Eating disorders (ED) usually develop during adolescence, and intervention to stop further weight loss is believed to improve outcome and long-term prognosis. Adolescents with ED who do not receive effective treatment risk poor outcome and even untimely death as adults. The first aim of this thesis was to investigate long-term mortality and causes of death in a series of female adults with chronic ED. The second aim was to study the one-year outcome of an unselected series of adolescent girls with anorexia nervosa (AN) and “other restrictive eating disorders” who had been treated within a specialist ED out-patient service focused on nutritional rehabilitation based on family therapy and without planned hospitalization. The third aim was to investigate the possible metabolic and hormonal side effects of olanzapine when used as an adjunct to facilitate nutritional rehabilitation. The fourth aim was to investigate the relationship between polyunsaturated fatty acid (PUFA) status and depression. In adult women with chronic ED, a very low body mass index and psychiatric co-morbidity confer a substantially increased risk of premature death. A treatment programme for adolescent ED with rapid access to assessment and prompt start of treatment with initial emphasis on nutritional rehabilitation proved efficient. The outcome was encouraging, as 43% of all patients with ED and 19% of those with AN did not have an ED at one-year follow-up. Of the remaining patients the vast majority had gained weight and regained menstruation, and were back in school on a full-time basis. Olanzapine was used to reduce anxiety, excessive exercise and rumination over weight and shape. Side effects were similar to those observed in normal-weight individuals, and do not preclude its use in underweight adolescents with ED. Low ω3 PUFA were associated with depression. The ω3 PUFA status improved during nutritional rehabilitation with ordinary foods and without supplementation. The investigations indicate that adolescent ED can be successfully treated in an out-/day-patient setting. An essential feature of the service is rapid handling and weight gain. Further weight loss can be avoided, and chronic disease hopefully prevented.

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.

This purpose of this thesis was to develop a pilot study to determine if omega-3 fatty acids and vitamin D3 will improve body weight loss and improve risk factors for Metabolic Syndrome within a weight loss program. Risk factors include obesity, hypertension, hyperglycemia, and dyslipidemia. Thirty-five men and women between 18 and 65 years of age with risk factors for Metabolic Syndrome were recruited for this study. All participants followed an energy-restricted, low glycemic-index based diet and exercise program for 16 weeks. Half of these participants received omega-3 fatty acid and vitamin D3 supplements. In those that received these supplements, it was seen that their serum 25-hydroxyvitamin D2/D3 levels and incorporation of docosahexaenoic acid and eicosapentaenoic acid into red blood cell phospholipids improved. The effect of supplementation on changes to body weight and risk factors for Metabolic Syndrome did not reach significance (p<0.05). It was however demonstrated, that an energy-restricted, low glycemic index diet with exercise was effective in inducing weight loss and improving Metabolic Syndrome risk factors with a 50% reduction in participants who had the criteria for diagnosis of Metabolic Syndrome by week 16.

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.

Bien que le régime méditerranéen (MED) soit considéré comme le meilleur régime alimentaire pour prévenir les maladies cardiaques, on ignore toujours si l'adoption de MED résulte en une amélioration de la résistance du myocarde à l'ischémie et la reperfusion et en une prévention des arythmies ventriculaires. En conséquence, nous avons mené deux études : (1) vérifier si un profile lipidique de type MED; faible en gras saturés et en acides gras oméga-6 (ω6) et riche en acides gras oméga-3 (ω3) d'origines végétale et marine; peut réduire la taille d'infarctus et une meilleure récupération de la fonction ventriculaire gauche (FVG) dans un modèle de rat. Les rats MED ont été comparés avec des rats recevant des régimes riches en acides gras saturés ou en acides gras ω6. Les résultats montrent une grande accumulation des ω3 et une diminution de l'acide arachidonique dans le plasma, les membranes des cellules cardiaques et dans les mitochondries. Pareillement, les rats MED avaient une taille infarctus plus réduite par rapport aux deux autres groupes, tandis que FVG récupération n'était pas différente dans les trois groupes. La deuxième étude épidémiologique a été menée au Centre Hospitalier Universitaire de Grenoble pour déterminer une éventuelle corrélation entre les oméga-3 et la survenue de complications rythmiques. Deux cent trente huit patients porteurs de défibrillateurs automatiques implantables (DEF) ont été inclus. La composition en acides gras des globules rouges a été analysé et l'index oméga-3 a été calculée à partir de l'acide eicosapentaénoïque et acide docosahexaénoïque. Aucune différence significative entre les acides gras oméga-3 (ALA, EPA et DHA) ou l'index oméga-3 et la survenue d'événements n'a été observée entre quartiles. Néanmoins, l'index oméga-3 chez ces patients était déjà à des niveaux qui ont été démontrés avoir un pouvoir cardioprotecteur (8.6±1.59 à 8,8±1.76).

