BMJ, 32(3):634-8 1997 Mar 1

OBJECTIVE: To examine the association between plasma vitamin C concentrations and the risk of acute myocardial infarction. DESIGN: Prospective population study. SETTING: Eastern Finland. SUBJECTS: 1605 randomly selected men aged 42, 48, 54, or 60 who did not have either symptomatic coronary heart disease or ischaemia on exercise testing at entry to the Kuopio ischaemic heart disease risk factor study in between 1984 and 1989. MAIN OUTCOME MEASURES: Number of acute myocardial infarctions; fasting plasma vitamin C concentrations at baseline. RESULTS: 70 of the men had a fatal or non-fatal myocardial infarction between March 1984 and December 1992.91 men had vitamin C deficiency (plasma ascorbate < 11.4 mumol/l, or 2.0 mg/l), of whom 12 (13.2%) had a myocardial infarction; 1514 men were not deficient in vitamin C, of whom 58 (3.8%) had a myocardial infarction. In a Cox proportional hazards model adjusted for age, year of examination, and season of the year examined (August to October v rest of the year) men who had vitamin C deficiency had a relative risk of acute myocardial infarction of 3.5 (95% confidence interval 1.8 to 6.7, P = 0.0002) compared with those who were not deficient. In another model adjusted additionally for the strongest risk factors for myocardial infarction and for dietary intakes of tea fibre, carotene, and saturated fats men with a plasma ascorbate concentration < 11.4 mumol/l had a relative risk of 2.5 (1.3 to 5.2, P = 0.0095) compared with men with higher plasma vitamin C concentrations. CONCLUSIONS: Vitamin C deficiency, as assessed by low plasma ascorbate concentration, is a risk factor for coronary heart disease.

Atherosclerosis, 1996 Jul, 124:1, 75-81

In this study we have measured circulating levels of autoantibodies to cardiolipin and oxidised low-density lipoprotein (ox-LDL) and correlated these with plasma concentrations of the anti-oxidant nutrients vitamin C, vitamin E and beta-carotene, in a group (79) of asymptomatic, male cigarette smokers and in non-smoking control subjects. Cigarette smoking, a well-known risk factor for development of atherosclerosis, was found to be associated with moderately elevated levels of autoantibodies to both cardiolipin and ox-LDL. Increased levels of these autoantibodies were most evident in the older smokers (> 30 years) and were significantly and inversely correlated with plasma vitamin C, but not with vitamin E or beta-carotene. Absorption studies designed to investigate the specificity of these autoantibodies demonstrated a high degree of cross-reactivity of cardiolipin antibodies with ox-LDL, while antibodies to the oxidatively modified lipoprotein tended to be specific for this antigen. These findings suggest that cigarette smoking promotes formation of autoantibodies to both cardiolipin and ox-LDL and that these may be involved in the initiation and/or perpetuation of atherosclerosis. Dietary intake of vitamin C may be a determinant of susceptibility to development of this cardiovascular disorder.

Diabetes, 41(2):167-73 1992 Feb

Twelve nondiabetic subjects consumed 1 g/day vitamin C for 3 mo. A fasting blood sample was taken at the start of the study and at the end of each month for the measurement of plasma and intraerythrocyte glucose, vitamin C, glycosylated hemoglobin (affinity chromatography and electrophoresis), and glycosylated albumin (affinity chromatography). Although there were no significant changes in fasting glycemia, glycosylated hemoglobin (affinity chromatography) decreased 18%, from 6.18 +/- 0.48% (mean +/- SD) at the start to 5.05 +/- 0.50% (P less than 0.0001) after 3 mo, whereas, HbA1 measured by electrophoresis increased 16%, from 6.17 +/- 0.61 to 7.16 +/- 0.59% (P less than 0.0001) in this period. Glycosylated albumin decreased 33%, from 1.56 +/- 0.24 to 1.04 +/- 1.01% (P less than 0.0001) after 3 mo. This discrepancy between glycosylated hemoglobin measured by electrophoresis and affinity chromatography was due to methodological differences between the two techniques, with affinity chromatography measuring "true glycosylated hemoglobin. The greater decrease found with glycosylated albumin was probably due to the different distribution of vitamin C between plasma and within the erythrocyte, levels after 1 mo of supplementation being 109 +/- 19 and 59 +/- 9 microM, respectively (P less than 0.001). This indicates that administration of oral vitamin C may inhibit the glycosylation of proteins in vivo by a competitive mechanism.

Am J Clin Nutr, 1997 Oct, 66:4, 911-6

We designed the present study to examine the cross-sectional relation between age-related lens opacities and vitamin C supplement use over a 10-12-y period before assessment of lens status in women without diagnosed cataract or diabetes. This design avoids biased measurement of nutrient intake that results when knowledge of lens opacities influences nutrition-related behavior or its reporting. The participants were 247 Boston-area women aged 56-71 y selected from the Nurses' Health Study cohort with oversampling of women with high or low vitamin C intakes. Lens opacities were graded with the Lens Opacification Classification System II. Use of vitamin C supplements for > or = 10 y (n = 26) was associated with a 77% lower prevalence of early lens opacities (odds ratio: 0.23; 95% CI: 0.09, 0.60) at any lens site and a 83% lower prevalence of moderate lens opacities (odds ratio: 0.17; 95% CI: 0.03, 0.85) at any lens site compared with women who did not use vitamin C supplements (n = 141) after adjustment for age and other potentially confounding variables. Women who consumed vitamin C supplements for < 10 y showed no evidence of a reduced prevalence of early opacities. These data, together with data from earlier experimental and epidemiologic studies, suggest that long-term consumption of vitamin C supplements may substantially reduce the development of age-related lens opacities.

JAMA, 1997 Nov, 278:20, 1682-6

CONTEXT: Much has been written about the potential role of antioxidants in the prevention of atherosclerosis. OBJECTIVE: To assess the short-term effect of a single high-fat meal with and without pretreatment with antioxidant vitamins on endothelial function in healthy, normocholesterolemic subjects. DESIGN: Observer-blinded randomized trial. SETTING: University hospital. PARTICIPANTS: Twenty healthy, normocholesterolemic (total and low-density lipoprotein cholesterol <5.2 mmol/L and <3.4 mmol/L [<200 mg/dL and <130 mg/ dL], respectively), male (7) and female (13) hospital employee volunteers, aged 24 to 54 years. INTERVENTION: Three randomly administered breakfasts: (1) a high-fat meal (3766 J [900 calories], 50 g of fat); (2) a low-fat meal (3766 J [900 calories], 0 g of fat); and (3) a high-fat meal and pretreatment with oral administration of vitamins C (1 g) and E (800 IU) (high-fat meal with vitamins). A subgroup of 10 subjects also ate the low-fat meal with the same vitamin pretreatment (low-fat meal with vitamins). MAIN OUTCOME MEASURE: High-resolution ultrasound assessed flow-mediated (endothelium-dependent) brachial artery vasodilation measured as percent diameter change before and hourly for 6 hours following each meal. RESULTS: Flow-mediated vasodilation fell from a mean+/-SD of 20%+/-8% before to 12%+/-6%, 10%+/-6%, and 8%+/-9% at 2, 3, and 4 hours, respectively, after the high-fat meal (P<.001). No significant changes in flow-mediated vasodilation occurred after the low-fat meal, high-fat meal with vitamins, or low-fat meal with vitamins. The change in flow-mediated vasodilation after the low-fat and high-fat meals correlated inversely with the 2-hour postprandial change in triglyceride levels (r=-0.54; P<.001). CONCLUSION: A single high-fat meal transiently reduces endothelial function for up to 4 hours in healthy, normocholesterolemic subjects, probably through the accumulation of triglyceride-rich lipoproteins. This decrease is blocked by pretreatment with antioxidant vitamins C and E, suggesting an oxidative mechanism.

