Ascorbic acid dynamics in the seriously ill and injured.

BACKGROUND: In addition to the known beneficial effects of ascorbic acid on wound healing and the immune response, it is also a potent extracellular antioxidant. Recent work in septic rats suggests that high-dose ascorbic acid total parenteral nutrition (TPN) supplementation may protect cells from free radical injury and improve survival. In this study, we determined ascorbic acid levels in the immediate post-injury/illness period and evaluated the ability of early short-term high levels of ascorbic acid in TPN to normalize plasma levels. MATERIALS AND METHODS: Ascorbic acid levels were determined in 12 critically injured patients and 2 patients with severe surgical infections. Each patient received TPN supplemented with increasing doses of ascorbic acid over a 6-day period. Therapeutic responses were determined by plasma and urine measurements using high-pressure liquid chromatography. RESULTS: The initial mean +/- SEM baseline plasma ascorbic acid concentration was depressed (0.11 +/- 0.03 mg/dl) and unresponsive following 2 days on 300 mg/day supplementation (0.14 +/- 0.03; P = 1.0) and only approached low normal plasma levels following 2 days on 1000 mg/day (0.32 +/- 0.08; P = 0.36). A significant increase was noted following 2 days on 3000 mg/day (1.2 +/- 0.03; P = 0.005). CONCLUSION: We confirmed extremely low plasma levels of ascorbic acid following trauma and infection. Maximal early repletion of this vitamin requires rapid pool filling early in the post-injury period using supraphysiologic doses for 3 or more days.

Postpartum thiamine deficiency in a Karen displaced population.

BACKGROUND: Before its recognition, infantile beriberi was the leading cause of infant death in camps for displaced persons of the Karen ethnic minority on Thailand's western border. OBJECTIVE: This study aimed to document thiamine status in the peripartum period to examine the current supplementation program and the correlation between the clinical manifestations of thiamine deficiency and a biochemical measure of thiamine status. DESIGN: Women were enrolled prospectively at 30 wk of gestation and were followed up weekly until delivery and at 3 mo postpartum. Thiamine supplementation during pregnancy was based on patient symptoms. RESULTS: At 3 mo postpartum, thiamine deficiency reflected by an erythrocyte transketolase activity (ETKA) > or = 1.20% was found in 57.7% (15/26) of mothers, 26.9% (7/26) of whom had severe deficiency (ETKA > 1.25%). No significant associations between ETKA and putative maternal symptoms or use of thiamine supplements were found. CONCLUSIONS: Biochemical postpartum thiamine deficiency is still common in Karen refugee women. This situation may be improved by educating lactating women to reduce their consumption of thiaminase-containing foods and by implementing an effective thiamine supplementation program.

Low serum and red blood cell folate are moderately, but nonsignificantly associated with increased risk of invasive cervical cancer in U.S. women.

Previous observational epidemiologic studies of folate and cervical cancer, as well as folate supplementation trials for cervical dysplasia, have produced mixed results. We examined the relationship between serum and RBC folate and incident invasive cervical cancer in a large, multicenter, community-based case-control study. Detailed in-person interviews were conducted, and blood was drawn at least 6 mo after completion of cancer treatment from 51% of cases and 68% of controls who were interviewed. Blood folate was measured with both microbiologic and radiobinding assays. Included in the final analyses were 183 cases and 540 controls. Logistic regression was used to control for all accepted risk factors, including age, sexual behavior, smoking, oral contraceptive use, Papanicolaou smear history and human papillomavirus (HPV)-16 serology. For all four folate measures, the geometric mean in cases was lower than in controls (e.g., 11.6 vs. 13.0 nmol/L, P < 0.01 for the serum radiobinding assay). Folate measures using microbiologic and radiobinding assays were correlated (serum: r = 0.90; RBC: r = 0.77). For serum folate, multivariate-adjusted odds ratios (OR) in the lowest vs. highest quartile were 1.3 [95% confidence interval (CI) = 0.8--2.9] and 1.6 (0.9--2.9), using the microbiologic and radiobinding assays, respectively. For RBC folate, comparable OR were 1.2 (0.6--2.2) and 1.5 (0.8--2.7). Similar risks were obtained when restricting analyses to subjects with a history of HPV infection. Thus, low serum and RBC folate were each moderately, but nonsignificantly, associated with increased invasive cervical cancer risk. These findings support a role for one-carbon metabolism in the etiology of cervical cancer.

