Hypertension detection and follow-up program study of serum retinol, retinol-binding protein, total carotenoids, and cancer risk: a summary.

In a recently reported study by us, no significant associations were found between retinol, retinol-binding protein (RBP), and total carotenoid levels in prediagnositic serum and the incidence of cancer at all sites combined. Inasmuch as other investigators, in addition to us, have not been able to confirm the two original reports of an inverse association between serum retinol and overall cancer incidence, the relationship, if it exists at all, is probably complex and limited to certain population subgroups. Such subgroups may be defined by extreme values of serum retinol, certain levels of other nutrients, or specific types of cancer. In the present study an inverse association was observed between serum retinol levels and cancer among subjects with low serum selenium levels and for subjects with gastrointestinal cancer. In addition, the risk of cancer was elevated for those individuals with the combination of low serum retinol and high RBP. However, since significant associations will arise by chance alone when many subgroups are examined, these findings are difficult to interpret. Additional studies will be needed to determine whether they are reproducible or are simply the results of chance.

Vitamin A supplementation and plasma retinol levels: a randomized trial among women.

Although dietary intake of vitamin A has little, if any, overall effect on blood retinol in generally well-nourished populations, subgroups may exist that would be responsive to supplementation. The hypothesis that vitamin A supplementation increases blood retinol in apparently well-fed individuals with lower than usual blood levels was tested in female health workers, with relatively low blood retinol values, who were randomly assigned to receive vitamin A (10,000 IU daily) or placebo. After 4 weeks the mean change in plasma retinol was -0.4 micrograms/dl for the group receiving placebo and +4.1 micrograms/dl (an increase of 9% over base-line values) for the group receiving vitamin A (P = .02). The results were similar when the base-line retinol level and several other covariates were considered. Thirteen women who had initially received placebo were then switched to vitamin A for 4 weeks. These women experienced a mean increase of 5.3 micrograms/dl in plasma retinol (P = .04). Responses to vitamin A supplementation tend to be greater among women with lower previous total vitamin A intake, as assessed by questionnaire [Spearman rank correlation coefficient (r) = 0.50; P = .01].

The roles of bile salts in the uptake of beta-carotene and retinol by rat everted gut sacs.

The effects of bile salts, Tween 20 and hexadecyltrimethylammonium-bromide on the uptake of beta-[3H]carotene and [3H]retinol by rat-everted gut sacs were studied in vitro under conditions simulating those present in the intestinal lumen during lipid absorption. 2. Micellar solutions significantly enhanced uptake over emulsions. Maximum uptake occurred at the critical micellar concentration of the bile salts mixture. At higher detergent concentrations beta-carotene uptake declined sharply; retinol absorption remained high. 3. In beta-carotene absorption bile salts functioned not only as micellar solubilizers but also may have been required for interaction with the cell membrane or as a transport carrier. In retinol uptake their primary function appeared only to be micellar solubilization. Both uptake and efflux of substrates were enhanced in bile salt micellar solutions compared to the other detergents. 4. Beta-carotene cleavage and conversion to retinyl esters occurred only in bile salts solutions. Retinol esterification was seen with all detergents. These effects increased as the tri/dihydroxy bile salts ratio was increased. 5. Beta-carotene uptake appeared to be reversible and passive at low concentrations. Retinol uptake was reversible, 7-30 times more rapid, and partially inhibited by 2,4-dinitrophenol at higher concentrations. An energy-requiring step may have been rate limiting.

Maternal vitamin A status and its importance in infancy and early childhood.

Early fetal vitamin A supplies must be regulated to avoid teratogenic consequences from too little or too much. Late in gestation, adequate maternal vitamin A status is important for newborn reserves and for sustaining adequate breast-milk concentrations. Vitamin A supplements are not needed for most pregnant women in Western countries who consume the recommended dietary allowance during their reproductive years. Increased consumption of vitamin A-rich foods can meet increased needs during lactation. Women in developing countries whose habitual intakes are near basal needs should receive an additional 100 micrograms retinol equivalents (RE) during pregnancy and 300 micrograms RE during lactation. Supplements not above 3000 micrograms RE (10,000 IU) daily are safe for fertile women where circumstances preclude obtaining the needed increment through diet. The first postpartum month is the only safe period during which to provide deficient lactating women with a single high-dose supplement to benefit the mother and breast-feeding infant for several months.

The effect of oral zinc supplementation on plasma levels of vitamin A and retinol-binding protein in cystic fibrosis.

