no / Agents which increase intracellular cyclic adenosine monophosphate (cAMP) may have an antagonistic effect on pro-inflammatory molecule production so that inhibitors of the cAMP degrading phosphodiesterases have been identified as promising drugs in chronic inflammatory disorders. Although many such inhibitors have been developed, their introduction in the clinic has been hampered by their narrow therapeutic window with side effects such as nausea and emesis occurring at sub-therapeutic levels. The latest generation of inhibitors selective for phosphodiesterase 4 (PDE4), such as apremilast and roflumilast, seems to have an improved therapeutic index. While roflumilast has been approved for the treatment of exacerbated chronic obstructive pulmonary disease (COPD), apremilast shows promising activity in dermatological and rheumatological conditions. Studies in psoriasis and psoriatic arthritis have demonstrated clinical activity of apremilast. Efficacy in psoriasis is probably equivalent to methotrexate but less than that of monoclonal antibody inhibitors of tumour necrosis factor (TNFi). Similarly, in psoriatic arthritis efficacy is less than that of TNF inhibitors. PDE4 inhibitors hold the promise to broaden the portfolio of anti-inflammatory therapeutic approaches in a range of chronic inflammatory diseases which may include granulomatous skin diseases, some subtypes of chronic eczema and probably cutaneous lupus erythematosus. In this review, the authors highlight the mode of action of PDE4 inhibitors on skin and joint inflammatory responses and discuss their future role in clinical practice. Current developments in the field including the development of topical applications and the development of PDE4 inhibitors which specifically target the subform PDE4B will be discussed.

Les basophiles sont les granulocytes les plus rares. Ils sont impliqués dans la polarisation des réponses immunitaires de type Th2, dans la différenciation des lymphocytes B et dans la protection contre les infections helminthiques. Les basophiles sont impliqués dans la modulation des réponses immunitaires, en particulier dans les maladies auto-immunes et inflammatoires. Des études récentes ont montré que les basophiles murins sont cellules présentatrices d’antigène (CPA) et induisent des réponses Th2 et IgE contre les allergènes et les infections helminthiques.Par conséquent, Nous avons exploré les fonctions des basophiles humains, en particulier comme CPA professionnelles. Les résultats montrent que les basophiles, contrairement aux cellules dendritiques et monocytes, n’expriment pas HLA-DR et les marqueurs de co-stimulations CD80 et CD86. De plus, la stimulation des basophiles par divers allergènes, comme des ligands de TLR et IgE, n’induit pas des changements dans l’expression de ces marqueurs. Enfin, nos résultats montrent que les basophiles ne favorise pas les réponses immunitaire de type Th2 ou Th17. Ainsi,notre étude montre que les basophiles humains circulant ne possèdent pas des fonctions de CPA professionnelles. Des plus, les basophiles sont impliqués dans la pathogenèse de maladies auto-immunes et inflammatoires dépendantes des réponses Th2 et médiées par les lymphocytes B. Puisque la dérégulation des basophiles joue un rôle important dans le développement des réponses immunitaires dans différentes conditions pathologiques, nous avons exploré les mécanismes de régulations qui modulent les fonctions les basophiles. En particulier, nous avons étudié le rôle suppresseur des lymphocytes T régulateurs (Tregs) CD4+CD25+FoxP3, des cellules clés dans la maintenance de l’homéostasie immune, sur les fonctions des basophiles. Nos résultats montrent que les fonctions des basophiles, contrairement à la majorité des cellules immunes, ne sont pas régulées par les Tregs. Bien au contraire, nos résultats montrent que les lymphocytes T favorisent l’activation des basophiles. En résumé, nous avons exploré de nouveaux mécanismes cellulaires et moléculaires impliqués dans la régulation des fonctions des basophiles humains. Ces résultats nous permettent de mieux comprendre le rôle des basophiles dans les conditions inflammatoires et dans le développement de nouvelles stratégies thérapeutiques. / Basophils are the rare granulocytes and play an important role in the polarization of Th2 responses, differentiation of B cells and protection against helminths. Basophils have a major influence on immune responses and various roles of these cells in autoimmune and inflammatory diseases are emerging. Recent reports showed that murine basophils function as antigen presenting cells (APCs) to induce Th2 and IgE responses to allergens and helminths. Therefore, I explored whether human basophils