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Biomedical subjects

Andrew M Prentice

Publications and source records attributed to Andrew M Prentice.

At least 19 recordsLinked to original sources
PubMed2006

Seasonal childhood anaemia in West Africa is associated with the haptoglobin 2-2 genotype.

BACKGROUND: Anaemia is a major cause of morbidity and mortality for children in Africa. The plasma protein haptoglobin (Hp) binds avidly to free haemoglobin released following malaria-induced haemolysis. Haptoglobin polymorphisms result in proteins with altered haemoglobin-binding capacity and different antioxidant, iron-recycling, and immune functions. Previous studies examined the importance of haptoglobin polymorphism in malaria and iron homeostasis, but it is unknown whether haptoglobin genotype might be a risk factor for anaemia in children in a malaria-endemic area. METHODS AND FINDINGS: A cohort of 780 rural Gambian children aged 2-6 y was surveyed at the start and end of the malaria season. Samples were taken to assess haemoglobin (Hb) concentration, iron status (ferritin, zinc protoporphyrin, transferrin saturation, and soluble transferrin receptor concentration), haptoglobin concentration, alpha-1-antichymotrypsin (a measure of inflammation), and malaria parasites on blood film. We extracted DNA and genotyped for haptoglobin, sickle cell, and glucose-6-phosphate (G6PD) deficiency. Mean Hb levels fell over the malaria season. Children with the haptoglobin 2-2 genotype (17%) had a greater mean drop in Hb level over the malaria season (an 8.9 g/l drop; confidence interval [CI] 5.7, 12.1) compared to other children (a 5.1 g/l drop; CI 3.8, 6.4). In multivariate regression analysis, controlling for baseline Hb level, age group, village, malaria parasites on blood film, iron status, haptoglobin concentration, and G6PD deficiency, haptoglobin genotype predicted Hb level at the end of the malaria season (p = 0.0009, coefficient = -4.2). Iron status was not influenced by haptoglobin genotype. CONCLUSIONS: The finding that haptoglobin 2-2 genotype is a risk factor for anaemia in children in a malaria-endemic area may reflect the reduced ability of the Hp2-2 polymer to scavenge free haemoglobin-iron following malaria-induced haemolysis. The magnitude of the effect of haptoglobin genotype (4 g/l Hb difference, p = 0.0009) was comparable to that of G6PD deficiency or HbAS (3 g/l difference, p = 0.03; and 2 g/l difference, p = 0.68, respectively).

Anemia↗
PubMed2006

Iron and infection: effects of host iron status and the iron-regulatory genes haptoglobin and NRAMP1 (SLC11A1) on host-pathogen interactions in tuberculosis and HIV.

There are many lines of evidence illustrating that iron plays a pivotal role in modulating the battle for survival between mammalian hosts and their pathogens. Each displays considerable genetic investment in a wide range of mechanisms for acquiring and maintaining iron. These competitive mechanisms are highly complex, existing within an interacting matrix of absorption, transport, storage and detoxification systems, each of which are iron-responsive and thus able to adapt to the different phases of infection. Considerable genetic polymorphism in some of these systems, with signals of geographic selection in the hosts, and niche selection in the pathogens, indicates that they are critical for species survival. In this review we briefly summarize the role of iron in host immune function before reviewing the available evidence that iron modulates susceptibility and disease outcomes in HIV and TB (tuberculosis). We then examine the putative role of iron-related host genes by focussing on two candidate genes, haptoglobin and NRAMP1, for which there are common polymorphic variants in humans with strong evidence of functionally distinct biochemical phenotypes that would be predicted to influence the course of HIV and TB infections. Finally, we examine the limited evidence so far available that nutrient-gene interactions are likely to influence the way in which gene variants can protect against infection. We conclude that there is a wealth of evidence associating alterations in iron balance and in iron-regulatory systems with disease progression, but that many issues related to the direction of causality, mechanisms of action and sensitivity to pharmacological intervention remain to be elucidated. Since iron is probably the most widely prescribed compound throughout the world, used in both preventative and treatment regimens, a deeper understanding of the host-pathogen interactions relating to iron constitutes an important area for both basic and clinical research.

