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Vitamin B 6

Vitamin B 6. Colleen Poling. Abstract.

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Vitamin B 6

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  1. Vitamin B6 ColleenPoling

  2. Abstract Vitamin B6 is a water soluble vitamin that plays in important roll as a coenzyme in over 100 different reactions within the body. Some examples are heme synthesis, gluconeogenisis and neurotransmitters synthesis, to name a few. Vitamin B6 is known to have three vitamer forms, one active form and one excretion form. The active form PLP plays the major roll in transamination of amino acids. Vitamin B6 is readily absorbed by passive diffusion in the duodenal cells, and is excreted in the urine. Vitamin B6 is abundant in a variety of food sources, and has its highest bioavailability in animal sources. Deficiency of Vitamin B6 can cause major problems involved in amino acid metabolism, which involves the nervous system, and cell synthesis. Toxicity of Vitamin B6 also causes changes in the nervous system, such as convulsion. Toxicity can lead to a variety of symptoms such as fatigue, lethargy and irritability. Vitamin plays a great roll in prevention of certain disease such as Alzheimer's, PMS, coronary atherosclerosis, depression and asthma. The following review will cover all these topics in depth.

  3. Purpose This review will be an overview of past and recent research concerning Vitamin B6, and will provide some basic knowledge and information about the Vitamin.

  4. What is Vitamin B6? • A Water soluble vitamin • Essential to life; cannot be synthesized by the body. • Has many forms • Important for many enzymatic functions in the body • A part of the Vitamin B2 complex • 1]Liao . Theoretical studies on pyridoxal 5′-phosphate-dependent transamination of α-amino acids. J

  5. History In 1934 PAUL GYÖRGY, proposed the existence of Vitamin B6 after discovering that vitamin B2 was a combination of different factors (including B6). In 1936 B6 was isolated. In 1938 the structures of B6 were determined. 2]In 1939 the synthesis was achieved. GYORGY, P.: Investigations on the vitamin B, complex. I. The differentiation of lactoflavin and the “Rat Antipellagra” factor. Biochem. J. 29: 741, 1935 3]Lepkovsky S. The isolation of factor one in crystalline form. J Bio Chem. 1938; 124: 125-128

  6. Functions: Co-Enzyme Role • Transamination of amino acids. (changing amino acids that cannot be deaminated, into ones that can be deaminated, by transferring the amino group to the vitamin B6.) This is critical in new cell formation. • Aspartate aminotransferase (AATase) is a PLP dependent enzyme. • Amino acid L-aspartate (donor amino acid) -> Keto-acid 2-oxoglutarate (Product ketone acid B)the amino group -NH2 is transferred onto the coenzyme vitamin B6, which then AATase assists in the enzymatic reaction. • The second part of the reaction: The Keto-acid oxalacetate (acceptor keto acid) -> Amino acid L-glutamate (Product amino acid) • 4]Liao . Theoretical studies on pyridoxal 5′-phosphate-dependent transamination of α-amino acids. J Comput Chem. 2008; 29:1919-1929.

  7. Functions… • Neurotransmitter synthesis- the enzymes that depend on B6 are involved in the making of serotonin, epinephrine, norepinephrine and gamma-aminobutyric acid by transamination of the amino group. • 5] Bagci S, Zschocke J, Hoffmann GF, Bast T, Klepper J, Müller A. Pyridoxal phosphate-dependent neonatal epileptic encephalopathy. Arch Dis Child Fetal Neonatal Ed . 2008; 151.

  8. Functions • Selenoamino acid metabolism- Selenomethionine is the plant dietary form of selenium. B6 is a cofactor that allows the enzymes to convert Se to the dietary form. • Synthesis of heme- PLP assists as a coenzyme to bind hemoglobin molecules in the red blood cells. Crucial for oxygen transport. • 6] Soda K, Oikawa T. 1999. Vitamin B6 enzymes participating in selenium amino acid metabolism. BioFactors. 10:257-262 • 7] Maxwell. Dogs and pigs lacking B6 showed signs of mycrocytic anemia. J Nutr.

