Errata slip inserted / Bibliography: leaves 178-199 / xxi, 199, [55] leaves, [3] leaves of plates : ill ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, and Rheumatology Unit, Royal Adelaide Hospital, 1994

Objective: The objective of this thesis was to facilitate clinical trials of the optimal lipid based approach (e.g.: omega-3 containing lipid emulsions or minimization of conventional lipid) for the prevention of Intestinal Failure Associated Liver Disease (IFALD). This was achieved through 3 related projects. Project 1: The first project examined the risk of advanced IFALD associated with exposure to conventional intravenous lipid in a logistic regression model. The study demonstrated that each day of conventional lipid (> 2.5 g/kg/day) was associated with a significant increase in the risk of advanced IFALD [Odds Ratio: 1.04 95% CI: 1.003 – 1.06]. Project 2: The second project surveyed experts in Intestinal Failure regarding their beliefs of the efficacy of lipid minimization and lipid emulsions containing omega-3 fatty acids relative to conventional emulsions. The goal of the project was to develop prior distributions of the treatment response for these therapies that can be used in Bayesian analyses of clinical trials. Our results demonstrated consistent expert opinion that the novel lipid based approaches are superior to conventional therapy. Estimates of the treatment effect were similar for the two approaches (median elicited treatment response, relative to conventional lipid, was a relative risk of 0.53 for omega-3 lipid and 0.45 for lipid minimization). Project 3: The final project was a pilot randomized controlled trial of an omega-3 emulsion. The study demonstrated that the randomized design is a feasible strategy for evaluating lipid based approaches for the prevention of IFALD. A Bayesian preliminary assessment of the results of the trial, suggests a high likelihood that the trial will demonstrate a difference between the conventional and omega-3 emulsion evaluated in the trial. However, since the analysis was blinded, the direction of the difference is not known. Conclusion: This thesis will contribute to the design and analysis of high quality and feasible randomized trials that will allow investigators to address the optimal lipid based approach to the management of IFALD.

We examined the effect of a functional oil (FctO), with potential weight-controlling and blood lipid-lowering attributes, vs beef tallow as control (C), on the cardiovascular risk profile of overweight women. The FctO comprised energy expenditure-enhancing medium chain triacylglycerols, cholesterol-lowering phytosterols and triacylglycerol-suppressing n-3 fatty acids. In a randomized, single-blind, crossover design, inpatient trial, 17 women consumed each oil as part of a controlled, supervised, energy-adjusted diet for 27 days. Body weight decreased similarly during both dietary periods. Plasma total and LDL cholesterol levels decreased by 4.8% and 10.4% following FctO, and were lower by 9.0% and 16.4% respectively, after FctO vs C. HDL cholesterol and circulating triacylglycerol levels were unaffected by treatment, though HDL:LDL and HDL:total cholesterol ratios increased by 19.5% and 9.4% on FctO. Plasma total homocysteine levels were higher on FctO vs C. Plasma glutathione increased with FctO supplementation. / We conclude that consumption of FctO improves the overall cardiovascular risk profile of overweight women.

Objective: The objective of this thesis was to facilitate clinical trials of the optimal lipid based approach (e.g.: omega-3 containing lipid emulsions or minimization of conventional lipid) for the prevention of Intestinal Failure Associated Liver Disease (IFALD). This was achieved through 3 related projects. Project 1: The first project examined the risk of advanced IFALD associated with exposure to conventional intravenous lipid in a logistic regression model. The study demonstrated that each day of conventional lipid (> 2.5 g/kg/day) was associated with a significant increase in the risk of advanced IFALD [Odds Ratio: 1.04 95% CI: 1.003 – 1.06]. Project 2: The second project surveyed experts in Intestinal Failure regarding their beliefs of the efficacy of lipid minimization and lipid emulsions containing omega-3 fatty acids relative to conventional emulsions. The goal of the project was to develop prior distributions of the treatment response for these therapies that can be used in Bayesian analyses of clinical trials. Our results demonstrated consistent expert opinion that the novel lipid based approaches are superior to conventional therapy. Estimates of the treatment effect were similar for the two approaches (median elicited treatment response, relative to conventional lipid, was a relative risk of 0.53 for omega-3 lipid and 0.45 for lipid minimization). Project 3: The final project was a pilot randomized controlled trial of an omega-3 emulsion. The study demonstrated that the randomized design is a feasible strategy for evaluating lipid based approaches for the prevention of IFALD. A Bayesian preliminary assessment of the results of the trial, suggests a high likelihood that the trial will demonstrate a difference between the conventional and omega-3 emulsion evaluated in the trial. However, since the analysis was blinded, the direction of the difference is not known. Conclusion: This thesis will contribute to the design and analysis of high quality and feasible randomized trials that will allow investigators to address the optimal lipid based approach to the management of IFALD.

