Whole Body Health Sale

Folic Acid and Vitamin B12 Capsules



Table of Contents
image Improved vascular endothelial function after oral B vitamins: An effect mediated through reduced concentrations of free plasma homocysteine.
image Serum folate and cardiovascular disease mortality among US men and women.
image Low serum folate but normal homocysteine levels in patients with atherosclerotic vascular disease and matched healthy controls.
image Dietary strategies for lowering homocysteine concentrations.
image Association of folate intake and serum homocysteine in elderly persons according to vitamin supplementation and alcohol use.
image Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort
image Vitamin intervention for stroke prevention (VISP) trial: rationale and design.
image Multivitamin/mineral supplementation improves plasma B-vitamin status and homocysteine concentration in healthy older adults consuming a folate-fortified diet.
image Nutritional and botanical interventions to assist with the adaptation to stress
image Methylcobalamin decreases mRNA levels of androgen-induced growth factor in androgen-dependent Shionogi carcinoma 115 cells
image Can reduced folic acid and vitamin B12 levels cause deficient DNA methylation producing mutations which initiate atherosclerosis?
image What level of plasma homocyst(e)ine should be treated? Effects of vitamin therapy on progression of carotid atherosclerosis in patients with homocyst(e)ine levels above and below 14 micromol/L
image Vitamin B 12 deficiency in the aged
image Vitamin B12 deficiency in the elderly
image Plasma homocysteine is a sensitive marker for tissue deficiency of both cobalamines and folates in a psychogeriatric population

bar

  

Improved vascular endothelial function after oral B vitamins: An effect mediated through reduced concentrations of free plasma homocysteine.

Circulation 2000 Nov 14;102(20):2479-83

BACKGROUND: Hyperhomocysteinemia is an independent risk factor for coronary heart disease (CHD). Dietary supplementation with B vitamins lowers plasma homocysteine by up to 30%. However, little is known about the potential beneficial effects of homocysteine lowering on vascular function in patients with CHD. METHODS AND RESULTS: We investigated 89 men with CHD (aged 56 [range 39 to 67] years). Brachial artery flow-mediated dilatation (endothelium dependent) and nitroglycerin-induced dilatation (endothelium independent) were measured before and 8 weeks after treatment with either (1) folic acid (5 mg) and vitamin B12 (1 mg) daily (n=59) or (2) placebo (n=30). Total, protein-bound, and free plasma homocysteine, serum folate, and vitamin B12 were measured at baseline and at 8 weeks. Flow-mediated dilatation improved after treatment with B vitamins (2.5+/-3.2% to 4.0+/-3.7%, P:=0.002) but not placebo (2.3+/-2.6% to 1.9+/-2.6%, P:=0.5). Vitamin therapy lowered plasma concentrations of total homocysteine (from 13.0+/-3.4 to 9.3+/-1.9 micromol/L, P:<0.001), protein-bound homocysteine (from 8.7+/-2.8 to 6.2+/-1.4 micromol/L, P:<0.001), and free homocysteine (from 4.3+/-1.2 to 3.0+/-0.6 micromol/L, P:<0.001) and raised concentrations of serum folate (from 10.3+/-4.3 to 31.2+/-10.8 ng/mL, P:<0.001) and vitamin B12 (from 314+/-102 to 661+/-297 pg/mL, P:<0.001). In regression analysis, improved flow-mediated dilatation correlated closely with the reduction in free plasma homocysteine (r=-0.26, P:=0.001), independent of changes in protein-bound homocysteine, folate, and vitamin B12. Nitroglycerin-induced dilatation was unchanged after both B vitamins and placebo.CONCLUSIONS: Folic acid and vitamin B12 supplementation improves vascular endothelial function in patients with CHD, and this effect is likely to be mediated through reduced concentrations of free plasma homocysteine concentrations. Our data support the view that lowering homocysteine, through B vitamin supplementation, may reduce cardiovascular risk.

Serum folate and cardiovascular disease mortality among US men and women.

