Theses - MRC Elsie Widdowson Laboratory
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Item Open Access The quantification of pregnancy-induced bone mineral mobilisation in the maternal appendicular skeleton with novel peripheral quantitative computed tomography (pQCT) techniques.(2019-10-26) Ó Breasail, MícheálThe quantification of pregnancy-induced bone mineral mobilisation in the maternal appendicular skeleton with novel peripheral quantitative computed tomography (pQCT) techniques. Adaptations in maternal calcium (Ca) economy occur during pregnancy to meet fetal demand and by birth a typical new-born contains 25-30g Ca. At the individual-level if Ca is mobilised it is important to identify where this occurs to identify any potential impact on fracture risk. At present, pregnancy is not considered a risk factor for osteoporosis but data are few. Trabecular bone is more metabolically active than cortical bone in part due to its structure, orientation and much greater surface area. During lactation, studies have consistently reported significant transient bone mineral mobilisation from trabecular-rich axial sites such as the hip and spine, while newer peripheral quantitative computed tomography (pQCT) techniques have found trabecular microarchitectural change in the appendicular skeleton also. My primary objective was to explore whether a similar pregnancy-induced bone mineral mobilisation could be observed in two distinct cohorts of pregnant women using novel pQCT techniques from mid- to late-pregnancy. These techniques provide non-invasive measurements of bone density, mass, geometry, distribution and strength at the radius and tibia. This thesis aims to determine: whether pregnancy-induced changes occur in a) the trabecular compartment, b) the cortical compartment, c) any potential predictors of a) and b); d) to explore the correlation and agreement of pQCT techniques in-vivo. Single-slice and high-resolution (HR) pQCT data were used to characterise maternal appendicular skeletal change during pregnancy in two studies in contrasting populations: 1) a resource poor subsistence farming Sub-Saharan African community with an habitually low Ca intake and high parity; 2) an affluent Cambridge based population, where Ca intake is higher but parity much lower. In The Gambia, existing pQCT data obtained at 14 and 30 weeks of pregnancy from women (n=811), aged 18-45 and accustomed to low habitual Ca intake, were analysed. In Cambridge, UK, I designed a study where pregnant women (n=53) and non-pregnant non-lactating (NPNL, n=37) controls aged 30-45 years were scanned with pQCT and HRpQCT at 14 and 36 weeks. These data were modelled to explore the maternal response to pregnancy in these distinct populations. Contrary to my primary hypothesis there was no evidence of trabecular bone mobilisation in Gambian women, however in contrast in the UK study a -0.5 SD decrease in trabecular vBMD was observed. In The Gambia total vBMD did not change at the radius or tibia, while in Cambridge both techniques detected decreases in total vBMD at the distal tibia. Changes in cortical bone were documented during pregnancy in both populations. In Gambian women small but significant increases in cortical vBMD and BMC were observed at the radius and tibia. In Cambridge at the tibia HRpQCT showed a decrease in cortical vBMD and cortical thickness with an increase in cortical porosity. There were fewer pregnancy-induced changes at the radius but at the cortical- rich diaphysis cortical thickness decreased and endosteal circumference increased. No consistent predictors of these changes were found in either population. These data from two contrasting populations show a “one size fits all” approach cannot be applied to the maternal skeletal response to pregnancy. In Gambian women with a habitually low Ca intake we have observed the conservation of bone mineral in the appendicular skeleton into the third trimester. In contrast in the Cambridge women evidence of trabecular and cortical mobilisation was observed at the distal tibia. At the radius changes were confined to the cortical-rich proximal radius and supported endosteal resorption during pregnancy. These data suggest that the maternal skeleton is a significant source of fetal Ca in a population accustomed to higher dietary Ca intakes. Further work is needed to determine what this mobilisation means at the individual level and to determine if