possess the features of APCs. I found that unlike dendritic cells (DCs) and monocytes, steady-state circulating human basophils did not express HLA-DR and co-stimulatory molecules CD80 and CD86. Basophils remained negative for these molecules following stimulation with various allergens, toll-like receptor ligands and IgE cross-linking.Unlike DCs, basophils did not promote Th2 and Th17 responses. Together, these results demonstrate the inability of circulating human basophils to function as professional APC. Further, basophils were also reported to be implicated in the pathogenesis of Th2 –associated and B cell-mediated autoimmune and inflammatory diseases. Considering the impact of dysregulated function of basophils on the outcome immune responses in various pathological conditions, it was essential to investigate the regulatory mechanisms by which basophil functions are kept in check. As CD4+CD25+FoxP3+ regulatory T cells (Tregs) are critical for the maintenance of immune homeostasis, I sought to investigate the interaction of Tregs with human basophils and its repercussion on basophil functions. My results indicated that unlike other immune cells that aresusceptible to Treg-mediated suppression, basophils are refractory to regulatory mechanism of Tregs. On the contrary I found that T cells could promote activation of basophils. My results thus provided an insight on cellular and molecular basis of regulation of human basophil functions. These data will have a repercussion in understanding role of basophils ininflammatory conditions and in designing therapeutic strategies.

Introduction : La résistance aux antibiotiques est une menace de santé, il est donc urgent de développer de nouveaux antibactériens. CIN-102, est un nouvel antibactérien développé par une industrie pharmaceutique. Il possède un large-spectre d’action et aucune résistance n’a été développée jusqu’à présent. Parmi les possibles applications thérapeutiques du CIN-102, notre recherche s’est focalisée sur les Maladies Inflammatoires Chroniques de l’Intestin (MICIs). Plusieurs facteurs contribuent à l’étiologie des MICIs. Les bactéries intestinales jouent un rôle important dans ces maladies et une augmentation de la charge bactérienne est observée pendant l’inflammation. Les objectifs de ce travail ont été : la caractérisation de l’activité antibactérienne du CIN-102, l’analyse de l’activité antibactérienne des agents anti-inflammatoires et antibiotiques utilisés en cas de MICI et la fabrication des formulations à ciblage colique pour le CIN-102. Le but est de diminuer la charge bactérienne colique par moyen du CIN-102 et améliorer, de cette façon, l’état de l’inflammation.Méthodes: La Concentration Minimale Inhibitrice (CMI), l’Effet Post-Antibiotique (EPA) et le temps de réduction logarithmique du CIN-102 ont été déterminés pour des bactéries aérobies et anaérobies. Les interactions entre le CIN-102 et des antibiotiques sur le marché ont été évaluées. La CMI de l’acide 5-aminosalicylique (5-ASA), GED-0507-34 et antibiotiques ont été déterminées pour des souches anaérobiques. Par rapport aux formulations à libération prolongée : des mini-granules contenant le CIN-102 ont été fabriqués par extrusion-sphéronisation puis pelliculés avec des mélanges de polymères insolubles et polysaccharides. Parallèlement, des mini-comprimés de CIN-102 ont été fabriqués par compression directe. La libération du CIN-102 in vitro, a été mesurée dans des milieux simulant l’estomac et l’intestin grêle. L’efficacité des systèmes à libération prolongée a été évaluée dans un modèle de colite chez la souris. Des prélèvements de selles et tissus coliques ont été soumis à des études bactériologiques. L’expression des cytokines a été mesurée à partir des tissus coliques.Résultats et discussion : Le large-spectre d’action du CIN-102 a été confirmé. Toutes les souches ont été inhibées par le CIN-102. CIN-102 présente un EPA et un temps de réduction logarithmique court. Il présente des interactions synergiques avec plusieurs antibiotiques, notamment la colistine et les aminoglycosides, en les rendant actifs contre des bactéries multirésistantes. Ces résultats in vitro doivent être poursuivis par des études chez l’animal. Des agents anti-inflammatoires utilisés contre les MICIs ne possèdent pas d’activité antibactérienne. Par ailleurs, les antibiotiques testés n’ont pas un large-spectre d’action contre des bactéries anaérobies généralement retrouvées dans l’intestin. Cela confirme le besoin d’un antibiotique à large spectre capable de réduire des charges bactériennes en cas d’inflammation. Dans ce but, des formulations capables de délivrer CIN-102 au niveau du colon ont été étudiées. La libération du CIN-102 