Correlates of total plasma homocysteine: folic acid, copper, and cervical dysplasia.

We examined correlates of total plasma homocysteine (tHcy) in 294 subjects with cervical intraepithelial neoplasia and 170 control subjects. Associations of tHcy with risk factors for cervical intraepithelial neoplasia and 24-h intakes and biochemical indices of nutrients were examined. Plasma and red blood cell folate and plasma B(12) were strong inverse correlates of tHcy (r = -0.35, -0. 31, and -0.27, respectively). Plasma copper and severity of dysplasia were positively correlated with tHcy (r = 0.14 and 0.21, respectively). A stepwise regression model that included red blood cell folate, plasma copper, grade of dysplasia, ethnicity, intake of polyunsaturated fatty acids, plasma vitamin B(12), intake of fat, and oral contraceptive use explained 29% of the variation in tHcy. Two hundred thirty-five subjects with cervical intraepithelial neoplasia were randomized to receive folic acid (10 mg/d) or placebo for 6 mo. After 2, 4, and 6 mo, mean tHcy in the folate-supplemented group (7.2 +/- 1.8, 7.0 +/- 1.9, and 7.0 +/- 2.3 micromol/L, respectively) was significantly lower than baseline and the placebo group at 2, 4, and 6 mo (8.9 +/- 3.1, 8.4 +/- 3.0, and 8.9 +/- 3.1 micromol/L, respectively). Supplementation lowered tHcy even in subjects in the highest quintile of baseline folate. Folate, vitamin B(12), copper, and severity of dysplasia are associated with tHcy. Folate supplementation significantly lowers tHcy even in folate-replete subjects.

Effect of total plasma homocysteine on cervical dysplasia risk.

We investigated whether total plasma homocysteine (tHcy) is associated with risk for cervical intraepithelial neoplasia (CIN). tHcy was evaluated, along with numerous risk factors for CIN and biochemical indexes of nutrients, in a previously reported study population of 294 subjects with CIN and 170 female controls without CIN. tHcy was significantly higher in cases than in controls (9.1 vs. 8.3 mumol/l, p = 0.002). Human papillomavirus type 16 infection [odds ratio (OR) = 6.7], oral contraceptive use (OR = 6.0), parity (OR = 2.2), and cigarette smoking (OR = 1.9) were significantly associated with CIN after adjustment for each other and for age, number of sexual partners, and plasma tHcy, folate, iron, and zinc. Human papillomavirus type 16 positivity increased risk for CIN more when tHcy was > 9.12 mumol/l (OR = 4.7) than when it was < or = 9.12 mumol/l (OR = 3.0). Cigarette use increased risk for CIN when tHcy was > 9.12 mumol/l (OR = 3.9), but not when tHcy was < or = 9.12 mumol/l (OR = 1.5). Parity increased risk for CIN more when tHcy was > 9.12 mumol/l (OR = 4.0) than when tHcy was < or = 9.12 mumol/l (OR = 2.0). These results suggest that elevated plasma tHcy is a risk factor for cervical dysplasia and that it enhances the effects of other risk factors. It is unknown whether tHcy is serving as a marker of folate deficiency or is acting through other mechanisms.

HIV-1 infection in women is associated with severe nutritional deficiencies.

Nutritional deficiencies may contribute to immune dysregulation, and have been shown to be sensitive markers of HIV-1 disease progression. Only limited information exists, however, regarding the nutritional profile of HIV-1-seropositive drug abusers. Immune and nutritional measurements were obtained in a subsample of 125 subjects from a larger cohort of drug users being followed for HIV-1 infection and cofactors of disease progression. Nutritional deficiencies, particularly vitamins A, E, and zinc, were widespread with up to 86% of the drug users exhibiting at least one nutritional alteration. Although immune parameters (CD4 count, CD8 count, beta2-microglobulin) were similar in the HIV-1-infected men and women, women had significantly poorer overall nutritional status, as measured by plasma proteins, which are considered to be sensitive markers of malnutrition. A comparison of individuals with advanced disease (CD4 count <200/mm3) revealed significantly lower levels of plasma prealbumin (p < .01), selenium, (p < .05), and greater deficiency of vitamins A (p < .01) and E (p < .05) in women than in men. The greater severity of nutritional deficiencies noted in HIV-1-infected women may be an important determinant of disease progression and survival.