the mobilised bone mineral is restored postpartum or whether there are lasting consequences for the woman’s bone health.Item Open Access Statistical models for estimating the intake of nutrients and foods from complex survey data(2019-03-02) Pell, David AndrewBackground: The consequences of poor nutrition are well known and of wide concern. Governments and public health agencies utilise food and diet surveillance data to make decisions that lead to improvements in nutrition. These surveys often utilise complex sample designs for efficient data collection. There are several challenges in the statistical analysis of dietary intake data collected using complex survey designs, which have not been fully addressed by current methods. Firstly, the shape of the distribution of intake can be highly skewed due to the presence of outlier observations and a large proportion of zero observations arising from the inability of the food diary to capture consumption within the period of observation. Secondly, dietary data is subject to variability arising from day-to-day individual variation in food consumption and measurement error, to be accounted for in the estimation procedure for correct inferences. Thirdly, the complex sample design needs to be incorporated into the estimation procedure to allow extrapolation of results into the target population. This thesis aims to develop novel statistical methods to address these challenges, applied to the analysis of iron intake data from the UK National Diet and Nutrition Survey Rolling Programme (NDNS RP) and UK national prescription data of iron deficiency medication. Methods: 1) To assess the nutritional status of particular population groups a two-part model with a generalised gamma (GG) distribution was developed for intakes that show high frequencies of zero observations. The two-part model accommodated the sources of data variation of dietary intake with a random intercept in each component, which could be correlated to allow a correlation between the probability of consuming and the amount consumed. 2) To identify population groups at risk of low nutrient intakes, a linear quantile mixed-effects model was developed to model quantiles of the distribution of intake as a function of explanatory variables. The proposed approach was illustrated by comparing the quantiles of iron intake with Lower Reference Nutrient Intakes (LRNI) recommendations using NDNS RP. This thesis extended the estimation procedures of both the two-part model with GG distribution and the linear quantile mixed-effects model to incorporate the complex sample design in three steps: the likelihood function was multiplied by the sample weightings; bootstrap methods for the estimation of the variance and finally, the variance estimation of the model parameters was stratified by the survey strata. 3) To evaluate the allocation of resources to alleviate nutritional deficiencies, a quantile linear mixed-effects model was used to analyse the distribution of expenditure on iron deficiency medication across health boards in the UK. Expenditure is likely to depend on the iron status of the region; therefore, for a fair comparison among health boards, iron status was estimated using the method developed in objective 2) and used in the specification of the median amount spent. Each health board is formed by a set of general practices (GPs), therefore, a random intercept was used to induce correlation between expenditure from two GPs from the same health board. Finally, the approaches in objectives 1) and 2) were compared with the traditional approach based on weighted linear regression modelling used in the NDNS RP reports. All analyses were implemented using SAS and R. Results: The two-part model with GG distribution fitted to amount of iron consumed from selected episodically food, showed that females tended to have greater odds of consuming iron from foods but consumed smaller amounts. As age groups increased, consumption tended to increase relative to the reference group though odds of consumption varied. Iron consumption also appeared to be dependent on National Statistics Socio-Economic Classification (NSSEC) group with lower social groups consuming less, in general. The quantiles of iron intake estimated using the linear quantile mixed-effects model showed that more than 25% of females aged 11-50y are below the LRNI, and that 11-18y girls are the group at highest of deficiency