Arch Intern Med 2000 Nov 27;160(21):3258-62

BACKGROUND: Folate has been linked to cardiovascular disease (CVD) through its role in homocysteine metabolism. OBJECTIVE: To assess the relationship between serum folate and CVD mortality. DESIGN: In this prospective study, serum folate concentrations were measured on a subset of adults during the Second National Health and Nutrition Examination Survey (1976-1980) and vital status ascertained after 12 to 16 years. SETTING AND PATIENTS: A national probability sample consisting of 689 adults who were 30 to 75 years of age and did not have a history of CVD at baseline. MAIN OUTCOME MEASURE: Vital status was determined by searching national databases that contained information about US decedents. RESULTS: The associations between serum folate and CVD and all-cause mortality differed by diabetes status (P =.04 and P =.03, respectively). Participants without diabetes in the lowest compared with the highest serum folate tertile had more than twice the risk of CVD mortality after adjustment for age and sex (relative risk [RR], 2.64; 95% confidence interval [CI], 1.15-6.09). This increased risk for participants in the lowest tertile was attenuated after adjustment for CVD risk factors (RR, 2.28; 95% CI, 0.96-5.40). Serum folate tertiles were not significantly associated with total mortality, although the age- and sex-adjusted risk was increased for participants in the lowest compared with highest tertile (RR, 1.74; 95% CI, 0.96-3.15). Risk estimates for participants with diabetes were unstable because of the small sample size (n = 52). CONCLUSION: These data suggest that low serum folate concentrations are associated with an increased risk of CVD mortality among adults who do not have diabetes.

Low serum folate but normal homocysteine levels in patients with atherosclerotic vascular disease and matched healthy controls.

Nutrition 2000 Jun;16(6):434-8

Mild hyperhomocysteinemia has been considered a cardiovascular risk factor. However, recent prospective studies have not demonstrated that hyperhomocysteinemia or the underlying genetic defect on methylentetrahydrofolate reductase is associated with a higher risk of coronary or peripheral artery disease. We compared serum homocysteine, folate, and vitamin B12 levels of patients with coronary and peripheral vascular disease with those of age- and sex-matched healthy individuals. Subjects taking multivitamins, with diabetes mellitus, or serum creatinine levels over 1.5 mg/dL were excluded from the study. Homocysteine was measured by fluorimetric high-performance liquid chromatography. Serum folate and vitamin B12 levels were measured by an ion-capture method. We studied 32 patients with peripheral vascular disease (10 female), aged 69.6 +/- 11 y, 24 age- and sex-matched control subjects, 52 patients with coronary artery disease (7 female), aged 59.5 +/- 10.4 y, and 42 age- and sex-matched control subjects. Serum homocysteine levels were 11.7 +/- 7.4 and 9.3 +/- 4.5 micromol/L in vascular patients and in the control counterparts, respectively (not significant). The levels for coronary patients and the control counterparts were 9.0 +/- 3.9 and 8.6 +/- 3.6 micromol/L, respectively (not significant). Folate levels were 4.48 +/- 2.42 and 7.14 +/- 4.04 ng/mL in vascular patients and control subjects, respectively (P < 0.02); the levels in coronary patients and control counterparts were 5.15 +/- 1.9 and 6.59 +/- 2.49 ng/mL, respectively (P < 0.01). No differences in vitamin B12 or tocopherol levels were observed between patients and control subjects. There were no differences in homocysteine levels, but lower serum folate levels were observed when comparing patients with atherosclerotic vascular disease and healthy control subjects.

Dietary strategies for lowering homocysteine concentrations.

Am J Clin Nutr 2000 Jun;71(6):1448-54

BACKGROUND: Elevated plasma total homocysteine (tHcy) concentrations are associated with increased risk of vascular disease, and there is a strong inverse association between dietary and blood folate and blood tHcy concentrations. Increased folate consumption may lower the risk of tHcy-mediated cardiovascular disease. OBJECTIVES: The objective was to determine the most appropriate means of increasing dietary folate to reduce plasma tHcy. DESIGN: Sixty-five free-living subjects aged 36 to 71 years with tHcy concentrations >/=9 micromol/L participated in a randomized, controlled trial to compare 3 approaches for increasing dietary folate to approximately 600 microg/d: folic acid supplementation, consumption of folic acid-fortified breakfast cereals, and increased consumption of folate-rich foods. RESULTS: An intake of 437 microg folic acid/d from supplements resulted in a 27-nmol/L increase in serum folate and a 21% reduction in tHcy, relative to the change in a control group. In subjects who consumed folic acid-fortified breakfast cereal, folate intake increased by an average of 298 microg, serum folate increased by 21 nmol/L, and tHcy concentrations decreased by 24%. Increased intakes of folate-rich foods resulted in a 418-microg increase in dietary folate, a 7-nmol/L increase in serum folate, and a 9% reduction in tHcy concentrations. The decrease in tHcy was negatively correlated (r = -0.66) with the increase in serum folate. CONCLUSIONS: Daily consumption of folic acid-fortified breakfast cereals and the use of folic acid supplements appear to be the most effective means of reducing tHcy concentrations. The reduction in tHcy was significantly negatively correlated with the increase in serum folate, which may be a useful marker for measuring dietary change.

