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Background: Young children in low- and middle-income countries frequently have inadequate vitamin B-12 (cobalamin) status. Poor folate status is also common and is associated with increased diarrheal and respiratory morbidity. Objective: The objective was to measure the effect of folic acid and/or vitamin B-12 administration on the incidence of diarrhea and acute lower respiratory tract infections. Design: One thousand North Indian children (6230 mo of age) were enrolled in a randomized, double-blind, placebo-controlled trial to receive 2 times the Recommended Dietary Allowance of folic acid and/or vitamin B-12 or placebo daily for 6 mo. Children were individually randomly assigned in a 1:1:1:1 ratio in blocks of 16. Primary outcomes were the number of episodes of acute lower respiratory infections, diarrhea, and prolonged diarrhea. Results: Folic acid and vitamin B-12 supplementation significantly improved vitamin B-12 and folate status, respectively. Neither folic acid nor vitamin B-12 administration reduced the incidence of diarrhea or lower respiratory infections. In comparison with placebo, children treated with folic acid alone or in combination with vitamin B-12 had a significantly higher risk of persistent diarrhea (OR: 2.1; 95% CI: 1.1, 3.8). Conclusions: Folic acid or vitamin B-12 supplementation did not reduce the burden of common childhood infections. In view of the increased risk of diarrhea, the safety of folic acid supplements in young children should be further assessed. This trial was registered at www.clinicaltrials.gov as NCT00717730 and at www.ctri.nic.in as CTRI/2010/091/001090. Am J Clin Nutr doi: 10.3945/ajcn. 113.059592.

BACKGROUND Iron deficiency anemia (IDA) is relatively common in the third trimester of pregnancy, but causal associations with low birth weight and compromised neonatal iron status are difficult to establish in human populations. OBJECTIVE The objective was to determine the effects of diet-induced IDA on intrauterine growth and neonatal iron status in an appropriate animal model for third-trimester IDA in women. DESIGN Hematologic and iron-status measures, pregnancy outcomes, and fetal and neonatal evaluations were compared between pregnant rhesus monkeys (n = 14) fed a diet containing 10 microg Fe/g diet from the time of pregnancy detection (gestation days 28-30) and controls (n = 24) fed 100 microg Fe/g diet. RESULTS By the third trimester, 79% of the iron-deprived dams and 29% of the control monkeys had a hemoglobin concentration

BACKGROUND The adolescent growth spurt and menarche increase iron and zinc needs and could precipitate functional deficiencies if dietary sources are inadequate. OBJECTIVE The effects of mild, combined zinc and iron deprivation during the growth spurt and the ability of meat as a common dietary source of zinc and iron to reverse these effects was studied. DESIGN Pubertal female rhesus monkeys were fed control diets (n = 8) or diets marginally deficient in zinc (2 microg/g diet; n = 8) and iron (10 microg/g diet; n = 8) for 3 mo. A powdered beef supplement (104 microg Zn/g and 43 microg Fe/g, 11 +/- 2 g/d) was then fed daily to half of the deprived group for 3 additional months. RESULTS Growth and hematology were not affected significantly by iron-zinc deprivation, but plasma zinc and iron were somewhat lower in the deprived group than in the control group after 3 mo. The deprived monkeys reduced their participation in behavioral testing, responded more slowly and less frequently to test stimuli, and were less active. The beef supplement increased participation in testing and stabilized activity levels, but response times remained depressed. Plasma ferritin was lower in the nonsupplemented deprived monkeys than in the controls by the end of the experiment. Four of 8 of the deprived monkeys had iron deficiency anemia compared with none of the controls and 1 of 8 who received the beef supplement. CONCLUSIONS Marginal zinc and iron deprivation in early adolescence can lead to behavioral and hematologic dysfunction in nonhuman primates and dietary beef supplements can prevent and reverse some of these effects.

Assessment of zinc nutriture is often compromised by the lack of reliable biomarkers. In the present study the effect of dietary zinc deprivation on plasma extracellular superoxide dismutase (EC SOD) activity was investigated in rat and rhesus macaque models. This enzyme, which contains both zinc and copper, is distinct from cytosolic copper-zinc SOD. Young, growing rats fed zinc-deficient diets (1.5 nmol Zn/g diet) were characterized by low plasma zinc concentrations and plasma EC SOD activities (16% and 56% of controls, respectively). Adolescent rhesus macaques fed diets that contained a marginal amount of zinc (30.6 nmol Zn/g diet) also had low plasma zinc concentrations and low EC SOD activities compared with controls fed diets containing 765 nmol Zn/g diet (75% and 40%, respectively). Enzyme activity was not affected after in vitro addition of zinc to plasma samples from control, restrict-fed, and zinc-deficient rats. Taken together, these data support the concept that plasma EC SOD activity can be a biomarker for zinc status. Am J Clin Nutr 1995 ;61 :1263-7.