High risk of HIV-related mortality is associated with selenium deficiency.

To determine the independent contribution of specific immunologic and nutritional factors on survival in HIV-1 disease, CD4 cell count, antiretroviral treatment, plasma levels of vitamins A, E, B6, and B12 and minerals selenium and zinc were considered in relation to relative risk for HIV-related mortality. Immune parameters and nutrients known to affect immune function were evaluated at 6-month intervals in 125 HIV-1-seropositive drug-using men and women in Miami, FL, over 3.5 years. A total of 21 of the HIV-1-infected participants died of HIV-related causes during the 3.5-year longitudinal study. Subclinical malnutrition (i.e., overly low levels of prealbumin, relative risk [RR] = 4.01, p < 0.007), deficiency of vitamin A (RR = 3.23, p < 0.03), vitamin B12 deficiency (RR = 8.33, p < 0.009), zinc deficiency (RR = 2.29.1, p < 0.04), and selenium deficiency (RR = 19.9, p < 0.0001) over time, but not zidovudine treatment, were shown to each be associated with HIV-1-related mortality independent of CD4 cell counts <200/mm3 at baseline, and CD4 counts over time. When all factors that could affect survival, including CD4 counts <200/mm3 at baseline, CD4 levels over time, and nutrient deficiencies were considered jointly, only CD4 counts over time (RR = 0.69, p < 0.04) and selenium deficiency (RR = 10.8, p < 0.002) were significantly associated with mortality. These results indicate that selenium deficiency is an independent predictor of survival for those with HIV-1 infection.

Decreased fat and nitrogen losses in patients with AIDS receiving medium-chain-triglyceride-enriched formula vs those receiving long-chain-triglyceride-containing formula.

OBJECTIVE: The purpose of this study was to compare two enteral formulas, differing only in fat source, for product acceptance, tolerance, and effect on fat malabsorption and nutritional status in subjects with acquired immune deficiency syndrome (AIDS). DESIGN: The double-blind, randomized 15-day trial was divided into a 3-day period in which solid food was consumed followed by a 12-day experimental period in which liquid formulas were consumed. SETTING/SUBJECTS: Twenty-three men and one woman with AIDS and fat malabsorption completed the study. The study was conducted in the General Clinical Research Center, University of Alabama Hospital, University of Alabama at Birmingham. Laboratory assays were performed in the Department of Nutrition Sciences. INTERVENTIONS: After 3 days of consuming a controlled, solid food diet containing 100 g fat per day from mixed sources to document fat malabsorption, subjects were randomly assigned to one of two groups. Each group received a liquid formula containing 35% of energy as fat for 12 days. One group received a formula containing 85% medium-chain triglycerides (MCTs) and the control group received a formula containing 100% long-chain triglycerides. MAIN OUTCOME MEASURES: Determinations included stool number, consistency, weight, and fat and nitrogen content; urine nitrogen and creatinine levels; and body weight. STATISTICAL ANALYSIS PERFORMED: Subject demographic and other baseline characteristics were compared using two-sample t tests; stool and urine assessments were compared between groups at the initial experimental period using two-sample t tests; changes from initial to final experimental periods were assessed by means of analysis of covariance; changes in pooled intake, body weight, and the number and consistency of bowel movements were also assessed using analysis of covariance. All statistical tests were two-tailed and considered significant at P < .05. RESULTS: Within-group comparisons indicated that subjects fed the MCT formula showed significantly decreased stool fat and stool nitrogen content (P = .01 and P = .03, respectively) and increased fat absorption (P = .03), whereas those fed the control formula did not. Differences in stool fat between the groups were not statistically significant. However, the difference in fat absorption from the initial to final formula period was significant (P = .04). Subjects consuming the MCT formula also tended to have a decreased number of bowel movements and abdominal symptoms, whereas subjects fed the control formula showed no improvement. All subjects maintained their body weights. APPLICATIONS: There may be advantages to using an MCT-based formula in the treatment of AIDS-associated malabsorption.

Effects of erythorbic acid on vitamin C metabolism in young women.