Oral zinc supplementation with 100 mg zinc sulfate over an 8-week period in 36 patients with cystic fibrosis and 17 siblings did not affect the vitamin A transport system, as evidenced by an absence of consistent and significant quantitative changes in plasma levels of vitamin A, retinol-binding protein, and zinc, nor did the exogenous zinc appear to stimulate growth or exert any clinical benefit to the cystic fibrosis patients. The lack of response to zinc supplementation might be explained by the fact that the group of cystic fibrosis subjects studied was fairly healthy in regard to clinical status and certain blood parameters, including zinc.

Vitamin A and retinol-binding protein in amniotic fluid.

Amniotic fluid and serum samples that had been obtained from mothers at 10 to 33 wk of gestation were analyzed for retinol and retinol-binding protein. No difference was found in serum retinol with advancing gestation. The concentration of retinol in amniotic fluid from 20 wk onward was significantly greater than at 16 to 18 wk. No esters of retinol and no carotenoids were detected in amniotic fluid. Serum and amniotic fluid samples from the same mothers were significantly correlated for retinol (p less than 0.02). Retinol-binding protein, detected by radial immunodiffusion, was found in amniotic fluid in molar excess of, and significantly (p less than 0.001) correlated with, retinol in amniotic fluid. Retinol in amniotic fluid obtained at 16 to 18 wk from pregnancies that ended in anencephaly or other congenital defects ranged from 2.3 to 18.0 micrograms/dl. The range of amniotic fluid values in abnormal pregnancy precludes using retinol or retinol-binding protein as a marker in prenatal diagnosis of abnormalities.

Effect of an infection on vitamin A status of children as measured by the relative dose response (RDR).

The effect of an infective episode of chickenpox on the vitamin A status of preschool-aged children was evaluated by use of the relative dose response (RDR) test. Status was determined before and 30, 120, and 180 d after administration of a single oral high-dosage (200,000 IU) supplement of vitamin A. No differences in mean blood levels of retinol or percentage of children showing a positive RDR were apparent until after the infective episode that occurred approximately 90 d after dosing. At 180 d postsupplementation, 74% of children who had been infected tested positive by the RDR, indicative of an inadequate liver reserve of vitamin A, in contrast to only 10% who had not been infected. Paired RDR observations at 0 and 180 d postsupplementation confirmed that the infective episode caused an accelerated depletion of liver reserves of vitamin A.

Diarrhea, respiratory infections, and growth are not affected by a weekly low-dose vitamin A supplement: a masked, controlled field trial in children in southern India.

Incidence, duration, and severity of diarrhea and respiratory symptoms were monitored weekly for 1 y in 15,419 children 6-60 mo of age in a randomized, placebo-controlled, masked clinical trial conducted in southern India. Half the children received weekly doses of 8.7 mumol (2500 microgram) vitamin A and 46 mumol (20 mg) vitamin E (treated) and the other half, 46 mumol vitamin E (control). Medical and ocular examinations and anthropometric measurements were obtained before and after 52 wk of intervention. Ocular examinations also were obtained after 26 wk. Supplements were delivered weekly from calibrated dispenser bottles by community health volunteers who also recorded each mother's recall of daily morbidity of her child during the previous week. Baseline characteristics of treated and control subjects were similar and documented a prevalence of 11% xerophthalmia and 72% undernutrition. Weekly treatment with the low-dose vitamin A supplement did not influence the incidence, severity, or duration of diarrhea or respiratory infections and did not influence linear or ponderal growth.

Serum retinol levels of persons aged 4-74 years from three Hispanic groups.

Previous research suggests that Hispanics in this country may have poor vitamin A status. Using serum retinol data from the Hispanic Health and Nutrition Examination Survey, we examined the vitamin A status of Mexican Americans (MA), Cubans, and Puerto Ricans (PR) aged 4-74 y. MA had lower mean serum retinol levels and higher prevalences of serum retinol in the range of 0.70-1.01 mumol/L than did Cubans in several age-sex groups. The prevalence (or percentage) of serum retinol in a range indicating possible risk of functional impairment was not elevated in any of the Hispanic groups except the females aged 18-44 y. However, a high percentage of children and adolescents in the three Hispanic groups had serum retinol values in ranges that might indicate less-than-optimal vitamin A status. Determination of vitamin A status requires a more definitive assessment than by serum vitamin A alone.

Assessment of marginal vitamin A deficiency in Brazilian children using the relative dose response procedure.

