Study 2A) of this thesis was to objectively measure changes in volume and pattern of PA and SB (using ActiGraph GT3X+ accelerometer) in patients with knee OA from baseline to six months after TKA and to assess changes in PROMs following TKA. Eighty-nine patients (13 males, 76 females between 55 and 80 years of age) scheduled for primary TKA took part in the study. Physical activity and SB were measured with an ActiGraph GT3X+ accelerometer for seven consecutive days (24 hours/day) and range of motion (ROM) was measured prior to TKA, and six weeks and six months after TKA. The University of California Los Angeles (UCLA) Activity index and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were used to assess self-reported activity and physical function respectively. Of the initial 89 patients recruited, 57 completed the six months followup and 45 had valid activity data at the 6 months follow-up. The proportion of time (% of waking day) patients spent in light physical activity (LPA) increased from baseline [29.0 (26.6-31.4)%] to 6 months [34.8 (31.3-38.3)%; p=0.008]. However, time spent in moderate to vigorous PA (MVPA) did not change from baseline [median (interquartile range): 2.0 (7.8) min/day] to six months after TKA [3.4 (11.6) min/day, p>0.05]. Approximately 9%, 5% and 18% of the patients met the PA guidelines at baseline, and six weeks and six months after TKA respectively. The proportion of time (% of waking day) patients spent in SB decreased after TKA [baseline: mean (95% CI): 70.1 (67.5-72.7)%; six months: 64.0 (60.6-67.9)%; p=0.009]. The interruptions to SB increased between baseline and six months after TKA [mean (95% CI): 85.0 (80.0-90.0) to 93.0 (88.0-98.0) breaks/day, p=0.014]. There was a significant improvement in WOMAC score [median (interquartile range): 71.0 (27.0) vs. 4.0 (11.3), p<0.001], UCLA score [median (interquartile range): 2.0 (1.0) vs. 5.0 (1.0), p<0.001] as well as ROM [mean range: (0.0 - 90.0)° vs (0.0 - 110)°, p<0.05] between baseline and six months after TKA. Study 2A showed that LPA increased and SB decreased as measured using ActiGraph GT3X+. In addition, self-reported functional capacity (FC) or functional ability (as measured with PROMs) improved after TKA. The third objective (Study 2B) of this thesis was to objectively assess changes in the times spent sitting, standing and walking following TKA and to examine their associations with the changes in PROMs after TKA. The same patients in Study 2A also wore a second activity monitor, the ActivPAL (which accurately measures low intensity activities and posture) for the same periods of time as described in Study 2A above. Patients spent significantly more of their waking wear time walking at six months after TKA (mean% (95% CI): 10.8% (9.4-12.1)), than preoperatively (mean% (95% CI): 8.3% (7.7-10.0)), p=0.039), however, the percentage of daily time spent standing did not change at six months after TKA (mean% (95% CI): 34.2% (29.8-38.6)) compared to percentage time preoperatively (mean% (95% CI): 32.4% (28.6-35.5)), p=0.530). Patients decreased their average daily time spent sitting from preoperative to six months after TKA by 33.7 mins/day (95% CI: -18.9 – 106.3, p=0.099). Patients took significantly more steps per day at six months after TKA [mean (95% CI: 3670 (2886-4020)] steps/day compared to preoperatively 2570 (2366-3189) steps/day, p<0.001. Participants also increased their cadence (steps/min) six months after surgery [mean (95% CI): 33 (31-34) vs. 38 (33-39), p=0.004]. There were no associations between objectively measured changes in the time spent sitting, standing and walking and changes in PROMs (p>0.05). The studies presented in this thesis have novel aspects that extend the body of knowledge on activity behaviours of patients with