Immunopharmacology, 39(1):31-8 1998 Mar

We investigated the effect of EPC-K1, which is a phosphodiester compound of vitamin E and vitamin C, on NF-kappaB activity in human cultured astrocytoma cells T98G. In TNFalpha-stimulated T98G cells, treatment with EPC-K1 inhibited both DNA binding activity and transactivation of NF-kappaB in a dose-dependent manner, and the suppressive effect of EPC-K1 was stronger than either that of vitamin E or vitamin C. Moreover, we showed that in TNFalpha-stimulated T98G cells treatment with EPC-K1 repressed NF-kappaB-dependent activation of the human immunodeficiency virus 1 promoter. In contrast, TNFalpha-induced activation of the human immunodeficiency virus 1 promoter was not completely inhibited by either treatment with vitamin E or vitamin C. We, thus, suggest that EPC-K1 is considered to be one of the inhibitory agents of NF-kappaB.

J Am Acad Dermatol, 38(1):45-8 1998 Jan

BACKGROUND: UV radiation causes acute adverse effects like sunburn, photosensitivity reactions, or immunologic suppression, as well as long-term sequelae like photoaging or malignant skin tumors. UV radiation induces tissues to produce reactive oxygen species, eicosanoids and cytokines. Inhibition of these mediators might reduce skin damage. Antioxidants such as ascorbic acid and d-alpha-tocopherol have been found to be photoprotective in some in vitro studies and animal experiments. OBJECTIVE: Our purpose was to assess the protective effect of systemic vitamins C and E against sunburn in human beings. METHODS: In a double-blind placebo-controlled study, each of 10 subjects took daily either 2 gm of ascorbic acid (vitamin C) combined with 1000 IU of d-alpha-tocopherol (vitamin E) or placebo. The sunburn reaction before and after 8 days of treatment was assessed by determination of the threshold UV dose for eliciting sunburn (minimal erythema dose [MED]) and by measuring the cutaneous blood flow of skin irradiated with incremental UV doses against that of nonirradiated skin. RESULTS: The median MED of those taking vitamins increased from 80 to 96.5 mJ/cm2 (p < 0.01), whereas it declined from 80 to 68.5 mJ/cm2 in the placebo group. Cutaneous blood flow changed significantly (p < 0.05) for most irradiation doses with decreases in those given vitamins and increases in the placebo group. CONCLUSION: Combined vitamins C and E reduce the sunburn reaction, which might indicate a consequent reduced risk for later sequelae of UV-induced skin damage. The increase of sunburn reactivity in the placebo group could be related to "priming" by the previous UV exposure.

Tissue Cell, 1996 Dec, 28:6, 687-701

Transmission and scanning electron microscopy and flow cytometry were employed to characterize the cytotoxic effects of vitamin C (VC), vitamin K3 (VK3), or VC-VK3 combinations on a human prostate carcinoma cell line (DU145) following a 1-h vitamin treatment and a 24-h incubation in culture medium. Cells exposed to VC exhibited membranous blebs, aberrant microvillar morphology, mitochondria with swollen cristae and intramitochondrial deposits, as well as nucleoli with segregated components. VK3-treated cells displayed a damaged cytoskeleton and membranes, a cytoplasm which contained large lumen, condensed polysomes, and severely damaged mitochondria with residual bodies, and nuclei which exhibited chromatic condensation, pyknosis, and karyolysis. VC-VK3-treated cells exhibited characteristics consistent with necrosis, i.e. swollen mitochondria and swollen, achromatic nuclei with marginated chromatin and intact envelopes, while other cells displayed characteristics consistent with apoptosis, i.e. expulsion of organelle-containing blebs, margination of nuclear chromatin, and segregation of nucleolar components. Vitamin treatment also decreased DNA synthesis, induced a S/G2 block in the cell cycle, and resulted in the accumulation of fragmented DNA. These results suggested that increased oxidative stress, subsequent membrane damage, and DNA fragmentation were responsible for enhanced cytotoxicity of the vitamin combination.

Am J Clin Nutr, 1995 Dec, 62:6 Suppl, 1385S-1392S

Antioxidant nutrients have been hypothesized to be protective against cancer. Vitamin C is a major circulating water-soluble antioxidant, and vitamin E is a major lipid-soluble antioxidant. Many case-control and cohort studies have related cancer risk to estimates of nutrient intake derived from food intake reports. Diets high in fruit and vegetables, and hence high in vitamin C, have been found to be associated with lower risk for cancers of the oral cavity, esophagus, stomach, colon, and lung. Diets high in added vegetable oils, and hence high in vitamin E, have been less consistently shown to be associated with cancer protection. This may be because vitamin E offers less protection against cancer or because the estimation of vitamin E intake is less accurate than is the estimation of vitamin C intake. In contrast with the findings from epidemiologic studies based on foods, observational studies of nutrients consumed in supplements and recent experimental trials provide little support for a strong protective role for vitamins C or E against cancer. If vitamins C or E are indeed protective against cancer, that protection may derive from their consumption in complex mixtures with other nutrients and with other bioactive compounds as found in the matrix provided by whole foods.

Prostate, 1997 Aug, 32:3, 188-95

BACKGROUND: Many studies describe the protective role of vitamin C (ascorbic acid) against cancer development and in treatment of established cancer. The present study investigated whether ascorbic acid demonstrates a therapeutic benefit for prostate cancer. METHODS: Androgen-independent (DU145) and androgen-dependent (LNCaP) human prostate cancer cell lines were both treated in vitro with vitamin C (0-10 mM). Cell counts, cell viability, and thymidine incorporation into DNA were determined. RESULTS: Treatment of DU145 and LNCaP cells with vitamin C resulted in a dose- and time-dependent decrease in cell viability and thymidine incorporation into DNA. Vitamin C induced these changes through the production of hydrogen peroxide; addition of catalase (100-300 units/ml), an enzyme that degrades hydrogen peroxide, inhibited the effects of ascorbic acid. Superoxide dismutase, an enzyme that dismutates superoxide and generates hydrogen peroxide, did not prevent decreases in cell number and DNA synthesis, suggesting further the involvement of hydrogen peroxide in vitamin C-induced changes. These results clearly indicate that reactive oxygen species (ROS) are involved in vitamin C-induced cell damage. However, that singlet oxygen scavengers such as sodium azide and hydroquinone and hydroxyl radical scavengers such as D-mannitol and DL-alpha-tocopherol did not counteract the effects of ascorbic acid on thymidine incorporation suggests that vitamin C-induced changes do not occur through the generation of these ROS. CONCLUSIONS: Vitamin C inhibits cell division and growth through production of hydrogen peroxide, which damages the cells probably through an as yet unidentified free radical(s) generation/mechanism. Our results also suggest that ascorbic acid is a potent anticancer agent for prostate cancer cells.

