![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
,3,
,**
*
Division of Human Nutrition and Epidemiology, Wageningen Agricultural University, 6700 EV Wageningen;
Department of Obstetrics and Gynaecology,
**
Department of Epidemiology, and
Department of Chemical Endocrinology, University Hospital St. Radboud, 6500 HB Nijmegen;
§
Laboratory of Metabolic Diseases, Wilhelmina Children's Hospital, 3501 CA Utrecht and
¶
Unilever Research Vlaardingen, 3130 AC Vlaardingen, the Netherlands.
3To whom correspondence and requests for reprints should be addressed
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
KEY WORDS: • humans • folate • homocysteine • vegetables • fruit
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
, Medical Research Council Vitamin Study Research Group 1991
). In both men and
women it improves the folate status and decreases elevated total plasma
homocysteine (tHcy) concentration, which is considered to be a risk
factor for cardiovascular disease (Boushey et al. 1995
)
and NTD (Mills et al. 1995
, Steegers-Theunissen et al. 1994
).
In several countries, women planning to become pregnant are advised to
take 400–500 µg of folate per day (Expert Advisory Group 1992
, US Public Health Service 1992
). It is
generally thought that this intake can only be reached by using folic
acid, the synthetic form of folate. Daily doses of 200–300 µg of
synthetic folic acid not only improve the folate status, but also
decrease tHcy levels (Brouwer et al. 1999
, Jacob et al. 1994
, O'Keefe et al. 1995
, Ward et al. 1997
). The effectiveness of these low doses of folic
acid suggests that a nutritional intervention with foods rich in folate
could also be feasible and successful. We, therefore, tested the
hypothesis that increased intake of dietary folate from vegetables and
citrus fruits improves the folate status and decreases tHcy
concentrations.
|
SUBJECTS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Healthy men and women aged 18–45 y were recruited. A total of 66 women and 28 men applied for enrollment in the study. Exclusion criteria were smoking; known gastrointestinal disorders; screening tHcy concentrations of >20 µmol/L; or use of vitamins, minerals, yeast or seaweed, malaria prophylactics, or anti-convulsants in the 4 mo prior to the experiment. Food products fortified with folic acid are not available in the Netherlands. Therefore, the habitual diet of the subjects contained no folic acid. None of the women were pregnant or planning to become pregnant within the first 6 mo after the study. Based on the selection criteria, 62 women and 25 men were eligible for participation. We included 52 of the women and 25 men in the trial. Ten of these subjects received treatment as part of a study on carotene bioavailability that will be published separately. Because only 77 subjects were required, all 25 men and 52 of the women entered the trial: 2 women decided not to participate for personal reasons and 8 were chosen at random for exclusion. Thus, the present study included 67 subjects. The study was approved by the Medical Ethical Committee of the Division of Human Nutrition and Epidemiology of Wageningen Agricultural University, and all participants gave their written informed consent.
Design.
The trial had a parallel design with three treatments. Group sizes were
selected to be able to detect, with a power of 80%, an 11%
decrease in tHcy concentrations after 4 wk of intervention with 500
µg of folic acid every-other-day (Brouwer et al. 1999
). The treatments for each group were as follows: dietary
folate group, a diet high in natural folate plus a placebo tablet
(n = 23); folic acid group, a diet low in folate
plus supplemental folic acid (n = 22); and placebo
group, the same low-folate diet as the folic acid group plus a
placebo tablet (n = 22).
All subjects were assigned to groups on the basis of initial tHcy concentration, energy intake, vegetarianism, and gender.
Diets.
Before the trial started, trained dietitians, using a validated food
frequency questionnaire (Feunekes et al. 1993
),
estimated the habitual energy intake of the subjects. This method was
validated for estimating fat and energy intake; however, it is not
suitable for estimating folate intake. Therefore, we did not estimate
habitual folate intake. The energy content of the diets was calculated
using the Dutch Nutrient Data Base (Brants & Hulshof
1995
, Stichting NEVO 1993
).
