Micronuclei in lymphocytes and exfoliated buccal cells of postmenopausal women with dietary changes in folate

Folate deficiency is associated with anemia, birth defects, cancer and neuropsychiatric disorders. The purpose of this study was to determine if a moderate folate deficiency during controlled changes in folate intake would affect chromosomal damage in lymphocytes and buccal cells. A study of nine healthy postmenopausal women volunteers (age 49-63 years) was carried out in a metabolic unit (baseline week with folate intake of 195 microg/day, five-week depletion at 56 microg/day, and gradual repletion including four weeks at 111 microg/day, 11 days at 286 microg/day and 9 days at 516 microg/day). Plasma folate, vitamin B-12, and homocysteine were measured weekly. Cytogenetic damage was assessed by scoring micronucleus (MN) frequency in lymphocytes and buccal cells three times: (1) at the beginning of the study, (2) at the end of depletion, and (3) after repletion. The MN frequency increased in binucleated lymphocytes, as well as in all lymphocytes, after depletion (p=0.037), and later decreased following repletion (p=0. 028). Both kinetochore-positive and kinetochore-negative MN were increased after depletion (p=0.015 and 0.028), but after repletion only the change in kinetochore-positive MN was statistically significant (p=0.048). The main variables affecting MN were: (1) vitamin B-12 level, (2) plasma folate level, and (3) baseline frequency of MN. The MN frequency in exfoliated buccal cells was decreased after dietary supplementation of 516 microg/day folate (p=0.010). Thus, low folate, without clinical symptoms of anemia, results in higher levels of cytogenetic damage in both the blood and oral cavity of postmenopausal women.     

Maternal folate status during extended lactation and the effect of supplemental folic acid

BACKGROUND: Folate requirements during lactation are not well established. OBJECTIVE: We assessed the effects of dietary and supplemental folate intakes during extended lactation. DESIGN: Lactating women (n = 42) were enrolled in a double-blind, randomized, longitudinal supplementation trial and received either 0 or 1 mg folic acid/d. At 3 and 6 mo postpartum, maternal folate status was assessed by measuring erythrocyte, plasma, milk, and dietary folate concentrations; plasma homocysteine; and hematologic indexes. Infant anthropometric measures of growth, milk intake, and folate intake were also assessed. RESULTS: In supplemented women, values at 6 mo for erythrocyte and milk folate concentrations and for plasma homocysteine were not significantly different from those at 3 mo. In supplemented women compared with unsupplemented women at 6 mo, values for erythrocyte folate (840 compared with 667 nmol/L; P < 0.05), hemoglobin (140 compared with 134 g/L; P < 0.02), and hematocrit (0.41 compared with 0.39; P < 0.02) were higher and values for reticulocytes were lower. In unsupplemented women, milk folate declined from 224 to 187 nmol/L (99 to 82 ng/mL), whereas plasma homocysteine increased from 6.7 to 7.4 micromol/L. Dietary folate intake was not significantly different between groups (380+/-19 microg/d) and at 6 mo was correlated with plasma homocysteine in unsupplemented women (r = -0.53, P < 0.01) and with plasma folate in supplemented women (r = 0.49, P < 0.02). CONCLUSIONS: A dietary folate intake of approximately 380 microg/d may not be sufficient to prevent mobilization of maternal folate stores during lactation.     