Circulation, 1997 Sep, 96:5, 1513-9

BACKGROUND: There is evidence for increased formation of free radicals in patients with hypertension, raising the possibility that NO is inactivated by free radicals, which impairs coronary endothelial function. Therefore, we tested the hypothesis that the antioxidant vitamin C could improve abnormal endothelial function of coronary arteries in patients with hypertension. METHODS AND RESULTS: In 22 hypertensive patients without relevant coronary artery stenoses, endothelium-dependent vascular responses of the left anterior descending coronary artery (LAD) to acetylcholine (0.01, 0.1, and 1.0 micromol/L) were determined before and immediately after intravenous infusion of 3 g vitamin C (17 patients) or placebo (5 patients). In a subgroup of 10 patients, papaverine-induced flow-dependent vasodilation (FDD) was measured before and after vitamin C (5 patients) or placebo (5 patients) infusion. Segmental responses of the coronary artery luminal area were analyzed with quantitative coronary angiography. Before vitamin C infusion, the mean changes of LAD luminal areas at increasing doses of acetylcholine were -6.1+/-2.2%, -15.2+/-4.9%, and -33.9+/-8.1% (negative numbers symbolize vasoconstriction) and during FDD, 5.4+/-1.0%. The vasoconstrictor response during acetylcholine was reduced and FDD was augmented by vitamin C. After vitamin C infusion, LAD luminal areas changed by -3.2+/-2.3%, -5.8+/-3.6%, and -10.2+/-5.6% (P<.05, acetylcholine) and 17.8+/-2.8% (P<.05, FDD). Doppler flow velocity (during baseline, acetylcholine, and FDD) was not significantly affected by vitamin C. CONCLUSIONS: Vitamin C improves the endothelium-dependent vasomotor capacity of coronary arteries in patients with hypertension and patent coronary arteries. These findings suggest that increased oxidative stress contributes to endothelial dysfunction in hypertensive patients.

Arterioscler Thromb Vasc Biol, 1997 Aug, 17:8, 1583-90

Oxidative modification of LDL by vascular cells has been proposed as a mechanism by which LDL becomes atherogenic. Antioxidants that can prevent LDL oxidation may therefore act as antiatherogens. We used endothelial cells (ECs) from human aortas (HAECs), human saphenous veins (HSECs), and bovine aortas (BAECs) to investigate the role of intracellular and extracellular vitamin C (ascorbate) in EC-mediated LDL modification. Incubation of LDL (0.1 mg protein per milliliter) with confluent HAECs in Ham's F-10 medium led to time-dependent modification of the lipoprotein. In contrast, incubation of LDL with HAECs in medium 199, which does not contain redox-active transition metal ions, did not lead to LDL modification. Both HAEC-mediated and cell-free LDL modifications in Ham's F-10 medium were strongly inhibited in a time- and dose-dependent manner by physiological concentrations of ascorbate. Confluent HAECs cultured under conventional conditions contained very little intracellular ascorbate (< 0.5 nmol/mg protein) but could be loaded with up to 20 nmol ascorbate per milligram protein in a time- and concentration-dependent manner. Ascorbate-loaded HAECs exhibited a lower capacity to modify LDL than did non-ascorbate-loaded control cells. When LDL was incubated with HSECs instead of HAECs, similar time- and concentration-dependent inhibitory effects on LDL modification of intracellular and extracellular ascorbate were observed. In contrast to human ECs, BAECs did not take up vitamin C and therefore only coincubation but not preincubation with ascorbate inhibited BAEC-mediated LDL modification. Our data show that enrichment of human vascular ECs with vitamin C lowers their capacity to modify LDL. In addition, extracellular vitamin C strongly inhibits EC-mediated, metal ion-dependent atherogenic modification of LDL.

Br J Clin Pharmacol, 1997 Jul, 44:1, 94-7

AIMS: Vitamin C (ascorbic acid) is a powerful antioxidant but there is limited information on its ability to prevent LDL oxidation and its interaction with other natural antioxidants in vivo. We assessed the effect of 4 weeks pharmacological supplementation with vitamin C 1 g day(-1) on copper induced LDL oxidation and lipid peroxidation. METHODS: Blood samples were obtained at baseline and at the end of 4 weeks supplementation from 11 healthy non-smokers and also from nine control subjects. Plasma lipid peroxides were measured as malondialdehyde (MDA) by h.p.l.c. The relationship between vitamin C and two other important antioxidants, vitamin E and glutathione, was also studied. RESULTS: There was no difference in baseline values between the two groups and the oxidizability of LDL, assessed as the lag phase of conjugated dienes production and the formation of thiobarbituric acid reactive substances (TBARS), remained unchanged after 4 weeks. In the vitamin C supplemented group only, there was a 2.2-fold increase in plasma ascorbic acid level and a 28% increase in red cell reduced glutathione (GSH) (P<0.001). Vitamin E, measured as alpha-tocopherol, in red cells increased significantly (P<0.02) and plasma MDA was reduced (P<0.01). CONCLUSIONS: Vitamin C did not alter LDL oxidation but it may have a protective role against lipid peroxidation as shown by decreased plasma MDA levels and enhanced vitamin E and GSH status.

Circulation, 1997 Jun, 95:12, 2617-22

BACKGROUND: Endothelium-dependent vasodilation is impaired in humans with hypercholesterolemia. Oxidative degradation of endothelium-derived nitric oxide plays a major role in endothelial dysfunction in animal models of hypercholesterolemia. To assess whether this mechanism is relevant to humans, we studied the effect of vitamin C, an antioxidant, on vasodilator function in forearm resistance vessels of patients with hypercholesterolemia. METHODS AND RESULTS: We studied 11 hypercholesterolemic and 12 healthy control subjects. Forearm blood flow was determined by venous occlusion plethysmography. Endothelium-dependent vasodilation was assessed by intra-arterial infusion of methacholine (0.3 to 10 micrograms/min). Endothelium-independent vasodilation was measured by intra-arterial infusion of nitroprusside (0.3 to 10 micrograms/min) and verapamil (10 to 300 micrograms/min). Forearm blood flow dose-response curves were determined for each drug before and during coadministration of vitamin C (24 mg/min). In hypercholesterolemic subjects, endothelium-dependent vasodilation to methacholine was augmented by coinfusion of vitamin C (P = .001); in contrast, endothelium-independent vasodilation to nitroprusside and verapamil were not affected by coinfusion of vitamin C (P = .8 and P = .3, respectively). In control subjects, vitamin C administration did not alter endothelium-dependent vasodilation (P = .2). CONCLUSIONS: We conclude that vitamin C improves endothelium-dependent vasodilation in the forearm resistance vessels of patients with hypercholesterolemia. These findings suggest that nitric oxide degradation by oxygen-derived free radicals contributes to abnormal vascular reactivity in hypercholesterolemic humans.

Arch Immunol Ther Exp (Warsz), 1997, 45:1, 87-91

Although many epidemiological studies indicate protective effect of vitamin C against a variety of human malignancies its mechanism(s) of action is questionable. The presented results show that the part of its effect may be accomplished by mononuclear cells, as necessary participants in body defence. Namely, in a long-term in vitro assay we tested vitamin C influence on random migration ability of malignant pleural effusion mononuclears (PEM) obtained from breast cancer patients. Vitamin C in a dose- (50-500 micrograms) and time-dependent (4-44 h) manner inhibited PEM motility, suggesting that immobilization of cells in situ may contribute to its beneficial effect in human cancers.