Association of folate intake and serum homocysteine in elderly persons according to vitamin supplementation and alcohol use.

Am J Clin Nutr 2001 Mar;73(3):628-37

BACKGROUND: The serum total homocysteine concentration (tHcy), an indicator of folate status and a possible risk factor for vascular disease, is elevated with impaired renal function and poor vitamin B12 status, which are common in the elderly. OBJECTIVE: Our objective was to determine the association between tHcy, folate intake, alcohol consumption, and other lifestyle factors in elderly persons. DESIGN: This cross-sectional study used linear regression to model changes in tHcy. Subjects were 278 men and women aged 66 to 94 years studied in 1993. RESULTS: Total folate intake was negatively associated with tHcy in models adjusted for age, sex, serum creatinine, and serum albumin. We found an interaction between food folate intake and supplement use. Food folate intake had an inverse dose-response relation with tHcy that was limited to nonusers of supplements. Predicted tHcy was 1.5 micromol/L lower in users of supplements containing folate and vitamin B12 than in nonusers and was independent of food folate intake. We found a positive dose-response relation of coffee and tea intake with tHcy, a positive association for alcohol intake of > or = 60 drinks/mo compared with low intake, and an interaction of alcohol use with folate intake and supplement use. Compared with alcohol users, nonusers had higher predicted tHcy and a lower inverse dose-response relation of food folate intake with tHcy. CONCLUSIONS: The inverse association between folate intake and tHcy was strongest among nonusers of supplements and among alcohol drinkers. Identifying modifiable factors related to tHcy, a possible risk factor for vascular disease, is especially important in elderly persons.

Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort

Am J Clin Nutr 2001 Mar;73(3):613-21

BACKGROUND: Established determinants of fasting total homocysteine (tHcy) concentration include folate and vitamin B12 status, serum creatinine concentration, and renal function. OBJECTIVE: Our objective was to examine the relation between known and suspected determinants of fasting plasma tHcy in a population-based cohort. DESIGN: We examined the relations between fasting plasma tHcy concentrations and nutritional and other health factors in 1960 men and women, aged 28 to 82 years, from the fifth examination cycle of the Framingham Offspring Study between 1991 and 1994, before the implementation of folic acid fortification. RESULTS: Geometric mean tHcy was 11% higher in men than in women and 23% higher in persons aged > or = 65 y than in persons aged < 45 y (P < 0.001). tHcy was associated with plasma folate, vitamin B12, and pyridoxal phosphate (P for trend < 0.001). Dietary folate, vitamin B-6, and riboflavin were associated with tHcy among non-supplement users (P for trend < 0.01). The tHcy concentrations of persons who used vitamin B supplements were 18% lower than those of persons who did not (P < 0.001). tHcy was positively associated with alcohol intake (P for trend = 0.004), caffeine intake (P for trend < 0.001), serum creatinine (P for trend < 0.001), number of cigarettes smoked (P for trend < 0.001), and antihypertensive medication use (P < 0.001). CONCLUSIONS: Our study confirmed, in a population-based setting, the importance of the known determinants of fasting tHcy and suggested that other dietary and lifestyle factors, including vitamin B6, riboflavin, alcohol and caffeine intakes as well as smoking and hypertension, influence circulating tHcy concentrations.

Vitamin intervention for stroke prevention (VISP) trial: rationale and design.

Neuroepidemiology 2001 Feb;20(1):16-25

Elevated plasma levels of homocyst(e)ine [H(e)] are surprisingly common and strongly associated with endothelial dysfunction and a marked increase in vascular risk. Treatment with a combination of folic acid, pyridoxine (vitamin B6) and cobalamin (vitamin B12) reduces plasma H(e) levels in most cases, restores endothelial function, and regresses carotid plaque, but there is no evidence that such treatment will reduce clinical events. The Vitamin Intervention for Stroke Prevention (VISP) study is a double-masked, randomized, multicenter clinical trial designed to determine if, in addition to best medical/surgical management, high-dose folic acid, vitamin B6, and vitamin B12 supplements will reduce recurrent stroke compared to lower doses of these vitamins. Patients at least 35 years old with a nondisabling ischemic stroke within 120 days, and screening plasma H(e) > the 25th percentile of benchmark population data are eligible. Secondary endpoints are myocardial infarction or fatal coronary heart disease. This paper describes the design and rationale of the study.

