Splenic clearance of rigid erythrocytes as an inherited mechanism for splenomegaly and natural resistance to malaria.

BACKGROUND: In malaria-endemic areas, subjects from specific groups like Fulani have a peculiar protection against malaria, with high levels of IgM but also frequent anaemia and splenomegaly. The mechanisms underlying this phenotype remain elusive. METHODS: In a cohort study set up in Benin, West Africa, after a careful evaluation of malaria-related phenotypes, we measured the deformability of circulating erythrocytes in genetically distinct groups (including Fulani) living in sympatry, using ektacytometry and microsphiltration, a mimic of how the spleen clears rigid erythrocytes. Heritability of erythrocytes deformability was calculated, followed by a genome-wide association study (GWAS) of the same phenotype. FINDINGS: Compared to non-Fulani, Fulani displayed a higher deformability of circulating erythrocytes, pointing to an enhanced clearance of rigid erythrocytes by the spleen. This phenotype was observed in individuals displaying markers of Plasmodium falciparum infection. The heritability of this new trait was high, with a strong multigenic component. Five of the top 10 genes selected by a population structure-adjusted GWAS, expressed in the spleen, are potentially involved in splenic clearance of erythrocytes (CHERP, MB, PALLD, SPARC, PDE10A), through control of vascular tone, collagen synthesis and macrophage activity. INTERPRETATION: In specific ethnic groups, genetically-controlled processes likely enhance the innate retention of infected and uninfected erythrocytes in the spleen, explaining splenomegaly, anaemia, cryptic intrasplenic parasite loads, hyper-IgM, and partial protection against malaria. Beyond malaria-related phenotypes, inherited splenic hyper-filtration of erythrocytes may impact the pathogenesis of other hematologic diseases. FUNDING: ANR, National Geographic Society, IMEA, IRD, and Région Ile-de-France.

Rural Beninese Children Are at Risk of Zinc Deficiency According to Stunting Prevalence and Plasma Zinc Concentration but Not Dietary Zinc Intakes.

BACKGROUND: Three commonly recommended indicators for risk assessment of population zinc deficiency are stunting rates among children aged <5 y, prevalence of inadequate dietary zinc intake, and prevalence of low plasma zinc (PZn). Data on zinc status in Benin are mainly drawn from stunting rates and data on PZn and dietary zinc intake are lacking. OBJECTIVES: The aims of this study were 1) to assess the risk of zinc deficiency in preschool and school-age children from rural communities in northern Benin by means of the 3 indicators for population assessment, 2) to evaluate their level of agreement, and 3) to identify predictors of PZn and height-for-age z scores (HAZ). METHODS: We analyzed preintervention data collected during 2 efficacy trials and cross-sectionally assessed the risk of zinc deficiency in preschool (1-5 y, n = 326) and school-age children (5-10 y, n = 272) by 1) conducting a 3-d weighed food record survey, coupled with direct zinc and phytic acid analysis of consumed foodstuffs, and calculating usual dietary zinc intakes in a subsample of school-age children (n = 36); 2) analyzing PZn in all children (n = 598); and 3) measuring anthropometry indexes for assessment of stunting (HAZ <-2 SD) in all children (n = 594) and in <5-y-old children only (n = 273). We derived predictors of PZn and HAZ by using multivariate regression with mixed-effect models. RESULTS: Prevalence of inadequate intakes of zinc ranged from 11% to 80% depending on whether the estimated average requirements (EARs) by the International Zinc Nutrition Consultative Group or the EARs derived from the WHO's recommended nutrient intakes were used. Prevalence of low PZn adjusted for acute-phase protein status was 45.7%, with higher rates among preschoolers than school-age children (P = 0.002). The stunting rate in <5-y-old children was 51.3%. PZn was predicted by age, methodologic factors, and socioeconomic status, whereas HAZ was predicted by age, sex, hemoglobin, and socioeconomic status. CONCLUSIONS: The prevalence of <5-y stunting and the prevalence of low PZn indicate that the risk of zinc deficiency is elevated in this population. Risk estimates based on the prevalence of inadequacy of zinc intakes varied depending on the EARs used, and a consensus would facilitate nutrition survey evaluations. These trials were registered at clinicaltrials.gov as NCT01472211 and NCT01790321.

Efficacy of highly bioavailable zinc from fortified water: a randomized controlled trial in rural Beninese children.