Each day, all subjects received a basal diet with a similar nutrient
composition (Table 1). The quantity of the basal diet was based on the habitual energy
intake for each subject. Body weights, without shoes, jackets, or heavy
clothing, were recorded twice weekly. Energy intake was adjusted when
necessary to compensate for any weight change. If subjects complained
about having either too much or not enough food, we weighed them more
often. In exceptional cases, for example when the subjects were hungry
or underwent more than usual physical activity, we provided energy
buns, which had a similar macronutrient composition as the rest of the
diet and a known folate content. The meals contained conventional foods
and beverages. Six different menus were provided over the 4-wk
intervention period.
|
. The
main sources of dietary folate were vegetables (spinach, green peas,
broccoli, Brussels sprouts, green beans, or a mixed vegetable dish,
~320 µg folate/d) and citrus fruit (1 orange or 2 tangerines and
orange juice, ~75 µg folate/d). Soup or ragout with fewer
vegetables, rice or pasta salad, and non-citrus fruit
(apples/pears) instead of citrus fruit were provided to the folic acid
and placebo groups. The energy content of the foods supplied in
addition to the basal diet was similar for all subjects in all three
intervention groups (1380 kJ/d). All foodstuffs were weighed for each subject. On weekdays at noon, hot meals were prepared and served under supervision at the Division of Human Nutrition and Epidemiology. If subjects could not finish their meal, dessert was packed and the subject took the remaining food home. At lunch time, food for the rest of the day was provided and subjects took the food home. On Friday, food for the weekend was provided for the subjects to eat at home. Subjects checked whether their own package of food was complete before leaving the Division. If the participant later discovered that something was missing, the missing item(s) was delivered to their house. If subjects could not come to the Division to eat their hot meal, food was either collected or delivered to their house. In addition to the food supplied, subjects were allowed a limited number of free-choice items low in folate and fat chosen from a list. The free-choice items were mainly non-alcoholic soft-drinks, alcoholic drinks [subjects were allowed to have no more than one beer (200 mL) each day], candy, and sweetbread fillings. All participants kept a diary in which they recorded illness, medication used, consumption of free-choice items, and any deviations from their diet. At the end of the trial, subjects were asked to complete an anonymous questionnaire regarding problems and noncompliance during the study.
Duplicate portions of the low and high folate diet were collected on
each of the 29 trial days for a fictitious participant with a daily
energy intake of 11 MJ. The folate content was analyzed in a
sub-sample (one from each menu; 12 samples total) by
microbiological assay with Lactobacillus casei as
described by Horne & Patterson (1988)
and modified by Tamura et al. (1990)
. The assay had an intra-assay CV of <10%. Before
extraction, 20 g sodium ascorbate/L was added to the sample. This
was followed by suspending the sample in 10 volumes of a buffer
containing 5 mmol 2-mercaptoethanol/L and 50 mmol potassium
tetraborate/L (Seyoum and Selhub 1993
). A chicken
pancreas conjugase preparation was used to convert polyglutamates into
monoglutamates. Macronutrients were analyzed in pooled samples. The
energy and nutrient content of the free-choice items were estimated
from data in food consumption tables (Stichting NEVO
1993
).
Tablets.
In addition to the food, the folic acid group received a tablet containing 500 µg folic acid every-other-day and a placebo tablet every-other-day, while the other two groups received one placebo tablet daily. Subjects were unaware whether they received folic acid or placebo tablets. Because of the varying amounts of vegetables, participants were aware of their diet category. All subjects noted on a tablet calendar whether they took the tablet. Supplementation compliance was monitored by counting the remaining tablets and inspection of the tablet calendars.
Blood sampling and analysis.
Venous blood samples were collected after an overnight fast at the start (d 0 and 1), after 2 wk (d 15), and at the end of the intervention period (d 29 and 30). tHcy and plasma folate concentrations were assessed in all samples. Red blood cell folate concentrations were determined on d 1 and 30.