in the UK. Predictions of spending on iron medication in the UK based on the linear quantile mixed-effects model showed areas of higher iron intake resulted in lower spending on treating iron deficiency. In a geographical display of expenditure, Northern Ireland featured the lowest amount spent. Comparing the results from the methods proposed here showed that using the traditional approach based on weighted regression analysis could result in spurious associations. Discussion: This thesis developed novel approaches to the analysis of dietary complex survey data to address three important objectives of diet surveillance, namely the mean estimation of food intake by population groups, identification of groups at high risk of nutrient deficiency and allocation of resources to alleviate nutrient deficiencies. The methods provided models of good fit to dietary data, accounted for the sources of data variability and extended the estimation procedures to incorporate the complex sample survey design. The use of a GG distribution for modelling intake is an important improvement over existing methods, as it includes many distributions with different shapes and its domain takes non-negative values. The two-part model accommodated the sources of data variation of dietary intake with a random intercept in each component, which could be correlated to allow a correlation between the probability of consuming and the amount consumed. This also improves existing approaches that assume a zero correlation. The linear quantile mixed-effects model utilises the asymmetric Laplace distribution which can also accommodate many different distributional shapes, and likelihood-based estimation is robust to model misspecification. This method is an important improvement over existing methods used in nutritional research as it explicitly models the quantiles in terms of explanatory variables using a novel quantile regression model with random effects. The application of these models to UK national data confirmed the association of poorer diets and lower social class, identified the group of 11-50y females as a group at high risk of iron deficiency, and highlighted Northern Ireland as the region with the lowest expenditure on iron prescriptions.Item Open Access Bone health in Gambian women: impact and implications of rural-to-urban migration and the nutrition transition(2018-10-20) Dalzell, Sarah; Dalzell, Sarah [0000-0001-6517-1247]Urbanisation and the associated nutrition transition have been linked with the recent rise in osteoporotic fragility fracture incidence in many countries. Predictions indicate that hip fracture incidence will increase 6-fold in Africa and Asia by 2050, partially attributed to demographic transition and population ageing. Differences in areal bone mineral density (aBMD) between rural and urban locations indicate that urban regions of high-income countries (HIC) have lower aBMD and a higher incidence of hip fracture. The few studies conducted in low and middle-income countries (LMIC) provide inconsistent results; in contrast to HIC, most have found higher aBMD in urban populations. To investigate the impact of migrating to an urban environment, detailed studies of bone phenotype and factors affecting bone health have been conducted in two groups of pre-menopausal Gambian women: urban migrant (n=58) and rural (n=81). Both groups spent their formative years in the same rural setting of Kiang West, urban women were known to have migrated to coastal districts, concentrated in Brikama and Kanifing, when aged ≥16 years. Bone phenotype (bone mineral content (BMC); bone area (BA); aBMD, and size-adjusted BMC (adjusted for height, weight and BA) of the whole-body, lumbar spine and hip) was measured by dual energy x-ray absorptiometry (DXA), with further characterisation by peripheral quantitative computed tomography (pQCT). Data were also collected on anthropometry, body composition, food and nutrient intakes, physical activity, socio-demographic characteristics, vitamin D status, and 24hr urinary mineral outputs (Na, K, P, and Ca). Mean age and height of rural and urban migrant groups were not significantly different (p>0.05). Urban migrant women were significantly heavier (p<0.01). Significant differences in BMC and aBMD were found between groups at all skeletal sites, with urban women having higher BMC and aBMD; BA was not significantly different. The greatest difference in