Studies were conducted to investigate: 1) desaturation of dietary trans-vaccenic acid (TVA, trans11-18:1) to the cis9,trans11-18:2 isomer of conjugated linoleic acid (9/11CLA), 2) effects of two conjugated linoleic acid isomers [9/11CLA or trans10,cis12-18:2 (10/12CLA)] and TVA on enzyme activities and mRNA abundance for lipogenic enzymes, and 3) regulation of stearoyl-CoA desaturase (SCD) gene transcription. In the first study, lactating mice were fed 3% linoleic acid (LA), or 2% LA plus 1% stearic acid (SA), 1% TVA, or 1% CLA mixture. Dietary TVA enriched the 9/11CLA content of carcass, liver, and mammary tissue of lactating mice. A similar enhancement of 9/11CLA also was observed in liver, but not carcass, of suckling pups nursing TVA-fed dams. The CLA mixture decreased mammary acetyl-CoA carboxylase (ACC) activity compared with other treatments. However, total fatty acid content of mammary tissue was reduced only when compared with TVA. In the second experiment, lactating mice were fed 3% canola oil (OA), or 2% OA plus 1% SA, 1% TVA, 1% 9/11CLA, or 1% 10/12CLA. Dietary TVA, 9/11CLA, and 10/12CLA decreased mRNA abundance for ACC and fatty acid synthase (FAS) in mammary tissue, suggesting each had the potential to reduce de novo fatty acid synthesis. However, only the CLA isomers decreased ACC activity in mammary tissue and concentration of medium-chain fatty acids (MCFA = 12:0+14:0+16:0) in milk fat. The 10/12CLA isomer caused greater reductions in MCFA and milk fat percentage than the 9/11CLA, indicating that 10/12CLA is the primary CLA isomer affecting lipid metabolism in the mammary gland. Dietary TVA, 9/11CLA, or 10/12CLA decreased SCD enzyme activity and mRNA abundance in mammary tissue. In study 3, mouse (COMMA-D/MME) and bovine (Mac-T) mammary epithelial cells were transfected with the putative promoter (600 bp) of SCD gene. The 9/11CLA reduced SCD gene transcription in mouse cells, but not bovine cells. Transcription, however, was reduced in both cell lines by 10/12CLA, linoleic acid, and linolenic acid. Thus, reduced SCD transcription in response to the CLA isomers in mouse mammary cells in vitro may provide an explanation for reduced SCD enzyme activity and mRNA abundance in mammary tissue when lactating mice were fed either of the CLA isomers. In contrast, stearic acid, oleic acid, and TVA did not affect SCD transcription. Although TVA did not reduce SCD transcription in mouse mammary cells in vitro, it did reduce SCD enzyme activity and mRNA abundance in mammary tissue when fed to lactating mice. The results suggested TVA may influence SCD mRNA processing or stability in the nucleus after transcription. Despite the reduction in SCD mRNA and enzyme activity, however, substantial quantities of TVA were desaturated to the 9/11CLA isomer when TVA was fed to lactating mice in the first two studies. Thus, dietary TVA provides an alternate supply of the anticarcinogenic 9/11CLA isomer in tissues. / Ph. D.