Young rhesus monkeys (Macaca mulatta, n = 14) 25-30 mo of age were fed a zinc-deficient (ZD) diet (2 micrograms Zn/g diet) (moderate zinc deprivation) over 15 week. The ZD diet period was compared with a zinc-adequate (ZA) diet period (50 micrograms Zn/g diet) of the same duration, which either preceded or followed it (crossover design). Plasma zinc was lower at the end of the ZD than after the ZA period. There were no overt signs of zinc deficiency or effects on growth rate. Spontaneous motor activity was lower and performance of a visual-attention task and short-term-memory task were poorer during the ZD period than during the ZA period. Behavioral effects were detected as changes from individual baseline values, and often represented a failure to improve. The results suggests that dietary zinc deprivation can modulate behavior in prepubertal monkeys without affecting growth.

Background: Consumption of fish and n‐3 (omega-3) long-chain polyunsaturated fatty acids (LCPUFAs) has been associated with reduced risk of coronary artery disease (CAD) mortality. Objective: The aim was to examine the relation between dietary intake of n‐3 LCPUFAs or fish and risk of future coronary events or mortality in patients with well-characterized CAD. Design: This was a substudy of 2412 participants in the Western Norway B Vitamin Intervention Trial with a median follow-up time of 57 mo. Patients aged .18 y diagnosed with CAD (81% men) completed a food-frequency questionnaire at baseline, from which daily intakes of eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids as well as fish were estimated on the basis of diet and intakes of supplements including fish and cod liver oils. The main endpoint was a composite of coronary events, including coronary death, nonfatal acute myocardial infarction, and unstable angina pectoris. Results: The mean (6SD) intakes of n‐3 LCPUFAs in quartiles 1‐4 were 0.58 6 0.29, 0.83 6 0.30, 1.36 6 0.44, and 2.64 6 1.18 g/d, respectively. We found no dose-response relation between quartiles of n‐3 LCPUFAs (based on intake as percentage of total energy) or fish and coronary events or separate endpoints. A post hoc additive proportional hazards model showed a slightly increased risk of coronary events at an intake of n‐3 LCPUFAs ,’ 0.30 g/d. Conclusion: Among Norwegian patients with CAD consuming relatively high amounts of n‐3 LCPUFAs and fish, there were no significant trends toward a reduced risk of coronary events or mortality with increasing intakes. This trial was registered at clinicaltrials.gov as NCT00354081. Am J Clin Nutr doi: 10.3945/ajcn. 2010.29175.

Growth retardation has been associated with zinc deficiency in adolescent human populations, but animal models were not available previously to explore this syndrome. Moderate dietary zinc deprivation (2 micrograms Zn/g diet) was introduced in female rhesus monkeys (Macaca mulatta; n = 10) from the beginning of puberty through menarche. Subgroups of animals (n = 4) continued to be fed the zinc-deficient diet through 45 mo of age (sexual maturity). Reduced weight gain and linear growth and lower plasma zinc concentrations (11.8 +/- 0.6 and 9.2 +/- 0.8 mumol/L in control and zinc-deficient monkeys, respectively) were evident during the premenarcheal growth spurt. Slower skeletal growth, maturation, and mineralization were recorded in the postmenarcheal period and some indicators of sexual maturation were delayed. Food intake was slightly higher in the zinc-deficient group than in controls. These data confirm that adolescent growth and maturation are vulnerable to disruption by moderate dietary zinc deprivation in nonhuman primates.

Fetal body movements were studied in three groups of gravid rhesus macaques fed different amounts of dietary zinc (100 micrograms Zn/g diet, control, n = 12; 4 micrograms Zn/g diet, marginal deprivation, n = 7; 2 micrograms Zn/g diet, moderate deprivation, n = 11). Sonographic examinations were conducted during the third trimester in awake chair-restrained dams. Movement categories, derived from the human biophysical profile, were motor activity (trunk and limb movements), startle, and breathing movements. Moderately deprived fetuses were more active than controls on gestational day (GD) 115; maternal plasma zinc concentrations were significantly correlated with fetal activity at this time. In addition moderately deprived fetuses exhibited fewer breathing episodes on GDs 115-135. Biometrics measures indicated growth retardation in one moderately deprived fetus. These data suggest that moderate, but not marginal, dietary zinc deprivation influences fetal status as evaluated by sonography.

