[Homocysteine and cardiovascular disease]. / Homocystein og hjerte-kar-sygdomme.

Treatment of highly increased plasma concentrations of homocysteine in patients with rare inborn errors of metabolism reduces their risk of vascular thromboses. Many, but not all, epidemiological studies show a relation between slightly increased plasma homocysteine and ischaemic cardiovascular disease. Folic acid supplements reduce plasma homocysteine. The results of ongoing studies of the effect of folic acid and other vitamins on the incidence of cardiovascular disease are expected within the next five years. The available data support the measurement of plasma homocysteine as a part of screening of patients with early and/or frequent vascular thromboses and a disparity between established risk factors and symptoms. Plasma homocysteine > 30 mumol/l in such patients should prompt a search for an inborn error of metabolism.

Is There a Causal Relationship between Iron Deficiency or Iron-Deficiency Anemia and Weight at Birth, Length of Gestation and Perinatal Mortality?

An extensive literature review was conducted to identify whether iron deficiency, iron-deficiency anemia and anemia from any cause are causally related to low birth weight, preterm birth or perinatal mortality. Strong evidence exists for an association between maternal hemoglobin concentration and birth weight as well as between maternal hemoglobin concentration and preterm birth. It was not possible to determine how much of this association is attributable to iron-deficiency anemia in particular. Minimal values for both low birth weight and preterm birth occurred at maternal hemoglobin concentrations below the current cut-off value for anemia during pregnancy (110 g/L) in a number of studies, particularly those in which maternal hemoglobin values were not controlled for the duration of gestation. Supplementation of anemic or nonanemic pregnant women with iron, folic acid or both does not appear to increase either birth weight or the duration of gestation. However, these studies must be interpreted cautiously because most are subject to a bias toward false-negative findings. Thus, although there may be other reasons to offer women supplemental iron during pregnancy, the currently available evidence from studies with designs appropriate to establish a causal relationship is insufficient to support or reject this practice for the specific purposes of raising birth weight or lowering the rate of preterm birth.

The novel 5-Hydroxytryptamine(1A) antagonist LY426965: effects on nicotine withdrawal and interactions with fluoxetine.

LY426965 [(2S)-(+)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]2-methyl- 2-phenyl-1-butanone monohydrochloride] is a novel compound with high affinity for the cloned human 5-hydroxytryptamine (HT)(1A) receptor (K(i) = 4.66 nM) and 20-fold or greater selectivity over other serotonin and nonserotonin receptor subtypes. Both in vitro and in vivo studies indicate that LY426965 is a full antagonist and has no partial agonist properties. LY426965 did not stimulate [(35)S]guanosine-5'-O-(3-thio) triphosphate (GTPgammaS) binding to homogenates of cells expressing the cloned human 5-HT(1A) receptor in vitro but did inhibit 300 nM 5-HT-stimulated [(35)S]GTPgammaS binding with a K(i) value of 3.07 nM. After both p.o. and s.c. administration, LY426965 blocked the lower lip retraction, flat body posture, hypothermia, and increase in rat serum corticosterone induced by the 5-HT(1A) agonist 8-OH-DPAT (8-hydroxy-2-dipropylaminotetralin). In pigeons, LY426965 dose-dependently blocked the stimulus cue induced by 8-OH-DPAT but had no 8-OH-DPAT-like discriminative properties. LY426965 completely reversed the effects of nicotine withdrawal on the auditory startle reflex in rats. In microdialysis experiments, LY426965 administered together with fluoxetine significantly increased extracellular levels of serotonin above those achievable with fluoxetine alone. In electrophysiological studies, the administration of LY426965 produced a slight elevation of the firing rate of 5-HT neurons in the dorsal raphe nucleus of anesthetized rats and both blocked and reversed the effects of fluoxetine on 5-HT neuronal activity. These preclinical results indicate that LY426965 is a selective, full 5-HT(1A) antagonist that may have clinical use as pharmacotherapy for smoking cessation and depression and related disorders.

Relationship between methylmalonic acid and cobalamin in uremia.

UNLABELLED: Relationship between methylmalonic acid and cobalamin in uremia. BACKGROUND: To evaluate the requirement for routine supplementation with vitamin B12 and to study the effect of a change from injection to oral B12 supplementation, we examined the relationship between cobalamin and methylmalonic acid in plasma from 67 patients on chronic hemodialysis, all in regular therapy with intramuscular cobalamin injections (1 mg) every third month. METHODS: Starting just before one cobalamin injection, blood samples were collected once a month during a nine-month withdrawal from regular cobalamin substitution to a final three-month period with cyanocobalamin tablets (1 mg) administered once daily. RESULTS: Plasma cobalamin was above the lower reference limit in all subjects, and from a peak value one month after the regular injection, the cobalamin concentration during the withdrawal period decreased to a level below the point of origin, followed by a significant rise after cyanocobalamin tablets. The methylmalonic acid concentrations were above the reference interval. In the withdrawal period, the concentrations significantly increased further, followed by a significant decrease after oral cyanocobalamin substitution. CONCLUSION: We demonstrated a within-patient inverse relationship between the concentrations of methylmalonic acid and cobalamin in plasma from these uremic patients. Despite the fact that only two of the patients developed subnormal plasma cobalamin values, we demonstrated a B12 depletion during the withdrawal period. Treatment with cyanocobalamin tablets once daily was found efficient, but the oral doses should possibly be increased.

