Re: No folic acid

November 21, 2010

particularly DHFR) be accepted provisionally as valid.

REFERENCES

Afman, L.A., Van Der Put, N.M., , C.M., Trijbels, J.M., Blom, H.J. Reduced

vitamin B12 binding by transcobalamin II increases the risk of neural tube

defects. QJM 2001;94:159-66.

Alpers DH. What is new in vitamin B12? Current Opinions in Gastroenterology

2005;21:183-6.

SW, Syslo MC, Ayling JE. An assay for dihydrofolate reductase in human

tissues by HPLC with fluorometric detection. FASEB 2002;16: A267 (abstr. #

217.4).

SW, Manilow MR, Hess DL, Duell PB, Upson BM, Graf EG, Ivin- A, Syslo

MC, Ayling JE. Unreduced folic acid in plasma of subjects consuming either folic

acid or 5-methyltetrahydrofolate. FASEB 2003;17: A311 (abstr. # 191.16).

Belshaw NJ, Elliott GO, EA, et al. Methylation of the ESR1 CpG island

in the colorectal mucosa is an `all or nothing' process in healthy human colon,

and is accelerated by dietary folate supplementation in the mouse. Biochem. Soc.

Trans. 2005;33:709-11.

Bonna KH. NORVIT: Randomised trial of homocysteine-lowering with B-vitamins for

secondary prevention of cardiovascular disease after acute myocardial

infarction. 2005 Internet:

http://www.escardio.org/knowledge/OnlineLearning/slides/

ESC_Congress_2005/BonaaFP1334/ (accessed 09 January 2006).

Brent RL, Oakley GP. The food and drug administration must require the addition

of more folic acid in " enriched " flour and other grains. Pediatrics

2005;116:753-755.

Buckley LE, Belshaw NJ, IT. The effects of dietary folate on methylation

of the ESR1 CPG-island in a rat model of colorectal neoplasia. Proceedings of

the Nutrition Society 2005;64:69A.

e R, Grimley J, Schneede J, Nexo E, Bates C, Fletcher A, Prentice A,

C, Ueland PM, Refsum H, Sherliker P, Birks J, Whitlock G, Breeze E,

JM. Vitamin B12 and folate deficiency in later life. Age and ageing

2004;33:34-41.

Department of Health. Folic acid and the prevention of Disease. Report on health

and social subjects 50. London : The Stationary Office, 2000.

Farber S. Some observations on the effect of folic acid anatagonists on acute

leukaemia and other forms of incurable cancer. Blood 1949;4:160-7.

Farber S, Cutler EC, Hawkins JW, on JH, Peirce 2.nd EC, Lenz GG. The

action of pteroylglutamic conjugates on man. Science 1947;106:619-21.

Farber S, Diamond LK, Mercer RD, Sylvester RF, Wolff JA. Temporary remissions in

acute leukaemia in children produced by folic acid antagonist,

4-aminopteroyl-glutamic acid (aminopterin). NEJM 1948;238:787-93.

Flynn, M.A., Herbert, V., Nolph, G.B., Krause, G. Atherogenesis and

homocysteine-folate-cobalamin triad: Do we need standardized analyses? J. Am.

Coll. Nutr. 1997;16:258-67.

A, Zanibbi K. Homocysteine and cognitive function in elderly people.

Canadian Medical Association Journal 2004;171:897-904.

Green R, JW. Vitamin B12 deficiency is the dominant nutritional cause of

hyperhomocysteinemia in a folic acid-fortified population. Clin. Chem. Lab. Med.

2005;43:1048-51.

JF, Quinlivan EP. In vivo kinetics of folate metabolism. Annu. Rev.

Nutr. 2002;22:199-20.

Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J. Neurologic aspects of

cobalamin deficiency. Medicine (Baltimore) 1991;70:229-245.

Hoffbrand V 2005 Does folic acid mask vitamin B12 deficiency? In `Symposium on

Folic Acid and Health', p4. Internet:

http://www.asbah.org/Downloads/ Folic%20Acid%20symposium%20REPORT.pdf (accessed

4 January 2006).

Hoffbrand AV, Weir DG. The history of folic acid. British Journal of Haematology

2001;113:579-89.

Hvas AM, Gravholt CH, Nexo E. Circadian variation of holo-transcobalamin

(holo-TC) and related markers. Clin. Chem. Lab. Med. 2005;43:760-4.

Hvas AM, Nexo E. Holotranscobalamin – a first choice assay for diagnosing early

vitamin B12 deficiency? Journal of Internal Medicine 1005;257:289-98.

Institute of Medicine. Dietary reference intakes for thiamin, riboflavin,

niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline.

A report of the Standing Committee on the Scientific Evaluation of Dietary

Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline and

Subcommittee on Upper Reference Levels of Nutrients, Food and Nutrition Board,

Institute of Medicine. Washington, D.C: National Academy Press, 2000.

Kalemba M, Wojciech U, Milewicz T, Kapiszewska M. The increased amount of

vitamin B12 in serum is neede to minimise the uracil misincorporation into DNA

during folate supplementation. Trends in Food Science & Technology

2005;16:317-20.

Kamen BA, Nylen PA, Whitehead VM, Abelson HT, Dolnick BJ, DW. Lack of

dihydrofolate reductase in human tumor and leukaemia cells in vivo. Cancer Drug

Delivery 1985;2:133-8.

P, McPartlin J, Goggins M, Weir DG, JM. Unmetabolized folic acid in

serum: acute studies in subjects consuming fortified food and supplements. Am.

J. Clin. Nutr. 1997;65:1790-5.

Khanna D, Park GS, us HE, et al. Reduction of the efficacy of methotrexate

by the use of folic acid: post hoc analysis from two randomised controlled

studies. Arthritis. Rheum. 2005;52:3030-8.

Kim Y-I. Will mandatory folic acid fortification prevent or promote cancer? Am.

J. Clin. Nutr. 2004;80:1123-8.

Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett TJ, Podell ER, Marcell,

PD, Stabler SP, RH. Neuropsychiatric disorders caused by cobalamin

deficiency in the absence of anaemia or macrocytosis. NEJM 1988;318:1720-8.

Lucock MD. Is folic acid the ultimate functional food component for disease

prevention? BMJ 2005;328, 211-4.

Lucock MD, Yates Z. Folic acid — vitamin and panacea or genetic time bomb?

Nature Reviews Genetics 2005;6:235-40.

March of Dimes. New research shows folic acid in grains has reduced birth

defects. Internet:

http://search.marchofdimes.com/cgi-bin/MsmGo.exe?grab_id=710 & page_id=11796480 & qu\

ery=B12 & hiword=B12+ (accessed 6th January 2006).

Mason JB. Intestinal transport of monoglutamyl folates in mammalian systems. In:

Picciano MF, Stokstad ELR, JF, eds. Contemporary issues in clinical

nutrition, 13. Folic acid metabolism in health and disease. New York: Wiley-Liss

Inc, 1990:47-63.

Majeed A, Aylin P. The ageing population of the United Kigdom and cardiovascular

disease. BMJ 2005;331:1362.

McCaddon A, Davies G. Co-administration of N-acetylcysteine, vitamin B12 and

folate in cognitively impaired hyperhomocysteinemic patients. International

Journal of Geriatric Psychiatry 2005;20:998-1000.

McCaddon A, Regland B, Hudson P, Davies G. Functional vitamin B12 deficiency and

Alzheimer's disease. Neurobiology 202;58:1395-9.

Melikian V, Paton A, Leeming RJ, Portman-Graham H. Site of reduction and

methylation of folic acid in man. Lancet 1971;2:955-7.

MC, DA, Bienias JL, et al. Dietary folate and vitamin B12 intake

and cognitive decline among community-dwelling older persons. Arch. Neurol.