Folate intake in Europe: recommended, actual and desired intake

OBJECTIVES: To evaluate possible inconsistencies between recommended, actual and desired folate intake in European adult populations. DESIGN: Review of dietary recommendations, of food consumption surveys, and of intervention and observational studies relating folate intake to the risk of neural tube defects and plasma homocysteine levels. RESULTS: In Europe, mean dietary folate intake in adults is 291 micrograms/d (range 197-326) for men and 247 micrograms/d (range 168-320) for women. The recommended intakes vary between 200-300 micrograms/d (men) and 170-300 micrograms/d (women). However, women with a previous pregnancy affected by a neural tube defect (NTD), are recommended to take 4000 micrograms/d of supplemental folic acid when planning a subsequent pregnancy. For those without a history of NTD, the use of 400 micrograms/d of supplemental folic acid is the best option to prevent the occurrence of NTDs. A daily dose of 650 micrograms supplemental folic acid normalises elevated plasma homocysteine levels, which is a risk factor for cardiovascular diseases. A dietary folate intake of at least 350 micrograms/d is desired to prevent an increase in plasma homocysteine levels of the adult population in general. CONCLUSIONS: Mean dietary folate intake in Europe is in line with recommendations, but the desired dietary intake of > 350 micrograms/d is only reached by a small part of studied European populations. It is considered unethical to investigate whether supplements with a dose lower than 400 micrograms/d of folic acid are also protective against NTDs. However, research to establish the lowest effective dose of dietary folate/supplemental folic acid to optimise homocysteine levels and research on the bioavailability of folate is required. This will enable the choice of a strategy to achieve desired folate intakes in the general population. In the meantime, consumption of plant foods like vegetables, fruits, and cereals should be stimulated to reach the desired level of 350 micrograms of dietary folate per day.     

Folate status response to controlled folate intake in pregnant women

A metabolic study (84-d) was conducted to investigate the folate status response of pregnant subjects (n = 12) during their second trimester and nonpregnant controls (n = 12) to folate intakes approximating the current (400 microg/d) and former (800 microg/d) recommended dietary allowance (RDA). The overall goal of the study was to provide metabolic data to assist in the interpretation of the current RDA for folate. Subjects were fed a controlled diet containing 120 +/- 15 microg/d (mean +/- SD) folate and either 330 or 730 microg/d synthetic folic acid. Outcome variables between and within supplementation groups were compared at steady state. Serum folate was higher (P 0.05) were detected in serum folate between pregnant and nonpregnant women within the same supplementation group. Urinary 5-methyl-tetrahydrofolate excretion was greater (P 0.05) in 5-methyl-tetrahydrofolate excretion were detected between pregnant and nonpregnant women within supplementation groups. Differences (P 相似文献   

Randomized, double-blind, placebo-controlled study of the effects of raloxifene and conjugated equine estrogen on plasma homocysteine levels in healthy postmenopausal women

OBJECTIVE: To investigate the long-term effects of raloxifene on fasting plasma homocysteine levels in postmenopausal women compared with conjugated equine estrogen (CEE). DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Outpatient department of a university hospital. PATIENT(S): Fifty-two hysterectomized, healthy postmenopausal women. INTERVENTION(S): Oral raloxifene in two dosages (60 mg/d [n=13] and 150 mg/d [n=13]), oral CEE (0.625 mg/d [n=13], and placebo (n=13) were given for 24 months. MAIN OUTCOME MEASURE(S): Fasting plasma homocysteine concentrations. RESULT(S): Plasma homocysteine levels were not altered in the placebo group. After 12 months, a significant reduction versus baseline in the mean plasma homocysteine level (-16%) was found only in the raloxifene 150-mg group. The mean change in plasma homocysteine levels within this group also was significantly different from the changes versus baseline found in the placebo group (+2%) and the raloxifene 60-mg group (-2%), but not different from those found in the CEE group (-8%). After 24 months, plasma homocysteine levels were decreased significantly in the raloxifene 150-mg and CEE groups compared with both baseline (-13% and -10%, respectively) and placebo values (-15% and -11%, respectively). No significant change in plasma homocysteine levels was observed in the raloxifene 60-mg group. CONCLUSION(S): Raloxifene has a favorable, dose-related effect on plasma homocysteine levels in postmenopausal women.     

