Original Article

European Journal of Clinical Nutrition (2008) 62, 1412–1418; doi:10.1038/sj.ejcn.1602881; published online 8 August 2007

Effect of vitamin A supplementation on immune function of well-nourished children suffering from vitamin A deficiency in China

J Lin1,2, F Song1,2, P Yao1,2, X Yang1,2, N Li1,2, S Sun1,2, L Lei1,2 and L Liu1,2

  1. 1Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, PR China
  2. 2Department of Nutrition and Food Hygiene, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, PR China

Correspondence: Professor L Liu, Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, 13 Hangkong Road, Wuhan, Hubei 430030, PR China. E-mail: lgliu@mails.tjmu.edu.cn

Received 4 October 2006; Revised 30 April 2007; Accepted 30 April 2007; Published online 8 August 2007.

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Abstract

Objective:

 

To clearly clarify the protective effect of vitamin A supplementation on immune function of well-nourished children suffering from vitamin A deficiency.

Methods:

 

Three hundred sixty-two children in two kindergartens in Wuhan China were enrolled. Detailed dietary assessment and anthropometry were undertaken to facilitate the exclusion of malnourished children. Seventy vitamin A-deficient children with informed consent were randomly divided into the vitamin A-deficient-supplemented group and vitamin A-deficient placebo group, 35 vitamin A-sufficient children (age- and sex-matched with the vitamin A-deficient-supplemented group children) were selected as vitamin A-sufficient placebo group. The baseline and follow-up level of selected immune parameters of the 105 children in three intervention groups were compared.

Results:

 

The total proportion of severe and marginal vitamin A-deficient children was 10.9 and 21.96%, respectively. At baseline, the serum complement C3 and sIgA level of vitamin A-sufficient children was significantly higher than that of vitamin A-deficient children (P<0.05). However, the serum lysozyme level of vitamin A-sufficient children was inversely lower. After intervention, vitamin A-deficient-supplemented children increased serum vitamin A, complement C3 and sIgA level, but their serum lysozyme level inversely decreased.

Conclusions:

 

Vitamin A deficiency was still a serious health problem in children in China cities. Vitamin A supplementation was efficacious in ameliorating serum vitamin A status and partially impaired immune function of well-nourished children suffering from vitamin A deficiency.

Keywords:

vitamin A deficiency, immune function, vitamin A supplementation, well-nourished children

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Introduction

Micronutrient deficiencies are common worldwide and easily affect vulnerable groups such as infants and pregnant women (FAO/WHO, 1992). Vitamin A is indispensable in a large number of physiological functions that encompass vision, growth, reproduction, hematopoiesis and immunity (Villamor and Fawzi, 2005) and its deficiency is of more immense clinical and public health relevance than other micronutrients. It is estimated that there are approximately 127 and 4.4 million preschool children with vitamin A deficiency and xerophthalmia, respectively (West, 2002).

Vitamin A and related retinoids play a major role in immune responses, including expression of mucins and keratins, lymphopoiesis, apoptosis, cytokine expression, production of antibody and the function of neutrophils, natural killer cells, monocytes or macrophages, T lymphocytes and B lymphocytes (Semba, 1999). Thus, deficient vitamin A status is associated with the occurrence of adverse health outcomes that are potentially related to immune responses (Janine et al., 2002). In countries where such deficiency is common and intervention programs are limited, millions of children die each year from the increased mortality and morbidity of measles and diarrheal infections, blindness and anemia (Villamor and Fawzi, 2000; Whitcher et al., 2001; Semba and Bloem, 2002). In vitamin A-deficient individuals, their lungs diminish the ability to remove diseases; this may contribute to the incidence of pneumonia (Ross and Stephensen, 1996; Gerster, 1997). However, findings of community-based trails about the protective effect of vitamin A supplement were varied. A number of studies have reported that the supplementation of vitamin A to preschool children resulted in a significant reduction in mortality (Sommer et al., 1986; Villamor and Fawzi, 2000), but not all such studies (Vijayaraghavan et al., 1990).

However, severe vitamin A deficiency (VAD) often coexists with severe protein-energy malnutrition in children in developing countries (Donnen et al., 1998; Bhaskaram, 2002). The interaction of them could probably aggravate vitamin A-deficient status (Bhaskaram, 2002). Thus protein-energy malnutrition could affect the effect of vitamin A supplementation on vitamin A-deficient children. To clarify clearly the protective effect of vitamin A supplementation on immune function of well-nourished children suffering from vitamin A deficiency, we chose vitamin A-deficient children without protein-energy malnutrition in cities as study group.