BMC was found at the lumbar spine (8.5% ± SE 3.0, p<0.01), a meaningful difference, equivalent to 0.76 of rural SD. T- Scores were also calculated using a young adult (white, female) reference population, mean T- scores were -1.03 and -0.22, for rural and urban groups respectively. After adjusting for size, differences in whole-body and hip BMC were mostly attenuated (p>0.05), but difference in spine BMC remained significant (6.2% ± SE 2.1, p<0.01). These results indicate that rural-to-urban migration is associated with higher BMC; BA and height were similar, and difference in body weight could not fully account for higher BMC at the lumbar spine. Calcium intakes were low in both groups, urban migrant 294mg/d (IQR: 235 to 385) and rural 305mg/d (IQR: 222 to 420). Urban women had significantly lower intakes of potassium, magnesium and dietary fibre (p<0.01), related to lower consumption of fruit, green leafy vegetables and groundnuts. 25-hydroxy vitamin D status was good in both groups, urban migrant 64.0 ± 14.2nmol/L and rural 68.3 ± 15.7nmol/L (M ± SD, p>0.05). Implications for bone health of the nutrition and demographic transition, principally future fracture risk and other non-communicable diseases require further research in LMICs. ORIGINAL CONTRIBUTION TO KNOWLEDGE To my knowledge, this is the first study investigating the impact of rural-to-urban migration on bone health to be conducted in sub Saharan Africa. It is the first study of bone health and determinants of bone health in an urban population in The Gambia.Item Controlled Access HIV, Antiretroviral Therapy, Pregnancy, Lactation and Bone Health in UgandaNabwire, FlorenceGlobally, ~17 million women and ~2.1 million children are living with HIV. Sub-Saharan Africa accounts for 70% of HIV-infected (HIV+) persons. Mother-To-Child Transmission of HIV (MTCT) during pregnancy, delivery and breastfeeding, is the main route of HIV infection in children. The World Health Organisation recommends lifelong antiretroviral therapy (ART) for all HIV+ pregnant and breastfeeding mothers to prevent MTCT, and breastfeeding for ≥24 months for optimal child health in resource limited settings (Option B+ strategy). Initiation of ART in HIV+ adults is associated with a 2-6% decrease in areal bone mineral density (aBMD) regardless of ART regimen, but data are limited in pregnant and lactating women. Tenofovir, a preferred first-line drug in Option B+ ART regimen, is associated with 1-2% greater decreases in aBMD. Pregnancy and lactation are associated with physiological changes in maternal bone mineral density, but most evidence shows that this is recovered after cessation of breastfeeding. The hypothesis of this thesis is that ART may accentuate the normal process of bone mobilisation during pregnancy and lactation, leading to bone loss that is not recovered in the mother and/or compromised infant growth and bone mineral accretion. The primary objective of this research was to investigate if HIV+ women experience greater reductions in bone mineral compared to HIV-uninfected (HIV-) counterparts. Two groups of pregnant women, 95 HIV+ on ART (Tenofovir-Lamivudine-Efavirenz, previously ART naïve) and 96 HIV- were followed prospectively in Kampala, Uganda. Data were collected at 36 wks gestation (PG36), 2 (PP2) and 14 wks postpartum (PP14). Dual-energy x-ray absorptiometry was used to measure bone phenotype (aBMD, bone mineral content (BMC), bone area (BA), and size-adjusted BMC (SA-BMC, adjusted for height or length, weight and BA) of the whole body (WB) and lumbar spine (LS) in mother-baby pairs, and total hip (TH) in mothers. The primary outcome was the difference between groups in % change (± SE) in maternal LS aBMD between PP2 and PP14. Secondary outcomes included changes in maternal markers of bone formation (P1NP and BAP) and resorption (CTX), serum 25-hydroxy vitamin D (25(OH)D), parathyroid hormone (PTH), plasma and urine concentrations of creatinine (Cr), calcium (Ca), phosphate (PO4) and magnesium (Mg), urine mineral:creatinine ratios, TmCa/GFR and TMP/GFR, respectively), breastmilk mineral composition (Ca, P, Na, K and Na/K ratio); and infant growth Z-scores and bone mineral. Statistical models were adjusted for potential confounders. Median maternal age was 24.5 (IQR 21.1, 26.9) yrs. Mean gestation was 40.9±1.8 wks and not significantly different between groups. All women were breastfeeding at PP2 and PP14. More HIV+ women