Thesis (Ph. D.)--University of Wisconsin--Madison, 1959. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 144-157).

Thesis (Ph. D.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 156-186).

Thesis (Ph.D.(Anatomy))--University of Pretoria, 2009. / Includes abstract in English. Includes bibliographical references (leaves 163-202). Also available online.

No description available.

L’étiologie et le développement des maladies inflammatoires chroniques de l’intestin (MICI), dont la maladie de Crohn (MC) et rectocolite hémorragique (RCH), sont encore mal compris. Il s’agit de maladies multifactorielles caractérisées par une dérégulation de la réponse immunitaire des muqueuses chez des individus génétiquement prédisposés, sous l’influence de facteurs environnementaux. À ce jour, seuls le tabagisme et l’appendicectomie sont décrits comme capables d’influencer le développement des MICI. Le rôle du tabac est ambivalent : il protège de la RCH mais aggrave le risque d’apparition de la MC. Néanmoins, malgré une littérature relativement abondante, il est à l’heure actuelle impossible d’assigner définitivement des propriétés immunomodulatrices particulières au tabac. De plus, aucun des modes d’actions du tabac proposés n’explique l’ambivalence observée entre la MC et la RCH. L’hypothèse la plus probable est celle d’un effet du tabac différent sur le côlon et l’intestin grêle.Partant de ces observations cliniques, ce travail a pour but de caractériser un (ou plusieurs) des mécanismes impliqués dans le rôle immunomodulateur du tabac d’une part au niveau du côlon et d’autre part au niveau de l’iléon, afin de réaliser une analyse différentielle sur ces deux organes.Deux modèles d’étude ont été mis en place sur des souris C57Bl/6. Les souris sont pré-exposées pendant 2 semaines à la fumée de cigarette via un protocole standardisé qui permet de mimer au mieux le tabagisme humain. Lors de la troisième semaine, l’inflammation est provoquée soit au niveau du côlon (traitement au DSS (Dextran Sodium Sulfate)), soit au niveau du grêle (traitement à l’indométacine). Chez les souris sauvages, l’exposition à la fumée de cigarette réduit significativement l’expression clinique de la colite et diminue l’expression des cytokines pro-inflammatoires Th1/Th17 dans le côlon. Cette protection est spécifique au côlon : aucune différence n’a pu être observée sur les paramètres cliniques de l’inflammation dans le modèle d’iléite.L’analyse des populations cellulaires met en évidence une augmentation de la proportion de lymphocytes iNKT au niveau du foie et du côlon (mais pas au niveau du grêle) des souris exposées. Ces cellules sont indispensables à l’effet protecteur lié à la fumée de cigarette au niveau du colon. En effet, la protection contre la colite au DSS liée à la fumée est abolie chez des souris déficientes en cellules NKT fonctionnelles. Par contre, dans le modèle d’iléite à l’indométacine, les souris déficientes en NKT montrent une sensible diminution de l’inflammation iléale lorsqu’elles sont exposées à la fumée de cigarette.Ces résultats semblent indiquer que les cellules iNKT joueraient un rôle différent en fonction de leur localisation dans le tractus intestinale, ou que des sous-populations différentes de cellules iNKT seraient impliquées dans le contrôle immunitaire dans le côlon et l’intestin grêle.Ce travail démontre clairement que, expérimentalement, la fumée de cigarette protège les souris de la colite mais pas de l’iléite. Pour la première fois, les cellules iNKT ont été identifiées comme ayant un rôle majeur dans la protection du côlon liée à la fumée de cigarette, tout en jouant potentiellement un rôle différent au niveau de l’iléon.Cette thèse apporte des données nouvelles et originales dans le domaine de la régulation de l’inflammation intestinale notamment par la fumée de cigarette, un facteur environnemental largement répandu. En outre, cibler les cellules iNKT pourrait constituer un nouveau moyen de contrôle de l’inflammation intestinale. La conception de nouvelles molécules agissant sur la polarisation des cellules iNKT pourrait faire l’objet d’une nouvelle voie thérapeutique visant à diminuer l’inflammation colique, en particulier au cours de la RCH. / Current hypothesis on the pathogenesis of inflammatory Bowel disease suggests that the disease development implicates a deregulated dialogue between the intestinal flora and components of both the innate and adaptive immune systems in genetically susceptible individuals and under the influence of environmental factors. To dateonly cigarette smoking and appendectomy have been shown to play a significant role. The effect of smoking appears to be ambivalent: it protects from ulcerative colitis (UC) but worsens Crohn’s disease (CD). Moreover, in CD it has been proposed that smoking might influence the disease location: CD patients who smoke were found to have a higher frequency of ileal disease and a lower frequency of colonic involvement. However, the molecular basis of the opposite effect of smoking in CD and UC still remain unexplained. Tobacco smoke molecules seem to possess various immunomodulatory properties but currently no clear conclusion can be drawn from in vitro and in vivo studies. To date, the influence of cigarette smoke on immune cells profile in the intestine remains unknown. The aim of this project was to characterize the effect of CS in murine models of intestinal inflammation, and the underlying mechanism implied in impact of CS in the colon and in the ileum at the cellular and molecular levels. To address this question, we developed a new model of exposition to CS using InExpose® exposure system (Scireq Inc) which allows us to accurately reproduce human smoking habits. We applied this protocol of exposure in two different animal models of intestinal inflammation: 1) the commonly used model of dextran sodium sulphate (DSS)-induced colitis and 2) the indomethacin-induced jejuno-ileitis model. C57BL/6 mice were pre-exposed to CS during two weeks before induction of one or another model of intestinal inflammationFirstly, we demonstrated in WT mice that CS exposure improved DSS-induced colitis but not indomethacin-induced ileitis. The colonic improvement was associated with a decrease in Th1/Th17 proinflammatory cytokines expression in the colon. This protection linked to CS exposure was specific to the colon since no modification of clinical and inflammatory parameters were observed in the jejuno-ileitis model.Secondly, we analyzed leukocyte population under CS exposure condition compared to control un-exposed mice. We showed by flow cytometry analysis that, in particular, iNKT cells were recruited by cigarette smoke in the colon and the liver (but not the small bowel) after CS exposure in non-inflammatory condition. To access the role of iNKT cells in CS dependant colonic protection, mice deficient in NKT cells (CD1dKO and J18KO mice) were exposed to the same protocols than WT mice. In NKT cell-deficient mice, CS exposure failed to improve colitis and to decrease the expression of proinflammatory cytokines. This implies that iNKT cells may be a major actor in the CS-dependent protection against DSS colitis. On the other hand, in NKT cell-deficient mice CS exposure seems to improve indomethacin-induced ileitis. This result indicates that iNKT cells could act differently according intestinal location or that the populations of iNKT in the different compartment of intestinal tracts may differ.In conclusion, this study demonstrated that mainstream CS exposure protects mice from experimental colitis but not from experimental ileitis. For the first time, we have identified iNKT cells as major player of the CS-dependent protection in colonic inflammation, whereas they might have a different role in the ileum. Therefore, our study contributes to better elucidate the impact of smoking, as a widespread environmental factor in IBD. Targeting iNKT cells would represent a novel therapeutic way. Design of new molecules acting on iNKT cells polarization could reproduce the effects of CS and allow decreasing the inflammation in the colon.