Thus, we conducted a randomized, double-blind, placebo-controlled, clinical trial among 105 well-nourished children in Wuhan China. The purpose of this study was to assess the adverse effect of vitamin A deficiency on immune function of well-nourished children and the interventional effects of vitamin A supplementation.

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Materials and methods

Subjects

The study was carried out in Hualou kindergarten and Qiyi kindergarten in Wuhan, which is an industrial center in central region of China. The two kindergartens were both located at the economic center of the city. Most inhabitants were middle-come, intellectuals. The purpose, methods and risks of the study were explained during a parent–teacher meeting and informed consent was obtained from parents before their children participated. The Ethics Committee of Tongji Medical College approved the study.

Design

The study was a randomized, double-blind, placebo-controlled, clinical trial to assess the adverse effect of vitamin A deficiency on immune function of well-nourished children suffering from vitamin A deficiency and the interventional effects of vitamin A supplementation. We contacted all the 392 children in the two kindergartens. However, 30 children without informed consent were excluded and we enrolled 362 children (182 female, 180, male), all between 2 and 7 years old. Data of baseline characteristics of the 362 children (that is, age, sex) were obtained from the document records in their kindergartens. Dietary assessment was also carried out then. According to serum vitamin A concentration, the 362 children were divided into 244 vitamin A-sufficient children and 118 vitamin A-deficient children. Diagnostic standard of VAD: children whose serum vitamin A concentration <20μg/dl (<0.70μmol/l) were severe VAD (Sommer and Davidson, 2002); 20–30μg/dl (0.70–1.1μmol/l) were marginal VAD; 30–70μg/dl (>1.1μmol/l) were at the reference range.

Children who had fever, diarrhea or preventive injection recently were excluded from the study. Underweight children with BMIless than or equal toage- and sex- specific 5th percentile of the first US National Health and Nutrition Examination Survey data were excluded (Wang et al., 2000). Children whose protein or energy intake <Chinese RDA were also excluded. Forty-eight vitamin A-deficient children and 68 vitamin A-sufficient children were then excluded, 176 vitamin A-sufficient children and only 70 vitamin A-deficient children remained. The remaining 70 vitamin A-deficient children were randomly and equally divided into vitamin A-deficient-supplemented group and vitamin A-deficient placebo group. Thirty five vitamin A-sufficient children who sex- and age-matched with the vitamin A-deficient-supplemented group children were selected as vitamin A-sufficient placebo group. All the 105 children in the three groups completed the study at 3 months (Figure 1).


Children of vitamin A-deficient-supplemented group were given 100000IU (retinol equivalent) vitamin A capsules every 2 weeks for 3 months (Grubesic, 2004). Children of vitamin A-sufficient placebo group and vitamin A-deficient placebo group received placebo capsules in the same way.

Baseline data collection

On admission to the study, the following baseline data were collected for each child from a parent or guardian: fever, diarrhea or preventive injection recently. A study physician also recorded weights and heights of the 362 children during a physical examination. Weight of children in light, indoor clothing was measured to the nearest 0.1kg with a beam balance scale. Height of children without shoes was measured to the nearest 0.1cm by using a portable stadiometer.

Dietary assessment

The dietary intake information of the 362 children at baseline was assessed by trained teachers using the 24-h recall method. Three consecutive days were randomly selected for the dietary assessment. Household food consumption of the children was determined by inquiring their parents and recorded by the trained teachers from the beginning to the end of each day. The dietary intakes in the kindergartens for them were also recorded. Dietary intake data were converted into nutrient values using the 1991 China Food Composition Table (Institute of Food and Nutrition Hygiene at Chinese Academy of Preventive Medicine, 1991).

Laboratory procedures

Five mililiters of fasting venous blood samples from 362 children with informed consent were taken for assessment of the baseline serum vitamin A level and Hb concentration before the intervention began. Additionally, the baseline immunological parameters of the blood samples of the 105 children in the three intervention groups were measured. Another 5ml fasting venous blood samples of the 105 children in the three intervention groups were also taken after intervention. The follow-up blood samples were taken 3 days after the completion of 3 months' follow-up, to exclude the probable short-term effect of vitamin A supplement. Serum vitamin A level, Hb concentration and immunological parameters were also measured and compared with the baseline status.