reported exclusive breastfeeding (PP2: 82.9% v 58.7%, p=0.0008; PP14: 86.7% v 66.2%, p=0.002). Body weight was 4-5% lower in HIV+ women. By PP14, mean duration of ART was 29.3±5.1 wks, adherence was >95%, and the median CD4 count was 403 (IQR 290-528) cells/mm3. Maternal aBMD decreased between PP2 and PP14 at all skeletal sites in both groups as expected in lactation. Reductions in LS aBMD were not significantly different between groups (-1.8±0.4% vs -2.5±0.4%, p=0.3). However, HIV+ women had a significantly greater reduction in TH aBMD which persisted after adjustment for body size (-3.7±0.3% vs -2.7±0.3%, p=0.04). Median serum 25(OH)D was 67.4 nmol/L (IQR 54.8, 83.7) at PG36 and 57.6 nmol/L (48.7, 70.1) at PP14 with no significant difference between groups. Changes in 25(OH)D and PTH from PG36 to PP14 were not significantly different between groups (25(OH)D: -13.9±4.1% vs -11.1±3.1%; PTH: +60.0±6.4% vs +57.6±6.4%; both p>0.05). However, HIV+ women had 33-35% greater plasma PTH concentrations at both PG36 and PP14. Bone formation and resorption markers increased in both groups between PG36 and PP14. HIV+ women had greater increases (CTX: +74.6±5.9% vs +56.2±5.9%; P1NP: +100.3±5.0% vs +72.6±5.0%; BAP: +67.2±3.6% vs +57.1±3.6%, all p<0.05). They also had a greater decrease in plasma Ca (-6.6±0.5% vs-3.8±0.5%, p≤0.0001) and greater increase in plasma phosphate (+14.4±2.0% vs +7.7±2.0%, p=0.02). Changes in plasma Cr and Mg, TmP/GFR and urine mineral:creatinine ratios were not significantly different between the groups. However, at both PG36 and PP14, HIV+ had significantly lower mean plasma Ca (PG36: -1.0±0.5%; PP14: -4.1±0.6%) and TmP/GFR (PG36: -11.4±3.1%; PP14: -7.2±3.0%) but higher PTH (PG36: +33.0±7.0%; PP14: +35.3±7.6%) compared to HIV- women (all p<0.05). Mean breastmilk Ca decreased between PP2 and PP14, and the changes were not different between the groups (-19.9±3.0% vs -24.2±3.1%, p=0.3). There were no significant changes in breastmilk phosphorus (P) in both groups, but HIV+ women had significantly higher concentrations (PP2: +9.7±3.8%, p=0.01; PP14:+9.6±3.5 %, p=0.007). Breastmilk P was significantly correlated with maternal plasma [CTX] in a separate ANCOVA model (β = +0.13±0.04% per 1% increase in CTX, p=0.0003). Mean breastmilk Na, K concentrations and Na/K decreased between PP2 and PP14 in both groups. However, HIV+ women had a smaller decrease in breastmilk Na (-44.3±8.9% vs -72.6±9.0%, p=0.03). They also had a trend towards smaller reduction in Na/K ratio (-22.2±9.3% vs -46.6.6±9.5%, p=0.07). Babies born to HIV+ mothers (HIV-exposed infants, HEI) had significantly lower gains in weight +53.0±1.4% vs +57.5±1.4%, p=0.02) compared to HIV-unexposed infants (HUI), and also lower weight-for-age (-0.47±0.16, p=0.003) and length-for-age (-0.53±0.18, p=0.005) Z-scores at PP14. HEI had a slower gain in WB BMC (+51.2±1.9% vs +57.3±1.9%, p=0.02), but the difference was not significant after adjustment for body size (-6.0±3.5% vs -7.6±3.8%, p=0.2); showing that the bone mineral accretion was appropriate for achieved infant size. In contrast, HEI had a greater increase in LS BMC (+29.5±1.7% vs +24.4±1.7%, p=0.03), a difference which remained after size-adjustment (+9.4±5.8% vs +4.3±6.2%, p=0.02). This is the first study to compare changes in maternal aBMD and bone metabolism between HIV+ mothers on Option B+ ART and HIV- counterparts. The results show a greater reduction in TH aBMD in Ugandan HIV+ women on Option-B+ ART compared to HIV- in the first three months of lactation, consistent with their greater increases in bone turnover markers, lower TmP/GFR and plasma phosphate, and higher breastmilk phosphorus concentration. Also, HEI have slower growth and whole body bone mineral accretion compared to HUI. It is important to determine if these changes are temporary or have long-term consequences for the bone health of the mother and child.Item Open Access THE ROLE OF ALPHA OXIDATION IN LIPID METABOLISM(2018-10-22) Jenkins, Benjamin JohnRecent findings have shown an inverse association between the circulating levels of pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0) with the risk of pathological development in type 2 diabetes, cardio vascular disease and neurological disorders. From previously published research, it has been said that both these odd chain fatty acids are biomarkers of their dietary intake and are significantly correlated to dietary ruminant fat