Cation Transport Proteins↗
PubMed2006

Early immunological development and mortality from infectious disease in later life.

In rural Gambia the risk of mainly infection-related mortality is 10-fold higher for adults born in the nutritionally-debilitating 'hungry' season, suggesting that immune function may be compromised by events early in life. The current programme of research focuses on the biological mechanisms underlying this hypothesis, exploring early-life environmental influences on immune development and the long-term functional consequences these influences may have. Results obtained to date show that thymus development during infancy is critically sensitive to environmental exposures, with smaller thymuses observed in the hungry season. Measurement of the frequency of T-cell receptor excision circles indicate that thymus function is also sensitive to seasonal influences, with further studies implicating variations in breast-milk IL-7 as a possible mediator of these effects. Studies in adults have shown that size at birth is positively correlated with antibody responses to vaccination with polysaccharide antigens, thus providing evidence for long-term functional deficits. The present paper will review progress made to date within this field of research.

Adult↗
PubMed2006

Statistical modelling of the seasonality of preterm delivery and intrauterine growth restriction in rural Gambia.

We have developed a methodology for comparing the seasonal influences on two outcomes, when those influences may act cumulatively or instantaneously. We have used this to compare the seasonal pattern of intrauterine growth retardation (IUGR, as reflected by weight-for-gestational-age) and preterm delivery (as assessed by Dubowitz scoring) among 1718 infants born in rural Gambia. Both outcomes were analysed as binary variables: small-for-gestational-age (SGA, <10th centile of reference standard) and preterm (<37 weeks) respectively. Percentages of preterm and SGA babies show divergent seasonal patterns that might indicate separate aetiologies. However, seasonal effects influencing intrauterine growth are likely to be cumulative over the last few months of pregnancy. By modelling seasonality with truncated Fourier series we were able to deconvolve the underlying seasonal influences on fetal growth from the pattern for SGA. This enabled us to use seemingly unrelated biprobit regression to compare the underlying seasonal pattern of intrauterine growth with that governing the incidence of preterm delivery. We conclude that, if the seasonal factors affecting intrauterine growth operate over more than the last 2 months of pregnancy, then the seasonal patterns of the factors causing IUGR and preterm delivery are indistinguishable if the factors are assumed to trigger preterm delivery immediately, but differ if preterm delivery is assumed to be programmed by factors acting at conception.

Epidemiologic Methods↗
PubMed2006

Effect of month of vaccine administration on antibody responses in The Gambia and Pakistan.

OBJECTIVE: To explore the relationship between calendar month of administration and antibody (Ab) response to vaccination in subjects from The Gambia and Pakistan, two countries with distinct patterns of seasonality. METHODS: Three cohorts were investigated: Responses to rabies and pneumococcal vaccine were assessed in 472 children (mean age 8 years, males 53%) from rural Gambia. Responses to tetanus, diphtheria and hepatitis B (HBsAg) were investigated in 138 infants also from The Gambia (birth to 52 weeks of age, males 54%). Responses to rabies and Vi typhoid vaccines were assessed in 257 adults from Lahore, Pakistan (mean age 29.4 years, males 57%). RESULTS: In Gambian children, significant associations were observed between month of vaccination and Ab response for the pneumococcal and rabies vaccines. As no consistent pattern by month was observed between the responses, it is assumed that different immunomodulatory stimuli or mechanisms were involved. In Pakistani adults, a significant pattern by month of vaccination was observed with both rabies and typhoid vaccine. No monthly influences were observed in the infant study to the tetanus, diphtheria or the HbsAg vaccines. CONCLUSIONS: Antibody responses to certain specific vaccines are influenced by month of administration. Further research is required to elucidate the precise mechanisms explaining these observations, but a co-stimulatory effect of seasonally variable environmental antigens is a likely cause. Future studies of Ab response to vaccination in countries with a seasonally dependent environment should consider month of vaccination when interpreting study findings.