  9. Functions… • Gluconeogenesis • Glucose synthesis from amino acids that is induced by glucagon. • helps speed up transamination reactions that provide the amino acids substrates for gluconeogenesis. • “You can see from the graph that hepatic G6Pase activity in the B6-deficient group significantly decreased compared to that in the pair-fed control group, which is likely due to a suppression of gluconeogenesis from amino acids.“ • And many more coenzyme activity, over 100. • 8] Inubushi T, Takasawa T, Tuboi Y, Watanabe N, Aki K, Katunuma N. 2005. Changes of glucose metabolism and skin-collagen neogenesis in vitamin B6 deficiency. BioFactors. 23(2):59-67.

  10. Functions: Non Co-Enzyme Role • Immune function • Can improve immune responses of critically ill patients if Vitamin B6 supplementation taken in large doses 50-100mg • Can support the immune system. 9] Cheng . Vitamin B6 supplementation increases immune responses in critically ill patients. Eur J Clin Nutr. 2006;60:1207-1213. 10] Robson LC, Schwarz MR. Vitamin B[sub6] deficiency and the lymphoid system. I. Effects on cellular immunity and in vitro incorporation of 3H-uridine by small lymphocytes. Cell Immunol 1975;16:135-44. 11] Robson LC, Schwarz MR. Vitamin B[sub6] deficiency and the lymphoid system. II. Effects of vitamin B[sub6] deficiency in utero on the immunological competence of the offspring. Cell Immunol 1975;16:145-52.

  11. Forms • Pyridoxine (PN)-given as supplement- Organic form of B6 (alcohol and vitamer) • Pyridoxal (PL) –Organic form of B6 (aldehyde and vitamer) • Pyridoxamine (PM)- Organic form of B6 (amine and vitamer) • Pyridoxal 5'-phosphate (PLP)-metabolically active vitamer with “most versatile organic cofactor in biology, and is used by a variety of enzymes in all organisms.” PLP displays “more than 140 distinct enzymatic activities that are catalogued by the Enzyme Commission (EC)”(Comprised of above three). Metabolized in the liver. • Pyridoxamine 5'-phosphate (PMP). • 4-Pyridoxic acid (PA) –Excreted in the urine 12] Casas JS, Castiñeiras A, Condori F, Couce MD, Russo U, Sánchez A. Diorganotin(IV)-promoted deamination of amino acids by pyridoxal: SnR2 2+ complexes of pyridoxal 5′-phosphate and of the Schiff base pyridoxal-pyridoxamine (PLPM), and antibacterial activities of PLPM and ... Polyhedron. 2003;22:53-65.

  12. Chemical Structures 12] Casas JS, Castiñeiras A, Condori F, Couce MD, Russo U, Sánchez A. Diorganotin(IV)-promoted deamination of amino acids by pyridoxal: SnR2 2+ complexes of pyridoxal 5′-phosphate and of the Schiff base pyridoxal-pyridoxamine (PLPM), and antibacterial activities of PLPM and ... Polyhedron. 2003;22:53-65.

  13. Pathways of B6 Metabolism Metabolism occurs in the liver, where the conversion of PLP takes place. 13] Stone WJ, Warnock LG, Wagner C. Vitamin B6 deficiency in uremia. Am J Clin Nutr.1975; 28:950-7.

  14. Toxicity 14] Schaumburg H, Kaplan J, Windebank A, Vick N, Rasmus S, Pleasure D, Brown MJ. TI Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med. 1983; 309:445-448. • Sensory neuropathy or neuronopathy syndromes • Basically causes an imbalance in nervous system activity.

  15. Toxicity… 15] Albin RL, Albers JW, Greenberg HS, Townsend JB, Lynn RB, Burke JM Jr, Alessi AG. Acute sensory neuropathy-neuronopathy from pyridoxine overdose. SO Neurology.1987; 37:1729-1732. Mild weakness Fatigue Irritability Lethargy

  16. Deficiency Eczema and Seborrheic Dermatitis- Since Vitamin b6 plays a role in making new cells, cells that turn over quickly are affected if there are inadequate amounts. The skin is the first to show problems. 16] Gyorgy P. Further investigations on vitamin B6 and related factors of the vitamin B2 complex in rats. Parts 1 and 2. West Res University. 1940;1143-1144.

