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Micronutrients and infectious diseases: thoughts on integration of mechanistic approaches into micronutrient research.

Results of field and laboratory studies provide convincing evidence that micronutrient deficiencies contribute to the mortality and morbidity of infectious diseases. Despite encouraging results in large trials, understanding the mechanisms by which micronutrients contribute to the outcome of the encounter between an individual and an infectious agent requires additional hypothesis-driven research. Presumably, such understanding should lead to translational studies with targeted nutritional therapy. Although these mechanistic studies are varied and complex, they must be done systematically and should include examination of the mechanisms by which micronutrients affect host-pathogen interactions, development of appropriate animal models and reliable methods for the assessment of micronutrient levels, and translation of the results of basic research findings into clinical studies. Moving the frontiers of micronutrient research from the laboratory to the field will be challenging. However, sound scientific research should lead toward better human health.

Communicable Diseases↗

Effect of daily and weekly micronutrient supplementation on micronutrient deficiencies and growth in young Vietnamese children.

BACKGROUND: Micronutrient deficiencies remain common in preschool children in developing countries. Interventions focus on single micronutrients and often lack effectiveness. Weekly instead of daily supplementation may improve effectiveness. OBJECTIVE: The efficacy of weekly and daily supplementation in reducing anemia prevalence and in improving the zinc, vitamin A, and growth status of 6-24-mo-old Vietnamese children was investigated. DESIGN: In this double-blind, placebo-controlled trial, the daily group (n = 55) received 8 mg elemental Fe (as iron sulfate), 5 mg elemental Zn (as zinc sulfate), 333 microg retinol, and 20 mg vitamin C 5 d/wk for 3 mo. The weekly group (n = 54) received 20 mg Fe, 17 mg Zn, 1700 microg retinol, and 20 mg vitamin C once a week. A third group (n = 54) received a placebo only. Venous blood samples were collected at the start and end of the supplementation period and anthropometric measurements were taken at the start and 3 mo after the end of supplementation. RESULTS: At baseline, 45.6% of subjects had hemoglobin concentrations < 110 g/L, 36.3% had zinc concentrations < 10.71 micromol/L, and 45.6% had retinol concentrations <0.70 micromol/L. Hemoglobin, retinol, and zinc concentrations of both the weekly and daily groups increased similarly compared with the placebo group (P < 0.001). There was no significant difference in growth between the supplemented groups and the placebo group. However, the height-for-age of subjects stunted at baseline increased with z scores of 0.48 (P < 0.001) and 0.37 (P < 0.001) for the daily and weekly groups, respectively. CONCLUSIONS: Weekly and daily supplementation improved hemoglobin, zinc, and retinol concentrations similarly. Neither intervention affected growth of the overall population, but growth of children stunted at baseline was improved through both types of supplementation.

Ascorbic Acid Deficiency↗

Comparison of micronutrient intake measured by a dietary questionnaire and biochemical indicators of micronutrient status.

We compared the intake of 12 micronutrients as reported on a semiquantitative food frequency questionnaire with corresponding biochemical indicators of nutrient status in a sample of 57 males and 82 females aged 40-83 y. Age-, sex-and energy-adjusted correlation coefficients ranged from near zero for thiamin, vitamin A, and zinc to 0.63 for folate. Correlation coefficients between intake and the biochemical measures were > 0.30 for carotenoids, vitamin D, vitamin E, vitamin B-12, folate, and vitamin C. Differences of 50% or more were observed between extreme quartiles of intake for mean plasma concentrations of folate, vitamin B-12, and vitamin C. Excluding nutrient supplement users generally reduced the correlations. These data demonstrate that food frequency questionnaires can provide valid information on intake for a number of micronutrients.

Adult↗

Long-term evaluation of a micronutrient-fortified biscuit used for addressing micronutrient deficiencies in primary school children.

