Dissertations / Theses on the topic 'Health aspects of Omega-3 fatty acids'

[Truncated abstract] The role of fish consumption and omega-3 polyunsaturated fatty acids (PUFAs) in the prevention of disease has been the subject of much investigation in recent years. A clue that these factors might be of importance was the observation that populations consuming high levels of marine omega-3 PUFAs had lower rates of morbidity and mortality from cardiovascular disease. From there, research in this area has expanded to include a range of chronic diseases and their prevention. An area of particular interest is the role of fish consumption in the prevention of various cancers. In Australia, one in three men and one in four women are expected to be diagnosed with cancer by the age of 75. Identifying preventive factors that can be translated into constructive health promotional messages is of great importance in addressing this group of diseases that has such a large impact on the health and wellbeing of the population. ... Results and conclusions Analysis of the data from the population-based case-control study suggests a protective effect of preserved fish consumption, possibly due to the high oil content of these fish. The developed questionnaire is a valid and reliable tool for measuring fish and seafood consumption as determined by regression analysis with an independent biomarker and reliability analysis using intra-class correlation. Importantly, reliability can be maintained despite asking a high level of detail from participants. For ranking according to overall fish consumption, detailed questioning is probably not necessary, however inclusion of variables representing multiple categories of fish and seafood consumption in a regression model enables us to better account for variation in blood omega-3 PUFA levels than a single variable representing overall consumption. For the purpose of questionnaire validation, plasma phospholipid and erythrocyte membrane levels of EPA and DHA are equivalent biomarkers of fish and seafood consumption. The choice between them by future investigators will be based on more practical aspects such as convenience and the fasting state of subjects. The tangible product of this thesis is additional evidence to support a protective association between fish consumption and prostate and breast cancers, and a valid and reliable questionnaire v for measuring habitual consumption of fish and seafood in a West Australian population, that could also be applied to other populations after minor adjustment for local fish and seafood consumption patterns.

Omega-3 Flerumettede Fettsyrer og Helse – Kliniske og Molekylære Aspekter Omega-3 fettsyrer tilhører gruppen essensielle fettsyrer. Det betyr at vi ikke kan lage dem selv, men at de må tilføres gjennom kosten, hvor de bl.a. finnes i fet fisk, plantefrø, oljer og nøtter. I kroppen brukes de bl.a. som byggesteiner i hjernevev, øyet og cellemembraner, og til å lage en rekke forskjellige signalmolekyler. Studier tyder på at disse fettsyrene kan ha helsebringende effekter på mange områder, deriblant hjerte- og karsykdommer, betennelsestilstander og kreft. Et for lavt inntak av omega-3 fettsyrer er skadelig. Dagens metoder er ikke ideelle for å påvise for lavt omega-3 kostinntak. Vi har derfor undersøkt om måling av genuttrykket av Δ-6 og Δ-5 desaturaser, som er viktige i omdannelsen av fettsyrer, kan brukes som en markør på omega-3 ernæringsstatus. Vi fant at hvite blodceller i cellekultur oppregulerte genuttrykket av desaturasene når omega-3 fettsyrer manglet. Tilsvarende fant vi at genuttrykket av desaturasene var høyere hos friske forsøkspersoner som ikke spiste fiske enn hos dem som spiste fisk. Denne forskjellen forsvant etter to uker med omega-3 tilskudd. Dette indikerer at genuttrykket av desaturasene er regulert av kostinntaket av omega-3 fettsyrer, men det trengs ytterligere studier for å fastslå om dette kan benyttes diagnostisk til å påvise et for lavt kostinntak av disse essensielle fettsyrene. Flere befolkningsstudier viser at et høyt inntak av omega-3 fettsyrer er assosiert med lav forekomst av visse typer kreft. Dette er best dokumentert for bryst-, prostata- og tykktarmskreft. I cellekultur hemmer omega-3 fettsyrer vekst av kreftceller og gir programmert celledød (apoptose). Imidlertid er de molekylære mekanismene involvert uklare. Studier av genuttrykket til humane leukemiceller (HL60) behandlet med omega-3 fettsyren EPA, viste aktivering av et signalspor kalt ufoldet protein respons (UPR). Dette er en normal stress- og forsvars respons som gir cellene en mulighet til å gjenopprette likevekten og reparere skader før de fortsetter normal cellesyklus. Dersom stresset er for stort kan cellen gå i apoptose. Endringer i kalsiumnivåer i cellen kan utløse UPR. E2R2 celler, en klon av HL60 celler, er motstandsdyktige mot visse endringer i kalsiumnivået. De var mindre følsomme for EPA, og fikk ikke aktivert UPR responsen. Det er derfor sannsynlig at den veksthemmende effekten til EPA skyldes endringer i kalsiumlikevekten, som igjen aktiverer UPR responsen. Vi undersøkte også hvordan fettsyren DHA hemmer vekst av ondartede tykktarmskreftceller (SW620). Analyser av gen- og proteinutrykk viste at flere målproteiner for cellegift i kreftbehandling ble påvirket gunstig. I motsetning til cellegift, er omega-3 ufarlig og uten bivirkninger. Resultatene indikerer at omega-3 kan ha en plass i kreftbehandling, for eksempel i kombinasjon med dagens terapimetoder. Flere studier er nødvendige for å fastslå om behandling med omega-3 kan redusere bruken og/eller øke effekten av konvensjonell kreftbehandling. De foreløpige resultatene synes imidlertid allerede nå å kunne gi grunnlag for å anbefale kreftpasienter omega-3 tilskudd.

Thesis (MNutr (Interdisciplinary Health Sciences. Human Nutrition))--University of Stellenbosch, 2006.
Background At least 40 - 80% of all cancer patients develop some degree of clinical malnutrition and cachexia. The complex and multi-factorial nature of cancer cachexia and the inability of conventional nutrition intervention to reverse or attenuate the effects of this syndrome have driven investigators to consider new therapies and approaches to manage the syndrome of cancer cachexia including eicosapentaenoic acid (EPA), an n-3 fatty acid of fish oil origin. Objectives The aim of this study was to review Phase I, Phase II and Phase III (RCT) trials investigating the safety and efficacy of n-3 supplementation in the treatment of cancer cachexia in adult patients with unresectable solid tumours, with special reference to weight loss, body composition, appetite, dietary intake, energy expenditure, functional status, acute phase response and quality of life. Adverse effects associated with EPA supplementation were also reviewed. Methodology and data collection The major databases were systematically searched for studies that met the inclusion criteria using a structured keyword search strategy or various combinations of these keywords. Relevancy of studies was assessed by two independent reviewers according to pre-determined inclusion and exclusion criteria. Quality was assessed by two independent reviewers using the Jadad scale. Data extraction was performed by the principal reviewer and one of the independent reviewers, and investigators of the included studies were contacted where further information was required. Meta-analysis was not appropriate due to heterogeneity of the data. However, where possible, the paired t-test was used for analysis of the data. Descriptive or non-quantitative analysis of the tabulated data provided a summary of the characteristics of the included studies enabling comparisons to be made between interventions and outcomes within the specified population. Results The search resulted in a total of 1408 citations, of which only 16 studies met the inclusion and exclusion criteria. Of these, only 4 studies were of a good quality. Although the reported data was incomplete and variable, the combined analyses suggested that the effect of EPA supplementation on weight, fat mass, dietary intake, energy expenditure, and acute phase response was not significant. Interestingly there appeared to be a significant increase increased or decreased? in lean body mass (p<0.05). There was little or no data to draw any conclusions regarding the effect of supplementation on appetite and quality of life. Conclusion Despite several limitations in this review, the data collected and analysed are suggestive of the beneficial effects of EPA supplementation, but there remains a significant lack of substantial evidence and conclusive statistical analysis to confirm that EPA supplementation is a safe and effective method of intervention in the management of patients with cancer cachexia.