2005;62:641-5.

MS. Homocysteine and Alzheimer's disease. Lancet Neurobiology

2003;2;425-8.

Nijhout HF, MC, Budu P, Ulrich CM. A mathematical model of the folate

cycle. Journal of Biological Chemistry 2004;279:55008-55016.

Reynolds EH. Benefits and risks of folic acid to the nervous system. J Neurol

Neurosurg Psychiatry [serial online] 2002;72:567-71. Internet:

http://jnnp.bmjjournals.com/cgi/content/full/72/5/567 (accessed 10 January

2006).

Rosenberg IH. Absorption and malabsorption of folates. Clin. Haematol.

1976;5:589-618.

Pfeiffer CM, Fazili Z, McCoy L, Zhang M, Gunter EW. Determination of folate

vitamers in human serum by stable-isotope-dilution tandem mass spectrometry and

comparison with radioassay and microbiologic assay. Clin. Chem. 2004;50:423-32.

Quinlivan EP, McPartlin J, McNulty H, ward M, Strain JJ, Weir DG, JM.

Importance of both folic acid and vitamin B12 in reduction of risk of vascular

disease. Lancet 2002;359:227-228.

SACN. A Framework for evaluation of evidence that relates food and nutrients to

health. Internet: http://www.sacn.gov.uk/pdfs/sacn_02_02a.pdf (Accessed 09

January 2006).

Savage D, Gangaidzo I, Lindenbaum J. Vitamin B12 deficiency is the primary cause

of megaloblastic anaemia in Zimbabwe. Br. J. Haematology 1994;86:844-50.

JM, Weir DG. Folic acid, homocysteine and one-carbon metabolism: a review

of the essential biochemistry. Journal of Cardiovascular Risk 1998;5:223-7.

Selhub J, Dhar GJ, Rosenburg IH. Gastrointestinal absorption of folates and

antifolates. Pharmacol. Ther. 1983;20:397-418.

LR. Cobalamin-responsive disorders in the ambulatory care setting:

unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Blood

2005;105:978-85.

Steinberg SE. Mechanisms of folate homeostasis. Am. J. Physiol.

1984;246:G319-24.

Sweeney MR, McPartlin J, Weir DG, et al. Evidence of unmetabolised folic acid in

cord blood of newborn and serum of 4-day-old infants. Br. J. Nutr.

2005;94:727-30.

Takacs P, L. High folic acid levels and failure of single-dose

methotrexate treatment in ectopic pregnancy. Int. J. Gynecol. Obstet.

2005;89:301-2.

Tani M, Iwai Z. High-performance liquid chromatographic separation of

physiological folate monoglutamate compounds. Investigation of absorption and

conversion of pteroylglutamic acid in the small intestine of the rat in situ. J.

Chromatogr. 1983;267:175-81.

Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional

effects on epigenetic gene regulation. Mol. Cell. Biol. 2003;23:5293-5300.

Whitehead VM, BA. Absorption of unaltered folic acid from the

gasto-intestinal tract in man. Br. J. Haematol. 1967;13:679-86.

Whitehead VM, Kamen BA, Beaulieu D. Levels of dihydrofolate reductase in livers

of birds, animals, primates and man. Cancer Drug Delivery 1987;4:185-9.

AJA, Finglas PM. New results from stable isotope studies show that folic

acid should not be used as a reference folate for estimating relative

absorptions of natural food folates. Nutrition Bulletin 2005;30:282-9.

AJA, Finglas PM, Dainty JR, et al. Differential kinetic behaviour and

distribution of pteroylglutamic acid and reduced folates: A revised hypothesis

of the primary site of PteGlu metabolism in humans. J. Nutr. 2005;135:619-23.

>

> Folic acid and autism take another look

> Anon DoR Nov.22-09

>

> In 1991, CDC recommended folic acid supplementation for women who previously

had had an infant or fetus affected by an NTD and who planned to have more

children (1).

> CDC recommended that these women take a 4-mg daily dose of folic acid (under a

physician's supervision) beginning at least 1 month before conception and

continuing throughout the first trimester of pregnancy. (2)However the data on

folic acids reduction in Spinal Bifida and NTD is not as impressive as one may

think. Advances in technologies and elected abortions may in fact be the true

decline in these disorders.

> Similarly the numbers of autistic type disorder have increase with women's

increase in folic acid supplementation.

> Peruvian women taking prenatal supplementation were found to have a lowered

zinc status.(3) Zinc is important for neuronal growth and immune function. Zinc

is also recognized as an anti-oxidant. Folic acid is capable of depleting zinc

and iron competes for zinc. This could possibly leave a child in a vulnerable

state.

> Improving maternal zinc status through prenatal supplementation may improve

fetal neurobehavioral development(4)

> Boris and Goldblatt found that 89% of their autistic study population was

positive for at least one snip in the MTHFR.(5)

> High amounts of folic acid may result in high dihydrofolate which in turn

inhibits MTHFR.(6)

> MTHFR is found to be involved in one carbon metabolism. One carbon metabolism

is responsible for detoxification,. Amino acid synthesis, fatty acid synthesis,

energy production ,and oxidative phosphorylation to name a few. It has been

found that folic acid interferes with one carbon metabolism(7)

> In addition, Fetal adaptations to a high-folate environment may interfere with

folate metabolism postnatally, with serious consequences for the epigenetic

regulation of gene expression.(8)

> Once one carbon metabolism is inhibited, the child is vulnerable to metals,

bacteria, and virus.

>

> In many autistic patients reduced natural killer cell activity has been

identified. Folic acid has been shown to reduce natural killer cell activity in

post menopausal women.(9) Lower estrogen amounts ,in post menopausal women has

been clearly defined .Autistic disorder is much higher among boys than girls.

>

> In sprue ,another common variant in autistic disorder, it has been found that

neurologic lesions have occurred during folic acid therapy. In pernicious anemia

neurologic lesions have been observed in patients receiving folic acid therapy.

Moreover, folic acid may interfere with glutamic acid metabolism making the

brain more susceptible to glutamate toxicity. Furthermore, Folic acid may

interfere with the nutrition of the spinal cord.(10)

> Many of these children have gut motility issues and high levels of folic acid

will serve to in fact feed undesirable inhabitants if the intestine.

> It is well established that excess folic acid in low B-12 status results in

cognitive decline(11)

> Similarly, the 2004 PDR Nurses Drug Handbook states that folic acid may cause

altered sleep patterns, difficulty in

concentration,irritability,overactivity,depression,confusion,abdominal

distention, flatulence, and bronchial spasm in addition to, prolonged folic acid

therapy may also cause decreased vitamin B-12 levels.

>

> Recent studies have also found that mothers whom in fact had taken folic acid

supplements had offspring who were at a higher risk for leukemia.

> The dangers of folic acid supplementation in the unborn fetus and small child

must be examined.

>

> 1.CDC Use of folic acid prevention of spinal bifida and other

neuraldefects1983-1991MMRW1991:40:513-6

>

> 2.Folic acid to reduce the number of cases of spinal bifida and other neural

tube defects MMWR1992;41(no.RR-14):1-7

>

> 3. O'Brien KO, Zavaleta N, Caufield LE, Yang D, Abrams SA. Influence of

prenatal iron and zinc supplements on supplemental iron absorption, red blood

cell iron incorporation, and iron status in prenant Peruvian women. Am J Clin

Nutr. 1999;69:509–15

>

> 4 Merialdi M; Caulfield LE; Zavaleta N; Figueroa A; DiPietro JA

> Center for Human Nutrition, Department of International Health, The s

Hopkins School of Hygiene and Public Health, Baltimore, MD, USA.

> AM J Obstet Gynecol.1999; 1809 (2 pt 1):483-90

>

> 5. http://www.nationalautismassociation.org/pdf/IOM-Bradstreet.pdf.