OBJECTIVE: To evaluate the long-term effect on micronutrient status of a beta-carotene-, iron- and iodine-fortified biscuit given to primary school children as school feeding. DESIGN: Children receiving the fortified biscuit were followed in a longitudinal study for 2.5 years (n = 108); in addition, cross-sectional data from three subsequent surveys conducted in the same school are reported. SETTING: A rural community in KwaZulu-Natal, South Africa. SUBJECTS: Children aged 6-11 years attending the primary school where the biscuit was distributed. RESULTS: There was a significant improvement in serum retinol, serum ferritin, haemoglobin, transferrin saturation and urinary iodine during the first 12 months of the biscuit intervention. However, when the school reopened after the summer holidays, all variables, except urinary iodine, returned to pre-intervention levels. Serum retinol increased again during the next 9 months, but was significantly lower in a subsequent cross-sectional survey carried out directly after the summer holidays; this pattern was repeated in two further cross-sectional surveys. Haemoglobin gradually deteriorated at each subsequent assessment, as did serum ferritin (apart from a slight increase at the 42-month assessment at the end of the school year). CONCLUSIONS: This study has shown that fortification of a biscuit with beta-carotene at a level of 50% of the Recommended Dietary Allowance (RDA) was enough to maintain serum retinol concentrations from day to day, but not enough to sustain levels during the long school holiday break. Other long-term solutions, such as local food production programmes combined with nutrition education, should also be examined. The choice of the iron compound used as fortificant in the biscuit needs further investigation.

Bread↗

Serum beta-carotene and antioxidant micronutrients in children with cancer. The 'Cancer in Children and Antioxidant Micronutrients' French Study Group.

Serum antioxidant vitamins A (retinol) and E (alpha-tocopherol), beta-carotene, zinc and selenium for 418 children with newly diagnosed malignancy were compared with those of 632 cancer-free controls. Incident cancer cases and controls were 1-16 years old and recruited in 1986-1989. Age- and sex-adjusted serum concentrations of retinol, beta-carotene and alpha-tocopherol were significantly inversely associated with cancer. In similar models, the odds ratio (OR) comparing the highest with the lowest quintile was 2.06 (95% confidence interval [CI] 1.40-3.02) for retinol, 3.87 (95% CI: 2.54-5.90) for beta-carotene, 2.15 (95% CI: 1.48-3.10) for alpha-tocopherol, 1.29 (95% CI: 0.75-2.23) for selenium, and 1.94 (95% CI: 1.17-2.23) for zinc. The cancer sites that were associated with serum beta-carotene were, in general, leukaemia, lymphoma, central nervous system, bone and renal tumours. Moreover, leukaemia was associated with low mean serum levels of retinol, selenium and zinc. Subjects with lymphoma, bone and renal tumours also had lower mean retinol and alpha-tocopherol levels than controls. Brain tumour patients had low vitamin E levels. Low serum values of antioxidant vitamins were associated with childhood neoplasm occurrence. Some site-specific effect was reported. Low peripheral nutrient levels are not considered as cancer promoters but rather as an impairment of the body's defence mechanism occurring during the cancer-related metabolic and nutritional disturbances and inflammation processes.

Adjuvants, Immunologic↗

Micronutrient programming of development throughout gestation.

Vitamins and minerals serve essential roles in cellular metabolism, maintenance and growth throughout life. They are also central components of many enzymes and transcription factors. However, the need for optimum amounts of key micronutrients at critical stages during the periovulatory period and subsequent embryonic and fetal life has become the focus of sustained research activity only recently. In addition to folic acid, the minerals zinc, iron and copper and the antioxidant vitamins A and E are of particular importance during pregnancy. Both excesses and deficiencies of these micronutrients can have profound and sometimes persistent effects on many fetal tissues and organs in the absence of clinical signs of deficiency in the mother. The consequences of micronutrient imbalance on the developing conceptus may not be apparent at the time of the nutritional insult, but may be manifest later in development. However, supplementary micronutrients provided later in gestation or during postnatal life cannot completely reverse the detrimental effects of earlier micronutrient imbalance. Importantly, deficiency of a specific micronutrient, such as zinc, during pregnancy can result in a greater incidence of fetal malformation and resorptions than general undernutrition. Given the range of micronutrients that affect development, the number of developmental stages susceptible to inappropriate micronutrient status and the diverse biochemical systems and types of tissue affected, it is challenging to propose a unifying hypothesis that could explain the effects of micronutrient imbalance on programming throughout gestation. Micronutrient imbalance can affect pregnancy outcome through alterations in maternal and conceptus metabolism, as a consequence of their essential role in enzymes and transcription factors and through their involvement in signal transduction pathways that regulate development. Micronutrient-induced disturbances in the balance between the generation of free oxygen radicals and the production of antioxidants that scavenge free radicals may provide an additional mechanistic explanation. The detrimental effects of many micronutrient deficiencies, particularly zinc and copper, can be alleviated by supplementary antioxidants, whereas deficiencies of antioxidant vitamins A and E are likely to reduce defence against free radical damage.