des mini-granules pelliculés et mini-comprimés a été réduite dans des milieux simulant l’estomac et l’intestin grêle. Des souris atteintes de colite et traitées avec les formulations du CIN-102 ont eu une diminution des diarrhées et du sang dans les selles. Les concentrations d’entérobactéries adhérentes à la muqueuse colique et dans les selles ont été significativement réduites chez les souris traitées avec le CIN-102. Ces résultats montrent que ces formulations peuvent délivrer CIN-102 dans le tractus gastro-intestinal inferieur, et que la diminution d’entérobactéries semble réduire les symptômes de la colite.Conclusion : CIN-102 est un nouvel antibactérien a large-spectre et des formulations à libération prolongée peuvent délivrer cet agent dans le colon, diminuant la charge d’entérobactéries qui pourrait influencer l’état de l’inflammation. / Introduction: Antibiotic resistance is a major threat to public health and new antimicrobials are urgently needed. CIN-102, a new antibacterial agent which resembles cinnamon essential oils composition, was developed by a pharmaceutical company. CIN-102 had a broad-spectrum of action and resistance was not developed until now. Between all the possible therapeutic applications for CIN-102, a future utilization against Inflammatory Bowel Diseases (IBD) is aimed. IBD are chronic pathologies with a multifactorial etiology. In this context, enteric bacteria are well-known to have an important role, and higher bacterial concentrations are found in the intestine under inflammatory conditions. The objectives of this work were: to characterize the bacteriological activity of CIN-102, to analyze the bacteriological activity of anti-inflammatory agents and antibiotics used in IBD and to fabricate multiparticulate CIN-102 pharmaceutical forms for colonic targeted drug release. The idea is to use CIN-102 to reduce colonic bacterial loads and improve the state of intestinal inflammation. Methodology: The Minimal Inhibitory Concentration (MIC), the Post-Antibiotic Effect (PAE) and the logarithmic reduction time of CIN-102 were determined against several aerobic and anaerobic bacterial isolates. The interactions between CIN-102 and commercialized antibiotics were evaluated. The MIC of 5-aminosalicilyc acid, GED-0507-34 and antibiotics were determined for anaerobic bacterial isolates. Concerning sustained released formulations: CIN-102 pellet cores were fabricated by extrusion-spheronization and subsequently coated with blends of insoluble polymers and natural biodegradable polysaccharides. CIN-102 mini-tablets were fabricated by direct compression. In vitro drug released was measured in simulated gastric and intestinal fluid. The efficacy of best sustained release formulations was assessed in a murine model of colitis. Samples of luminal contents and sections of the colon were taken to perform a bacteriological analysis. Expression of cytokines was analyzed from colonic tissues.Results and discussion: The broad-spectrum activity of CIN-102 was confirmed. All aerobic and anaerobic strains were susceptible to CIN-102. Furthermore, CIN-102 had an important PAE and exerted a fast logarithmic reduction of bacterial inoculum. It interacts synergistically with several antibiotics, mostly with colistin and aminoglycosides, restoring the antibiotic activity against multi-resistant bacteria. The promising in vitro activity of CIN-102 has to be further confirmed by animal studies. Anti-inflammatory agents used against IBD were not provided of antibacterial activity and neither of the antibiotics tested possessed a broad-spectrum of action against anaerobic isolates commonly found in the intestine. These results confirm the need of a broad-spectrum antibiotic capable of reduced increased bacterial loads during inflammation. Following this aim, oral dosage forms able to deliver CIN-102 into the colon were studied. Concerning the sustained release forms, in vitro CIN-102 release from coated-pellets and mini-tablets was reduced in simulated gastric and intestinal fluids. Colitic mice treated with CIN-102 controlled release formulations had less diarrhea and bloody stools. Furthermore, the concentrations of enterobacteria in colonic tissue and stool were significantly reduced in CIN-102 treated mice. These results show that sustained release formulations can effectively deliver CIN-102 in the lower part of the gastrointestinal tract, where the reduction of enterobacteria seems to ameliorate the course of colitis.Conclusion: CIN-102 is novel broad-spectrum antibacterial and sustained release formulations can effectively deliver this agent into the colon, reducing bacterial loads which might influence the state of intestinal inflammation.