The study was designed to develop a nutraceutical product from by-products of fish processing. Fish oil was extracted from mackerel tissues (skin, viscera and muscle) using hexane-isopropanol (3:2 v/v) and chloroform-methanol (2:1 v/v) solvent systems. An oxidative study was carried out to determine the best processing and storage conditions to minimize autooxidation of mackerel oil. Urea complexation was used to concentrate polyunsaturated fatty acids (PUFA) from the extracted fish oil. The urea complexation process was optimized to determine the best reaction conditions for high yield of the omega-3 fatty acids in particular, and total PUFA. / Conjugated linoleic acid (CLA) was synthesized from four vegetable oils (sunflower, canola, soybean and corn) by alkaline isomerization. The CLA isomers and PUFA concentrated from mackerel tissues were used to synthesize triglycerides by lipase-catalyzed esterification. The effect of temperature, reaction medium, enzyme, moisture removal system and glycerol to fatty acid ratio on extent of synthesis were investigated. The synthesis process was also optimized using central composite design to determine the best conditions for high synthesis yield. The fatty acid composition and positional analyses were determined by GC-FID and electrospray ionization mass spectrometry (EI-MS) / The results showed that mackerel skins were most suitable for concentrating PUFA. The eicosapentaenoic acid (EPA) and -docosahexaenoic acid (DHA) content of fish oil from the tissues examined ranged between 6.3--9.7 (wt%) with an iodine value of 134 +/- 5.0. The baseline total PUFA content was increased from ca 21.0 to ca 83.0 (wt%) with an associated iodine value of 296 +/- 7.0 using urea complexation. Low (50 ppm and 100 ppm) levels of alpha-tocopherol in combination with low storage temperature (-40°C) showed lowest oxidation after 66 days of storage. High levels (250 and 500 ppm) of alpha-tocopherol were observed to be prooxidant based on TBARS, peroxide and conjugated diene measurements. Urea to fatty acid ratio and temperature were predominant effectors influencing the amounts of individual omega-3 fatty acids and total PUFA concentrated by urea complexation. The model developed for the optimized urea complexation process were capable of predicting the yields of EPA, DHA, total PUFA and Iodine values to a high degree of accuracy at R2 = 0.87, 0.96, 0.95, and 0.92 respectively. / Sunflower oil was most suitable for synthesizing conjugated linoleic acid by alkaline isomerization, compared with soybean, canola and corn oil. Two CLA isomers, c9,t11 and t10, c12 were most abundant and occurred in approximately equal proportions irrespective of vegetable oil used. Total CLA synthesized from sunflower oil was 93.5 +/- 3.5 (wt%) with the two major isomers making up 89 +/- 3.5 (wt%). Candida antartica lipase showed more synthesis activity than Mucor meihie in both organic and solvent-free systems. Analysis of isolated synthesized triglycerides by GC-FID and mass spectrometry showed that DHA, EPA, CLA and linolenic acid were the main fatty acids incorporated into the triglycerides. DHA and EPA were mostly esterified at the sn-2 position.

The aim of this thesis was to examine possible effects of omega-3 fatty acids on children’s cognition and behavior. Longitudinal as well as cross-sectional comparisons were made among children with typical development and children with ADHD /at risk developing ADHD. The specific purposes were to examine (1) breast-feeding in relation to cognition; (2) relation between long chain poly unsaturated fatty acids (LCPUFAs) in mothers breast-milk and children´s cognition; (3) effects of EPA supplementation on cognition and behavior in children with ADHD; (4) if LCPUFAs have differential effects on working memory, inhibition, problem-solving and theory of mind (ToM). The main conclusions were as follows; (1) duration of breast-feeding was positively correlated to children levels of intelligence (IQ); (2) LCPUFAs in breast-milk was related to children’s ToM and IQ, the quotient DHA/AA, together with length of breastfeeding and gestation week explained 76% of the variance of total IQ; (3) subtypes of children with ADHD responded to EPA supplementation with significant reductions in symptoms, but there were no effects in the whole group with ADHD; (4) ToM ability was related to LCPUFAs, but not to any other cognitive measures as working memory, inhibition and problem-solving. To conclude, these results indicate that fatty acid status in breast-milk at birth affect general cognitive function in children at 6.5 years of age, including ToM. Short-term intervention with omega-3 fatty acids does not affect cognition in children with ADHD, but improves clinical symptoms as assessed by means of teacher ratings. These results further indicate that hot executive function and social cognition may be an area of interest for future research. / Syftet med denna avhandling var att undersöka möjliga effekter av omega-3 fettsyror för barns kognition och beteende. Både kortsiktiga och långsiktiga effekter undersöktes och studierna involverade både barn med typisk utveckling och barn med ADHD. De specifika syftena var att undersöka; (1) amning i relation till barns kognitiva utveckling; (2), relationen mellan långa fleromättade fettsyror (LCPUFA) i mammans bröstmjölk och barns kognition; (3) effekter på kognition och beteenden hos barn med ADHD av ett EPA tillskott; (4) om LCPUFA hade några differentiella effekter på arbetsminne, inhibering eller Theory of Mind (ToM). De huvudsakliga slutsatserna var följande; (1) amningslängden var positivt korrelerad med barnens intelligenskvot (IK); (2) LCPUFA i bröstmjölken var associerad med barnens ToM och IK, kvoten DHA/AA, tillsammans med amningslängd och graviditetslängd förklarade 76% av variansen i totala IK; (3) subgrupper av barn med ADHD svarade på EPA behandlingen med signifikant reducerade symptom, men för hela gruppen med ADHD hittades inga effekter; (4) ToM var relaterat till LCPUFA, men inga andra kognitiva mått som arbetsminne, inhibering eller problemlösning. Sammanfattningsvis indikerar dessa resultat att fettsyrestatus i bröstmjölk påverkar generell kognitiv förmåga, samt ToM, hos barn 6,5 år gamla. Korttidsintervention med omega-3 fetter påverkar inte kognition hos skolbarn med ADHD, men minskar kliniska symptom skattade i lärarskattningsskalor. Vidare indikerar resultaten att ”heta” exekutiva funktioner och social kognition kan vara av intresse för framtida forskning.