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

Understanding thermal transport in nanoscale is important for developing nanostructured thermolelectric materials and for heat management in nanoelectronic devices. This dissertation is devoted to understand thermal transport through SiGe based superlattices. First, we systematically studied the cross-plane thermal conductivity of SiGe superlattices by varying the thickness of Si(Ge) spacers thickness. The observed additive character of thermal resistance of the SiGe nanodot/planar layers allows us to engineer the thermal conductivity by varying the interface distance down to ~1.5 nm. Si-Ge intermixing driven by Ge surface segregation is crucial for achieving highly diffusive phonon scattering at the interfaces. By comparing the thermal conductivity of nanodot Ge/Si superlattices with variable nanodot density and superlattices with only wetting layers, we find that the effect of nanodots is comparable with that produced by planar wetting layers. This is attributed to the shallow morphology and further flattening of SiGe nanodots during overgrowth with Si. Finally, the experiments show that the interface effect on phonon transport can be weakened and even eliminated by reducing the interface distance or by enhancing Si-Ge intermixing around the interfaces by post-growth annealing. The results presented in this dissertation are expected to be relevant to applications requiring optimization of thermal transport for heat management and for the development of thermoelectric materials and devices based on superlattice structures. / Verständnis des thermischen Transport auf Nanoskala ist sowohl grundlegend für die Entwicklung nanostrukturierter Materialien, als auch für Temperaturkontrolle in nanoelektronischen Bauteilen. Diese Dissertation widmet sich der Erforschung des thermischen Transports durch SiGe basierenden Übergittern. Variationen, der Si(Ge) Schichtdicken, wurden zur systematischen Untersuchung der Normalkomponente zur Wachstumsrichtung der Wärmeleitfähigkeit, von SiGe Übergittern, genutzt. Die Beobachtung des additiven Charakters, des thermischen Widerstands, der SiGe Schichten, mit oder ohne Inselwachstum, ermöglicht die Erstellung von Strukturen mit bestimmter Wärmeleitfähigkeiten durch die Variation der Schichtdicken bis zu einer Minimaldistanz zweier Schichtübergänge von ~1.5nm. Die Ge Segregation führt zu einer Vermischung, von Si und Ge, welche eine essentielle Rolle zur diffusen Phononenstreuung spielt. Unsere Untersuchungen, von planaren Übergittern und Übergittern mit variabler Inseldichte, zeigen, dass Inseln und planare Schichten zu einer vergleichbaren Reduktion, der Wärmeleitfähigkeit, führen. Diese Beobachtung lässt sich, sowohl auf die flache Morphologie als auch die Abplattung der SiGe Inseln, aufgrund der Überwachsung mit Si, zurückführen. Die Experimente zeigen außerdem, dass sich der Barriereneffekt, der Schichtgrenzen, durch Reduktion der Schichtabstände und durch verstärkte Vermischung im Bereich der Schichtgrenzen, durch Erhitzung, eliminieren lässt. Die präsentierten Messungen sind sowohl, für die Entwicklung jener Bauteile, die eine Optimierung des thermischen Transports oder Temperaturmanagment erfordern, als auch von thermoelektrischen Matieralien und Bauteilen, basierend auf Übergittern, relevant.