Drug and environmental factors associated with adverse pregnancy outcomes. Part III: Folic acid: pharmacology, therapeutic recommendations, and economics

OBJECTIVE: To review folic acid's mechanism of action, adverse effects, therapeutic recommendations, compliance, and cost. DATA SOURCES: A MEDLINE search was conducted through December 1997. Additional sources were obtained from Current Contents and citations from the references obtained. Search terms included folate, folic acid, neural tube defect, homocysteine, and methylenetetrahydrofolate reductase. STUDY SELECTION: Animal and human studies examining the effects of folate were reviewed. DATA EXTRACTION: Data collected included mechanism of action, safety issues, dosing recommendations, compliance with recommendations, and economics. DATA SYNTHESIS: Folic acid decreases neural tube defect risk through an effect on methionine-homocysteine metabolism. In addition, increased folate intake may reduce cardiovascular morbidity and mortality. Since toxicity is minimal, everyone can potentially benefit from increased folate consumption. To help achieve this, the Food and Drug Administration has mandated that cereal grain be fortified with 140 micrograms of folic acid per 100 g of grain, which will add approximately 0.1 mg of folate to the average diet. Studies recommend supplementing with 0.2 mg to promote optimal homocysteine concentrations and for preventing neural tube defects. CONCLUSIONS: Despite fortification, most women will still receive less folate than the 0.4 mg/d recommended by the Public Health Service. All population groups would benefit from increased folate intake. Current studies indicate 200 micrograms/d may be the minimum effective amount of fortification needed for normalizing homocysteine concentrations and preventing a significant number of neural tube defects; thus, a higher level of food fortification may be warranted.     

Atherogenesis and the homocysteine-folate-cobalamin triad: do we need standardized analyses?

BACKGROUND: Bioscientists, physicians and nutritionists are newly interested in the homocysteine-folate-cobalamin triad, in part because homocysteine may be important both in atherogenesis and thrombogenesis. Homocysteine imbalance may be an early marker for cobalamin disorders because cobalamin is a cofactor in remethylation of homocysteine to methionine. METHODS: In 139 men and 32 women of similar mean age of 65 years, we measured markers which have been cited as risk for atherosclerosis: serum homocysteine, folate, total cobalamin, holotranscobalamin I and II, (TCI and TCII), total serum cholesterol (SCHOL), high density lipoprotein cholesterol (HDLC), triglycerides (STG) as well as red blood cell (RBC) folate, food records and body composition by whole body counting of potassium-forty (40K). RESULTS: Statistical relationships among the data showed healthy women had lower mean serum homocysteine and their mean RBC folate and TCI and TCII were higher than men. Eighty-three subjects had TCII much lower than 60 pg/ml (subnormal), yet only 11 of these men and two women had total cobalamin < 200 pg/ml (abnormal). Fifty-two subjects with serum homocysteine greater than 17.5 nmol/ml had TCII less than 60 pg/ml, suggesting serum homocysteine may be a marker for early cobalamin negative balance. None of the subjects in the study had serum folate below abnormal values, i.e., less than 1.6 mg/ml. All subjects had RBC folate within normal range. Serum homocysteine showed inverse relationship with RBC folate and serum total cobalamin, TCI and TCII. CONCLUSIONS: 1) importance of using serum holotranscobalamin TCI and TCII as markers of cobalamin deficiency, 2) necessity to use documented quantitative components of dietary intake if strong comparisons are to be made among quantitative values of serum or plasma homocysteine, folate, cobalamin, and nutrients in food intake.     