Syfte: Syftet med studien var att beskriva unga människors upplevelser av att leva med en inflammatorisk tarmsjukdom (IBD), samt att beskriva hur sjukdomen påverkar livskvaliteten. Vidare var syftet att beskriva artiklarnas kvalitet utifrån den metodologiska aspekten urval.Metod: Beskrivande litteraturstudie baserad på 14 vetenskapliga artiklar, som söktes i databaserna Cinahl och PubMed via Högskolan i Gävle. Sökorden som användes var: Inflammatory bowel disease, Quality of life, Chronic disease, Experience och Adolescents. Sökningarna var begränsade inom publiceringsåren 2009 - 2013.Huvudresultat: De unga människorna upplevde många olika besvärande symtom som sågs som ett hinder till ett ”normalt” liv, och symtomen visade sig ha ett samband med ungdomarnas sömnkvalitet samt ångest och depression. Sjukdomen påverkade ungdomarnas skolgång och deras fritidsaktiviteter på så vis att de ibland var tvungna att avstå. Detta kunde vara känsligt då ungdomarna ville vara som alla andra, och inte behöva sticka ut på grund av sin sjukdom. Ju mer symtom och sjukdomsaktivitet ungdomarna hade desto lägre var den hälsorelaterade livskvaliteten. Ungdomarna uppskattade den omsorg och stöd som familjen gav, speciellt stödet av föräldrarna. En relation till en högre makt/stöd av Gud, böner, meditation och avkoppling kunde även användas för att bidra till deras välmående.Slutsats: Unga människor med IBD har inte bara en kronisk tarmsjukdom, de befinner sig också i en kritisk utvecklingsperiod i livet. Upplevelserna av sjukdomen och påverkan på livskvaliteten var individuell och uppfattades på olika sätt. Fysiska, psykosociala och andliga upplevelser identifierades som kunde ge upphov till påverkan på det vardagliga livet. Avslutningsvis menar författarna till föreliggande litteraturstudie att sjuksköterskan kan ha stor nytta att känna till hur unga människor upplever sin sjukdom, och hur sjukdomen påverkar deras livskvalitet, för att på bästa sett kunna erbjuda dem god omvård. / Aim: The aim of the study was to describe young people's experiences of living with an inflammatory bowel disease (IBD), and to describe how the disease affects quality of life. A further aim was to describe the quality of the articles based on the methodological aspect selection.Methods: Descriptive literature review based on 14 scientific articles, which were searched in the databases Cinahl and PubMed via the University of Gävle. Keywords used were: Inflammatory bowel disease, Quality of life, Chronic Disease, Experience and Adolescents. The searches were limited within the publication period 2009 - 2013.Main results: The young people experienced many troubling symptoms that were seen as an obstacle to a "normal" life, and the symptoms were shown to be associated with young people's sleep quality, anxiety and depression. The disease affected young people's education and their leisure activities such that they sometimes had to abstain. This could be sensitive when young people wanted to be like everyone else, and not have to stand out because of their illness. The more symptoms and disease activity young people had, the lower was the health-related quality of life. The young people appreciated the care and support that the family gave, especially the support of the parents. A relationship to a higher power / support of God, prayers, meditation and relaxation could also be used to contribute to their well-being.Conclusion: Young people with IBD have not only a chronic bowel disease, they are also in a critical period of development in life. The experiences of the disease and the impact on quality of life were individual and perceived in different ways. Physical, psychosocial and spiritual experiences were identified that could give rise to the impact on everyday life. Finally, the authors of this literature wants to emphasize that nurses can greatly benefit from knowing how young people feel about their disease, and how the disease affects their quality of life, to provide them with good nursing.