Adult↗
PubMed2006

Plasma homocysteine, folate and vitamin B(12) compared between rural Gambian and UK adults.

The disease risk indicator plasma total homocysteine (tHcy) is influenced by genetic and environmental factors, including folate and vitamin B(12) status. Little is known about the determinants of tHcy in rural West Africa. We explored the hypothesis that tHcy in rural Gambian adults might vary between the sexes and physiological groups, and/or with folate and vitamin B(12) status. Comparisons were made with a British national survey. Non-pregnant Gambian women (n 158) had tHcy concentrations (geometric mean 9.0 micromol/l) similar to those of non-pregnant UK women (n 449; 9.4 micromol/l), whereas pregnant Gambian women (n 12) had significantly lower values (6.2 micromol/l). Gambian men (n 22) had significantly higher values (14.7 micromol/l) than British men (n 354; 10.8 micromol/l). Gambian lactating women and British men and women exhibited significant inverse relationships between log(e)(tHcy) and folate status; however, only the British subjects exhibited significant inverse relationships between loge(tHcy) and vitamin B(12) status. In the British sample, and in Gambian lactating women, folate and vitamin B(12) status variations together accounted for 20-25 % of the variation in log(e)(tHcy). Within the UK, black-skinned adults had folate and tHcy levels similar to those of their white-skinned counterparts, but significantly higher vitamin B(12) values. We conclude that, whereas folate and vitamin B(12) status are similar between British and rural Gambian populations, tHcy is higher in Gambian men and lower in pregnant Gambian women, and that serum vitamin B(12) values appear to be higher in black-skinned than white-skinned British subjects. Possible reasons are discussed.

Adult↗
PubMed2005

The emerging epidemic of obesity in developing countries.

Thirty years ago international nutritionists were focussing on childhood malnutrition, the 'protein gap' and how to feed the world's burgeoning population, and medical services in the developing world were concentrated on the fight against infectious diseases. Today the World Health Organization (WHO) finds itself needing to deal with the new pandemic of obesity and its accompanying non-communicable diseases (NCDs) while the challenge of childhood malnutrition has far from disappeared, TB and malaria rates are escalating, and the scourge of AIDS has emerged. This has created a 'double burden' of disease that threatens to overwhelm the health services of many resource-poor countries. WHO warns that the greater future burden of obesity and diabetes will affect developing countries, and the projected numbers of new cases of diabetes run into the hundreds of millions within the next 2 decades. The obesity pandemic originated in the US and crossed to Europe and the world's other rich nations before, remarkably, it penetrated even the world's poorest countries especially in their urban areas. The pandemic is transmitted through the vectors of subsidized agriculture and multinational companies providing cheap, highly refined fats, oils, and carbohydrates, labour-saving mechanized devices, affordable motorized transport, and the seductions of sedentary pastimes such as television. This paper briefly reviews these macro-environmental trends as well as considering some of the socio-behavioural influences on weight gain in traditional societies. It concludes, pessimistically, that the pandemic will continue to spread for the foreseeable future, and that, apart from educational campaigns, the governments and health services of poor countries will have few effective public health levers with which they can try to arrest the trend.

Developing Countries↗
PubMed2005

Early influences on human energy regulation: thrifty genotypes and thrifty phenotypes.

Early influences on human ingestive behavior and other aspects of energy homeostasis can be defined according to two very different time scales: the evolutionary time frame responsible for selection of behavioral and metabolic traits embedded within the genome; and the life-course time frame responsible for setting the phenotype. Evolutionary influences: Famine has been a constant threat to human survival leading to the selection of thrifty genes. Thriftiness can take many forms: metabolic (an 'energy-sparing' super-efficient metabolism); adipogenic (a propensity to rapid fat gain); physiologic (an ability to switch off non-essential processes); gluttony (a tendency to gorge when food is available); sloth (a tendency to conserve energy through inactivity); or behavioral (hoarding, meanness, theft, etc). Life-course influences: The nutritional environment of the early embryo can have a major impact on its survival, and its immediate and later physiology. Subsequently, the fetus is sensitive to its nutrient supply that in turn is affected by maternal fuel supply and by the constraints of the utero-placental unit. Adaptive plasticity also continues through infancy. Ingestive behavior in terms of appetite and satiety could theoretically be affected by some of these metabolic adaptations. This paper will describe the key elements of the thrifty genotype and phenotype and review the evidence base relating these early effects to differences in ingestive behavior.