Neuroepidemiology, 1997, 16:2, 69-77

The relations of dietary antioxidants vitamin C and beta-carotene to 30-year risk of stroke incidence and mortality were investigated prospectively in the Chicago Western Electric Study among 1,843 middle-aged men who remained free of cardiovascular disease through their second examination. Stroke mortality was ascertained from death certificates, and nonfatal stroke from records of the Health Care Financing Administration. During 46, 102 person-years of follow-up, 222 strokes occurred; 76 of them were fatal. After adjustment for age, systolic blood pressure, cigarette smoking, body mass index, serum cholesterol, total energy intake, alcohol consumption, and diabetes, relative risks (and 95% confidence intervals) for nonfatal and fatal strokes (n = 222) in highest versus lowest quartiles of dietary beta-carotene and vitamin C intake were 0.84 (0.57-1.24) and 0.71 (0.47-1.05), respectively. Generally similar results were observed for fatal strokes (n = 76). Although there was a modest decrease in risk of stroke with higher intake of beta-carotene and vitamin-C intake, these data do not provide definitive evidence that high intake of antioxidant vitamins decreases risk of stroke.

Int J Sport Nutr, 1997 Mar, 7:1, 1-9

Vitamin C (ascorbic acid) was supplemented (1 g/day) for 1 day and 2 weeks in the same subjects. Plasma thiobarbituric acid reacting substances (TBARS) and oxygen radical absorbance capacity (ORAC) before and after 30 min submaximal exercise were measured. Different vitamin C supplementations did not affect resting TBARS or ORAC. Following 30 min exercise, values for TBARS were 12.6 and 33% above rest with 1 day and 2 weeks of vitamin C supplementation, respectively, compared to 46% higher with placebo. ORAC did not significantly change (11%) after exercise with a placebo, nor when subjects were given vitamin C supplements for 1 day or 2 days (4.9% and 5.73%, respectively). TBARS:ORAC, a ratio representing oxidative stress, increased 32% (p < .05) with placebo compared to 5.8 and 25.8% with vitamin C supplements for 1 day and 2 weeks, respectively. It was concluded that exercise-induced oxidative stress was highest when subjects did not supplement with vitamin C compared to either 1 day or 2 weeks of vitamin C supplementation.

J Am Coll Nutr, 1996 Dec, 15:6, 586-91

OBJECTIVE: The purpose of this study was to determine whether carnitine metabolism or histamine degradation would be useful parameters for investigating the optimal requirement for vitamin C. METHODS: Twenty-two non-scorbutic subjects with subnormal vitamin C status (plasma vitamin C < 28 mumol/L) were placed on a metabolic diet low in vitamin C for 3 weeks and repleted with graded doses of vitamin C: 10, 30 and 60 mg vitamin C daily (group 1) or 10,125 and 250 mg vitamin C daily (group 2) for weeks 1, 2 and 3, respectively. Fasting blood samples were collected weekly and analyzed for plasma vitamin C, plasma free carnitine and blood histamine. RESULTS: Group 1 subjects remained in a subnormal vitamin C state throughout the 3-week study, and blood histamine and plasma free carnitine were not impacted by the experimental treatment. Plasma vitamin C in group 2 subjects rose significantly during the study, and these subjects finished the study with an ample vitamin C status indicative of vitamin C intakes above the recommended dietary allowance. Both blood histamine and plasma free carnitine were inversely related to vitamin C status in group 2 subjects. CONCLUSIONS: These data indicate that blood histamine and plasma free carnitine are altered in individuals with subnormal, non-scorbutic vitamin C status and provide evidence that metabolic changes independent of collagen metabolism occur prior to the manifestation of scurvy. Thus utilizing scurvy as an end-point to determine vitamin C requirements may not provide adequate vitamin C to promote optimal health and well-being.

Eur J Clin Nutr, 1996 Sep, 50:9, 573-9

OBJECTIVE: To examine the cross sectional relationship between respiratory function and plasma vitamin C. DESIGN: Cross sectional analysis. SETTING: Population based study. SUBJECTS: 835 Men and 1025 women aged 45 to 75 registered with GP practices in Norfolk. INTERVENTIONS: Completion of health and lifestyle questionnaire and attendance for a health check. MAIN OUTCOME MEASURES: Forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and non fasting plasma vitamin C. RESULTS: Plasma vitamin C was positively correlated, after adjustment for age and height, with both FEV1 (r = 0.17, P < 0.001) and FVC (r = 0.14, p < 0.001) in men. The association in women was weaker and not statistically significant. Adjusting for other possible factors and exclusion of various groups did not alter the observed associations. The differences in FEV1 and FVC in men, adjusted for age, height and cigarette smoking, for a 50 micromol/L difference in vitamin C were 0.22 litres (95% CI 0.10-0.33) and 0.23 litres (95% CI 0.09-0.37) respectively. The population distribution was shifted such that 12.1% of men with vitamin C levels < or = 30 micromol/L had an FEV1 of less than two litres, compared with 4.6% with levels > or = 60 micromol/L. CONCLUSIONS: These findings are consistent with other studies of vitamin C and respiratory function and suggest that vitamin C may be protective for lung function through the whole normal range of dietary intake and lung function.

Int J Sports Med, 1996 Jul, 17:5, 379-83

Several studies have observed an increased risk of respiratory infections in subjects doing heavy physical exercise. Vitamin C has been shown to affect some parts of the immune system, and accordingly it seems biologically conceivable that it could have effects on the increased incidence of respiratory infections caused by heavy physical stress. In this report the results of three placebo-controlled studies that have examined the effect of vitamin C supplementation on common cold incidence in subjects under acute physical stress are analyzed. In one study the subjects were school-children at a skiing camp in the Swiss Alps, in another they were military troops training in Northern Canada, and in the third they were participants in a 90 km running race. In each of the three studies a considerable reduction in common cold incidence in the group supplemented with vitamin C(0.6-1.0 g/day) was found. The pooled rate ratio (RR) of common cold infections in the studies was 0.50 (95% CI: 0.35-0.69) in favour of vitamin C groups. Accordingly, the results of the three studies suggest that vitamin C supplementation may be beneficial for some of the subjects doing heavy exercise who have problems with frequent upper respiratory infections.

Am J Respir Crit Care Med, 1996 Nov, 154:5, 1401-4

Antioxidants in the lung have a protective role against oxidative damage. We have investigated whether dietary antioxidant intake in elderly people is related to lung function. Dietary intakes of ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) and lung function were assessed in 178 men and women aged 70 to 96 yr selected on the basis of reported respiratory symptoms. After adjustment for age, gender, height, smoking habits, total energy intake, and vitamin C intake by multiple linear regression, vitamin E intake was significantly associated with FEV1 p = 0.012 and FVC p = 0.003. There was no evidence of any interaction between vitamin E intake and current tobacco smoking as determinants of lung function. For every extra milligram increase in vitamin E in the daily diet, FEV1 increased by an estimated 42 ml and FVC by an estimated 54 ml. These results suggest that dietary intake of vitamin E may influence lung function in the elderly, but food frequency questionnaires in this study were not of sufficient sensitivity to explore this hypothesis further.

