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Food Science and Human Nutrition Department, College of Agricultural and Life Sciences, University of Florida, Gainesville, FL 32611;
*
Blake Medical Center, Bradenton, FL 34209;
Division of Biostatistics, Department of Statistics, University of Florida, Gainesville, FL 32611;
**
General Clinical Research Center, University of Florida, Gainesville, FL 32611; and
Department of Gastroenterology and Nutrition, College of Medicine, University of Florida, Gainesville, FL 32611
4To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • folate • homocysteine • requirements • elderly • women
|
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Jacob et al. 1994
, Koehler et al. 1996
, Selhub et al. 1993
). Numerous
investigators (Kang et al. 1987
, Koehler et al. 1996
, Tucker et al. 1996
) have reported that
increased plasma tHcy concentrations are reduced in response to
supplemental folic acid (FA). Elevations in plasma tHcy concentrations
are considered an indication of functional impairment of folate status;
when measured in addition to blood folate concentrations, they provide
a better indicator of adequacy of folate intake than blood folate
concentrations alone (IOM 1998
).
During the process of estimating the 1998 Dietary Reference Intakes
(DRI) for folate, data were insufficient to derive separate estimates
for age categories 
51 y. Limited observational data were available
from population surveys of older individuals including women >60 y old
(Garry et al. 1982
, Koehler et al. 1997
,
Selhub et al. 1993
). Data from controlled metabolic
studies have been obtained primarily in younger individuals
(Caudill et al. 1997
, Herbert 1962
,
Jacob et al. 1994
, O’Keefe et al. 1995
,
Sauberlich et al. 1987
), and only one study has been
completed in women 49–63 y of age (Jacob et al. 1998
).
No controlled metabolic studies have been conducted in older women
(>65 y) to estimate changes in folate status in response to controlled
folate intake.
Data from a diet-controlled metabolic study in young adult women
(O’Keefe et al. 1995
) indicated that the Recommended
Dietary Allowance (RDA) published previously (Food and Nutrition Board 1989
) for adult women (180 µg/d) was
inadequate to maintain normal folate status relative to 400
µg/d. The current study was designed to assess the
relative adequacy of 200 vs. 400 µg/d in elderly women
based on normalization of folate status after consumption of a
moderately folate-deplete diet. This study was designed before the
introduction of the new term, dietary folate equivalents (DFE), a
conversion unit developed by the Institute of Medicine Panel (IOM) to
express the most recent folate DRI (IOM 1998
). A
detailed description of DFE was published recently (Suitor and Bailey 2000
). The quantities of folate presented in this paper
are 200 and 415 µg/d, not µg of DFE because
this allows direct comparison with previously published studies in
younger women (Jacob et al. 1998
, O’Keefe et al. 1995
). Current diets in the U.S. contain varying quantities of
foods fortified with FA, which may or may not be consumed with
folate-dense foods; therefore a secondary objective of this study
was to compare the relative efficacy of a folate-dense food source
(i.e., orange juice; OJ) in improving folate status compared with FA
added to a low folate diet.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Healthy women (n = 33; 60–85 y old) completed the
depletion phase of the study (7 wk) and 30 subjects completed the
entire protocol (14 wk). The University of Florida Institutional Review
Board approved the study protocol, and informed consent was obtained
from each subject. Screening for the study consisted of phone and
personal interviews followed by a blood chemistry profile and physical
exam. Exclusion criteria included the following: history of chronic
diseases (i.e., renal disease, cancer, diabetes mellitus, malabsorptive
disorders, cardiovascular disease and/or hypertension); abnormal blood
chemistry profile; body weight > 120% of ideal; use of tobacco
products; chronic alcohol consumption; and use of all prescription
medication including estrogen replacement drugs. Normal renal function
was confirmed by age-adjusted creatinine clearance values
(Rowe et al. 1976
), with a normal range determined to be
73.1–88.0 mL/(min · 1.73 m2). Serum and RBC folate, and
vitamin B-6 and B-12 concentrations were within normal limits for
subjects at baseline (i.e., 7 nmol/L, 317 nmol/L, 20 nmol/L and
130 pmol/L, respectively), as were plasma tHcy concentrations (i.e.,
16 µmol/L).