Animals↗

Micronutrients: interaction between physical activity, intakes and requirements.

The present literature review examines the following questions: (a) What is the evidence that micronutrient requirements are increased in physically active people? (b) Is there an association between physical activity and micronutrient intake? (c) Are there any significant differences between indices of micronutrient status between physically active and inactive people? The available data suggest that micronutrient requirements are increased in physically active people because of increased losses through sweat, urine and faeces, and an increased need for defence against free radicals. However the evidence is controversial, and it is not possible to make any quantitative estimations. Micronutrient requirements in moderately active people are not likely to be very much above the levels recommended for the general population. The intake of micronutrients increases with increasing energy intake. Therefore, physically highly active people (athletes) have higher micronutrient intakes than untrained subjects. However, moderate physical activity does not necessarily affect daily micronutrient intake. The available indices of micronutrient status do not support the belief that micronutrient status is compromised in highly trained athletes, even without use of dietary supplements. Hence, there are no reasons to believe that the situation would be different in people who are only moderately active. The results suggest that micronutrient status is adequate for health and functional performance in physically active people who follow a normal, mixed Western diet.

Dietary Supplements↗

Multiple micronutrient supplementation increases the growth of Mexican infants.

BACKGROUND: The role of single micronutrient deficiencies in the etiology of growth retardation has recently gained attention. However, because multiple micronutrient deficiencies are common in children in developing countries, it is possible that more than one micronutrient may limit growth and, hence, the correction of a single deficiency may not be enough to improve growth substantially. OBJECTIVE: The objective was to evaluate the effect of multiple micronutrient supplementation on the growth of children aged 8-14 mo whose diets were poor in several micronutrients. DESIGN: Children were randomly assigned to 1 of 2 groups. One group received a multiple micronutrient supplement containing the recommended dietary allowance (RDA) or 1.5 times the RDA of vitamins A, D, E, K, C, B-1, B-6, B-12, riboflavin, niacin, biotin, folic acid, and pantothenic acid, and iron, zinc, iodine, copper, manganese, and selenium. The other group received a placebo. Supplements were administered 6 d/wk for an average of 12.2 mo. Body length was measured at baseline and monthly thereafter until the end of supplementation. RESULTS: Supplemented infants initially aged <12 mo had significantly greater length gains than did the placebo group, with a difference of 8.2 mm (length-for-age z score: 0.3) at the end of supplementation. In contrast, differences in length gains between the supplemented and placebo groups initially aged > or =12 mo were not significant. CONCLUSIONS: Micronutrient deficiencies limited the growth of the Mexican infants studied. Improving micronutrient intakes should be a component of interventions to promote growth in infants living in settings where micronutrient intakes are inadequate.

Age Factors↗

Effects of micronutrients on metal toxicity.

There is growing evidence that micronutrient intake has a significant effect on the toxicity and carcinogenesis caused by various chemicals. This paper examines the effect of micronutrient status on the toxicity of four nonessential metals: cadmium, lead, mercury, and arsenic. Unfortunately, few studies have directly examined the effect of dietary deficiency or supplementation on metal toxicity. More commonly, the effect of dietary alteration must be deduced from the results of mechanistic studies. We have chosen to separate the effect of micronutrients on toxic metals into three classes: interaction between essential micronutrients and toxic metals during uptake, binding, and excretion; influence of micronutrients on the metabolism of toxic metals; and effect of micronutrients on secondary toxic effects of metals. Based on data from mechanistic studies, the ability of micronutrients to modulate the toxicity of metals is indisputable. Micronutrients interact with toxic metals at several points in the body: absorption and excretion of toxic metals; transport of metals in the body; binding to target proteins; metabolism and sequestration of toxic metals; and finally, in secondary mechanisms of toxicity such as oxidative stress. Therefore, people eating a diet deficient in micronutrients will be predisposed to toxicity from nonessential metals.