knee OA undergoing TKA. The studies in this thesis report the first systematic review on changes in SB of knee OA patients following TKA. This thesis is the first to objectively measure the detailed patterns of PA and SB in patients with knee OA undergoing TKA from a low-middle income country (South Africa). Furthermore, this thesis is also the first to use two accelerometers to generate detailed activity behaviour in patients with knee OA undergoing TKA. Lastly, this thesis is the first to assess the association between changes in times spent sitting, standing and walking in relation to changes in health outcomes in knee OA patients after TKA. In conclusion, the systematic review showed that SB has been superficially described and there is insufficient evidence to suggest that time spent in SB decreases following TKA. Majority of the studies reported no change in SB after TKA. The longitudinal study showed that, following TKA, there was a decrease in the overall time spent in SB and an increase in the number of breaks in SB that appeared to be replaced by LPA. Participants’ volume and average daily cadence increased following TKA. In addition, participants decreased their time spent sitting by over half an hour at six months after TKA. However, there were no associations between changes in the times spent sitting, standing and walking and changes in measures of participants’ health outcomes (PROMs) following TKA. Both objective and subjective measures should be used to accurately assess improvements in patients’ health outcomes following TKA. This comprehensive analysis of detailed daily activity behaviours can be used to employ feasible interventions for increasing the duration of LPA (standing and walking) and decreasing sedentary time (sitting/lying) to improve quality of life and overall health following TKA. / XL2019

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Doctor of Philosophy Johannesburg, 2019 / Background Evidence shows that the global prevalence of knee osteoarthritis (KOA) is high, with limited data on the management of the disease. The use of novel modalities to treat the condition is low due to poor understanding of their clinical effects. Therefore there are gaps in the knowledge on the prevalence and treatment modalities for patients diagnosed with KOA. Aim: The aim was threefold; (i) to determine the prevalence of KOA in South Africa aged 45yrs-75yrs; (ii) to determine the current management of KOA; and (iii) to determine the effect of Low Level Laser therapy (LLLT) on the structural and functional components related to KOA in a South African cohort, aged 45-75yrs. Methods: The methodology will be discussed in terms of the three specified objectives; (i) prevalence study data - a self-reported data collection sheet listing 19 relevant ICD 10 codes; completed by South African medical aid providers. (ii) The treatment paradigm study, which encompassed a deemed KOA management paradigm validated questionnaire sent electronically to 742 general, specialist and allied practitioners, identifying the incidence of KOA and deemed efficacy and compliance of various management tool. These practitioners were identified from a database of medical and allied practitioners in both the private and public sector of South Africa. The questionnaire consisted of two close ended questions indicating the incidence of KOA and bilateral KOA patients consulted at the practice; one choice question indicating the most suggested mode of therapy from a choice of pharmaceutical, surgical, homeopathic, physical exercise therapy and LLLT and finally, 3 Likert type scale questions on the deemed efficacy and compliance of the modes of therapy as stated above. (iii) The intervention study which was a randomized controlled trial (RCT) utilizing