  17. Deficiency… • Depression- • B6 is a cofactor in the tryptophan-serotonin pathway-which is linked to depression. Patients with symptoms of depression have low plasma levels of PLP. • 17] Hvas A, Juul S, Bech P, Nex E. Vitamin B6 level is associated with symptoms of depression. Psychother Psychosom 2004;73:340-343.

  18. Deficiency… • Nervous system changes • Convulsions • Because the vitamin B6 is involved in making specific neurotransmitters. Deficiency in vitamin B6 can result in convulsions. • An early study done on pigs in 1942 showed that vitamin B6 deficiency resulted in these symptoms. • 18] Maxwell M, Wintrobe, Mitchell H, Miller, Richard H, Follis, JR, Harold J, Stein, Cecil M, Humphreys S. Sensory neuron degeneration in pigs. J Nutr.1942; 4:345.

  19. Deficiency… • Anemia • Since the role of vitamin B6 helps to make new cells, it plays a roll in red blood cell formation also. • This type related to Vitamin B6 deficiency is considered to be microcytic hypochromic, (pernicious) anemia, because it can be treated by adequate vitamin b6 intake • 19] Maxwell. Dogs and pigs lacking B6 showed signs of mycrocytic anemia. J Nutr. • 20] Fouts P. Production of microcytic hypochromic anemia in puppies on synthetic diet deficient in rat antidermatitis factor (vitamin b6). J Nutr. 1938; 16: 117-120.

  20. B6Deficiency Survey Study It was previously thought that B6 deficiency was rare in the USA; now finding out otherwise- “Researchers evaluated plasma levels of PLP (pyridoxal 5’ phosphate) in 7822 males and females, age one and older and found that participants with inadequate vitamin B6 status even though they reported consuming more than the Recommended Daily Allowance of B6, which is less than 2 milligrams per day”. “Women of reproductive age had highest rate of deficiency, especially current and former users of oral contraceptives, male smokers, non-Hispanic African American men, and men and women over age 65”. 21] Morris M, Picciano M, Jacques P, Selhub J. Plasma pyridoxal 5'-phosphate in the U.S. population: the National Health and Nutrition Examination Survey. Am J Clin Nutr. 2008; 87: 1446-1454

  21. Good Food Sources of Vitamin B6 Meat-rabbit, wild duck, egg, kidney beans, peanuts, chicken breast, chickpeas Organ-liver Fish- clams, white fish, finfish, tuna Vegetables- potato, spinach, bell peppers, turnip greens, celery, asparagus, broccoli, cabbage, kale Fruit-banana Whole grains-brown rice, whole wheat bread Dairy products-cheese, yogurt, milk Other-Molasses, sunflower seeds, fortified breakfast cereals, instant oatmeal 22] USDA National Database for Standard References. US Department of Agriculture. Available at http://www.nal.usda.gov/fnic/foodcomp/search/ . Accessed on October 10th, 2008. 23] Hidiroglou N. Levels of folate, pyridoxine, niacin and riboflavin in traditional foods of Canadian Arctic Indigenous Peoples. J. Food Compos. Anal. 2008; 21:474-480. 24] Hassinen JB, Durbin T, Bernhart FW. The Vitamin B6 content of milk products. J Nutr. 1954; 249-252.

  22. Food Sources Highest Bioavailability of Vitamin B6 is from animal sources. In meat sources the pyridoxal 5'-phosphate (PLP) form is present. Most of the vitamin B6 is lost during the cooking or processing process. (also high acidity and freezing). 23] Hidiroglou N. Levels of folate, pyridoxine, niacin and riboflavin in traditional foods of Canadian Arctic Indigenous Peoples. J. Food Compos. Anal. 2008; 21:474-480. Hidiroglou N. Levels of folate, pyridoxine, niacin and riboflavin in traditional foods of Canadian Arctic Indigenous Peoples. J. Food Compos. Anal. 2008; 21:474-480.

  23. Vitamin B6 Content in Food 22] USDA National Database for Standard References. US Department of Agriculture. Available at http://www.nal.usda.gov/fnic/foodcomp/search/ . Accessed on October 10th, 2008.