Multivitamin/mineral supplementation improves plasma B-vitamin status and homocysteine concentration in healthy older adults consuming a folate-fortified diet.

J Nutr 2000 Dec;130(12):3090-6

LE Magazine August 2001

Page 4 of 4

Improved vascular endothelial function after oral B vitamins: An effect mediated through reduced concentrations of free plasma homocysteine.

BACKGROUND: Hyperhomocysteinemia is an independent risk factor for coronary heart disease (CHD). Dietary supplementation with B vitamins lowers plasma homocysteine by up to 30%. However, little is known about the potential beneficial effects of homocysteine lowering on vascular function in patients with CHD. METHODS AND RESULTS: We investigated 89 men with CHD (aged 56 [range 39 to 67] years). Brachial artery flow-mediated dilatation (endothelium dependent) and nitroglycerin-induced dilatation (endothelium independent) were measured before and 8 weeks after treatment with either (1) folic acid (5 mg) and vitamin B12 (1 mg) daily (n=59) or (2) placebo (n=30). Total, protein-bound, and free plasma homocysteine, serum folate, and vitamin B12 were measured at baseline and at 8 weeks. Flow-mediated dilatation improved after treatment with B vitamins (2.5+/-3.2% to 4.0+/-3.7%, P:=0.002) but not placebo (2.3+/-2.6% to 1.9+/-2.6%, P:=0.5). Vitamin therapy lowered plasma concentrations of total homocysteine (from 13.0+/-3.4 to 9.3+/-1.9 micromol/L, P:<0.001), protein-bound homocysteine (from 8.7+/-2.8 to 6.2+/-1.4 micromol/L, P:<0.001), and free homocysteine (from 4.3+/-1.2 to 3.0+/-0.6 micromol/L, P:<0.001) and raised concentrations of serum folate (from 10.3+/-4.3 to 31.2+/-10.8 ng/mL, P:<0.001) and vitamin B12 (from 314+/-102 to 661+/-297 pg/mL, P:<0.001). In regression analysis, improved flow-mediated dilatation correlated closely with the reduction in free plasma homocysteine (r=-0.26, P:=0.001), independent of changes in protein-bound homocysteine, folate, and vitamin B12. Nitroglycerin-induced dilatation was unchanged after both B vitamins and placebo. CONCLUSIONS: Folic acid and vitamin B12 supplementation improves vascular endothelial function in patients with CHD, and this effect is likely to be mediated through reduced concentrations of free plasma homocysteine concentrations. Our data support the view that lowering homocysteine, through B vitamin supplementation, may reduce cardiovascular risk.

Circulation 2000 Nov 14;102(20):2479-83

Serum folate and cardiovascular disease mortality among US men and women.

BACKGROUND: Folate has been linked to cardiovascular disease (CVD) through its role in homocysteine metabolism. OBJECTIVE: To assess the relationship between serum folate and CVD mortality. DESIGN: In this prospective study, serum folate concentrations were measured on a subset of adults during the Second National Health and Nutrition Examination Survey (1976-1980) and vital status ascertained after 12 to 16 years. SETTING AND PATIENTS: A national probability sample consisting of 689 adults who were 30 to 75 years of age and did not have a history of CVD at baseline. MAIN OUTCOME MEASURE: Vital status was determined by searching national databases that contained information about US decedents. RESULTS: The associations between serum folate and CVD and all-cause mortality differed by diabetes status (P =.04 and P =.03, respectively). Participants without diabetes in the lowest compared with the highest serum folate tertile had more than twice the risk of CVD mortality after adjustment for age and sex (relative risk [RR], 2.64; 95% confidence interval [CI], 1.15-6.09). This increased risk for participants in the lowest tertile was attenuated after adjustment for CVD risk factors (RR, 2.28; 95% CI, 0.96-5.40). Serum folate tertiles were not significantly associated with total mortality, although the age- and sex-adjusted risk was increased for participants in the lowest compared with highest tertile (RR, 1.74; 95% CI, 0.96-3.15). Risk estimates for participants with diabetes were unstable because of the small sample size (n = 52). CONCLUSION: These data suggest that low serum folate concentrations are associated with an increased risk of CVD mortality among adults who do not have diabetes.

Arch Intern Med 2000 Nov 27;160(21):3258-62

Low serum folate but normal homocysteine levels in patients with atherosclerotic vascular disease and matched healthy controls.