pre marked questionnaire sheets on 111 participants. Participants were randomized into one of three intervention groups; (1) exercise group (n=39), (2) LLLT group (n=40), and (3) combined exercise-LLLT group (n=32). Data on knee circumference, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), knee range of motion (ROM) and the one minute timed sit–to-stand test was used. These tests were done at four time points: (T1) baseline, (T2) post-12 session intervention, (T3) one month post intervention and (T4) three months post intervention. Results: The results will be discussed in terms of the three specified objectives; (i) The prevalence of KOA was reported as 17.5%, 28.0% and 38.5% in a South African population over 45yrs. (ii) Four hundred and thirteen clinicians completed the questionnaire, reporting a KOA patient intake of 53%. Pharmacology (36.3%) and physical exercise (35.3%) was the most common management protocols compared to surgical intervention, homeopathy and LLLT. Pharmacotherapy (73%) and physical exercise (92%) were observed as effective treatments. Seventy five percent of all practitioners responded with an answer of “no comment” when asked the deemed efficacy of LLLT. Practitioners viewed patients with KOA to have low compliance with physical exercise and pharmacotherapy (iii) the participant demographic included 86 females and 25 males, the average age reported was 61.8 ± 5.6yrs. At 12-week follow-up, knee circumference decreased significantly in all groups (p<0.05), the effect was highest in the LLLT group. All groups experienced improvements in the WOMAC pain scale, but the LLLT group showed the greatest improvement (p<0.05). Knee ROM values improved significantly across all three groups; however, the effect of the intervention was most significant (p<0.005) in the combined LLLT-exercise group. Physical functionality scores showed a greater improvement in the combined LLLTexercise group at all three data collection points. Conclusions: The estimated prevalence of KOA is 17-35% based on data collected from a specified South African cohort. Pharmacotherapy is a commonly suggested KOA management mode, whilst clinicians view physical exercise as effective. LLLT was not a known tool for the treatment of KOA. In addition to the improved functionality observed, pain was lowered significantly, particularly in the combined exercise-LLLT group. Study results have shown that LLLT used in isolation or in combination with physical exercise is an effective management tool. / MT 2020

Hui, Pok Shun. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 274-293). / Abstracts in English and Chinese. / Abstract --- p.i / 摘要 --- p.iv / Acknowledgements --- p.vii / Publications Based on Work in this Thesis --- p.viii / Abbreviations --- p.ix / Table of Contents --- p.xi / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- The Mast Cell --- p.2 / Chapter 1.1.1 --- Origin and Development of Mast Cells --- p.3 / Chapter 1.1.2 --- Heterogeneity of Mast Cells --- p.5 / Chapter 1.1.2.1 --- Heterogeneity of Rodent Mast Cells --- p.5 / Chapter 1.1.2.2 --- Heterogeneity of Human Mast Cells --- p.6 / Chapter 1.1.3 --- Activation of Mast Cells --- p.8 / Chapter 1.1.3.1 --- IgE-dependent Activation of Mast Cells --- p.8 / Chapter 1.1.3.1.1 --- FceRI Aggregation and Tyrosine Residue Phosphorylation --- p.9 / Chapter 1.1.3.1.2 --- PLC Activation and Calcium Mobilization --- p.10 / Chapter 1.1.3.1.3 --- PKC and MAPK Activation --- p.11 / Chapter 1.1.3.2 --- IgE-independent Activation of Mast Cells --- p.14 / Chapter 1.1.3.2.1 --- Activation by IgG --- p.14 / Chapter 1.1.3.2.2 --- Activation by Basic Secretagogues --- p.14 / Chapter 1.1.3.2.3 --- Activation by Calcium Ionophores --- p.15 / Chapter 1.1.4 --- Mast Cell Mediators --- p.16 / Chapter 