>

> 6.Is folate good for everyone?

> ,Kim,Refsim Americam Journal of clinical nuritionVol.87,no.3,517-533

march 2008

>

> 7. Sauer, B. Mason, Sang-Woon Choi too much folate: A risk for

cancer and cardiovascular disease? Current opinion in clinical nutrition and

metabolic care 2009,12:30-36

>

> 8. C Sugden - Nutrition research reviews, 2006 - Cambridge Univ Press

>

> 9.Aron M. Troen ,Breeana ,Bess Sorensen ,Mark H. Wener, Abbey

ston, Brent

> Wood, Selhub, Anne McTiernan, Yutaka Yasui, Evrim Oral, D. Potter,

> Cornelia M. Ulrich J. Nutr. 136:189-194, January 2006

>

> 10. Anonymous. A warning regarding the use of folic acidNEJM;237;713-5

>

> 11. Martha Savaria , F Jacques, Irwin H Rosenberg and Selhub

> American Journal of Clinical Nutrition, Vol. 85, No. 1, 193-200, January 2007

>

> HIGH BLOOD PRESSURE AND KIDNEY DISORDER

>

> The blood pressures of the rats are recorded

> on table 1. After six weeks of treatment, the

> rats receiving pteroylglutamic acid had uniformly

> developed a significant hypertension "

> Although the kidneys of treated rats were

> equal in weight to those of controls, the renalcortex surface in 15 of the 17

animals receiving

> pteroylglutamic acid was dotted with whitish,

> slightly contracted scars of from 0.5 to 2.0

> mm. in diameter. These areas extended 1.0

> to 3.0 mm. into the cortical parenchyma as

> small wedge-shaped lesions containing nu-merous fibroblasts. Cells of the

proximal

> and distal convoluted tubules within and

> immediately adjacent to these regions were

> usually moderately shrunken, with pyknotic

> nuclei and eosinophilic cytoplasm. The remainder

> of the renal cortex and the medulla,

> despite the number and extent of cortical scars,

> compared favorably with that of the control

> animals. Sections of the kidneys from one

> rat treated with pteroylglutamic acid showed

> rare atrophic glomeruli, but the other animals

> failed to demonstrate this change. Occasional

> dilatation of the convoluted tubules bordering

> the scarred portions was observed in approximately

> 50 per cent of the animals, but casts

> in the renal tubules were not observed.

> The tubular damage observed in these

> animals generally agrees with that previously

> described by others in kidneys of guinea pigs10

> and rats " treated with pteroylglutamic acid.

> The mechanism by which a significant hypertension

> is obtained in rats treated with pteroylglutamic

> acid is at present obscure. Its associatiotn

> with renal lesions possibly suggests a renal

> factor comparable to that brought about by

> interference with renal blood flow, as with

> renal artery clamps, perinephric packs, or

> renal ligation. An excess of dietary pteroylglutamic

> acid, however, is associated with a

> reduced activity of liver d-amino acid oxidase

> and xanthine oxidase in the chick,12 13 and

> diminished xanthine oxidase activity in the

> rat.'4 Liver choline oxidase in the rat may also

> be altered by an increase in dietary pteroylglutamic

> acid.'4 It is conceivable that large

> amounts of parenteral pteroylglutamic acid

> might similarly interfere with the activity of

> certain renal or other enzyme systems that

> normally may inactivate endogenous hypertensive

> factors, and in this manner induce a

> sustained blood pressure elevation. Another

> possible explanation of the hypertension is

> suggested by recent demonstrations that

> pteroylglutamic acid is imminently concerned

> in transmethylation and the synthesis of

> choline and methionine.1 " - " 1 In addition, under

> certain specific experimental conditions, the

> administration of pteroylglutamic acid accelerates

> methylation of a toxic substance and

> results in a consequent loss of available methyl

> groups from the body.'9 In these circumstances,

> the development of a yellow, fat-infiltrated

> liver and a reduced growth rate suggests a

> choline deficiency. This possible antilipotrophic

> nature of pteroylglutamic acid under induced

> conditions is of interest. In the present study,

> pteroylglutamic acid may have accelerated

> transmethylation in the body to a degree

> sufficient to induce a significant over-all deficiency

> of accessible methyl groups. The onset

> of hypertension subsequent to a brief transient

> period of choline deficiency in early life is well

> established in rats. " " By producing a relative

> insufficiency of choline, or other methyl donator

> substances, administration of pteroylglutamic

> acid may result in hypertension perhaps

> by a metabolic action less direct than specific

> enzyme inhibition.

> http://circ.ahajournals.org/cgi/reprint/5/6/903.pdf

>

> A Low, Rather than a High, Total Plasma Homocysteine Is an Indicator of Poor

Outcome in Hemodialysis Patients

> Kamyar Kalantar-Zadeh*,, Gladys Block, H. Humphreys, J.

McAllister and D. Kopple*,||

> *Division of Nephrology and Hypertension, Harbor-UCLA Medical Center,

Torrance, California, and Geffen School of Medicine at UCLA, Los Angeles,

California; Division of Public Health Nutrition and Epidemiology, School of

Public Health, University of California, Berkeley, California; University of

California, San Francisco, San Francisco, California, and Division of

Nephrology, San Francisco General Hospital, San Francisco, California; DaVita,

Inc., Torrance, California; and ||UCLA School of Public Health, Los Angeles,

California

>

> Correspondence to Dr. Kamyar Kalantar-Zadeh, Departments of Medicine and

Pediatrics, Division of Nephrology and Hypertension, Harbor-UCLA Medical Center,

Harbor Mailbox 406, 1000 West Carson Street, Torrance, CA 90509-2910. Phone:

310-222-3891; Fax: 310-782-1837; E-mail: kamkal@...

>

> ABSTRACT. An increased level of total plasma homocysteine (tHcy) is a risk

factor for poor cardiovascular outcome in the general population. However, a

decreased, rather than an increased, tHcy concentration may predict poor outcome

in maintenance hemodialysis (MHD) patients, a phenomenon referred to as reverse

epidemiology. Associations were examined between tHcy level and markers of

malnutrition-inflammation complex syndrome and 12-mo prospective hospitalization

and mortality in 367 MHD patients, aged 54.5 ± 14.7 (mean ± SD) years, who

included 199 men and 55% individuals with diabetes. tHcy was 24.4 ± 11.8 µmol/L,

and 94% of the patients had hyperhomocysteinemia (tHcy >13.5 µmol/L). tHcy had

weak to moderate but statistically significant bivariate and multivariate

correlations with some laboratory markers of nutrition (serum albumin,

prealbumin, creatinine, and urea nitrogen) but no significant correlation with

serum C-reactive protein or two

> proinflammatory cytokines (IL-6 and TNF-). During 12 mo of follow-up, 191 MHD

patients were hospitalized, 37 died, nine underwent renal transplantation, and

38 transferred out. Hospitalization rates were significantly higher in patients

with lower tHcy levels. Mortality rate in the lowest tHcy quartile (17.4%) was

significantly higher compared with other three quartiles (6.5 to 9.8%;

Kaplan-Meier P = 0.04). Relative risk of death for the lowest tHcy quartile,

even after adjustment for case-mix and serum albumin, was 2.27 (95% confidence

interval, 1.14 to 4.53; P = 0.02). Hence, tHcy may be a more exclusive

nutritional marker in MHD patients with no association with inflammatory

measures. Despite a very high prevalence of hyperhomocysteinemia in MHD

patients, lower values of tHcy are paradoxically associated with increased

hospitalization and mortality. The lowest tHcy quartile confers a twofold

increase in risk of death independent of hypoalbuminemia.

> The nutritional feature of tHcy in MHD patients may explain its reverse

association with outcome.