Hyperhomocysteinaemia--a common finding in a psychogeriatric population

Plasma homocysteine concentration is a sensitive marker for cobalamin and folate deficiency. The previously reported high incidence of increased plasma homocysteine in psychogeriatric patients and the association between reduced concentrations of cobalamin, folate and neuropsychiatric symptoms led to the present study on 741 consecutive psychogeriatric patients. The concentrations of plasma homocysteine correlated significantly with blood folate, serum cobalamin and serum creatinine both in demented (n = 295) and in non-demented patients with other psychiatric disorders (n = 215). Plasma homocysteine concentrations were significantly increased in both the demented and the non-demented patients, whereas only the demented patients had lower blood folate and serum creatinine concentrations than 163 control subjects. Almost all of the different diagnostic groups of demented and non-demented patients exhibited significantly increased plasma homocysteine concentrations compared with control subjects. Significantly decreased blood folate concentrations were mainly found in the different diagnosis groups of demented patients. Plasma homocysteine concentrations in both demented and non-demented patients with serum cobalamin and blood folate above the lower 20th percentile of these vitamins in the control subjects were also studied. Despite these vitamin concentrations, both groups of patients still exhibited significantly higher plasma homocysteine concentrations than the control subjects, which may indicate an increased frequency of impaired genetic capacity to metabolize homocysteine in these patients. Patients with either dementia of vascular cause or a history of other occlusive arterial disease had a significantly higher plasma homocysteine concentration than those without a history of vascular disease.     

The growth and development of the Annals of Human Biology: a 25-year retrospective

Several fundamental questions relating to the biochemical basis of megaloblastic hemopoiesis in vitamin B12 (B12) and folate deficiency and neurological damage in B12 deficiency remain to be answered. Among them is the explanation underlying (1) the failure of B12-deficient animals to develop megaloblastic hemopoiesis despite indirect evidence of impaired thymidylate synthesis and (2) the inverse relationship between the extent of hematologic and neurological damage in B12 deficiency. Diagnostic advances have led to the awareness that many patients with B12 or folate deficiency are hematologically normal and that subtle hematologic or neuropsychiatric manifestations may be found at a fairly early stage of developing B12 deficiency. Studies of the mechanism of absorption of B12 in food have identified the syndrome of food B12 malabsorption in which the degree of B12 deficiency is commonly, although not invariably, mild. Folate intake influences the prevalence of neural tube defects (NTDs) and a suboptimal folate status may be associated with an increased risk for dysplasia and cancer. The latter may be at least partly the result of uracil misincorporation into DNA and consequent DNA strand breaks. Folate status has also been linked to arteriosclerotic vascular disease through its effect on serum homocysteine levels. Uracil misincorporation into DNA and increased serum homocysteine levels may also be found in B12 deficiency. These adverse associations form the basis of a case for improving B12 or folate status in individuals with a mild degree of deficiency. Because inadequate folate intake is relatively common, especially in the elderly and the poor, the fortification of staple foods with folate is currently under active consideration.     

Folic acid deficiency enhances oral contraceptive-induced platelet hyperactivity

In previous studies conducted in female rats and in women, oral contraceptives (OC) were found to induce a platelet hyperactivity that was related to an oxidative stress. Because cases of megaloblastic anemia have been reported to occur in women taking OC, these treatments are suspected of depleting folate stores. In the study presented herein, which was conducted in rats, we sought to determine the influence of dietary folic acid deficiency (FD) on the thrombogenicity of OC. Animals were fed for 6 weeks with either a folic acid-deficient diet (250 micrograms/kg folic acid) or a control diet (750 micrograms/kg). One-half of the animals in each group were treated with OC (ethinyl estradiol plus lynestrenol). FD and OC individually potentiated platelet aggregation in response to thrombin and ADP and the release and metabolism of arachidonic acid, in particular, the biosynthesis of thromboxane. These platelet activities were further enhanced in animals given both the folic acid-deficient diet and the OC treatment. In addition, FD enhanced the pro-oxidant state in OC-treated rats characterized by (1) a fall in platelet and plasma n-3 fatty acids, (2) an increase in plasma lipid peroxidation products such as conjugated dienes, lipid peroxides, and thiobarbituric reactive substances, (3) a rise in ex vivo erythrocyte susceptibility to free radicals. Moreover, we found that OC treatment led to a reduction of plasma and erythrocyte folate concentrations associated with a moderate hyperhomocysteinemia. Under our experimental conditions, we did not find significant synergistic effects between OC and FD. We propose that, although the untoward effects associated with the OC treatment may not primarily be dependent on FD, the folic acid deficiency magnified OC-induced oxidative stress, which resulted in platelet hyperactivity by elevating the pro-oxidant homocysteine plasma concentration. Despite the limitations of this animal model, the data of the present study suggest that in addition to cigarette smoking, inadequate folic acid intake might predispose those taking OC to vascular thrombosis.     