1.1.4.1 --- Preformed Mediators --- p.16 / Chapter 1.1.4.2 --- Newly Synthesized Lipid Mediators --- p.18 / Chapter 1.1.4.3 --- Cytokines and Chemokines --- p.19 / Chapter 1.1.5 --- Pathophysiological Roles of Mast Cells --- p.21 / Chapter 1.2 --- Arthritis --- p.23 / Chapter 1.2.1 --- Epidemiology of Arthritis --- p.23 / Chapter 1.2.2 --- Clinical Features of Arthritis --- p.25 / Chapter 1.2.2.1 --- Angiogenesis and Vasodilation --- p.25 / Chapter 1.2.2.2 --- Synovial Changes --- p.25 / Chapter 1.2.2.3 --- Cartilage Degradation and Bone Erosion --- p.26 / Chapter 1.2.3 --- Pathogenesis of Arthritis --- p.27 / Chapter 1.2.3.1 --- Roles of T Cells --- p.27 / Chapter 1.2.3.2 --- Roles of B Cells --- p.28 / Chapter 1.2.3.3 --- Roles of Mast Cells --- p.28 / Chapter 1.2.3.4 --- Roles of Cytokines --- p.31 / Chapter 1.2.4 --- Treatments of Arthritis --- p.32 / Chapter 1.2.4.1 --- NSAIDs --- p.33 / Chapter 1.2.4.2 --- Glucocorticoids --- p.34 / Chapter 1.2.4.3 --- DMARDs --- p.35 / Chapter 1.2.4.4 --- New Drugs --- p.36 / Chapter 1.3 --- Proteinase-Activated Receptor (PAR) --- p.38 / Chapter 1.3.1 --- Introduction to PARs --- p.38 / Chapter 1.3.2 --- Discovery of PARs --- p.39 / Chapter 1.3.2.1 --- PAR1 --- p.39 / Chapter 1.3.2.2 --- PAR2 --- p.39 / Chapter 1.3.2.3 --- PAR3 --- p.40 / Chapter 1.3.2.4 --- PAR4 --- p.41 / Chapter 1.3.3 --- Structure of PARs --- p.43 / Chapter 1.3.4 --- Activation of PARs --- p.43 / Chapter 1.3.4.1 --- Serine Proteinases --- p.44 / Chapter 1.3.4.1.1 --- Thrombin --- p.44 / Chapter 1.3.4.1.2 --- Trypsin --- p.46 / Chapter 1.3.4.1.3 --- Mast Cell Tryptase --- p.46 / Chapter 1.3.4.2 --- PAR Activating Peptides (PAR-APs) --- p.47 / Chapter 1.3.4.3 --- Proteinase Binding and the Tethered Ligand Mechanism --- p.49 / Chapter 1.3.5 --- Signaling of PARs --- p.50 / Chapter 1.3.5.1 --- Signaling of PAR1 --- p.51 / Chapter 1.3.5.2 --- Signaling of PAR2 --- p.52 / Chapter 1.3.5.3 --- Signaling of PAR 3 and PAR4 --- p.53 / Chapter 1.3.6 --- Termination of Signals and Antagonism of PARs --- p.53 / Chapter 1.3.6.1 --- Termination of Signals by Proteolysis --- p.53 / Chapter 1.3.6.2 --- Termination of Signals by Receptor Desensitization --- p.54 / Chapter 1.3.6.3 --- Antagonism of PARs --- p.55 / Chapter 1.3.7 --- Roles of PARs in Immune Responses --- p.56 / Chapter 1.3.7.1 --- PARs and Mast Cells --- p.57 / Chapter 1.3.7.2 --- PARs and A rthritis --- p.58 / Chapter 1.4 --- Aims of Study --- p.60 / Chapter Chapter 2 --- Materials and Methods --- p.62 / Chapter 2.1 --- Materials --- p.63 / Chapter 2.1.1 --- Materials for Study of PAR Gene Expression in Mast Cells by RT-PCR --- p.63 / Chapter 2.1.1.1 --- Materials for RNA Extraction --- p.63 / Chapter 2.1.1.2 --- Materials for cDNA Synthesis by Reverse Transcription --- p.63 / Chapter 2.1.1.3 --- Materials for Gene Amplification by PCR --- p.64 / Chapter 2.1.1.4 --- Materials for Agarose Gel Electrophoresis --- p.64 / Chapter 2.1.1.5 --- Miscellaneous --- p.64 / Chapter 2.1.2 --- Materials for Study of Histamine Release from RPMCs and LAD2 Cells --- p.65 / Chapter 2.1.2.1 --- Drugs --- p.65 / Chapter 2.1.2.1.1 --- Peptides --- p.65 / Chapter 2.1.2.1.2 --- Serine Proteinases --- p.65 / Chapter 2.1.2.1.3 --- Mast Cell Secretagogues --- p.66 / Chapter 2.1.2.1.4 --- Other Drugs --- p.66 / Chapter 2.1.2.2 --- Materials for Rat Sensitization --- p.66 / Chapter 2.1.2.3 --- Materials for LAD2 Cell Culture --- p.66 / Chapter 2.1.2.4 --- Materials for Buffers --- p.67 / Chapter 2.1.2.5 --- Materials for Spectrofluorometric Analysis of Histamine Contents --- p.67 / Chapter 2.1.2.6 --- Miscellaneous --- p.68 / Chapter 2.1.3 --- Materials for Histological Study of Synovial Mast Cells --- p.69 / Chapter 2.1.3.1 --- Drugs --- p.69 / Chapter 2.1.3.2 --- Chemicals --- p.69 / Chapter 2.1.3.3 --- Miscellaneous --- p.69 / Chapter 2.1.4 --- Materials for Study of Rat Knee Joint Inflammation --- p.70 / Chapter 2.1.4.1 --- Drugs --- p.70 / Chapter 2.1.4.1.1 --- Peptides --- p.70 / Chapter 2.1.4.1.2 --- Other Drugs --- p.70 / Chapter 2.1.4.2 --- Materials for Assessment of Vascular Permeability --- p.71 / Chapter 2.1.4.3 --- Miscellaneous --- p.71 / Chapter 2.2 --- Methods --- p.72 / Chapter 2.2.1 --- Study of PAR Gene Expression in Mast Cells by RT-PCR --- p.72 / Chapter 2.2.1.1 --- Animals --- p.72 / Chapter 2.2.1.2 --- LAD2 Cell Culture --- p.72 / Chapter 2.2.1.3 --- Preparation of Buffers --- p.73 / Chapter 2.2.1.4 --- RNA Extraction --- p.73 / Chapter 2.2.1.5 --- Heparinase and DNase Treatments --- p.74 / Chapter 2.2.1.6 --- cDNA Synthesis by Reverse Transcription --- p.75 / Chapter 2.2.1.7 --- Gene Amplification by PCR --- p.75 / Chapter 2.2.1.8 --- Agarose Gel Electrophoresis --- p.77 / Chapter 2.2.2 --- Study of Histamine Release from RPMCs and LAD2 Cells --- p.77 / Chapter 2.2.2.1 --- Rat Sensitization --- p.77 / Chapter 2.2.2.2 --- Preparation of Buffers --- p.75 / Chapter 2.2.2.3 --- Preparation of Stock Solutions --- p.78 / Chapter 2.2.2.3.1 --- Stock Solutions of Peptides --- p.75 / Chapter 2.2.2.3.2 --- Stock Solutions of Serine Proteinases --- p.79 / Chapter 2.2.2.3.3 --- Stock Solutions of Mast Cell Secretagogues and Other Drugs --- p.79 / Chapter 2.2.2.4 --- Preparation of Mast Cells --- p.80 / Chapter 2.2.2.4.1 --- Isolation and Purification of RPMCs --- p.80 / Chapter 2.2.2.4.2 --- Preparation of LAD2 Cells --- p.81 / Chapter 2.2.2.4.3 --- Determination of Cell Number and Viability --- p.81 / Chapter 2.2.2.5 --- General Protocol for Histamine Release Assay --- p.82 / Chapter 2.2.2.5.1 --- RPMC Experiments --- p.52 / Chapter 2.2.2.5.2 --- LAD2 Cell Experiments --- p.53 / Chapter 2.2.2.6 --- Spectrofluorometric Analysis of Histamine Contents --- p.83 / Chapter 2.2.2.6.1 --- Manual Analysis --- p.85 / Chapter 2.2.2.6.2 --- Automated Analysis --- p.85 / Chapter 2.2.2.7 --- Data Analysis --- p.86 / Chapter 2.2.2.7.1 --- Calculation of Histamine Release --- p.86 / Chapter 2.2.2.7.2 --- Data Presentation and Statistical Analysis --- p.87 / Chapter 2.2.3 --- Histological Study of Synovial Mast Cells --- p.88 / Chapter 2.2.3.1 --- Preparation of Buffers and Chemicals --- p.88 / Chapter 2.2.3.2 --- Preparation of Drugs --- p.88 / Chapter 2.2.3.3 --- Intra-peritoneal Injections of Compound 48/80 --- p.88 / Chapter 2.2.3.4 --- Fixation --- p.89 / Chapter 2.2.3.5 --- Processing --- p.89 / Chapter 2.2.3.6 --- Embedding --- p.90 / Chapter 2.2.3 --- Sectioning --- p.90 / Chapter 2.2.3.8 --- Staining --- p.90 / Chapter 2.2.4 --- Study of Rat Knee Joint Inflammation --- p.91 / Chapter 2.2.4.1 --- Animals --- p.91 / Chapter 2.2.4.2 --- Preparation of Drugs --- p.92 / Chapter 2.2.4.3 --- Induction of Anaesthesia --- p.92 / Chapter 2.2.4.4 --- Intra-articular Injection of Drugs --- p.93 / Chapter 2.2.4.5 --- Topical Administration of Drugs --- p.93 / Chapter 2.2.4.6 --- Assessment of Mechanical Allodynia --- p.93 / Chapter 2.2.4.7 --- Assessment of Joint Oedema --- p.94 / Chapter 2.2.4.8 --- Assessment of Hyperaemia --- p.95 / Chapter 2.2.4.9 --- Assessment of Vascular Permeability --- p.95 / Chapter 2.2.4.10 --- Data Analysis --- p.96 / Chapter Chapter 3 --- Studies of Roles of PAR in Mast Cells --- p.97 / Chapter 3.1 --- Introduction --- p.98 / Chapter 3.2 --- Materials and Methods --- p.103 / Chapter 3.2.1 --- Study of PAR Gene Expression in Mast Cells by RT-PCR --- p.103 / Chapter 3.2.2 --- Study of Effects of PAR Agonists on Histamine Release from Mast Cells --- p.103 / Chapter 3.2.3 --- Study of Signaling Pathways Induced by PAR Agonists in Mast Cells --- p.104 / Chapter 3.3 --- Results --- p.105 / Chapter 3.3.1 --- Study