Anemia Offers Stronger Protection Than Sickle Cell Trait Against the Erythrocytic Stage of Falciparum Malaria and This Protection Is Reversed by Iron Supplementation.

BACKGROUND: Iron deficiency causes long-term adverse consequences for children and is the most common nutritional deficiency worldwide. Observational studies suggest that iron deficiency anemia protects against Plasmodium falciparum malaria and several intervention trials have indicated that iron supplementation increases malaria risk through unknown mechanism(s). This poses a major challenge for health policy. We investigated how anemia inhibits blood stage malaria infection and how iron supplementation abrogates this protection. METHODS: This observational cohort study occurred in a malaria-endemic region where sickle-cell trait is also common. We studied fresh RBCs from anemic children (135 children; age 6-24months; hemoglobin <11g/dl) participating in an iron supplementation trial (ISRCTN registry, number ISRCTN07210906) in which they received iron (12mg/day) as part of a micronutrient powder for 84days. Children donated RBCs at baseline, Day 49, and Day 84 for use in flow cytometry-based in vitro growth and invasion assays with P. falciparum laboratory and field strains. In vitro parasite growth in subject RBCs was the primary endpoint. FINDINGS: Anemia substantially reduced the invasion and growth of both laboratory and field strains of P. falciparum in vitro (~10% growth reduction per standard deviation shift in hemoglobin). The population level impact against erythrocytic stage malaria was 15.9% from anemia compared to 3.5% for sickle-cell trait. Parasite growth was 2.4 fold higher after 49days of iron supplementation relative to baseline (p<0.001), paralleling increases in erythropoiesis. INTERPRETATION: These results confirm and quantify a plausible mechanism by which anemia protects African children against falciparum malaria, an effect that is substantially greater than the protection offered by sickle-cell trait. Iron supplementation completely reversed the observed protection and hence should be accompanied by malaria prophylaxis. Lower hemoglobin levels typically seen in populations of African descent may reflect past genetic selection by malaria. FUNDING: National Institute of Child Health and Development, Bill and Melinda Gates Foundation, UK Medical Research Council (MRC) and Department for International Development (DFID) under the MRC/DFID Concordat.

The effects of maternal iron deficiency on infant fibroblast growth factor-23 and mineral metabolism.

Fibroblast growth factor-23 (FGF23), a phosphate(Phos)-regulating hormone, is abnormally elevated in hypophosphataemic syndromes and an elevated FGF23 is a predictor of mortality in kidney disease. Recent findings suggest iron deficiency as a potential mediator of FGF23 expression and murine studies have shown in utero effects of maternal iron deficiency on offspring FGF23 and phosphate metabolism. Our aim was to investigate the impact of maternal iron status on infant FGF23 and mineral metabolites over the first 2years of life. Infants born to mothers with normal (NIn=25,) and low (LIn=25) iron status during pregnancy, from a mother-infant trial (ISRCTN49285450) in rural Gambia, West Africa, had blood and plasma samples analysed at 12, 24, 52, 78 and 104weeks (wk) of age. Circulating intact-FGF23 (I-FGF23), Phos, total alkaline phosphatase (TALP) and haemoglobin (Hb) decreased and estimated glomerular filtration rate increased over time [all P≤0.0001)]. C-terminal-FGF23 (C-FGF23) and TALP were significantly higher in LI compared with NI, from 52wk for C-FGF23 [Beta coefficient (SE) 18.1 (0.04) %, P=0.04] and from 24wk for TALP [44.7 (29.6) U/L, P=0.04]. Infant Hb was the strongest negative predictor of C-FGF23 concentration [-21% (4%) RU/mL, P≤0.0001], Phos was the strongest positive predictor of I-FGF23 [32.0(3.9) pg/mL, P≤0.0001] and I-FGF23 did not predict C-FGF23 over time [-0.5% (0.5%), P=0.3]. In conclusion, this study suggests that poor maternal iron status is associated with a higher infant C-FGF23 and TALP but similar I-FGF23 concentrations in infants and young children. These findings further highlight the likely public health importance of preventing iron deficiency during pregnancy. Whether or not children who are born to iron deficient mothers have persistently high concentrations of these metabolites and are more likely to be at risk of impaired bone development and pre-disposed to rickets requires further research.