A marginal state of zinc deficiency was induced in the pregnant nonhuman primate, Macaca mulatta, by feeding a diet containing 4 ppm zinc beginning at conception. Pregnancy outcome of marginally zinc-deficient monkeys (ZD) was compared to both pair-fed (PF) and ad libitum fed (AL) control animals (100 ppm zinc). Stillbirths, abortions, and delivery complications were more frequent in both ZD and PF dams than in AL controls; no malformations were detected (maternal plasma zinc was normal during organogenesis). Male ZD neonates weighed significantly less than same sex controls; also, in relation to colony norms, 7/8 ZD males, 2/8 ZD females, and 1/10 PF controls were of low birth weight. Further, plasma zinc and iron levels were lower in ZD neonates than in AL and PF controls. ZD neonates also had reduced muscle tonus. Birth weight and maternal plasma zinc concentration were negatively correlated in ZD group but positively correlated in AL and PF groups. Indeed, maternal plasma zinc concentration alone did not identify a state of zinc deficiency which impaired fetal growth in monkeys.

Skeletal maturation was evaluated from ages 1 to 3 y in rhesus monkeys that had been subjected to a diet marginally deficient in zinc (4 micrograms/g Zn) from conception through age 3 y. Skeletal development was assessed at 18, 24, 30, and 36 mo of age and compared with that of controls fed ad libitum. Skeletal maturation was determined by the presence of epiphyseal ossification centers. To evaluate endochondral bone mineralization the appearance of the zone of provisional calcification on the metaphyseal side of the growth plate and the width of the growth plate were observed. Marginal Zn deprivation was associated with delayed skeletal maturation in monkeys up to age 3 y. Defective mineralization of bone was evident in these monkeys up to age 6 mo. Between ages 6 mo and 3 y bone mineralization increased in some of the marginal-Zn monkeys to values that were only slightly below those for control monkeys.

Arrested adolescent growth and sexual maturation are striking symptoms of severe dietary zinc deprivation. More general implications of mild or marginal Zn deficiency during adolescence are not known. Five marginally Zn-deprived (ZD) male monkeys (4 mg Zn/kg diet) were compared with five controls pair fed a diet containing 100 mg Zn/kg during early adolescence. Mean plasma Zn levels were 38% lower in ZD group than in controls when evaluations began. During rapid growth plasma Zn decreased in controls but not ZD animals. ZD animals had delayed onset of accelerated weight gain and linear growth; loss of subcutaneous fat typical of early adolescence did not occur. ZD monkeys required two to three times more trials for both learning and reversal a visual discrimination task. Immune function was depressed 20-30% as reflected in early reduced proliferative response of peripheral lymphocytes and later lower immunoglobulin levels. Marginal dietary Zn deprivation affects growth and function in adolescence without producing frank developmental retardation.

Growth was evaluated in rhesus monkey infants that were the offspring of females given a marginally zinc-deficient diet (4 micrograms/g zinc) from the beginning of pregnancy and through 12 months of postnatal life. These zinc-deficient (ZD) infants were compared to controls whose mothers were fed a complete diet, either ad libitum or pair-fed to zinc-deficient dams, throughout gestation and lactation. Male ZD infants had evidence of growth retardation at birth. In contrast, growth retardation in female ZD infants was not observed until 1 month of age. From 3 to 9 months of age (late lactation and subsequent to weaning) ZD infants attained weights similar to those of the control group. However, analysis of crown-rump and femur length indicated that ZD infants' growth was less than optimal throughout the entire 1st yr of observation. In addition, skinfold thickness was markedly higher in ZD than in control infants in the postweaning period. In the juvenile period (9-12 months of age) both male and female ZD animals fell behind controls in body weight. ZD juveniles were also hypogeusic, as determined by a quinine acceptance test. Low weight ZD infants had reduced somatic growth as reflected in sitting height, long bone growth, head circumference, and limb circumference. Regression analysis indicated that impaired growth rates from 9 to 12 months were associated with both lower food intake and reduced food use efficiency. Plasma zinc concentration was, in general, inversely related to weight gain in both groups during the 1st yr.

