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Having been awarded the 2019 British Nutrition Foundation Annual Prize I had looked forward to delivering a lecture to assembled guests at the BNF Annual Day at the Royal College of Physicians in London, in 2020. Unfortunately, this was not to be; the COVID‐19 global pandemic prevented a face‐to‐face meeting, and my talk was delivered remotely. In the paper, I shall summarise some of the research that I have carried out during my career as a nutrition scientist. I shall not dwell in much detail on any single aspect of my work but rather I shall attempt to show how my research interests developed over the decades, how one thing led to another, so to speak. The elements of my work that I have selected, in order to make this short walk together, commence with vitamin B2, riboflavin and a consideration of two particular aspects of function. I then move on to folate in the context of homocysteine metabolism and cardiovascular disease and finally consider the role of this vitamin and other methyl donors in cancer risk and outcome. [ABSTRACT FROM AUTHOR]

The copper catalysed oxidation of homocysteine has been studied by electron paramagnetic resonance (EPR) spectroscopy and spin trapping techniques to determine the nature of free radical species formed under varying experimental conditions. Three radicals; thiyl, alkyl and hydroxyl were detected with hydroxyl being predominant. A reaction mechanism is proposed involving Fenton chemistry. Inclusion of catalase to test for intermediate generation of hydrogen peroxide showed a marked reduction in amount of hydroxyl radical generated. In contrast, the addition of superoxide dismutase showed no significant effect on the level of hydroxyl radical formed. Enhanced radical formation was observed at higher levels of oxygen, an effect which has consequences for differential oxygen levels in arterial and venous systems. Implications are drawn for a higher incidence of atherosclerotic plaque formation in arteries versus veins. [ABSTRACT FROM AUTHOR]

We have previously reported that supplementation with folic acid (1.2 mg day(-1) for 12 week) elicited a significant improvement in the folate status of 61 healthy volunteers. We have examined effects of this supplement on markers of genomic stability. Little is known about the effect of folate supplementation on DNA stability in a cohort, which is not folate deficient. Preintervention, there was a significant inverse association between uracil misincorporation in lymphocyte DNA and red cell folate (P < 0.05). In contrast, there were no associations between folate status and DNA strand breakage, global DNA methylation or DNA base excision repair (measured as the capacity of the lymphocyte extract to repair 8-oxoGua ex vivo). Folate supplementation elicited a significant reduction in uracil misincorporation (P < 0.05), while DNA strand breakage and global DNA methylation remained unchanged. Increasing folate status significantly decreased the base excision repair capacity in those volunteers with the lowest preintervention folate status (P < 0.05). Uracil misincorporation was more sensitive to changes in folate status than other measures of DNA stability and therefore could be considered a specific and functional marker of folate status, which may also be relevant to cancer risk in healthy people. [ABSTRACT FROM AUTHOR]

In the past decade, the understanding of folate bioavailability, metabolism and related health issues has increased, but several problems remain, including the difficulty of delivering the available knowledge to the populations at risk. Owing to the low compliance of taking folic acid supplements, for example, among women of child-bearing age who could lower the risk of having a baby with a neural tube defect, food-based strategies aimed at increasing the intake of folate and other B-group vitamins should be a priority for future research. These should include the development of a combined strategy of supplemental folate (possibly with vitamin B12), biofortification using engineered plant-derived foods and micro-organisms and food fortification for increasing folate intakes in the general population. Currently, the most effective population-based strategy to reduce NTDs remains folic acid fortification. However, the possible adverse effect of high intakes of folic acid on neurologic functioning among elderly persons with vitamin B12 deficiency needs urgent investigation. The results of ongoing randomized controlled studies aimed at reducing the prevalence of hyperhomocysteinemia and related morbidity must be available before food-based total population approaches for treatment of hyperhomocysteinemia can be recommended. Further research is required on quantitative assessment of folate intake and bioavailability, along with a more thorough understanding of physiological, biochemical and genetic processes involved in folate absorption and metabolism.European Journal of Clinical Nutrition (2006) 60, 287–294. doi:10.1038/sj.ejcn.1602315; published online 26 October 2005 [ABSTRACT FROM AUTHOR]