Limbal cell autograft transplantation for severe ocular surface disorders

OBJECTIVE: To determine if poor dietary intake can explain the cobalamin-related abnormalities often seen in the elderly. DESIGN: Prospective laboratory survey with a follow-up dietary assessment. SETTING: Social centers for the elderly and an outpatient clinic. SUBJECTS: Ninety-five free-living subjects >60y old with abnormal or suspicious findings in cobalamin-related tests and 78 subjects >60y old with normal results. INTERVENTIONS: Serum cobalamin, methylmalonic acid and homocysteine determinations to assess cobalamin status and a one year food-frequency questionnaire to assess cobalamin intake. RESULTS: Only three of the 173 subjects (1.7%), one of whom had normal cobalamin status, ingested <2 microg cobalamin/d, the Recommended Daily Allowance. Sixty-nine subjects (39.9%) ingested <6 microg/d, but they did not have more abnormal serum cobalamin or metabolite values than those ingesting >6 microg. Ordering all subjects by quintiles according to cobalamin intake revealed no significant trends or differences in any of the serum values either. Moreover, arranging subjects by results of tests of cobalamin status showed that the subjects with abnormal cobalamin status did not differ in cobalamin intake from those with normal cobalamin status, although they did differ in use of supplements. Finally, cobalamin intake, with or without supplements, did not correlate with serum cobalamin or metabolite levels. The absence of any association between cobalamin status and intake contrasts sharply with the significant correlation between folate intake and folate status (P = 0.0001). CONCLUSIONS: The high frequency of mildly abnormal cobalamin status in the elderly cannot be attributed to poor intake of cobalamin. Nondietary explanations, such as malabsorption and other phenomena, must always be sought to explain mild cobalamin deficiency in the elderly.     

Vitamin requirements for the treatment of hyperhomocysteinemia in humans

We have previously shown that a modest vitamin supplement containing folic acid, vitamin B-12 and vitamin B-6 is effective in reducing elevated plasma homocysteine concentrations. The effect of supplementation of the individual vitamins on moderate hyperhomocysteinemia has now been investigated in a placebo-controlled study. One hundred men with hyperhomocysteinemia were randomly assigned to five groups and treated with a daily dose of placebo, folic acid (0.65 mg), vitamin B-12 (0.4 mg), vitamin B-6 (10 mg) or a combination of the three vitamins for 6 wk. Folic acid supplementation reduced plasma homocysteine concentrations by 41.7% (P < 0.001), whereas the daily vitamin B-12 supplement lowered homocysteine concentrations by 14.8% (P < 0.01). The daily pyridoxine dose did not reduce significantly plasma homocysteine concentrations. The combination of the three vitamins reduced circulating homocysteine concentrations by 49.8%, which was not significantly different (P = 0.48) from the reduction achieved by folate supplementation alone. Our results indicate that folate deficiency may be an important cause of hyperhomocysteinemia in the general population.     