Chronic inflammation is an essential mechanism during the development of cardiovascular and metabolic diseases. The outcome of diseases depends on the balance between the migration and accumulation of macrophages in damaged tissues. Macrophage motility is highly regulated by adhesive receptors, integrins. Namely, intermediate expression of integrin supports macrophage migration, while a high integrin density inhibits it. Our studies are focused on evaluation of the contribution of related integrins αDβ2 and αMβ2 to macrophage migration and development of chronic inflammation. We found that integrin αDβ2 is upregulated on M1-macrophages in vitro and pro-inflammatory macrophages in atherosclerotic lesions. Interestingly, the expression of ligand-sharing integrin αMβ2 remains unaltered. Using in vitro three-dimensional migration and in vivo tracking of adoptively-transferred fluorescently-labeled macrophages during the resolution of inflammation, we found that robust adhesion of M1-activated macrophages translates to weak 3D migration, which depends on the high expression of αDβ2, since αD-deficiency decreases M1-macrophage adhesion and improves macrophage migration. In contrast, αD- and αM-knockouts decrease M2-macrophages migration, demonstrating that moderate integrin expression supports cell motility. In model of high fat diet-induced diabetes, αD-deficiency prevents the retention of inflammatory macrophages in adipose tissue and improves metabolic parameters, while αM-deficiency does not affect macrophage accumulation. We detected a new ligand for integrins αMβ2 and αDβ2, 2-(ω-carboxyethyl)pyrrole (CEP). CEP is preferentially generated during inflammation-mediated oxidation and forms adduct with ECM proteins generating novel substrate for αMβ2 and αDβ2. Targeting CEP-dependent macrophage adhesion can be a useful approach to control αDβ2-mediated chronic inflammation. Using specially designed peptide library, protein-protein interaction and adhesion assay, we identified a peptide, called P5, which significantly inhibited αD-CEP binding. P5 peptide regulates macrophage migration in three-dimensional matrix in vitro and reduced macrophage accumulation during thioglycollate-induced peritoneal inflammation. Effect of P5 is completely eliminated in αD-deficient macrophages. Tracking of adoptively-transferred fluorescently-labeled WT and αD-/- monocytes in diabetic mice confirmed that αD-dependent inhibition of macrophage accumulation in adipose tissue is mediated by P5 peptide. Taken together, these results demonstrate the importance of αDβ2 and αDβ2-CEP interaction for the accumulation of infiltrating macrophages during inflammation and propose P5 peptide as a potential inhibitor of atherogenesis and diabetes.

Over the past century, the prevalence of immune-mediated inflammatory diseases (IMIDs) has increased worldwide. It has been identified that exposures to environmental factors early in life are associated with increased risk of these diseases. However, hypothesis-driven analyses do not always identify all risk or protective factors, nor do they adequately explain interactions between variables on the risk of disease. Data mining has the capability of exploring the data without considering specific a priori hypotheses, instead providing possible hypotheses for further analysis. Though, data mining techniques are still not popular among epidemiologists as a trustworthy analytical tool to analyze population-based diseases due to inexplicability of some of the methods (e.g., neural networks), unfamiliarity with, or uncommon use of machine learning and data mining methods in real-world health care applications. At the same time, large amounts of routinely collected health data are amassed as a matter of operating electronic health systems. Routinely collected health data are not collected for research purposes; however, they are great sources of information for research as a secondary use of the data. In this study, following the design science research methodology, we developed a methodology to reliably analyze health administrative data using data mining techniques to provide reproducible, reliable, and trustworthy findings. The reliable data mining methodology on health administrative data was designed in this study to address impartiality, validity, and sustainability concerns in five stages: Data Selection, Preprocessing, Modelling, Evaluation, and Feedback. As part of the main contributions, we developed two unique preprocessing guidelines as the key components of the designed methodology in order to standardize technical steps and address contextual sources of bias. While the proposed methodology is general in its design, to evaluate the designed methodology, we implemented it in several case studies on the real health administrative data housed at ICES, Ontario, first to analyze children