Animals↗

Micronutrients and innate immunity.

Micronutrients such as zinc, selenium, iron, copper, beta-carotene, vitamins A, C, and E, and folic acid can influence several components of innate immunity. Select micronutrients play an important role in alteration of oxidant-mediated tissue injury, and phagocytic cells produce reactive oxidants as part of the defense against infectious agents. Thus, adequate micronutrients are required to prevent damage of cells participating in innate immunity. Deficiencies in zinc and vitamins A and D may reduce natural killer cell function, whereas supplemental zinc or vitamin C may enhance their activity. The specific effects of micronutrients on neutrophil functions are not clear. Select micronutrients may play a role in innate immunity associated with some disease processes. Future studies should focus on issues such as age-related micronutrient status and innate immunity, alterations of micronutrients in disease states and their effect on innate immunity, and the mechanisms by which micronutrients alter innate immunity.

Deficiency Diseases↗

Breeding strategies for biofortified staple plant foods to reduce micronutrient malnutrition globally.

One sustainable agricultural approach to reducing micronutrient malnutrition among people at highest risk (i.e., resource-poor women, infants and children) globally is to enrich major staple food crops (e.g., rice, wheat, maize, beans and cassava) with micronutrients through plant-breeding strategies. These target groups are dependent on these staples for their sustenance. Available research has demonstrated that micronutrient-enrichment traits are available within the genomes of these major staple food crops that could allow for substantial increases in the levels of Fe, Zn and provitamin A carotenoids (as well as other nutrients and health-promoting factors) without negatively impacting crop yield. Furthermore, Fe- and Zn-dense seeds can increase crop yields when sowed to soils deficient in these nutrients ensuring their adoption by farmers in these regions once they are developed. Importantly, micronutrient bioavailability issues must be addressed when using a plant-breeding approach to eliminating micronutrient malnutrition. The reduction of antinutrient substances that inhibit micronutrient bioavailability or the increase in substances that promote micronutrient bioavailability from staple plant foods are both options that could be pursued in breeding programs, although care needs to be taken not to compromise agronomic performance and sufficient attention paid to possible beneficial roles of compounds which reduce the bioavailability of trace minerals. The time has come to invest in agricultural technologies to find sustainable solutions to micronutrient malnutrition. Plant breeding is one such technology that should be adopted by the world's agricultural community and that should be supported by the world's nutrition and health communities.

Agriculture↗

Strategies for control of micronutrient malnutrition.

Micronutrient malnutrition, particularly vitamin A deficiency (VAD), iron deficiency anaemia (IDA) and iodine deficiency disorders (IDD), poses a serious threat to the health of vulnerable segments of population. Dietary Inadequacy is the primary cause of VAD and IDA, while poor iodine content of soil and water due to environmental iodine deficiency is the main determinant of IDD. Three major intervention strategies are available for the control of micronutrient malnutrition: supplementation of the specific micronutrients; fortification of foods with micronutrients; and horticulture intervention to increase production and nutrition education to ensure regular consumption of micronutrient rich foods. In India currently the national nutrition programmes being implemented for preventing these deficiencies are based on short term supplementation like periodic mega dosing of vitamin A, distribution of iron and folic acid tablets, and salt iodisation. Though these have been in operation for over two decades, there has been no perceptible biological impact on the prevalence of micronutrient malnutrition. Among the constraints, the most important are: lack of coordination, shortage of resources and manpower, inadequate and irregular supplies, lack of proper orientation and training to the functionaries, poor monitoring and supervision and absence of nutrition education. Integrated and multi-sectoral approaches are required to achieve the goals set under the National Nutrition Policy. These should include community-friendly nutrition education to increase awareness and motivation; active people's participation; food fortification; nutrient supplementation; nutrition oriented horticulture programmes; orientation of functionaries, and establishment of integrated micronutrient surveillance. Concerted and focussed efforts are needed to combat micronutrient malnutrition by the 2000 AD.