of PAR Gene Expression in Mast Cells by RT-PCR --- p.105 / Chapter 3.3.1.1 --- PAR Gene Expression in RPMCs --- p.105 / Chapter 3.3.1.2 --- PAR Gene Expression in LAD2 Cells --- p.105 / Chapter 3.3.2 --- Study of Effects of PAR Agonists on Histamine Release from Mast Cells --- p.106 / Chapter 3.3.2.1 --- Effects of Serine Proteinases on Histamine Release from RPMCs --- p.106 / Chapter 3.3.2.1.1 --- Thrombin --- p.106 / Chapter 3.3.2.1.2 --- Trypsin --- p.106 / Chapter 3.3.2.1.3 --- Tryptase --- p.107 / Chapter 3.3.2.2 --- Effects of PAR-APs on Histamine Release from RPMCs --- p.107 / Chapter 3.3.2.2.1 --- TFLLR-NH2 (PAR1-AP) --- p.107 / Chapter 3.3.2.2.2 --- SLIGRL-NH2 (PAR2-AP) --- p.108 / Chapter 3.3.2.2.3 --- 2-Furoyl-LIGRLO-NH2 (PAR2-AP) --- p.108 / Chapter 3.3.2.2.4 --- SFNGGP-NH2 (PAR3-AP) --- p.109 / Chapter 3.3.2.2.5 --- AYPGKF-NH2 (PARrAP) --- p.110 / Chapter 3.3.2.3 --- Effects of PAR Control Peptides on Histamine Release from RPMCs --- p.111 / Chapter 3.3.2.4 --- Effects of PAR-APs on Histamine Release from LAD2 Cells --- p.111 / Chapter 3.3.3 --- Study of Signaling Pathways Induced by PAR Agonists in Mast Cells --- p.112 / Chapter 3.3.3.1 --- Effect of PTX on PAR-AP-induced Histamine Release from RPMCs --- p.112 / Chapter 3.3.3.2 --- Effect of BAC on PAR-AP-induced Histamine Release from RPMCs --- p.113 / Chapter 3.4 --- Discussion --- p.115 / Chapter 3.5 --- Figures and Tables --- p.132 / Chapter Chapter 4 --- Studies of Roles of PAR in Rat Knee Joint Inflammation --- p.175 / Chapter 4.1 --- Introduction --- p.176 / Chapter 4.2 --- Materials and Methods --- p.181 / Chapter 4.2.1 --- Histological Study of Synovial Mast Cells --- p.181 / Chapter 4.2.2 --- Study of Rat Knee Joint Inflammation Induced by Intra-articular Injections of PAR-APs --- p.181 / Chapter 4.2.3 --- Study of Rat Knee Joint Blood Flow Changes Induced by Topical Administration of PAR-APs --- p.182 / Chapter 4.2.4 --- Study of the Involvement of Bradykinin B2 Receptors in Rat Knee Joint Inflammation Induced by PAR-APs --- p.183 / Chapter 4.3 --- Results --- p.184 / Chapter 4.3.1 --- Histological Study of Synovial Mast Cells --- p.184 / Chapter 4.3.2 --- Study of Rat Knee Joint Inflammation Induced by Intra-articular Injections of PAR-APs --- p.185 / Chapter 4.3.2.1 --- Intra-articular Injections of Carrageenan and Ovalbumin --- p.185 / Chapter 4.3.2.2 --- Intra-articular Injections of PAR-APs --- p.187 / Chapter 4.3.2.2.1 --- TFLLR-NH2 (PARrAP) --- p.187 / Chapter 4.3.2.2.2 --- 2-Furoyl-LIGRLO-NH2 (PAR2AP) --- p.187 / Chapter 4.3.2.2.3 --- SFNGGP-NH2 (PARrAP) --- p.189 / Chapter 4.3.2.2.4 --- AYPGKF-NH2 (PAR4-AP) --- p.190 / Chapter 4.3.2.3 --- Intra-articular Injections of PAR Control Peptides --- p.191 / Chapter 4.3.3 --- Study of Rat Knee Joint Blood Flow Changes Induced by Topical Administration of PAR-APs --- p.191 / Chapter 4.3.3.1 --- Topical Administration of 2-Furoyl-LIGRLO-NH2 (PAR2-AP) --- p.191 / Chapter 4.3.3.2 --- Topical Administration of A YPGKF-NH2 (PAR4-AP) --- p.192 / Chapter 4.3.4 --- Study of the Involvement of Bradykinin B2 Receptors in Rat Knee Joint Inflammation Induced by PAR-APs --- p.193 / Chapter 4.3.4.1 --- Effect of HOE 140 on Rat Knee Joint Inflammation Induced by Bradykinin --- p.193 / Chapter 4.3.4.2 --- Effect of HOE 140 on Rat Knee Joint Inflammation Induced by 2-Furoyl-LIGRLO-NH2 (PAR2-AP) --- p.194 / Chapter 4.3.4.3 --- Effect of HOE 140 on Rat Knee Joint Inflammation Induced by AYPGKF-NH2 (PARrAP) --- p.195 / Chapter 4.4 --- Discussion --- p.196 / Chapter 4.5 --- Figures and Tables --- p.209 / Chapter Chapter 5 --- General Discussions and Concluding Remarks --- p.261 / Chapter 5.1 --- General Discussions --- p.262 / Chapter 5.2 --- Further Studies --- p.267 / Chapter 5.3 --- Conclusion --- p.271 / References --- p.274