Lfc is a Rho specific guanine nucleotide exchange factor (GEF) that is bound and inhibited by the microtubule (MT) cytoskeleton. In epithelial cells, Lfc promotes actomyosin contractility in response to MT depolymerization; however, its role in leukocytes has not been assessed. Through genetic ablation, we generated an Lfc knockout mouse (Lfc-/-) and tested biochemical and cell biological responses to MT depolymerization in bone marrow derived cells. Lfc was necessary for characteristic actomyosin based contractile behaviours of neutrophils and macrophages, in response to MT depolymerization. Gout is a painful arthritic inflammatory disease, caused by buildup of monosodium urate (MSU) crystals in the joints. Colchicine, a MT-depolymerizing agent that is used in prophylaxis and treatment of acute gout flare, blocks neutrophil infiltration to sites of MSU crystal-induced inflammation. We found that Lfc was necessary for the ability of colchicine to inhibit MSU-induced neutrophil infiltration in two in vivo models of gout-like inflammation. Efficient recruitment of leukocytes from the vasculature is a critical step in the immune response to infection. Leukocyte extravasation, which includes rolling, crawling, and diapedesis across the endothelial barrier, is enhanced by fluid shear stress. Through comparison of Lfc+/+ and Lfc-/- mice, we found that Lfc was necessary for in vivo leukocyte crawling and emigration out of the vasculature. Lfc-/- mice also showed defective neutrophil infiltration in response to acute inflammatory insults, and increased mortality in response to polymicrobial infection. In vitro, we found that Lfc was necessary for neutrophil responses to shear stress.

Lfc is a Rho specific guanine nucleotide exchange factor (GEF) that is bound and inhibited by the microtubule (MT) cytoskeleton. In epithelial cells, Lfc promotes actomyosin contractility in response to MT depolymerization; however, its role in leukocytes has not been assessed. Through genetic ablation, we generated an Lfc knockout mouse (Lfc-/-) and tested biochemical and cell biological responses to MT depolymerization in bone marrow derived cells. Lfc was necessary for characteristic actomyosin based contractile behaviours of neutrophils and macrophages, in response to MT depolymerization. Gout is a painful arthritic inflammatory disease, caused by buildup of monosodium urate (MSU) crystals in the joints. Colchicine, a MT-depolymerizing agent that is used in prophylaxis and treatment of acute gout flare, blocks neutrophil infiltration to sites of MSU crystal-induced inflammation. We found that Lfc was necessary for the ability of colchicine to inhibit MSU-induced neutrophil infiltration in two in vivo models of gout-like inflammation. Efficient recruitment of leukocytes from the vasculature is a critical step in the immune response to infection. Leukocyte extravasation, which includes rolling, crawling, and diapedesis across the endothelial barrier, is enhanced by fluid shear stress. Through comparison of Lfc+/+ and Lfc-/- mice, we found that Lfc was necessary for in vivo leukocyte crawling and emigration out of the vasculature. Lfc-/- mice also showed defective neutrophil infiltration in response to acute inflammatory insults, and increased mortality in response to polymicrobial infection. In vitro, we found that Lfc was necessary for neutrophil responses to shear stress.

Thesis (Ph.D.)--Victoria University of Wellington, 2008. / Includes bibliographical references.