Overeating: the health risks.

Overeating is a relative term. It refers to the consumption of an energy intake that is inappropriately large for a given energy expenditure, thus, leading to obesity. There are several key environmental and cultural factors that have converged in the past few decades to markedly increase the risk of both active and passive (inadvertent) overeating. Chief among these are the increased availability and promotion of cheap energy-dense diets (usually high in fat) and the transition toward extremely sedentary lifestyles. The importance of considering these factors together must be stressed. Data ranging from highly controlled metabolic studies to large-scale epidemiological and ecological analysis illustrate the strong interactions between diet and physical activity in relationship to the over-consumption of energy. Overeating of certain specific dietary components may also lead to health risks. Obvious examples are saturated and trans-fatty acids. More recently attention has switched to high glycemic foods and to n-6 fatty acids. Theories that excess consumption of these may be independent risk factors for obesity and ill health remain controversial but merit closer examination and additional research. The main barriers to changing widely prevalent overeating include the following: public and corporate ignorance about the effects of energy-dense diets in inducing passive over-consumption, commercial willfulness concerning energy density and portion sizes, and public ignorance about the profound health effects of inactive lifestyles. These represent key targets for the design of public health initiatives.

Macronutrient disposal during controlled overfeeding with glucose, fructose, sucrose, or fat in lean and obese women.

BACKGROUND: Previous short-term studies (< or =6 h) showed differences in energy expenditure (EE) and macronutrient oxidation in response to overfeeding with different types of dietary carbohydrate. This finding could have implications for obesity. OBJECTIVE: We used 96-h continuous whole-body calorimetry in 8 lean and 5 obese women to assess metabolic disposal (energy dissipation and glycogen or fat storage) of a controlled excess of dietary energy supplied as different carbohydrate sources or as fat. DESIGN: Five dietary treatments were applied in random order: energy balance (control) and overfeeding by 50% of energy requirements with fat (O(fat)) or predominantly with glucose, fructose, or sucrose (O(cho)). Macronutrient oxidation rates were assessed from nonprotein gaseous exchanges. Net macronutrient balances were calculated as cumulative differences between intake and oxidation. RESULTS: Increased EE in response to overfeeding dissipated 7.9% of the energy excess with a variation in EE of <1.7% across overfeeding treatments (NS). EE during the O(fat) treatment significantly exceeded that during the control treatment in the lean but not in the obese women. There were no significant differences between lean and obese women in macronutrient oxidation or balances, so data were pooled. O(cho) induced glycogen storage on day 1 ( approximately 100 g) but thereafter progressively stimulated carbohydrate oxidation so that balance was reached on days 3 and 4. Fat oxidation was proportionately suppressed. Of the excess carbohydrate, 74% was oxidized; there were no significant differences between the various O(cho) treatments. O(fat) stimulated fat oxidation by 18% and suppressed carbohydrate oxidation. On average, 12% of the excess energy was stored as glycogen and 88% as fat; there was no significant difference between overfeeding treatments. CONCLUSION: There was no significant difference in fat balance during controlled overfeeding with fat, fructose, glucose, or sucrose.

Leptin: physiology and pathophysiology.

The identification and sequencing of the ob gene and its product, leptin, in late 1994 opened new insights in the study of the mechanisms controlling body weight and led to a surge of research activity. During this time, a considerable body of knowledge regarding leptin's actions has been accumulated and the field continues to expand rapidly. Currently there is particular interest in the interaction of leptin with other peripheral and neural mechanisms to regulate body weight, reproduction and immunological response. In this review, we attempt to place the current state of knowledge about leptin in the broader perspective of physiology, including its structural characteristics, receptors, binding proteins, signalling pathways, regulation of adipose tissue expression and production, secretion patterns, clearance mechanisms and functional effects. In addition, leptin's involvement in the pathophysiology of obesity, anorexia nervosa, diabetes mellitus, polycystic ovary syndrome, acquired immunodeficiency syndrome, cancer, nephropathy, thyroid disease, Cushing's syndrome and growth hormone deficiency will be reviewed.