BACKGROUND: Zinc deficiency and contaminated water are major contributors to diarrhea in developing countries. Food fortification with zinc has not shown clear benefits, possibly because of low zinc absorption from inhibitory food matrices. We used a novel point-of-use water ultrafiltration device configured with glass zinc plates to produce zinc-fortified, potable water. OBJECTIVE: The objective was to determine zinc bioavailability from filtered water and the efficacy of zinc-fortified water in improving zinc status. DESIGN: In a crossover balanced study, we measured fractional zinc absorption (FAZ) from the zinc-fortified water in 18 healthy Swiss adults using zinc stable isotopes and compared it with zinc-fortified maize porridge. We conducted a 20-wk double-blind randomized controlled trial (RCT) in 277 Beninese school children from rural settings who were randomly assigned to receive a daily portion of zinc-fortified filtered water delivering 2.8 mg Zn (Zn+filter), nonfortified filtered water (Filter), or nonfortified nonfiltered water (Pump) from the local improved supply, acting as the control group. The main outcome was plasma zinc concentration (PZn), and the 3 groups were compared by using mixed-effects models. Secondary outcomes were prevalence of zinc deficiency, diarrhea prevalence, and growth. RESULTS: Geometric mean (-SD, +SD) FAZ was 7-fold higher from fortified water (65.9%; 42.2, 102.4) than from fortified maize (9.1%; 6.0, 13.7; P < 0.001). In the RCT, a significant time-by-treatment effect on PZn (P = 0.026) and on zinc deficiency (P = 0.032) was found; PZn in the Zn+filter group was significantly higher than in the Filter (P = 0.006) and Pump (P = 0.025) groups. We detected no effect on diarrhea or growth, but our study did not have the duration and power to detect such effects. CONCLUSIONS: Consumption of filtered water fortified with a low dose of highly bioavailable zinc is an effective intervention in children from rural African settings. Large community-based trials are needed to assess the effectiveness of zinc-fortified filtered water on diarrhea and growth. These trials were registered at clinicaltrials.gov as NCT01636583 and NCT01790321.

Total iron absorption by young women from iron-biofortified pearl millet composite meals is double that from regular millet meals but less than that from post-harvest iron-fortified millet meals.

Iron biofortification of pearl millet (Pennisetum glaucum) is a promising approach to combat iron deficiency (ID) in the millet-consuming communities of developing countries. To evaluate the potential of iron-biofortified millet to provide additional bioavailable iron compared with regular millet and post-harvest iron-fortified millet, an iron absorption study was conducted in 20 Beninese women with marginal iron status. Composite test meals consisting of millet paste based on regular-iron, iron-biofortified, or post-harvest iron-fortified pearl millet flour accompanied by a leafy vegetable sauce or an okra sauce were fed as multiple meals for 5 d. Iron absorption was measured as erythrocyte incorporation of stable iron isotopes. Fractional iron absorption from test meals based on regular-iron millet (7.5%) did not differ from iron-biofortified millet meals (7.5%; P = 1.0), resulting in a higher quantity of total iron absorbed from the meals based on iron-biofortified millet (1125 vs. 527 µg; P < 0.0001). Fractional iron absorption from post-harvest iron-fortified millet meals (10.4%) was higher than from regular-iron and iron-biofortified millet meals (P < 0.05 and P < 0.01, respectively), resulting in a higher quantity of total iron absorbed from the post-harvest iron-fortified millet meals (1500 µg; P < 0.0001 and P < 0.05, respectively). Results indicate that consumption of iron-biofortified millet would double the amount of iron absorbed and, although fractional absorption of iron from biofortification is less than that from fortification, iron-biofortified millet should be highly effective in combatting ID in millet-consuming populations.

Iron bioavailability from a lipid-based complementary food fortificant mixed with millet porridge can be optimized by adding phytase and ascorbic acid but not by using a mixture of ferrous sulfate and sodium iron EDTA.

Home fortification with lipid-based nutrient supplements (LNSs) is a promising approach to improve bioavailable iron and energy intake of young children in developing countries. To optimize iron bioavailability from an LNS named complementary food fortificant (CFF), 3 stable isotope studies were conducted in 52 young Beninese children. Test meals consisted of millet porridge mixed with CFF and ascorbic acid (AA). Study 1 compared iron absorption from FeSO4-fortifed meals with meals fortified with a mixture of FeSO4 and NaFeEDTA. Study 2 compared iron absorption from FeSO4-fortifed meals without or with extra AA. Study 3 compared iron absorption from FeSO4-fortified meals with meals containing phytase added prior to consumption, once without or once with extra AA. Iron absorption was measured as erythrocyte incorporation of stable isotopes. In study 1, iron absorption from FeSO4 (8.4%) was higher than that from the mixture of NaFeEDTA and FeSO4 (5.9%; P < 0.05). In study 2, the extra AA increased absorption (11.6%) compared with the standard AA concentration (7.3%; P < 0.001). In study 3, absorption from meals containing phytase without or with extra AA (15.8 and 19.9%, respectively) increased compared with meals without phytase (8.0%; P < 0.001). The addition of extra AA to meals containing phytase increased absorption compared with the test meals containing phytase without extra AA (P < 0.05). These findings suggest that phytase and AA, and especially a combination of the two, but not a mixture of FeSO4 and NaFeEDTA would be useful strategies to increase iron bioavailability from a CFF mixed with cereal porridge.