> J. Am. Soc. Nephrol. 2004 15: A26-A29

> http://jasn.asnjournals.org/cgi/content/abstract/15/2/442

>

> CARDIAC

> Too much folate: a risk factor for cancer and cardiovascular disease?

> Sauer J, Mason JB, Choi SW.

>

> Vitamins and Carcinogenesis Laboratory, Mayer USDA Human Nutrition

Research Center on Aging, Tufts University, Boston, Massachusetts 02111, USA.

>

> PURPOSE OF REVIEW: The intent of this evidence-based review is to analyze the

role of folate in chronic diseases, focusing on cancer and cardiovascular

disease. RECENT FINDINGS: Low folate status has been shown to be a risk factor

for cancer and cardiovascular disease. Although epidemiological data suggest an

inverse association between folate status and disease risk, intervention studies

give equivocal results, suggesting the response to folate intake does not follow

a linear continuum. Moreover, recent folate intervention trials raise concern

about possible adverse effects of folate supplementation and suggest that too

much folate in inopportune settings may be potentially harmful in individuals at

higher risk for cardiovascular disease and cancer. SUMMARY: Although folate

intake at sufficient levels appears to be an effective cancer chemopreventive

strategy, high-dose supplementation of folate has generally not been effective

in reducing recurrence of

> cardiovascular events or colorectal adenomas in clinical intervention trials.

Although controversial, high folate status achieved through folate fortification

or supplementation may increase the risk of certain chronic diseases among

certain individuals, possibly by interfering with the homeostasis of one-carbon

metabolism. Further research is urgently needed to accurately define the

relationship between supraphysiological intake of folate and chronic diseases.

> PMID: 19057184 [PubMed - indexed for MEDLINE]

>

> HEP_B HEAVY METALS MIXED WITH SACCHAROMYCES LOADED FOLATE

> http://www.inchem.org/documents/pims/pharm/folicaci.htm#SectionTitl...

> " Folic acid is incompatible with oxidizing and reducing

> agents and with heavy metal ions (McEvoy, 1990). "

>

> " It should be given with caution to patients with abnormal

> renal function "

>

> CONVULSIONS ATAXIA FOLIC ACID NEUROTOXICITY IN THE PYRIFORM CORTEX AND

AMYGDALA

> Folic acid is relatively non-toxic. Toxicity studies in

> mice showed that folic acid could cause convulsions,

> ataxia and weakness. Histopathological studies in some

> strains of mice showed that toxic doses may also cause

> acute renal tubular necrosis. A possible relationship

> between folic acid neurotoxicity and cholinergic

> receptors in the pyriform cortex and amygdala has been

>

> shown (McGeer et al, 1983).

>

> FOLATE BRAIN LESIONS

>

> J Child Neurol. 2010 Mar 31. [Epub ahead of print]

>

> Maternal Methylenetetrahydrofolate Reductase (MTHFR) Homozygosity and Neonatal

Outcome: Follow-Up of 42 Pregnancies at Risk.

> Pogliani L, Muggiasca L, Arrigoni L, Rossi E, Zuccotti G.

>

> Department of Pediatrics, Università di Milano, Luigi Sacco Hospital, Milan,

Italy.

>

> Abstract

> From February 2006 to March 2008, 42 pregnant women homozygous for the

677CT-methylenetetrahydrofolate reductase (MTHFR) allele were recruited in our

obstetrics service for pregnancy at risk. All had antithrombotic prophylaxis

with low-dose aspirin and/or low-molecular-weight heparin, supplemented with

folic acid. In all, 2 women lost the fetus and 4 were lost to follow-up before

delivery. A total of 36 women delivered term infants who all underwent

transfontanellar ultrasonography within 24 hours of birth. Six (16.6%) had

ischemic or hemorrhagic cerebral lesions. No differences were observed in

gestational age, birth weight, or umbilical cord pH between the 30 healthy

infants and the 6 with cerebral lesions. Neonatal outcomes were negative in

spite of maternal folic acid supplementation and antithrombotic prophylaxis

during pregnancy. This suggests a relationship between maternal homozygous

mutation in the 677CT-MTHFR allele and neonatal cerebral

> lesions.

>

> PMID: 20357240 [PubMed - as supplied by publisher]

>

> MYCOSIS

>

> Antifolates as antimycotics? Connection between the folic acid cycle and the

> ergosterol biosynthesis pathway in Candida albicans.

>

> Navarro-Martínez MD, Cabezas-Herrera J, Rodríguez-López JN.

>

> Grupo de Investigación de Enzimología, Departamento de Bioquímica y Biología

> Molecular A, Facultad de Biología, Universidad de Murcia, E-30100 Espinardo,

> Murcia, Spain.

>

> The increased incidence of invasive mycoses and the emerging problem of

> antifungal drug resistance have encouraged the search for new antifungal

agents

> or effective combinations of existing drugs. Infections due to Candida

albicans

> are usually treated with azole antifungals such as fluconazole, ketoconazole

or

> itraconazole. Whilst azoles may have little or no toxicity, they generally

offer

> rather poor fungicidal activity. Even in the absence of resistance, treatment

> failures or recurrent infections are not uncommon, especially in

> immunocompromised individuals. Here we demonstrate that the non-classical

> antifolate pyrimethamine shows synergy with azole antifungal compounds and

> interferes with the ergosterol biosynthesis pathway in C. albicans. By

> disturbing folate metabolism in this fungus, pyrimethamine can inhibit

> ergosterol production. The molecular connection between the folic acid cycle

and

> the ergosterol biosynthesis pathway is discussed and we show that the

> filamentous form of this fungus is more susceptible to methotrexate than the

> yeast form because the drug is more effectively transported through the

membrane

> of the filamentous form. When used to treat the hyphal form, methotrexate

showed

> synergy with other antifungals such as azoles and terbinafine. This finding

> could have important clinical applications, as a combination of azoles with

> antifolates and/or inhibitors of folic acid synthesis could represent an

> attractive alternative for the treatment of C. albicans infections.

>

> Publication Types:

> Research Support, Non-U.S. Gov't

> PMID: 17046206 [PubMed - indexed for MEDLINE

>

> FOLATE AND YEAST

> Growth inhibition of Candida albicans by folate pathway inhibitors. Their

> potential in the selection of auxotrophs.

>

> Henson OE, McClary DO.

>

> Growth studies were conducted on C. albicans in a glucose - salts - biotin

(GSB)

> medium in the presence of folate inhibitors. Sulfanilamide inhibited growth

> which was restored by PABA or tetrahydrofolate (THF). Aminopterin inhibited

> growth to about the same level as did sulfanilamide, but this inhibition was

not

> reversed with PABA nor THF, singly or in combination. Inhibition by combined

> sulfanilamide and aminopterin was synergistic, reducing growth by more than

90%

> for 48 h. The sulfanilamide component of the combined inhibition was reversed

by

> PABA or THF to the level of that of aminopterin alone. Cytochrome synthesis

was

> not affected by the inhibitors, but marked increases occurred in

> alpha-ketoglutarate, malate, isocitrate, and pyruvate dehydrogenases,

especially

> in the presence of both inhibitors. The pyrimidines in combination with

> sulfanilamide were as inhibitory as was the combination of aminopterin and

> sulfanilamide, but they had no effect when added alone or in combination with

> aminopterin. Unlike the pyrimidines, the purines stimulated about a 50%

recovery

> from inhibition by either of the inhibitors. Growth inhibition by combined

> sulfanilamide and aminopterin was overcome by about 50% by the addition of the

> THF-mediated end-produits: deoxythymidylate, adenine, histidine and

methionine.

> The use of GSB medium containing adenine, histidine, methionine and the folate

> inhibitors but without deoxythymidylate resulted in thymineless death of

> prototrophic cells providing a method for the selection of auxotrophic

mutants.