Anemia, Iron-Deficiency↗

Daily micronutrient supplements enhance delayed-hypersensitivity skin test responses in older people.

A placebo-controlled double-blind trial of the effects of daily micronutrient supplements on circulating vitamin and trace metal concentrations and delayed-hypersensitivity skin test (DHST) responses was conducted. Subjects, aged 59-85 y, were randomly assigned to placebo (n = 27) or micronutrient (n = 29) treatment groups. DHST and circulating concentrations of nine micronutrients were measured before and after 6 and 12 mo of micronutrient ingestion. For the micronutrient group, there were statistically significant increases at 6 and/or 12 mo in the mean serum concentrations of ascorbate, beta-carotene, folate, vitamin B-6, and alpha-tocopherol. There was a significant increase at 12 mo in the number of subjects in the placebo group with one or more low concentrations. DHST responses to a panel of seven recall antigens were significantly increased at 12 mo in the micronutrient group but not the placebo group. This study demonstrates that daily supplementation with low-to-moderate doses of micronutrients can prevent low concentrations of some micronutrients and can improve DHST responses in healthy, independently living older adults.

Aged↗

Plasma micronutrient antioxidant in cancer patients.

The distribution of breast, colon, gastric, thyroid, oral, rectal, pancreatic and renal cancers were determined in 71 Kuwaitis, 45 other Arabs, and 26 Indians. Plasma levels of micronutrient antioxidants, retinol, alpha-tocopherol, lycopene, and beta-carotene were measured in the groups and in 90 matched controls for comparison. Cholesterol was measured to determine its association with the micronutrient antioxidants. Pancreatic cancer occurred exclusively in Kuwaitis, while breast and colon cancers were disproportionately higher in Kuwaitis than in the other groups. Micronutrient antioxidant levels were similar in the groups, except for higher lycopene levels in Kuwaitis. In most instances, the micronutrient antioxidants, except beta-carotene, decreased significantly in levels in patients than in controls. Low levels of retinol, lycopene, and beta-carotene were strongly associated with pancreatic cancer. Compared to controls, significantly increased levels of beta-carotene occurred in breast, colon, thyroid, and renal cancers; increased lycopene occurred in oral cancer, and increased alpha-tocopherol occurred in pancreatic cancer. Alpha-tocopherol strongly correlated with cholesterol. Generally, changes in alpha-tocopherol/ cholesterol ratios mimicked those of alpha-tocopherol levels. Micronutrient antioxidant levels were significantly lower in male patients than female patients. Age showed a negative but statistically insignificant relationship with micronutrient antioxidants. Lycopene strongly correlated with alpha-carotene and alpha-tocopherol with retinol. Among the patients, all micronutrient antioxidants except retinol decreased significantly in levels in smokers than nonsmokers, suggesting susceptibility to cigarette smoke oxidative stress. We conclude that micronutrient antioxidant depletions and altered associations may imply tumor utilization or antioxidant burden in oxidative stress or both. Furthermore, the incidence of pancreatic, colon and breast cancers among Kuwaitis warrants further study.

Adolescent↗

Growth and micronutrient needs of adolescents.