Manipulation of dietary fat and energy density and subsequent effects on substrate flux and food intake.

Dietary fat has traditionally been viewed as being particularly lipogenic because of its high energy density, metabolic efficiency, and palatability. If these attributes of dietary fat were counteracted by a high satiating power, or if the body made autoregulatory adjustments in fat utilization in response to high fat intakes, energy balance would not necessarily be displaced. However, recent experiments have shown that neither of these hold true: human and animal trials consistently show that covert manipulation of dietary fat can induce hyperphagia, which can readily lead to spontaneous fat storage of 50-100 g/d in humans. Experiments with isoenergy-dense diets show that this high-fat hyperphagia (with diets of similar palatability) is caused by the high energy density of fatty foods rather than by their other attributes. Hyperphagia has therefore been termed passive overconsumption because it occurs unintentionally and without the consumption of excess bulk. When palatability is allowed to vary normally, high-fat foods may additionally induce active overconsumption in response to the enhanced organoleptic qualities of fats. In terms of substrate flux, fat is at the bottom of an oxidative hierarchy that determines fuel selection. Whereas alcohol, carbohydrates, and protein elicit powerful autoregulatory adjustments in their oxidation in response to changes in intake, fat fails to elicit such a response and fat balance is therefore easily displaced. These physiologic observations provide mechanistic support for secular-trend, cross-cultural, and cross-sectional epidemiologic studies investigating the role of energy-dense diets in the etiology of obesity.

Changes in macronutrient balance during over- and underfeeding assessed by 12-d continuous whole-body calorimetry.

Alterations in energy balance must be accommodated by adjustments in the net storage of the major energy-yielding macronutrients: carbohydrate, protein, and fat. This study used continuous whole-body calorimetry to measure changes in energy expenditure and substrate oxidation during a 12-d imposed energy imbalance in six lean men on mixed diets (overfeeding: 16.5 MJ/d, +33%, n = 3; underfeeding: 3.5 MJ/d, -67%, n = 3). Changes in total energy expenditure (TEE) and its components were modest; TEE changed by +6.2% (overfeeding) and -10.5% (underfeeding). In consequence, body weight changed by +2.90 and -3.18 kg. Marked changes in metabolic fuel selection occurred over the course of the study. Carbohydrate intake (540 and 83 g/d for overfeeding and underfeeding, respectively) exerted direct autoregulatory feedback on carbohydrate oxidation (551 and 106 g/d at day 12 for overfeeding and underfeeding, respectively). Subjects were close to balance by day 5. Changes in protein oxidation were small and not sufficient to prevent the oxidation of body protein mass, or its accretion, in response to energy deficit or surplus. Fat oxidation (59 and 177 g/d for overfeeding and underfeeding, respectively) was not sensitive to dietary fat intake (150 and 20 g/d, for overfeeding and underfeeding, respectively), rather, its oxidation was inversely related to the oxidation of other substrates. Changes in fat balance accounted for 74.1% and 84.0% of the energy imbalance during overfeeding and underfeeding, respectively. This study shows a clear oxidative hierarchy for the macronutrients. Metabolic fuel selection is dominated by the need to maintain carbohydrate balance. This induces inappropriate counterregulatory alterations in fat oxidation during energy surplus.

Energy density and its role in the control of food intake: evidence from metabolic and community studies.

This review discusses the role that dietary composition and energy density play in the control of eating behaviour. The effect of dietary manipulations of fat and carbohydrate on energy intake remains controversial. We suggest this to be largely a consequence of different study designs. When low-fat foods are included in the diet and thus only some items manipulated subsequent food choice commonly ensures compensation and energy intake remains constant. However, when all items are manipulated and macronutrient composition fixed, an alteration in the energy density results in a parallel change in energy intake and there is no energy compensation. In addition, we hypothesise that hyperphagia on high-fat diets is a consequence of a high energy density rather than fat content per se. Independent of fat content, low energy dense diets generate greater satiety than high energy dense diets, suggesting that an important regulatory signal may be the weight or volume of food consumed. Epidemiological studies confirm that energy intake increases with energy density and thus weight loss may be best achieved on a low energy dense diet. Although the use of low-fat items may not reduce intake during covert manipulation, it may be successful during periods of deliberate dieting, providing that food-substitutions are not counter-balanced by other high density items.