Doctor of Philosophy
Department of Human Nutrition
Mark D. Haub
Mark D. Haub
Psychological problems and human error are leading causes of death and disability among military service members. Strategies to improve the psychological health and cognitive performance of those in the military are much needed. Recent advances in neuroscience suggest that omega-3 fatty acids may play an important role in the psychological well-being of those in the military. The purpose of this research was to explore the relationship between omega-3 status and psychological outcome variables among soldiers deploying to combat. Data collection was preceded by the development and reliability testing of a novel food frequency questionnaire (FFQ) designed to capture intake from contemporary sources of omega-3 fatty acids including functional foods and supplements. Based on the instrument assessment study (Chapter 2) conducted among university students (n = 165), this FFQ appears to be a comprehensive and reliable (n = 54, ρ = 0.86, p < 0.001) instrument for measuring docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) intakes in young adults. As described in Chapter 3, intake of EPA + DHA as estimated by the FFQ was positively correlated (r = 0.39, p < 0.001) with biomarker measurements of omega-3 status. Primary data were obtained from a volunteer sample of soldiers (n = 272) scheduled for deployment to Iraq. Preliminarily analyses revealed relationships between attention deficit hyperactivity disorder (ADHD) screening scores and psychological outcome variables (Chapter 4). Primary analyses (Chapter 5) indicated intake of EPA + DHA was not significantly correlated with mood, nor were omega-3 exposure variables correlated with cognitive performance based on the required p value (< 0.001) calculated using the Bonferroni correction for multiple tests. Among participants with EPA + DHA intakes at or below the median, omega-3 HUFA was related (p < 0.002) to happiness (β = -0.46), depression (β = 0.44), and fatigue (β = 0.43). Although exploratory in nature, the results of this study suggest a relationship between omega-3 fatty acids and mood. Given the current concerns regarding the psychological health of those in the military, additional research is warranted.

Macrophages are a major source of pro-inflammatory factors in the arterial intima and play a central role in the development of atherosclerotic plaque. Macrophages express toll-like receptor 4 (TLR4), a plasma membrane receptor, which when activated triggers the nuclear factor κB (NFκB) and mitogen-activated protein kinase signaling pathways leading to the production of pro-inflammatory cytokines. TLR4 expression and signaling have been positively associated with atherosclerotic lesion formation. Very long-chain polyunsaturated fatty acids, specifically, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have anti-inflammatory effects on macrophages, while saturated fatty acids have pro-inflammatory effects. However, the effect of enriching macrophages with EPA, DHA, or a saturated fatty acid on TLR4 cell surface expression and TLR4-mediated production of pro-inflammatory cytokines is not well characterized. We hypothesized that the production of pro-inflammatory cytokines would be downregulated in EPA- or DHA-enriched macrophages stimulated with TLR4 ligand, which may be mediated by a reduction in cell surface expression of TLR4 and its associated molecules CD14 and MD2, while enrichment of macrophages with a saturated fatty acid would have the opposite effect.

The objective of this thesis was to use the murine macrophage cell line, RAW 264.7 to determine the effect of enriching the cell membrane with EPA, DHA, or a saturated fatty acid, myristic acid (MA), on TNFα and IL-6 production, cell surface expression of TLR4, and associated molecules CD14 and MD2 induced by ultra-pure LPS stimulation (a TLR4-specific agonist). The involvement of cAMP response element-binding protein (CREB), prostaglandin E₂ (PGE₂) and nuclear factor κB (NFκB) in mediating the differential effect of DHA on TNFα and IL-6 production were also studied.

EPA- and DHA-enrichment decreased the inflammatory response of RAW 264.7 cells to ultra-pure LPS stimulation relative to control cells: a reduction in TNFα, IL-6 and PGE₂ production, as well as NFκB activity was observed. In contrast, MA-enrichment did not potentiate the effect of ultra-pure LPS relative to control cells. EPA and DHA had a greater inhibitory effect on IL-6 compared to TNFα in both secretion and mRNA expression. This suggests an interference of signaling downstream of TLR4. Focusing on DHA, we found no effect on cell surface expression of TLR4, TLR4-MD2 complex or CD14, or the level of LPS-cell binding. Since NFκB is a major positive regulator of both TNFα and IL-6 gene transcription, we hypothesized that the weaker inhibitory effect of DHA on TNFα compared to IL-6 production may be due to the decrease in PGE₂ production, since PGE₂ has been previously reported to inhibit TNFα (possibly through the activation of CREB), and enhance IL-6 production. Addition of exogenous PGE₂ had a dose-dependent inhibitory effect on TNFα mRNA expression after 3 h of stimulation, but only at concentrations higher than that found to be secreted by our cells. However, inhibiting PGE₂ production by a cyclooxygenase 2 inhibitor also resulted in a small reduction in TNFα mRNA levels after 3 h but not 6 h of stimulation, suggesting that PGE₂ had a minor stimulatory effect (if any) on TNFα production under the conditions evaluated in our system. Neither increasing nor decreasing PGE₂ concentration had any effect on IL-6 mRNA expression. Although these data confirm differential regulation of TNFα and IL-6 by PGE₂, it does not seem to be likely that a reduced PGE ₂ production potentially induced by DHA is a significant contributing factor to the observed weak inhibitory effect of DHA on TNFα production. Since DHA had no significant effect on CREB activity, the involvement of this transcription factor in the DHA-induced inhibition of TNFα and IL-6 was not pursued. The effect of chemically reducing NFκB activity resulted in a larger inhibitory effect on IL-6 compared to TNFα mRNA expression, which is similar to the effect of DHA. These data suggest that the differential effect of DHA on TNFα and IL-6 mRNA expression may be mediated primarily by a reduction in NFκB activity, and that regulatory mechanisms are partially different between the TNFα and IL-6 genes.

The results of this research add to the current understanding of the effect of very-long chain polyunsaturated fatty acids and saturated fatty acids on TLR4 activation and signaling, and address the cytokine-specific effects of EPA and DHA in TLR4-activated macrophages. These data will advance the efforts to develop more specifically defined anti-inflammatory effects of EPA and DHA, which will lead to better understanding of the influence of EPA and DHA on atherosclerotic lesion progression.

Multiple sclerosis is an inflammatory and demyelinating multifactorial disease that results from the interplay between environmental factors and a susceptible genetic background. Omega (ω)-3/ω-6 polyunsaturated fatty acids (PUFAs) and some vitamins have been shown to reduce the number and severity of relapses and the overall progression of disability in multiple sclerosis patients, however clinical trials remain inconclusive due to a plethora of reasons. In this randomized, double blinded, placebo controlled trial aiming to provide concrete conclusions for the role of PUFAs and vitamins A and E (both gamma (γ) and alpha (α)) in multiple sclerosis. By measuring the incorporation and changes of the lipid composition in red blood cell (RBC) membranes before and after the dietary intervention, and by correlating the efficacy of the different interventions with disease progression, it was shown that supplementation with these specific molecules (that can either act on their own or synergistically) could probably cause the decrease of arachidonic acid (AA) and linoleic acid (LA) from the RBC membranes and the subsequent substitution by eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These events parallel the clinical observations where this can be correlated with the increased number of relapse activity occurring in the first six months of treatment and later with a prolonged period of remission. Supplementation with the mixture of PUFAs (both ω3 and ω6), vitamin E as gamma tocopherol significantly reduced the annualised relapse rate (ARR) and the risk of sustained disability progression without any reported serious adverse events.