>

> PMID: 386943 [PubMed - indexed for MEDLINE]

>

> ANEMIA ICP AND BRAIN HERNIATION

> Craniocephalic Disproportion with Increased Intracranial Pressure and Brain

Herniation: A New Clinical Syndrome in Anemic Patients: Report of Two Cases

> Rengachary, Setti S. MD; Blount, MD; Heros, Deborah MD; Bowers,

MD; Truwit, MD

>

> Abstract

> OBJECTIVE AND IMPORTANCE: We describe a new clinical syndrome in two patients

with chronic anemia. The major manifestation of the syndrome is herniation of

the brain resulting in death caused by long-standing craniocephalic

disproportion. The disproportion was caused by extreme thickening of the cranium

because of erythroid hyperplasia.

>

> CLINICAL PRESENTATION: Two patients with known chronic anemia presented with

chronic increase in intracranial pressure with acute deterioration resulting in

brain herniation.

>

> INTERVENTION: Despite maximum medical therapy, both patients died as a result

of uncontrollable increase in intracranial pressure.

>

> CONCLUSION: Patients with chronic anemia presenting with progressive headaches

should be monitored for this newly described clinical phenomenon

>

> Reynolds 1972

> " There is evidence that treatment with folic acid for three months or longer

may result in a significant fall in B-12 levels sometimes to subnormal values "

>

> " 2004 PDR Nurses Drug Handbook states that folic acid may cause altered sleep

patterns, difficulty in

concentration,irritability,overactivity,depression,confusion,abdominal

distention, flatulence, and bronchial spasm in addition to, prolonged folic acid

therapy may also cause decreased vitamin B-12 levels "

>

> Re safety and FA " Careful review

> of that research shows that after giving folic acid to

> treat

> " pernicious anaemia " there was sometimes brief

> temporary symptomatic neurological improvement

> before the more fl orid and sometimes explosive

> deterioration,9,28 and after the obvious but suboptimal

> haematological improvement there was commonly alater

> insidious haematological relapse.8,28 A similar

> number of patients have neurological and haematological

> relapse, although often dissociated (fi gure 2).8 In other

> words, both the nervous system and the blood may show

> improvement and relapse but to diff erent degrees and at

> diff erent rates, which may in turn refl ect profound

> diff erences in structure, function, and cellular turnover

> in the two tissues.

> Patients with neurological complications of vitamin-B12

> deficiency have significantly higher serum folate

> concentrations than those without such CNS disorders.37,38

> full:

>

http://www.direct-ms.org/pdf/NutritionMS/B12%20folic%20acid%20nervous%20system.p\

df

>

> DEMYELINATION DUE TO B-12 DIFICIENCY

> Surtees1

>

> (1) Institute of Child Health, London, UK

>

> Summary In humans, subacute combined degeneration of the spinal cord and

brain, a primary demyelinating disease, is caused by cobalamin or

methyltetrahydrofolate deficiency. Experimental studies into its pathogenesis

suggest that dysfunction of the methyl-transfer pathway may be the cause.

Compelling evidence for this comes from the study of inborn errors of cobalamin

metabolism where deficiency of methylcobalamin, but not deoxyadenosylcobalamin,

is associated with demyelination. Recent studies have focused upon inborn errors

of the methyl-transfer pathway. Cerebrospinal fluid concentrations of

metabolites of the methyl-transfer pathway have been measured in humans with

sequential errors of the pathway and correlated with demyelination demonstrated

on magnetic resonance imaging of the brain. This has provided new data

suggesting that deficiency ofS-adenosylmethionine is critical to the development

of demyelination in cobalamin deficiency.

> http://www.springerlink.com/content/xt6r43x857485236/

> RISK OF NEUROLOGICAL COMPLICATIONS

> IN PERNICIOUS ANAEMIA

> TREATED WITH FOLIC ACID

> BY

> M. C. G. ISRAELS, M.D., M.Sc., F.R.C.P.

> AND

> JOHN F. WILKINSON, M.D., M^Sc., Ph.D., F.R.C.P.

> (From the Department of Haematology, University and Royal

> Infirmary, Manchester)

> The identification and synthesis of pteroyl-y-glutamic acid

> (folic acid*) by Angier et al. (1945, 1946) led to the early

> recognition of its quite unexpected and remarkable effects

> in the treatment of pernicious anaemia ( et al., 1945)

> and of nutritional macrocytic anaemia (Spies et al., 1945).

> The results in pernicious anaemia were very striking

> at first, as many workers reported, including ourselves

> (Wilkinson, Israels, and Fletcher, 1946). It soon became

> evident, however, that even when the blood counts were

> restored to normal levels relapses were occurring, and

> signs of involvement of the peripheral nerves, such as paraesthesiae

> and numbness in the limbs, and of the spinal

> cord tracts, like ataxia and loss of vibration sense, might

> not be improved or might become worse.

> Even more important, however, was the fact that

> some patients who had not previously shown signs of

> nervous system disturbances developed such signs, often

> very acutely, after being treated with folic acid for variable

> periods. Since 1946 several groups of workers

> have become aware of this disquieting fact, and in consequence

> the widespread enthusiasm for folic acid, at least

> for the treatment of pernicious anaemia, has been rapidly

> waning.

> In Table I we have included all the available references

> to the development of subacute combined degeneration of

> the spinal cord in patients with pernicious anaemia, or the

> worsening of neurological symptoms already present, after

> treatment with pteroyl-y-glutamic acid.

> From a careful study of the various reports it was

> obvious that many of them referred to the same groups

> of cases, since some authors have published their results

> and cases in several journals, often without cross-references,

> and in some reports no details are given at all, other than

> *In this paper folic acid is used synonymously with and refers to

> the synthetic pteroyl-y-glutamic acid.

> Folic acid treatment was immediately discontinued, and

> she was given liver extract intramuscularly and 30 g. of

> desiccated stomach daily by mouth. After one month her walking

> was improved, but the right plantar response was still

> extensor; after two months she was ambulant again and both

> plantar responses were flexor; after eight months all symptoms

> had disappeared and she has remained well since.The results therefore show

that in a three-year period

> 80% of the patients who were being treated with folic

> acid had developed or had increased signs and symptoms

> of nervous system disease that could be quite quickly controlled

> in the early stages by treatment with intramuscular

> liver extracts or oral desiccated stomach preparations.

> Thus there is obviously serious risk that patients with pernicious

> anaemia treated solely with folic acid may develop

> signs of disturbance of the central nervous system, or that

> any initial cord involvement or peripheral neuritis may get

worse.Consequently, it is our

> considered opinion that folic acid ordinarily should-not be

> used in the treatment of pernicious anaemia, and never in

> subacute combined degeneration of the spinal cord.Therefore, whatever the

circumstances, folic acid, if used

> at all, should be replaced by liver or stomach as soon as

> possible, and those patients having folic acid should be

> seen at frequent and regular intervals so that the onset of

> neurological complications can be corrected without delay.its use was

allowable in the treatment of other

> megaloblastic anaemias that do not develop cord lesions,

> like those occurring in sprue, steatorrhoea, and pregnancy.This must now be

reconsidered carefully in view of the

> recent observation by Meyer (1948) that combined system

> disease occurred in a patient with macrocytic anaemia

> secondary to ulcerative colitis of long standing. After treatment

> with folic acid for 18 months he quite quickly

> developed ataxia, loss of vibration and position sense in the

> legs, and positive pyramidal signs. These neurological complications

> appeared when the patient's haemoglobin level

> was normal and his weight satisfactory. son and

> Girdwood (1948) have also reported the onset of neurological

> signs in two patients with idiopathic steatorrhoea who

> were having folic acid treatment; the signs in these patients

> could have been due to peripheral neuritis, and no pyramidal

> lesion was detected. It is only reasonable to point

> out that this neurological complication of non-ian

> types of anaemia is extremely rare.