The feeding portion of the study was conducted as four separate trials. Subjects consumed breakfast and dinner in the General Clinical Research Center and lunch and an evening snack were provided for consumption at home. Subjects consumed all of the foods served and only those foods and beverages provided to them by the research staff. Compliance was assessed by daily interaction with subjects and weekly serum folate analysis. Weight was monitored on a weekly basis and changes of >5% from baseline resulted in a slight modification in energy provided for that individual. Over-the-counter medications were limited to occasional ibuprofen as an analgesic and stool softeners given for mild constipation.
Experimental design and diet.
The 14-wk study period was divided into two equal time periods of
49 d (7 wk) each (Fig. 1
). During the first 49 d of the study (depletion phase), subjects
consumed a folate-restricted diet providing ~118 ± 25
µg folate/d (mean ± SD). During the
repletion phase (49 d), subjects consumed the folate-restricted
diet supplemented with either FA or a combination of FA and endogenous
food folate from OJ. The FA was provided in 40 mL of apple juice and
was consumed daily in conjunction with the diet. For the repletion
phase, subjects were randomized into one of four treatment groups.
Subjects in Groups A and C consumed an average of 200 µg
folate/d, whereas subjects in Groups B and D consumed an average of 415
µg folate/d. During repletion, the quantity
(µg/d) of FA and folate from OJ for each dietary group was
as follows: A (10 FA; 70 OJ); B (137 FA; 155 OJ); C (82 FA; 0 OJ);
D(301 FA; 0 OJ)(Fig. 1)
. The average folate content of the orange juice
was 73.7 ± 4.5 µg/240 g juice (225 mL).
|
). The same 5-d cycle was used throughout the study, except
during repletion when subjects in Groups A and B received OJ as a
substitute for a portion of the apple and cranberry juice consumed as
part of the folate-restricted diet. Nutrient content of the diets
was analyzed using the Minnesota Nutrient Data System (Version 2.7;
Nutrition Coordinating Center at the University of Minnesota,
Minneapolis, MN). Subjects consumed an average of 7929 kJ (1895 kcal)
per day. The percentages of energy provided by protein, carbohydrate,
and fat were ~13, 65 and 22%, respectively. Caffeine intake was
limited to the equivalent of one cup (~180 mL) of caffeinated coffee
and one 12-oz (355 mL) caffeinated soda per day. To maintain body
weight within ± 5% of the subject’s initial weight, minor
dietary adjustments were made on an as-needed basis (i.e.,
substituting higher or lower energy versions of selected food items
into individuals’ meals).
To minimize the amount of naturally occurring folate in the diet, low
folate foods such as canned fruits (mixed fruit, pears, peaches) and
vegetables were served. Furthermore, items such as rice, chicken,
potatoes, green beans and carrots were boiled three times and the
cooking water was discarded after each boiling to help leach endogenous
folate from the food (Caudill et al. 1997
,
Herbert 1963
, O’Keefe et al. 1995
).
To ensure that subjects received equal amounts of nutrients (except
folate) and received at least 100% of the 1989 RDA for all other
nutrients, subjects were given a custom-formulated FA-free
vitamin-mineral supplement (Tishcon, Westbury, NY) twice daily.
Three different vitamin-mineral formulations were developed as
follows: one for all subjects during the depletion phase and for Groups
C and D during repletion, and two additional supplements formulated
specifically for the subjects in Groups A and B during repletion.
Subjects also received a daily iron supplement providing 18 mg iron/d
(General Nutrition Center, Pittsburgh, PA). Folate content of the diet
and orange juice was determined throughout the study using a
modification of the trienzyme extraction method of Martin et al. (1990)
and analysis by the microplate adaptation of the
Lactobacillus casei microbiological assay (Horne and Patterson 1988
, Tamura 1990
).
Specimen collections and analytical methods.
