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Medical Forum / General / Nutrition / September 2004

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Study backs folic acid as means to cut birth defects

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tcomeau - 27 Sep 2004 19:44 GMT
http://www.cbc.ca/story/science/national/2004/09/27/folic_acid040927.html

OTTAWA - Fortifying grain products with folic acid has led to a
dramatic decline in the rate of birth defects such as spina bifida, a
new study by Health Canada shows.

FROM AUG. 6, 2002: Folic acid in cereal cuts birth defects by half,
studies find

 
Dark green, leafy vegetables are high in folate.  
The proportion of babies born with neural tube defects in Newfoundland
and Labrador dropped by 78 per cent after the federal government
required folic acid to be added to flour, cornmeal and pasta,
researchers found.

Folic acid is the synthetic form of folate, also called vitamin B-9,
which is found in citrus fruits, nuts, liver and dark green, leafy
vegetables.

The vitamin has many important functions in the body, but it was in
the mid-1960s that scientists discovered that folate deficiency might
be the cause of neural tube defects, in which the central nervous
system fails to develop fully in the fetus.

Neural tube defects can lead to spina bifida, a defect of the spinal
cord and back bones, and less common defects of the brain such as
anencephaly, when the brain doesn't develop fully.

Scientists don't know how folic acid reduces the risk of neural tube
defects in developing babies.

Since 1992, many medical authorities have told women of child-bearing
age to take folic acid supplements.

The Canadian government introduced mandatory fortification of some
foods with folic acid in 1998.

Continue to fortify food, scientists say

Dr. Catherine McCourt, with Health Canada's population and public
health branch in Ottawa, and her colleagues studied the effects of
folic acid fortification in women aged 19 to 44 and in seniors in
Newfoundland and Labrador.

The study looked at women in St. John's, Nfld. and the rural area of
Clarenville, Port Blandford in the Random Island area.

Historically, the province has had one of the highest rates of neural
tube defects in North America, the researchers said in the Sept. 27
issue of BMC Pregnancy and Childbirth.

McCourt's team found the fortification boosted dietary intake of folic
acid by 70 micrograms per day, on average.

The incidence of neural tube defects in the province fell by 78 per
cent, from an average of 4.36 defects per 1,000 births between 1991
and 1997, prior to fortification, to an average of 0.96 defects per
1,000 births between 1998 and 2001.

"Based on these findings, mandatory food fortification in Canada
should continue at the current levels," the researchers concluded.

There is no way to tease out the contributions of food fortification
and supplement use on the decline of neural tube defects, the
researchers noted.

"Public education regarding folic acid supplement use by women of
childbearing age should also continue," the study's authors added.

***********

So a diet high in cereal grains that are NOT enriched with folic acid
leads to folic acid deficiency. Has it not occurred to them that a
diet high in cereal grains will also lead to other vitamin
deficiencies? Cereal grains contain little or no Vitamin C and B12 as
well as others.

There are two options here. Fortify all cereal grains with all
vitamins that it is deficient in. Or cut back on consuming these
nutrient deficient cereal grains and eat other more complete
nutrient-rich foods.

Cereal crains are for the birds, literally.

TC
Jan - 27 Sep 2004 21:35 GMT
> ***********
>
[quoted text clipped - 10 lines]
>
> Cereal crains are for the birds, literally.

Just look at this data, which shows that even unfortified cereal grains
are much higher in folate than meat:

FOLATE PER 100 g:
Millet 85 mcg
Rye 60 mcg
Rice, white 58 mcg
Oats 56 mcg
...
Beef 13 mcg
Pork 6 mcg

(Source: NutritionData)
So, meat is the bad guy, not cereal grains.

Jan
Matti Narkia - 27 Sep 2004 22:27 GMT
27 Sep 2004 13:35:32 -0700 in article
<1096317332.144573.227440@k26g2000oda.googlegroups.com> "Jan"
<shantigiri@luukku.com> wrote:

>> ***********
>>
[quoted text clipped - 25 lines]
>(Source: NutritionData)
>So, meat is the bad guy, not cereal grains.

Meat may be the bad guy, but not because of your data, which just shows that
unfortified grains are not so hot sources of folate and meats are even
worse. Fishes are also poor sources of folate, but they are not regarded as
the bad guys. Compare your data with the following data, which shows that
liver products are the best sources of folate:

Folate, µg/100g:

Roast liver       1461.1
Pork liver        1391.2
Baking yeast      1250.0
Liver average     1226.0
Wheat germ         520.0
Basil              448.0
Soy meal, white    410.0
Soya flour low-fat 410.0
Bean brown/white   394.0
Soya beans         353.1
Kidney             353.1
Wheat bran         195.0
Asparagus          175.0
Chick pea in
 unsalted water   172.0
Parsley            170.0
Onion              166.0
Egg yolk           158.9
Red beet/beetroot  150.0   
Bean white, cooked 149.7
 Green bean/
broad bean         145.0
Carrot             143.0
Kale               120.0
Broccoli           113.1
Lentils green/
 brown            110.0
Peanut             110.0

For more comprehensive lists see

Folate (HPLC), All food classes, µg/100g
<URL:http://www.fineli.fi/topfoods.php?compid=2273&fuclass=all&specdiet=none&items=50
0&from=top&portion=100g&lang=en
>

Folate (HPLC) in fish, µg/100g
<URL:http://www.fineli.fi/topfoods.php?compid=2273&fuclass=fish&specdiet=none&items=5
00&from=top&portion=100g&lang=en
>

Signature

Matti Narkia

Wolfbrother - 28 Sep 2004 06:58 GMT
> 27 Sep 2004 13:35:32 -0700 in article
> <1096317332.144573.227440@k26g2000oda.googlegroups.com> "Jan"
[quoted text clipped - 74 lines]
> Folate (HPLC) in fish, µg/100g
> <URL:http://www.fineli.fi/topfoods.php?compid=2273&fuclass=fish&specdiet=none&items=5
00&from=top&portion=100g&lang=en
>

Yes liver is one of the ultimate sources of high quality nutrients.
No plant source even comes close.  All traditional meat eating
cultures relished and prized such organs above all else.  Her
generalization of "meat" is ignorant and narrow minded.  Our ancestors
did not consider "meat" in the limited fashion that most people do
today in our modern society and they understood its superiority over
plant foods to support optimal human health.  This knowledge was
universal from one end of the earth to the other and in the most
remote isolated regions despite total lack of communication between
cultures.  That is a powerful testament to the undeniable truth of
such knowledge gained by so many cultures on their own over thousands
of years.
Jan - 28 Sep 2004 07:00 GMT
> Folate, µg/100g:
>
> Roast liver       1461.1
> Pork liver        1391.2
> Baking yeast      1250.0
> Liver average     1226.0

As you know there are other reasons why organ meats should not be
favored as a source of folate.

http://www.nutritiondata.com/foods-000073000000000000000-w.html

Liver also collects toxic substances. It is healthier to rely on
vegetarian sources of folate.