Asthma, gout and hypothyroidism are common chronic medical disorders encountered in general practice. Optimal disease management according to standard guidelines are fundamental to disease control. This study aimed to objectively and subjectively assess the quality of care provided in a private general practice to patients with asthma, gout and hypothyroidism by means of a practice audit and questionnaire based survey. These tools proved to be an effective measure for the quality of care provided and identified areas needing improvement. Patient’s understanding of the disease process plays an important role in both patient satisfaction ratings and success of disease control. The medical audit identified and highlighted specific areas of care that can be improved. Evidence from the practice audit showed that control for asthma based on the PEFR readings, gout based on the serum uric acid reading and hypothyroidism based on a blood TSH reading, was found at 56.7%, 43.3%, and 66.7 % respectively. In addition acute attacks of asthma and gout occurred in 22.7% and 32.8% respectively. This does not represent good control. Definition of disease control for each condition is placed in the text. The survey revealed overall patient understanding for the disease processes of asthma, gout and hypothyroidism to be 69.6%, 73.3% and 66.8% respectively. The patient survey satisfaction rating for asthma, gout and hypothyroidism was 93.1%, 93.9% and 89.2% respectively. Patient suggestions for improvement included three dominant themes: better assessment of disease control, education about their chronic disease and implementation of a clearer referral process. The study concludes that disease control can be achieved if patients are educated about their chronic disease and regularly followed up to assess disease control based on standard management guidelines. Patients' disease education was a major contributing factor for satisfaction rating bias. The study confirms that in spite of high satisfaction ratings, patients are not optimally managed with substandard disease control. It would be expected that as disease education improves, the quality of care will improve, but satisfaction ratings will decrease.

No description available.

No description available.

La goutte est une maladie inflammatoire particulièrement prévalente causée par la formation de dépôts articulaires et péri-articulaires de cristaux d’urate monosodique (UMS ou MSU) et dépendante de la cytokine interleukine-1β (IL-1β). En 2006, l’inflammasome NLRP3 a été montré comme nécessaire pour la maturation de l’IL-1β, in vitro, en réponse aux cristaux de MSU. Néanmoins, sa nécessité in vivo est un sujet de controverse. Mon travail de thèse a porté sur la caractérisation d’un modèle murin d’inflammation aiguë uratique et l’analyse de la contribution des inflammasomes dans cette pathologie. J’ai d’abord montré que notre modèle par injection sous-cutanée de cristaux de MSU donne lieu une forte inflammation des tissus mous comme cela est souvent observé lors des crises de goutte chez l’Homme. L’emploi de souris invalidées génétiquement et d’inhibitions pharmacologiques m’a permis de décrire son indépendance vis-à-vis de plusieurs composants des inflammasomes et confirme le rôle majeur de l’IL-1β. De manière intéressante, j’ai ensuite montré qu’il est possible de réduire fortement l’inflammation dans ce modèle par un traitement topique à base d’imiquimod (crème ALDARA®), un ligand synthétique de TLR7. Des expériences réalisées in vivo et in vitro m’ont permis de relier l’effet de l’imiquimod à une baisse importante de l’Il1b au niveau transcriptionel, via une signalisation faisant probablement intervenir les interférons de type I et possiblement le facteur RUNX3. Mes données montrent donc que la production d’IL-1β, dans ce modèle, est visiblement indépendante de NLRP3 mais peut être fortement abaissée par l’application topique d’imiquimod. L’imiquimod pourrait ainsi représenter une piste thérapeutique attractive. / Gout is a prevalent inflammatory disease caused by the deposition of monosodium urate crystals (MSU) in articular/periarticular areas, which strongly depends on interleukine-1β (IL-1β). In 2006, the NLRP3 inflammasome has been shown to perform IL-1β maturation in vitro after MSU crystal exposure. However, its in vivo dependence is still matter of controversy. In my thesis project, I focused on the characterization of a murine acute uratic inflammation and analysed the contribution of inflammasome components. I first showed that the subcutaneous injection of MSU crystals in mice generate a strong soft tissue inflammation as observed in human gouty crises. Then, by using genetically-modified mouse lines and pharmacological inhibitions, I demonstrated that this model is inflammasome-independent, while still requiring IL-1β secretion. Interestingly, I observed that the topical application of imiquimod (ALDARA® cream), which is a synthetic TLR7 ligand, strongly dampens inflammation. In vivo and in vitro experiments further demonstrated that this effect is linked to reduced Il1b gene expression, which linkely involves type I interferon signaling and eventually the transcription factor RUNX3. Altogether, my results show that IL-1β production is NLRP3-independent in this mouse model but can be strongly decreased by topical application of imiquimod. Therefore, imiquimod might be an attractive therapeutic option for gouty patients.