intake. However, there are profound studies that show the contrary where they do not display this biomarker correlation. Additionally, several astute studies have suggested or shown odd chain fatty acid endogenous biosynthesis, most often suggested via alpha oxidation; the cleavage of a single carbon unit from a fatty acid chain within the peroxisomes. To better understand the correlations and interactions between these two fatty acids with pathological development, the origin of these odd chain fatty acids needed to be determined, along with confirming their association with the disease aetiology. To minimise animal & human experimentation we made use of existing sample sets made available through institutional collaborations, which produced both animal and human interventional study samples suitable for odd chain fatty acid investigations. These sample collaborations allowed us to comprehensively investigate all plausible contributory sources of these odd chain fatty acids; including from the intestinal microbiota, from dietary contributions, and derived from novel endogenous biosynthesis. The investigations included two intestinal germ-free studies, two ruminant fat diet studies, two dietary fat studies and an ethanol intake study. Endogenous biosynthesis was assessed through: a stearic acid infusion, phytol supplementation, and an Hacl1 knockout mouse model. A human dietary intervention study was used to translate the results. Finally, a study comparing circulating baseline C15:0 and C17:0 levels with the development of glucose intolerance. We found that the circulating C15:0 and C17:0 levels were not significantly influenced by the presence or absence of intestinal microbiota. The circulating C15:0 levels were significantly and linearly increased when the C15:0 dietary composition increased; however, there was no significant correlation in the circulating C17:0 levels with intake. Circulating levels of C15:0 were affected by the dietary composition and factors affecting the dietary intake, e.g. total fat intake and ethanol, whereas circulating C17:0 levels were found to be independent of these variables. In our studies, the circulating C15:0 levels were not significantly affected by any expected variations in alpha oxidation caused by pathway substrate inhibition or gene knockout. However, C17:0 was significantly related, demonstrating it is substantially endogenously biosynthesised. Furthermore, we found that the circulating C15:0 levels, when independent of any dietary variations, did not correlate with the progression of glucose intolerance when induced, but the circulating C17:0 levels did significantly relate and linearly correlated with the development of glucose intolerance. To summarise, the circulating C15:0 and C17:0 levels were independently derived; the C15:0 levels substantially correlated with its dietary intake, whilst the C17:0 levels proved to be separately derived from its endogenous biosynthesis via alpha oxidation of stearic acid. C15:0 was found to be minimally endogenously biosynthesised via a single cycle of beta oxidation of C17:0 in the peroxisomes, however, this did not significantly contribute to the circulating levels of C15:0. Additionally, only the baseline levels of C17:0 significantly correlated with the development of glucose intolerance. These findings highlight the considerable differences between both of these odd chain fatty acids that were once thought to be homogeneous and similarly derived. On the contrary, they display profound dietary, metabolic, and pathological differences.Item Open Access The Safety and Immunostimulatory Properties of Amorphous Silica Nanoparticles <10 nm in Diameter(2018-02-07) Vis, BradleyHumans are exposed to high levels of amorphous silica on a daily basis, via the diet and the use of cosmetic and pharmaceutical products. Amorphous silica particles (10-200 nm) have also been developed for use in biomedical applications, including as binding agents in tissue repair, drug and gene therapy delivery agents, coatings for medical contrast agents and as vaccine adjuvants. Numerous studies have already been conducted to evaluate the cellular toxicity of these silica particles but still little is known about their effects both in vitro and in vivo, especially of nanosilica particles under 10 nm in diameter. The aim of this thesis was to investigate the cellular and in vivo activity of < 10 nm diameter nanosilica