The purpose of this study was to determine if supplementation of two grams of fish oil for 90 days would significantly lower cardiovascular disease (CVD) risk in Hispanics with type 2 diabetes. The Hispanic American population is at an increased risk for CVD. Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) in fish oil have been found to reduce risk of CVD. Subjects were randomly divided into two groups and received either two grams of fish oil or corn oil (control) per day for 90 days. Before and after the trial, participant blood lipids and plasma fatty acids were evaluated. Respired air samples were obtained to evaluate plasma fatty acids. Although analysis of blood lipids and plasma fatty acids did not show sufficient evidence to disprove the null hypothesis, this study is an important model for future studies concerning fish oil to lower CVD risk in Hispanics with type 2 diabetes.

Background: Gestational diabetes mellitus (GDM) has adverse effects on the level of docosahexaenoic acid (DHA) in phospholipids of maternal and cord red blood cells and cord plasma. This finding was of major concern because DHA is vital for maternal wellbeing and health, and for optimal development of foetal brain and retina. GDM is also associated with increased oxidative stress. There is controversy about omega-3 LCPUFA supplementation and oxidative damage. This ambiguity needs to be explored to reveal its role as modulator of oxidative stress in GDM. Specific Aims: To investigate if (1) GDM adversely affects the plasma omega-3 and omega-6 long-chain polyunsaturated fatty acid (LCPUFA) levels in pregnant women. (2) High BMI is associated with adverse plasma fatty acid profile in GDM women. (3) Supplementation with DHA-enriched formula, enhances the level of the nutrient in the GDM women and their neonates. (4) Antioxidant vitamins status is enhanced by DHA-enriched supplementation in GDM women and their newborns. Methods: Women with (n = 142; 72 active-group, 70 placebo) and without gestational diabetes (n = 28; 10 active-group, 18 placebo) were supplemented from the recruitment (at Newham University Hospital, London) until delivery. Both active- and placebo-groups received 2 capsules of either DHA-enriched formula or high oleic acid sunflower seed oil respectively. Each active supplement capsule contained 300 mg of DHA, 42 mg of eicosapentaenoic acid (EPA) and 8.4 mg of AA, and placebo 721 mg of oleic acid. Blood samples taken from the mothers at recruitment and delivery (maternal and cord) were analysed for plasma fatty acid composition and antioxidant vitamins levels. Results: At recruitment, no significant difference was found in the DHA level in plasma phospholipids (CPG, 4.9% vs. 4.4%, P > 0.05) and neutral lipids (CE, 0.9% vs. 0.9%, P > 0.05), (TG, 0.9% vs. 0.9%, P > 0.05) between healthy pregnant and GDM women respectively. When categorized on the basis of their BMI, obese and over-weight GDM women had lower omega-3 (ALA, P < 0.05) and higher omega-6 PUFA (AA, P < 0.05) levels as compared to normal-weight GDM women. A total of 140 women completed the trial. GDM active-group compared with GDM placebo-group had significantly higher percentage of DHA in plasma CPG (4.4% vs. 3.7%, P < 0.05), CE (1.1% vs. 0.9%, P < 0.05), and TG (1.2% vs. 0.8%, P < 0.05) at delivery. There was no significant difference in the cord plasma [CPG (5.4% vs. 5.8%, P > 0.05), CE (1.1% vs. 1.0%, P > 0.05), TG (2.9% vs. 3.3%, P > 0.05)] DHA between GDM placebo and active-treatment groups. Though not significantly, the levels of vitamin A and β-carotene were reduced, however, the level of vitamin E was comparable between GDM and healthy pregnant women, at recruitment (P > 0.05). At delivery, no significant difference was found in maternal plasma vitamin A (21.1 μg/dl vs. 18.0 μg/dl, P > 0.05), vitamin E (1.4 mg/dl vs. 1.4 mg/dl, P > 0.05) and β-carotene (16.1 μg/dl vs. 11.1 μg/dl, P > 0.05) levels between GDM placebo- and active-treatment groups. Neonatal plasma antioxidant vitamins levels were also comparable between GDM active-treatment and placebo groups (P > 0.05). Conclusion: The present study shows that the plasma DHA and AA levels are not compromised by gestational diabetes in pregnant women. It may be that the comparable plasma DHA and AA levels observed in the GDM women is linked to a failure to incorporate these fatty acids into the phospholipids of the red cell membrane and/or impaired placental transport. Moreover, the majority of samples were collected during the third trimester (between 28-32 weeks), so it is plausible that the duration of the diabetes was very short to produce an obvious adverse effect on the plasma DHA and AA levels. Additionally, this study shows that higher pre-pregnancy BMI is associated with higher n-6 PUFA and lower n-3 PUFA levels in GDM women. However, it is difficult to establish whether BMI causes adverse fatty acids profile, or whether the direction of this association is reversed. This unique study also demonstrated that supplementation with a daily dose of DHA (600mg) from diagnosis until delivery was effective in enhancing the level of the nutrient in plasma of GDM women but not foetal. The inefficacy of the supplement to improve foetal status suggests that the transfer of DHA across the placenta may be impaired in the GDM women. This finding has implications for the management of neonates born to GDM women because they are born with a lower level of DHA and the condition is considered to be linked with a risk of neuro-developmental deficit. We suggest that the provision of a DHA supplement should be integrated with the antenatal care of pregnant women with gestational diabetes to optimize foetal development and avert maternal DHA depletion in pregnancy. Also, the babies of the GDM women, particularly those not sucking mother’s milk, similar to those who born prematurely require formula milk containing a higher level of DHA. This study demonstrates that DHA-enriched supplement did not improve yet not deteriorate the antioxidant vitamins status in GDM women. This may be because of small dose and short duration of supplementation. We can allude that the moderate amounts of omega-3 LCPUFA in dietary intake for longer duration may reduce the incidence and complications associated with oxidative stress in diabetic pregnancy.

Introduktion: Torra ögon (DES) och Sjögrens syndrom (SjS) är inflammatoriska sjukdomar som drabbar ögonen. DES drabbar tårkörtelns funktionella del vilket ger ögonsmärta och suddig syn. SjS är en kronisk autoimmun sjukdom som ger skada på tår- och salivproducerande körtlar. Det leder till kliniska symtom i form av mun- och ögontorrhet. Essentiella fettsyror bildar proinflammatoriska och antiinflammatoriska cytokiner som kan hjälpa vid behandling av dessa sjukdomar. Metod och syfte: En litteraturstudie genomfördes för att ta reda på om fleromättade fetter kan lindra symtomen vid SjS och DES. Resultat: Resultaten för studierna visade resultat på OSDI, Schirmers test, BUT, IL-17, tårosmolaritet, tårvolym, ostimulerat salivflöde, stimulerat salivflöde, sonderingsdjup, PGE1, van Bijstervelds poäng och flourscein infärgning. Diskussion: Resultatet visar signifikanta skillnader för vissa doser av n-3 och n-6. Det som skiljer resultaten åt är de olika doserna av fettsyror samt vad dess placebokontroller intog. OSDI visade främst skillnader på de patienter med DES men endast på en grupp med SjS som intog n-3 för behandling av torr mun. Schirmers test och BUT visade en ökning hos patienterna med mild och måttlig DES men inte på patienterna med SjS. Patienterna med SjS visade förbättringar på stimulerat salivflöde och OSDI för torr mun samt PGE1 nivåer och flourscein infärgning samtidigt som en del studier inte visade några signifikanta förbättringar på några mätvariabler. Det kan grunda sig i intaget av fettsyror, sjukdomstillstånd eller längden på behandling. Slutsats: En del personer kan få förbättrade symtom av att inta n-3 eller n-6 tillskott men skillnaderna är inte alltid statistiskt signifikanta för studierna.
Introduction: Dry eye syndrome (DES) and Sjögren ́s syndrome (SjS) are inflammatory diseases that affect the eyes. DES affects the lacrimal glands functional unit, causing eye pain and blurred vision. SjS is a chronical autoimmune disease that causes damage to tear and salivary glands. It leads to clinical symptoms in the form of mouth and eye irritation. Essential fatty acids form pro-inflammatory and anti-inflammatory cytokines that can help in the treatment of these diseases. Method and purpose: A literature study was performed to study if essential fatty acids can relieve the symptoms of DES and SjS. Results: The results for the studies showed results on OSDI, Schirmer ́s test, BUT, IL- 17, tear osmolarity, tear volume, unstimulated salivary flow, stimulated salivary flow, depth of probing, van Bijsterveld ́s score and flourscein staining. Discussion: The result shows significant differences for certain doses of n-3 and n-6. What separates the results are the different doses of fatty acids and what their placebo controls took. OSDI showed major differences in patients with DES but only in one group of patients with SjS who took n-3 for treating dry mouth. Schirmer ́s test and BUT showed an increase in patients with mild and moderate DES but not in patients with SjS. Patients with SjS showed improvements in stimulated salivary flow, dry mouth OSDI, PGE1 levels and flourscein staining, while some studies did not show any significant improvements in any measurement variables. It may be due to the intake of fatty acids, disease states or the length of treatment. Conclusion: Some people may get improved symptoms of taking n- 3 or n-6 supplements, but the differences are not always statistically significant for the studies.