Vitamin A status was determined using fasting plasma levels and the relative dose response (RDR) procedure before and 30, 120, and 180 days after administration of an oral massive (200,000 IU) dose of vitamin A. The study was carried out in Recife, Brazil among 93 children of 7 yr or less from low income families who attended two day-care programs. The RDR procedure is conducted by obtaining a fasting blood (A0), feeding 450 retinol equivalents and obtaining a second blood specimen after 5 h (A5). The RDR-(A5-A0)/A5 X 100. A single massive oral dose of vitamin A was given after conducting the base-line RDR test. The RDR procedure was repeated at 30, 120, and 180 days. Weight and height measurements were obtained at each observation and the bloods were analyzed for Hb, total protein, and serum iron, as well as vitamin A. Serum albumin was determined in 120- and 180-day bloods. Serum iron levels were improved 30 days after supplementation with the massive dose of vitamin A. The RDR procedure was found practical to apply in mildly undernourished children under nonclinical condition. In this group of low income children presumed to be habitually ingesting minimally adequate diets, a serum vitamin A level of 20 micrograms/dl or less invariably was associated with an elevated RDR test. Blood levels between 20 to 40 micrograms/dl were not consistently predictive of the RDR response. All elevated RDR tests reverted to normal after supplementation with vitamin A, presumably indirectly indicating a presupplementation inadequate vitamin A status. Hence, the RDR was a more sensitive indicator of inadequate vitamin A status than was only a serum level of vitamin A when blood levels were above 20 micrograms/dl.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of the relative dose response test for vitamin A nutriture in cirrhotics.

The rise in serum vitamin A 5 h after a 450 microgram oral dose of the vitamin (retinyl palmitate) was used to assess vitamin A nutriture in patients with alcoholic cirrhosis. The test was carried out on 21 hospitalized male patients and 12 normal age and sex-matched control subjects. The relative dose response (RDR), expressed as percentage, was calculated as A5 - A0/A5 X 100 where A0 = the fasting serum retinol level and A5 = the serum retinol 5 h postdosing. Vitamin A-deficient patients (those with serum retinol levels less than 30 microgram/dl and an abnormal dark adaptation test or RDR greater than or equal to 14%) were treated with 4 wk of oral vitamin A (10,000 microgram/day), then repeat RDR and dark adaptation tests were carried out. Among eight cirrhotics with abnormal dark adaptation, the mean +/- SEM RDR was 21 +/- 9 versus 3 +/- 3% in patients with normal dark adaptation (p less than 0.01). RDR tests of patients with normal dark adaptation did not differ from those of 12 normal age and sex-matched control subjects (normal RDR response 0 to 14%). Among patients found to be vitamin A-deficient, treatment with vitamin A resulted in the mean +/- SEM RDR declining from 21 +/- 9 to 5 +/- 2%. However, this fall failed to reach statistical significance (p = 0.06). The RDR test appears to be useful as a predictor of vitamin A deficiency, even among patients with far advanced hepatic disease.

Vitamins A, E, and carotene: effects of supplementation on their plasma levels.

We conducted a randomized, double-blind trial among 59 generally well-nourished adults to determine the effects of vitamin A, vitamin E, and beta-carotene supplements on plasma retinol, alpha-tocopherol, and carotenoid levels. Over a period of 16 wk a daily alpha-tocopherol supplement of 800 IU approximately doubled plasma alpha-tocopherol levels (p less than 0.001), caused a small decrease in plasma carotenoids (p = 0.02), and produced a slight and statistically insignificant reduction in plasma retinol. A daily beta-carotene supplement of 30 mg (5000 retinol equivalents) approximately tripled plasma carotenoid levels (p less than 0.001) but did not affect plasma retinol or alpha-tocopherol. A daily retinyl palmitate supplement of 25,000 IU (13,750 retinol equivalents) did not appreciably affect plasma retinol, alpha-tocopherol, or carotenoid.

Oral contraceptives: effect of long-term use on liver vitamin A storage assessed by the relative dose response test.