> full free

> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2051766/pdf/brmedj03650...

>

> FOLATE AND FATTY ACID METABOLISM

> Abnormal Fatty Acid Metabolism in Peripheral

> Nerves of Patients with Pernicious Anemia

> INTRODUCTION

> The administration of vitamin B12 to patients with pernicious

> anemia (PA)' results in correction of the hematopoietic

> abnormalities as well as stabilization or improvement

> in the neurologic lesions. It has been known

> for some time that folic acid administration is also capable

> of repairing the megaloblastic state (1) but that it

> fails to improve and may in fact worsen the neurologic

> disease (2, 3). The explanation for the folic acid effect

> is thought to be as follows: In man vitamin B12 is

> known to participate in the methyltransferase reaction

> (Ns-methyltetrahydrofolate methyltransferase) where homocysteine

> conversion to methionine provides tetrahydrofolate

> for a variety of chemical reactions (Fig. 1)

> (4). The source of folate in this reaction is the storage

> form of folate, N -methyltetrahydrofolic acid. The clinical

> expression of vitamin B12 deficiency, via interference

> with this pathway, is based upon the need of B12 as a

> coenzyme for the methyltransferase reaction. Thus B12

> deficiency results in a " trapping " of this storage folate

> reducing available active folate coenzyme forms.

> free full

> http://ukpmc.ac.uk/picrender.cgi?artid=153071 & blobtype=pdf

> FOLATE FORTIFICATION DANGERS

> Folic acid fortification: a double-edged sword

>

> Lucock M, Yates Z.

> School of Environmental & Life Sciences, University of Newcastle, P.O. Box

127, Brush Road, Ourimbah, NSW 2258, Australia. Mark.Lucock@...

> Curr Opin Clin Nutr Metab Care. 2009 Nov;12(6):555-64.

>

> PURPOSE OF REVIEW: To examine the impact of folic acid fortification,

including its use as a functional food component, on human health. RECENT

FINDINGS: There is a consensus view that folic acid supplementation has numerous

health benefits, many of which are significant in their impact. However,

emerging evidence suggests that increased population exposure to folic acid may

also have a negative impact with respect to certain developmental and

degenerative disorders. As examples, presently much attention is focused on the

role of folic acid fortification augmenting colon cancer risk, whereas earlier

in the life cycle, the vitamin may additionally influence insulin resistance.

Without question, conditions that are influenced by folic acid are both diverse

and many - from concerns relating to cognitive decline, breast cancer and

vascular disease through to preconceptional issues where maternal folate levels

might conceivably alter the phenotype of

> offspring via epimutations. SUMMARY: The highly complex and critical

biological importance of folic acid-related molecular nutrition makes it a

difficult micronutrient to deploy as a simple intervention at a population level

- it has far too many biochemical spheres of influence to predict effects in a

generalized way. Additionally, several gene variants and other nutrients are

interactive factors. It is, therefore, hardly surprising that the scientific

community does not have a true consensus view on whether mandatory fortification

is appropriate as a population measure. This latter point not withstanding, any

ultimate decisions on fortification should be well rooted in scientific fact

rather than political expediency.

>

> FOLATE AND BLOOD BRAIN BARRIER

>

> " focal epileptic discharges may result from accumulation of folate at the

site of the focus as a result of local damage to the blood brain barrier "

> Obbens 1973

>

> FOLIC ACID IN BRAIN METABOLISM

> It is suggested that folic acid may interfere with the metabolism of 1(+)

glutamic acid in the central nervous system and possibly disturb the formation

or function of acetylcholine.

>

> http://bloodjournal.hematologylibrary.org/cgi/content/abstract/3/1/68

>

> WITH FOLATE DISTURBANCE OF ACETYLCHOLINE WE LOOK NOW TO ACETYL CHOLINE

METHIONINE SAH-SAM

> Choline-related supplements improve abnormal plasma methionine-homocysteine

metabolites and glutathione status in children with cystic fibrosis.

> Innis SM, son AG, Melynk S, SJ.

>

> Department of Paediatrics, University of British Columbia, Vancouver, BC,

Canada. sinnis@...

>

> BACKGROUND: Liver triacylglycerol accumulation and oxidative stress are common

in cystic fibrosis (CF) and also occur in choline deficiency. Previously, we

showed an association between elevated plasma homocysteine, reduced ratios of

S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH) and of

phosphatidylcholine to phosphatidylethanolamine, and phospholipid malabsorption

in children with CF. OBJECTIVE: The objective was to address a possible relation

between altered methionine-homocysteine metabolism and choline metabolism in

children with CF. DESIGN: Children with CF were assigned without bias to

supplementation with 2 g lecithin/d (n = 13), 2 g choline/d (n = 12), or 3 g

betaine/d (n = 10) for 14 d. Plasma concentrations of methionine, adenosine,

cysteine, cysteinyl-glycine, glutathione, glutathione disulfide (GSSG), and

fatty acids; SAM:SAH; and red blood cell phospholipids were measured within each

group of children with CF before and after

> supplementation. Plasma from healthy children without CF (n = 15) was

analyzed to obtain reference data. RESULTS: Children with CF had higher plasma

homocysteine, SAH, and adenosine and lower methionine, SAM:SAH, and

glutathione:GSSG than did children without CF. Supplementation with lecithin,

choline, or betaine resulted in a significant increase in plasma methionine,

SAM, SAM:SAH, and glutathione:GSSG and a decrease in SAH (n = 35).

Supplementation with choline or betaine was associated with a significant

decrease in plasma SAH and an increase in SAM:SAH, methionine, and

glutathione:GSSG. Supplementation with lecithin or choline also increased plasma

methionine and SAM. CONCLUSION: We showed that dietary supplementation with

choline-related compounds improves the low SAM:SAH and glutathione redox balance

in children with CF.

>

> FOLATE AND BEHAVIOR AND GASTRO

> TOXICITY OF FOLIC ACID GIVEN IN PHARMACOLOGICAL DOSES TO HEALTHY VOLUNTEERS

> Original Text Hunter a, Joanna a, H.F. Oakeley b, D.M. s

c

> Abstract

> A trial to elucidate the effect of folic acid in pharmacological doses (15 mg.

daily) on serum-vitamin-B12 levels in a group of fourteen healthy volunteers was

abandoned after 1 month of a projected 3-month period because of the unexpected

development of increasingly disturbing toxic effects in the majority. Most of

the subjects experienced mental changes, sleep disturbance and gastrointestinal

symptoms. Possible mechanisms of these effects are discussed.

>

> Subacute combined degeneration of the cord, dementia and parkinsonism due to

an inborn error of folate metabolism.

> P T Clayton,

> I ,

> B Harding,

> K Hyland,

> J V Leonard,

> R J Leeming

> Abstract

> A 2-year-old girl with 5,10-methylenetetrahydrofolate reductase deficiency

developed subacute combined degeneration of the cord and a leuco-encephalopathy

which was confirmed at necropsy. Total folate concentrations in serum, red cells

and CSF were markedly reduced whereas vitamin B12 concentrations were normal. In

addition the patient had Parkinsonism and reduced concentrations of homovanillic

acid, 5-hydroxyindoleacetic acid and total biopterins in cerebrospinal fluid.

Folic acid administration was accompanied by fits and acute deterioration in the

movement disorder. At necropsy the basal ganglia showed no detectable

abnormality.

> http://www.ncbi.nlm.nih.gov/pubmed/3755752

>

> Science NewsLow Levels Of Salivary Cortisol Associated With Aggressive

Behavior

> (Jan. 20, 2000) — Consistently low salivary levels of the stress hormone

cortisol in boys aged 7 to 12 are associated with early onset and persistence of

extremely aggressive behavior report researchers from the University of Chicago

in the Archives of General Psychiatry.