Animals↗
PubMed2005

Maternal preconceptional weight and gestational length.

Recent animal studies suggest that preconceptional undernutrition shortens gestation. We retested this idea among rural Gambian women who experience annual fluctuations in energy balance caused by the rains (with lowest weights in September to November) using records from 1918 infants. Pregnancies conceived in September to November were significantly shorter than those from better-fed months (38.6 vs 39.0 weeks; log-rank chi 2 = 17.4, P < .0001).

Body Composition↗
PubMed2005

Starvation in humans: evolutionary background and contemporary implications.

Although there is extensive evidence that caloric restriction (CR) extends lifespan in several species the evidence base for humans is weak. We are still at the stage of applying inductive reasoning and of framing hypotheses to be tested. It is known that a genetic background contributes about 25% to the variation in human longevity, but thought unlikely that any genes conferring longer lifespan have been positively selected to do so. It is more likely that any such benefits are unintended consequences arising from other adaptations. If there is an association between CR and longevity in humans it may have been selected by previous exposures to famine. This paper briefly reviews the historical evidence on the extent and frequency of famines in human history. It is concluded that starvation has been one of the major selective pressures on the human genome and has left abundant evidence of adaptive survival traits. Many of these are mediated through effects on reproduction. However, interpretation of the possible links between these energy-sparing mechanisms and any association between CR and ageing is handicapped by an absence of data on the latter and will remain a matter of debate for many years to come.

Aging↗
PubMed2005

Measuring lymphocyte kinetics in tropical field settings.

Studies involving in-vivo labelling of lymphocyte DNA with 6,6-2H2-glucose to track T-cell turnover have contributed to understanding lymphocyte homeostasis in health and disease. Applying such studies in tropical settings (where diseases that affect T-cells are prevalent) requires protocol modifications including non-intravenous label administration, applicability in outpatient facilities, and T-cell sorting methods independent of a fluorescence activated cell sorter (FACS). Such protocols were validated in UK pilot studies and applied in The Gambia. Healthy adult subjects (n=12) were recruited from three Gambian villages. 6,6-2H2-glucose was administered orally in an outpatient clinic and T-cell subpopulations isolated from peripheral blood using plastic adherence, and Multisorttrade mark magnetic cell sorting (MACStrade mark) to obtain CD8+CD45R0+, CD8-CD45R0+, CD8+CD45R0- and CD8-CD45R0- subsets. To achieve high cell purity and yield, CD45R0- cells were reincubated with CD45R0 beads. T-cell proliferation and disappearance were quantified using gas chromatography mass spectrometry. Results were consistent with those of other studies showing higher turnover in memory (CD45R0+) than in naïve (CD45R0-) T-cell subsets, and an association between recent cell proliferation and susceptibility to cell death. Cell kinetics research is applicable in tropical settings, and can contribute to further understanding the regulation of adaptive immunity in response to infections and other insults.

Adolescent↗
PubMed2005

Macronutrients as sources of food energy.

This background paper considers the extent to which the development of new recommendations for dietary energy requirements needs to account for the macronutrient (fat, carbohydrate, protein and alcohol) profiles of different diets. The issues are discussed from the dual perspectives of avoiding under-nutrition and obesity. It is shown that, in practice, human metabolic processes can adapt to a wide range of fuel supply by altering fuel selection. It is concluded that, at the metabolic level, only diets with the most extreme macronutrient composition would have any consequences by exceeding the natural ability to modify fuel selection. However, diets of different macronutrient composition and energy density can have profound implications for innate appetite regulation and hence overall energy consumption.