Serum cobalamin, homocysteine, and methylmalonic acid concentrations in a multiethnic elderly population: ethnic and sex differences in cobalamin and metabolite abnormalities.

BACKGROUND: Low cobalamin concentrations and mild hyperhomocysteinemia are common in the elderly but ethnic differences have not been defined. OBJECTIVE: Our objective was to determine the demographic characteristics of cobalamin deficiency in the elderly and its role in their hyperhomocysteinemia. DESIGN: We measured serum cobalamin, total homocysteine (Hcys), and methylmalonic acid (MMA) concentrations in 725 subjects >60 y old, and folate concentrations in 520 subjects. RESULTS: After exclusion of subjects taking cobalamin supplements or with renal insufficiency, high prevalences of low cobalamin (11.8%), high MMA (16.6%), and high Hcys (26.1%) concentrations were seen. Most cobalamin concentrations <140 pmol/L appeared to reflect deficiency because 78. 3% of them were accompanied by abnormal metabolites. Subjects with cobalamin concentrations of 140-258 pmol/L had significantly fewer metabolic abnormalities. A low cobalamin concentration and renal insufficiency were the strongest predictors of abnormal Hcys concentrations. Elderly men had higher Hcys concentrations than did women (P = 0.0001). Whites and Latin Americans had lower cobalamin concentrations than did blacks and Asian Americans (P < 0.005). Whites also had higher Hcys concentrations than all the other groups (P < 0.05). When included in the analysis, renal insufficiency in subjects was associated with 23.8% of all high Hcys and 25.5% of all high MMA concentrations; most with renal insufficiency were Asian American and black men. CONCLUSIONS: Mild cobalamin deficiency is most common in elderly white men and least common in black and Asian American women. Hyperhomocysteinemia, which is most strongly associated with low cobalamin concentrations, is also most common in elderly whites, whereas that associated with renal insufficiency is more common in blacks and Asian Americans. Ethnic differences in cobalamin deficiency and the Hcys patterns associated with it or with renal insufficiency warrant consideration in supplementation strategies. Extending suspicion of deficiency to persons with cobalamin concentrations of 140-258 pmol/L appears to provide more disadvantages than advantages.

Within-person variation of plasma homocysteine and effects of posture and tourniquet application.

BACKGROUND: Frequently, the result of only a single determination of total homocysteine in plasma (P-Hcy) is used to distinguish between the probability of the presence or absence of risk for vascular disease. A prerequisite for the interpretation of a single P-Hcy test is knowledge of the magnitude of within-person variation and the possible effects of preanalytical variables. However, data on within-person variation are still sparse and inconsistent, and data for the effect on P-Hcy of posture and tourniquet application during venipuncture are not available. METHODS: The within-person variation of P-Hcy and the effects of posture and tourniquet application during venipuncture were studied in 24 healthy subjects. The analytical imprecision of our stable-isotope dilution assay was 3.1%. RESULTS: The within-person variation (CV) was 8.1%. Daily supplementation with 0.4 mg of folic acid for 2 weeks produced a small but significant decrease in P-Hcy, but there were no significant changes in within-person variation before and after supplementation. After 30 min in the horizontal posture, P-Hcy declined by 6.3%. A 3-min tourniquet application caused a 2.8% increase of P-Hcy. CONCLUSIONS: Our value for within-person variation is consistent with results from studies reported recently in the literature. A 3-min tourniquet application does not add appreciable variation to the measurement of P-Hcy, but the posture of the subject during venipuncture contributes considerably to the within-person variation. We recommend that blood collection when the patient is in a supine position be avoided.

Impact of food supplementation during lactation on infant breast-milk intake and on the proportion of infants exclusively breast-fed.

To evaluate whether milk production can be improved by increasing food intake, a randomized, double-blind, supplementation trial was completed among 102 lactating Guatemalan women. The subjects were undernourished, as indicated by their low values for calf circumference (CC) and the small size of their infants at birth. A high-energy (2.14 MJ/d, HES) and a low-energy (0.50 MJ/d, LES) supplement were distributed 6 d/wk from wk 5 to 25 of lactation. Data were evaluated using repeated-measures analysis of variance on the increments from initial values for each outcome variable with one-tailed tests of statistical significance. The maternal energy intake increased 1.18 MJ/d (P < 0.01) more among the HES than the LES women. Benefit from supplementation was more evident among the more undernourished (CC

Linking maternal and infant benefits of a nutritional supplement during pregnancy and lactation.