Blood samples were drawn into EDTA vacutainer tubes (Venoject II,
Terumo, Madrid, Spain). For the determination of tHcy and plasma folate
concentration, samples were immediately placed on ice and centrifuged
within 60 min at 3000 x g for 10 min. Plasma was
separated and stored at -35°C for folate determination and at -80°C
for total homocysteine determination. For the determination of folate
concentrations in red blood cells, whole blood was diluted fourfold
with an ascorbic acid solution (10 g/L) and stored at -35°C. Before
measurement, the hemolysates were further diluted with IMx Folate RBC
Lysis Reagent (Abbott Laboratories, North Chicago, IL). To be able to
express the folate concentration in red blood cells, hematocrits were
also measured. Corrections were made for the concentration of folate in
plasma. tHcy was measured by HPLC with fluorimetric detection
(Araki & Sako 1987
). The intra- and inter-assay CV
were <8%. Folate concentrations in blood were determined with the
Abbott IMx Folic Acid assay, which is based on ion-capture
technology for the IMx automated immunoassay system (Abbott
Laboratories). The intra-assay CV was <6%, and the
inter-assay CV was <10%. All samples from each subject were
analyzed concurrently.
Calculations of bioavailability of folic acid.
We calculated the bioavailability of dietary folate from vegetables and
citrus fruits relative to the bioavailability of folic acid. This
calculation assumes a linear response between 0 µg added folic acid
and the amount administered and between 0 µg added dietary folate and
the amount administered. For each endpoint (change in concentration of
plasma folate, red blood cell folate, and tHcy), it was calculated as
follows:
 |
For each subject, average values for tHcy and plasma folate concentration were taken for d 0 and d 1 (wk 0) and for d 29 and d 30 (wk 4). Response to the various treatments was calculated for each subject as the change in each endpoint, between the start (wk 0) and the end (wk 4) of the intervention period.
Statistics.
One-way ANOVA on log-transformed data was used to analyze differences in baseline levels of tHcy, plasma folate, and red blood cell folate concentrations among the three groups. Changes in folate and tHcy concentrations were normally distributed as checked by visual inspection of the normal probability plots (univariate procedure; SAS Institute, Cary, NC). To analyze differences in endpoint response between the intervention groups and the placebo group, Student's t-tests were used with a significance level of P < 0.025 to maintain an overall significance level of P < 0.05. Values in the text are means ± SD.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The nutrient and energy intakes of the subjects are shown in Table 1
.
The energy intake from the free-choice items was fixed for each
level of daily energy intake and was 11.2% ± 1.3 of total energy.
Neither the questionnaires, nor the diaries, revealed any deviations from the protocol that might have affected the results. Two subjects missed three supervised hot meals, six subjects two supervised meals, and 16 subjects missed one supervised meal. In all these cases, the meals were eaten outside the Division. The remaining 42 subjects attended all supervised hot meals. One man withdrew from the study on the second day because he could not adhere to the diet.
Counting the remaining tablets and checking the tablet calendars revealed that seven subjects in the folic acid group failed to take one tablet during the intervention period. None of the subjects failed to take more than one folic acid tablet during the study.
Stratification was successful because tHcy, energy intake, vegetarianism, and gender were not different among the groups. The mean age was 23.0 ± 7.5 y, and the body mass index was 22.4 ± 2.0 kg/m2. Over the 29 d of the trial, subjects' body weights decreased by 0.6 ± 0.9 kg.
Folate status.
Baseline plasma folate and red blood cell folate concentrations were
not significantly different among the three groups. After 4 wk of
intervention, the plasma folate concentrations increased in both the
dietary folate and the folic acid group (Table 2). The most distinct increase in plasma folate concentrations
occurred during the first 2 wk. Red blood cell folate concentrations
also increased in both the dietary folate group and the folic acid
group (Table 2)
.
|
At baseline, the median (25%, 75%) of the tHcy concentration was 10.1
(8.0, 11.6) µmol/L. Baseline tHcy concentrations were not
significantly different among the groups. Four weeks of intervention
decreased the tHcy concentrations in both the dietary folate and the
folic acid group (Table 2)
. After correction for changes in the placebo
group, the mean decrease was 2.0 µmol/L (95% CI, 1.0–3.0) in the
dietary folate group and 2.4 µmol/L (1.4–3.4) in the folic acid
group. Concentrations of tHcy decreased gradually during the entire
4-wk intervention period (Table 2)
.