Jan
Matti Narkia - 28 Sep 2004 13:23 GMT
27 Sep 2004 23:00:01 -0700 in article
<1096351201.554770.33500@h37g2000oda.googlegroups.com> "Jan"
<shantigiri@luukku.com> wrote:

>> Folate, µg/100g:
>>
[quoted text clipped - 7 lines]
>
>http://www.nutritiondata.com/foods-000073000000000000000-w.html

Compared with trans-fats and saturated fats, cholesterol in food is a minor
issue. I've eaten 80 grams of cooked pork brain (brain foods are most
cholesterol containing food items) and raw egg yolks daily for 10 years with
no problems whatsoever, my serum lipid profile has in fact improved. But
then I try to avoid trans- and saturated fats and eat my fatty fish and
veggies, too, with extra virgin olive oil of course :-).

>Liver also collects toxic substances. It is healthier to rely on
>vegetarian sources of folate.

The safest bet is to use folic acid supplements (or eat foods fortified with
folic acid, if they are reasonably unprocessed and healthy).

Signature

Matti Narkia

Wolfbrother - 28 Sep 2004 21:06 GMT
> > Folate,  g/100g:
> >
[quoted text clipped - 12 lines]
>
> Jan

LOL!  Cholesterol is your "other reason"?? Oh my god what a joke.  You
are so pathetic.  Dietary cholesterol is just another reason why they
are GOOD.  Stop spouting your baseless garbage and fear mongering
against healthy foods.  You are doing a huge disservice to people and
should be ashamed.
Robert - 29 Sep 2004 21:49 GMT
> > > Folate,  g/100g:
> > >
[quoted text clipped - 18 lines]
> against healthy foods.  You are doing a huge disservice to people and
> should be ashamed.

You are right. Eat anything you want and if your cholesterol is high then
take statins. Eat whatever you want but the bottom line is your cholesterol
level. I agree.
Matti Narkia - 30 Sep 2004 00:16 GMT
27 Sep 2004 23:00:01 -0700 in article
<1096351201.554770.33500@h37g2000oda.googlegroups.com> "Jan"
<shantigiri@luukku.com> wrote:

>> Folate, µg/100g:
>>
[quoted text clipped - 10 lines]
>Liver also collects toxic substances. It is healthier to rely on
>vegetarian sources of folate.

I don't eat liver mainly for fear of toxic substances. But when I tried to
search for information about this, I ended up almost empty handed. Seems
that vegetables and fish have more environmental pollutants than liver, or
for some reason liver's contamination is under reported.

Liver is loaded with nutrients, and liver-carrot juice was used Gerson's
metabolic diet cancer therapy for decades until they stopped it due to
difficulties getting sufficiently safe (not contaminated by toxic substances
or hormones) calf livers. That may be problem in USA (or Mexico), but what's
the situation Europe?

At least some people still seem to think that calf's liver is a health food:

<URL:http://www.whfoods.com/genpage.php?tname=foodspice&dbid=129>

Also Nutritiondata seems to appreciate liver and other organ meats:

343 Lamb, Veal, and Game Products
With the highest ND Ratings
<URL:http://www.nutritiondata.com/foods-017998000000000000000.html>

719 Beef Products
With the highest ND Ratings
<URL:http://www.nutritiondata.com/foods-013998000000000000000.html>

222 Pork Products
With the highest ND Ratings
<URL:http://www.nutritiondata.com/foods-010998000000000000000.html>

346 Poultry Products
With the highest ND Ratings
<URL:http://www.nutritiondata.com/foods-005998000000000000000.html>

Cholesterol is of course high, but that is a minor issue, if the diet is low
in trans and saturated fatty acids and contains a lot of vegetables and
monounsaturated and omega-3 fatty acids. Besides, who would want to eat
liver daily?

So how about liver as an occasional health food? ;-). Perhaps once or twice
in a month?

Signature

Matti Narkia

Jan - 30 Sep 2004 09:56 GMT
> 27 Sep 2004 23:00:01 -0700 in article
> <1096351201.554770.33500@h37g2000oda.googlegroups.com> "Jan"
> <shantigiri@luukku.com> wrote:

> >Liver also collects toxic substances. It is healthier to rely on
> >vegetarian sources of folate.
[quoted text clipped - 8 lines]
> difficulties getting sufficiently safe (not contaminated by toxic substances
> or hormones) calf livers.

Gerson was assured about the health benefits of natural enzymes and
that was the basis of his raw juice cancer therapy. As far as I know
the main reason for Gerson to use calf-liver juice were the living
enzymes it contained, not so much the other nutrients. Another holistic
health practioner, Paul Pitchford, estimates that it is difficult to
get liver that would be safe enough and so he recommends sprouts,
cereal-grass products and raw sauerkraut instead of liver as rich
sources of natural food enzymes.

Jan
N-H-P - 28 Sep 2004 23:37 GMT
> Compare your data with the following data, which shows that
> liver products are the best sources of folate:

May I suggest eating a raw salad?

Geesh!!! Folate from liver???  I mean really.

Folate requires vitamin B-12 to convert it into folic acid.  B-12 is a
limiting factor which comes from meat sources.

smn seems to be regressing. :(
--
John Gohde
Matti Narkia - 29 Sep 2004 02:03 GMT
28 Sep 2004 15:37:26 -0700 in article
<16a9b594.0409281437.3f0ffe1e@posting.google.com>

>> Compare your data with the following data, which shows that
>> liver products are the best sources of folate:
>
>May I suggest eating a raw salad?

Well, I do ;-). So? How much folate you expect to get from it into your
circulation?