Adaptation, Physiological↗
PubMed2005

Insights from the developing world: thrifty genotypes and thrifty phenotypes.

Few researchers would dispute that the pandemic of obesity is caused by a profound mismatch between humanity's present environmental circumstances and those that have moulded evolutionary selection. This concept was first articulated when gestational diabetes was described as being the result of a 'thrifty genotype rendered detrimental by progress'. More recently, this hypothesis has been extended to the concept of a 'thrifty phenotype' to describe the metabolic adaptations adopted as a survival strategy by a malnourished fetus; changes that may also be inappropriate to deal with a later life of affluence. Both the thrifty genotype and the thrifty phenotype hypotheses would predict that populations in some areas of the developing world would be at greater risk of obesity and its co-morbidities; a proposition to be explored in the present paper. To date thrifty genes remain little more than a nebulous concept propagated by the intuitive logic that man has been selected to survive episodic famine and seasonal hungry periods. Under such conditions those individuals who could lay down extra energy stores and use them most efficiently would have a survival advantage. The search for candidate thrifty genes needs to cover every aspect of human energy balance from food-seeking behaviour to the coupling efficiency of oxidative phosphorylation. The present paper will describe examples of attempts to find thrifty genes in three selected candidate areas: maternally-transmitted mitochondrial genes; the uncoupling proteins; apoE4, whose geographical distribution has been linked to a possible thrifty role in lipoprotein and cholesterol metabolism.

Adaptation, Physiological↗
PubMed2005

Association of physical activity with body-composition indexes in children aged 6-8 y at varied risk of obesity.

BACKGROUND: Physical inactivity increases the risk of obesity, but the relations between reported levels of physical activity (PA) and measures of body fatness (BF) in children are remarkably inconsistent. OBJECTIVE: We examined the relation between objective measures of PA and body-composition indexes in nonobese children. DESIGN: A cross-sectional study was conducted in 100 children aged 6-8 y who were recruited according to their risk of future obesity: high-risk children had >/=1 obese parent [body mass index (BMI; in kg/m(2)): >30] and low-risk children had 2 nonobese biological parents (BMI: <30). Free-living activity energy expenditure (AEE) and PA level were calculated from 7-d doubly labeled water measurements, time spent in light-intensity activity was assessed by heart rate monitoring, and body composition was determined from isotopic dilution. To adjust for body size, fat mass and fat-free mass were normalized for height and expressed as fat mass index (FMI) and lean mass index (LMI), respectively. RESULTS: High-risk children had significantly higher BMI, LMI, and FMI than did low-risk children, but no group differences in PA were found. AEE and PA level were positively associated with LMI and, after adjustment for sex and fat-free mass, negatively associated with FMI but not with BMI. Boys who spent more than the median time in light-intensity activities had significantly higher FMI than did less sedentary boys. This difference was not observed in girls. CONCLUSIONS: AEE and PA level were negatively associated with BF in nonobese children. Accurate measures of body composition are essential to appropriate assessment of relations between PA and obesity risk.

Body Composition↗
PubMed2005

Differential effects of seasonality on preterm birth and intrauterine growth restriction in rural Africans.

BACKGROUND: Low birth weight (LBW) can result from prematurity or intrauterine growth restriction (IUGR) and result in small-for-gestational-age (SGA) infants. Prematurity and IUGR may have different etiologies and consequences. OBJECTIVE: Our objective was to analyze seasonal patterns of prematurity and SGA in a rural African community and to compare them against variations in nutritional and ecologic variables that may provide insight into likely causative factors. DESIGN: Fourier series were used to compare the seasonality of prematurity (<37 wk) and SGA (<10th percentile of the reference standard) among 1916 live infants born over 26 y in 3 Gambian villages. The resultant patterns were compared against monthly variations in birth frequency, maternal energy status, maternal work, and malaria infections. RESULTS: The incidence of LBW was 13.3%, of prematurity was 12.3%, and of SGA was 25.1%. Prematurity and SGA showed divergent patterns of seasonality. Incidence of SGA was highest at the end of the annual hungry season, from August to December (peaking in November at 30.6%), with a nadir of 12.9% in June. Rates of SGA varied inversely with maternal weight changes. This pattern was not seen for rates of prematurity, which showed 2 peaks-in July (17.2%) and October (13.9%). The lowest proportion of preterm births occurred in February (5.1%). The peaks in prematurity closely paralleled increases in agricultural labor (July) and malaria infections (October). CONCLUSION: We conclude that a reduction in LBW in such communities may require multiple interventions because of the variety of precipitating factors.