  24. DietaryReferenceIntakes 23] Food and Nutrition Board, Institute of Medicine. Vitamin B6. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington D.C.: National Academies Press; 1998:150-195.

  25. Absorption Pyridoxine enters the duodenal cell by passive diffusion and then phosphorylation (alkaline phosphatase) which takes place intracellularly. Must be hydrolyzed to PM or PL before absorption. Muscle contains the majority of Vitamin B6,70-80% 24] Tsuji, T., Yamada, R. & Nose, Y. Intestinal absorption of vitamin B6. I. Pyridoxol uptake by rat intestinal tissue. J. Nutr. Sci. Vitaminol. 1973;19, 401-417. 25] Coburn P. Pyridoxic acid excretion during low vitamin B-6 intake, total fasting, and bed rest. Am J Clin Nutr. 62: 979.

  26. Excretion Most of the Vitamin B6 is excreted in the form of 4-Pyridoxic acid after 3 hours Large doses will not be excreted through the kidneys, but rather tubules in the kidney. Also plays a small roll with Enterohepatic circulation (Vitamin B6 binds to bile, and presents itself back in to the GI tract). 26] Lui A, Lumeng L, Li T. Biliary Excretion of 14C-Labeled Vitamin B-6 in Rats. J. Nutr. 1983;113: 893-898.

  27. Assessment Large amounts can be found in small doses in the urine or feces. The UL for Vitamin B6 50 times higher than the RDA, leaving a large margin. Deficiency can be detected by taking a two sample of blood from the patient and adding the active form (PLP) into the one of the samples. If there is no reaction then the patient is considered to be within range. 33] Turnlund JR, Betschart AA, Liebman M, Kretsch MJ, Sauberlich HE. “Vitamin B-6 depletion followed by repletion with animal- or plant- source diets and calcium and magnesium metabolism in young women.” Am. J. Clinical Nutrition, Nov 1992; 56: 905 - 910.

  28. Vitamin B6 and Disease 27] Reynolds RD, Natta CL. Depressed plasma pyridoxal phosphate concentrations in adult asthmatics. J of ClinNutr. 1985; 41: 684-688. • Asthma • Suggests that inadequate pyridoxine could be related to asthma. • Still need more research to result in a stronger conclusion

  29. Vitamin B6 and Disease… • Premenstrual syndrome (PMS) • May improve psychiatric symptoms (moodiness, anxiety, depression, unreasonable crying). • More research is still needed to provide a stronger conclusion. • 28] Kashanian M. Pyridoxine (vitamin B6) therapy for premenstrual syndrome. Internat. Jour. of Gynecology. 2007; 6:43-44.

  30. Vitamin B6 and Disease… • Depression- • “ The study suggests that a low level of plasma PLP is associated with symptoms of depression. “ • “Randomized trials are now justified and needed in order to examine whether treatment with vitamin B6 may improve symptoms of depression.” • 17] Hvas A, Juul S, Bech P, Nex E. Vitamin B6 level is associated with symptoms of depression. Psychother Psychosom. 2004;73:340-343.

  31. Vitamin B6 and Disease… 29] Lerner V, Miodownik C, Kaptsan A, Cohen H, Matar M, Loewenthal U, Kotler M. Vitamin B(6) in the treatment of tardivedyskinesia: a double-blind, placebo-controlled, crossover study. Am J Psychiatry. 2001;158:1511-1514. • Tardive dyskinesia- • Defined as a range of uncontrolled/involuntary movements. • Related to Parkinson’s Disease. • appears to be affective in reducing symptoms.

  32. Vitamin B6 and Disease… • Coronary atherosclerosis- • High levels of homocysteine have been linked to cardiovascular risks. By taking Vitamin B6, this is a treatment therapy for Hyperhomocysteinemia, and significantly lowers the adverse cardiac events. • 30] Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. So Jama. 2002;288:973-979.