See

Folate Deficiency Widespread Worldwide
<URL:http://www.sph.emory.edu/PAMM/folicacid.htm>

   "...  Recent research has shown that almost all people who do not
    consume supplemental folic acid are folate deficient. ..."

Remember, that folate from the food is absorbed less efficiently by our
bodies than folic acid from supplements or fortified food:

<URL:http://www.ext.colostate.edu/pubs/columnnn/nn000829.html>

   "... It is important to note that cooking and storing food
   can destroy some natural folate. The amount of the vitamin
   available to the body varies widely among foods and the
   condition of the food when it is eaten. On the other hand,
   the body can absorb nearly 100 percent of the synthetic form
   of folic acid. This has led the Institute of Medicine, the
   Centers for Disease Control and Prevention and the March of
   Dimes to recommend that all women of reproductive age take
   400 micrograms of synthetic folic acid daily either through
   fortified breakfast cereals or a multi-vitamin. ..."

<URL:http://www.cce.cornell.edu/food/expfiles/topics/stover/folicqanda.html>

  "Q. What's the difference between the terms folic acid and
   folate?
   
   A.In cells, folic acid exists in many chemical forms with
   respect to its oxidation state, one-carbon substitutions and
   number of glutamate residues. In general, the term folates,
   when used in the generic sense, refers to all chemical forms
   of folic acid. The term folic acid refers to the oxidized,
   monoglutamate form of folate otherwise known as
   pteroylglutamic acid.
   
   Q. Is there a difference in bioavailability between folic
   acid in foods versus supplements?
   
   A. The bioavailability of food folate is difficult to
   predict. In general, the oxidized, monoglutamate form of
   folate, the form found in supplements and the form used to
   fortify foods, has a much greater bioavailability than food
   folate which tends to be in a chemically reduced and in a
   polyglutamated form. The absorption of supplement folate
   during fasting is near 100%. Prior to absorption, folate
   polyglutamates must be enzymatically converted to folate
   monoglutamates, and the efficiency of this reaction varies
   depending upon the food source of folate. Therefore, while
   all sources are important, more folate is absorbed from
   fortified foods and supplements. Folic acid supplements are
   even more bioavailable if taken between meals."

<URL:http://users.umassmed.edu/martin.marinus/Mph200/FolicAcidMetabolism.pdf>

   "DHF and THF from natural sources are polyglutamated and
   need to be enzymatically converted to the monoglutamate for
   absorption from the small intestine."
(DHF=dihydrofolic acid; THF=tetrahydrofolic acid)

<URL:http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/fol_0110.shtml>
 
 "PHARMACOKINETICS

   Folic acid or pteroylglutamic acid (PGA) is the form of
   folate used in food fortification and the principal form of
   folate found in nutritional supplements. Natural food
   folates are pteroylpolyglutamate derivatives.
   Pteroylpolyglutamate derivatives are hydrolyzed to
   pteroylmonoglutamate forms prior to absorption from the
   small intestine. The enzyme that catalyzes the cleavage is
   called folate conjugase or gamma-glutamylhydrolase. The
   monoglutamate forms of folate, including folic acid, are
   transported across the proximal small intestine via a
   saturable pH-dependent process. Higher doses of the
   pteroylmonoglutamates, including folic acid, are absorbed
   via a nonsaturable passive diffusion process. The efficiency
   of absorption of the pteroylmonoglutamates is greater than
   that of the pteroylpolyglutamates.

   Because of the difference in absorption efficiency between
   natural food folate and folic acid, the concept of dietary
   folate equivalents (DFEs) has been introduced. Folic acid
   taken on an empty stomach is twice as available as food
   folate. Folic acid taken with food is 1.7 times as available
   as food folate. For example, 400 micrograms of folic acid
   taken on an empty stomach is equivalent to 470 micrograms of
   folic acid taken with food and is equivalent to 800
   micrograms of food folate. DFEs can be calculated as
   follows:

   1 microgram of DFEs = 1 microgram of food folate = 0.5
   micrograms of folic acid taken on an empty stomach = 0.6
   micrograms of folic acid taken with meals.

   Following absorption of physiological amounts of folic acid
   into the enterocytes, a certain percentage undergoes
   reduction. Reduced folate is transported to the liver via
   the portal circulation. Much of a pharmacological dose of
   folic acid is transported to the liver as such, without
   first undergoing metabolism in the enterocytes. The various
   natural pteroylmonoglutamate forms undergo some metabolism
   in the enterocytes to pteroylpolyglutamate forms, but for
   the most part are also transported as their unmetabolized
   forms via the portal circulation to the liver. The folates
   are taken up by the liver and metabolized to polyglutamate
   derivatives (principally pteroylpentaglutamates), via the
   action of folylpolyglutamate synthase. Folates are stored in
   tissue in their polyglutamate forms. Folate is metabolized
   to its various metabolic forms in the liver. The various
   pteroylpolyglutamate forms are the active cellular cofactor
   forms of folate. Folate polyglutamates are released from the
   liver to the systemic circulation and to the bile. When
   released from the liver into the circulation, the
   polyglutamate forms are hydrolyzed by gamma-
   glutamylhydrolase and reconverted to the monoglutamate
   forms.

   The principal folate in the plasma is 5-
   methyltetrahydrofolate in its monoglutate form. 5-
   Methyltetrahydrofolate circulates in erythrocytes in its
   polyglutamate form. Approximately two-thirds of folate in
   plasma is protein bound. All tissue forms of folate are
   polyglutamates, while circulating forms of folate are
   monoglutamates. When pharmacological doses of folic acid are
   administered, a significant amount of unchanged folic acid
   is found in the plasma. The liver contains approximately 50%
   of the body stores of folate, or about 6 to 14 milligrams.
   The total body store of folate is about 12 to 28 milligrams.

   Folate is excreted in the urine as folate cleavage products.
   Intact folate enters the glomerulus and is reabsorbed into
   the proximal renal tubule. Very little intact folate is
   excreted in the urine. Folate is excreted in the bile and
   much of it is reabsorbed via the enterohepatic circulation."

>Geesh!!! Folate from liver???  I mean really.

The fact remains that liver products are the richest sources of folate. Live
with it. No recommendations were given.

>Folate requires vitamin B-12 to convert it into folic acid.  