Erythorbic acid, an epimer of L-ascorbic acid, is used in the United States as a food additive. Studies were conducted to determine whether the ingestion of erythorbic acid in the diet had any beneficial or adverse effects on the human requirement for vitamin C. Young women were fed diets that contained controlled amounts of erythorbic acid and ascorbic acid. In pharmacokinetic evaluations, erythorbic acid and ascorbic acid were rapidly absorbed with little interaction. Erythorbic acid cleared from the body more rapidly than ascorbic acid. Some subjects received diets deficient in vitamin C for periods < or = 30 d. Increasing intakes of erythorbic acid or prolonged intakes of < or = 1 g erythorbic acid/d did not indicate any interactions with ascorbic acid. Consumption of erythorbic acid resulted in the presence of erythorbic acid in mononuclear leukocytes. Ascorbic acid concentrations in these cells were not affected by the presence of erythorbic acid. Erythorbic acid disappeared quickly from these cells with cessation of erythorbic acid supplements. Prolonged ingestion of erythrobic acid by young women neither antagonized nor spared their vitamin C status.

Micronutrients and HIV-1 disease progression.

OBJECTIVE: To determine whether nutritional status affects immunological markers of HIV-1 disease progression. DESIGN: A longitudinal study, to evaluate the relationship between plasma levels of nutrients and CD4 cell counts, along and in combination with beta 2-microglobulin (beta 2M; AIDS index) over an 18-month follow-up. METHODS: Biochemical measurements of nutritional status including plasma proteins, zinc, iron and vitamins B1, B2, B6, B12 (cobalamin), A, E, C and folate and immunological markers [lymphocyte subpopulations (CD4) and beta 2M] were obtained in 108 HIV-1-seropositive homosexual men at baseline and over three 6-month time periods. Changes in nutrient status (e.g., normal to deficient, deficient to normal), were compared with immunological parameters in the same time periods using an autoregressive model. RESULTS: Development of deficiency of vitamin A or vitamin B12 was associated with a decline in CD4 cell count (P = 0.0255 and 0.0377, respectively), while normalization of vitamin A, vitamin B12 and zinc was associated with higher CD4 cell counts (P = 0.0492, 0.0061 and 0.0112, respectively). These findings were largely unaffected by zidovudine use. For vitamin B12, low baseline status significantly predicted accelerated HIV-1 disease progression determined by CD4 cell count (P = 0.041) and the AIDS index (P = 0.005). CONCLUSIONS: These data suggest that micronutrient deficiencies are associated with HIV-1 disease progression and raise the possibility that normalization might increase symptom-free survival.

Vitamin B-6 requirement and status assessment: young women fed a depletion diet followed by a plant- or animal-protein diet with graded amounts of vitamin B-6.

The vitamin B-6 requirement of young women consuming a high-protein diet (1.55 g/kg body wt) and the effect of protein quality on this requirement was studied. In addition, the response of clinical, functional, and biochemical measures of vitamin B-6 nutriture to short-term depletion and step-wise repletion of vitamin B-6 were evaluated. Eight healthy young women resided in a metabolic unit and were fed a formula depletion diet (< 0.05 mg vitamin B-6/d) for 11-28 d followed by either an animal-protein (AP) or plant-protein (PP) diet with successively increasing vitamin B-6 intakes (0.5, 1.0, 1.5, and 2.0 mg/d) for periods of 14-21 d. Animal proteins were primarily from dairy and poultry sources and plant proteins were primarily from legumes. Vitamin B-6 status measures were assessed at weekly intervals. Results showed that a PP diet does not elevate the vitamin B-6 requirement over that required for an AP diet given the high amount of dietary protein used in this study. It was also found that 0.015 mg vitamin B-6/g protein intake normalized most biochemical indexes of vitamin B-6 status (including those indicative of functional status), and that 0.020 mg/g protein normalized all biochemical measures except total urinary vitamin B-6. Adding a margin of safety to either the 0.015 or 0.020 mg/g protein intake would raise the vitamin B-6 requirement for young women above the currently recommended dietary allowance of 0.016 mg/g protein.

Elevated IgE level in relationship to nutritional status and immune parameters in early human immunodeficiency virus-1 disease.