particles with different properties (e.g., size and dissolution rate in dilute conditions) as it may infer upon safety after exposure via the diet and intravenous administration (biomedical applications). First, the cytotoxicity of sub-10 nm nanosilica particles, fully characterized by size, dissolution rate, zeta-potential and by NMR spectroscopy, on immune cell function was assessed using transformed and cancerous cell lines and primary cells. The particles were toxic to the immune cells in a dose dependent manner and impaired certain cellular functions. Primary cells were most susceptible to nanosilica induced death and, of the primary cells, phagocytes were most susceptible to its cytotoxicity. Further investigations were conducted to assess the effect of nanosilica on T cells, as there was evidence suggesting that nanosilica particles were directly interacting with these cells. Nanosilica particles 3.6 nm in diameter were found to have a significant effect on T cell function. The particles induced numerous markers of T cell activation, including CD25 and CD69 on CD4 T cells, CD8 T cells, gamma-delta T cells and NK/NKT cells, CD95 on CD4 and CD8 T cells, CD40L, FoxP3, LAP, GARP on CD4 T cells, and IFN-gamma production, but it did not induce T cell proliferation. The particles were found to activate T cells regardless of their antigenic specificity. Further investigations showed that nanosilica interacts with the T cell receptor complex, the first documented case of a non MHC-coated nanoparticle directly interacting with this receptor complex. The nanoparticulate induced signalling through Zap70, LAT, and, eventually, through NFAT but not through MAPK. Similar signalling in the literature has been shown to induce a hyporesponsive T cell state (anergy) or activation induced cell death. The induction of the CD25 and CD69 T cell activation markers was limited to nanosilica particles below 10 nm in size, while similarly sized iron hydroxide nanoparticles (3-5 nm) only induced low levels of CD69 expression on T helper cells. Finally, it was shown that nanosilica is capable of inducing T cell activation in whole blood, though the T cell responses were greatly attenuated. Although identification of activation pathway in vivo remains elusive, the nanosilica particles were shown to have therapeutic value, decreasing murine subcutaneous tumour growth rate and significantly reducing the formation of lung metastases. Whether these in vivo responses are related to T cell activation identified in vitro remains unclear.Item Open Access Maternal nutrition, breast milk micronutrients and infant growth in rural GambiaEriksen, Kamilla GehrtMaternal nutrition, breast milk micronutrients and infant growth in rural Gambia The World Health Organization recommends exclusive breastfeeding for the first six months of an infant’s life. However, the evidence base to support the adequacy of breast milk with respect to infant micronutrient status, across the duration of exclusive breastfeeding, among women who enter pregnancy and lactation with a poor nutritional status is limited. The research presented in this thesis explores the relationship between maternal nutritional status, breast milk micronutrients and infant status in a rural sub-Saharan context. Existing evidence for associations between maternal dietary intake and nutritional status and breast milk micronutrient composition were systematically reviewed. Most effected by maternal nutrition were breast milk water-soluble vitamin concentrations (except for folic acid), fat-soluble vitamin concentrations were less influenced, and mineral concentrations were generally unaffected (except for iodine and selenium). Next, the impact of feeding practice on infant growth in rural Gambia was explored. In this population, where growth faltering across the first two years of life is endemic, exclusive breastfeeding to six months of age had limited benefit on infant growth. Finally, the impact of maternal multiple micronutrient supplementation on breast milk iodine, thiamin, riboflavin, vitamin B6 and B12 was explored. Supplementation during pregnancy positively influenced maternal status for all investigated micronutrients, and modestly increased breast milk iodine and riboflavin concentrations across the first six months of lactation. No effects on breast milk concentrations of thiamin, vitamin B6 or B12, and limited effect on infant postpartum