Birth Weight↗
PubMed2004

Birth weight predicts response to vaccination in adults born in an urban slum in Lahore, Pakistan.

BACKGROUND: Substantial evidence exists linking small size at birth to later-life susceptibility to chronic disease. Evidence is also emerging that some components of immune function may be programmed in early life. However, this evidence is limited and requires confirmation. OBJECTIVE: We investigated the association between size at birth and response to vaccination in a cohort of 257 adults (mean age: 29.4 y; 146 men) born in an urban slum in Lahore, Pakistan, during 1964-1978. DESIGN: A single dose of Vi polysaccharide vaccine for Salmonella typhi and 2 doses of rabies vaccine were given to each subject. Antibody titers were measured in prevaccination serum samples (Vi) and in postvaccination samples (Vi and rabies). RESULTS: The mean birth weight of the subjects was 3.24 kg; 14% of the subjects had low birth weights (<2.5 kg). Vaccine responses were not consistently associated with contemporary variables (month of study, sex, current age, or indicators of wealth). Response to typhoid vaccination was positively related to birth weight (anti-Vi immunoglobulin G: r = 0.138, P = 0.031; anti-Vi immunoglobulin M: r = 0.197, P = 0.034). Response to the rabies vaccine was not significantly associated with birth weight. CONCLUSIONS: These findings add to a growing body of evidence suggesting that components of the immune system may be permanently programmed by events in early life. The contrasting effects on typhoid and rabies responses suggest that antibody generation to polysaccharide antigens, which have greater B cell involvement, is compromised by fetal growth retardation.

Adult↗
PubMed2004

Improved thymic function in exclusively breastfed infants is associated with higher interleukin 7 concentrations in their mothers' breast milk.

BACKGROUND: In rural Gambians, the season of birth strongly predicts adult mortality. Those born during the harvest season have longer life spans than do those born during the hungry season, and the deaths associated with infectious diseases suggest permanent early-life influences on immunity. Thymic measurements showed significantly smaller thymuses in infants born during the hungry season than in those born during the harvest season. The differences were greatest at 8 wk of age, a time when all infants were exclusively breastfed, which suggests the involvement of breast milk factors. OBJECTIVE: This study tested whether thymic size differences reflect thymic output and ascertained whether thymic output is associated with breast milk interleukin 7 (IL-7) concentrations. DESIGN: We studied thymic size and output in a prospective cohort of 138 Gambian infants born in either the hungry or the harvest season by measuring signal-joint T cell receptor-rearrangement excision circles (sjTRECs) at birth and at 8 wk of age. IL-7 concentrations in breast milk were measured by using an enzyme-linked immunosorbent assay. RESULTS: By age 8 wk, those born in the hungry season had significantly lower sjTREC counts than did those born in the harvest season (0.97 and 2.12 sjTRECs/100 T cells, respectively; P = 0.006). At 1 wk postpartum, the breast milk of mothers of infants born in the hungry season had significantly lower IL-7 than did that of mothers of infants born in the harvest season (79 and 100 pg/mL, respectively; P = 0.02). The findings were similar at 8 wk postpartum. CONCLUSION: These data show a plausible pathway linking external seasonal insults to mothers with thymic development in their infants, which suggests possible implications for long-term programming of immunity.

Breast Feeding↗