To monitor changes in folate status, weekly blood samples and 24-h
urine collections were obtained to determine SF, RBC folate, urinary
folate and plasma tHcy concentrations (Fig. 1)
. To monitor the general
health of the subjects, clinical chemistry profiles (SMAC; Chemzyme
Plus), hematologic indices and complete blood count with differential
(CBC-D) were performed by Smith Kline Laboratories (Gainesville, FL)
using blood samples obtained at baseline, and wk 7 and 14. Hematocrit
was monitored on a weekly basis.
Fasting venous samples were obtained at baseline and weekly thereafter
(Fig. 1)
. Additional blood samples were obtained three times during the
study (baseline, wk 7 and 14) for clinical chemistry profiles and
CBC-D. Hematocrit, whole blood folate, and plasma tHcy
determinations were made using blood collected in EDTA tubes
(Vacutainer, Becton Dickinson, Rutherford, NJ). Plasma and the buffy
coat were obtained after centrifugation (2000 x g,
30 min, 4°C). Samples for SF determinations were collected in serum
separator (SST) gel and clot activator tubes (Vacutainer, Becton
Dickinson) and serum was collected after centrifugation (650 x g, 15 min, 21°C). Baseline and weekly 24-h urine
samples were collected and stored refrigerated in 2.5-L opaque
containers containing 3 g of sodium ascorbate. Folate
concentrations of blood and urine specimens were determined using a
microplate adaptation of the L. casei microbiological
assay (Horne and Patterson 1988
, Tamura 1990
). The intra- and interassay CV for the microbiological
assay were 8.7 and 7.1%, respectively.
Plasma tHcy concentrations were determined using a modification of the
method of Vester and Rasmussen (1991)
using an isocratic
HPLC system with fluorescence detection. A Dionex DX 500 chromatography
system was used (Pump GP40, Universal Interface UI20, and autosampler
AS3500, Dionex, Sunnyvale, CA; FD300 dual monochromator fluorescence
detector, SpectroVision, Concord, MA). The fluorescence intensities
were measured with excitation at 381 nm and emission at 515 nm. The
intra- and interassay CV for the HPLC assay were 2.4 and 5.4%,
respectively.
Creatinine clearance, an index of kidney function, was calculated using urinary creatinine and serum creatinine concentrations determined using a commercially available kit (Sigma Diagnostic 555, St. Louis, MO).
Statistical methods.
One-way ANOVA was used to test for differences in age, weight, vitamin
status, hematocrit and plasma tHcy concentrations among groups at
baseline. In addition, ANOVA was used to evaluate mean change and
percentage of change from baseline and wk 7 over the depletion and
repletion phases, respectively. To account for subject variability upon
entry into the study, analysis of covariance (ANCOVA) was used to
evaluate group differences in SF, RBC folate and plasma tHcy
concentrations at wk 7 and 14, adjusting for either baseline or wk 7
values, respectively. The least squares (LS) means were used to
describe the magnitude of the differences between each group and were
evaluated at the average covariate value (baseline for the wk 7
analysis and wk 7 for the wk 14 comparison). Multiple pairwise
comparisons within each ANOVA and ANCOVA were carried out using a
Bonferroni correction. For example, any of the six possible pairwise
comparisons were considered significant at 
= 0.05/6 = 0.0083. Expected and observed proportions for trends of SF and plasma
tHcy concentrations during the depletion and repletion phases were
compared using a sign test of proportion for trends analysis
(Cox and Stuart 1955
). Regression analysis was used to
determine the slope for each subject’s SF and plasma tHcy response
during folate depletion and repletion. The signs of the regression
slope values (positive or negative) were tallied and the observed
proportion tested against the proportion of responses expected by
chance alone (i.e., the four possible combination of trends are +/+,
+/-, -/+, and -/-, such that by chance alone the proportion of any
possible combination is 25% or 0.25). Differences were considered
significant at P 0.05. Statistics were computed
using SAS 6.12 (SAS Institute, Cary, NC). Values are means ± SD.
|
RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The overall mean age of subjects was 72 ± 7 y. No significant differences in age, weight, or SF, RBC folate, urinary folate excretion, plasma tHcy, vitamin B-6 and vitamin B-12 concentrations were detected among treatment groups at baseline. The subjects’ hematocrits did not change significantly over the 14-wk study period (P = 0.46).