J Urol, 1996 Jun, 155:6, 1847-51

PURPOSE: The association between the intake of vitamins C and B6, and kidney stone formation was examined. MATERIALS AND METHODS: We conducted a prospective study of the relationship between the intake of vitamins C and B6 and the risk of symptomatic kidney stones in a cohort of 45,251 men 40 to 75 years old with no history of kidney calculi. Vitamin intake from foods and supplements was assessed using a semiquantitative food frequency questionnaire completed in 1986. RESULTS: During 6 years of followup 751 incident cases of kidney stones were documented. Neither vitamin C nor vitamin B6 intake was significantly associated with the risk of stone formation. For vitamin C the age-adjusted relative risk for men consuming 1,500 mg. daily or more compared to less than 250 mg. daily was 0.78 (95% confidence interval 0.54 to 1.11). For vitamin B6 the age-adjusted relative risk for men consuming 40 mg. daily or more compared to less than 3 mg. daily was 0.91 (95% confidence interval 0.64 to 1.31). After adjusting for other potential stone risk factors the relative risks did not change significantly. CONCLUSIONS: These data do not support an association between a high daily intake of vitamin C or vitamin B6 and the risk of stone formation, even when consumed in large doses.

Cancer, 63(5):901-6 1989 Mar 1

The effects of sodium ascorbate (vitamin C) and 2-methyl-1,4-naphthoquinone (vitamin K3) administered separately or in combination on the in vitro cultured human neoplastic cell lines MCF-7 (breast carcinoma), KB (oral epidermoid carcinoma), and AN3-CA (endometrial adenocarcinoma) have been examined. When given separately, vitamin C or K3 had a growth inhibiting action only at high concentrations (5.10(3) mumol/1 and 10(5) nmol/l, respectively). Combined administration of both vitamins demonstrated a synergistic inhibition of cell growth at 10 to 50 times lower concentrations. At this level separately given vitamins are not toxic. The sensitivity to this treatment was somewhat different in the three cell lines, being slightly higher for KB line. This tumor cell growth inhibitory effect was completely suppressed by the addition of catalase to the culture medium containing vitamins C and K3, suggesting an excessive production of hydrogen peroxide as being implied in mechanisms responsible for the above-mentioned effects.

Diabetes Res, 6(3):151-4 1987 Nov

Recent evidence has suggested that diabetic microangiopathy is associated with increased free radical induced oxidative damage. Ascorbic acid (AA) is a free radical scavenger and using a specific HPLC method we have investigated its concentration and that of its oxidized metabolite dehydroascorbic acid (DHAA) in diabetic patients and matched normal controls. The findings have been related to the presence of microangiopathy and to glycaemic control. Ascorbic acid levels were significantly lower in diabetics (mean +/- SD 42.5 +/- 26.2 mumol/l) compared with controls (58 +/- 21 mumol/l p less than 0.02). Although there was no differences in DHAA levels between the groups the ratio DHAA/AA was increased in diabetics (0.72 +/- 0.8) compared with controls (0.4 +/- 0.2 p less than 0.05). There were no significant differences between insulin and non-insulin dependent patients in these measurements and there was no association with the presence of microangiopathy or poor glycaemic control. The plasma ratio DHAA/AA may be a reflection of increased oxidative stress and our results suggest that diabetics may be less able to prevent oxidative damage occurring due to their lower AA concentrations.

J Can Dent Assoc, 6(3):705-7 1989 Sep

Maintaining natural dentition is a realistic goal given today's improved caries control and attention to good oral hygiene. Expanding knowledge in the area of periodontal diseases provides further insight into health promotion practices which can be effective in preventing tooth loss. Vitamin C's role in maintaining the health of teeth and gingivae remains unchallenged. Now clinical evidence indicates that vitamin C functions in improving host defence mechanisms and is thereby implicated in preserving periodontal health. Common sense tells us that the monitoring of the vitamin C status of individuals, especially those at high risk (e.g., diabetics, smokers, elderly, etc.) for inadequate intakes, will yield positive results for periodontal health. Patient education programs that stress the importance of good nutrition, while at the same time providing practical information for the selection of a well balanced diet, are simple measures that will benefit many.

Cor Vasa, 34(3):246-54 1992

The aim of the study was to establish whether it is possible, in a group of deliberately selected subjects with hyperlipidaemia, to modulate cholesterol levels by ascorbic acid administered at a dose of 500 mg/day. The authors assessed the levels of vitamin C, total and HDL cholesterol, triacylglycerols in the blood serum of 140 probands assigned to an 83-member experimental group, and to a 57-member control group. The experimental group was provided Celaskon effervescens Spofa at a dose of 500 mg/day/person. The experiment lasted for 18 months. Blood collections were made in the whole cohort at six-month intervals. Administration of L-ascorbic acid led to a highly significant decrease in the levels of total and LDL cholesterol. After 12 months of study, a highly significant decrease in atherogenic index and an increase in HDL cholesterol levels were found persisting until the end of the experiment.

BMJ, 305(6859):925-7 1992 Oct 17

OBJECTIVE--To evaluate the contribution of specific nutritional deficiencies (as indicated by zinc; vitamin A, C, and E; albumin; and haemoglobin concentrations) to the risk of pressure sores. DESIGN--Observational cohort study. SETTING--St James's University Hospital, Leeds. SUBJECTS--21 elderly patients presenting consecutively to the orthopaedic unit with femoral neck fracture. MAIN OUTCOME MEASURE--Full thickness epidermal break over a pressure bearing surface. RESULTS--10 patients (48%) developed a pressure sore during their hospital stay. Indices of zinc status and concentrations of albumin, haemoglobin, and vitamins A and E were similar in patients who developed a pressure sore and those who did not. Mean leucocyte vitamin C concentration, however, was 6.3 (SD 2.2) micrograms/10(8) cells in patients who developed a pressure sore as compared with 12.8 (4.6) micrograms/10(8) cells in patients who did not. CONCLUSIONS--Low concentrations of leucocyte vitamin C appear to be associated with subsequent development of pressure sores in elderly patients with femoral neck fractures.

J Am Coll Nutr, 11(2):139-44 1992 Apr

Diet has been linked to cardiovascular disease risk by its influence on low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and blood pressure (BP). Recent evidence suggests that vitamin C may play a role in regulation of cholesterol and BP. The cross-sectional relationships of plasma ascorbic acid (PAA) with cholesterol and BP are described in three Boston area samples: 1) 249 males and 447 females (aged 60-100 years), 2) 100 Chinese-American males and 159 Chinese-American females (aged 60-96 years), and 3) 225 male and 192 female participants (aged 20-60 years) in a randomized field trial of vitamin C supplementation. Results indicate 3.7-9.5% higher levels of HDL-C, 4.1% lower levels of LDL-C, and 1.9-5.5% lower levels of BP with each 30 mumol/L increment in PAA. These relationships may be stronger at lower levels of PAA.

Ann N Y Acad Sci, 498(Evans A):110-23 1987

The present epidemiological data support and extend previous evidence in men and animals. Thus, a poor plasma status of vitamin C (less than 23 microM = 0.4 mg/dl) and/or of cholesterol-standardized vitamin E (less than 20-21.5 microM = 9 mg/l) occurs in westernized countries with an increased risk of IHD. A poor status in the major essential antioxidants may be a hitherto underrated, at least permissive, risk factor of IHD that could, at least in some European countries, substantially complement the previously established risk factors such as hypercholesterolemia.