The baseline and follow-up blood samples (5ml) were taken by venipuncture. The blood samples were kept in a dark box at ambient temperature (25°C) and sent to laboratory no more than 6h. Into an EDTA-treated tube, 0.5ml was taken and analyzed for Hb using the cyanmethaemoglobin (colorimetric) method (Mahalanabis et al., 2005). The remaining 4.5ml samples were centrifuged at 800g at ambient temperature for 10min. Serum was separated, transferred to 1.5ml Eppenderf tubes and stored at −80°C until assayed (Tang et al., 1999). Serum vitamin A level was assessed by microimmunofluorescence (standard preparation was provided by Sigma Co., Sigma-aldrich CHEMIE GmbH, Steinheim, Germany, the instrument was Japan F-3000 spectrofluorometer).

Serum immunoglobulin A, G and M (IgG, IgA and IgM) levels were assessed by single immunodiffusion method (Mancini et al., 1965; Bhat et al., 1995; Pare and Simard, 2004) using commercially available tripartigen plates (separate for each immunoglobulin). Each plate contained a pre-prepared solidified agar gel into which H-chain-specific anti-serum (produced by immunization of goats) to the respective immunoglobulins (that is, IgG, IgA and IgM) was already incorporated. Each plate had 12 wells, made out by cutting into the solidified agar. In one 5μl of control standard serum (WHO Reference serum No. 67/97, containing 770mg IgG, 135mg IgA and 81mg IgM in 100ml) was put and rest of the wells were filled with 5μl of the test serum. As instructed, the plates were closed and left to stand at room temperature, till the diffusion was complete (50h in case of IgG and 80h in case of IgM). Precipitin ring diameters were measured, using a specific calibrated scale. The immunoglobulin concentration related to the measured diameters were read directly from the table of reference values.

Serum complement C3 level was also assessed by single immunodiffusion method and lysozyme level was determined by agar plate method (Lie et al., 1986). The salivary samples for sIgA analyses were collected at the day when the blood samples were taken and assessed using radioimmunity method.

Statistical analysis

Data analysis and statistic: data were presented as means±s.e.m. of all children in one group. Statistical analysis was performed using one-way analysis of variance followed by Dunnett's or Bonferroni's test. Values of P<0.05 were considered significant.

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Results

Baseline nutrition status and vitamin A level of the 362 children

The mean daily energy and protein intakes were nearly sufficient in all age groups as compared with Chinese RDA (Table 1). However, the retinol-equivalent and Ca intakes were relatively scarce. Unexpectedly, the iron intake in the children was about twice the Chinese RDA, which was consistent with another study (Du et al., 2000). The total proportion of severe and marginal vitamin A-deficient children was 10.9 and 21.96%, respectively (Table 2). The proportion of marginal vitamin A deficiency in children aged 2–4 years was higher than in other age groups, but the proportion of severe vitamin A deficiency in them was inversely lower. The proportion of marginal and severe vitamin A deficiency had no significant difference in children aged 5–7 years.



Supplemental effect on the 105 children in the three intervention groups

Baseline characteristics of the three intervention groups (that is, age, sex, weight to age and height to age) were similar (Table 3). The mean serum vitamin A level of vitamin A-deficient placebo group and vitamin A-deficient-supplemented group was not different at baseline, which were both significantly lower than the vitamin A-sufficient group (Figure 2). After intervention, vitamin A-deficient-supplemented children significantly increased serum vitamin A level. Furthermore, after intervention completed, the mean serum vitamin A level of vitamin A-deficient-supplemented children had no significant difference as compared with vitamin A-sufficient children. However, without vitamin A supplementation, the mean serum vitamin A level of vitamin A-deficient placebo group had no significant change.

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

The serum vitamin A levels of the three groups were measured at baseline and after vitamin A supplement (n=35). 1Significantly different from the VA-deficient placebo group, 1P<0.05. 2Significantly different from the baseline, 2P<0.05.

Full figure and legend (28K)


The serum complement C3 and sIgA level of vitamin A-sufficient children was significantly higher than that of vitamin A-deficient children at baseline, but the serum lysozyme level of them was inversely lower (Table 4). After intervention, vitamin A-deficient-supplemented children significantly increased serum complement C3 and sIgA level, which was higher than in vitamin A-deficient children given placebo. However, the serum lysozyme level of them significantly decreased. For the end of study survey, the mean serum complement C3, lysozyme and sIgA levels of vitamin A-deficient-supplemented children had no significant difference as compared with vitamin A-sufficient children. No significant differences were observed between the three groups in serum IgG, IgA or IgM level at baseline or after intervention.