Correlates of plasma total homocysteine in patients with hyperlipidaemia

The study sought to define the relation of plasma total homocysteine to biological and clinical variables and to serum vitamin concentrations in patients with primary hyperlipidaemia. Fasting plasma total homocysteine was measured in 219 men and 159 women; vitamin concentrations were available for about 60% of the sample. Men had significantly higher plasma total homocysteine than women [median (25th, 75th percentiles) 9.4 (8.2, 11.5) mumol L-1 vs. 8.5 (7.0, 10.2) mumol L-1; P = 0.0001]. Plasma total homocysteine was lower in women taking lipid-lowering drugs than in women who were not taking drugs. Serum folate and vitamin B12 concentrations were normal for all but one and four subjects respectively. Correlations (P < or = 0.06) were found between plasma total homocysteine and age, triglyceride concentration in women, uric acid concentration in men, serum folate, vitamin B12 and creatinine concentrations. In multiple regression analysis, the association between plasma total homocysteine and sex and between plasma total homocysteine and use of lipid-lowering drugs disappeared when creatinine concentration was entered into the analysis. This study shows that plasma total homocysteine is related to vitamin concentrations within the normal range, suggesting that plasma total homocysteine may be modifiable by diet in hyperlipidaemic subjects with normal vitamin nutrition. Sex-related differences appear to be related to men's higher creatinine concentration. Whether lipid-lowering drugs interact with total homocysteine concentration requires further study.     

Nursing diagnoses in patients with leukemia

Valproate (VPA) has been shown to induce neural tube defects (NTDs) in humans and mice, but the mechanism of action has not been elucidated. Folate supplementation has been reported to prevent the defect. It was the aim of our experiment to reveal effects of VPA and of folate coadministration on amino acid metabolism in an NTD mouse model. After treating pregnant mice intraperitoneally with 2.1 mmol VPA/kg body weight, plasma homocysteine concentrations were found to be increased. Coadministration of 4 mg/kg folate decreased this level. Plasma methionine levels were reduced under both experimental conditions. Fifteen min after treating mice with 3 mmol VPA/kg body weight, hepatic levels of both S-adenosylmethionine (SAM) and S-adenosylhomocysteine were found to be increased by +175% and +348%, respectively; but the levels had normalized again 30 min after VPA injection. Simultaneously, plasma methionine and serine levels had decreased by -43% and -51%, respectively, while homocysteine and cysteine increased by +71% and +81%, respectively. Reduced glutathione (GSH) decreased by -45%, but total glutathione did not change. These changes were statistically significant, and they occurred dose-dependently. We proposed that VPA induces methionine deficiency inhibition of folate metabolism and homocysteine remethylation, increase in aminothiols, and suppression of the GSH system in maternal blood within 1 h after application. These changes may be responsible for the teratogenic potential of VPA. Folate may prevent NTDs by changing homocysteine catabolism.     

Antibacterial activity of bovine lactoferrin and its peptides against enterohaemorrhagic Escherichia coli O157:H7

OBJECTIVES: To assess the long term effects of small increases in dietary folic acid on the concentration of plasma homocysteine, an independent risk factor for occlusive vascular disease, in a general population. DESIGN: A randomized double-blind placebo-controlled intervention study. SUBJECTS: One hundred and nineteen healthy volunteers, whose intake of fortified or supplemental folic acid was low, were recruited by letter from the patient register of a large inner-city group general practice. METHODS: Volunteers were randomized to receive unfortified cereals, or cereals fortified with 200 microg of folic acid per portion, with or without other vitamins. Blood samples were taken presupplement and at 4, 8 and 24 weeks on treatment and analysed for plasma homocysteine, cysteine and vitamin B12 and serum and red cell folate. Ninety-four subjects completed the study providing blood samples on all four occasions. RESULTS: There were no significant changes in any measured parameter in those eating unfortified cereals. Overall, folic acid fortification of cereals led to significant increases (P < 0.001) in serum folate (66%), and red cell folate (24%), and a decrease in plasma homocysteine (10%; P < 0.001). There were no changes in vitamin B12 or cysteine. The homocysteine decrease persisted until the end of the study and was primarily seen in those who initially had the highest plasma homocysteine or the lowest serum folate. CONCLUSIONS: If homocysteine is found to be a causative risk factor in occlusive vascular disease, food fortification with physiological levels of folic acid should have a significant impact on the prevalence of the disease in the general population.     