Objective:To test whether supplementary antioxidants immediately following acute ischaemic stroke will enhance antioxidant capacity and mitigate oxidative damage.Design:A randomised controlled trial.Setting:A university teaching hospital.Subjects:A total of 48 acute ischaemic stroke patients within 12 h of symptom onset.Intervention:Daily oral 800 IU (727 mg) of α-tocopherol and 500 mg of vitamin C (n=24), or no treatment (n=24) for 14 days. Treatment group and controls were matched for stroke subtype and age.Main outcome measures:α-Tocopherol, ascorbic acid, total antioxidant capacity (TAOC), plasma malondialdehyde (MDA) and C-reactive protein (CRP) before treatment, at day 7 and day 14 following recruitment.Results:In all, 14 days of vitamin supplementation significantly improved plasma α-tocopherol and ascorbic concentrations in the treatment group compared with the decrease seen in the control group (P<0.005 for difference in cumulative changes). TAOC increased significantly in the treatment group compared with controls (P<0.003). There was a significant reduction in plasma MDA concentration in the treatment group, in contrast to the increase seen in the control group (P<0.002).Conclusion:Supplementation with antioxidant vitamins within 12 h of onset of acute ischaemic stroke increased antioxidant capacity, reduced lipid peroxidation products and may have an anti-inflammatory effect.Sponsorship:Sheffield Teaching Hospital NHS Trust.After adjusting for clinical complications CRP concentrations within 90 days postinfarct were significantly lower in the treatment group compared with controls.European Journal of Clinical Nutrition (2005) 59, 1367–1373. doi:10.1038/sj.ejcn.1602248; published online 10 August 2005 [ABSTRACT FROM AUTHOR]

BACKGROUND:: Various mechanisms have been proposed to explain the association between plasma total homocysteine (tHcy) and risk of cardiovascular disease, including oxidative activity of homocysteine. OBJECTIVE:: To explore the putative role of reactive oxygen species in the association between plasma tHcy and risk of cardiovascular disease in healthy individuals. DESIGN:: A double-blind, placebo-controlled crossover intervention to increase folate intake through diet (increased consumption of folate-rich foods) and supplement (400 ug folic acid) was carried out in 126 healthy men and women. Measurements were made of antioxidant activity in red blood cells and plasma, and products of oxidant damage in plasma. RESULTS:: Diet and supplement-based interventions led to an increase in measures of folate status and a reduction in plasma tHcy. This was not associated with any significant change in measures of antioxidant activity (plasma and red blood cell glutathione peroxidase activity and red blood cell superoxide dismutase activity) or oxidant damage (plasma malondialdehyde), although an improvement in plasma total antioxidant capacity just failed to reach significance. CONCLUSIONS:: In healthy individuals lowering plasma tHcy does not have any functional implications regarding oxidative damage.European Journal of Clinical Nutrition (2003) 57, 483-489. doi:10.1038/sj.ejcn.1601554 [ABSTRACT FROM AUTHOR]

The term 'optimum nutrition' has evolved from a perceived need to base recommendations for nutrient intakes firmly in the context of function. It follows that 'optimum nutritional status' for individual nutrients should be defined in terms of biochemical or physiological markers having some functional value but also showing an appropriate relationship to nutrient intake. The present short review considers the current position regarding such markers for riboflavin, pyridoxine and niacin. It is concluded that whilst there are several biochemical measures which respond to changes in intake of each of these vitamins, no single measure is wholly satisfactory as a marker of optimum status. [ABSTRACT FROM AUTHOR]

The effects of maternal intake and gestational age on materno-fetal transport of vitamin C were investigated in female Dunkin-Hartley guinea-pigs. Twenty-four time-mated dams were fed on either a moderate-vitamin C (group A) or a high-vitamin C (group B) diet, throughout pregnancy. At days 49, 63 and 66 of gestation, and at term, three animals from each group were killed and fetuses removed by hysterectomy. Plasma, liver, kidney, lungs, heart, placenta and amniotic fluid were collected from dams and fetuses and subsequently analysed for vitamin C. Fetal plasma and amniotic fluid concentrations showed negative associations with gestational age for both dietary groups, independent of an effect of dam (P < 0.001). A similar, though not significant, effect of gestational age was observed on placental vitamin C and group A fetal tissue concentrations. Fetal plasma, placental and amniotic fluid vitamin C concentrations were significantly higher in group B than group A (P < 0.001), suggesting the influence of maternal diet. Although the level of maternal vitamin C intake can influence the circulating concentration in the fetus, there is a decrease associated with increasing gestational age, independent of the maternal diet. The gestational age-dependent change in the fetal accumulation of vitamin C may reflect changes in the rate of placental transfer. [ABSTRACT FROM PUBLISHER]

Abstract:The impaired absorption and metabolism of Fe seen in riboflavin defiaency is attributed, at least in part, to a hyperproliferative response in the small intestine, associated with an altered morphology. Studies were conducted in female weanling Wistar rats to explore further the effect of riboflavin deficiency on the cytokinetics and structure of the small intestine. Feeding a riboflavin-deficient diet for 8 weeks from weaning resulted in a significantly lower villus number, a significant increase in villus length and an increased rate of transit of enterocytes along the villi, compared with weight-matched controls. A second experiment focused on the 3 weeks after weaning and showed that riboflavin deficiency inhibits the increase in villus number observed in control animals over this period. We suggest that riboflavin deficiency induced at weaning impairs the normal increase in villus number and that prolonged deficiency leads to an adaptive increase in length of villi and depth of crypts. [ABSTRACT FROM PUBLISHER]