A dissertation submitted in partial compliance with the requirements for the Master's Degree in technology: Chiropractic, Technikon Natal, 2001. / The purpose of this study was to evaluate the relative effectiveness of manipulation versus meloxicam (a Non-Steroidal Anti-Inflammatory Drug) to determine which is more beneficial in treating osteoarthritis of the knee. This was a prospective, randomized clinical trial consisting of a population of sixty voluntary subjects, diagnosed as suffering from osteoarthritis of the knee. The patients were divided equally into two groups of thirty, with Group A receiving chiropractic manipulative therapy on eight consultations over three weeks, and Group B receiving meloxicam 7,5mg tablets once daily for three weeks. Capturing of the subjective and objective data for both groups took place on the first, fourth and eighth consultations. Subjective data was captured using the Numerical Pain Rating scale-l 01, the Visual Analogue scale, as well as the Patient -Specific functional scale. Objective data was gathered from goniometric and pressure algometer measurements. / M

No description available.

Gold compounds have been used for the treatment of rheumatoid arthritis since the mid 20th century as a disease modifying anti-rheumatic drug. Auranofin, an oral anti-rheumatic drug, has been used for many years in the treatment of rheumatoid arthritis (RA). Although the drug has been successful in treating the symptoms of RA, many patients discontinue its use due to severe toxicity over long periods of continued treatment. Since the introduction of auranofin in 1985 there has been no new clinically approved gold drug. Drug discovery research is directing focus on overcoming these toxicity problems. Much of the problems related to the toxicity related to auranofin are due to its lipophilicity. As a result, three compounds (Asa-fin, Mpta-fin and Pta-fin) with varying substituents were synthesised and hence the lipophilic- hydrophilic balance was modulated. All compounds including auranofin were tested against normal cells to determine its toxicity as well as its anti-inflammatory activity. Three novel auranofin derivatives were compared to auranofin with regards to lipophilicity, toxicity and anti-inflammatory properties The lipophilicity of the three compounds were compared to auranofin using the octanol-water partition coefficient method. All the novel compounds showed variable lipophilicity compared to auranofin, with Pta-fin and Mpta-fin being more hydrophilic than auranofin. The cytotoxicity of these novel gold compounds Asa-fin, Mpta-fin and Pta-fin were compared to auranofin using primary porcine hepatocytes and chicken embryo fibroblasts cultures. A metabolic assay based on the reactivity of 3-[4,5-dimethylyhiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) with viable cells was done to measure the effect of the drugs on the growth of cultures. All three novel compounds proved less toxicity at comparable concentrations in primary porcine hepatocytes and in fibroblast proliferation, Asa-fin and Mpta-fin proved less toxic than Auranofin. The Anti-inflammatory activity of the experimental compounds was determined by testing the effects of the experimental compounds on human lymphocyte proliferation. The MTT assay was used to measure the effect of the drugs on the growth of the cell cultures. All three compounds inhibited the proliferation of human lymphocytes with Pta-fin having the least effect. The effect of these drugs was also evaluated on the reactive oxidant production by chemiluminescence and flow cytometry on resting, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) and Phorbol Myristate Acetate (PMA) stimulated human neutrophils. Oxidant production by neutrophils was measured after a 45-minute incubation period with luminol enhanced chemiluminescence. Treatment of neutrophils with auranofin and the three compounds showed that auranofin, Asa-fin and Mpta-fin had a biphasic activity on hydrogen peroxide production with higher concentrations decreasing hydrogen peroxide production, possibly leading to the anti-inflammatory action of these drugs. With Pta-fin no decrease in hydrogen peroxide was observed. Using flow cytometry three dyes specific to different reactive oxygen species were used. 2’, 7’-Dichloroflourescein diacetate (DCFH) is specific for detecting nitric oxide, Dihydrorhodamine 123 (DHR) is specific