Vitamin A status measured by the relative dose response (RDR) test was determined among groups of Northern Thai women who had used estrogen-containing oral contraceptives (OCs) with or without multivitamin supplements through 13 cycles. Mean serum vitamin A values were elevated approximately 40% above those of control subjects (intrauterine contraceptive device (IUCD) users) during OC usage. Daily (one capsule) or periodic (two capsules 7 d/mo) multivitamin supplementation that included 1700 micrograms vitamin A per capsule did not significantly influence vitamin A serum values. The RDR test after 13 cycles was elevated in one individual who had taken OCs and the periodic multivitamin supplement. It reverted to normal after supplementation with vitamin A. A single high-dose vitamin A supplement (68,000 micrograms) did not change circulating levels of the vitamin. Among this population there is little evidence that use of estrogen-containing OCs for greater than 1 y resulted in a physiologically significant deterioration of vitamin A status.

PIP: Vitamin A status measured by the relative dose response (RDR) test was determined among groups of Northern Thai women who had used estrogen- containing oral contraceptives (OCs) with or without multivitamin supplements through 13 cycles. Mean serum vitamin A values were elevated approximately 40% above those of control subjects (IUD users) during OC usage. Daily (1 capsule) or periodic (2 capsules 7 days/month) multivitamin supplementation that included 1700 mcg vitamin A/capsule did not significantly influence vitamin A serum values. The RDR test after 13 cycles was elevated in 1 individual who had taken OCs and the periodic multivitamin supplement. It reverted to normal after supplementation with vitamin A. A single high-dose vitamin A supplement (68,000 mcg) did not change circulating levels of the vitamin. Among this population there is little evidence that use of estrogen-containing OCs for more than 1 year resulted in a physiologically significant deterioration of vitamin A status.

Ethnic and racial differences in serum vitamin A levels of children aged 4-11 years.

Interpretation of differences in serum vitamin A levels observed between Hispanic and non-Hispanic children may be complicated by confounding environmental factors. Data from the Mexican-American portion of the Hispanic Health and Nutrition Examination Survey and the second National Health and Nutrition Examination Survey were used to explore these differences in 4-11-y-old Mexican Americans and non-Hispanic blacks and whites before and after accounting for vitamin-mineral supplement use and poverty status. Initial differences in mean serum vitamin A levels and prevalences less than 20 micrograms/dL (0.70 mumol/L) or less than 25 micrograms/dL (0.87 mumol/L) among the three ethnic or racial groups were reduced or eliminated after accounting for the two descriptive variables. These results support the hypothesis that differences in serum vitamin A levels between Mexican-American and non-Hispanic children in the United States are due more to environmental factors than to ethnicity.

Serum alpha-tocopherol levels of Mexican Americans, Cubans, and Puerto Ricans aged 4-74 y.

Data from the Hispanic Health and Nutrition Examination Survey were used to examine serum alpha-tocopherol levels (in subjects aged 4-74 y) and ratios of alpha-tocopherol to cholesterol plus triglyceride and to cholesterol (in subjects aged 20-74 y) of Mexican Americans (MA), Cubans, and Puerto Ricans (PR). Neither alpha-tocopherol nor the alpha-tocopherol-lipid ratios differed between sexes. PR had lower mean alpha-tocopherol and alpha-tocopherol-lipid ratios and higher prevalences of alpha-tocopherol less than 11.6 mumol/L than did MA or Cubans in several age groups. MA and Cuban adolescents had lower alpha-tocopherol levels than children had. Mean alpha-tocopherol levels and alpha-tocopherol-lipid ratios increased and prevalences of alpha-tocopherol less than 11.6 mumol/L decreased during adulthood in all three ethnic groups.

Serum vitamin A distribution curve for children aged 2-6 y known to have adequate vitamin A status: a reference population.

Serum vitamin A was determined before and 30-45 d after the administration of 60.6 mg (212 mumol) vitamin A to 544 Brazilian children residing in slum areas of Recife. The frequency-distribution curves were compared in a subgroup of children whose vitamin A status was assessed initially by the relative-dose-response (RDR) test. The curves of children with negative (adequate status) and positive (inadequate status) RDR tests were different. The difference disappeared after supplementation. The shape of the distribution curve after supplementation was close to normal with a mean, median, and 95% confidence interval of 1.78 +/- 0.49, 1.68, and 1.02-2.90 mumol/L, respectively. The postsupplementation curve derived from this underprivileged child population may serve as a reference for diagnostic, surveillance, and program-evaluation purposes.

Validation of a dietary questionnaire with plasma carotenoid and alpha-tocopherol levels.