Serum folate.
Overall SF concentrations decreased significantly (P < 0.001) over the depletion phase, decreasing 32.6 ± 22.8 nmol/L
(Table 1
), which is a 65 ± 15% decrease from baseline. No differences
were detected among treatment groups for mean change (P
= 0.07) or percentage of change (P = 0.49) in SF
concentrations during depletion, and the mean SF concentrations of the
treatment groups were not significantly different at wk 7 (P
= 0.33). At baseline, all subjects had SF concentrations 7
nmol/L (3 ng/mL). By wk 7, twelve subjects (36%) had SF concentrations
between 7 and 14 nmol/L (3 and 6 ng/mL), and 7 subjects (21%) had SF
concentrations 7 nmol/L (3 ng/mL).
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. Comparing the effect of dietary treatment on
mean SF concentrations of the four treatment groups at wk 14, a
significant difference was detected between Group D (415
µg/d; diet and FA) and Group A (200 µg/d;
diet, FA and OJ) (P = 0.0053) (Table 1)
. No differences
were detected within similar groups of folate intake (i.e., 200 and 415
µg/d; P = 0.32 and P = 0.72, respectively) (Table 1)
. At the end of repletion, all subjects
had SF concentrations >7 nmol/L (3 ng/mL), and all subjects consuming
415 µg/d of dietary folate had SF concentrations >14
nmol/L (6 ng/mL). In contrast, consumption of 200 µg
folate/d resulted in SF concentrations between 7 and 14 nmol/L (3 and 6
ng/mL) in 50% of subjects in this folate intake group (i.e., 4
subjects in Group A and 3 subjects in Group C). Red blood cell folate.
Overall mean RBC folate concentrations decreased significantly (P < 0.001) over the depletion phase from 1889 ± 752 to 1487 ± 555 nmol/L, representing an average 429 ± 295 nmol/L decrease (21 ± 10%; mean ± SD). No differences were detected among treatment groups for mean change (P = 0.06) or percentage of change (P = 0.08) in RBC folate concentrations during depletion, and the mean RBC folate concentrations of the treatment groups were not significantly different at wk 7 (P = 0.14). The decrease in overall mean RBC folate concentrations was followed by a further decline of 105 ± 220 nmol/L during repletion to an overall mean of 1336 ± 492 nmol/L (mean ± SD) (significant decrease over time, P < 0.001). No differences were detected among treatment groups for mean change (P = 0.21) or percentage of change (P = 0.21) in RBC folate concentrations during repletion, and the mean RBC concentrations of the treatment groups were not significantly different at wk 14 (P = 0.16). Although mean RBC folate concentrations decreased significantly (P < 0.001) throughout the course of the 14-wk study period, no subject at any time was found to have a RBC folate concentration indicative of marginal or full folate deficiency (i.e., 317–363 nmol/L or < 317 nmol/L, respectively).
Total urinary folate.
Overall mean urinary folate excretion decreased significantly (P = 0.002) over the depletion phase, decreasing an average of 83 ± 257 nmol/d (mean ± SD). No differences in urinary folate excretion were detected among the groups at wk 7 (P = 0.20). Mean urinary folate excretion did not change significantly (P = 0.27) over the repletion phase. Mean urinary folate excretion for Groups A, B, C and D was 15.7 ± 4.3, 26.6 ± 3.3, 15.0 ± 1.9 and 48.7 ± 22.5 nmol/d, respectively (P = 0.37).
Plasma homocysteine.
Mean overall plasma tHcy concentration increased significantly
(P < 0.001) over the depletion phase, increasing an
average of 2.1 ± 2.0 µmol/L (Table 2
). Using a sign test for trends based upon the sign combination (-/+)
of each individual’s regression slope, an inverse relationship between
SF and plasma tHcy concentrations was observed in 94% of the subjects
during depletion (P < 0.001). Differences between the
wk 7 means of the two folate intake levels and among the four treatment
groups were not detected (P = 0.12 and P
= 0.21, respectively). At the end of the depletion period, four
subjects had plasma tHcy concentrations >16 µmol/L.