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Discussion

This randomized, double-blind, placebo-controlled clinical trail showed that vitamin A supplementation was efficacious in ameliorating serum vitamin A status and partially impaired immune function in the population of essentially well nourished and vitamin A-deficient children we studied. Because of the frequent association of vitamin A deficiency with protein-energy malnutrition, it may be difficult to assess the vitamin A supplemental effect on vitamin A-deficient children alone (Semba et al., 1992). Thus, detailed dietary assessment and anthropometry was undertaken in our study to facilitate the exclusion of underweight children and malnourished children whose protein or energy intake <Chinese RDA. An age distribution was also drawn to show the epidemiological information on prevalence of vitamin A deficiency in children in China cities.

In this study the total proportion of severe and marginal vitamin A-deficient children was 10.9 and 21.96%, respectively. These data were higher than the results of Chinese national nutrition and health survey in 2002. This might because the children in our study, aged from 2 to 7, were younger than the children in the national survey. It indicated that vitamin A deficiency was more prevalent in younger children and still a serious health problem in children in China cities. Chinese national nutrition and health survey in 2002 found that children in China cities nowadays had enough, sometimes even too much protein and energy intakes, but conventional plant-based foods supplies for them were not sufficient (Li et al., 2005). Conventional plant-based foods that contain a large number of essential nutrients (that is, vitamin, mineral, minor element) are all absolutely necessary for children growth and development. Furthermore, they can maintain body stores of vitamin A in children (Tang et al., 1999). It suggested that the irrationality of dietary pattern might be the reason why vitamin A deficiency was so common in children in China cities.

We surveyed the protein, energy, Ca, Fe and retinol-equivalent intakes of all the 362 children at baseline. Unexpectedly, the iron intake in the children was about twice the Chinese RDA, which was consistent with another study by Du et al. (2000). The mean daily iron intake in adults aged 18–60 years was about 177% of the Chinese RDA or 209% of US RDA in that study, it suggesting that in China, as in many other developing countries, dietary iron intake was high, but much of the iron consumed came from food sources with low bioavailability.

Vitamin A-deficient children who were given 100000IU vitamin A every 2 weeks for 3 months significantly increased serum vitamin A level as compared with vitamin A-deficient children given placebo. These data were consistent with the results of a prospective cohort study by Pangaribuan et al. (2003) in Indonesia, in which the proportion of children with lower serum vitamin A concentration decreased from 18.8 to 14.5% by receiving a single dose of 200000IU vitamin A. However, our study differed from that study in that all the vitamin A-deficient-supplemented children in our study increased their serum vitamin A level (data not shown) and the follow-up mean serum vitamin A level of them even reached the normal level as compared with vitamin A-sufficient children. This meant that the vitamin A-deficient status in the children with vitamin A supplementation totally recovered in our study. A more likely explanation for that was that the vitamin A-deficient children in our study were clinically normal and well nourished and vitamin A supplementation could be more efficacious in ameliorating deficient vitamin A status in such children. The vitamin-A deficient children in our study were all living in cities and their socioeconomic status was better. They had adequate protein-energy intakes and their VAD could be caused by not enough conventional plant-based foods supplies. Thus, with adequate protein-energy intakes, those vitamin A-deficient children in our study were apparently healthy.

The analysis of serum samples drawn before the intervention showed that the initial serum complement C3 and sIgA level was higher in vitamin A-sufficient children than in vitamin A-deficient children. However, vitamin A-sufficient children inversely had a lower lysozyme level. It indicated that vitamin A deficiency could impair mucosal immunity, complement system and lysozyme activities. However, a previous study did not agree with our results. A similar clinical trail by Coutsoudis in Africa showed no difference in serum complement C3 level between the intervention group and placebo group even eight or 42 days after intervention, but comparisons with baseline were not made in that study (Coutsoudis et al., 1992). The serum IgG, IgA or IgM levels were similar between the three intervention groups. This suggested that humoral immunity might be unaffected by vitamin A status. However, that was just an indirect assessment of the potential effects of vitamin A status on B-cell function of antibodies production. The direct effects of vitamin A status on the proliferation or activation of B lymphocytes in vivo was still unclear (review in Stephensen, 2001).

