Background: Obesity and overweight are increasing problems to the health of Western populations, both in adults and children. Overweight or obesity in childhood are predictors of obesity and various chronic diseases in adulthood. Constituents of the diet, in particular dietary energy intake, are at least part of the reason for this, so the measurement of childhood diet has considerable public health importance. However, the assessment of children's diets is usually costly and often inaccurate. Aims: This PhD involved the design, development and testing of a novel website method of assessment of dietary energy and macronutrient intake for school-age children, with the aim of maximising participation and completion rates, while keeping costs lower than those associated with paper-and-ink survey techniques, such as food diaries. The results from this new method were tested for their agreement with the results obtained from a 5-day food diary used in the same subjects. Methods: Participants were 164 children aged 9-10 years from a range of schools in the North East of England. The website's content was based on recent evidence of important sources of energy in this age group, and its design was informed by research into children's memory and reporting of foods and drinks. Colour photographs of a range of foods were provided on a website, selected from keyage-specific references and refined during a pilot study, along with time-cued questions regarding their usual diet. A computer database automatically compiled and coded each child's responses, in order to produce an estimate of mean daily energy and macronutrient intakes. The food diary was adapted from an existing tool which has been used previously in similar participants, and mean daily nutrient intake calculations were made using the same database as the website. The two methods were compared in their calculated mean daily energy and macronutrient intakes, and their relative cost of use. Results: 154 children completed both the website and the diary in full. Significant correlations were found between the two methods' ranking of mean daily energy and macro nutrients intakes (r=0.193 p<0.05, to r=0.230 p<0.01). However, this did not reach the levels of correlation identified as adequate to make the new tool useful in public health research, i.e. correlation above r=0.5, more than 50% agreement on tertiles of intake, and weighted kappa greater than k=O.4. The mean daily energy intakes reported to the website and the diary were 14.46MJ and 6.04MJ respectively. Bland-Altman (difference) plots and limits of agreement modelling revealed systematic under-reporting to the website at lower levels of intake of all nutrients, and over-reporting at high levels, when compared with the diary. Analysis of sources of energy showed closer correlation between the two techniques (r=0.245 to 0.351, all p<O.O 1), but again this fell short of the specified threshold. A simple economic analysis showed substantial cost savings of the website over the diary technique. Discussion: The analysis of the novel website method of dietary assessment showed some strengths, such as high participation rate in the study and low but significant correlation with the more established technique. However, important limitations including a lack of agreement between the website and the diary, with the appearance of over-reporting in the website method mean this tool cannot be recommended to measure energy and macronutrient intake in children in its current form. Possible extensions and modifications to the website are suggested, including some which would aim to address the over-reporting, and hence improve its usefulness as a tool in public health research.

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Engineering tissue for external ear reconstruction could replace the standard and painful method of harvesting and carving costal cartilage. This thesis provides a critical analysis of the literature and investigates several significant challenges ahead including finding adequate sources of cells, generating auricular cartilage, and exploring cartilage/material interactions to generate flexible cartilage characteristic of the external ear. Chondrocytes form cadaveric sources could provide potentially limitless cell numbers and avoid donor site morbidity but the antigenicity of these cells is unknown. Contrary to previously published findings, human chondrocytes were found to express class II major histocompatibility antigens as well as class I antigens possibly limiting their potential use clinically if they stimulate immune rejection by the host. The adhesion and integration of engineered cartilage to various substrates was studied to explore: 1) cartilage fixation;2) infrastructure to strengthen the engineered cartilage; and 3) lamination of the engineered cartilage with materials to add flexibility to the engineered cartilage. In all settings, cartilage was engineered by encapsulating porcine chondrocytes in fibrin scaffolds that were polymerized with thrombin and placed in vivo for up to three months. Engineered cartilage placed between discs of bone or porous polythylene (PPE) formed mechanically functional bonds with the substrate as determined by mechanical testing in tension. Those data validate cartilage formation by chondrocytes from different sources. Integration of the neocartilage with substrates would permit fixation to bone and possible lamination with PPE to strengthen the new tissue. Additional studies are presented showing that coating PPE with collagen or polylysine permits enhanced cell attachment in the early phases and may be a favourable adjunct for chondrocyte/material interaction. Lastly, laminating constructs with a perichondrium or psedo-perichondrium, such as fascia, collagen sheeting, small intestinal submucosa, or lyophilized perichondrium, added flexibility to the engineered construct. These laminates in combination with a core of PPE could provide a composite model for flexible cartilaginous construct for auricular reconstruction.