Perhaps not exactly so. B12 is needed to convert circulating 5-
methyltetrahydrofolate (5-methyl THFA), omce inside the cell, to THFA, the
active form participating in folate-dependent enzymatic reactions. In the
absence of B12, folate is "trapped" as 5-methyl THFA.

But, dietary folate is either monoglutamate or polyglutamate.  Most is
polyglutamate and it can not be absorbed at all.  All supplement folic acid
is monoglutamate and it is absorbed very well. The human gut has a peptidase
that hydrolyzes all of the glutamate off the polyglutamate to give the
monoglutamate form. Now, if I remember corrctly, this enzyme will not work
without B12. Low B12 will cause a folate deficiency unless a folic acid
supplement is used. The page

<URL:http://www.feinberg.northwestern.edu/nutrition/factsheets/folate.html>

seems to agree with me:

   "... Only about half of the folate consumed from food
   sources has acceptable bioavailability. Folate occurs
   naturally attached to multiple glutamic acid molecules which
   must be removed by hydrolysis prior to absorption by a
   vitamin B12-dependent enzyme to form pteroylmonoglutamate.
   In general, foods with high proportions of the monoglutamate
   form have higher folate bioavailability irrespective of the
   total amount. ..."

So B12 is needed both for the absorption of dietary folate and for the
folate metabolism inside the cell.

See also

<URL:http://www.emedicine.com/MED/topic802.htm>:

  "Folic acid is composed of a pterin ring connected to p-
   aminobenzoic acid (PABA) and conjugated with one or more
   glutamate residues. It is distributed widely in green leafy
   vegetables, citrus fruits, and animal products. Humans do
   not generate folate endogenously because they cannot
   synthesize PABA, nor can they conjugate the first glutamate.
   
   Folates are present in natural foods and tissues as
   polyglutamates because these forms serve to keep the folates
   within cells. In plasma and urine, they are found as
   monoglutamates because this is the only form that can be
   transported across membranes. Enzymes in the lumen of the
   small intestine convert the polyglutamate form to the
   monoglutamate form of the folate, which is absorbed in the
   proximal jejunum via both active and passive transport.
   
   Within the plasma, folate is present, mostly in the 5-
   methyltetrahydrofolate (5-methyl THFA) form, and is loosely
   associated with plasma albumin in circulation. The 5-methyl
   THFA enters the cell via a diverse range of folate
   transporters with differing affinities and mechanisms (ie,
   adenosine triphosphate [ATP]–dependent H+ cotransporter or
   anion exchanger). Once inside, 5-methyl THFA may be
   demethylated to THFA, the active form participating in
   folate-dependent enzymatic reactions. Cobalamin (B-12) is
   required in this conversion, and in its absence, folate is
   "trapped" as 5-methyl THFA.
   
   From then on, folate no longer is able to participate in its
   metabolic pathways, and megaloblastic anemia results. Large
   doses of supplemental folate can bypass the folate trap, and
   megaloblastic anemia will not occur. However, the
   neurologic/psychiatric abnormalities associated with B-12
   deficiency ensue progressively.
   
   The biologically active form of folic acid is
   tetrahydrofolic acid (THFA), which is derived by the 2-step
   reduction of folate involving dihydrofolate reductase. THFA
   plays a key role in the transfer of 1-carbon units (such as
   methyl, methylene, and formyl groups) to the essential
   substrates involved in the synthesis of DNA, RNA, and
   proteins. More specifically, THFA is involved with the
   enzymatic reactions necessary to synthesis of purine,
   thymidine, and amino acid. Manifestations of folate
   deficiency thereafter, not surprisingly, would involve
   impairment of cell division, accumulation of possibly toxic
   metabolites such as homocysteine, and impairment of
   methylation reactions involved in the regulation of gene
   expression, thus increasing neoplastic risks."

>B-12 is a
>limiting factor which comes from meat sources.

And how much B12 is in raw salad? ;-).

See also

<URL:http://users.umassmed.edu/martin.marinus/Mph200/FolicAcidMetabolism.pdf>

   "* Increased excretion/loss: Increased excretion of folate
   can occur subsequent to vitamin B-12 deficiency. During the
   course of vitamin B-12 deficiency, methylene THFA is known
   to accumulate in the serum, which is known as the folate
   trap phenomenon. In turn, large amounts of folate filter
   through the glomerulus, and urine excretion occurs. Another
   mechanism of excess excretion occurs in people with chronic
   alcoholism who can have increased excretion of folate into
   the bile. Patients undergoing hemodialysis also have been
   known to have excess folate loss during procedures."

Signature

Matti Narkia

Matti Narkia - 29 Sep 2004 16:50 GMT
Wed, 29 Sep 2004 04:03:28 +0300 in article
<5iqjl05gb60vlk2sjlcng0doq9vfkffmdh@4ax.com> Matti Narkia
<mnng1_REMOVE_THIS@despammed.com> wrote:

><URL:http://www.cce.cornell.edu/food/expfiles/topics/stover/folicqanda.html>
>
[quoted text clipped - 9 lines]
>    pteroylglutamic acid.
>    
See also

<URL:http://europa.eu.int/comm/food/fs/sc/scf/out80e_en.pdf>:

   "Folate is the generic name for a number of compounds having
   a similar activity as folic acid (pteroylglutamic acid,
   PGA), i.e. being involved in single carbon (C1-) transfer
   reactions. Folic acid (PGA) is a synthetic folate compound
   used in food supplements and in food fortification because
   of its stability, and becomes biologically active after
   reduction. Natural (dietary) folates are mostly reduced
   folates, i.e. derivatives of tetrahydrofolate (THF), such as
   5-methyl- THF (5-MTHF), 5- formyl-THF and 5,10-methylene-
   THF, and exist mainly as pteroylpolyglutamates, with up to
   nine additional glutamate molecules attached to the
   pteridine ring."

and

Folate (Folic acid): Implications for health and disease
<URL:http://www.teknoscienze.com/agro/pdf/may_june03/folate.PDF>:   

   "Folate, a member of the B vitamin family, is the generic
   name for a number of chemical forms, which are structurally
   related and that have similar biological activity (1).
   Folate received its name from the Latin word folium, which
   means “foliage”, because it is found in high concentrations
   in green leafy vegetables like spinach, kale, beet greens,
   and chard. Other good sources of folate include legumes,
   whole grains, oranges, broccoli and cabbage (2).