>

> In a four-year study of boys with behavioral problems, those with consistently

low cortisol levels began antisocial acts at a younger age, exhibited three

times the number of aggressive symptoms, and were three times as likely to be

singled out by their classmates as mean or combative as those who had higher or

fluctuating cortisol concentrations.

> The finding may help psychiatrists better understand differences between

adolescent males undergoing a short-term dalliance with delinquent behavior and

those with severe and lasting conduct disorder, which is notoriously difficult

to treat. Children with persistent conduct disorder tend to remain disruptive

for decades and account for a hugely disproportionate percentage of total crimes

and violent acts.

>

> The finding also suggests that there is a " lasting biological and not just

parental or short-term environmental component to this type of chronic

antisocial behavior, " said McBurnett, Ph.D., assistant professor of

psychiatry at the University of Chicago and lead author of the study. " Children

with persistent conduct disorder may have genes that predispose them to produce

certain hormones differently, or their hormone production may have been altered

before or soon after birth. "

>

> For four years, the researchers followed 38 boys who had been referred to a

psychiatric clinic for disruptive behavior. They collected saliva samples from

each boy in years two and four of the study. Through psychiatric evaluations and

interviews with parents and teachers, the researchers assessed the boys'

aggressive behaviors and tallied symptoms such as starting fights, using

weapons, being cruel to people or animals, stealing, or forcing sexual acts.

>

> Each child in the study was also evaluated by his peers at school; classmates

were asked to rate all their fellow students on several behavioral categories,

including naming the three boys in class who were meanest, and fought most.

>

> The researchers found that salivary cortisol levels were " strongly and

inversely related to aggressive conduct disorder, peer aggression nominations

and oppositional defiant disorder. " The 12 children with low cortisol levels on

both samples averaged 5.2 symptoms of conduct disorder, compared to 1.5 such

symptoms in the 26 boys who had a higher level on either sample. More than one

third of boys with low cortisol were nominated by their peers as the " meanest "

in the class, compared with 10.5 percent of boys who had at least one higher

cortisol reading.

>

> Eleven of the 12 boys with consistently low cortisol developed aggressive

symptoms before age ten. Less than half of those with at least one higher

cortisol level showed symptoms before age ten.

>

> The groups with low, varied or high cortisol levels all had similar IQs,

socioeconomic and ethnic characteristics.

>

> Although the mechanism connecting cortisol levels to aggressive behavior is

unclear, McBurnett suspects that variation in levels may serve as a marker for

abnormalities in the production of various stress hormones that influence the

body's response to a challenge or confrontation.

>

> Cortisol is secreted in response to stressful or threatening situations. Low

levels may indicate how these young males will respond to potentially stressful

situations, suggests McBurnett. " Boys with consistently lower cortisol levels

may not be as afraid of retribution, " he suggested. " In many aggressive

children, the system that responds to the threat of punishment does not react

normally.

>

> They may not feel stress in the same way and so they don't avoid stressful

situations. "

>

> Other researchers contributing to this report include Lahey, Ph.D.,

and Rathouz, Ph.D., of the University of Chicago, and Rolf Loeber, Ph.D.,

of the University of Pittsburgh and Free University, Amsterdam, the Netherlands.

Support for the research was provided by the National Institutes of Health.

>

> EXCESS FOLATE AND TOLOMERE LENGTH CANCER INCREASES

> Ligi 09 Telomere Length in

> > PBMCs Folate Status in Men

> >

> > > " Human chromosomes are capped by telomeres, which

> > consist of tandem repeats of DNA and associated proteins.

> > The length of the telomeres is reduced with increasing cell

> > divisions except when the enzyme telomerase is active, as in

> > stem cells and germ cells. Telomere dysfunction has been

> > associated with development of age-related pathologies,

> > including cancer, cardiovascular disease, Alzheimer's

> > disease, and Parkinson's disease. DNA damage in the

> > telomeric region causes attrition of telomeres. Because

> > folate provides precursors for nucleotide synthesis and thus

> > affects the integrity of DNA, including that of the

> > telomeric region, folate status has the potential to

> > influence telomere length. Telomere length is epigenetically

> > regulated by DNA methylation, which in turn could be

> > modulated by folate status. In this study, we determined

> > whether folate status and the 677C > T polymorphism of

> > the methylene tetrahydrofolate reductase (MTHFR) gene are

> > associated with the telomere length of peripheral blood

> > mononuclear cells in healthy men. The results of our study

> > showed that plasma concentration of folate was associated

> > with telomere length of peripheral blood mononuclear cells

> > in a nonlinear manner. When plasma folate concentration was

> > above the median, there was a positive relationship between

> > folate and telomere length. In contrast, there was an

> > inverse relationship between folate and telomere length when

> > plasma folate concentration was below the median. The MTHFR

> > 677C > T polymorphism was weakly associated (P = 0.065)

> > with increased telomere length at below-median folate

> > status. We propose that folate status influences telomere

> > length by affecting DNA integrity and the epigenetic

> > regulation of telomere length through DNA methylation. "

>

> MORE FOLATE CANCER

> http://bloodjournal.hematologylibrary.org/cgi/content/abstract/103/...

> Here, we provide additional evidence on the protective role of these

polymorphisms in acute lymphoblastic leukemia (ALL), the most common pediatric

cancer. A case-control study was conducted in 270 ALL patients and 300 healthy

controls of French-Canadian origin. The TT677/AA1298 and CC677/CC1298

individuals were associated with reduced risk of ALL (crude odds ratio [OR] =

0.4; 95% confidence interval [CI], 0.2-0.9; and OR = 0.3; 95% CI, 0.1-0.6;

respectively). Further stratification in patients born before and after January

1996 (approximate time of Health Canada recommendation for folic acid supplement

in pregnancy) revealed that the protective effect of MTHFR variants is

accentuated and present only in children born before 1996. eg protective against

cancer only in the group whom was not subjected to folate during development

>

> The reluctance to proceed to mandatory food fortification with folic acid in

Europe has been fuelled primarily by concern regarding the potential risk of

masking the symptoms of pernicious anaemia caused by vitamin B12 deficiency. If

undiagnosed, there is potential for irreversible neurological damage in those at

high risk of this This work was completed on behalf of the EuroFIR Consortium

(FOOD-CT-2005-513944) and funded under the EU 6th Framework Food Quality and

Safety Programme deficiency, namely the elderly. Fortifying flour with vitamin

B12 along with folic acid does not seem to be a feasible option as the high dose

of B12 required to improve status among elderly people could put others in the

population at risk of excess intakes. Any action on fortification with folic

acid would, however, need to consider the adequacy of arrangements to routinely

detect B12 deficiency. There have been some reports of possible increases in

twinning associated with

> periconceptional folic acid but this association is thought by many

researchers to be due to the confounding effect of folic acid supplementation

being much more common among women using assisted reproductive technology and

the fact that use of this technology may be significantly under-reported (Berry

et al. 2005). There is concern, however, about the possibility that high intakes

of folic acid may enhance the development of undiagnosed pre-malignant and

malignant lesions.