Mild hyperhomocysteinemia has been considered a cardiovascular risk factor. However, recent prospective studies have not demonstrated that hyperhomocysteinemia or the underlying genetic defect on methylentetrahydrofolate reductase is associated with a higher risk of coronary or peripheral artery disease. We compared serum homocysteine, folate, and vitamin B12 levels of patients with coronary and peripheral vascular disease with those of age- and sex-matched healthy individuals. Subjects taking multivitamins, with diabetes mellitus, or serum creatinine levels over 1.5 mg/dL were excluded from the study. Homocysteine was measured by fluorimetric high-performance liquid chromatography. Serum folate and vitamin B12 levels were measured by an ion-capture method. We studied 32 patients with peripheral vascular disease (10 female), aged 69.6 +/- 11 y, 24 age- and sex-matched control subjects, 52 patients with coronary artery disease (7 female), aged 59.5 +/- 10.4 y, and 42 age- and sex-matched control subjects. Serum homocysteine levels were 11.7 +/- 7.4 and 9.3 +/- 4.5 micromol/L in vascular patients and in the control counterparts, respectively (not significant). The levels for coronary patients and the control counterparts were 9.0 +/- 3.9 and 8.6 +/- 3.6 micromol/L, respectively (not significant). Folate levels were 4.48 +/- 2.42 and 7.14 +/- 4.04 ng/mL in vascular patients and control subjects, respectively (P < 0.02); the levels in coronary patients and control counterparts were 5.15 +/- 1.9 and 6.59 +/- 2.49 ng/mL, respectively (P < 0.01). No differences in vitamin B12 or tocopherol levels were observed between patients and control subjects. There were no differences in homocysteine levels, but lower serum folate levels were observed when comparing patients with atherosclerotic vascular disease and healthy control subjects.

Nutrition 2000 Jun;16(6):434-8

Dietary strategies for lowering homocysteine concentrations.

BACKGROUND: Elevated plasma total homocysteine (tHcy) concentrations are associated with increased risk of vascular disease, and there is a strong inverse association between dietary and blood folate and blood tHcy concentrations. Increased folate consumption may lower the risk of tHcy-mediated cardiovascular disease. OBJECTIVES: The objective was to determine the most appropriate means of increasing dietary folate to reduce plasma tHcy. DESIGN: Sixty-five free-living subjects aged 36 to 71 years with tHcy concentrations >/=9 micromol/L participated in a randomized, controlled trial to compare 3 approaches for increasing dietary folate to approximately 600 microg/d: folic acid supplementation, consumption of folic acid-fortified breakfast cereals, and increased consumption of folate-rich foods. RESULTS: An intake of 437 microg folic acid/d from supplements resulted in a 27-nmol/L increase in serum folate and a 21% reduction in tHcy, relative to the change in a control group. In subjects who consumed folic acid-fortified breakfast cereal, folate intake increased by an average of 298 microg, serum folate increased by 21 nmol/L, and tHcy concentrations decreased by 24%. Increased intakes of folate-rich foods resulted in a 418-microg increase in dietary folate, a 7-nmol/L increase in serum folate, and a 9% reduction in tHcy concentrations. The decrease in tHcy was negatively correlated (r = -0.66) with the increase in serum folate. CONCLUSIONS: Daily consumption of folic acid-fortified breakfast cereals and the use of folic acid supplements appear to be the most effective means of reducing tHcy concentrations. The reduction in tHcy was significantly negatively correlated with the increase in serum folate, which may be a useful marker for measuring dietary change.

Am J Clin Nutr 2000 Jun;71(6):1448-54

Association of folate intake and serum homocysteine in elderly persons according to vitamin supplementation and alcohol use.

BACKGROUND: The serum total homocysteine concentration (tHcy), an indicator of folate status and a possible risk factor for vascular disease, is elevated with impaired renal function and poor vitamin B12 status, which are common in the elderly. OBJECTIVE: Our objective was to determine the association between tHcy, folate intake, alcohol consumption, and other lifestyle factors in elderly persons. DESIGN: This cross-sectional study used linear regression to model changes in tHcy. Subjects were 278 men and women aged 66 to 94 years studied in 1993. RESULTS: Total folate intake was negatively associated with tHcy in models adjusted for age, sex, serum creatinine, and serum albumin. We found an interaction between food folate intake and supplement use. Food folate intake had an inverse dose-response relation with tHcy that was limited to nonusers of supplements. Predicted tHcy was 1.5 micromol/L lower in users of supplements containing folate and vitamin B12 than in nonusers and was independent of food folate intake. We found a positive dose-response relation of coffee and tea intake with tHcy, a positive association for alcohol intake of > or = 60 drinks/mo compared with low intake, and an interaction of alcohol use with folate intake and supplement use. Compared with alcohol users, nonusers had higher predicted tHcy and a lower inverse dose-response relation of food folate intake with tHcy. CONCLUSIONS: The inverse association between folate intake and tHcy was strongest among nonusers of supplements and among alcohol drinkers. Identifying modifiable factors related to tHcy, a possible risk factor for vascular disease, is especially important in elderly persons.