suffering with an IMID in Ontario, predict new cases, and, most importantly, generate new hypotheses. The first case study was extended to a second one to narrow focus from all IMIDs to asthma which formed the majority of the IMID cases. Eventually, a third case study was implemented focusing on inflammatory bowel disease (IBD) and systemic autoimmune rheumatic diseases (SARDs) to better compare the findings. We applied both predictive and descriptive modelling techniques such as decision tree, neural network, logistic regression, and k-means clustering on the prepared datasets with more than 700K records and over 80 input variables. We built classification models with notable quality of performance (AUC of 68%), identified the significant factors associated to IMIDs, and extracted multifactorial rules causing protectiveness against or high risk of developing asthma, IBD, and SARDs. The factors that highly contributed to the extracted multifactorial rules were “general childhood infection”, “use of antibiotics”, “streptococcus pyogenes”, “respiratory infection”, “gastroenteritis”, “mother's prevalence of any IMID”, and “baby's sex”. The findings were evaluated and verified by health experts. Most data mining studies which are applied to health data do not handle bias and confounding in their work. However, the systematic errors were identified, and their risks were assessed in these case studies due to following the designed reliable methodology. The results with high risk of bias were reported to disregard. Therefore, this process allowed us to apply data mining techniques to discover new multifactorial rules and identify the factors with the highest impact among the 128 factors observed in the past epidemiological studies, while preserving the trust of domain experts in the results.

Macrophages are mononuclear phagocytes which derive either from blood-borne monocytes or reside as resident macrophages in peripheral (Kupffer cells of the liver, marginal zone macrophages of the spleen, alveolar macrophages of the lung) and central tissue (microglia). They occur as M1 (pro-inflammatory; classic) or M2 (anti-inflammatory; alternatively activated) phenotypes. Macrophages possess P2X7 receptors (Rs) which respond to high concentrations of extracellular ATP under pathological conditions by allowing the non-selective fluxes of cations (Na+, Ca2+, K+). Activation of P2X7Rs by still higher concentrations of ATP, especially after repetitive agonist application, leads to the opening of membrane pores permeable to ~900 Da molecules. For this effect an interaction of the P2X7R with a range of other membrane channels (e.g., P2X4R, transient receptor potential A1 [TRPA1], pannexin-1 hemichannel, ANO6 chloride channel) is required. Macrophagelocalized P2X7Rs have to be co-activated with the lipopolysaccharide-sensitive toll-like receptor 4 (TLR4) in order to induce the formation of the inflammasome 3 (NLRP3), which then activates the pro-interleukin-1 (pro-IL-1)-degrading caspase-1 to lead to IL-1 release. Moreover, inflammatory diseases (e.g., rheumatoid arthritis, Crohn’s disease, sepsis, etc.) are generated downstream of the P2X7R-induced upregulation of intracellular second messengers (e.g., phospholipase A2, p38 mitogen-activated kinase, and rho G proteins). In conclusion, P2X7Rs at macrophages appear to be important targets to preserve immune homeostasis with possible therapeutic consequences.

Psoriasis is a chronic inflammatory disease of the skin and joints. More recent data emphasize an association with dysregulated glucose and fatty acid metabolism, obesity, elevated blood pressure and cardiac disease, summarized as metabolic syndrome. TNF-a and IL-17, central players in the pathogenesis of psoriasis, are known to impair bone formation. Therefore, the relation between psoriasis and bone metabolism parameters was investigated. Two serum markers of either bone formation—N-terminal propeptide of type I procollagen (P1NP) or bone resorption—C-terminal telopeptide of type I collagen (CTX-I)—were analyzed in a cohort of patients with psoriasis vulgaris. In patients with psoriasis, P1NP serum levels were reduced compared to gender-, age-, and body mass index-matched healthy controls. CTX-I levels were indistinguishable between patients with psoriasis and controls. Consistently, induction of psoriasis-like skin inflammation in mice decreases bone volume and activity of osteoblasts. Moreover, efficient anti-psoriatic treatment improved psoriasis severity, but did not reverse decreased P1NP level suggesting that independent of efficient skin treatment psoriasis did affect bone metabolism and might favor the development of osteoporosis. Taken together, evidence is provided that bone metabolism might be affected by psoriatic inflammation, which may have consequences for future patient counseling and disease monitoring.