for detecting hydrogen peroxide and Hydroethidine (HE) is specific for detecting superoxide. Oxidant production was measured after a 30 minute incubation period with the relative dyes on a flow cytometer. Auranofin and Asa-fin decreased hydrogen peroxide and superoxide production. None of the drugs had an effect on nitric oxide production. The expression of the â2-integrin adhesion molecule, CR3, on resting and PMA stimulated neutrophils treated with the experimental compounds was measured by flow cytometry. CR3 expression by neutrophils was measured after 10 minute incubation in the dark with CD11b FITC monoclonal antibody. Treatment of neutrophils with auranofin and the three experimental compounds showed a decrease in CR3 expression on resting and stimulated neutrophils, however the effect was more marked in stimulated neutrophils. The Anti-inflammatory activity of the experimental compounds was determined by testing the effects of the experimental compounds on cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX 2) in resting and lipopolysaccharide (LPS) stimulated human monocytes. COX 1 and 2 production was measured by flow cytometry. Treatment of monocytes with the experimental compounds showed a decrease in COX 2 production in stimulated monocytes but an increase in COX 2 production in resting monocytes. No effect on COX 1 production was observed with the experimental compounds. Prostaglandin E2 (PGE2) was measured with a Prostaglandin E2 Enzymeimmunoassay (ELISA) kit on human macrophages. Auranofin, Asa-fin, Mpta-fin and Pta-fin inhibited the production of PGE2. Auranofin and Asa-fin inhibited the PGE2 directly proportional to the drug concentration. The effect of these drugs was also evaluated on various inflammatory cytokines using an inflammatory cytokine kit and measured on a flow cytometer. The cytometric bead array (CBA) human inflammation kit was used to quantitatively measure interlukin-8(IL-8), interlukin-1â (IL-1â), interlukin-6 (IL-6), interlukin-10 (IL-10), tumour necrosis factor alpha (TNFá) and interlukin-12p70 (IL-12p70). Auranofin and Asa-fin decreased IL 10, TNFá, and IL1â in stimulated cells. No effect was observed on IL 8, IL-12p70 and IL 6. With Mpta-fin and Pta-fin, no significant effect was observed in the cytokines tested. Drug toxicity was evaluated in mice using all four compounds in BALB/c inbred mice. Aspartate transaminase (AST), gamma glutamine transferase (GGT), urea and creatine levels were measured in the test mice. The group receiving the highest dose of Asa-fin showed the greatest elevation of AST . The lowest dose of the auranofin treatment group showed the greatest elevation in GGT, however this increase was not seen in the subsequent higher dosing groups. None of the treatment groups indicated an increase in urea levels. Mpta-fin and Pta-fin showed no increase in the liver enzymes or in urea and creatine. The results of this work are indicative that novel gold compounds could play a promising role in anti arthritic applications. Asa-fin exhibited similar anti-inflammatory activity to auranofin but in vivo toxicity was high. Mpta-fin showed slightly inferior anti-inflammatory activity to auranofin but in vivo toxicity profiles were much more promising. Pta-fin showed the least anti-inflammatory activity of the three novel compounds tested with a similar in vivo toxicity profile as Mpta-fin. / Dissertation (MSc)--University of Pretoria, 2009. / Pharmacology / unrestricted

No description available.

Evidence from many recent studies has linked uncontrolled inflammatory processes to aging and aging-related diseases. Decreased a nuclear receptor subfamily of transcription factors, peroxisome proliferator-activated receptors (PPARs) activity is closely associated with increased levels of inflammatory mediators during the aging process. The anti-inflammatory action of PPARs is substantiated by both in vitro and in vivo studies that signify the importance of PPARs as major players in the pathogenesis of many inflammatory diseases. In this review, we highlight the molecular mechanisms and roles of PPARα, γ in regulation of age-related inflammation. By understanding these current findings of PPARs, we open up the possibility of developing new therapeutic agents that modulate these nuclear receptors to control various inflammatory diseases such as atherosclerosis, vascular diseases, Alzheimer's disease, and cancer.