Systemic lupus erythematosus (SLE) is an autoimmune disease involving the inflammatory damages of multiple organs. Lupus nephritis (LN) as the manifestation in the kidney occurs in more than 50% of SLE patients and is a major cause of morbidity and mortality. Current treatments consist of immunosuppressants that always lead to compromised immune responses with increased risks of infections as the major side effect. To minimize this side effect, it is crucial to develop new treatments that are more natural and specific. Vitamin A, particularly in the form of its functional metabolite, retinoic acid, has shown some beneficial effects against LN in both lupus-prone mouse models and clinical cases. However, a more systemic evaluation of vitamin A treatment in lupus had not been investigated. In our study, we found paradoxical effects of all-trans-retinoic acid (tRA) on lupus-like disease in MRL/lpr lupus-prone mice. Starting at 6 weeks old when the inflammatory environment had been established in MRL/lpr mice, tRA administration reduced immune cell numbers in the secondary lymphoid organs and improved glomerulonephritis. However, circulating autoantibodies and inflammation in renal tubulointerstitium and other organs were increased. The detrimental effects of tRA were not present in MRL control mice, which didn't have an established inflammatory environment at 6 weeks old as shown in MRL/lpr mice, suggesting that the pro-inflammatory effects of tRA are dependent on the pre-existing inflammatory environment. Therefore, to successfully apply vitamin A-based treatment, it is important to avoid the detrimental effects of tRA on lupus by identifying and then specifically eliminating the critical pro-inflammatory immune cell types in lupus. As treatments usually start after the onset of apparent symptoms in patients at the effector stage of autoimmune responses, targeting the inflammatory contributors at this stage appears to be more practical and critical. Among different types of leukocytes, we chose to focus on dendritic cells (DCs), because they are highly diverse and critical in the immune responses as a bridge between the innate and adaptive immune systems. Plasmacytoid DCs (pDCs) as a candidate target have been demonstrated to be crucial for the initiation of lupus development by producing IFNα. However, we demonstrated that although pDCs produced a large amount of IFNα during disease initiation, those from late-stage lupus mice were found to be defective in producing IFNα, suggesting that pDC-targeted treatments should be performed at the initiation stage. This will depend on the progress in early diagnosis in the future. Besides pDCs, we identified a CD11c+ cell population absent at the early-stage but gradually accumulating at the late-stage in the kidneys of lupus mice. These cells have a phenotype of mature monocyte-derived DCs, with particularly high CX3CR1 expression on the surface. Consistent with their pathogenic cytokine profile, in vivo administration of anti-CX3CR1-saporin conjugates to dysfunction these cells in MRL/lpr mice significantly reduced proteinuria scores. Ex vivo activation of renal-infiltrating CD4+ T cells showed increased survival rate, proliferation and IFN-γ production of activated CD4+ T cells when they were cultured with these renal-infiltrating CD11c+ cells. These results suggest that the renal-infiltrating CD11c+ cells are pathogenic and promote inflammation in the kidney at the later effector stage of lupus by interacting with renal-infiltrating CD4+ T cells. In conclusion, although vitamin A showed anti-inflammatory effects on reducing glomerulonephritis, its use in lupus treatment should be guarded due to the other potential pro-inflammatory effects induced by the pre-existing inflammatory environment. IFNα-producing pDCs and CX3CR1highCD11c+ monocyte-derived DCs could be specific therapeutic targets to reduce the established inflammation at the early stage and late stage of LN, respectively. Therefore, it is worthwhile to further investigate the comprehensive effects of combination therapy on lupus, with vitamin A administration and pDCs-specific depletion at the early stage, and CX3CR1highCD11c+ monocyte-derived DCs-specific depletion at the late stage. / Ph. D.

Oxidative stress plays a vital role in the pathogenesis of many chronic and acute inflammatory diseases. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are two key mediators that are known to induce cellular and tissue oxidative stress. The generation of ROS and RNS is mediated by innate immune signaling processes. Lipopolysaccharide (LPS), a major inflammatory signal, is known to be a potent inducer of ROS/RNS. Thus, strategies that may block LPS-mediated generation of free radicals may hold promise in treating various inflammatory disease processes. However, the molecular mechanisms underlying LPS-mediated ROS/RNS production are not fully defined. Interleukin-1 Receptor associated kinase (IRAK-1), an intracellular kinase downstream of Toll-like Receptor 4 (TLR4) has been shown to contribute to the inflammatory cascade associated with LPS-TLR4 signaling pathway. However, its role in ROS production has not been defined. Therefore, we tested the hypothesis that IRAK-1 plays an important role in regulating ROS/RNS production. Both in vitro and in vivo studies were conducted to investigate the role of IRAK-1 in modulating free radicals as well as oxidative stress. In vitro studies demonstrate that IRAK-1 is a critical molecule involved in the induction of ROS/RNS. IRAK-1 deletion ablated free radical production following LPS challenge in a variety of cell types including macrophages, fibroblasts and microglia. Mechanistically, we observed that IRAK-1 is required for optimal expression and activity of NADPH oxidase subunits and iNOS. IRAK-1 deletion reduced LPS-triggered p47phox membrane translocation, suppressed NOX-1 expression and protein levels as well as hampered Rac1 activation. On the other hand, IRAK-1 deletion sustained antioxidative enzyme activity and levels in IRAK-1-/- macrophages and fibroblasts. In terms of the in vivo physiological consequences, IRAK-1-/- mice exhibited attenuated lipid peroxidation in vital organs, attenuated histopathological lesions in liver and kidney, and reduced endotoxemia-associated mortality. Taken together, IRAK-1 may, at least in part, serve as an important therapeutic target in the treatment of various inflammatory disease processes. / Ph. D.