Presence and consequence of uracil in preneoplastic DNA from folate/methyl-deficient rats

Uracil can arise in DNA by misincorporation of dUTP into nascent DNA and/or by cytosine deamination in established DNA. Based on recent findings, both pathways appear to be promoted in the methyl-deficient model of hepatocarcinogenesis. A chronic increase in the ratio dUTP:dTTP with folate/methyl deficiency can result in a futile cycle of excision and reiterative uracil misincorporation leading to premutagenic apyrimidinic (AP) sites, DNA strand breaks, DNA fragmentation and apoptotic cell death. The progressive accumulation of unmethylated cytosines with chronic methyl deficiency will increase the potential for cytosine deamination to uracil and further stress uracil mismatch repair mechanisms. Uracil is removed by a highly specific uracil-DNA glycosylase (UDG) leaving an AP site that is subsequently repaired by sequential action of AP endonuclease, 5'-phosphodiesterase, a DNA polymerase and DNA ligase. Since the DNA polymerases cannot distinguish between dUTP and dTTP, an increase in dUTP:dTTP ratio will promote uracil misincorporation during both DNA replication and repair synthesis. The misincorporation of uracil for thymine (5-methyluracil) may constitute a genetically significant form of DNA hypomethylation distinct from cytosine hypomethylation. In the present study a significant increase in the level of uracil in liver DNA as early as 3 weeks after initiation of folate/methyl deficiency was accompanied by parallel increases in DNA strand breaks, AP sites and increased levels of AP endonuclease mRNA. In addition, uracil was also detected within the p53 gene sequence using UDG PCR techniques. Increased levels of uracil in DNA implies that the capacity for uracil base excision repair is exceeded with chronic folate/methyl deficiency. It is possible that enzyme-induced extrahelical bases, AP sites and DNA strand breaks interact to negatively affect the stability of the DNA helix and stress the structural limits of permissible uracil base excision repair activity. Thus substitution of uracil for thymine induces repair-related premutagenic lesions and a novel form of DNA hypomethylation that may relate to tumor promotion in the methyl-deficient model of hepatocarcinogenesis.     

Plasma thyroid hormone kinetics are altered in iron-deficient rats

Iron deficiency anemia is associated with lower plasma thyroid hormone concentrations in rodents and, in some studies, in humans. The objective of this project was to determine if plasma triiodothyronine (T3) and thyroxine (T4) kinetics were affected by iron deficiency. Studies were done at a near-thermoneutral temperature (30 degrees C), and a cool environmental temperature (15 degrees C), to determine plasma T3 and T4 kinetics as a function of dietary iron intake and environmental need for the hormones. Weanling male Sprague-Dawley rats were fed either a low Fe diet [iron-deficient group (ID), <5 microg/g Fe] or a control diet [control group (CN), 35 microg/g Fe] at each temperature for 7 wk before the tracer kinetic studies. An additional ID group receiving exogenous thyroid hormone replacement was also used at the cooler temperature. For T4, the disposal rate was >60% lower (89 +/- 6 vs. 256 +/- 53 pmol/h, P < 0.001) in ID rats than in controls at 30 degrees C, and approximately 40% lower (192 +/- 27 vs. 372 +/- 26 pmol/h, P < 0.01) in ID rats at 15 degrees C. Exogenous T4 replacement in a cohort of ID rats at 15 degrees C normalized the T4 concentration and the disposal rate. For T3, the disposal rate was significantly lower in ID rats in a cool environment (92 +/- 11 vs. 129 +/- 11 pmol/h, P < 0.01); thyroxine replacement again normalized the T3 disposal rate (126 +/- 12 pmol/h). Neither liver nor brown fat thyroxine 5'-deiodinase activities were sufficiently different to explain the lower T3 disposal rates in iron deficiency. Thus, plasma thyroid hormone kinetics in iron deficiency anemia are corrected by simply providing more thyroxine. This suggests a central regulatory defect as the primary lesion and not peripheral alterations.     

