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Neonates, particularly those born preterm (PTB) and low birthweight (LBW), are especially susceptible to bacterial infections that cause an estimated 225,000 deaths annually. Iron is a vital substrate for the most common organisms causing septicaemia. Full-term babies elicit an immediate post-natal hypoferremia assumed to have evolved as an innate defence. This thesis aimed to test whether preterm and low birthweight newborns are capable of a similar response. A longitudinal observational study was conducted in 430 hospital-delivered Gambian babies. Demographic, anthropometric and haematological data were collected from 152 babies who were either PTB (between ≥32- < 37 weeks gestational age) and/or LBW (< 2500g) (PTB/LBW) and 278 full-term, normal-weight babies (FTB/NBW). Blood was sampled from the umbilical cord and matched venous blood samples from all neonates between 6-24 hours after delivery. An additional matched venous blood sample was taken from all full-term, normal birth weight newborns between 24-192 hours of life. In both FTB/NBW and PTB/LBW neonates, serum iron decreased 3-fold compared to umbilical blood concentrations within 12h of delivery (23·3±0·35 vs 7·5±0·22 ng/ml, P < 0.001, n=425). Hepcidin levels doubled (27·0±0·96 vs 52·9±1·63 ng/ml, P < 0·001, n=425). In FTB/NBW neonates, a steady increase in serum iron and TSAT follows (to 16.5±3.9μmol/L and 36.7±9.2% respectively by 136-192hrs postdelivery), even in the presence of relatively high serum hepcidin levels (45.2±19.1ng/ml) suggestive of hepcidin resistance possibly caused by iron saturation of macrophages. Our findings confirm that a very rapid hypoferremia occurs in the early hours of post-natal life with evidence that it is mediated by an increase in hepcidin. The strength and consistency of this effect in all neonates indicates that it may have evolved as an innate immune response designed to protect newborns from bacterial septicaemia.

The Ketogenic diet (KD) is an alternative treatment option for people with drug-resistant epilepsy. It can reduce seizure frequency, but it is resource-intensive and may cause adverse side effects. Predictors of response – which, in the absence of specific metabolic disorders, are unknown – would improve patient selection and may enhance understanding of how the KD exerts its antiseizure effect. This project is concerned with identifying possible genetic markers of response to the KD. DNA was extracted from capillary blood taken from individuals who were following the KD for their epilepsy, or who had done so in the past. Individuals were classed as responders if they achieved ≥50 seizure reduction. Response was classified at various follow-up points, as well as a summary of response over time. Association studies were conducted using candidate gene (KCNJ11 and BAD) sequencing, genome-wide single nucleotide polymorphism array, and whole exome sequencing data to determine whether there was an over-representation of specific gene variants in KD responders, compared to non-responders. Common variation in KCNJ11 and BAD was not significantly associated with KD response. rs12204701 reached significance in the array-based genome-wide association study including common variants, with 3-month diet response as the phenotype. No significant results were obtained when summary diet response was taken as the phenotype. Using the gene-based c-alpha test with the exome sequencing data, including all exonic and splicing variants, ANKRD36C reached significance; using a pathway-based count of case-unique alleles test, the ‘ERBB1 Internalisation’ pathway reached significance. No further significant results were obtained from the exome sequencing data when using other gene- and pathway-based tests or when variants were further filtered according to predicted functional consequence. Other genes with large differences in responder/non-responder minor or alternative allele counts are also of interest. It is unknown how these may contribute to variability in KD response. Some common themes were identified amongst the genes and pathways of significance and suggestive significance: cell cycling, apoptosis, glucose homeostasis, neurological processes and triglyceride biosynthesis. It is biologically plausible that these processes influence KD response, although it is likely that many genes play a role. A larger sample size is needed in order to improve power to detect genotypic-phenotypic associations and increase confidence in the importance of the genes of interest.