To assess long-term effects of marginal zinc deprivation on pregnancy, adult non- pregnant female rhesus monkeys were fed diets containing 100 or 4 ppm zinc for 1 yr, then mated; effects on pregnancy and its outcome are under study. During this year, food intake was not depressed in zinc-deprived (ZD) monkeys, and there were relatively few effects on biochemical or hematological indices. By the end of the year, plasma zinc concentration was somewhat lower in ZD monkeys than in controls. Several immune variables, including serum IgM and IgG levels and polymorphonuclear leukocyte (PMN) function, were depressed in the ZD group, changes closely reflecting circannual fluctuations in plasma zinc levels in both diet groups. Endotoxin-activated plasma from ZD monkeys had less potential to promote chemotaxis than that from control monkeys, suggesting that defective PMN function may relate to a plasma effect. Marginal zinc deprivation may thus influence immune function before other variables are affected. Am J C/in Nuir 1987;45:l492-502.

Adult nonpregnant female rhesus monkeys fed purified diets containing 100 or 4 ppm zinc for 1 yr were mated then studied through midgestation. At mating, zinc-deprived (ZD) monkeys showed maternal lymphocyte response to mitogens concanavalin A (Con A) and phytohemagglutinin (PHA), serum uric acid and carbon dioxide, and WBC lower than in control (C) monkeys. There was a significant positive association between plasma zinc and PHA response. At midgestation, discriminant analysis revealed that maternal lymphocyte response to Con A, fetal abdominal circumference (by ultrasound), plasma fibrinogen, serum IgM, and amniotic fluid iron level were discriminators for diet group, all lower in ZD than in C monkeys. Maternal plasma and RBC zinc at midgestation were positively associated with fetal growth and plasma uric acid. These observations suggest that immune function (ie, mitogen response and serum immunoglobulin level) is a strong discriminator of dietary zinc deprivation in rhesus monkeys, both before and during pregnancy.

Skeletal maturation was evaluated in newborn and infant rhesus monkeys that had been subjected to a marginally zinc-deficient diet (4 ppm zinc) from conception through 12 months of postnatal life. Serial radiographic assessment of skeletal development was performed and compared to both ad libitum and pair-fed controls. Radiographs were obtained at birth and at 1, 3, 9, and 12 months of age. In each age group a maturation indicator was selected to identify individuals with abnormal skeletal maturation defined on the basis of presence of epiphyseal ossification centers. Animals were compared only within a given sex group. Additionally, to evaluate endochondral bone mineralization, the appearance of the zone of provisional calcification on the metaphyseal side of the growth plate and the width of the growth plate were assessed. A marginal level of zinc deprivation during gestation and during the 1st yr of life was found to be associated with significantly delayed skeletal maturation and defective mineralization. This abnormality of bone mineralization has many features similar to human rachitic syndromes and suggests that zinc plays an important role in endochondral bone formation.

Studies of marginal zinc deficiency in rhesus monkeys have demonstrated that plasma Zn levels are often a poor indication of Zn status. To better assess the Zn status of these animals, we examined their liver concentration of Zn as well as of other minerals, metabbothionein (MT), and superoxide dismutase (SOD). Liver-wedge biopsies were obtained from adult rhesus monkeys fed for 15 mo, either a control (100 �g Zn/g) or a marginally Zn deficient diet (4 �tg/g; ZD). Liver Zn and MT concentrations were lower in ZD monkeys than in controls whereas iron concentration was higher in ZD monkeys than in controls. Liver copper, manganese, and magnesium concentrations and activities ofCuZnSOD and MnSOD were similar in the two groups. Data from the groups were pooled for regression analysis. Measurement ofliver Zn and MT concentrations are useful in the assessment ofthe effects of long-term Zn deprivation in primates. Am J C/in Nuir l988;47:104l-5.