Am J Clin Nutr 2001 Mar;73(3):628-37

Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort.

BACKGROUND: Established determinants of fasting total homocysteine (tHcy) concentration include folate and vitamin B12 status, serum creatinine concentration, and renal function. OBJECTIVE: Our objective was to examine the relation between known and suspected determinants of fasting plasma tHcy in a population-based cohort. DESIGN: We examined the relations between fasting plasma tHcy concentrations and nutritional and other health factors in 1960 men and women, aged 28 to 82 years, from the fifth examination cycle of the Framingham Offspring Study between 1991 and 1994, before the implementation of folic acid fortification. RESULTS: Geometric mean tHcy was 11% higher in men than in women and 23% higher in persons aged > or = 65 y than in persons aged < 45 y (P < 0.001). tHcy was associated with plasma folate, vitamin B12, and pyridoxal phosphate (P for trend < 0.001). Dietary folate, vitamin B-6, and riboflavin were associated with tHcy among non-supplement users (P for trend < 0.01). The tHcy concentrations of persons who used vitamin B supplements were 18% lower than those of persons who did not (P < 0.001). tHcy was positively associated with alcohol intake (P for trend = 0.004), caffeine intake (P for trend < 0.001), serum creatinine (P for trend < 0.001), number of cigarettes smoked (P for trend < 0.001), and antihypertensive medication use (P < 0.001). CONCLUSIONS: Our study confirmed, in a population-based setting, the importance of the known determinants of fasting tHcy and suggested that other dietary and lifestyle factors, including vitamin B6, riboflavin, alcohol and caffeine intakes as well as smoking and hypertension, influence circulating tHcy concentrations.

Am J Clin Nutr 2001 Mar;73(3):613-21

Vitamin intervention for stroke prevention (VISP) trial: rationale and design.

Elevated plasma levels of homocyst(e)ine [H(e)] are surprisingly common and strongly associated with endothelial dysfunction and a marked increase in vascular risk. Treatment with a combination of folic acid, pyridoxine (vitamin B6) and cobalamin (vitamin B12) reduces plasma H(e) levels in most cases, restores endothelial function, and regresses carotid plaque, but there is no evidence that such treatment will reduce clinical events. The Vitamin Intervention for Stroke Prevention (VISP) study is a double-masked, randomized, multicenter clinical trial designed to determine if, in addition to best medical/surgical management, high-dose folic acid, vitamin B6, and vitamin B12 supplements will reduce recurrent stroke compared to lower doses of these vitamins. Patients at least 35 years old with a nondisabling ischemic stroke within 120 days, and screening plasma H(e) > the 25th percentile of benchmark population data are eligible. Secondary endpoints are myocardial infarction or fatal coronary heart disease. This paper describes the design and rationale of the study.

Neuroepidemiology 2001 Feb;20(1):16-25

Multivitamin/mineral supplementation improves plasma B-vitamin status and homocysteine concentration in healthy older adults consuming a folate-fortified diet.

Elevated homocysteine has been identified as an independent risk factor for cardiovascular and cerebrovascular disease. Although multivitamin use has been associated with low plasma homocysteine concentrations in several observational studies, no clinical trials have been conducted using multivitamin/mineral supplements to lower homocysteine. We determined whether a multivitamin/mineral supplement formulated at about 100% Daily Value will further lower homocysteine concentration and improve B-vitamin status in healthy older adults already consuming a diet fortified with folic acid. In this randomized, double-blind, placebo-controlled trial, 80 free-living men and women aged 50 to 87 years with total plasma homocysteine concentrations of > or =8 micromol/L received either a multivitamin/mineral supplement or placebo for 56 d while consuming their usual diet. After the 8-wk treatment, subjects taking the supplement had significantly higher B-vitamin status and lower homocysteine concentration than controls (P: < 0.01). Plasma folate, pyridoxal phosphate (PLP) and vitamin B12 concentrations were increased 41.6, 36.5 and 13.8%, respectively, in the supplemented group, whereas no changes were observed in the placebo group. The mean homocysteine concentration decreased 9.6% in the supplemented group (P: < 0.001) and was unaffected in the placebo group. There were no significant changes in dietary intake during the intervention. Multivitamin/mineral supplementation can improve B-vitamin status and reduce plasma homocysteine concentration in older adults already consuming a folate-fortified diet.