   The naturally occurring forms of folate include 5-
   methyltetrahydrofolate (5-MTHF), 5-formyltetrahydrofolate
   (5-formyl-THF), 5,10-methylenetetrahydrofolate (5,10-
   methylene-THF) and five other chemicals, most of which are
   considered pteroylpolyglutamates because of their chemical
   structure. Common among these folates are two to seven
   glutamates joined in peptide linkages to the gamma-carboxyl
   of glutamate (1).

   One of the natural folates, folinic acid, is used as a
   pharmaceutical agent. Also known as 5-formyl-THF, folinic
   acid is used as rescue therapy following high dose
   methotrexate regimens (1). It is also used in the treatment
   of megaloblastic anemia due to folate deficiency and its
   combination with 5-fluorouracil has until recently been
   standard therapy for colorectal cancer.

   Folic acid is the synthetic form of folate, which is used
   for nutritional supplements and food fortification. Folic
   acid or pterolyglutamic acid is the most oxidized and stable
   form of folate and is comprised of para-aminobenzoic acid
   linked at one end to a pteridine ring and at the other end
   to glutamic acid (1,3) – see Figure 1 for chemical structure
   of folic acid).

>>Folate requires vitamin B-12 to convert it into folic acid.  
>
[quoted text clipped - 26 lines]
>So B12 is needed both for the absorption of dietary folate and for the
>folate metabolism inside the cell.

See also

<URL:http://europa.eu.int/comm/food/fs/sc/scf/out80e_en.pdf>:

   "Food folates, mainly present as polyglutamates, have to be
   hydrolysed by a (brush border associated) deconjugase enzyme
   in the gut before absorption can occur. Folate absorption
   from natural food is generally lower than synthetic forms
   (e.g. folic acid) contained in supplements, due to matrix
   effects and the presence of inhibitors of the conjugase
   enzyme in some foods. Folic acid (PGA) enters the folate
   cycle after reduction by a (dihydro-)folate reductase. This
   enzyme is present in the intestinal mucosal cell, but also
   in other tissues, such as liver and kidney. Reduction of PGA
   may be a slow process in some subjects and at higher intake
   levels (> ca 260 µg) PGA may appear unchanged in the
   circulation (i.e. in the postprandial state after supplement
   use (Kelly et al., 1997). Under normal conditions 5-MTHF (as
   monoglutamate) is the only form present in plasma, mainly
   protein-bound. Tissue uptake is carrier-mediated and/or
   through folate binding proteins. In tissues folates are
   retained as polyglutamates and the folate coenzymes can be
   interconverted in numerous (de-)methylation reactions, such
   as in DNA synthesis (formation of thymidilate from
   deoxyuridine), amino acid interconversions, such as the
   remethylation of homocysteine to methionine. In this latter
   methionine synthase (MS) reaction vitamin B12 is also
   involved as a cofactor. About 50% of the folate body store,
   estimated to be 13-28 mg, is considered to be present in the
   liver (for review see Report of the Standing Committee on
   the scientific evaluation of dietary reference intakes
   (DRIs) and its panel on folate and other B-vitamins and
   choline. Food and Nutrition Board, Institute of Medicine,
   1998)."

and

Folate (Folic acid): Implications for health and disease
<URL:http://www.teknoscienze.com/agro/pdf/may_june03/folate.PDF>:   

   "Natural food folates, or pteroylpolyglutamates are
   hydrolyzed to pteroylmonoglutamate forms prior to absorption
   in the small intestine. The monoglutamate forms of folate,
   including folic acid, are transported across the proximal
   small intestine via a saturable pH-dependent process. Higher
   doses of folic acid are absorbed via a nonsaturable passive
   diffusion process (1,3).

   The bioavailability of ingested folate monoglutamates is
   significantly greater than that of folate polyglutamates
   presumably because of the requirement for hydrolysis of the
   latter (3). The enzyme responsible for hydrolysis (i.e.
   folate conjugase) of folate polyglutamates may be
   specifically inhibited by food factors in yeast and beans
   and may be nonspecifically impaired at acid pH (3). The
   absorption efficiency of natural folates is approximately 50
   percent that of synthetic folic acid (1-3). Folic acid taken
   on an empty stomach is twice as available as food folate,
   and folic acid taken with food is 1.7 times as available as
   food folate. For instance, 400 µg of folic acid taken on an
   empty stomach is equivalent to 470 µg of folic acid taken
   with food and is equivalent to 800 µg of food folate (1)."

Additional reading:

Chapter 4. Folate and folic acid
<URL:http://www.fao.org/DOCREP/004/Y2809E/y2809e0a.htm>
(in
 Human Vitamin and Mineral Requirements
 Report of a joint FAO/WHO expert consultation
 Bangkok, Thailand
 <URL:http://www.fao.org/DOCREP/004/Y2809E/y2809e00.htm>)

Folate
Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6,
Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline  (1998)
Institute of Medicine (IOM)
<URL:http://books.nap.edu/books/0309065542/html/196.html>

4. Absorption of Vitamins and Minerals
<URL:http://gastroresource.com/GITextbook/En/Chapter7/7-4.htm>
(in
 First Principles of Gastroenterology
 <URL:http://gastroresource.com/GITextbook/en/Default.htm>)

Bailey LB, Gregory JF 3rd.
Folate metabolism and requirements.
J Nutr. 1999 Apr;129(4):779-82. Review.
<URL:http://www.nutrition.org/cgi/content/full/129/4/779>

Jacob RA.
Folate, DNA methylation, and gene expression: factors of nature and nurture.
Am J Clin Nutr. 2000 Oct;72(4):903-4.
<URL:http://www.ajcn.org/cgi/content/full/72/4/903>

Duthie SJ, Narayanan S, Brand GM, Pirie L, Grant G.
Impact of folate deficiency on DNA stability.
J Nutr. 2002 Aug;132(8 Suppl):2444S-2449S.
<URL:http://www.nutrition.org/cgi/content/full/132/8/2444S>

Choi SW, Mason JB.
Folate status: effects on pathways of colorectal carcinogenesis.
J Nutr. 2002 Aug;132(8 Suppl):2413S-2418S. Review.
<URL:http://www.nutrition.org/cgi/content/full/132/8/2413S>