After intervention, vitamin A-deficient-supplemented children recovered their partially impaired immune function. Moreover, the mean serum complement C3, sIgA and lysozyme level of them reached the normal level, which could be attributed to the recovery of vitamin A status by vitamin A supplementation. Vitamin A supplementation might also preserve mucosal IgA level by stimulating Th2 cytokine production (Nikawa et al., 1999). This indicates that our intervention program (100000IU vitamin A every 2 weeks for 3 months) was efficacious in correcting the partially impaired immune function of the children. A similar study by Coutsoudis also showed the protective effect of vitamin A supplementation, in which there was an increase in total number of lymphocytes (day 42, P=0.05) and measles IgG antibody concentrations (day 8, P=0.02) in the treated group. During the 1940s, a number of therapeutic trials were conducted on the effect of vitamin A supplementation on infection-related outcomes (Stephensen, 2001). Later in the 1980s, a lot of community-based studies concentrated on the protective effect of vitamin A supplementation on child mortality from infectious diseases (Villamor and Fawzi, 2000). Our findings reinforced the results from these trails that the recovered immune function of vitamin A-deficient-supplemented children maybe the reason why vitamin A supplementation decreased the children mortality from measles, diarrhea and other infections (Villamor and Fawzi, 2000; Stephensen, 2001).

In conclusion, we found that vitamin A supplementation was efficacious in ameliorating serum vitamin A status and partially impaired immune function of well nourished and vitamin A-deficient children, and vitamin A deficiency was still a serious health problem in children in China cities.