Dans la littérature, plusieurs hypothèses étiologiques de démence ont été émises, notamment l'apport alimentaire en acides gras trans, une exposition modifiable. Le présent projet de recherche visait à évaluer l'association entre les pourcentages d'acides gras trans des membranes érythrocytaires et le risque de déclin cognitif et de démence à partir des données biologiques des sujets qui ont participé à l'Étude sur la santé et le vieillissement au Canada (ESVC). L’ESVC est une étude de cohorte longitudinale de trois phases sur 10 ans (1991/92 – 2001/02) incluant au départ 10 263 sujets, un échantillon représentatif de la population âgée canadienne de 65 ans et plus. Les échantillons sanguins d’un souséchantillon de 664 sujets, initialement cognitivement normaux, ont été mesurés pour leur composition en acides gras trans. De ces sujets, 151 ont développé une démence en cours de suivi dont 107 cas de maladie d’Alzheimer et 30 cas de démence vasculaire. Une imputation multiple a permis de traiter les données manquantes pour un échantillon final de 670 sujets. Des modèles de régression de Cox et de régression à mesures répétées, ajustés pour plusieurs facteurs de confusion potentiels ont été créés pour évaluer les associations entre les acides gras trans (naturels et totaux) et les issues cognitives (démence tous types, maladie d’Alzheimer, démence vasculaire et déclin cognitif basé sur les scores du Modified Mini-Mental State Examination). Tous les résultats étaient négatifs. Toutefois, les données de l’ESVC ne permettaient pas de trancher sur le caractère nocif des acides gras trans de type industriel étant la quasi absence d’acides gras trans industriels spécifiques dans le jeu de données de cet échantillon. En conclusion, les résultats de ce projet de recherche ne montrent pas de lien entre les acides gras trans et le déclin cognitif chez les personnes âgées.

In recent years, there have been a number of studies looking at inhibition of microorganisms by spices, herbs or their extracts.  Many of these products have been shown to have antimicrobial activity against foodborne pathogens.  The purpose of this research was to evaluate the antimicrobial activity of three essential oil (EO) compounds (thymol, eugenol, and trans-cinnamaldehyde) alone and in combination with three naturally-occurring apple aroma (AA) compounds (hexanal, trans-2-hexenal and 1-hexanol) to identify the minimum inhibitory concentrations necessary to inhibit E. coli O157:H7.  Three commercial apple juice flavoring mixtures (natural apple cinnamon, natural apple spice and natural red apple) were additionally tested alone for antimicrobial activity against E. coli O157:H7. The standard agar dilution method (SAD) and checkerboard assay were used to evaluate the efficacy of the nine compounds, alone and in combination against E. coli O157:H7.  In general, the EO compounds were significantly more effective against E. coli O157:H7 than the AA compounds (P<0.05).  Cinnamaldehye, with an MIC of 0.2 mg/mL, exhibited the highest degree of activity, followed by thymol, eugenol and trans-2-hexenal, which each had individual MIC values of 1.6 mg/mL.  No synergism was found in the combinations of EO compounds with AA compounds. / Master of Science in Life Sciences

Yes / Objectives: This study aimed to determine the impact on radiation dose and image quality of a new cardiac interventional X-ray system for trans-catheter aortic valve implantation (TAVI) patients compared to the previously-used cardiac X-ray system. Methods: Patient dose and image data were retrospectively collected from a Philips AlluraClarity (new) and Siemens Axion Artis (reference) X-ray system. Patient dose area product (DAP) and fluoroscopy duration of 41 patient cases from each X-ray system were compared using a Wilcoxon test. Ten patient aortograms from each X-ray system were scored by 32 observers on a continuous scale to assess the clinical image quality at the given phase of the TAVI procedure. Scores were dichotomised by acceptability and analysed using a Chi-squared test. Results: Significant reductions in patient dose (p<<0.001) were found for the new system with no significant change in fluoroscopy duration (p=0.052); procedure DAP reduced by 55%, fluoroscopy DAP by 48% and “cine” acquisition DAP by 61%. There was no significant difference between image quality scores of the two X-ray systems (p=0.06). Conclusions: The new cardiac X-ray system demonstrated a very significant reduction in patient dose with no loss of clinical image quality. Advances in Knowledge: The huge growth of TAVI may impact on the radiation exposure of cardiac patients and particularly on operators including anaesthetists; cumulative exposure of interventional cardiologists performing high volume TAVI over 30-40 years may be harmful. The Phillips Clarity upgrade including improved image enhancement and optimised X-ray settings significantly reduced radiation without reducing clinically acceptable image quality.