Ann N Y Acad Sci, 498(Leggott PJ):333-46 1987

Biochemical indices of AA clearly showed that the young men in this study were brought into various states of AA depletion and repletion according to their dietary AA intakes. While previous studies have postulated that supplemental intakes of AA may adversely affect body status of vitamins B6 and B12, we found no changes in the B vitamin status of the young men receiving varying AA intakes. Moderate AA supplementation (605 mg/day) showed no antagonistic effect on markers of vitamins B6 and B12. Blood markers of fat-soluble vitamins A and E and iron status were not affected by AA intakes. The propensity of the gingiva to become inflamed or bleed on probing was reduced after normal (65 mg/day) AA intakes as compared to deficient (5 mg/day) intakes and upon supplementary (605 mg/day) AA intakes as compared to normal intakes. The results suggest that AA status may influence early stages of gingival inflammation and crevicular bleeding, and warrant further study of the relationship between AA and periodontal health.

Age Ageing, 20(3):169-74 1991 May

Thirty elderly long-stay patients were randomly allocated to receive either placebo or dietary supplementation with vitamins A, C and E for 28 days. Nutritional status and cell-mediated immune function were assessed before and after the period of supplementation. Following vitamin supplementation, cell-mediated immune function improved as indicated by a significant increase in the absolute number of T cells (p less than 0.05), T4 subsets (p less than 0.05), T4 to T8 ratio (p less than 0.01) and the proliferation of lymphocytes in response to phytohaemagglutinin (p less than 0.01). In contrast, no significant changes were noted in the immune function of the placebo group. We conclude that supplementation with the dietary antioxidants vitamins A, C and E can improve aspects of cell-mediated immune function in elderly long-stay patients.

Prostate, 32(3):188-95 1997 Aug 1

BACKGROUND: Many studies describe the protective role of vitamin C (ascorbic acid) against cancer development and in treatment of established cancer. The present study investigated whether ascorbic acid demonstrates a therapeutic benefit for prostate cancer. METHODS: Androgen-independent (DU145) and androgen-dependent (LNCaP) human prostate cancer cell lines were both treated in vitro with vitamin C (0-10 mM). Cell counts, cell viability, and thymidine incorporation into DNA were determined. RESULTS: Treatment of DU145 and LNCaP cells with vitamin C resulted in a dose- and time-dependent decrease in cell viability and thymidine incorporation into DNA. Vitamin C induced these changes through the production of hydrogen peroxide; addition of catalase (100-300 units/ml), an enzyme that degrades hydrogen peroxide, inhibited the effects of ascorbic acid. Superoxide dismutase, an enzyme that dismutates superoxide and generates hydrogen peroxide, did not prevent decreases in cell number and DNA synthesis, suggesting further the involvement of hydrogen peroxide in vitamin C-induced changes. These results clearly indicate that reactive oxygen species (ROS) are involved in vitamin C-induced cell damage. However, that singlet oxygen scavengers such as sodium azide and hydroquinone and hydroxyl radical scavengers such as D-mannitol and DL-alpha-tocopherol did not counteract the effects of ascorbic acid on thymidine incorporation suggests that vitamin C-induced changes do not occur through the generation of these ROS. CONCLUSIONS: Vitamin C inhibits cell division and growth through production of hydrogen peroxide, which damages the cells probably through an as yet unidentified free radical(s) generation/mechanism. Our results also suggest that ascorbic acid is a potent anticancer agent for prostate cancer cells.

Tomoda, H., M. Yoshitake, et al. (1996). Am J Cardiol 78(11): 1284-6 97119921.

In this preliminary study to assess the possibility of using ascorbic acid to prevent post-percutaneous transluminal coronary angiography (PTCA) restenosis, the incidence of restenosis was significantly less in 50 patients receiving 500 mg/day of oral ascorbic acid than in 51 control patients. Thus, ascorbic acid, a potent natural antioxidant, appeared to be possibly effective in attenuating post-PTCA restenosis.

Epidemiology 3(3): 194-202 92273688

We examined the relation between vitamin C intake and mortality in the First National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study cohort. This cohort is based on a representative sample of 11,348 noninstitutionalized U.S. adults age 25- 74 years who were nutritionally examined during 1971-1974 and followed up for mortality (1,809 deaths) through 1984, a median of 10 years. An index of vitamin C intake has been formed from detailed dietary measurements and use of vitamin supplements. The relation of the standardized mortality ratio (SMR) for all causes of death to increasing vitamin C intake is strongly inverse for males and weakly inverse for females. Among those with the highest vitamin C intake, males have an SMR (95% confidence interval) of 0.65 (0.52-0.80) for all causes, 0.78 (0.50-1.17) for all cancers, and 0.58 (0.41-0.78) for all cardiovascular diseases; females have an SMR of 0.90 (0.74-1.09) for all causes, 0.86 (0.55-1.27) for all cancers, and 0.75 (0.55-0.99) for all cardiovascular diseases. Comparisons are made relative to all U.S. whites, for whom the SMR is defined to be 1.00. There is no clear relation for individual cancer sites, except possibly an inverse relation for esophagus and stomach cancer among males. The relation with all causes of death among males remains after adjustment for age, sex, and 10 potentially confounding variables (including cigarette smoking, education, race, and disease history).

Acta Neurochir 123(1-2): 87-91 94026432

Neuronal cell damage following ischaemia is postulated to be due to free radical induced lipid peroxidation, and ascorbic acid is supposedly an important non-enzymatic scavenger of such free radicals. This study was undertaken to evaluate the protective effect of ascorbic acid on the brain in a primate model after focal cerebral ischemia. Consumption of ascorbic acid in the monkey brain following ischaemia and its effect on macroscopic infarct size as demonstrated by 2, 3, 5, Triphenyl tetrazolium chloride (TTC) staining were used as parameters. The monkeys in the treated group were given 1 gram ascorbic acid parenterally every day for six days. The mean level of total ascorbic acid in right basal ganglia was 35.1 +/- 4.2 micrograms/mg of protein in the treated group as opposed to 22.9 +/- 2.1 micrograms/mg of protein in the nontreated group both before ischaemia. After right middle cerebral artery occlusion to produce focal cerebral ischaemia, the total ascorbic acid in the right basal ganglia 2 hours post ischaemia was 13.3 +/- 3.1 micrograms/mg of protein in the treated group as opposed to 9 +/- 1.6 micrograms/mg of protein in the untreated group. The average consumption of total ascorbic acid was 21.8 micrograms/mg of protein in the treated group and 13.9 micrograms/mg of protein in the nontreated group. Macroscopic infarct size as determined by TTC staining in the right cerebral hemisphere was 11.7 +/- 6.9 in treated group whereas it was 24.4 +/- 4.4 (expressed as percentage of right hemisphere) in the non-treated group. There was significant reduction in the size of the infarct in the treated group.