An increased interest in functional beverages is occurring, and omega-3 fatty acids (FA) are one of the most commonly sought ingredients to fortify such beverages. Omega-3 FA produce beneficial health effects, likely due to their anti-inflammatory properties. The majority of current omega-3 FA-fortified products include marine-derived omega-3 FA sources, often producing undesired flavors due to lipid oxidation. Little research regarding incorporation of alpha-linolenic acid in functional beverage formulation has been conducted. Alpha-linolenic acid is less susceptible to oxidation and may be a candidate to deliver omega-3 FA into the diet via functional products. Flaxseed is the richest plant source for alpha-linolenic acid; consumption may increase omega-3 FA intake and lower the omega-6:omega3 FA ratio, thereby, attenuating inflammation. Finely ground flaxseed was, therefore, incorporated into a chocolate milk foundation ("flaxmilk") to increase dietary omega-3 FA. An untrained consumer panel tasted and rated flaxmilk's palatability using a 9-point hedonic scale. A score of "6.0" ("like slightly") was targeted. A mean hedonic score of 6.35 was achieved, surpassing the targeted score and indicating an acceptable product. Sensory and analytical analyses of flaxmilk were conducted and compared to standard chocolate milk. Flaxmilk was significantly different in most physical, chemical and sensory characteristics compared to chocolate milk. A reduction in the omega-6:omega-3 FA ratio may attenuate inflammation; inflammation has been linked to osteoporosis. Thus, a secondary analysis of data collected from 202 women was conducted to estimate the dietary omega-6:omega-3 FA ratio and examine relationships between the omega-6:omega-3 FA ratio and total body and site-specific bone mineral density (BMD). The omega-6:omega-3 FA ratio had no appreciable association with any measure of BMD in the overall sample of women or in younger or older subsamples of women. In summary, consumers found flaxmilk to be an acceptable product, despite sensory and compositional differences compared to chocolate milk. The relationship between the omega-6:omega-3 FA ratio and BMD remains unclear. / Ph. D.

Heparan sulfate (HS), an unbranched sulfated carbohydrate chain, and the HS-degrading enzyme heparanase play important roles in physiological and pathological processes during all stages of life, from early embryogenesis to ageing. Accumulated information shows that HS and heparanase are involved in inflammatory processes and associated diseases, e.g. rheumatoid arthritis (RA) and Alzheimer’s disease. In this thesis I have investigated the role of HS and heparanase (Hpa) in inflammatory-related pathologies. In the first project, Hpa overexpressing mice (Hpa-tg) were induced with a murine model of RA. We found a pro-inflammatory role of Hpa through enhancing the activity of T-cells and innate immune cells, which contributed to an augmented severity of clinical symptoms in the Hpa-tg mice. In my second project, we revealed co-current interaction of heparin with both ApoA1 and SAA of HDL isolated from plasma of inflamed mouse. Mass spectrometry analysis indicated close proximity of ApoA1 and SAA on the HDL surface, providing a molecular and structural mechanism for the simultaneous binding of heparin to apoA1 and SAA. In my third project, we investigated the role of Hpa in AA amyloid formation and resolution in mice in a model of AA-amyloidosis. We found a similar degree of amyloid formation in Hpa-KO mice compared to the wildtype control mice, but the resolution process was faster in Hpa-KO mice. The rapid clearance of deposited SAA in Hpa-KO mice was associated with upregulated expression of matrix metalloproteases. The results suggest an associated function of ECM proteases with heparanase in the process of AA amyloid resolution. In my fourth project, we found that overexpression of heparanase impaired inflammation associated beta amyloid (Aβ) clearance in the brain of an Alzheimer’s disease mouse model. Examination of the cytokine profile of brain lysates revealed an overall lower inflammatory reaction in the double transgenic (tgHpa*Swe) mice compared to single APP-tg (tg-Swe) mice in response to LPS-induced inflammation.