Bioavailability.
The bioavailability of folate from vegetables and citrus fruits relative to folic acid was, for the different endpoints, 60% based on tHcy concentration, 78% based on plasma folate concentration, and 98% based on red blood cell folate concentration.
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
, Cuskelly et al. 1996
, Jacob et al. 1994
, O'Keefe et al. 1995
, Ward et al. 1997
). However, studies
investigating the effects of natural food folate on tHcy and folate
status are scarce. A cross-sectional study showed that intake of
dietary folate was inversely correlated with tHcy concentrations and
positively correlated with the plasma folate concentration
(Tucker et al. 1996
). Cuskelly et al. (1996)
found a
nonsignificant increase of 11% (95% CI: -6, 29) in red blood cell
folate concentration in young, healthy women after 3 mo of intervention
with natural-food folate. Our study shows a significant 17% (CI:
8–26) increase in red blood cell folate concentration after 4 wk of
intervention (Table 2)
. This discrepancy can be explained by
differences in the study hypotheses and designs. Cuskelly et al. (1996)
investigated whether fortified foods, supplements, and consumption of
natural-food folate would have equal effects on folate status in a
free living situation in which the subjects selected their own foods.
They included no more than 10 women in each group, and the average
intake of additional dietary folate was calculated to be 200 µg/d
(Cuskelly et al. 1996
). In contrast, our study was a
controlled dietary intervention study with 22 subjects in each group.
We supplied the subjects in the dietary folate group with vegetables
and fruits containing 350 µg of additional dietary folate per day, a
relatively high amount. Nevertheless, because their study lasted three
times longer than ours, a higher response would have been expected in
the study of Cuskelly et al. (1996)
.
The 350 µg of additional dietary folate consumed daily in the dietary
folate group was 1.4 times the 250 µg of folic acid provided to
subjects in the folic acid group. Depending on the endpoint chosen, the
bioavailability of dietary folate from vegetables and citrus fruit
relative to folic acid was calculated to be between 60 and 98%. This
estimate is higher than the 
50% suggested by the study of Sauberlich et al. (1987)
who determined the bioavailability of folate from a mixed
diet by using responses in plasma folate. Based on the response in red
blood cell folate concentration, our estimate of relative folate
bioavailability of 98% is high compared to the 39% estimated from the
study of Cuskelly et al. (1996)
. The difference in bioavailability
between the studies might be explained by the fact that we used only
vegetables and citrus fruits as a source of folate, whereas the other
two studies fed a wider range of food products (Cuskelly et al. 1996
, Sauberlich et al. 1987
). However, the
difference might also be attributable to the higher degree of
compliance in fruit and vegetables consumption in our study.
In our study, the relative bioavailability was considerably lower when calculated from the change in tHcy (60%) than from the change in folate concentrations in plasma (78%) and red blood cells (98%). These differences cannot be explained by differences in intestinal absorption between synthetic folic acid and folate from foods, but would appear to be related to the chemical form of the vitamin ingested. Tablets contain the fully oxidized form of pteroylglutamic acid, whereas in food the vitamin exists with two or four additional hydrogen atoms and is conjugated to glutamic acid. Food folate appears to be less effective in reducing tHcy concentrations than folic acid. On the other hand, it tends to accumulate more in red blood cells than in plasma.
For practical reasons we provided 500 µg of folic acid on alternate
days instead of 250 µg each day. It is likely that the estimate of
bioavailability of the dietary folate based on changes in tHcy (60%)
would have been slightly lower if we had provided 250 µg of folic
acid each day. We assumed linearity in response between 0 added folic
acid and the 500 µg/2d. However, Kelly et al. (1997)
showed that an
intake of folic acid in addition to that in the diet of >266 µg/d
results in significant amounts of unmetabolized folic acid in the
blood. This suggests that not all folic acid supplied is available for
the remethylation of homocysteine to methionine. The
homocysteine-lowering response is thus not linear over the whole
range, which implies an overestimation of the relative bioavailability
for dietary folate.