This project was carried out under a broad theme of Maori health and investigates the genetics of rheumatoid arthritis (RA) and gout within two Maori case-control cohorts. In addition, it reports on the developmental stages of a whanau project focussing on the compilation of our whakapapa and collation of information relating to type 2 diabetes within the Parata whanau, which I whakapapa to. My conducting this research in light of me being Maori is also considered: much of the prevailing literature on Maori and science describes science as the handmaid of colonisation, and singles out genetic research as being "neo-colonial". I reject those that would label me a "sell-out" and show how my research is shaped by, and consistent with, the history of my immediate tipuna, and my iwi more generally, since European contact. RA is an autoimmune disease of the joints and affects approximately 1% of the general population. There is currently very little data available on its prevalence in New Zealand although it is thought that it is similar to those of the rest of the world. Gout is the most common form of inflammatory arthritis in Caucasian males and recent data suggests a worldwide increase in prevalence in many populations. Gout is characterised by the deposition of monosodium urate or uric acid crystals in the joints, which produces an inflammatory response. In New Zealand, the prevalence of gout is estimated to be 3% in Caucasians and twice this in Maori. Both RA and gout are complex arthritic diseases and are influenced by a combination of genetic and environmental factors. It is likely that numerous genetic susceptibility loci are responsible for the genetic components of these diseases. This project tests various genetic regions for susceptibility to or protection against both RA and gout in two separate Maori case cohorts and a common control cohort. To do this, the confounding factor of population stratification, resulting from population admixture, was overcome via developing a method specific for these Maori cohorts. This tool utilised genotype data from a set of unlinked genome-wide markers and the structure and STRAT software packages, allowing valid case-control studies to be carried out in the presence of population stratification. These data showed that four sub-populations exist in the Maori RA case-control cohort and three in the Maori gout case-control cohort. A number of studies have confirmed the HLA region as the major genetic determinant of autoimmunity and recently, PTPN22 and CTLA-4 variants have been shown to be common to the onset of a number of autoimmune phenotypes. The IDDM6 region on chromosome 18 has also been implicated in type 1 diabetes, RA and autoimmune thyroiditis and contains a number of candidate genes for a role in RA, many of which were investigated in this thesis. Polymorphisms within the PTPN22, CTLA-4, BCL2, SMAD4, DCC, TNFRSF11A, PADI4, CCR5 and CCL3L1 genes were tested for association with RA in the Maori cohort (98 cases and 109 controls) with some significant association results obtained. The HLA-DRB1*02 and HLA-DRB1*08 loci were associated with the protection against and susceptibility for RA, respectively (P = 0.004 and 0.017). The deviation of CCL3L1 copy-number from the cohort mean (two copies) was also associated with the RA development. Copy-number <2 indicated association with protection against RA (P = 0.012) and copy-number >2 indicated association with susceptibility to RA (P = 0.002). However, it must be stressed that these results were obtained without accounting for the presence of population stratification. The organic anion transporter (OAT) and the urate transporter 1 (URAT1) genes, involved in the regulation of blood urate levels, are members of the solute carrier transporter (SLC) family and provide good candidates for a role in gout. A number of polymorphisms within the OAT, URAT1 and the SLC5A8 genes were tested for association with gout in the Maori cohort (72 cases and 109 controls) with some success. The SLC5A8 rs1709189 SNP was significantly associated with gout in this cohort (P = 0.004). Polymorphisms within two alcohol dehydrogenase (ADH) genes were also tested for association due to their role in alcohol metabolism and the association between alcohol consumption and gout. The ADH2 rs1229984 SNP was also significantly associated with gout in this cohort (P = 0.012). These significant results were obtained after population stratification was taken into account. The data presented in this thesis confirm the presence of population stratification in the two Maori case-control cohorts and demonstrate some association of the HLA-DRB1 region and CCL3L1 with RA and the SLC5A8 and ADH2 genes with gout. An extensive whakapapa of our whanau has also been compiled and associated type 2 diabetes information collected. However, this is by no means a completed task and work will continue on this project under the guidance of the Parata whanau.