OBJECTIVE: This paper focuses on micronutrients in relation to needs throughout adolescence, a period which involved growth and development that occur through a complex interaction of genetic instructions, hormones and environmental influences, many of them of dietary origin. In the context of micronutrient 'needs' it is of special importance to differentiate between the 'nutritional needs' and 'metabolic needs'. Two main questions arise in relation to the micronutrient needs: (1) why are micronutrients necessary? and (2) how are their needs assessed? RESULTS: The 'necessary' amount will differ according to the objectives pursued: (a) to achieve a satisfactory rate of growth and development; and (b) to maintain 'optimal health'. The assessment of micronutrient needs and status has proved to be difficult, but when elucidating and establishing them, it is imperative to arrive at the estimates in the light of their interdependent role in metabolism and functions. The knowledge of micronutrient metabolic needs can be approached through epidemiological observations, bioavailability studies and clinical trials. However, there is a nearly total absence of reports on the particular metabolic and dietary needs of adolescents. CONCLUSION: Thus more studies are required in relation to the effect of features associated with adolescence on 'needs', evaluating their impact on bioavailability and turnover (storage and losses), and the interactions among micronutrients in the assessment of metabolic and nutritional needs. Another aim should be to establish static and functional indexes, reference values and cut-off points in adolescence, to be used in clinical and epidemiological studies. Future studies should focus on needs to determine those required to maintain 'optimal functions' and regarding the potential prevention of chronic adult diseases.

Adolescent↗

Non-milk extrinsic sugars in the diets of pre-school children: association with intakes of micronutrients, energy, fat and NSP.

Concern has been expressed that high dietary concentrations of non-milk extrinsic sugars (NMES) may potentially compromise nutrient intakes in population groups with low energy intakes (Department of Health, 1991). The objective of the present study was to examine data from the National Diet and Nutrition Survey of Children Aged 1.5 to 4.5 years (Gregory et al. 1995) for evidence of an inverse association between energy from NMES and micronutrient intakes, and if possible to quantify a level of NMES-energy at which micronutrient intakes may, theoretically, be compromised. Energy and nutrient intakes were compared across quintiles of NMES-energy for boys (n 848) and girls (n 827). As the concentration of NMES increased, energy intake rose (in boys only) while percentage energy from fat fell from 40 to 32% across quintiles 1 to 5. Intakes of most micronutrients also fell, while intakes of vitamin C rose. Mean intakes of most micronutrients (Ca, thiamin, riboflavin, niacin, folate and vitamin C) were adequate in comparison with dietary reference values. However, intakes of Fe, Zn and vitamin D were low at all levels of NMES-energy and fell below the estimated average requirement for Fe and Zn for NMES concentrations exceeding 24% of energy. Lower Intakes of milk, meat, bread and vegetables, and higher intakes of fruit juice largely explain the observed trends in micronutrient intake. It is concluded that the inverse association of NMES with micronutrient intakes is of most significance for the 20% of children with diets highest in NMES. However, further work is required to establish whether the associations observed have biological significance with regard to micronutrient status.

Animals↗

Micronutrient deficiency in children.

Malnutrition increases morbidity and mortality and affects physical growth and development, some of these effects resulting from specific micronutrient deficiencies. While public health efforts must be targeted to improve dietary intakes in children through breast feeding and appropriate complementary feeding, there is a need for additional measures to increase the intake of certain micronutrients. Food-based approaches are regarded as the long-term strategy for improving nutrition, but for certain micronutrients, supplementation, be it to the general population or to high risk groups or as an adjunct to treatment must also be considered. Our understanding of the prevalence and consequences of iron, vitamin A and iodine deficiency in children and pregnant women has advanced considerably while there is still a need to generate more knowledge pertaining to many other micronutrients, including zinc, selenium and many of the B-vitamins. For iron and vitamin A, the challenge is to improve the delivery to target populations. For disease prevention and growth promotion, the need to deliver safe but effective amounts of micronutrients such as zinc to children and women of fertile age can be determined only after data on deficiency prevalence becomes available and the studies on mortality reduction following supplementation are completed. Individual or multiple micronutrients must be used as an adjunct to treatment of common infectious diseases and malnutrition only if the gains are substantial and the safety window sufficiently wide. The available data for zinc are promising with regard to the prevention of diarrhea and pneumonia. It should be emphasized that there must be no displacement of important treatment such as ORS in acute diarrhea by adjunct therapy such as zinc. Credible policy making requires description of not only the clinical effects but also the underlying biological mechanisms. As findings of experimental studies are not always feasible to extrapolate to humans, the biology of deficiency as well as excess of micronutrients in humans must continue to be investigated with vigour.

Breeding↗