>

> EPIGENETIC CHANGES

> Is folic acid good for everyone?1,2

> A 1, Young-In Kim1 and Helga Refsum1

> Fortification of food with folic acid to reduce the number of neural tube

defects was introduced 10 y ago in North America. Many countries are considering

whether to adopt this policy. When fortification is introduced, several hundred

thousand people are exposed to an increased intake of folic acid for each neural

tube defect pregnancy that is prevented. Are the benefits to the few outweighed

by possible harm to some of the many exposed? In animals, a folic acid–rich diet

can influence DNA and histone methylation, which leads to phenotypic changes in

subsequent generations. In humans, increased folic acid intake leads to elevated

blood concentrations of naturally occurring folates and of unmetabolized folic

acid. High blood concentrations of folic acid may be related to decreased

natural killer cell cytotoxicity, and high folate status may reduce the response

to antifolate drugs used against malaria, rheumatoid arthritis, psoriasis, and

cancer. In the

> elderly, a combination of high folate levels and low vitamin B-12 status may

be associated with an increased risk of cognitive impairment and anemia and, in

pregnant women, with an increased risk of insulin resistance and obesity in

their children. Folate has a dual effect on cancer, protecting against cancer

initiation but facilitating progression and growth of preneoplastic cells and

subclinical cancers, which are common in the population. Thus, a high folic acid

intake may be harmful for some people. Nations considering fortification should

be cautious and stimulate further research to identify the effects, good and

bad, caused by a high intake of folic acid from fortified food or dietary

supplements. Only then can authorities develop the right strategies for the

population as a whole.

>

> Key Words: Folate • folic acid • vitamin B-12 • fortification • supplements •

cancer • antifolates • cognition • epigenetics • public health

> http://www.ajcn.org/cgi/content/full/87/3/517

>

> The data reported by Pfeiffer et al (26) show that the section of

> theUSpopulation with the highest blood concentrations of folate

> after fortification is children aged5 y, 43% ofwhomhad serum

> folate concentrations 45.3 nmol/L. Ten percent of these children

> had concentrations 77.3 nmol/L. We can estimate the

> intake of folic acid equivalents needed to achieve these concentrations

> from the formula provided by Quinlivan and

> (25): 43% of children aged5 y are consuming the equivalent of

> 780 g folic acid/d, ie, double the proposed tolerable upper

> limit (300–400 g/d) for children of that age. It is striking that

> 10% are consuming1320 g folic acid/d, which is well above

> the tolerable upper limit of 1000g/d for adults. The next highest

> blood concentrations were found in children aged 6–11 y; the

> third highest concentrations occurred in those aged 60y, of

> whom 38% had45.3 nmol/L. We simply do not know whether

> these concentrations may cause harm, but it must be of concern

> that such high concentrations occur, particularly in children at a

> rapid stage of development, when it likely that epigenetic

> changes are occurring in many tissues. A recent study in mice

> showed that varying the methyl donor status of the postweaning

> diet in mice could influence the methylation status and the expression

> of imprinted genes (180). Could the same thing happen

> in young children?

>

> Hereditary Folate Malabsorption.

> Goldman ID, Min SH, Sandoval C, Kronn D.

> In: Pagon RA, Bird TC, Dolan CR, s K, editors. GeneReviews [internet].

Seattle (WA): University of Washington, Seattle; 1993-.

> 2008 Jun 17.

>

> Excerpt

> Disease characteristics. Hereditary folate malabsorption (HFM) is

characterized by impaired intestinal folate absorption and impaired folate

transport into the CNS. Findings include poor feeding and failure to thrive,

anemia often accompanied by leukopenia and/or thrombocytopenia, diarrhea and/or

oral mucositis, hypoimmunoglobulinemia, and infection with unusual organisms.

Neurologic manifestations include seizures and developmental delay in infants.

Ataxia and cognitive impairment may occur in older untreated individuals.

Diagnosis/testing. Diagnosis of HFM is confirmed by impaired absorption of an

oral folate load and low cerebrospinal fluid (CSF) folate concentration (even

after correction of the serum folate concentration). SLC46A1, encoding the

proton-coupled folate transporter (PCFT) protein, a member of the superfamily of

facilitative carriers, is the only gene known to be associated with HFM.

Sequence analysis has identified either homozygous or

> compound heterozygous mutations in all 11 families tested to date.

Management. Treatment of manifestations: for systemic manifestations of folate

deficiency, low-dose parenteral (intramuscular) (1.0 to 5.0 mg/day) or high-dose

oral (~150-200 mg/day) 5-methyltetrahydrofolate (5-methylTHF) (Metafolin®) or

5-formyltetrahydrofolate (5-formylTHF) (folinic acid or Leucovorin®); neurologic

signs can be more difficult to correct. Prevention of primary manifestations:

Early treatment with 5-methylTHF or 5-formylTHF before symptoms appear can

prevent the metabolic consequences of folate deficiency. Surveillance: to assess

adequacy of treatment, periodic complete blood counts and measurements of the

concentrations of serum and CSF folate. Testing of relatives at risk: for sibs

of a proband, molecular genetic testing when the family-specific disease-causing

mutations are known; otherwise, assessment of intestinal absorption of folate

and CSF folate concentration.

> Other: Folic acid should not be used for treatment of HFM; it is not a

physiologic folate and binds irreversibly to the folate receptors that transport

folates into cells. Genetic counseling. HFM is inherited in an autosomal

recessive manner. Heterozygotes (carriers) are asymptomatic and do not have

evidence of folate deficiency. At conception, each sib of an affected individual

has a 25% chance of being affected, a 50% chance of being an asymptomatic

carrier, and a 25% chance of being unaffected and not a carrier. In families in

which the disease-causing mutations are known, carrier testing for at-risk

relatives and prenatal testing for pregnancies at increased risk may be possible

through laboratories offering custom genetic testing.

> PMID: 20301716 [PubMed]

> http://www.ncbi.nlm.nih.gov/pubmed/20301716

> GENDER DIFFERENCE

> Effect of maternal multiple micronutrient supplements on cord blood hormones:

a randomized controlled trial.

> Roberfroid D, Huybregts L, Lanou H, Henry MC, Meda N, Kolsteren P.

>

> Child HealthNutrition Unit Department of Public Health Institute of Tropical

Medicine Antwerp Belgium.

>

> Abstract

> BACKGROUND: Fetal growth improves in pregnant women who take daily maternal

multiple micronutrients [united Nations International Multiple Micronutrient

Preparation (UNIMMAP)] rather than iron and folic acid (IFA) alone. OBJECTIVE:

Our objective was to test whether such an effect was mediated by changes in

concentrations of cord hormones. DESIGN: In a double-blind, controlled trial

carried out in Burkina Faso, we randomly assigned 1426 pregnant women to receive

UNIMMAP or IFA supplements. We measured concentrations of insulin-like growth

factor I (IGF-I), leptin, insulin, free thyroxine, and cortisol in cord serum in

a subsample of 294 live single newborns. We performed mediation analysis with an

Aroian test. RESULTS: UNIMMAP supplementation had no significant effect on cord

hormone concentrations. However, UNIMMAP supplementation significantly affected

concentrations of IGF-I (+30%; 95% CI: 8%, 52%; P = 0.009) and leptin in male

newborns. In these

> infants, 51.1% (P = 0.08) of the effect of UNIMMAP supplementation on birth

weight was mediated through IGF-I, whereas for female newborns, this proportion

was negligible. UNIMMAP supplementation also increased cortisol concentrations

by 36% (P = 0.009) in cord blood in primiparae (P for interaction = 0.02).

Growth-retarded babies had 41.2% lower IGF-I (P < 0.0001) and 27.3% lower leptin

(P = 0.04) than did infants with normal growth. Offspring of primiparae had

reduced IGF-I and insulin concentrations, and their cortisol concentrations were

25% higher (P = 0.05). Male newborns had lower concentrations of IGF-I, leptin,

and insulin than did female newborns. CONCLUSIONS: UNIMMAP supplementation had

sex-specific effects on cord IGF-I and leptin concentrations that were of

unclear clinical significance. Other pathways may have been involved in the

action of UNIMMAP on fetal growth. The specific hormonal pattern in primiparae

could be related to constrained

> fetal growth. Confirmatory studies are warranted. This trial was registered

at clinicaltrials.gov as NCT00642408.

> http://www.ncbi.nlm.nih.gov/pubmed/20375185