We assessed the validity of a self-administered semiquantitative food frequency questionnaire by comparing carotene and vitamin E intake scores derived from form with plasma carotenoid and alpha-tocopherol levels among a group of 59 men and women. The simple correlation between carotene intake and plasma carotenoid was 0.29 (p = 0.02) and the partial correlation was 0.35 (p = 0.005) after adjustment for age, sex, total caloric intake, and plasma cholesterol and triglycerides. The simple correlation between vitamin E intake and plasma alpha-tocopherol was 0.12 (p = 0.19). However, adjustment for total caloric intake and plasma lipids each substantially increased this association so that the partial correlation adjusting simultaneously for caloric intake, plasma lipids, age, and sex was 0.34 (p = 0.006). As expected on the basis of previous randomized trials, the correlation between preformed vitamin A intake and plasma retinol was weak and not statistically significant. These data support the utility of self-administered food frequency questionnaires for use in epidemiological studies. In addition, they illustrate the importance of adjusting blood alpha-tocopherol levels for lipid concentrations when the former are used as surrogates for vitamin E intake.

Gabapentin does not interact with a contraceptive regimen of norethindrone acetate and ethinyl estradiol.

Anticonvulsants that induce hepatic metabolism increase clearance of oral contraceptive hormones and thereby cause contraceptive failure. Gabapentin is not metabolized in humans and has little liability for causing metabolic-based drug-drug interactions. In healthy women receiving 2.5 mg norethindrone acetate and 50 microg ethinyl estradiol daily for three consecutive menstrual cycles, concurrent gabapentin administration did not alter the steady-state pharmacokinetics of either hormone. Thus, gabapentin is unlikely to cause contraceptive failure.

PIP: Anticonvulsants that induce hepatic metabolism increase the clearance of synthetic estrogens and progestogens used in oral contraceptives (OCs), thereby potentiating contraceptive failure. In contrast, the anticonvulsant drug gabapentin is not metabolized in humans and has little liability for metabolic-based drug interactions. The present study sought to confirm whether concurrent administration of gabapentin would alter the pharmacokinetics of norethindrone acetate (2.5 mg) and ethinyl estradiol (50 mcg) in healthy US women. A total of 13 women were enrolled for three menstrual cycles each. Pharmacokinetic values did not change appreciably as a result of the addition of gabapentin. The rate and extent of absorption of both hormones were unaffected by the anticonvulsant. Gabapentin plasma concentration time profiles and pharmacokinetic values from this study were similar to historical values after administration of gabapentin alone. The observed lack of interaction between gabapentin and norethindrone acetate or ethinyl estradiol is consistent with the fact that gabapentin is not metabolized, is not an inducer or inhibitor of hepatic drug metabolizing enzymes, is absorbed via a specific transport system for amino acids, and is not bound to plasma proteins. Anticonvulsant drugs that do not interact with OCs should be considered for the treatment of epileptic women of childbearing age who are using this method of fertility control.

Biochemical and histological methodologies for assessing vitamin A status in human populations.

In recent years, new biochemical and histological methodologies have been developed for assessing vitamin A nutritional status in humans at subclinical levels of nutriture. Insensitive static blood levels no longer are the only practical assessment parameter. Some of the newer functional methodologies require additional testing of their sensitivity and specificity under a variety of conditions existing in human populations and that frequently are associated with an inadequate vitamin A status. Some of these conditions could confound the interpretation when only a single assessment method is applied.

Weaning practices in deprived environments: the weaning dilemma.

The weaning process varies widely among different cultures as to when the practice is initiated and terminated; in the variety, quality, and quantity of the weaning foods; and in the manner in which the endogenous food is provided. The variations in practices range from providing a food source even before the first breast-feeding to feeding nothing but breast milk for as long as 9 to 12 months, and include feeding from a cupped hand to use of a modern feeding bottle. The advice often given healthy mothers is to breast-feed for as long as possible and compatible with life-style. Most often, when breast-feeding is prolonged, the practice is to provide some complementary food from the early postpartum months onward. However, among some poor traditional societies and in deprived environments, this food may be limited and monotonous in flavor and texture. The monotony of the diet may act synergistically with the consequences of repeated infectious morbidity, and result in chronically depressed appetite and limited acceptance of additional food in quantity and variety at the time when this becomes critical for meeting the nutritional needs of the growing infant. The serious malnutrition prevalent in the 1 to 3 year olds in many deprived environments may have its antecedent etiology in the complementary feeding practices established in the first year of life. Effective interventions to reverse growth faltering of infants reared in deprived environments where breast-feeding is prolonged may require increased attention to providing variety in the weaning diet from at least 4 months onward.