Female Wistar rats were weaned onto a diet deficient in riboflavin and compared with weight-matched and ad lib.-fed controls. The effects of riboflavin deficiency on villus morphometry and enterocyte number on the villi in the upper small intestine were studied. Riboflavin depletion was associated with increased villus length and a proportional increase in the number of cell positions along the villi. The total DNA, RNA and protein contents in the intestinal mucosa were not significantly different between any of the groups. Villus hypertrophy in the absence of increased cell number in the small intestine suggests that villus number may be reduced in riboflavin deficiency. Riboflavin deficiency did not influence the number of mucus-producing goblet cells or the amount of mucosal glycoprotein in the small intestine. Impaired production of mucus appeared not to be involved in the structural and functional changes seen in riboflavin deficiency. [ABSTRACT FROM PUBLISHER]

Aim: To evaluate the relative importance of biochemical markers of antioxidant status, gestational age, and parameters of neonatal care in the clinical outcome of premature infants.Method: A prospective, observational, longitudinal study of the association between these factors was conducted. Blood was collected from an in situ arterial line within two hours of birth and at intervals thereafter, when blood was drawn for routine clinical purposes. Outcome was assessed as death, or survival with or without bronchopulmonary dysplasia (BPD). One hundred and forty four babies of 22 to 39 weeks of gestation, who required intensive care at the Jessop Hospital for Women, between January 1993 and April 1994, were recruited.Results: Low gestational age at birth was the most important predictor of mortality and the development of BPD. Having corrected for gestational age, low plasma antioxidant activity at birth was an independent risk factor for mortality. Plasma vitamin C at birth was significantly higher in the babies who died compared with those with a good outcome, but this effect was not sustained after correcting for gestational age. Repeated measures of Analysis of Variance revealed a postnatal increase in antioxidant activity, caeruloplasmin, retinol, cholesterol corrected alpha tocopherol, and red blood cell superoxide dismutase (SOD) activity. Vitamin C, on the other hand, declined in all groups after birth. Logistic regression analysis revealed that the greater the number of packed cell transfusions received during intensive care, and the higher the concentration of vitamin C on the second day of life, the greater the risk of developing BPD.Conclusions: After correcting for the effect of gestational age, low plasma antioxidant activity at birth was an independent risk factor for mortality. Frequent blood cell transfusions over the first week of life are associated with an increased risk of developing BPD. This association may be causal. [ABSTRACT FROM AUTHOR]

Concentrations of circulating antioxidants may be important in the aetiology of disease in premature infants. Blood samples were taken from 49 premature infants within two hours of birth. Plasma ascorbic acid, caeruloplasmin, and the ability of plasma to prevent lipid peroxidation in vitro were measured. Plasma ascorbic acid concentrations at birth ranged from 26.3 to 185.4 mumol/l. Plasma antioxidant activity at birth (microliter plasma required to inhibit lipid peroxidation) showed a strong negative correlation with plasma ascorbic acid and the plasma ascorbic acid to caeruloplasmin ratio. After correcting for gestational age and birth weight, plasma antioxidant activity at birth remained a significant predictor of mortality. Such plasma antioxidant activity is partly determined by the ferroxidase activity of caeruloplasmin. This may be modulated by high concentrations of ascorbic acid which may inhibit the antioxidant activity of plasma and thereby influence outcome. [ABSTRACT FROM AUTHOR]

BACKGROUND: Impaired iron handling in riboflavin deficiency is thought to be partially a result of significant morphological and cytokinetic changes within the small intestine. AIMS: The aim of the study was to find out if the responses of the rat small intestine to riboflavin deficiency induced at weaning could be reversed upon repletion. SUBJECTS: 48 female weanling Wistar rats were used for the purpose of the study. METHODS: Rats were fed a riboflavin deficient diet or a complete control diet for a period of five weeks followed by a repletion period of up to three weeks. Rats were killed on day 0, 2, 7, or 21 of repletion. The duodenum was removed and fixed for subsequent analysis. RESULTS: Five weeks of riboflavin deficiency significantly changed the morphology and cytokinetics of the duodenum; the changes were not reversed within the 21 day repletion period despite biochemical evidence for a correction of the deficiency. CONCLUSIONS: The results show that the small intestine cannot readily recover from a period of riboflavin deficiency induced at weaning, supporting the notion that the weaning period is a critical time for gastrointestinal development and highlighting the importance of adequate nutrition during infancy. [ABSTRACT FROM PUBLISHER]