Childhood obesity is reaching epidemic proportions worldwide and has both long and short term impacts on health. While lifestyle factors play a role, the influence of ‘early life programming' of body composition development is increasingly investigated. However, the mechanisms that drive the programming process are still poorly understood. Research now suggests epigenetics may be a potential mechanism, specifically the effect of imprinted genes and therefore requires further investigation. The aim of this study was to investigate (1) whether the intrauterine growth programmes later body composition, and (2) whether expression of the imprinted gene IGF2 is associated with childhood lean or fat mass. 65 twin pairs (38 DZ twins and 27 MZ twins) were recruited along with 28 of their siblings aged between 6 and 19 years. Anthropometry and 4 component measurements were obtained on all participants. Birthweight was used as a proxy for in utero growth, while post natal weight gain was calculated as change in weight between birth and follow-up. The results showed that birthweight was largely unassociated with body composition outcomes but showed trends towards associations with lean mass in boys and fat mass in girls that might become significant with a larger sample size. In contrast, the postnatal growth period was shown to be consistently significantly associated with body composition outcomes for both fat and mean mass. Expression of lGF2 was not associated with either lean or lat components of body composition. The conclusion therefore is that the postnatal period appears to be the period that most influences body composition in later life, therefore interventions during this period could help alter the trajectory of growth that could possibly lead to poor body composition development. However, there was little evidence that lGF2 is a key component of the programming process whereby growth impacts on later body composition.

To investigate the regulation of flavin-containing monooxygenase 5 (FM05) by xenobiotics in mouse liver, a method for isolating primary mouse hepatocytes was designed. Fmo5 expression was up-regulated by hormones (estradiol, progesterone), dietary supplements (lipoic acid) and other xenobiotics (rifampicin, ethanol) in primary mouse hepatocytes and HepG2 cells. Gene reporter assays showed that Fmo5 expression in HepG2 cells is mediated by pregnane-x-receptor (PXR) ligands. To uncover more about the endogenous role of FMOs, two knockout mouse models, Fmol, 2, 4 (-/-) and Fmo5 (-/-), were studied. Fmol, 2, 4 (-/-) males weighed less and had less gonadal fat than their wild-type counterparts. The bodyweight of the Fmol, 2, 4 (-/-) females was greater than that of the wild-type females. Histology shows that the adipocytes in the Fmol, 2, 4 (-/-) male mice are 50% smaller than wild-type male adipocytes, and the liver histology shows the Fmol, 2, 4 (-/-) males had less fat in the liver compared to wild-type males. Fmol, 2, 4 (-/-) mice had higher plasma total-, HDL- and LDL-cholesterol than the wild-type mice. On a high-fat diet, the male Fmol, 2, 4 (-/- ) mice gain weight and gonadal fat weight. The Fmo5 (-/-) mice have a similar bodyweight and fat weight to the wild-type animals, but Fmo5 (-/-) mice have lower plasma HDL cholesterol and lower plasma iron than WT mice. The results therefore show that a deficiency in FMOs interferes with endogenous fat metabolism. Lipoic acid is an endogenous substrate of FMOl, so to see if the inability to metabolise lipoic acid is the reason for the lower bodyweight and fat weight in Fmol, 2, 4 (-/-) males, the mice were fed a 0.1% lipoic acid diet. All knock-out and wild-type mice lose a similar amount of weight. This implies that the metabolism of lipoic acid is not the fundamental endogenous role of FMOs.

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