Ageing is accompanied by a progressive decline in skeletal muscle mass and strength which may lead to impaired ability to perform activities of daily living in older adults. Although the exact cause of the gradual decline in muscle mass is unknown, identifying efficient strategies aiming to prevent age-related loss of muscle mass and strength is important in order to promote healthy ageing. The overall aim of this thesis was to explore the effects of resistance training alone or combined with a healthy diet on skeletal muscle mass and function of healthy recreationally active older women and to determine mechanisms by which elevated systemic inflammation may contribute to the age-related decline of muscle mass in older adults. The combination of resistance training and a healthy diet induced gains in leg lean mass as well as greater gains in dynamic explosive force than resistance training alone in healthy recreationally active older women. The observed gains in leg lean mass were accompanied by increases in the size of type IIA muscle fibres together with down-regulation in gene expression of a pro-inflammatory factor (IL-1β) and upregulation in gene expression of a regulator of cellular growth (mTOR) in skeletal muscle of older women. Additionally, reduced muscle protein synthesis and size of muscle cells may mediate the detrimental effects of elevated circulating markers of inflammation on muscle mass in older adults. In conclusion, the present thesis depicts mechanistic links between elevated systemic marker of inflammation and muscle mass and provides new information on the effects of combined resistance training and healthy diet on muscle mass and strength in a group of healthy recreationally active older women. This knowledge is instrumental for development of strategies aiming to prevent age-related loss of muscle mass and function.

Contexte : De la conception à l'âge adulte, de nombreux déterminants environnementaux influencent le neurodéveloppement. Des études montrent que durant la fin de la grossesse et les premiers mois de vie, une grande quantité d'acides gras polyinsaturés (AGPI), notamment à longue chaîne (AGPI-LC), se fixe dans le tissu cérébral. Un apport optimal durant ces périodes critiques pourrait soutenir précocement le bon développement du cerveau et de ses fonctions.Objectifs : Étudier les relations entre les expositions pré- et postnatales précoces aux AGPI, et le neurodéveloppement d'enfants de 2 et 3 ans.Population : Les données utilisées étaient celles de l'étude EDEN, une cohorte mère enfant ayant recruté 2002 femmes enceintes dans les maternités de Nancy et Poitiers entre 2003 et 2006. L'alimentation maternelle pendant la grossesse a été évaluée par un questionnaire de fréquence alimentaire et une table de composition nutritionnelle. Quatre questionnaires postnatals ont permis d'évaluer la durée d'allaitement maternel, et la composition lipidique du colostrum des mères allaitantes a été analysée par chromatographie en phase gazeuse. Des questionnaires parentaux (2 et 3 ans) et un examen neuropsychologique (3 ans) ont permis d'évaluer plusieurs aspects du neurodéveloppement. Les analyses statistiques ont été réalisées par régressions linéaires multivariées, après ajustement sur de nombreux facteurs de confusion potentiels.Résultats : Les scores de neurodéveloppement à 2 et 3 ans des enfants allaités étaient plus élevés que ceux des enfants non allaités. Chez les enfants allaités, la durée d'allaitement maternel était associée positivement au neurodéveloppement. Le rapport n 6/n 3 dans l'alimentation maternelle en acides gras en fin de grossesse était négativement associé à plusieurs mesures du neurodéveloppement, et cette association était renforcée chez les enfants non allaités. La composition du colostrum en AGPI et en AGPI-LC reflétait amplement les apports nutritionnels en AGPI et en AGPI-LC en fin de grossesse. L'utilisation de matières grasses alimentaires était aussi associée à la composition du colostrum. Les différences de neurodéveloppement des enfants allaités ne semblait pas être expliquées par la composition du colostrum en AGPI ni en AGPI-LC, à l'exception de la teneur en acide linoléique qui était négativement associée à certaines mesures du neurodéveloppement. Dans l'ensemble, les associations avec le neurodéveloppement étaient plus fréquemment retrouvées avec les questionnaires parentaux, mais certaines évaluations par les psychologues venaient parfois conforter ces résultats.Conclusion : Associés à ceux de la littérature, ces résultats soulignent le rôle notable des AGPI durant les périodes pré- et postnatale précoce pour le neurodéveloppement de l'enfant. Le suivi des enfants de l'étude EDEN jusqu'à leur 5 ans permettra d'étudier la persistance de ces résultats. Dans une perspective de santé publique, ces travaux rappellent la nécessité de promouvoir l'allaitement maternel dans la durée et de surveiller l'équilibre des apports nutritionnels en AGPI pendant la grossesse et la période de lactation.

The desire to enhance and make ourselves better is not a new one and it has continued to intrigue throughout the ages. Individuals have continued to seek ways to improve and enhance their well-being for example through nutrition, physical exercise, education and so on. Crucial to this improvement of their well-being is improving their ability to remember. Hence, people interested in improving their well-being, are often interested in memory as well. The rationale being that memory is crucial to our well-being. The desire to improve one’s memory then is almost certainly as old as the desire to improve one’s well-being. Traditionally, people have used different means in an attempt to enhance their memories: for example in learning through storytelling, studying, and apprenticeship. In remembering through practices like mnemonics, repetition, singing, and drumming. In retaining, storing and consolidating memories through nutrition and stimulants like coffee to help keep awake; and by external aids like notepads and computers. In forgetting through rituals and rites. Recent scientific advances in biotechnology, nanotechnology, molecular biology, neuroscience, and information technologies, present a wide variety of technologies to enhance many different aspects of human functioning. Thus, some commentators have identified human enhancement as central and one of the most fascinating subject in bioethics in the last two decades. Within, this period, most of the commentators have addressed the Ethical, Social, Legal and Policy (ESLP) issues in human enhancements as a whole as opposed to specific enhancements. However, this is problematic and recently various commentators have found this to be deficient and called for a contextualized case-by-case analysis to human enhancements for example genetic enhancement, moral enhancement, and in my case memory enhancement (ME). The rationale being that the reasons for accepting/rejecting a particular enhancement vary depending on the enhancement itself. Given this enormous variation, moral and legal generalizations about all enhancement processes and technologies are unwise and they should instead be evaluated individually. Taking this as a point of departure, this research will focus specifically on making a case for ME and in doing so assessing the ESLP implications arising from ME. My analysis will draw on the already existing literature for and against enhancement, especially in part two of this thesis; but it will be novel in providing a much more in-depth analysis of ME. From this perspective, I will contribute to the ME debate through two reviews that address the question how we enhance the memory, and through four original papers discussed in part three of this thesis, where I examine and evaluate critically specific ESLP issues that arise with the use of ME. In the conclusion, I will amalgamate all my contribution to the ME debate and suggest the future direction for the ME debate.