Circulation, 1996 Mar, 93:6, 1107-13

BACKGROUND: In the setting of atherosclerosis, endothelial vasomotor function is abnormal. Increased oxidative stress has been implicated as one potential mechanism for this observation. We therefore hypothesized that an antioxidant, ascorbic acid, would improve endothelium-dependent arterial dilation in patients with coronary artery disease. METHODS AND RESULTS: Brachial artery endothelium-dependent dilation in response to hyperemia was assessed by high-resolution vascular ultrasound before and 2 hours after oral administration of either 2 g ascorbic acid or placebo in a total of 46 patients with documented coronary artery disease. Plasma ascorbic acid concentration increased 2.5-fold 2 hours after treatment (46+/-8 to 114+/-11 micromol/L, P=.001). In the prospectively defined group of patients with an abnormal baseline response (<5% dilation), ascorbic acid produced marked improvement in dilation (2.0+/-0.6% to 9.7+/-2.0%), whereas placebo had no effect (1.1+/-1.5% to 1.7+/-1.5%, P=.003 for ascorbic acid versus placebo). Ascorbic acid had no effect on hyperemic flow or arterial dilation to sublingual nitroglycerin. CONCLUSIONS: Ascorbic acid reverses endothelial vasomotor dysfunction in the brachial circulation of patients with coronary artery disease. These findings suggest that increased oxidative stress contributes to endothelial dysfunction in patients with atherosclerosis and that endothelial dysfunction may respond to antioxidant therapy.

Circulation, 1998 Feb, 97:4, 363-8

BACKGROUND: Chronic heart failure (CHF) is associated with endothelial dysfunction including impaired endothelium-mediated, flow-dependent dilation (FDD). There is evidence for increased radical formation in CHF, raising the possibility that nitric oxide is inactivated by radicals, thereby impairing endothelial function. To test this hypothesis, we determined the effect of the antioxidant vitamin C on FDD in patients with CHF. METHODS AND RESULTS: High-resolution ultrasound and Doppler was used to measure radial artery diameter and blood flow in 15 patients with CHF and 8 healthy volunteers. Vascular effects of vitamin C (25 mg/min IA) and placebo were determined at rest and during reactive hyperemia (causing endothelium-mediated dilation) before and after intra-arterial infusion of N-monomethyl-L-arginine (L-NMMA) to inhibit endothelial synthesis of nitric oxide. Vitamin C restored FDD in patients with heart failure after acute intra-arterial administration (13.2+/-1.7% versus 8.2+/-1.0%; P<.01) and after 4 weeks of oral therapy (11.9+/-0.9% versus 8.2+/-1.0%; P<.05). In particular, the portion of FDD mediated by nitric oxide (ie, inhibited by L-NMMA) was increased after acute as well as after chronic treatment (CHF baseline: 4.2+/-0.7%; acute: 9.1+/-1.3%; chronic: 7.3+/-1.2%; normal subjects: 8.9+/-0.8%; P<.01). CONCLUSIONS: Vitamin C improves FDD in patients with CHF as the result of increased availability of nitric oxide. This observation supports the concept that endothelial dysfunction in patients with CHF is, at least in part, due to accelerated degradation of nitric oxide by radicals.

J Am Coll Cardiol, 1998 Apr, 31:5, 980-6

OBJECTIVES: This study sought to investigate the relations between plasma antioxidant status, extent of atherosclerosis and activity of coronary artery disease. BACKGROUND: Previous studies indicate that increased antioxidant intake is associated with decreased coronary disease risk, but the underlying mechanisms remain controversial. METHODS: Plasma samples were obtained from 149 patients undergoing cardiac catheterization (65 with stable angina, 84 with unstable angina or a myocardial infarction within 2 weeks). Twelve plasma antioxidant/oxidant markers were measured and correlated with the extent of atherosclerosis and the presence of an unstable coronary syndrome. RESULTS: By multiple linear regression analysis, age (p < 0.001), diabetes mellitus (p < 0.001), male gender (p < 0.001) and hypercholesterolemia (p = 0.02) were independent predictors of the extent of atherosclerosis. No antioxidant/oxidant marker correlated with the extent of atherosclerosis. However, lower plasma ascorbic acid concentration predicted the presence of an unstable coronary syndrome by multiple logistic regression (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.40 to 0.89, p = 0.01). The severity of atherosclerosis also predicted the presence of an unstable coronary syndrome (OR 1.7, 95% CI 1.14 to 2.47, p = 0.008) when all patients were considered. When only patients with significant coronary disease were considered (at least one stenosis >50%), ascorbic acid concentration (OR 0.56, 95% CI 0.37 to 0.85, p = 0.008) and total plasma thiols (OR 0.52, 95% CI 0.34 to 0.80, p = 0.004) predicted the presence of an unstable coronary syndrome, whereas the extent of atherosclerosis did not. CONCLUSIONS: These data are consistent with the hypothesis that the beneficial effects of antioxidants in coronary artery disease may result, in part, by an influence on lesion activity rather than a reduction in the overall extent of fixed disease.

J Clin Invest, 1998 Jul, 102:1, 67-71

Enhanced formation of superoxide radicals has been proposed to play a major role in the development of nitrate tolerance in humans. We tested the effects of vitamin C (Vit-C) supplementation on glyceroltrinitrate (GTN)-induced hemodynamic effects during 3-d nonintermittent transdermal administration of GTN (0.4 mg/h) in nine healthy subjects. Tolerance development was monitored by changes in arterial pressure, dicrotic digital pulse pressure, and heart rate. Studies with GTN, Vit-C, or GTN/Vit-C were successively carried out at random in three different series in the same subjects. GTN treatment caused an immediate rise in arterial conductivity (a/b ratio of dicrotic pulse), but within 2 d of initiating GTN, the a/b ratio progressively decreased and reached basal levels. In addition, there was a progressive loss of the orthostatic decrease in blood pressure. However, coadministration of Vit-C and GTN fully maintained the GTN-induced changes in the orthostatic blood pressure, and the rise of a/b ratio was augmented by 310% for the duration of the test period. Changes in vascular tolerance in GTN-treated subjects were paralleled by upregulation of the activity of isolated platelets, which was also reversed by Vit-C administration. These findings demonstrate that dietary supplementation with Vit-C eliminates vascular tolerance and concomitant upregulation of ex vivo-washed platelet activity during long-term nonintermittent administration of GTN in humans.

J Hypertens, 1998 Jul, 16:7, 925-32

OBJECTIVE: To characterize relationships among blood pressure, pulse rate, vitamin C status and other protective and risk factors for older British people, from a national survey. DESIGN: A cross-sectional analysis of survey data. SETTING: A population study, representative of mainland Britain. SUBJECTS: Among 914 people of both sexes living in the community, 373 were taking blood-pressure-lowering drugs and were therefore excluded from the analyses. INTERVENTIONS: Completion of an interview on health, lifestyle and dietary habits, recording of a 4-day dietary record, anthropometry and taking of a blood sample to determine haematological and biochemical status. MAIN OUTCOME MEASURES: Systolic and diastolic blood pressures, pulse rate, indices of micronutrient status including plasma ascorbate concentration, nutrient intake and haematology. RESULTS: Plasma ascorbate concentration was inversely correlated to systolic and diastolic blood pressures and pulse rate. Other covariates of blood pressure included age, sex, domicile, plasma retinol, fibrinogen and gamma-tocopherol concentrations, erythrocyte count, prothrombin time and urine sodium: creatinine ratio. Covariates of pulse rate included sex, domicile, plasma fibrinogen and platelet count. Blood pressure was also correlated to intake of vitamin C. CONCLUSIONS: Plasma ascorbate concentration and intake of vitamin C are covariates of blood pressure in older people living in Britain. New intervention studies are now needed, to test for possible causalities.