Signature

Matti Narkia

Matti Narkia - 30 Sep 2004 02:01 GMT
Tue, 28 Sep 2004 00:27:32 +0300 in article
<prvgl09grdeebt23n2qal51qu4ikkd30ei@4ax.com> Matti Narkia
<mnng1_REMOVE_THIS@despammed.com> wrote:

>27 Sep 2004 13:35:32 -0700 in article
><1096317332.144573.227440@k26g2000oda.googlegroups.com> "Jan"
[quoted text clipped - 71 lines]
>Folate (HPLC), All food classes, µg/100g
><URL:http://www.fineli.fi/topfoods.php?compid=2273&fuclass=all&specdiet=none&items=50
0&from=top&portion=100g&lang=en
>

The list above was from the Finnish National Health Institute's database.
The U.S. list provided by Nutritiondata expectedly looks different, it's
dominated by fortified cereals, but I didn't expect it to show so different
values for liver products:

999 Foods
Highest in Folate
(based on levels per 100 grams)
<URL:http://www.nutritiondata.com/foods-000112000000000000000-w.html>

Do the domestic animals feeding program differ so much in different
countries, and even if they do, could they explain such vast differences?

Signature

Matti Narkia

Matti Narkia - 29 Sep 2004 16:57 GMT
27 Sep 2004 11:44:18 -0700 in article
<b550f406.0409271044.5e03886e@posting.google.com> tunderbar@hotmail.com

>http://www.cbc.ca/story/science/national/2004/09/27/folic_acid040927.html
>
>OTTAWA - Fortifying grain products with folic acid has led to a
>dramatic decline in the rate of birth defects such as spina bifida, a
>new study by Health Canada shows.

The reference is

Liu S, West R, Randell E, Longerich L, O'Connor KS, Scott H, Crowley M, Lam
A, Prabhakaran V, McCourt C.
A comprehensive evaluation of food fortification with folic acid for the
primary prevention of neural tube defects.
BMC Pregnancy Childbirth. 2004 Sep 27 [Epub ahead of print]
PMID: 15450123 [PubMed - as supplied by publisher]
<URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra
ct&list_uids=15450123
>

Abstract:

   "BACKGROUND: Periconceptional use of vitamin supplements
   containing folic acid reduces the risk of a neural tube
   defect (NTD). In November 1998, food fortification with
   folic acid was mandated in Canada, as a public health
   strategy to increase the folic acid intake of all women of
   childbearing age. We undertook a comprehensive population
   based study in Newfoundland to assess the benefits and
   possible adverse effects of this intervention. METHODS: This
   study was carried out in women aged 19-44 years and in
   seniors from November 1997 to March 1998, and from November
   2000 to March 2001. The evaluation was comprised of four
   components: I) Determination of rates of NTDs; II) Dietary
   assessment; III) Blood analysis; IV) Assessment of knowledge
   and use of folic acid supplements. RESULTS: The annual rates
   of NTDs in Newfoundland varied greatly between 1976 and
   1997, with a mean rate of 3.40 per 1,000 births. There was
   no significant change in the average rates between 1991-93
   and 1994-97 (relative risk [RR] 1.01, 95% confidence
   interval [CI] 0.76-1.34). The rates of NTDs fell by 78% (95%
   CI 65%-86%) after the implementation of folic acid
   fortification, from an average of 4.36 per 1,000 births
   during 1991-1997 to 0.96 per 1,000 births during 1998-2001
   (RR 0.22, 95% CI 0.14-0.35). The average dietary intake of
   folic acid due to fortification was 70 ug/day in women aged
   19-44 years and 74 ug/day in seniors. There were significant
   increases in serum and RBC folate levels for women and
   seniors after mandatory fortification. Among seniors, there
   were no significant changes in indices typical of vitamin
   B12 deficiencies, and no evidence of improved folate status
   masking hematological manifestations of vitamin B12
   deficiency. The proportion of women aged 19-44 years taking
   a vitamin supplement containing folic acid increased from
   17% to 28%. CONCLUSIONS: Based on these findings, mandatory
   food fortification in Canada should continue at the current
   levels. Public education regarding folic acid supplement use
   by women of childbearing age should also continue."

Signature

Matti Narkia

Matti Narkia - 29 Sep 2004 17:38 GMT
Some people with genetic or metabolic abnormalities or diseases may have
higher than normal requirements for folate (or other vitamins or nutrients).
A large part, 5-15% of general population have a genetic abnormality which
causes folate deficiency even if they are meeting the current dietary
reference intake, see the study

Molloy AM, Daly S, Mills JL, Kirke PN, Whitehead AS, Ramsbottom D, Conley
MR, Weir DG, Scott JM.
Thermolabile variant of 5,10-methylenetetrahydrofolate reductase associated
with low red-cell folates: implications for folate intake recommendations.
Lancet. 1997 May 31;349(9065):1591-3.
PMID: 9174561 [PubMed - indexed for MEDLINE]
<URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9
174561&dopt=Abstract
>

Abstract:

   "BACKGROUND: The dietary reference values for folate, as for
   other nutrients, are targeted to the general and supposedly
   normal population, not people with special needs, such as
   those with genetic or metabolic abnormalities or diseases.
   However, 5-15% of general populations are homozygous for a
   thermolabile variant of 5,10-methylenetetrahydrofolate
   reductase (C677T) which causes mild hyperhomocysteinaemia
   and is positively associated with the development of
   vascular disease and the risk of neural-tube defects. If
   tissue-folate status is compromised in large sectors of the
   population by this or other genetic variants, the present
   dietary reference values may need to be changed. METHODS: We
   identified the C677T genotype and measured red-cell folate
   concentrations in two groups of healthy women (pregnant,
   242, not pregnant, 318). We then analysed the effect of
   genotype on red-cell folates, which are a reliable marker
   for tissue folate stores. FINDINGS: In the pregnant group
   there were 20 TT homozygotes, 114 wild-type CC homozygotes,
   and 108 CT heterozygotes. In the non-pregnant group, the
   numbers were 41, 148, and 129. In both pregnant and non-
   pregnant groups, red-cell folate was significantly lower
   among TT homozygous than CC homozygous women (mean 252 [95%
   CI 202-317] vs 347 [321-372] micrograms/L, p = 0.002 for
   pregnant women; 284 [250-327] vs 347 [342-372] micrograms/L,
   p = 0.01 for non-pregnant women). Plasma folate was also
   significantly lower in TT homozygous than in CC homozygous
   women in the pregnant group (p = 0.009) but not in the non-
   pregnant group. INTERPRETATION: These results suggest that a
   substantial minority of people in general populations may
   have increased folate needs. Future studies may show the
   presence of other common genetic variants that interact with
   particular nutrients and place doubts on the validity of
   assuming "normality" for nutrient requirements in any
   general population."