Overall plasma tHcy concentrations decreased (P < 0.001) during the folate repletion phase, decreasing an average of 0.9
± 2.2 µmol/L (mean ± SD). At wk
14, the LS mean plasma tHcy concentration of the 200 µg/d
treatment group was significantly higher (P = 0.009)
than that of the 415 µg/d treatment group (Table 2)
. The
mean percentage of decrease in plasma tHcy for the groups consuming 415
µg folate/d was 11.7%, which was significantly higher
(P = 0.005) than that for the groups consuming 200
µg folate/d (1%). Comparing the effect of dietary
treatment on mean plasma tHcy concentrations of the four treatment
groups at wk 14, a significant difference was detected between Group D
(415 µg/d; diet and FA) and Group A (200
µg/d; diet, FA and OJ) (P = 0.0008) (Table 2)
. During repletion, an inverse relationship between SF and plasma
tHcy concentrations was observed in 58% of subjects (P
< 0.001; sign test for trends). This inverse relationship was
demonstrated in 88% (P < 0.001) of subjects in each
group receiving 415 µg folate/d (Groups B and D), whereas
subjects receiving 200 µg folate/d (Groups A and C)
demonstrated this inverse relationship 22% (P = 0.57)
and 38% (P = 0.26) of the time, respectively. At the
end of the repletion period, two subjects (both in the 200
µg/d treatment group) had plasma tHcy concentrations >16
µmol/L.
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|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and 1989
). This decrease
was based on limited data from intake and status studies, suggesting
that the average folate intake was 180 µg/d, as well as
limited national survey data (Food and Nutrition Board 1989
). In estimating the new DRI for folate for adult women,
indicators of folate adequacy including SF, RBC folate and plasma tHcy
concentrations from population-based studies (Garry et al. 1982
, Koehler et al. 1997
, Selhub et al. 1993
) were reviewed (IOM 1998
). Data from only
one metabolic study (n = 10) were available for women
>55 y (Jacob et al. 1998
). Because that study included
women 49–63 y, the data were insufficient to estimate age-specific
DRI for women >50 y. The data from the present study are the first
from a folate-controlled metabolic study that included women >63
y. The primary objective of this study was to assess the adequacy of
diets containing 200 or 415 µg/d of folate provided as
mixtures of endogenous food folate and FA to normalize folate status
after consumption of a moderately folate-deplete diet.
At the end of the depletion period, overall SF concentrations had
decreased an average of 65% compared with baseline, similar to the
responses to folate depletion observed by Sauberlich et al. (1987)
(60%) and Jacob et al. (1998)
(58%).
Postdepletion, 58% of total subjects had SF concentrations suggestive
of moderate folate inadequacy [i.e., <14 nmol/L (6 ng/mL)]. At the
end of the repletion period, subjects in the 415 µg/d
treatment group had significantly higher SF concentrations than
subjects in the 200 µg/d treatment group. Half of the
subjects consuming 200 µg folate/d had SF concentrations
indicative of moderate folate deficiency, whereas all subjects in the
415 µg treatment group had normal SF concentrations
[i.e., >14 nmol/L (6 ng/mL)]. These data suggest that under the
conditions of our study protocol, a folate intake of ~400
µg/d was more effective in restoring normal folate status
than 200 µg folate/d. Serum folate concentrations within
intake groups (i.e., 200 or 415 µg/d) responded similarly
during repletion regardless of the source of folate (i.e., FA or OJ).
However, due to limitations of sample size, it is difficult to draw
definitive conclusions regarding differences within intake groups.
Overall mean RBC folate concentrations decreased an average of 22%
during depletion and further decreased (mean 5%) during repletion. The
reduction during depletion was similar to the reduction (15%) observed
by Sauberlich et al. (1987)
in response to folate
depletion. This continued decrease in overall RBC folate concentrations
after repletion may be attributable to the fact that red blood cells
have a life span of 120 d and can accumulate folate only during
formation (Shane 1995
), resulting in a delay in response
to folate repletion (Herbert 1987
). Significant
differences in RBC folate concentration in response to the various
treatment groups may have been observed with a longer folate repletion
period.