Yes / Background Walking down slopes and/or over uneven terrain is problematic for unilateral trans-tibial amputees. Accordingly, ‘ankle’ devices have been added to some dynamic-response feet. This study determined whether use of a microprocessor controlled passive-articulating hydraulic ankle–foot device improved the gait biomechanics of ramp descent in comparison to conventional ankle–foot mechanisms. Methods Nine active unilateral trans-tibial amputees repeatedly walked down a 5° ramp, using a hydraulic ankle–foot with microprocessor active or inactive or using a comparable foot with rubber ball-joint (elastic) ‘ankle’ device. When inactive the hydraulic unit's resistances were those deemed to be optimum for level-ground walking, and when active, the plantar- and dorsi-flexion resistances switched to a ramp-descent mode. Residual limb kinematics, joints moments/powers and prosthetic foot power absorption/return were compared across ankle types using ANOVA. Findings Foot-flat was attained fastest with the elastic foot and second fastest with the active hydraulic foot (P < 0.001). Prosthetic shank single-support mean rotation velocity (p = 0.006), and the flexion (P < 0.001) and negative work done at the residual knee (P = 0.08) were reduced, and negative work done by the ankle–foot increased (P < 0.001) when using the active hydraulic compared to the other two ankle types. Interpretation The greater negative ‘ankle’ work done when using the active hydraulic compared to other two ankle types, explains why there was a corresponding reduction in flexion and negative work at the residual knee. These findings suggest that use of a microprocessor controlled hydraulic foot will reduce the biomechanical compensations used to walk down slopes.

c/o is a space that carries and amplifies queer voices. It's a place for organising, discussing and creating collectively, where activities will be held that promotes publishing as activism. c/o explores how queer archives and personal printed matter can be used as means for care and resistance, with the purpose to build a framework and community for publishing and activism. This is achieved through resource sharing, DIY or DIT zine culture and protest typography. I aim to document queer resistance by translating our collective histories into contemporary communication with a queered expression. I believe this to be a way to imagine/enable alternative futures that challenge conventional ideals in favour of queer realities.

This master’s thesis investigates normative lifelines, time and space in relation to a nonbinary gender identity. My research questions focused on nonbinary aging, orientation in regards to identity and spaces, and views on maturity. I wanted to know how temporality and spatiality can be used as a theoretic framework to better understand nonbinary people’s experiences. This was achieved by interviewing seven Swedish nonbinary subjects aged 30-41 about norms regarding time and place. The results show that the nonbinary informants use gender norms to orient themselves in relation to gender identity. Aging is shown to be a gendered practice and therefore nonbinary aging and what the future will hold is made unclear for the participants. Nonbinary people seek not to be a hindrance or annoyance to the outside world and are aware that their identity often is viewed as childish, made up and illegitimate. Despite fears that they take up too much space I have shown that there is not enough space for nonbinary subjects to comfortably find a place in most rooms.

The aim of this thesis was to determine the biomechanical adaptations made by active unilateral trans-tibial amputees when they used a prosthesis incorporating a hydraulically-damped, articulating ankle-foot device compared to non-hydraulically attached devices. Kinematic and kinetic data were recorded while participants ambulated over a flat and level surface at their customary walking speeds and at speeds they perceived to be faster and slower using the hydraulic device and their habitual foot. Use of the hydraulic device resulted in increases in self-selected walking speeds with a simultaneous reduction in intact-limb work per meter travelled. Use of the device also attenuated inappropriate fluctuations in the centre-of-pressure trajectory beneath the prosthetic foot and facilitated increased residual-knee loading-response flexion and prosthetic-limb load bearing during stance. These changes occurred despite the hydraulic device absorbing more, and returning less, energy than the participants’ habitual ankle-foot devices. The changes were present across all walking speeds but were greatest at customary walking speeds. The findings suggest that a hydraulic ankle-foot device has mechanical benefits, during overground gait, for active unilateral trans-tibial amputees compared to other attachment methods. The findings also highlight that prosthetic ankle-foot device ‘performance’ can be evaluated using surrogate measures and without modelling an ‘ankle joint’ on the prosthetic limb.