  33. Vitamin B6 and Disease… Coronary atherosclerosis Kaplan-Meier Survival Curves for Freedom From Major Adverse Events in 553 Patients The rate of event-free survival was significantly higher among patients assigned to receive folate+B12+B6 therapy than among control patients. The relative risk of a major adverse event with folate+B12+B6 therapy was 0.60 (95% confidence interval [CI], 0.40-0.91; log-rank P = .02) at 6 months and 0.68 (95% CI, 0.48-0.96; log-rank P = .03) at 1 year (mean [SD] follow-up, 11 [3] months). 30] Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. So Jama. 2002;288:973-979.

  34. Vitamin B6 and Disease… • Alzheimer’s Disease- • High plasma levels of homocysteine have been linked with poor cognition, dementia and Alzheimer’s. • Vitamin B6 is a treatment for Hyperhomocysteinemia, and but shows no improvement to slow the decline in cognitive abilities. • Previous studies were not large enough in size and duration to make a accurate result, but recent studies show no improvement with B6 supplementation. 31] Aisen P, Schneider L, Sano M, Diaz-Arrastia R, van Dyck C, Weiner M, Bottiglieri T, Jin S, Stokes K. High-Dose B Vitamin Supplementation and Cognitive Decline in Alzheimer Disease. JAMA. 2008; 300:1774-1783. 32] Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. SO N Engl J Med. 2002;346:476-483.

  35. Conclusion: Vitamin B6 is… • A Water soluble vitamin • Essential to life; cannot be synthesized by the body. • Has many forms. • Important for many enzymatic functions in the body • 1]Liao . Theoretical studies on pyridoxal 5′-phosphate-dependent transamination of α-amino acids. J Comput Chem. 2008; 29:1919-1929.

  36. Sources • 1]Liao . Theoretical studies on pyridoxal 5′-phosphate-dependent transamination of α-amino acids. J Comput Chem. 2008; 29:1919-1929. • 2]In 1939 the synthesis was achieved. GYORGY, P.: Investigations on the vitamin B, complex. I. The differentiation of lactoflavin and the “Rat Antipellagra” factor. Biochem. J. 29: 741, 1935 • 3]Lepkovsky S. The isolation of factor one in crystalline form. J Bio Chem. 1938; 124: 125-128. • 4]Liao . Theoretical studies on pyridoxal 5′-phosphate-dependent transamination of α-amino acids. J Comput Chem. 2008; 29:1919-1929. • 5] Bagci S, Zschocke J, Hoffmann GF, Bast T, Klepper J, Müller A. Pyridoxal phosphate-dependent neonatal epileptic encephalopathy. Arch Dis Child Fetal Neonatal Ed . 2008; 151. • 6] Soda K, Oikawa T. 1999. Vitamin B... enzymes participating in selenium amino acid metabolism. BioFactors. 10:257-262 • 7] Maxwell. Dogs and pigs lacking B6 showed signs of mycrocytic anemia. J Nutr. • 8] Inubushi T, Takasawa T, Tuboi Y, Watanabe N, Aki K, Katunuma N. 2005. Changes of glucose metabolism and skin-collagen neogenesis in vitamin B6 deficiency. BioFactors. 23(2):59-67. • 9] Cheng . Vitamin B6 supplementation increases immune responses in critically ill patients. Eur J Clin Nutr. 2006;60:1207-1213. • 10] Robson LC, Schwarz MR. Vitamin B[sub6] deficiency and the lymphoid system. I. Effects on cellular immunity and in vitro incorporation of 3H-uridine by small lymphocytes. Cell Immunol 1975;16:135-44. • 11] Robson LC, Schwarz MR. Vitamin B[sub6] deficiency and the lymphoid system. II. Effects of vitamin B[sub6] deficiency in utero on the immunological competence of the offspring. Cell Immunol 1975;16:145-52. • 12] Casas JS, Castiñeiras A, Condori F, Couce MD, Russo U, Sánchez A. Diorganotin(IV)-promoted deamination of amino acids by pyridoxal: SnR2 2+ complexes of pyridoxal 5′-phosphate and of the Schiff base pyridoxal-pyridoxamine (PLPM), and antibacterial activities of PLPM and ... Polyhedron. 2003;22:53-65. • 13] Stone WJ, Warnock LG, Wagner C. Vitamin B6 deficiency in uremia. Am J Clin Nutr.1975; 28:950-7. • 14] Schaumburg H, Kaplan J, Windebank A, Vick N, Rasmus S, Pleasure D, Brown MJ. TI Sensory • neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med. 1983; 309:445-448 • 15] Albin RL, Albers JW, Greenberg HS, Townsend JB, Lynn RB, Burke JM Jr, Alessi AG. Acute sensory • neuropathy-neuronopathy from pyridoxine overdose. SO Neurology.1987; 37:1729-1732. • 16] Gyorgy P. Further investigations on vitamin B6 and related factors of the vitamin B2 complex in rats. Parts 1 and 2. West Res University. 1940;1143-1144. • 17] Hvas A, Juul S, Bech P, Nex E. Vitamin B6 level is associated with symptoms of depression. Psychother Psychosom 2004;73:340-343.