Comments in the "Talking Points" section in the same issue of the Lancet:

Rethinking nutrient recommendations
Lancet. 1997 May 31;349(9065)
<URL:http://www.thelancet.com/journal/vol349/iss9065/full/llan.349.9065.talking_point
s.8590.1
>

   "The dietary reference-value system lists recommendations
   for the daily intake of nutrients based on the average need
   of the general population. However, Molloy and colleagues
   argue that for groups with genetic or metabolic
   abnormalities or diseases, these recommendations may not be
   appropriate. Pregnant and non-pregnant women were genotyped
   for the thermolabile variant of the 5,10-
   methylenetetrahydrofolate reductase enzyme (C677T). Women
   with the thermolabile variant are at risk of neural-tube
   defects developing in their babies. 8·3% of pregnant women
   were homozygous for the thermolabile variant and had
   significantly lower red-cell folate concentrations. This
   finding, the authors conclude, means that a substantial
   minority of the population is at a disadvantage because of
   current recommendations for folate intake, and the
   reference-value system should take this into account."

This study was at the time of it's publication also commented in a Yahoo's
news article, from which I've saved a few excerpts:

 "As many as 15% of people may have a genetic variation causing a
 deficiency in the vitamin folic acid, even if they are meeting
 nutritional guidelines for the vitamin, according to results
 of a new study.

 "These results suggest that a substantial minority of people in general
 populations may have increased folate needs," write the team of Irish
 and America researchers. "

 [...]

 "If this genetic variation is as common as the study results indicate,
 and if there are similar genetic variations affecting other important
 nutrients, current dietary guidelines may lose their relevance, say the
 authors of a study published in this week's issue of The Lancet.

 "Future studies may show the presence of other common genetic variants
 that interact with particular nutrients and place doubts on the validity
 of assuming 'normality' for nutrient requirements in any general
 population," write the study authors. "

 [...]

 A few years ago, a research team led by Dr. Anne Molloy, of Trinity
 College, Dublin, identified a mutation in the gene for a particular
 enzyme, called 5,10 methylenetetrahydrofolate reductase. The enzyme
 activates folate within the cells, and a mutation in the gene makes the
 enzyme much less effective.

 People with two copies of the abnormal gene had a higher risk of having
 a neural tube defect, compared with people who had two normal genes or
 just one copy of the abnormal gene.

 About 5% to 15% of people have two copies of the abnormal gene, a figure
 that varies with the population being studied.

 The researchers went on to look for the mutation in blood samples from
 Irish women, a population in which there is a relatively high rate of
 neural tube defects. Twenty of 242 pregnant women and 41 of 318
 non-pregnant women tested had two copies of the abnormal gene.

 Women with two copies of the abnormal gene also had lower levels of
 folate in their red blood cells than other women. This suggests, but
 does not prove, that the women with two abnormal genes have a higher
 folate requirement than the rest of the population, the authors say.

 [...]

 The study "challenges the assumption underlying the recommended daily
 allowance (RDA) -- that virtually everyone can take the same amount of a
 vitamin and do fine," Mills stated in a press release from the NICHD.

 The current RDA for folate is 400 micrograms per day for pregnant women,
 180 micrograms for other adult women, and 200 micrograms for adult men.

 The RDA was created to reflect the dietary requirements for an average
 person. "If genetic variants that cause altered nutrient status are
 common, as this study suggests, there may be no such thing as a 'normal'
 population with respect to nutrient requirements," the researchers
 concluded."

Related studies:

Nair KG, Nair SR, Ashavaid TF, Dalal JJ, Eghlim FF.
Methylenetetrahydrofolate reductase gene mutation and hyperhomocysteinemia
as a risk factor for coronary heart disease in the Indian population.
J Assoc Physicians India. 2002 May;50 Suppl:9-15.
PMID: 12186157 [PubMed - indexed for MEDLINE]
<URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra
ct&list_uids=12186157
>

de Franchis R, Botto LD, Sebastio G, Ricci R, Iolascon A, Capra V, Andria G,
Mastroiacovo P.
Spina bifida and folate-related genes: a study of gene-gene interactions.
Genet Med. 2002 May-Jun;4(3):126-30.
PMID: 12180146 [PubMed - indexed for MEDLINE]
<URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra
ct&list_uids=12180146
>

Schwahn B, Rozen R.
Polymorphisms in the methylenetetrahydrofolate reductase gene: clinical
consequences.
Am J Pharmacogenomics. 2001;1(3):189-201. Review.
PMID: 12083967 [PubMed - indexed for MEDLINE]
<URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra
ct&list_uids=12083967
>

Friso S, Choi SW, Girelli D, Mason JB, Dolnikowski GG, Bagley PJ, Olivieri
O, Jacques PF, Rosenberg IH, Corrocher R, Selhub J.
A common mutation in the 5,10-methylenetetrahydrofolate reductase gene
affects genomic DNA methylation through an interaction with folate status.
Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5606-11. Epub 2002 Apr 02.
PMID: 11929966 [PubMed - indexed for MEDLINE]
<URL:http://www.pnas.org/cgi/content/full/99/8/5606>

Garcia-Fragoso L, Garcia-Garcia I, de L, Renta J, Cadilla CL.
Presence of the 5,10-methylenetetrahydrofolate reductase C677T mutation in
Puerto Rican patients with neural tube defects.
J Child Neurol. 2002 Jan;17(1):30-2.
PMID: 11913566 [PubMed - indexed for MEDLINE]
<URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra
ct&list_uids=11913566
>