Includes bibliographical references (leaves 237-257).
xx, 257 leaves : ill. ; 30 cm.
Title page, contents and abstract only. The complete thesis in print form is available from the University Library.
Investigates the mechanisms underlying the antiarrhythmic effects of omega-3 polyunsaturated fatty acids using adult rat ventricular cardiac myocytes.
Thesis (Ph.D.)--Adelaide University, Dept. of Physiology, 2001

The current obesity epidemic has intensified research on lifestyle interventions aimed at combating obesity and associated cardiovascular (CV) and metabolic risk. This clustering of risk factors with obesity is known as the “Metabolic Syndrome” (MS). There is now a large body of evidence detailing the ability of omega-3 fatty acids (n-3 FA) and regular moderate exercise to independently ameliorate several CV risk factors; however the combination of these interventions may be a more effective strategy in reducing CV risk than either treatment alone. This thesis describes the independent and combined effects of supplementation with docosahexaenoic acid (DHA) rich fish oil, and regular moderate exercise, on CV, metabolic and inflammatory biomarkers. Sedentary, overweight volunteers (BMI > 25kg/m2) with mild hypertension (140/90 – 160/100mmHg), elevated plasma triglycerides (TAG) (>1.6mmol/L) or elevated total cholesterol (TC) (>5.5mmol/L) were recruited in three cohorts for a 12-week intervention trial. Subjects were randomised to one of the following interventions: fish oil, fish oil and exercise, sunflower oil (placebo), sunflower oil and exercise. Subjects consumed 6 g/day of DHA-rich fish oil (26% DHA, 6% EPA; ~1.9g n-3 FA) or sunflower oil. The exercise groups walked 3 days/wk for 45 min, at 75% age-predicted maximal heart rate (HR). Outcome measures were assessed and compared across each intervention group at Weeks 0, 6 and 12, with the exception of body composition, heart rate variability (HRV) and immune functions, which were assessed at Weeks 0 and 12 only. Apart from the consumption of allocated capsules, all subjects were instructed to maintain their normal diet during the study. If not asked to exercise as part of the intervention subjects were also instructed to maintain their normal level of physical activity. Supplementation with DHA rich fish oil resulted in substantial increases in total long chain n-3 FA and DHA levels in erythrocyte membranes, accompanied by reduction of TAG, increase of high-density lipoprotein (HDL) cholesterol and reduction of superoxide production by stimulated neutrophils. Both the increase in HDL and the decrease in superoxide production were correlated with the change in erythrocyte DHA. Endothelium dependent arterial vasodilation (assessed by flow-mediated dilatation, FMD), HRV and HR response to exercise were also improved in subjects supplemented with the DHA-rich fish oil. Regular moderate intensity exercise, either alone or in addition to the DHA-rich fish oil supplementation, had no effect on these parameters, although it improved the compliance of small resistance arteries. Interestingly, however, both DHA-rich fish oil and regular exercise reduced body fat and these effects were additive when the interventions were combined. The change in fat mass was accompanied by an increase in fat oxidation during exercise, as measured by the respiratory exchange ratio. For the population as a whole, reductions in total and abdominal fat mass were associated with reductions in blood pressure. In summary, this study is the first to evaluate the metabolic and CV benefits that can be achieved by combining n-3 FA supplementation from fish oil and regular aerobic exercise in overweight/obese adults. While this combination did not produce any synergistic effects, several independent benefits were attained. The high compliance rate (>85%) within this study indicates that this intervention is well tolerated and may therefore be sustainable in the longer term. Future research should evaluate the mechanisms underlying the n-3 FA - mediated improvements in body composition.
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Thesis (PhD) -- School of Molecular and Biomedical Science, 2007

Periodontitis is an infective disease caused predominantly by gram negative anaerobic bacteria. However it is apparent that alveolar bone loss, which characterises periodontitis, is a result of the host inflammatory response to pathogenic bacteria, not the infectious agents directly. Omega-3 polyunsaturated fatty acids (O-3 PUFAs) are recognised, and used widely, for their anti-inflammatory effects. Evidence is emerging that their oxygenated derivatives are key chemical mediators in the resolution of inflammation. We hypothesised that dietary supplementation with fish oil rich in the O-3 PUFA docosahexaenoic acid would modify inflammatory reactions within the periodontium and thus reduce alveolar bone loss in mice infected with periodontopathic bacteria. Eighty mice were fed experimental diets containing either 10% tuna oil (40) or a sunola oil (40) which contained no traceable O-3 PUFAs for 57 days. After two weeks each dietary set was split into four groups of ten mice, with these groups being inoculated with either a) Porphyromas gingivalis b) P. gingivalis and Fusobacterium nucleatum (combined inoculum) c) Carboxymethylcellulose (control) or d) No inoculations (control). Of the twenty mice which received no inoculations, half were sacrificed after fifteen days and half at the end of the experiment to enable comparative fatty acid analysis of the oral soft tissues. Results demonstrated that eicosapentoic acid and docosahexaenoic acid were found in significantly higher proportions in the oral soft tissues of mice fed a tuna oil diet, and that animals receiving this diet exhibited an average of 54 - 72% less alveolar bone resorption in response to the different bacterial infections. Irrespective of diet, the combined inoculum resulted in slightly more alveolar resorption than P. gingivalis alone. The findings of this study suggest that fish oil dietary supplementation may have potential benefits as a host modulatory agent in the adjunctive management of periodontitis. Given its advantages in terms of safety, cost effectiveness and widespread availability, this dietary supplement warrants further research in human trials to assess its ability to modulate alveolar bone loss in individuals with periodontitis.
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Thesis (D.Clin.Dent.) - University of Adelaide, School of Dentistry (Periodontics), 2008

This thesis concerns the role of nutrients in cognitive and behaviour problems associated with child attention deficit hyperactivity disorder (ADHD). Study 1 investigated relationships between Conners' ADHD Index ratings, fatty acid deficiency symptoms (FADS), and cognitive performance in a normal population of children. Studies 2 and 3 comprised a 30 week intervention trial investigating effects of n-3 PUFA supplementation on ADHD symptoms in 7-12 year old children with high ADHD scores.

碩士
中山醫學大學
營養學系碩士班
101
Systemic inflammation and osteoporosis are common complications in patients with COPD (chronic obstructive pulmonary disease). The level of physical activity and quality of life could be significantly affected in severe cases. Several inflammation markers (CRP, IL-1, IL-6, IL-11 and TNF-α) have been known to enhance osteoclastic activity and bone resorption, and to inhibit bone formation on the other hand, and thus increase the risk for osteoporosis and fractures in these patients. The results of earlier studies show that omega-3 polyunsaturated fatty acids of fish oil may inhibit local inflammation, and reduce the heart rate and overall oxygen consumption when performing steady-state submaximal exercise. In addition, intervention with pulmonary rehabilitation and physical activity may be able to slow down the deterioration of lung function and improve the quality of life in COPD patients. The current study was carried out to investigate the effects of omega-3 polyunsaturated fatty acids and exercise rehabilitation on bone health status and inflammatory response in COPD patients of GOLD II to IV. Thirty subjects with COPD were recruited from the outpatient clinic of chest medicine in Chung Shan Medical University Hospital, Taichung. Daily dose of fish oil supplementation was 957 mg of EPA plus 638 mg of DHA. The duration of intervention was 6 months. All subjects were asked to record the items and length of time of their daily home-based pulmonary rehabilitation and physical activity during the intervention. Data were collected at baseline and at the third and sixth month post-intervention, including the medical history, anthropometric measurements, blood samples, questionnaire and assessment of activity capacity, and lung function measurements as well. Bone mass were measured by dual-energy X-ray absorptiometry at baseline and at the sixth month post-intervention. Venous blood samples were analyzed for serum levels of markers for bone resorption (cross-linked carboxy-terminal telopeptide of type I collagen, ICTP) and bone formation (osteocalcin, OST), as well as inflammation markers, including IL-6 (interleukin-6) and Hs-CRP (high sensitivity C-reactive protein). The results showed that the mean bone mineral density at lumbar spine and femoral neck, and inflammation markers 6 months post-intervention did not significantly differ from baseline. However, there appeared to be trends toward an increase in the result of activity capacity (six-minute walking distance) and improvement in lung function measurements, and a downward trend in St George’s Respiratory Questionnaire (SGRQ) scores was also observed. At six months post-intervention, there were also trends observed for an elevation in serum level of OST, and a decrease in serum ICTP, although not statistically significant. In conclusion, supplementation of fish oil and intervention with pulmonary rehabilitation may slow down the rate of bone loss and the deterioration of lung function, and may improve activity capacity and quality of life in patients with COPD. Whether the effects sustain or if a longer period of time for intervention is necessary to observe significant effects need to be further studied.

Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid (n-3 PUFA) required for fetal neurodevelopment. Increased DHA levels are associated with 17β-estradiol levels, as DHA is higher in women relative to men and in pregnant relative to non-pregnant women, suggesting a maternal adaptation to supply DHA to the fetus. DHA can be synthesized in the body from shorter n-3 PUFA through sequential elongation-desaturation, with Δ6-desaturase being the rate-limiting enzyme. The goal of the present thesis was to characterize the mechanism underlying higher DHA in situations of altered 17β-estradiol status by examining the expression of DHA synthesis enzymes in rodent models. Fatty acid composition of several lipid classes was measured by gas chromatography and enzyme expression was measured by RT-qPCR and immunoblotting. Hepatic Δ6-desaturase and phospholipid DHA was higher in female relative to male, and in pregnant relative to non-pregnant rats. Similarly, 17β-estradiol supplementation of ovariectomized rats resulted in increased hepatic Δ6-desaturase expression and DHA content, while ovariectomy itself had no effects on DHA levels despite controlling for hyperphagia. Mice deficient in the DNA binding activity of estrogen receptor α (ERα) had no differences in hepatic Δ6-desaturase or DHA levels. These results suggest that 17β-estradiol mediates the higher DHA levels in females and during pregnancy through increasing hepatic Δ6-desaturase expression, although the effects of removing 17β-estradiol signalling through ovariectomy or ERα disruption are less clear. This work helps to explain findings of altered DHA status in response to changes in 17β-estradiol concentrations, possibly resulting in more appropriately tailored dietary DHA recommendations. Also, increased understanding of the regulation of DHA synthesis may improve DHA yields in agri/aquaculture and enable increased content of DHA in the food supply.

Epidemiological studies have suggested that the consumption of fish may reduce the risk of cardiovascular disease. Compared to the number of studies using fish oils, few studies have used fish itself. Those which have used fish have generally used fattier fish such as mackerel and salmon as part of an uncontrolled diet. In this study, 23 healthy men consumed 200g each of Chinook salmon, Dover sole, and sablefish in a three-way crossover design for 18-day periods with three-week washout periods in between. The diets had the approximate composition of the 'Western' diet: 45% carbohydrates, 36% fat, and 16% protein with the sole diet containing 1.95 g omega-3 (n-3) fatty acids, the salmon diet 3.99 g n-3, and the sablefish diet 3.42 g n-3 fatty acids. Serum total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG), bleeding time (BT), blood pressure (BP), platelet aggregation (PA) using ADP and collagen as agonists, platelet fatty acid profiles (FAP), thromboxane B2 (TXB2) , and apolipoprotein B (Apo B) were measured at the beginning and end of each period. TC, and HDL-C, and TG changed significantly when compared to the prefish diet while both LDL-C and apo B demonstrated diet effect. LDL-C increased on both the salmon and sablefish diets (p = 0.08) compared to the sole diet, and increased approximately 15% on the former two diets compared to the prefish diet. Bleeding time was significantly longer when the salmon diet was consumed (p = 0.06). The impact of the three diets on PA depended upon the agonist. With collagen, only the sablefish diet decreased aggregation compared to the prefish diet. When ADP was used, aggregation decreased on both the fattier fish diets compared to the low fat fish (sole). Similar results were demonstrated for TXB₂: the fattier fish produced statistically equivalent decreases (p = 0.06) among the diets, and lowered TXB₂ compared to the prefish diet. There were no significant differences among the diets for either systolic or diastolic BP though there was a significant decrease (p = 0.01) in diastolic pressure compared to the prefish diet when the salmon diet was consumed. Platelet fatty acid profiles reflected diet composition.
Graduation date: 1993

Intrauterine infection with the oral commensal anaerobe Fusobacterium nucleatum has been associated with adverse pregnancy outcomes. We have previously established a mouse model to study the mechanism of hematogenous F. nucleatum leading to fetal and neonatal death. Here, we report that Toll-like Receptor 4 (TLR4) from the maternal rather than paternal, and endothelial rather than hematopoietic cells mediate placental inflammation, especially the production of the proinflammatory cytokine interleukin-1 beta. Downstream of TLR4, a spatiotemporal pattern of the transcription factor NF-kB activation was observed spreading from the decidual endothelium to the surrounding spongiotrophoblasts within the first six hours of infection. Maternal TRIF, an adaptor protein downstream of TLR4 pathway, but not NLRP3, a cytosolic signaling receptor that constitutes inflammasome complex, mediated the fetal and neonatal death. In an effort to find a prophylactic preventive method against the detrimental birth outcome induced by F. nucleatum placental infection, omega-3 fatty acids were tested for their anti-inflammatory properties. Omega-3 oil supplementation in pregnant mice inhibited the transcription and release of inflammatory cytokines, prevented fetal and neonatal death, and also suppressed the proliferation of F. nucleatum in the placenta. Moreover, omega-3 supplementation was shown to enhance neutrophil recruitment to the site of infection. However, omega-3 supplementation did not protect the pregnancy from Listeria monocytogenes infection in vivo, despite the in vitro results where inflammation induced by both Gram-negative and Gram-positive bacteria were suppressed by omega-3 fatty acids. This study presents the first direct evidence of maternal, rather than fetal, signal leading to adverse pregnancy outcome, and suggests an exciting therapeutic potential of dietary omega-3 fatty acids.

Salmon is a good source of long chain (LC) omega 3 fatty acids and selenium; these are well recognised for their health benefits. Recommendations for LC omega 3 fatty acid intakes presume equivalence between fish and fish oil. The aim of this research was to compare the effects of consuming salmon with salmon oil capsules on LC omega 3 fatty acid and selenium status. Forty four healthy subjects were randomly assigned to consume either two servings of 120 g farmed New Zealand King (FNZK) salmon/week or 2, 4 or 6 capsules of salmon oil/day for 8 weeks. Fasting blood samples, anthropometric measures, food consumption habits information and blood pressure (BP) measurements were obtained at the study commencement and ending. Each subject’s intake of LC omega 3 fatty acids and selenium was determined by analysing the fatty acid and selenium content of duplicate portions of cooked salmon and capsules. The amount of salmon consumed was then calculated by subtracting unconsumed amounts of salmon and then calculating the intake of LC omega 3 fatty acids as grams of LC omega 3 fatty acids consumed per day. Percentage of compliance to capsule intake, based on counts of unconsumed capsules, was calculated to determine the amount of LC omega 3 fatty acids consumed per day from capsules. Change in red blood cells (RBC) LC omega 3 fatty acid levels from equivalent amounts of LC omega 3 fatty acids consumed from capsules and salmon were compared using linear regression analysis predictive models fitted to the capsule data. Omega 3 index was calculated. LC omega 3 fatty acid intakes from salmon and 2, 4 and 6 capsules were 0.82, 0.24, 0.47 and 0.68 g/day, respectively. Equal amounts of LC omega 3 fatty acids consumed from salmon and capsules resulted in similar increases in RBC LC omega 3 fatty acids and omega 3 index (RBC eicosapentaenoic acid (EPA): 0.80 [0.58 – 1.02] vs. 1.00 [0.71 – 1.27] %; RBC docosahexaenoic acid (DHA): 0.93 [0.58 – 1.29] vs. 0.99 [0.68 – 1.31] %; omega 3 index: 1.92 [1.46 – 2.38] vs. 2.25 [1.65 – 2.83] %). The capsules did not contain selenium, but the salmon provided 6.84 µg selenium/day. Plasma selenium concentrations increased significantly in the salmon group compared to the capsule