La thèse souvre par le constat dune absence détudes véritablement consacrées à lhistoire du goût. La remarque peut surprendre, car les intitulés de la riche bibliographie des Food Studies laissent croire que les études gustatives foisonnent dans les bibliothèques, notamment depuis les travaux de Jean-Louis Flandrin qui, parmi les premiers, a contribué à faire de lalimentation un sujet digne dhistoire. Une analyse plus attentive du contenu révèle cependant une tendance massive des chercheurs à réduire le goût au seul registre culinaire, laissant dans lombre les autres dimensions quil pourrait prendre. Depuis peu cependant, un nouveau champ de recherches paraît émerger des Food Studies, majoritairement représenté par des ouvrages anglo-saxons, centré non sur ce qui se mange, mais sur ce qui se dit et se pense du goût, dans la mesure où ce qui se dit et se pense traduit une expérience collective et son intériorisation culturelle. Refusant de cantonner létude du goût au seul registre culinaire, létude proposée sinscrit dans cette perspective nouvelle, se situant au croisement de lhistoire culturelle des sensibilités, des Food Studies et de lanthropologie historique, utilisant notamment les réflexions fécondes de Philippe Descola. Plus que lhistoire de la cuisine, elle propose de mettre en lumière lhistoire dun sens, révélant dans son sillage lévolution dun rapport au monde des hommes dAncien Régime. Elle interroge notamment les raisons historiques qui ont permis lémergence de la gastronomie au XIXe siècle, témoignage dune valorisation inédite du goût sur la scène sociale. Consacrée à létude des représentations du goût dans l'aire culturelle française des XVIIe et XVIIIe siècles, la thèse se base sur lexploitation dun corpus documentaire large composé de sources de natures variées. Les discours philosophiques, religieux, culinaires et médicaux constituent les quatre registres principaux de cette étude. Explorant la genèse et la construction dune culture gustative moderne, elle révèle dabord la dévalorisation séculaire du goût. Situé traditionnellement au bas de la hiérarchie des sens, le goût est longtemps perçu comme un sens inférieur, matériel, corporel et animal. Il se réduit à la seule dimension de lextériorité, révélant la porosité des frontières entre lhomme et lanimal, que lhomme classique voudrait oublier. Considéré comme inutile au développement de la connaissance par rapport à un sens éminent comme la vue et dangereux pour la vertu avec la gourmandise , le goût est pendant longtemps laissé à la marge du savoir. Mais entre lépoque classique et celle des Lumières, des indices de représentations nouvelles apparaissent, témoins dun déplacement des significations culturelles du goût. Les premiers à le suggérer sont les cuisiniers qui, au milieu du XVIIe siècle, décident de consacrer les préfaces de leurs livres de recettes à des propos plus généraux sur le goût ou la cuisine, premières tribunes dune célébration des plaisirs gourmands. Les intellectuels trouvent par ailleurs désormais utile de consacrer de larges débats au goût, dès lors quil est doté dun sens figuré, propice à lémergence dun faisceau de métaphores les plus variées « goût de Dieu » des mystiques, « bon goût » de lhonnête homme et « Goût » esthétique. Toutes cependant, malgré leurs différences intrinsèques, se rejoignent pour révéler lémergence dune nouvelle modalité sensorielle, qui se caractérise par limmédiateté de son action et lémotion quelle occasionne. Mais surtout, le goût se caractérise par lindicible dun sens profondément individuel. Longtemps laissé à la périphérie des discours, le goût, désormais devenu une entité duelle, à la croisée du corps et de lesprit, se déploie dans lespace dune intériorité proprement humaine, ce qui lui permet dêtre pensé et discuté par les savants, les philosophes et le monde cultivé dans son ensemble.