Elevation of IgE has been associated with T-cell dysregulation and with the occurrence of opportunistic infections in patients with acquired immunodeficiency syndrome. The precise cause of IgE overproduction during the early stages of human immunodeficiency virus (HIV)-1 disease, however, has not been established. In light of reports demonstrating that IgE production may be affected by vitamin E levels in an animal model, we evaluated nutritional status in relationship to plasma IgE levels and immune parameters in 100 asymptomatic HIV-1-seropositive and 42 HIV-1-seronegative homosexual men. Approximately 18% of the HIV-1-seropositive population demonstrated biochemical evidence of plasma vitamin E deficiency (< 5 micrograms/ml). Subsequent analysis of available samples indicated a dramatic elevation of IgE levels (308 +/- 112 IU/ml) in vitamin E-deficient seropositive subjects (n = 9) as compared with age and CD4-matched HIV-1-seropositive persons with adequate vitamin E levels (n = 16, 118.1 +/- 41.1 IU/ml) and significantly lower levels (59.5 +/- 15.7 IU/ml) in HIV-1-seronegative men (n = 20, p = 0.01). This effect, which was independent of CD4 cell count, did not appear to be influenced by atopic or gastrointestinal parasitic disease. The low plasma vitamin E levels were related at least in part to dietary intake (r = 0.552, p = 0.01), suggesting that supplementation may be warranted in HIV-1-infected persons in whom vitamin E deficiency develops. Analysis of covariance revealed a strong relationship between IgE levels and CD8 cell counts (p < 0.006), and between IgE level and vitamin E deficiency (p < 0.039).(ABSTRACT TRUNCATED AT 250 WORDS)

Immunoglobulin E levels in relationship to HIV-1 disease, route of infection, and vitamin E status.

Our recent studies have demonstrated that in early HIV-1 infection, elevation of plasma immunoglobulin E (IgE) levels precedes the decline of CD4 cell count and is influenced by vitamin E status. In order to further investigate the role of IgE elevation in HIV-1 infection, we determined IgE levels in HIV-1-seropositive and -seronegative intravenous drug users (IDUs) (n = 38), in relationship to cellular and humoral immune function, liver enzymes, and vitamin E status. To examine the possible impact of the route of HIV-1 infection on IgE levels, comparisons between the cohorts of the HIV-1-seropositive and -seronegative IDUs and homosexual men (n = 45) were also conducted. All HIV-1-seropositive participants had significantly higher (P = 0.003) IgE levels than the HIV-1-seronegative subjects. The HIV-1-seropositive IDUs, moreover, demonstrated significantly higher (P = 0.01) IgE levels than HIV-1-seropositive homosexual men, despite similar CD4 cell counts. Stepwise regression analysis was used to evaluate the possible variables contributing to the IgE variation. HIV-1 status (P = 0.0009), intravenous drug use (P = 0.014), CD8 cell counts (P = 0.0001), plasma level of vitamin E (P = 0.006), and alcohol intake (P = 0.047) were significant, accounting for 71% of the IgE elevation. These findings suggest that IgE may serve as a sensitive marker to reflect the evolution of HIV-1 disease in individuals from different risk groups.

Plasma homocyst(e)ine, folate, and vitamin B-12 concentrations and risk for early-onset coronary artery disease.

High plasma homocyst(e)ine (Hcy) concentrations may be a determinant of coronary artery disease (CAD). Folate and vitamin B-12 are required for the primary metabolic pathway to reduce Hcy concentrations. The interrelationships of Hcy and these two vitamin cofactors were investigated in a case-control study of 101 white males aged 30-50 y with angiographically demonstrated CAD, and 108 white male, similarly aged, control subjects living in the same community as the patients. The odds ratio (OR) of CAD per quartile increase of plasma Hcy concentration based on control values was 1.6 (95% CI: 1.3, 2.1). After age, HDL and LDL cholesterol, body mass index, smoking, hypertension, and diabetes were controlled for, Hcy remained an independent risk factor (OR: 1.4; 95% CI: 1.0, 2.0). The OR change per quartile increase of folate concentration was 0.8 (95% CI: 0.6, 1.0). This difference was reduced (OR: 0.9; 95% CI: 0.7, 1.2) after Hcy adjustment. No difference in the geometric mean of vitamin B-12 concentration was found between patients and control subjects, both 5.8 nmol/L. However, after Hcy and the other CAD risk factors were controlled for, the OR per quartile increase in vitamin B-12 concentration was 1.5 (95% CI: 1.0, 1.8). Reduction in plasma Hcy by interventions to increase plasma folate concentration may decrease CAD risk.