The relationship between dietary zinc, vitamin A, and retinol-binding protein (RBP) was studied in pregnant rhesus monkeys. Beginning on day 0 of gestation, monkeys were divided into three groups; 1) eight ad libitum-fed controls (AL) fed a diet containing 100 micrograms/g zinc, 2) 15 zinc-deprived (ZD) fed a diet containing 4 micrograms/g zinc, 3) 11 pair-fed controls (PF) fed the 100 micrograms/g control diet in amounts equal to those consumed by ZD animals. ZD monkeys had lower plasma zinc levels than did the AL and PF groups at day 135 of gestation, and at 1 and 3 months gestation. A positive correlation between plasma vitamin A and plasma zinc was observed (r = 0.5150, p less than 0.05) and between RBP and zinc (r = 0.883, p less than 0.001) in the ZD group at day 135 of pregnancy. By 3 months postpartum, plasma zinc levels increased in all groups; a positive correlation between zinc and vitamin A was observed in the ZD group (r = 0.5162, p less than 0.05) and in the PF group (r = 0.6353, p less than 0.05); however, no correlation between zinc and RBP was observed. In ZD monkeys, the ratio of RBP to vitamin A was higher (p less than 0.05) than in controls at day 135 of pregnancy. Polynomial regression of the interaction between plasma vitamin A and zinc, and the RBP/vitamin A and zinc, indicated a curvilinear relationship between plasma zinc and these two parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Rhesus monkey infants were marginally deprived of zinc (4 ppm diet) from con- ception and were compared to controls (lOO ppm diet) during the first year of life in development ofreflexes and motor patterns, mother-infant interaction, delayed response performance, discrimination learning and reversal, and open field behavior. Deficits in amount and variety of behavior were recorded in deprived infants; spontaneous locomotor activity was 50% below control levels in males at 1 mo of age; spontaneous activity was 7- 10% lower in both males and females at 3 mo of age; response latencies were 50% lower than controls at 7-9 mo; failure to reach discrimination reversal criterion was seen in 7 1% of deprived infants as compared to 10% of controls at 10 mo of age; and abnormally low levels of climbing and exploration were seen in two of six deprived infants at 12 mo of age. No abnormalities in the rate of behavioral development or in emotional adaptability were observed. These and other results suggest that syndromes of lethargy, apathy, and hypoactivity are characteristic of behavioral effects of marginal zinc deprivation in primates. Am J ClinNutr 1985;42: 1229-1239.

Rhesus monkeys were fed a diet marginally deficient in zinc (4 ppm zinc) throughout pregnancy and were monitored for changes in hematological, biochemical, and immunological parameters. This dietary zinc level was chosen because it did not produce an overt deficiency syndrome when fed for 10 wk to nonpregnant monkeys. Deprived animals were compared to control groups fed a zinc replete (100 ppm) diet ad libitum or on a food restricted (pair fed) basis. Beginning in the 3rd trimester zinc-deprived monkeys exhibited characteristic signs of deficiency including dermatitis, anorexia, and low levels of plasma zinc (less than 65 �g/ 100 ml) and of serum alkaline phosphatase activity. The extent of plasma zinc depression in deficient monkeys was dependent on total food intake; severely anorexic monkeys lost weight but maintained normal plasma zinc levels; monkeys that gained 20 to 30% of their body weight during pregnancy had severely depressed plasma zinc. Plasma vitamin A was reduced in the deprived group while copper, magnesium, and folate levels remained similar to controls. He- matological changes indicative of iron deficiency anemia (reduced packed cell volume, mean corpuscular volume, and Hb) were also seen in severely deficient monkeys. In addition, the peripheral lymphocyte mitogen response was reduced in deficient dams. We conclude that marginal deficiency of dietary zinc can produce significant abnormalities of nutritional status and has the potential for producing serious immunohematological dysfunction during preg- nancy. Am J C/in Nuir l984;39:265-280.

Rhesus monkey infants fed a marginally zinc-deficient diet (4 ppm) from conception through 12 mo of postnatal life were monitored for changes in hematological, biochemical, and immunological parameters. These zinc-deprived (ZD) infants were compared to control infants whose motherswere feda zinc-replete (100 ppm) diet either ad libitum (AL) or pair-fed (PF) throughout gestation and lactation. Blast transformation of peripheral blood lymphocytes tophytohemagglutinin (PHA-P), concanavalin A (Con A), and pokeweed mitogen (PWM), was dramatically depressedin the zinc-deficient (ZD) group. Similarly, ZD infants had reduced polymorphonuclear leukocyte function as measured by chemotaxis to endotoxin-activated plasma and phagocytosis of Candida albicans. Levels of serum 1gM were significantly altered in zinc- deficient infants compared to controls. Serum concentrations of IgG and IgA were similar in zinc- deficient and control infants. ZD infants also manifested a hypochromic microcytic anemia at one month of age, reduced activity of the zinc metalloenzyme alkaline phosphatase, and lower activity of SOFT. Am J C/in Nuir l985;42:252-262.