Introduction: Gout affects approximately 15% of Maori and Pacific men, these men being at risk of early onset, severe disease with formation of gouty tophi and joint damage. Gout most frequently affects the foot, particularly the big toe and midfoot. This disease initially presents as self-limiting attacks of severe joint inflammation, and in the presence of persistent hyperuricaemia, tophaceous disease may also develop. Tophi are collections of monosodium urate crystals surrounded by chronic inflammatory cells and connective tissue. Tophi typically occur in both subcutaneous tissues and within affected joints, and may cause pain, cosmetic problems, mechanical obstruction of joint movement, and joint destruction. Despite the predilection of gout to the foot, the impact of gout on foot function is currently unknown and only case studies relating to hallux pain, tibial sesamoid pain and longitudinal tears in peroneal tendons have been reported in the literature. The aim of this study is to assess the intra-tester reliability of certain biomechanical tests to evaluate foot structure and function (plantar pressure measurements, gait parameters, range of motion at the ankle and first MTPJ and the foot posture index) in individuals with gout and to assess the differences between disability, impairment, foot structure and function between individuals with gout and non-gout controls. Subjects: A total of 25 patients with chronic gout with a mean age of 61.2 (11.7) years old were recruited from a rheumatology clinic within the Auckland District Health Board. A further 25 age-and sex-matched controls with a mean age of 57.3 (12.2) years old were recruited from AUT University. Methods: Disability, impairment, foot structure and foot function were assessed for the gout and the control group. Disability and impairment was assessed using the Health Assessment Questionnaire, Foot Function Index, Leeds Foot Impact Scale and Lower Limb Task Questionnaire. Foot structure was investigated using the Foot Posture Index, first metatarsophangeal joint (MTPJ) dorsiflexion, ankle dorsiflexion movement, subtalar joint and midtarsal joint motion, Foot Problem Score, tophi count and muscle strength of extrinsic and intrinsic foot muscles. Foot function was investigated using an in-shoe pressure system measuring mean peak plantar pressures and pressure-time integrals. Temporal-spatial gait parameters were evaluated, as well as peripheral sensation and vibration perception threshold. Plantar pressures were assessed using the Tekscan pressure insole system, gait parameters were measured using the Gaitmat walkway system, peripheral sensation and vibration threshold were assessed using 10gm monofilament and biothesiometer respectively. Intra-tester reliability was investigated using ICC, Standard Error of Measurement and Smallest Real Difference in the gout group for key measures (Foot Posture Index, first MTPJ dorsiflexion, ankle dorsiflexion movement, peak plantar pressures, pressure-time integrals and gait parameters). To investigate the significant difference between the groups, the left and right foot in gout were compared with the left foot of the control group using ANOVA with post-hoc comparisons. Non-parametric tests were used for muscle strength, peripheral sensation and Foot Problem Score and motion at the subtalar and midtarsal joints for comparison between the groups. Walking velocity, cadence and disability and impairment scores between the groups were assessed using an independent t-test with 95% confidence intervals. Significance for all these measures was set to 0.05 except for Chi square where a significance of 0.02 was set. Results: The ICC for the intra-tester reliability was excellent with low measurement error for the measured outcomes. The gout group recorded significantly higher disability and impairment scores than controls (p<0.01). Significant differences between the two groups were recorded for vibration pressure threshold, muscle strength, Foot Problem Score, first MTPJ dorsiflexion, foot motion and gait parameters (p<0.05). Significant differences were demonstrated under the toes for mean plantar pressures and under the lateral heel, midfoot and hallux regions for pressure-time integrals in the gout cases (p<0.05). Conclusions: Individuals with gout have reduced quality of life due to greater disability and impairment. The gouty foot is slightly supinated with reduced dorsiflexion at the first MTPJ. Rearfoot and forefoot motions are limited with a high incidence of digital deformities and dermatological lesions. The foot function in gout is characterized by reduced walking velocity, cadence, step and stride length. The plantar pressures are reduced under the toes with increased duration of loading under the hallux, lateral heel and midfoot regions. Further research using three-dimensional gait analysis is recommended to quantify motion at the foot and ankle joints and also to ascertain the role of proximal joints. Future work could be undertaken to evaluate the impact of acute gout on objective measures of foot function, and to determine predictors of poor foot function in patients with this disease. This will allow further work to investigate or formulate a podiatric management plan in conjunction with pharmacological therapy to improve impairment, disability and function in chronic gout.