A significant increase in mean plasma tHcy concentrations was
observed when subjects consumed the low folate diet for 7 wk. The
inverse relationship observed between decreasing SF concentrations and
increasing plasma tHcy concentrations in 94% of our subjects supports
the hypothesis that plasma tHcy concentrations increase when folate
intake is inadequate (Kang et al. 1987
, Koehler et al. 1996
, Tucker et al. 1996
). Plasma tHcy
concentrations have been found to be elevated in postmenopausal women
(Brattstrom et al. 1985
, Wouters et al. 1995
) and may be affected by factors such as age, sex and
hormonal status, which were controlled in our study.
Our data suggest that 200 µg folate/d was not sufficient
to simultaneously increase SF concentrations and decrease plasma tHcy
concentrations. Eighty-eight percent of subjects in the 415
µg/d intake group experienced a simultaneous increase in
SF and decrease in plasma tHcy over the repletion phase, whereas 36%
of subjects in the 200 µg/d treatment group responded in
this manner. Postrepletion, there were significant differences between
the LS mean plasma tHcy concentrations in the 200 and 415
µg/d treatment groups, suggesting that 415 µg
folate/d was more effective in lowering plasma tHcy concentrations.
Similarly, Jacob et al. (1998)
estimated that folate
intakes >300 µg/d (with the majority provided as FA) were
necessary to lower plasma tHcy concentrations significantly in
postmenopausal women. The inclusion of additional dietary folate
repletion groups such as 300 and 600 µg/d would have
allowed more definitive conclusions relative to adequacy of intake in
the present study.
Unlike protocols designed to address issues of folate bioavailability
(Pfeiffer et al. 1997
, Wei et al. 1996
),
the primary focus of this study was to compare the relative efficacy of
200 vs. 400 µg/d in normalizing folate status in elderly
women. It is well established that the bioavailability of FA is higher
than that of endogenous food folate as reviewed by Gregory (1997)
. Data from European studies (Brouwer et al. 1999
, Cuskelly et al. 1996
) suggest that it is
necessary to consume large quantities of folate-dense food sources
to significantly enhance folate status. However, diets in the U.S.,
unlike those in Europe, include FA consumed as enriched cereal grain
products in addition to a relatively low folate diet. One objective of
the present study was to assess the efficacy of small quantities of a
folate-dense food in enhancing folate status when consumed in the
context of a typical U.S. diet containing FA. Orange juice was chosen
as the endogenous food folate source because it is one of the primary
contributors of folate to the diet of Americans (Koehler et al. 1997
, Subar et al. 1989
, Tucker et al. 1996
). This dietary approach to maintaining normal folate
status is especially relevant in the elderly because food consumption,
including folate-dense food sources, may be restricted
(Popkin et al. 1992
). Our results indicate that orange
juice, when consumed as a part of a mixed diet providing a total folate
intake of ~400 µg/d, was effective in normalizing folate
indices.
In summary, the findings of the current study suggest that ~ 400 µg folate/d maintains folate status in elderly women more adequately than does 200 µg/d, thus providing age-specific data for future revisions of the DRI. These data agree with those obtained previously in young adult women demonstrating the inadequacy of 200 µg/d of folate to ensure normal folate status in women across all age categories.
|
ACKNOWLEDGMENTS |
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FOOTNOTES |
|---|
2 Supported in part by Florida Department of Citrus grant #95044 and National Institutes of Health CRC grant #RR0082.
3 This is Florida Agricultural Experiment Station paper no. R-07279.
5 Abbreviations used: CBC-D, complete blood count with differential; DFE, dietary folate equivalents; DRI, Dietary Reference Intakes; FA, folic acid; IOM, Institute of Medicine; LS, least squares; OJ, orange juice; RDA, Recommended Dietary Allowance; SF, serum folate; SMAC, Sequential Multiple Analysis Chemistry; SST, serum separator tube; tHcy, total homocysteine.
Manuscript received November 30, 1999. Initial review completed January 18, 2000. Revision accepted February 24, 2000.
|
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