status, were observed. The research presented in this thesis suggests that concentrations of breast milk micronutrients may be insufficient in settings where maternal micronutrient status is poor, with likely consequences for infant health. This research supports the need for interventions to improve the nutritional status of pregnant and lactating women in resource-poor settings alongside the promotion of exclusive breastfeeding for optimal health outcomes for infants as well as their mothers. Kamilla Gehrt Eriksen, September 2017Item Open Access HIV, body composition, bone and vitamin D status in South African women(2013-10-08) Hamill, MatthewItem Open Access The muscle-bone in children and adolescents with and without cystic fibrosis(2016-09-01) riddell, amy; riddell, amy [0000-0002-7646-8860]Puberty is a crucial period for rapid changes in bone mineral, size, geometry, and microarchitecture. The mechanostat theory postulates that increased mechanical loading will affect bone phenotype and strength during development and in later life. Individuals with cystic fibrosis(CF) have an increased risk of developing osteoporosis and fragility fractures in young adulthood, which may be caused by poor growth. The aim was to investigate whether sex and disease status modified the relationship between: 1) puberty and bone, and 2) muscle and bone. This would contribute to the understanding of how sex(malesvs.females) and disease group(CFvs.controls) alters the relationship between bone and muscle in children and adolescents as they transition through puberty and who, on a population level, differ in the prevalence of osteoporosis and risk of fracture in later life. This observational study used novel imaging and muscle assessment techniques to measure bone and muscle parameters in White Caucasian children and adolescents, aged 8 to 16 years, living in the UK, with children with CF(n=65) and controls(n=151). Anthropometry and pubertal status were assessed. Dual energy x-ray absorptiometry, peripheral quantitative computed tomography(pQCT), high-resolution pQCT, and jumping mechanography were used to measure bone and muscle outcomes. ANCOVA with Scheffé post hoc and multiple linear regression tests were performed. Data were adjusted according to the research aims and included covariates; sex, disease group, pubertal stage, age, quadratic age, height, weight, maximum force(Fmax), and maximum power(Pmax). Data are presented as beta-coefficient(%) and p-value, with the significance level set to p<0.05. In height adjusted analyses, among healthy participants, females had smaller bones and lower bone density compared to males. With pubertal maturation, females had lower apparent gains in the distal and proximal total area(Tt.ArandCSA), distal cortical porosity(Ct.Po) and proximal bone strength(SSI) but higher apparent gains in distal and proximal cortical bone density(Ct.BMD,Ct.TMD,vBMD). Females had consistently lower distal total area(total CSA) and density(totalvBMD), distal trabecular density(BV/TV) and number(Tb.N), and proximal cortical area(CSA) compared to males, across all stages of puberty. With increasing muscle force(Fmax), females had higher apparent gains in total body less head bone mineral(TBLH BMC) and bone area(BA), distal total and trabecular density(totalandtrabvBMD) compared to males. In contrast, with increasing muscle power (Pmax), females had higher apparent gains in distal total and cortical densities(D100,Ct.BMDandCt.TMD), and distal trabecular thickness(Tb.Th), and proximal cortical density(corticalvBMD) but lower apparent gains in distal cortical porosity(Ct.Po) and trabecular number(Tb.N) compared to males. In height adjusted analyses, participants with CF had smaller bones and lower bone density compared to controls. With increasing pubertal maturation, participants with CF had lower apparent gains in total body less head bone mineral and bone area, and in distal trabecular density, cortical porosity, and trabecular thickness compared to controls. Participants with CF had consistently lower distal total and cortical area, distal total and trabecular densities and proximal bone strength compared to controls, across all stages of puberty. With increasing muscle force, participants with CF had lower apparent gains in total body less head bone mineral and bone area, distal total density, trabecular density, and trabecular number. In contrast, with increasing muscle