Diet and plasma lipids in women. I. Macronutrients and plasma total and low-density lipoprotein cholesterol in women: the Framingham nutrition studies

This study examined relationships between diet and plasma total and LDL cholesterol levels in a population-based sample of 695 premenopausal and 727 postmenopausal women participating in the Framingham Offspring/Spouse Study. Regression analyses controlled for age, caloric intake, apolipoprotein E isoform type, estrogen use, and important CVD risk factors indicated that plasma total and LDL-cholesterol levels were directly associated with consumption of saturated fat and inversely associated with total calorie intake. In contrast, dietary cholesterol was not a predictor of plasma total or LDL cholesterol levels. Total cholesterol levels were also directly associated with total fat, oleic acid, and animal fat, and inversely associated with carbohydrate intake. Stepwise regressions with key nutrients indicated that saturated fat was consistently associated with total and LDL cholesterol levels in Framingham women. These analyses suggest that diet explains 2% of the variability in these lipid levels in a cross-sectional sample of women; the full model explains 22-27%.     

Methylenetetrahydrofolate reductase polymorphism affects the change in homocysteine and folate concentrations resulting from low dose folic acid supplementation in women with unexplained recurrent miscarriages

To determine the effects of daily supplementation of 0.5 mg folic acid on homocysteine and folate concentrations, we investigated 49 women with a history of unexplained recurrent miscarriages. A methionine loading test (including the vitamin concentrations of concern) was used preceding and after 2 mo of folic acid intake. Subsequently, these effects were studied after stratification for C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism. Folic acid supplementation (for 2 mo) reduced the median fasting and delta (after-load minus fasting) total plasma homocysteine (tHcy) concentrations 27% (P < 0.001) and 14% (P < 0.05), respectively. Median serum and red cell folate concentrations increased 275 and 70%, respectively (P < 0.01). The homocysteine-lowering effect was most marked in women with the highest tHcy concentrations at baseline. All MTHFR-genotypes (homozygous T/T, n = 8; heterozygous T/C, n = 23; wild type C/C, n = 18) had a different response to the supplementation. After 2 mo, homozygous women showed the greatest decline in median fasting (-41%; P < 0.01) tHcy concentrations, but the lowest absolute increase in serum folate concentration (+26 nmol/L; P < 0.05). In conclusion, 2 mo of daily supplementation of 0. 5 mg folic acid in women with a history of unexplained recurrent miscarriages caused, in general, substantially reduced tHcy concentrations. This effect was most distinct in women with the highest tHcy concentrations at baseline and in women homozygous for the 677 C-->T mutation of the MTHFR-gene.     

Evidence for leptin regulation of food intake in humans

The adipocyte hormone leptin regulates body weight in mice by decreasing food intake and increasing energy expenditure. Whether leptin is of physiological importance for these processes in humans is, however, not clear. We therefore studied the relation between leptin and habitual food intake in 64 healthy postmenopausal women. Dietary habits were assessed with a modified diet history method. Body fat content was measured using bioelectrical impedance. In the 64 women, aged 58.6+/-0.4 yr (mean+/-SD), serum leptin was 19.3+/-12.7 ng/mL, body mass index was 25.0+/-3.5 kg/m2, body fat content was 31.6+/-4.3%, fasting glucose was 4.6+/-0.5 mmol/L, and fasting insulin was 56+/-21 pmol/L. Leptin levels were negatively correlated to total energy intake (r=-0.34; P=0.006), carbohydrate intake (r=-0.36; P=0.004), and total (r=-0.27; P=0.034) as well as saturated fat intake (r=-0.31; P=0.014). Leptin was correlated to the absolute, but not to the percent, intake of these nutrients. When normalized for body fat content, the correlations remained significant. Our results suggest that plasma leptin is involved in the physiological regulation of food intake in humans, and that leptin is related to the quantity rather than the quality of habitual food intake.