Pharmacology of vitamin C.

A better understanding of the functions of ascorbic acid would help clarify the magnitude of the influence of this vitamin on health-related conditions. Many of the purported benefits require confirmation as well as a knowledge of the mechanism of action. The majority of investigations of the association of vitamin C with various types of cancer, with cardiovascular risk, and with cataract formation were epidemiologic studies. Often it was not possible to discern whether the apparent protective effect was due to vitamin C, vitamin E, or carotene, or to a combined effect of these nutrients or of additional factors. Human intervention trials may provide definitive and quantitative assessments of the role of vitamin C in health maintenance. We need to gain a more thorough understanding of the interactions of vitamin C with other nutrients, such as vitamin E and carotenoids, in order to appreciate the role of vitamin C in disease prevention. Investigators are increasingly recognizing the diverse functions of vitamin C in the body in addition to its role in collagen synthesis. However, the functional consequences of these many important roles of vitamin C remain essentially unknown. Excluding scurvy, the health consequences of inadequate vitamin C status are not well characterized. Nonetheless, epidemiologic evidence suggests a role for vitamin C in cancer and heart disease as well as in a number of other diseases.

Inadequate dietary intake and altered nutrition status in early HIV-1 infection.

Recent studies indicate that multiple nutritional abnormalities occur relatively early in the course of human immunodeficiency virus (HIV-1) infection. Decreased plasma levels of vitamins B6, B12, A, and E and zinc have been correlated with dietary intake and associated with significant alterations in immune response and cognitive function. To determine the level of intake consistent with normal plasma nutrient levels, we examined nutrition status in relation to food consumption and nutrient supplementation in HIV-1-seropositive (HIV+) and -seronegative (HIV-) homosexual men. The mean level of total intake (diet plus supplements) for all nutrients was significantly higher in HIV+ men. To achieve normal plasma nutrient values, the HIV+ men appeared to require intake in multiples of the recommended dietary allowance (RDA) for vitamins A, E, B6, and B12 and zinc. For the HIV+ men, a relatively high proportion of biochemical deficiency was associated with consumption of vitamin B6 and zinc at the RDA level. Because little evidence of deficiency was observed with elevated intake in both groups, an effective program of nutritional supplementation may be beneficial in maintaining adequate plasma nutrient levels.

Evaluation of three nutritional assessment methods in a group of women.

We conducted a reproducibility study of four 24-hour dietary recalls (N = 224) and four biochemical assessments of nutritional status (N = 265) in a group of women in Alabama. For 24-hour recalls, the variance component ratios were all greater than 1, and the intraclass correlation coefficients ranged from 0.16 to 0.27 for macronutrients, and from 0.09 to 0.37 for vitamins and minerals. The intraclass correlation coefficients for biochemical assessments ranged between 0.39 and 0.74 with corresponding variance component ratios of 1 or below for most nutrients. The correlation coefficients between the food frequency questionnaire on the usual dietary intake during the year preceding the beginning of study and the mean values of four 24-hour dietary recalls administered at the initial visit and again after 2, 4, and 6 months ranged from 0.3 to 0.4 for most nutrients. We found plasma beta-carotene levels to be moderately correlated with dietary vitamin A (r = 0.20) and beta-carotene (r = 0.22).

Vitamin B-6 depletion followed by repletion with animal- or plant-source diets and calcium and magnesium metabolism in young women.

An 84-98-d study was conducted in young women to determine the effect of vitamin B-6-deficient diets on calcium and magnesium metabolism. A vitamin B-6-deficient formula diet fed initially was followed by either animal- or plant-source protein food diets containing four increasing amounts of vitamin B-6. Calcium balance was negative during vitamin B-6 depletion. Serum calcium was higher and calcium balance negative with the plant protein diets. Magnesium balance was negative during vitamin B-6 depletion due to increased urinary magnesium excretion. Urinary calcium decreased during vitamin B-6 depletion and increased as dietary vitamin B-6 increased. Urinary oxalate was significantly higher at the end than at the beginning of vitamin B-6 depletion and was higher with plant than animal protein diets. The results suggest that vitamin B-6 depletion may alter calcium and magnesium metabolism and that dietary components associated with the protein source may influence calcium retention.