Nutritional and botanical interventions to assist with the adaptation to stress

Altern Med Rev 1999 Aug;4(4):249-65

Prolonged stress, whether a result of mental/emotional upset or due to physical factors such as malnutrition, surgery, chemical exposure, excessive exercise, sleep deprivation, or a host of other environmental causes, results in predictable systemic effects. The systemic effects of stress include increased levels of stress hormones such as cortisol, a decline in certain aspects of immune system function such as natural killer cell cytotoxicity or secretory-IgA levels, and a disruption of gastrointestinal microflora balance. These systemic changes might be a substantial contributor to many of the stress-associated declines in health. Based on human and animal research, it appears a variety of nutritional and botanical substances-such as adaptogenic herbs, specific vitamins including ascorbic acid, vitamins B1 and B6, the coenzyme forms of vitamin B5 (pantethine) and B12 (methylcobalamin), the amino acid tyrosine, and other nutrients such as lipoic acid, phosphatidylserine, and plant sterol/sterolin combinations-may allow individuals to sustain an adaptive response and minimize some of the systemic effects of stress.

Methylcobalamin decreases mRNA levels of androgen-induced growth factor in androgen-dependent Shionogi carcinoma 115 cells

Nutr Cancer 1999;35(2):195-201

Methylcobalamin (MeCbl) is an important enzyme cofactor required for methionine synthase activity. It also inhibits, in a dose-dependent manner, the proliferation of an androgen-dependent cell line, SC-3, derived from an androgen-dependent mouse mammary tumor (Shionogi carcinoma 115). In SC-3 cells, androgen induces the production of androgen-induced growth factor (AIGF), an autocrine growth factor increasing the proliferation of SC-3 cells. MeCbl treatment suppressed the androgen-induced, AIGF-mediated growth of SC-3 cells, as well as the androgen-induced increase of AIGF mRNA. In SC-3 cells, androgen receptors linked with androgen form complexes that tightly bind DNA and act as transcription factors in the nucleus to regulate the expression of specific genes such as AIGF. The number and dissociation constants of androgen receptors in control and MeCbl-treated SC-3 cells were the same. Similarly, the extent of binding of normal androgen receptors in nuclei from control and MeCbl-treated cells was virtually identical. The androgen receptors from control and MeCbl-treated cells showed similar capacities for conversion to a form that tightly binds to DNA on heat activation. These results suggest that the reduction of AIGF mRNA, subsequent to the nuclear binding of androgen receptors, may be a partial cause of the growth-inhibitory activity of MeCbl in SC-3 cells.

Can reduced folic acid and vitamin B12 levels cause deficient DNA methylation producing mutations which initiate atherosclerosis?

Med Hypotheses 1999 Nov;53(5):421-4

Atherosclerosis of the vascular system has classically been attributed to elevated serum cholesterol concentrations. Recently, it has been found that reduced serum levels of folic acid, vitamin B12, and vitamin B6 are related to the etiology of atherosclerosis and coronary heart disease. These deficiencies lead to inadequate production of S-adenosyl-methionine, creating a condition of hypomethylation. It is hypothesized that this causes hypomethylation of the DNA in cells in the arterial intima resulting in mutation and proliferation of smooth-muscle cells which lead to the formation of atheroma. It is further hypothesized that such action can be reversed by supraphysiological doses of these three vitamins to reduce or remove existing atheroma. It is recommended that all patients suffering from atherosclerosis and having deficiencies of any of these three vitamins and/or an elevation of serum homocysteine receive supplementation to prevent worsening of their condition.

What level of plasma homocyst(e)ine should be treated? Effects of vitamin therapy on progression of carotid atherosclerosis in patients with homocyst(e)ine levels above and below 14 micromol/L