Folate is the nutrient most likely to be responsible for the reduction
in tHcy concentrations because it was present in large quantities in
the diet of the dietary folate group and because folate concentrations
in plasma and red blood cells increased significantly during the
intervention period. In addition to folate, vitamin B-12 is also
involved as a cofactor in the remethylation process. However, vitamin
B-12 is only present in animal products and, therefore, could not have
caused the observed reduction in tHcy concentrations in our study.
Apart from the remethylation to methionine, homocysteine can also be
converted to cysteine by transsulfuration by the vitamin B-6-dependent
enzyme, cystathionine synthase. Even though vitamin B-6 is present in
vegetables and fruit, and even though an intake of vitamin B-6 above
the recommended daily allowances might protect women against coronary
heart disease (Rimm et al. 1998
), it is not likely to
have caused the observed effect on tHcy in fasting subjects. Vitamin
B-6 administration in tablet form was shown to have a marked effect on
tHcy concentrations after methionine loading, whereas the effect of
vitamin B-6 administration on fasting tHcy concentrations is regarded
as negligible (Ubbink et al. 1994
).
This study was designed to determine the efficacy of dietary folate from vegetables and citrus fruits to improve the folate status and to decrease tHcy concentrations. Therefore, we chose the strategy of supplying the subjects with a high amount of folate in a controlled setting rather than to examine the effects that can be observed under field conditions. As a consequence, the intake of 350 g of vegetables and one piece of citrus fruit and 200 mL of citrus fruit juice given in our study in addition to the basal diet (total folate content in the dietary folate group: 560 µg/d) was higher than what can be expected to be eaten by the general population.
In summary, we have shown that the intake of folate-dense vegetables and citrus fruits significantly enhances the folate status and decreases tHcy concentrations in healthy volunteers.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
2 This work was supported by the Zorg Onderzoek
Nederland/Dutch Prevention Fund (28–2559), The Hague, and Unilever
Research Vlaardingen. Tablets were supplied by Pharmachemie BV,
Haarlem, the Netherlands. Abbott Diagnostics, Maidenhead, UK provided
the IMx diagnostic kits.
4 Abbreviations used: NTD, neural tube defect;
tHcy, total plasma homocysteine
Manuscript received December 2, 1998. Initial review completed January 7, 1999. Revision accepted March 5, 1999.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1. Araki A., Sako Y. Determination of free and total homocysteine in human plasma by high performance liquid chromatography with fluorescence detection. J. Chromatogr. 1987;422:43-52[Medline]
2. Boushey C. J., Beresford S.A.A, Omenn G. S., Motulsky A. G. A quantitative assessment of plasma homocysteine as a risk factor for cardiovascular disease. JAMA 1995;274:1049-1057[Abstract]
3. Brants H.A.M, Hulshof K.F.A.M. De ontwikkeling van een voedingsmiddelentabel met foliumzuurgehalten 1995 TNO Nutrition Zeist, the Netherlands.
4.
Brouwer I. A., van Dusseldorp M., Thomas C.M.G., Duran M., Hautvast J.G.A.J., Eskes T.K.A.B., Steegers-Theunissen R.P.M. Low-dose folic acid supplementation decreases plasma homocysteine: A randomized trial. Am. J. Clin. Nutr. 1999;69:99-104
5. Cuskelly G. J., McNulty H., Scott J. M. Effect of increasing dietary folate on red-cell folate: Implications for prevention of neural tube defects. Lancet 1996;347:657-659[Medline]
6. Czeizel A. E., Dudás I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N. Engl. J. Med. 1992;327:1832-1835[Abstract]
7. Expert Advisory Group Folic acid and the prevention of neural tube defects 1992 Department of Health London, UK.
8.
Feunekes G.I.J, van Staveren W. A., de Vries J.H.M, Burema J., Hautvast J. G.A.J. Relative and biomarker-based validity of a food-frequency questionnaire estimating intake of fats and cholesterol. Am. J. Clin. Nutr. 1993;58:489-496
9.