Objectif: Définir l’effet des lipides et du traitement de la dyslipidémie sur les cancers de la prostate et de la vessie en utilisant différents devis d’étude et en tenant compte de la présence de plusieurs biais, particulièrement le biais du temps immortel. Devis: Le premier volet utilise un devis rétrospectif de type cas témoins. Un questionnaire semi-quantitatif de fréquence de consommation alimentaire validé a été utilisé. Le génotype COX2 de neuf polymorphisme nucléotidique unique (SNP) a été mesuré avec une plateforme Taqman. Des modèles de régression logistique non conditionnelle ont été utilisés pour comparer le risque de diagnostic d’un cancer de la prostate et l’interaction. Le deuxième volet utilise un devis rétrospectif de type cohorte basée sur les données administratives de la Régie de l’assurance-maladie du Québec (RAMQ). Des modèles de régression de Cox ont été employés pour mesurer l’association entre les statines et l’évolution du cancer de la vessie. Le troisième volet, porte un regard méthodologique sur le biais du temps immortel en examinant sa présence dans la littérature oncologique. Son importance est illustrée avec les données de la cohorte du deuxième volet, et les méthodes de correction possibles son appliquées. Résultats: L’étude du premier volet démontre qu’une diète riche en acides gras oméga-3 d’origine marine était fortement associée à un risque diminué de cancer de la prostate agressif (p<0.0001 pour la tendance). Le ratio de cote pour le cancer de la prostate du quartile supérieur d’oméga-3 était de 0.37 (IC 95% = 0.25 à 0.54). L’effet diététique était modifié par le génotype COX-2 SNP rs4648310 (p=0.002 pour l’interaction). En particulier, les hommes avec faible apport en oméga-3 et la variante rs4648310 avait un risque accru de cancer de la prostate (ratio de cote = 5.49, IC 95%=1.80 à 16.7), effet renversé par un apport en oméga-3 plus grand. L’étude du deuxième volet a observé que l’utilisation de statines est associée à une diminution du risque de progression du cancer de la vessie (risque relatif = 0.44, IC 95% = 0.20 à 0.96, p=0.039). Cette association était encore plus forte pour le décès de toute cause (HR = 0.57, 95% CI = 0.43 to 0.76, p=0.0001). L’effet des statines semble être dose-dépendant. L’étude du troisième volet démontre que le biais du temps immortel est fréquent et important dans les études épidémiologiques oncologiques. Il comporte plusieurs aspects dont certains sont mieux prévenus au stade du choix du devis d’étude et différentes méthodes statistiques permettent un contrôle de ce biais. Conclusion: 1) Une diète riche en oméga-3 aurait un effet protecteur pour le cancer de la prostate. 2) L’utilisation de statines aurait un effet protecteur sur la progression du cancer non invasif de la vessie. Les lipides semblent avoir un effet sur les cancers urologiques.
Purpose: To define the effects of dietary lipids and of treatment of dyslipidemia with statins on prostate and bladder cancers, using different epidemiologic study designs and accounting for biases, particularly immortal time bias. Study Design: The first part used a retrospective a case-control study design. Diet was assessed with a semi-quantitative food frequency questionnaire, and nine COX-2 tag single nucleotide polymorphisms (SNPs) were genotyped. We used logistic regression models to estimate odds ratios (ORs), 95% confidence intervals (CIs), and p-values for association and interaction. The second part used a retrospective cohort study design based on administrative databases of Québec, Canada. Cox regression models were used to measure association between statin use and bladder cancer evolution. The third part focuses on the immortal time bias by describing its presence in the oncologic literature. The importance of this bias is illustrated with data from the cohort used in the second part and statistical correction methods are applied. Results: The first part showed that an increasing intake of omega-3 fatty acids of marine origin was strongly associated with a decreased risk of aggressive prostate cancer (trend p<=0.0001). The OR (95% CI) for prostate cancer comparing the highest to the lowest quartile of omega-3 intake was of 0.37 (0.25 – 0.54). The dietary effect was modified by the rs4648310 COX-2 SNP (interaction p=0.02). This reflected the observation that men with low marine omega-3 intake and the variant rs4648310 SNP had an increased risk of disease (OR = 5.49; 95% CI: 1.80-16.7), which was reversed by increasing intake of marine omega-3. The second part showed that statin use was associated with a decreased risk of bladder cancer progression (HR = 0.44, 95% CI = 0.20 to 0.96, p=0.0388). The inverse association was even stronger for risk of mortality from all causes (HR = 0.57, 95% CI = 0.43 to 0.76, p=0.0001). The statin use effect appears dose-dependent. The third part showed that the immortal time bias is frequent and important in many epidemiological studies in oncology. It has many aspects and some of these are better prevented at time of study design selection. Various statistical methods also allowed control of this bias. Conclusion. 1) Dietary omega-3 appears to decrease prostate cancer risk. 2) Statin use appears to decrease risk of bladder cancer progression. Lipids seem to have an effect on urological cancers.