J Am Coll Nutr, 1998 Apr, 17:2, 105-8

The cellular uptake of vitamin C (ascorbic acid, ASC) is promoted by insulin and inhibited by hyperglycemia. If a rise in plasma ASC is uncoupled from insulin replacement in insulin-dependent diabetes mellitus (IDDM) then the degree of hyperglycemia could account for "tissue scurvy" in IDDM. Leukocyte ASC is lower in IDDMs compared with nondiabetics when vitamin C consumption is adequate and our data suggest that this is a variable component of the pathophysiology of IDDM. The complications of diabetes mellitus are believed to result from either the intracellular accumulation of sorbitol or the nonenzymatic glycoxidation of proteins or both. With respect to the abnormal cellular accumulation of sorbitol, vitamin C supplementation has been shown to be effective in several studies of adults with diabetes; the situation regarding the prevention of protein glycoxidations by supplementation is presently unclear. The roles of ASC as an aldose reductase inhibitor and a water soluble antioxidant in body fluids are potentially very important as adjuncts to tight glycemic control in the management of diabetes. Tissue saturation and maximal physiologic function in IDDM may require supplemental vitamin C intake.

J Am Coll Nutr, 1998 Jun, 17:3, 250-5

OBJECTIVE: To examine the relation of serum ascorbic acid level to serum lipid and lipoprotein levels among a random sample of the US adult population. METHODS: Using linear regression, the relation of serum ascorbic acid level to serum lipid and lipoprotein levels was examined among 5,412 women and 5,116 men enrolled in the Second National Health and Nutrition Examination Survey (NHANES II), 1976-1980. Age, race, body mass index, level of physical activity, level of education, alcohol intake, and dietary energy, cholesterol, and fat intakes, and other potential confounders were included in the multivariate models. RESULTS: Serum ascorbic acid level was independently associated with high-density lipoprotein cholesterol (HDL-C) among women; each 1 mg/dl increase in serum ascorbic acid level (range 0.1 to 2.7 mg/dl) was associated with a 2 mg/dl increase in HDL-C level (p = 0.001). Because other investigators have demonstrated an inverse relation between ascorbic acid intake or blood levels and total serum cholesterol in individuals with elevated total serum cholesterol levels, we analyzed four subgroups of NHANES II participants with total serum cholesterol levels > 200 mg/dl. Among women with total serum cholesterol levels > or = 200 mg/dl, each 1 mg/dl increase in serum ascorbic acid level was independently associated with an increase of 2 to 3 mg/dl in HDL-C level (p < or = 0.05). Serum ascorbic acid level was not significantly associated with other serum lipids or lipoproteins. CONCLUSIONS: If the observed associations are linked causally, they would suggest that ascorbic acid is a factor in cholesterol homeostasis among women and may be particularly important for women at increased risk for coronary heart disease.

Epidemiology, 1998 May, 9:3, 316-21

To examine the relation between serum ascorbic acid level and the prevalence of cardiovascular disease, we analyzed data from 6,624 U.S. men and women enrolled in the Second National Health and Nutrition Examination Survey. We calculated odds ratios and 95% confidence intervals to estimate the relative prevalence of cardiovascular disease, defined as self-reported coronary heart disease or stroke, or a diagnosis of peripheral vascular disease based on physical examination. Serum ascorbic acid levels were independently associated with prevalence of coronary heart disease and stroke; a 0.5-mg per dl increase in serum ascorbic acid level was associated with an 11% reduction in coronary heart disease and stroke prevalence. We also analyzed the relation of ascorbic acid, grouped into low to marginal, normal, and saturation serum categories, to cardiovascular disease. Compared with participants with low to marginally low serum ascorbic acid levels, we found a 27% decreased prevalence of coronary heart disease (95% confidence interval = 10-41%) and a 26% decreased prevalence of stroke (95% confidence interval = 3-44%) among participants in the highest serum ascorbic acid category. Serum ascorbic acid levels were not consistently associated with prevalence of peripheral vascular disease. These results are consistent with the hypothesis that increased ascorbic acid intake may decrease the risk of coronary heart disease and stroke.

J Am Coll Cardiol, 1998 Jul, 32:1, 103-9

OBJECTIVES: This study sought to examine effect of vitamin C, an antioxidant, on the abnormal vasomotor reactivity in spasm coronary arteries. BACKGROUND: Oxygen free radicals generated in the arterial walls have been shown to cause endothelial vasomotor dysfunction. METHODS: Responses of the epicardial arterial diameters of the left coronary arteries to the intracoronary infusion of acetylcholine (ACh) (10 and 50 microg/min) were measured by quantitative coronary angiography before and during combined intracoronary infusion of vitamin C (10 mg/min) or saline as a placebo in 32 patients with coronary spastic angina and in 34 control subjects. RESULTS: Vitamin C infusion suppressed the constrictor response of the epicardial diameter to ACh in spasm coronary arteries but had no significant effect in the control coronary arteries (percent change in distal diameter in response to 10 microg/min of ACh [constriction (-), dilation (+), mean +/- SEM] before vitamin C: -8.2 +/- 2.9% in spasm arteries, +8.4 +/- 2.9%* in control arteries; during vitamin C: +0.2 +/- 3.8%* in spasm arteries, +7.2 +/- 1.3%* in control arteries [*p < 0.01 vs. spasm arteries before vitamin CI). The coronary sinus-arterial difference in plasma thiobarbituric acid reactive substances during ACh infusion, an indicator of lipid peroxidation in coronary circulation, was higher in patients with coronary spastic angina than in control subjects (p < 0.01) but was suppressed in patients with coronary spastic angina to comparable levels in control subjects by combined infusion of vitamin C. Saline infusion had no effect. CONCLUSIONS: The results indicate that vitamin C attenuates vasomotor dysfunction in epicardial coronary arteries in patients with coronary spastic angina. Oxygen free radicals may at least in part play a role in the abnormal coronary vasomotor reactivity in response to ACh in spasm coronary arteries.

Am J Epidemiol, 134(5):501-11 1996 Sep 1

In 1981-1984, the nutritional status of 747 noninstitutionalized Massachusetts residents aged 60 years and over was assessed. Nine to 12 years later, the vital status of these subjects was determined. The data of a subset of 725 community-dwelling volunteers was used to examine associations between mortality and the nutrient antioxidants (carotenoids and vitamins C and E) in plasma, diet, and supplements. Results indicated that subjects with plasma vitamin C levels in the middle and high quintiles had a lower overall mortality (relative risk (RR) = 0.64, 95% confidence interval (CI) 0.44-0.94 and RR = 0.54, 95% CI 0.32-0.90, respectively) than those in the lowest quintile even after adjustment for potential confounders. These associations were largely due to reduced mortality from heart disease. Subjects in the highest quintile of total intake of vitamin C also had a significantly lower risk of overall mortality (RR = 0.55, 95% CI 0.32-0.93) and mortality from heart disease (RR = 0.38, 95% CI 0.19-0.75) than did those in the lowest quintile after potential confounders were controlled for. Intake of vegetables was inversely associated with overall mortality (p for trend = 0.003) and mortality from heart disease (p for trend = 0.04). No other significant associations were observed. In conclusion, the results indicate that high intakes and plasma levels of vitamin C and frequent consumption of vegetables may be protective against early mortality and mortality from heart disease.