Fetal Alcohol Spectrum Disorders (FASD) are the most common cause of cognitive impairment in the United States (Sokol et al., 2003). In young school children in North America and some Western European countries, recent reports have estimated the prevalence of FASD to be as high as 2-5% (May et al., 2009). Currently there are no widely accepted treatment options for FASD, mainly due to the fact that the underlying neurological deficits that occur with prenatal ethanol exposure (PNEE) are still largely unknown. This thesis examines the long-lasting changes that occur in the hippocampus following PNEE using biochemical and electrophysiological techniques. We find that PNEE produces a reduction of the endogenous antioxidant glutathione (GSH), resulting in an increase in oxidative stress that is accompanied by long-lasting reductions in long-term potentiation (LTP) of synaptic efficacy. Interestingly, males exhibited greater deficits in synaptic plasticity than females, despite similar reductions in GSH in both sexes. By depleting GSH in control animals we determined that LTP in the DG of female animals is more resistant to changes in GSH, which may explain the sexual dichotomy observed in these studies of PNEE. Based on these findings, ethanol-exposed animals received postnatal dietary supplementation with either a precursor of GSH, N-Acetylcysteine (NAC) or Omega-3 fatty acids. These supplements helped to counteract the effects of PNEE and improved hippocampal function. The findings in this thesis support the hypothesis that increasing antioxidant capacity can enhance hippocampal function, which in turn may improve learning and memory in FASD, providing a therapeutic avenue for children suffering with these disorders. / Graduate / 0570 Nutrition / 0317 Neuroscience / anna.r.patten@gmail.com

Fetal Alcohol Spectrum Disorders (FASD) are the most common cause of cognitive impairment in the United States (Sokol et al., 2003). In young school children in North America and some Western European countries, recent reports have estimated the prevalence of FASD to be as high as 2-5% (May et al., 2009). Currently there are no widely accepted treatment options for FASD, mainly due to the fact that the underlying neurological deficits that occur with prenatal ethanol exposure (PNEE) are still largely unknown. This thesis examines the long-lasting changes that occur in the hippocampus following PNEE using biochemical and electrophysiological techniques. We find that PNEE produces a reduction of the endogenous antioxidant glutathione (GSH), resulting in an increase in oxidative stress that is accompanied by long-lasting reductions in long-term potentiation (LTP) of synaptic efficacy. Interestingly, males exhibited greater deficits in synaptic plasticity than females, despite similar reductions in GSH in both sexes. By depleting GSH in control animals we determined that LTP in the DG of female animals is more resistant to changes in GSH, which may explain the sexual dichotomy observed in these studies of PNEE. Based on these findings, ethanol-exposed animals received postnatal dietary supplementation with either a precursor of GSH, N-Acetylcysteine (NAC) or Omega-3 fatty acids. These supplements helped to counteract the effects of PNEE and improved hippocampal function. The findings in this thesis support the hypothesis that increasing antioxidant capacity can enhance hippocampal function, which in turn may improve learning and memory in FASD, providing a therapeutic avenue for children suffering with these disorders. / Graduate / 0570 Nutrition / 0317 Neuroscience / anna.r.patten@gmail.com

Thesis (Ph.D.)--Flinders University, School of Medicine, Dept. of Gastroenterology. / Typescript bound. Includes bibliographical references: (leaves 215-233) Also available in an electronic version via the Web.

Thesis (M.S.)--West Virginia University, 2009. / Title from document title page. Document formatted into pages; contains iv, 60 p. : ill. (some col.). Includes abstract. Includes bibliographical references.