Horne D. W., Patterson D. Lactobacillus casei microbiological assay of folic acid derivatives in 96-well microtiter plates. Clin. Chem. 1988;34:2357-2359
10. Jacob R. A., Wu M.-M., Henning S. M., Swenseid M. E. Homocysteine increases as folate decreases in plasma of healthy men during short-term dietary folate and methyl group restriction. J. Nutr. 1994;124:1072-1080
11.
Kelly P., McPartlin J., Goggins M., Weir D. W., Scott H. M. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am. J. Clin. Nutr. 1997;65:1790-1795
12. Medical Research Council Vitamin Study Research Group Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet 1991;338:131-137[Medline]
13. Mills J. L., McPartlin J. M., Kirke P. N., Lee Y. L., Conley M. R., Weir D. G., Scott J. M. Homocysteine metabolism in pregnancies complicated by neural-tube defects. Lancet 1995;345:149-151[Medline]
14. O'Keefe C. A., Bailey L. B., Thomas E. A., Hofler S. A., Davis B. A., Cerda J. J., Gregory J. F., III Controlled dietary folate affects folate status in nonpregnant women. J. Nutr. 1995;125:2717-2725
15.
Rimm E. B., Willett W. C., Hu F. B., Sampson L., Colditz G. A., Manson J. E., Hennekes C., Stampfer M. J. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998;279:359-364
16.
Sauberlich H. E., Kretsch M. J., Skala J. H., Johnson H. L., Taylor P. C. Folate requirement and metabolism in nonpregnant women. Am. J. Clin. Nutr. 1987;46:1016-1028
17. Seyoum E., Selhub J. Combined affinity and ion pair column chromatographies for the analysis of food folate. J Nutr. Biochem. 1993;4:488-494
18. Steegers-Theunissen R.P.M, Boers G.H.J, Trijbels J.M.F, Finkelstein J. D., Blom H. J., Thomas C.M.G., Borm G. F., Wouters M.G.A.J., Eskes T.K.A.B. Maternal hyperhomocysteinemia: A risk factor for neural-tube defects?. Metabolism 1994;43:1475-1480[Medline]
19. Stichting NEVO. (1993) Dutch Nutrient Data Base 1993. Voorlichtingsbureau voor de Voeding, Den Haag.
20. Tamura T., Freeberg L. E., Cornwell P. E. Inhibition of EDTA of growth of Lactobacillus casei in the folate microbiological assay and its reversal by added manganese or iron. Clin. Chem. 1990;36:1993[Medline]
21. Tucker K. L., Selhub J., Wilson P.W.F, Rosenberg I. H. Dietary intake pattern relates to plasma folate and homocysteine concentrations in the Framingham Heart Study. J. Nutr. 1996;126:3025-3031
22. Ubbink J. B., Vermaak W.J.H, van der Merwe A., Becker P. J., Delport R., Potgieter H. C. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J. Nutr. 1994;124:1927-1933
23. US Public Health Service Recommendation for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. Morbid. Mortal. Weekly Rep. 1992;41:1-7
24.