Contexte : La dysfonction du tissu adipeux blanc (TAB) favorise les facteurs de risque de diabète de type 2 (DbT2), c’est-à-dire la résistance à l’insuline (RI), l’hyper sécrétion d’insuline glucostimulée (SIGS), le délai de clairance des gras et les concentrations élevées d’apoBlipoprotéines (apoB plasmatique) incluant les lipoprotéines de faible densité (LDL). De récentes études de notre laboratoire et d’autres suggèrent que le niveau élevé d’apoB plasmatique (hyperapoB) est une cause et non seulement une conséquence de la dysfonction du TAB. De plus, une internalisation augmentée d’apoB-lipoprotéines via les récepteurs tels que le récepteur aux LDLs (LDLR) et le cluster de différenciation 36 (CD36), favorise le risque de DbT2. Cependant, les mécanismes sous-jacents de même que les interventions nutritionnelles pour les cibler demeurent incertains. L'activation de la voie de l’inflammasome NLRP3/ interleukine (IL) -1β favorise la dysfonction du TAB et les facteurs de risque de DbT2 et est activée par les LDLs oxydées dans les cellules immunitaires. L'acide eicosapentaénoïque (AEP) et l'acide docosahexaénoïque (ADH) réduisent l'hyperapoB, l'activité de l’inflammasome NLRP3 dans les cellules immunitaires et les facteurs de risque de DbT2 chez l’humain. Ils sont synthétisés de façon endogène par l’entremise des désaturases d’acides gras δ-5 (D5D) et δ-6 (D6D). Chez l’humain, de faibles niveaux d’AEP et d’ADH circulants et d’activité de la D5D et une activité élevée de la D6D prédisent l'incidence de DbT2 et la RI par des mécanismes inconnus. Objectifs : L'hypothèse de ma thèse est que l'AEP et l’ADH améliorent les facteurs de risque de DbT2, soit la dysfonction du TAB, le délai de clairance des gras, la RI et l’hyper SIGS, ceci via une baisse de l'apoB plasmatique et de l’activité de l’inflammasome NLRP3 dans le TAB. Les objectifs sont d'examiner si: 1) les associations entre les activités de la D5D et de la D6D et les facteurs de risque de DbT2 dépendent de l'apoB plasmatique; 2) la supplémentation en AEP+ADH réduit l'apoB plasmatique, l'expression du LDLR et du CD36 dans le TAB, l'activité de l’inflammasome NLRP3 dans le TAB et les facteurs de risque de DbT2; 3) l’AEP+ADH inhibe la sécrétion d'IL-1β par le TAB humain stimulée par des signaux canoniques ou les LDLs natives. Méthodes: Des hommes et des femmes postménopausées normoglycémiques ont été testés à l’état basal et après une supplémentation en AEP (1,8 g/jour) et ADH (0,9 g/jour) de 12 semaines. Les activités de la D5D et de la D6D ont été estimées à partir des acides gras produits/précurseurs dans les phospholipides plasmatiques. Nous avons mesuré la SIGS, la RI et le disposition index lors d’un clamp Botnia. Après un repas à 66% de gras, le délai de clairance des gras a été mesuré par l’aire sous la courbe (sur 6 h) des triglycérides (TG) ou de l’apoB48 (chylomicrons) plasmatiques. Ex vivo dans une biopsie de TAB, nous avons mesuré l'expression de surface du LDLR et du CD36 par immunohistochimie, l'ARNm de NLRP3 et IL1B par RT-qPCR et la sécrétion d'IL-1β par alpha-LISA en l’absence ou en présence d’une stimulation par le lipopolysaccharide (LPS), l'adénosine triphosphate (ATP) et/ou les LDLs humaines natives et lors d’une co-incubation avec l’AEP+ADH. Résultats: À l’état basal (N=98), l'activité de la D5D corrélait négativement avec l'apoB plasmatique, la 2e phase de SIGS, la RI et le délai de clairance des chylomicrons et ces associations étaient dépendantes de l'apoB plasmatique. Inversement, l'activité de la D6D corrélait positivement avec la SIGS, la RI et le délai de clairance des chylomicrons indépendamment de l'apoB plasmatique. Chez les sujets ayant complété la supplémentation en AEP+ADH (N=30), on notait une amélioration de la 1e phase de SIGS, du disposition index et de la clairance des TGs. Des niveaux initiaux plus élevés d'apoB plasmatique, de TGs postprandiaux plasmatiques et de RI, et dans le TAB d'expression du LDLR et du CD36, de sécrétion d’IL-1β et d'ARNm de NLRP3 prédisaient une plus grande réduction de ces paramètres. En comparaison à l'acide palmitique, l’AEP+ADH inhibait la sécrétion d'IL-1β par le TAB, en l’abscence ou en présence d’une stimulation par le LPS, l'ATP et/ou les LDLs natives de ces sujets. Conclusion: Les associations inverses entre l'activité de la D5D avec les facteurs de risque de DbT2 sont dépendantes de l'apoB plasmatique. Les meilleurs répondants à la supplémentation en AEP et ADH, en termes de réduction d'apoB plasmatique, d’expression du LDLR et du CD36 dans le TAB, d'activité de l’inflammasome NLRP3 dans le TAB, de TGs postprandiaux et de RI, sont les sujets avec des niveaux initiaux élevés de ces paramètres. L’AEP et l’ADH inhibent directement la sécrétion d'IL-1β par le TAB humain induite par les LDLs natives ou d'autres signaux. Nous proposons que la supplémentation en AEP et ADH puisse cibler l'activité de l’inflammasome NLRP3 dans le TAB, induite par un niveau élevé d’apoB-lipoprotéines plasmatiques ou internalisées par les récepteurs, et ainsi aider à prévenir le DbT2.
Background: White adipose tissue (WAT) dysfunction promotes risk factors for type 2 diabetes (T2D), namely insulin resistance (IR), high glucose-stimulated insulin secretion (GIIS), delayed fat clearance and high concentrations of apoB-lipoproteins (measured as plasma apoB) including low density lipoproteins (LDL). Recent studies from our lab and others suggest that high plasma apoB (hyperapoB) is a cause and not only a consequence of WAT dysfunction. Moreover, upregulated receptor-mediated uptake of apoB-lipoproteins via LDL receptor (LDLR) and cluster of differentiation 36 (CD36), promotes the risk for T2D. However, underlying mechanisms as well as nutritional interventions to target them remain unclear. Activation of the NLRP3 inflammasome/interleukin (IL)-1β pathway promotes WAT dysfunction and risk factors for T2D and is activated by oxidized LDLs in immune cells. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce hyperapoB, NLRP3 inflammasome activity in immune cells and risk factors for T2D in humans. They are synthesized endogenously through δ-5 (D5D) and δ-6 (D6D) fatty desaturases. In humans, low levels of circulating EPA and DHA and D5D activity and high D6D activity predict the incidence of T2D and IR by unknown mechanisms. Objectives: The hypothesis of my thesis is that EPA and DHA improve T2D risk factors, namely WAT dysfunction, delayed fat clearance, IR and high GIIS, this via a reduction of plasma apoB and WAT NLRP3 inflammasome activity. The objectives are to examine whether: 1) the associations between the levels of D5D and D6D activities and the risk factors for T2D are dependent on plasma apoB; 2) supplementation with EPA+DHA reduces plasma apoB, WAT LDLR and CD36 expression, WAT NLRP3 inflammasome activity and T2D risk factors; 3) EPA+DHA directly inhibits IL-1β secretion from human WAT stimulated by canonical signals or native LDLs. Methods: Normoglycemic men and postmenopausal women were tested at baseline and after supplementation with EPA (1.8 g/day) and DHA (0.9 g/day) for 12 weeks. The activities of D5D and D6D were estimated from the product/precursor fatty acids in plasma phospholipids. We measured GIIS, IR and disposition index by a Botnia clamp. Following a 66% fat meal, delayed fat clearance was measured as the area under the curve (over 6 h) of plasma triglycerides (TG) or apoB48 (chylomicrons). Ex vivo in a WAT biopsy, we measured LDLR and CD36 surface expression by immunohistochemistry, NLRP3 and IL1B mRNA by RT-qPCR, and IL-1β secretion by alpha-LISA either unstimulated or stimulated by lipopolysaccharide (LPS), adenosine triphosphate (ATP), and/or native human LDLs, and during co-incubation with EPA+DHA. Results: At baseline (N=98), D5D activity correlated negatively with plasma apoB, 2nd phase GIIS, IR and delayed chylomicron clearance and these associations were dependent on plasma apoB. Conversely, D6D activity correlated positively with GIIS, IR, and delayed chylomicron clearance independently of plasma apoB. In subjects who completed the EPA+DHA supplementation (N=30), there was an amelioration in 1st phase GIIS, disposition index and TG clearance. Higher baseline levels of plasma apoB, plasma postprandial TGs, IR, WAT LDLR and CD36 surface expression, WAT IL-1β secretion and WAT NLRP3 mRNA predicted a greater reduction of these parameters. In comparison with palmitic acid, EPA+DHA inhibited IL-1β secretion from WAT, either unstimulated or stimulated by LPS, ATP and/or subjects’ native LDLs. Conclusion: The negative associations of D5D activity with risk factors for T2D are dependent on plasma apoB. Best responders to EPA and DHA supplementation to reduce plasma apoB, WAT LDLR and CD36 expression, WAT NLRP3 inflammasome activity, delayed TG clearance, and IR are subjects with elevated baseline levels of these parameters. EPA and DHA directly inhibit IL-1β secretion from human WAT induced by native LDLs or other signals. We propose that EPA and DHA supplementation may target upregulated WAT NLRP3 inflammasome activity induced by high plasma concentrations, or receptor-mediated uptake, of apoB-lipoproteins, and thus help prevent T2D.