Am J Hypertens 2000 Jan;13(1 Pt 1):105-10

High levels of plasma homocyst(e)ine (H[e]) are associated with increased vascular risk. Treatment is being contemplated, but the level at which patients should be treated is not known. We compared the response of carotid plaque to vitamin therapy in patients with H(e) above and below 14 micromol/L, a level commonly regarded as high enough to warrant treatment. Two-dimensional B-mode ultrasound measurement of carotid plaque was used to assess the response to vitamin therapy with folic acid 2.5 mg, pyridoxine 25 mg, and cyanocobalamin 250 microg daily, in 101 patients with vascular disease (51 with initial plasma levels above, and 50 below 14 micromol/L). Among patients with plasma H(e) >14 micromol/L, the rate of progression of plaque area was 0.21 +/- 0.41 cm2/year before vitamin therapy, and -0.049 +/- 0.24 cm2/year after vitamin therapy (P2 = .0001; paired t test). Among patients with levels <14 micromol/L, the rate of progression of plaque was 0.13 +/- 0.24 cm2/year before vitamin therapy and -0.024 +/- 0.29 cm2/year after vitamin therapy (P2 = .022, paired t test). The change in rate of progression was -0.15 +/- .44 cm2/year below 14 micromol/L, and -0.265 +/- 0.46 cm2/year above 14 micromol/L (P = 0.20). Vitamin therapy regresses carotid plaque in patients with H(e) levels both above and below 14 micromol/L. These observations support a causal relationship between homocyst(e)ine and atherosclerosis and, taken with epidemiologic evidence, suggest that in patients with vascular disease, the level to treat may be <9 micromol/L.

Vitamin B 12 deficiency in the aged

Presse Med 1999 Oct 23;28(32):1767-70

A COMMON CONDITION: Vitamin B12 deficiency is common in the elderly. Search for deficiency should be undertaken whenever the clinical situation could lead to vitamin deficiency whether macrocytic anemia is present or not as its development may come late. PATHOPHYSIOLOGICAL IMPLICATIONS: The potential relationships between degenerative neuropsychiatric disorders and cerebrovascular or cardiovascular disease, mainly via hyperhomocysteinemia, emphasize the importance of searching for vitamin B12 deficiency in the elderly. SPECIFIC CAUSES: In the elderly, it is important to recognize specific causes of vitamin B12 deficiency, mainly resulting from vitamin malabsorption.

Vitamin B12 deficiency in the elderly

Annu Rev Nutr 1999;19:357-77

Vitamin B12 deficiency is estimated to affect 10%-15% of people over the age of 60, and the laboratory diagnosis is usually based on low serum vitamin B12 levels or elevated serum methylmalonic acid and homocysteine levels. Although elderly people with low vitamin B12 status frequently lack the classical signs and symptoms of vitamin B12 deficiency, e.g. megaloblastic anemia, precise evaluation and treatment in this population is important. Absorption of crystalline vitamin B12 does not decline with advancing age. However, compared with the younger population, absorption of protein-bound vitamin B12 is decreased in the elderly, owing to a high prevalence of atrophic gastritis in this age group. Atrophic gastritis results in a low acid-pepsin secretion by the gastric mucosa, which in turn results in a reduced release of free vitamin B12 from food proteins. Furthermore, hypochlorhydria in atrophic gastritis results in bacterial overgrowth of the stomach and small intestine, and these bacteria may bind vitamin B12 for their own use. The ability to absorb crystalline vitamin B12 remains intact in older people with atrophic gastritis. The 1998 recommended daily allowance for vitamin B12 is 2.4 micrograms, but elderly people should try to obtain their vitamin B12 from either supplements or fortified foods (e.g. fortified ready-to-eat breakfast cereals) to ensure adequate absorption from the gastrointestinal tract. Because the American food supply is now being fortified with folic acid, concern is increasing about neurologic exacerbation in individuals with marginal vitamin B12 status and high-dose folate intake.

Plasma homocysteine is a sensitive marker for tissue deficiency of both cobalamines and folates in a psychogeriatric population

Dement Geriatr Cogn Disord 1999 Nov-Dec;10(6):476-82

The concentration of blood folates was decreased and the concentration of plasma homocysteine was increased in a psychogeriatric population, whereas the concentrations of methylmalonic acid or serum cobalamins were not changed compared with healthy subjects. The highest frequency of abnormal values was shown by plasma homocysteine concentration, which was increased in 88 of 168 patients. In 29 of these 88 patients increased concentration of plasma homocysteine could possibly be attributed to tissue cobalamin deficiency. One patient had only a lowered concentration of blood folate. Thirteen patients had elevated concentrations of serum creatinine which could explain increased plasma homocysteine concentration. Even if the remaining patients (n = 45) had normal vitamin levels in circulation, the increased plasma homocysteine concentration in most cases must be attributed to tissue deficiency of cobalamins and/or folates. Thus, many patients with increased plasma homocysteine concentrations need further vitamin supplementation despite their normal vitamin levels in serum and blood.