Ward M., McNulty H., McPartlin J., Strain J. J., Weir D. G., Scott J. M. Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. Q. J. Med. 1997;90:519-524
This article has been cited by other articles:
|
|
 |
|
  S. C. Larsson, S. Mannisto, M. J. Virtanen, J. Kontto, D. Albanes, and J. Virtamo Folate, Vitamin B6, Vitamin B12, and Methionine Intakes and Risk of Stroke Subtypes in Male Smokers Am. J. Epidemiol., April 15, 2008; 167(8): 954 - 961. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Velasquez-Mieyer, C. P. Neira, R. Nieto, and P. A. Cowan Review: Obesity and cardiometabolic syndrome in children Therapeutic Advances in Cardiovascular Disease, October 1, 2007; 1(1): 61 - 81. [Abstract] [PDF]
|
|
|
|
 |
|
 S. E Chiuve, E. L Giovannucci, S. E Hankinson, S. H Zeisel, L. W Dougherty, W. C Willett, and E. B Rimm The association between betaine and choline intakes and the plasma concentrations of homocysteine in women Am. J. Clinical Nutrition, October 1, 2007; 86(4): 1073 - 1081. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M Winkels, I. A Brouwer, E. Siebelink, M. B Katan, and P. Verhoef Bioavailability of food folates is 80% of that of folic acid Am. J. Clinical Nutrition, February 1, 2007; 85(2): 465 - 473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Halliwell Dietary polyphenols: Good, bad, or indifferent for your health? Cardiovasc Res, January 15, 2007; 73(2): 341 - 347. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J McKillop, H. McNulty, J. M Scott, J. M McPartlin, J. Strain, I. Bradbury, J. Girvan, L. Hoey, R. McCreedy, J. Alexander, et al. The rate of intestinal absorption of natural food folates is not related to the extent of folate conjugation Am. J. Clinical Nutrition, July 1, 2006; 84(1): 167 - 173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. L Lutsey, L. M Steffen, H. A Feldman, D. H Hoelscher, L. S Webber, R. V Luepker, L. A Lytle, M. Zive, and S. K Osganian Serum homocysteine is related to food intake in adolescents: the Child and Adolescent Trial for Cardiovascular Health Am. J. Clinical Nutrition, June 1, 2006; 83(6): 1380 - 1386. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Weikert, K. Hoffmann, J. Dierkes, B.-C. Zyriax, K. Klipstein-Grobusch, M. B. Schulze, R. Jung, E. Windler, and H. Boeing A Homocysteine Metabolism-Related Dietary Pattern and the Risk of Coronary Heart Disease in Two Independent German Study Populations J. Nutr., August 1, 2005; 135(8): 1981 - 1988. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. L. Yang, J. Hung, M. A. Caudill, T. F. Urrutia, A. Alamilla, C. A. Perry, R. Li, H. Hata, and E. A. Cogger A Long-Term Controlled Folate Feeding Study in Young Women Supports the Validity of the 1.7 Multiplier in the Dietary Folate Equivalency Equation J. Nutr., May 1, 2005; 135(5): 1139 - 1145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Brevik, S. E. Vollset, G. S Tell, H. Refsum, P. M. Ueland, E. B. Loeken, C. A Drevon, and L. F. Andersen Plasma concentration of folate as a biomarker for the intake of fruit and vegetables: the Hordaland Homocysteine Study Am. J. Clinical Nutrition, February 1, 2005; 81(2): 434 - 439. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Wentzel, M. Gareskog, and U. J. Eriksson Folic Acid Supplementation Diminishes Diabetes- and Glucose-Induced Dysmorphogenesis in Rat Embryos In Vivo and In Vitro Diabetes, February 1, 2005; 54(2): 546 - 553. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Ganji and M. R Kafai Frequent consumption of milk, yogurt, cold breakfast cereals, peppers, and cruciferous vegetables and intakes of dietary folate and riboflavin but not vitamins B-12 and B-6 are inversely associated with serum total homocysteine concentrations in the US population Am. J. Clinical Nutrition, December 1, 2004; 80(6): 1500 - 1507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P Hannon-Fletcher, N. C Armstrong, J. M Scott, K. Pentieva, I. Bradbury, M. Ward, J. Strain, A. A Dunn, A. M Molloy, M. A Kerr, et al. Determining bioavailability of food folates in a controlled intervention study Am. J. Clinical Nutrition, October 1, 2004; 80(4): 911 - 918. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Gao, O. I. Bermudez, and K. L. Tucker Plasma C-Reactive Protein and Homocysteine Concentrations Are Related to Frequent Fruit and Vegetable Intake in Hispanic and Non-Hispanic White Elders J. Nutr., April 1, 2004; 134(4): 913 - 918. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Melse-Boonstra, C. E West, M. B Katan, F. J Kok, and P. Verhoef Bioavailability of heptaglutamyl relative to monoglutamyl folic acid in healthy adults Am. J. Clinical Nutrition, March 1, 2004; 79(3): 424 - 429. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Verwei, K. Arkbage, H. Mocking, R. Havenaar, and J. Groten The Binding of Folic Acid and 5-Methyltetrahydrofolate to Folate-Binding Proteins during Gastric Passage Differs in a Dynamic In Vitro Gastrointestinal Model J. Nutr., January 1, 2004; 134(1): 31 - 37. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Gao, M. Yao, M. A. McCrory, G. Ma, Y. Li, S. B. Roberts, and K. L. Tucker Dietary Pattern Is Associated with Homocysteine and B Vitamin Status in an Urban Chinese Population J. Nutr., November 1, 2003; 133(11): 3636 - 3642. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Samman, G. Sivarajah, J. C. Man, Z. I. Ahmad, P. Petocz, and I. D. Caterson A Mixed Fruit and Vegetable Concentrate Increases Plasma Antioxidant Vitamins and Folate and Lowers Plasma Homocysteine in Men J. Nutr., July 1, 2003; 133(7): 2188 - 2193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Verwei, K. Arkbage, R. Havenaar, H. van den Berg, C. Witthoft, and G. Schaafsma Folic Acid and 5-Methyltetrahydrofolate in Fortified Milk Are Bioaccessible as Determined in a Dynamic In Vitro Gastrointestinal Model J. Nutr., July 1, 2003; 133(7): 2377 - 2383. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lokk News and Views on Folate and Elderly Persons J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2003; 58(4): M354 - 361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J Venn, J. I Mann, S. M Williams, L. J Riddell, A. Chisholm, M. J Harper, and W. Aitken Dietary counseling to increase natural folate intake: a randomized, placebo-controlled trial in free-living subjects to assess effects on serum folate and plasma total homocysteine Am. J. Clinical Nutrition, October 1, 2002; 76(4): 758 - 765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Melse-Boonstra, A. de Bree, P. Verhoef, A. L. Bjorke-Monsen, and W.M. M. Verschuren Dietary Monoglutamate and Polyglutamate Folate Are Associated with Plasma Folate Concentrations in Dutch Men and Women Aged 20-65 Years J. Nutr., June 1, 2002; 132(6): 1307 - 1312. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. J. Howard, E. G. Sides, G. C. Newman, S. N. Cohen, G. Howard, M. R. Malinow, and J. F. Toole Changes in Plasma Homocyst(e)ine in the Acute Phase After Stroke Stroke, February 1, 2002; 33(2): 473 - 478. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.C. Verhaar, E. Stroes, and T.J. Rabelink Folates and Cardiovascular Disease Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 6 - 13. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-L. Silaste, M. Rantala, M. Sampi, G. Alfthan, A. Aro, and Y. A. Kesaniemi Polymorphisms of Key Enzymes in Homocysteine Metabolism Affect Diet Responsiveness of Plasma Homocysteine in Healthy Women J. Nutr., October 1, 2001; 131(10): 2643 - 2647. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. de Bree, W. M. Verschuren, H. J Blom, and D. Kromhout Association between B vitamin intake and plasma homocysteine concentration in the general Dutch population aged 20-65 y Am. J. Clinical Nutrition, June 1, 2001; 73(6): 1027 - 1033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Gregory III Case Study: Folate Bioavailability J. Nutr., April 1, 2001; 131(4): 1376S - 1382. [Abstract] [Full Text]
|
|
|
|
|
|
C. S. Johnston, C. A. Taylor, and J. S Hampl More Americans Are Eating "5 A Day" but Intakes of Dark Green and Cruciferous Vegetables Remain Low J. Nutr., December 1, 2000; 130(12): 3063 - 3067. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M Kurowska, J D. Spence, J. Jordan, S. Wetmore, D. J Freeman, L. A Piche, and P. Serratore HDL-cholesterol-raising effect of orange juice in subjects with hypercholesterolemia Am. J. Clinical Nutrition, November 1, 2000; 72(5): 1095 - 1100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. B Rasmussen, L. Ovesen, I. Bulow, N. Knudsen, P. Laurberg, and H. Perrild Folate intake, lifestyle factors, and homocysteine concentrations in younger and older women Am. J. Clinical Nutrition, November 1, 2000; 72(5): 1156 - 1163. [Abstract] [Full Text] [PDF]
|
|