Energy expenditure and wasting in human immunodeficiency virus infection.

BACKGROUND: Increased expenditure of energy at rest has been considered a contributing factor to the negative energy balance and weight loss that occur in patients with human immunodeficiency virus (HIV) infection. However, the true determinant of energy balance is not resting but total energy expenditure. We sought to determine the contribution of total energy expenditure to weight changes in patients with HIV-associated wasting. METHODS: We performed 51 assessments of energy metabolism in 27 men with HIV infection at different stages of disease, including periods of both rapid and slow weight loss. Resting energy expenditure was measured by indirect calorimetry, total energy expenditure by the doubly-labeled-water technique, and energy intake by recording the weight of food consumed. The results were compared with the rate of weight loss or gain. RESULTS: The mean (+/- SD) total energy expended by the HIV-infected men was 2750 +/- 670 kcal per day, no more than that expended by normal men. There was a significant positive relation between total energy expenditure and the rate of weight change (r = 0.61, P < 0.001); thus, during rapid weight loss, total energy expenditure was reduced to 2180 +/- 580 kcal per day (P = 0.009), primarily because of reduced physical activity. During rapid weight loss, the negative energy balance (-850 +/- 580 kcal per day) was primarily the result of the reduction in energy intake, to 1330 +/- 610 kcal per day; intake correlated strongly with the rate of weight change (r = 0.84, P < 0.001). CONCLUSIONS: In patients with HIV infection, total energy expenditure is reduced during episodes of weight loss. Reduced energy intake, not elevated energy expenditure, is the prime determinant of weight loss in HIV-associated wasting.

In vivo measurement of changes in body composition: description of methods and their validation against 12-d continuous whole-body calorimetry.

The accuracy of a variety of in vivo body-composition techniques (densitometry, total body water, skinfold thicknesses, whole-body impedance and resistance, body mass index, and two three-compartment models) was assessed by comparison with fat balance. Three subjects were overfed and three underfed while confined to a 30-m3 whole-body calorimeter continuously for 12 d. Mean weight changes were +2.90 kg during overfeeding and -3.47 kg during underfeeding. The change in fat mass accounted for 37.1% during overfeeding and 59.3% during underfeeding. In comparison with energy and nitrogen balance, a three-compartment model yielded the least bias and greatest precision. The smallest change in fat mass that can be measured by such a method in an individual subject is 1.54 kg (2 SD). Of the prediction techniques considered, skinfold thicknesses or the body-mass-index formula appear to be more precise than estimates based on resistance or impedance.

Daily energy expenditure in free-living children: comparison of heart-rate monitoring with the doubly labeled water (2H2(18)O) method.

Total energy expenditure (TEE) was measured simultaneously in 36 free-living children aged 7, 9, 12, and 15 y over 10-15 d by the doubly labeled water (DLW) method and for 2-3 separate days by heart-rate (HR) monitoring. The 95% confidence limits of agreement (mean difference +/- 2SD) were -1.99 to +1.44 MJ/d. HR TEE discrepancies ranged from -16.7% to +18.8% with 23 values lying within +/- 10% of DLW TEE estimates. Boys and girls spent 462 +/- 108 and 318 +/- 120 min/d, respectively, in total physical activity (P less than 0.01). Time spent in moderate and vigorous physical activity (MVPA) was 68 +/- 37 min/d by younger children (7-9 y) and 34 +/- 24 min/d by older children (12-15 y) (P less than 0.001). Younger boys engaged in MVPA (91 +/- 33 min/d) and vigorous physical activity (VPA) (35 +/- 15 min/d) significantly longer than younger girls (MVPA, 39 +/- 16 min/d, P less than 0.001; VPA, 10 +/- 4 min/d, P less than 0.01) as did older boys (MVPA, 52 +/- 21 min/d; VPA, 30 +/- 18 min/d) compared with older girls (MVPA, 15 +/- 10 min/d; VPA, 8 +/- 5 min/d). HR monitoring provides a close estimation of the TEE of population groups and objective assessment of associated patterns of physical activity.