Quere I, Perneger TV, Zittoun J, Bellet H, Gris JC, Daures JP, Schved JF,
Mercier E, Laroche JP, Dauzat M, Bounameaux H, Janbon C, de Moerloose P.
Red blood cell methylfolate and plasma homocysteine as risk factors for
venous thromboembolism: a matched case-control study.
Lancet. 2002 Mar 2;359(9308):747-52.
PMID: 11888585 [PubMed - indexed for MEDLINE]
<URL:http://www.thelancet.com/journal/vol359/iss9308/full/llan.359.9308.original_rese
arch.20160.1
>

Fujimura H, Kawasaki T, Sakata T, Ariyoshi H, Kato H, Monden M, Miyata T.
Common C677T polymorphism in the methylenetetrahydrofolate reductase gene
increases the risk for deep vein thrombosis in patients with predisposition
of thrombophilia.
Thromb Res. 2000 Apr 1;98(1):1-8.
PMID: 10706928 [PubMed - indexed for MEDLINE]
<URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra
ct&list_uids=10706928
>

Lalouschek W, Aull S, Serles W, Wolfsberger M, Deecke L, Pabinger-Fasching
I, Mannhalter C.
The relation between erythrocyte volume and folate levels is influenced by a
common mutation in the methylenetetrahydrofolate reductase (MTHFR) gene
(C677T).
J Investig Med. 2000 Jan;48(1):14-20.
PMID: 10695265 [PubMed - indexed for MEDLINE]
<URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra
ct&list_uids=10695265
>

Bjorke-Monsen AL, Ueland PM, Schneede J, Vollset SE, Refsum H.
Elevated plasma total homocysteine and C677T mutation of the
methylenetetrahydrofolate reductase gene in patients with spina bifida.
QJM. 1997 Sep;90(9):593-6.
PMID: 9349452 [PubMed - indexed for MEDLINE]
<URL:http://qjmed.oupjournals.org/cgi/reprint/90/9/593>

Signature

Matti Narkia

Matti Narkia - 29 Sep 2004 21:14 GMT
Additional articles of interest:

Halsted CH.
The intestinal absorption of folates.
Am J Clin Nutr. 1979 Apr;32(4):846-55. Review.
<URL:http://www.ajcn.org/cgi/content/abstract/32/4/846>

Antony AC
The biological chemistry of folate receptors.
Blood. 1992 Jun 1;79(11):2807-20. Review.
<URL:http://www.bloodjournal.org/cgi/reprint/79/11/2807>

Reynolds E.
Fortification of flour with folic acid. Fortification has several potential
risks.
BMJ. 2002 Apr 13;324(7342):918.
<URL:http://bmj.bmjjournals.com/cgi/content/full/324/7342/918>

Oakley GP.
Delaying folic acid fortification of flour.
BMJ. 2002 Jun 8;324(7350):1348-9.
<URL:http://bmj.bmjjournals.com/cgi/content/full/324/7350/1348>

Lucock M.
Is folic acid the ultimate functional food component for disease prevention?
BMJ. 2004 Jan 24;328(7433):211-4. Review.
<URL:http://bmj.bmjjournals.com/cgi/content/full/328/7433/211>

Smith R
"Let food be thy medicine..."
BMJ. 2004 Jan 24;328(7433) Editorial
<URL:http://bmj.bmjjournals.com/cgi/content/full/328/7433/0-g>

Dickinson CJ.
Does folic acid harm people with vitamin B12 deficiency?
QJM. 1995 May;88(5):357-64. Review.
<URL:http://qjmed.oupjournals.org/cgi/content/abstract/88/5/357>

Carmel R, Green R, Rosenblatt DS, Watkins D.
Update on cobalamin, folate, and homocysteine.
Hematology (Am Soc Hematol Educ Program). 2003;:62-81. Review.
<URL:http://www.asheducationbook.org/cgi/content/full/2003/1/62>

Verhaar MC, Stroes E, Rabelink TJ.
Folates and cardiovascular disease.
Arterioscler Thromb Vasc Biol. 2002 Jan;22(1):6-13. Review.
<URL:http://atvb.ahajournals.org/cgi/content/full/22/1/6>

Tice JA, Ross E, Coxson PG, Rosenberg I, Weinstein MC, Hunink MG, Goldman
PA, Williams L, Goldman L.
Cost-effectiveness of vitamin therapy to lower plasma homocysteine levels
for the prevention of coronary heart disease: effect of grain fortification
and beyond.
JAMA. 2001 Aug 22-29;286(8):936-43.
<URL:http://jama.ama-assn.org/cgi/content/full/286/8/936>

Brattstrom L, Wilcken DE.
Homocysteine and cardiovascular disease: cause or effect?
Am J Clin Nutr. 2000 Aug;72(2):315-23. Review.
<URL:http://www.ajcn.org/cgi/content/full/72/2/315>

Wald DS, Law M, Morris JK.
Homocysteine and cardiovascular disease: evidence on causality from a
meta-analysis.
BMJ. 2002 Nov 23;325(7374):1202.
<URL:http://bmj.bmjjournals.com/cgi/content/full/325/7374/1202>

Brown AA, Hu FB.
Dietary modulation of endothelial function: implications for cardiovascular
disease.
Am J Clin Nutr. 2001 Apr;73(4):673-86. Review.
<URL:http://www.ajcn.org/cgi/content/full/73/4/673>

van der Put NM, van Straaten HW, Trijbels FJ, Blom HJ.
Folate, homocysteine and neural tube defects: an overview.
Exp Biol Med (Maywood). 2001 Apr;226(4):243-70. Review.
<URL:http://www.ebmonline.org/cgi/content/full/226/4/243>

Brent RL, Oakley GP Jr, Mattison DR.
The unnecessary epidemic of folic acid-preventable spina bifida and
anencephaly.
Pediatrics. 2000 Oct;106(4):825-7.
<URL:http://pediatrics.aappublications.org/cgi/content/full/106/4/825>

Reynolds EH.
Benefits and risks of folic acid to the nervous system.
J Neurol Neurosurg Psychiatry. 2002 May;72(5):567-71. Review.
<URL:http://jnnp.bmjjournals.com/cgi/content/full/72/5/567>

Reynolds EH.
Folic acid, ageing, depression, and dementia.
BMJ. 2002 Jun 22;324(7352):1512-5. Review.
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