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References

  1. Bhaskaram P (2002). Micronutrient malnutrition, infection, and immunity: an overview. Nutr Rev 60 (Suppl), S40–S45. | Article | PubMed | ISI |
  2. Bhat GA, Mubarik M, Bhat MY (1995). Serum immunoglobulin profile in normal Kashmiri adults. J Postgrad Med 41, 66–69. | PubMed | ChemPort |
  3. Coutsoudis A, Kiepiela P, Coovadia HM, Broughton M (1992). Vitamin A supplementation enhances specific IgG antibody levels and total lymphocyte numbers while improving morbidity in measles. Pediatr Infect Dis J 11, 203–209. | PubMed | ISI | ChemPort |
  4. Donnen P, Dramaix M, Brasseur D, Bitwe R, Vertongen F, Hennart P (1998). Randomized placebo-controlled clinical trial of the effect of a single high dose or daily low doses of vitamin A on the morbidity of hospitalized, malnourished children. Am J Clin Nutr 68, 1254–1260. | PubMed | ISI | ChemPort |
  5. Du S, Zhai F, Wang Y, Popkin BM (2000). Current methods for estimating dietary iron bioavailability do not work in China. J Nutr 130, 193–198. | PubMed | ISI | ChemPort |
  6. FAO/WHO (1992). International Conference on Nutrition. World Declaration and Plan of Action. FAO: Rome.
  7. Gerster H (1997). Vitamin A-functions, dietary requirements and safety in humans. Int J Vitam Nutr Res 67, 71–90. | PubMed | ISI | ChemPort |
  8. Grubesic RB (2004). Children aged 6 to 60 months in Nepal may require a vitamin A supplement regardless of dietary intake from plant an animal food sources. Food Nutr Bull 25, 248–255. | PubMed |
  9. Institute of Food and Nutrition Hygiene at Chinese Academy of Preventive Medicine (1991). Food Composition Table. People's Medical Publishing House: Beijing, China.
  10. Janine J, Archibald LK, Nwanyanwu OC, Sowell AL, Buchanan I, Larned J et al. (2002). Vitamin A level and immunity in humans. Clin Diagn Lab Immunol 3, 616–621.
  11. Li LM, Rao KQ, Kong LZ, Yao CH, Xiang HD, Zhai FY et al. (2005). A description on the Chinese national nutrition and health survey in 2002. The technical working group of China national nutrition and health survey. Zhonghua Liu Xing Bing Xue Za Zhi 26, 478–484. | PubMed |
  12. Lie O, Syed M, Solbu H (1986). Improved agar plate assays of bovine lysozyme and haemolytic complement activity. Acta Vet Scand 27, 23–32. | PubMed | ISI | ChemPort |
  13. Mahalanabis D, Islam MA, Shaikh S, Chakrabarty M, Kurpad AV, Mukherjee S et al. (2005). Haematological response to iron supplementation is reduced in children with asymptomatic Helicobacter pylori infection. Br J Nutr 94, 969–975. | Article | PubMed | ISI | ChemPort |
  14. Mancini G, Carbonara AD, Heremans IF (1965). Immuno-chemical quantitation of antigens by single radial immunodiffusion. Immuno-chemistry 2, 235. | Article | ChemPort |
  15. Nikawa T, Odahara K, Koizumi H, Kido Y, Teshima S, Rokutan K et al. (1999). Vitamin A prevents the decline in immunoglobulin A and Th2 cytokine levels in small intestinal mucosa of protein-malnourished mice. J Nutr 129, 934–941. | PubMed | ISI | ChemPort |
  16. Pangaribuan R, Erhardt JG, Scherbaum V, Biesalski HK (2003). Vitamin A capsule distribution to control vitamin A deficiency in Indonesia: effect of supplementation in pre-school children and compliance with the programme. Public Health Nutr 6, 209–216. | Article | PubMed | ISI |
  17. Pare J, Simard C (2004). Comparison of commercial enzyme-linked immunosorbent assays and agar gel immunodiffusion tests for the serodiagnosis of equine infectious anemia. Can J Vet Res 68, 254–258. | PubMed | ISI | ChemPort |
  18. Ross AC, Stephensen CB (1996). Vitamin A and retinoids in antiviral responses. FASEB J 10, 979–985. | PubMed | ISI | ChemPort |
  19. Semba RD (1999). Vitamin A and immunity to viral, bacterial and protozoan infections. Proc Nutr Soc 58, 719–727. | PubMed | ISI | ChemPort |
  20. Semba RD, Bloem MW (2002). The anemia of vitamin A deficiency: epidemiology and pathogenesis. Eur J Clin Nutr 56, 271–281. | Article | PubMed | ISI | ChemPort |
  21. Semba RD, Muhilal, Scott AL, Natadisastra G, Wirasasmita S, Mele L et al. (1992). Depressed immune response to tetanus in children with vitamin A deficiency. J Nutr 122, 101–107. | PubMed | ISI | ChemPort |
  22. Sommer A, Davidson FR (2002). Assessment and control of vitamin A deficiency: the Annecy accords. J Nutr 132 (Suppl), S2845–S2851.
  23. Sommer A, Tarwotjo I, Djunaedi E, West Jr KP, Loeden AA, Tilden R et al. (1986). Impact of vitamin A supplementation on children mortality. Lancet 1, 1169–1173. | Article | PubMed | ISI | ChemPort |
  24. Stephensen CB (2001). Vitamin A, infection, and immune function. Annu Rev Nutr 21, 167–192. | Article | PubMed | ISI | ChemPort |
  25. Tang GW, Gu XF, Hu SM, Xu QM, Qin J, Dolnikowski GG et al. (1999). Green and yellow vegetables can maintain body stores of vitamin A in Chinese children. Am J Clin Nutr 70, 1069–1076. | PubMed | ISI | ChemPort |
  26. Vijayaraghavan K, Radhaiah G, Prakasam BS, Sarma KV, Reddy V (1990). Effect of massive dose vitamin A on morbidity and mortality in India children. Lancet 336, 1342–1345. | Article | PubMed | ISI | ChemPort |
  27. Villamor E, Fawzi WW (2000). Vitamin A supplementation: implications for morbidity and mortality in children. J Infect Dis 182 (Suppl 1), S122–S133. | Article | PubMed | ISI | ChemPort |
  28. Villamor E, Fawzi WW (2005). Effects of vitamin a supplementation on immune responses and correlation with clinical outcomes. Clin Microbiol Rev 18, 446–464. | Article | PubMed | ISI | ChemPort |
  29. Wang Y, Ge K, Popkin BM (2000). Tracking of body mass index from childhood to adolescence: a 6-y follow-up study in China. Am J Clin Nutr 72, 1018–1024. | PubMed | ISI | ChemPort |
  30. West Jr KP (2002). Extent of vitamin A deficiency among preschool children and women of reproductive age. J Nutr 132 (Suppl), 2857S–2866S. | PubMed | ISI | ChemPort |
  31. Whitcher JP, Srinivasan M, Upadhyay MP (2001). Corneal blindness: a global perspective. Bull World Health Organ 79, 214–221. | PubMed | ISI | ChemPort |
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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant no. 30471460).

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