  37. Sources… • 18] Maxwell M, Wintrobe, Mitchell H, Miller, Richard H, Follis, JR, Harold J, Stein, Cecil M, Humphreys S. Sensory neuron degeneration in pigs. J Nutr.1942; 4:345. • 19] Maxwell. Dogs and pigs lacking B6 showed signs of mycrocytic anemia. J Nutr. • 20] Fouts P. Production of microcytic hypochromic anemia in puppies on synthetic diet deficient in rat antidermatitis factor (vitamin b6). J Nutr. 1938; 16: 117-120. • 21] Morris M, Picciano M, Jacques P, Selhub J. Plasma pyridoxal 5'-phosphate in the U.S. population: the National Health and Nutrition Examination Survey, 2003–2004. Am J Clin Nutr. 2008; 87: 1446-1454 • 22] USDA National Database for Standard References. US Department of Agriculture. Available at http://www.nal.usda.gov/fnic/foodcomp/search/ . Accessed on October 10th, 2008. • 23] Hidiroglou N. Levels of folate, pyridoxine, niacin and riboflavin in traditional foods of Canadian Arctic Indigenous Peoples. J. Food Compos. Anal. 2008; 21:474-480. • 24] Hassinen JB, Durbin T, Bernhart FW. The Vitamin B6 content of milk products. J Nutr. 1954; 249-252. • 23] Food and Nutrition Board, Institute of Medicine. Vitamin B6. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington D.C.: National Academies Press; 1998:150-195. • 24] Tsuji, T., Yamada, R. & Nose, Y. Intestinal absorption of vitamin B6. I. Pyridoxol uptake by rat intestinal tissue. J. Nutr. Sci. Vitaminol. 1973;19, 401-417. • 25] Coburn P. Pyridoxic acid excretion during low vitamin B-6 intake, total fasting, and bed rest. Am J Clin Nutr. 62: 979. • 26] Lui A, Lumeng L, Li T. Biliary Excretion of 14C-Labeled Vitamin B-6 in Rats. J. Nutr. 1983;113: 893-898. • 27] Reynolds RD, Natta CL. Depressed plasma pyridoxal phosphate concentrations in adult asthmatics. J of Clin Nutr. 1985; 41: 684-688. • 28] Kashanian M. Pyridoxine (vitamin B6) therapy for premenstrual syndrome. Internat. Jour. of Gynecology. 2007; 6:43-44. • 29] Lerner V, Miodownik C, Kaptsan A, Cohen H, Matar M, Loewenthal U, Kotler M. Vitamin B(6) in the treatment of tardive dyskinesia: a double-blind, placebo-controlled, crossover study. Am J Psychiatry. 2001;158:1511-1514. • 30] Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. So Jama. 2002;288:973-979. • 31] Aisen P, Schneider L, Sano M, Diaz-Arrastia R, van Dyck C, Weiner M, Bottiglieri T, Jin S, Stokes K. High-Dose B Vitamin Supplementation and Cognitive Decline in Alzheimer Disease. JAMA. 2008; 300:1774-1783. • 32] Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. SO N Engl J Med. 2002;346:476-483. • 33] Turnlund JR, Betschart AA, Liebman M, Kretsch MJ, Sauberlich HE. “Vitamin B-6 depletion followed by repletion with animal- or plant- source dietsand calcium and magnesium metabolism in young women.” Am. J. Clinical Nutrition, Nov 1992; 56: 905 - 910.

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