Potential contribution of leisure activity to the energy expenditure patterns of sedentary populations.

Total daily energy expenditure (TEE) by the doubly-labelled (2H218O) water method and basal metabolic rate (BMR) by indirect calorimetry were measured in thirty-two healty free-living adults in Northern Ireland. Habitual physical activity patterns in occupational and discretionary activities were assessed by interview questionnaire. Expressed as a multiple of BMR the TEE values for the sixteen males (1.88 (SD 0.28), range 1.44-2.57) and sixteen females (1.77 (SD 0.16), range 1.50-2.06) were compatible with current Department of Health and Social Security (DHSS; 1979) and Food and Agriculture Organization/World Health Organization/United Nations University (FAO/WHO/UNU; 1985) estimates of energy requirements. The results suggest that discretionary physical activity is now emerging as an equally important determinant of energy expenditure in the UK as the occupational classifications currently used as the basis of DHSS (1979) and FAO/WHO/UNU (1985) recommendations for energy requirements. Therefore, realistically achievable inputs of recreational exercise can have a significant impact in counteracting low levels of energy expenditure which are associated with modern lifestyles and are implicated as a risk factor for coronary heart disease and obesity.

The effect of improved nutrition on plasma prolactin concentrations and postpartum infertility in lactating Gambian women.

A substantial increase in food consumption of lactating Gambian women has been shown to be associated with a reduction in their plasma prolactin concentration. Women receiving food supplements during pregnancy as well as in lactation exhibited an even greater lowering of the postpartum plasma levels of this hormone. Consequently prolactin values of supplemented women returned more quickly to levels which allowed the resumption of menstrual and ovulatory activity. Concurrent measurements of the plasma concentrations of estradiol and progesterone in addition to prolactin allowed the calculation of prolactin values at which half the lactating women could be expected to have resumed menstruation and ovulation. These values were 1007 and 759 microU/ml, respectively. Dietary improvement during lactation alone resulted in these critical prolactin concentrations being reached 21 wk earlier than in nonsupplemented counterparts, while those receiving the extra food in both pregnancy and lactation showed a 35-wk shortening of postpartum amenorrhea and infertility.

PIP: A substantial increase in food consumption of lactating Gambian women has been shown to be associated with a reduction in their plasma prolactin concentration. Women receiving food supplements during pregnancy as well as in lactation exhibited an even greater lowering of the postpartum plasma levels of this hormone. Consequently prolactin values of supplemented women returned more quickly to levels which allowed the resumption of menstrual and ovulatory activity. Concurrent measurements of the plasma concentrations of estradiol and progesterone in addition to prolactin allowed the calculation of prolactin values at which 1/2 the lactating women could be expected to have resumed menstruation and ovulation. These values were 1007 and 759 U/ml, respectively. Dietary improvement during lactation alone resulted in these critical prolactin concentrations being reached 21 weeks earlier than in nonsupplemented counterparts, while those receiving the extra food in both pregnancy and lactation showed a 35-week shortening of postpartum amenorrhea and infertility.

The relative effectiveness of iron and iron with riboflavin in correcting a microcytic anaemia in men and children in rural Gambia.

Adult males and children between 4 and 12 years in a subsistence farming community in The Gambia were screened for haematological status. 80 men and 80 children with initially poor status were identified and allocated to three treatment groups comprising: a placebo, ferrous sulphate, and ferrous sulphate with riboflavin. Over a period of 6 weeks of supplementation there was a general improvement in haematological status in the two supplemented groups. The inclusion of riboflavin in the supplement enhanced recovery, particularly in those individuals with strikingly low levels of haemoglobin at the outset.