To evaluate the effect of a nutritional supplement on change in women's weight during a reproductive cycle and on the difference in birth weight between one infant and the previous one, we analyzed data on 176 complete reproductive cycles from an experiment that was conducted in rural Guatemala. Women with an initial weight <50 kg were classified as marginally nourished or malnourished. Women whose intake of the supplement was in the top 2 tertiles were distinguished from those whose intake was in the lowest tertile. Linear regression modeling was used to estimate the effect of supplementation on these outcomes and to control for confounding factors. Malnourished women gained weight during the reproductive cycle, but their second (study) infant tended to weigh less at birth than their prior-born infant. Higher intakes of supplement were associated with a less negative difference in birth weight. Marginally nourished women lost weight during the reproductive cycle and their second (study) infant tended to weigh more at birth than their prior-born infant. Higher intakes of supplement were associated with a less negative weight [corrected] trend for the women themselves. Well-nourished women and their infants did not show any of these benefits from supplementation. These findings help explain past contradictory findings on maternal depletion as well as on the benefits of nutritional supplementation for mothers and their infants.

Folate and neural tube defects. Recommendations from a Danish working group.

A working group was established to evaluate the need for an increased folate intake in Danish women to decrease the risk of neural tube defects (NTDs). NTD are birth defects which include anencephaly, encephalocele and spina bifida. In Denmark the incidence is about 1.4 per 1,000 pregnancies. Folate is a B-vitamin found in most food groups. In case-control studies and randomised studies, a protective effect of folic acid supplements on NTDs has been found. The studies show that a periconceptional folic acid supplement of 360 micrograms to 4 mg daily decreases the recurrence rate of NTDs. Likewise, in the few studies which calculate folate intake from the diet, a lower risk of NTD with higher intake of folate from the diet has been found. The folate intake can be increased by the diet, by folic acid supplements or by fortification of food with folic acid. It is concluded that the incidence of NTDs in Denmark will decrease if the folate intake in fertile women increases. All women planning pregnancy should receive dietary counselling. Women who do not eat according to the Nordic Nutrition Recommendations, and women with an increased risk due to diseases are recommended a supplement of 400 micrograms folic acid daily from a multivitamin/folic acid tablet. Women who have had a child with NTD and women who themselves have NTDs are recommended a supplement of 5 mg folic acid daily. Dietary changes and supplements should be initiated when pregnancy is planned.

Breast milk or animal-product foods improve linear growth of Peruvian toddlers consuming marginal diets.

Although breast-feeding is widely accepted as important for infant health, its benefits during the second year of life have been questioned. We analyzed data from 107 breast-fed and weaned Peruvian children living in a periurban community to determine whether breast milk contributed to improved linear growth between 12 and 15 mo of age. Breast-feeding frequency was self-reported; intakes of complementary foods and animal products were estimated from a food-frequency survey. Multivariate-linear-regression analysis was used to predict the length of the children at 15 mo of age. Determinants of length included length and weight-for-length at 12 mo of age (US National Center for Health Statistics standards), interval between 12- and 15-mo measurements, breast-feeding frequency, incidence of diarrhea, and intakes of complementary and animal-product foods. Complementary foods, animal-product foods, and breast milk all promoted toddlers' linear growth. In subjects with low intakes of animal-product foods, breast-feeding was positively associated (P < 0.05) with linear growth. There was a 0.5-cm/3 mo difference in linear growth between weaned toddlers and children who consumed the average number of feedings of breast milk. Linear growth was also positively associated with intake of animal-product foods in children with low intakes of complementary foods. The negative association between diarrhea and linear growth did not occur in subjects with high complementary-food intakes. When the family's diet is low in quality, breast milk is an especially important source of energy, protein, and accompanying micronutrients in young children. Thus, continued breast-feeding after 1 y of age, in conjunction with feeding of complementary foods, should be encouraged in toddlers living in poor circumstances.

PIP: The contribution of prolonged breast feeding to linear growth at 12-15 months of age was investigated in 107 breast-fed and weaned toddlers from a low-income neighborhood in Lima, Peru. The median duration of breast feeding in this sample was 17.1 months; by 15 months, 46 children had been weaned. The prevalence of stunting (length-for-age score -2 SD below the reference standard) was 17.8% at 12 months and 24.3% at 15 months; no child was wasted. Complementary foods, animal product foods, and breast milk all promoted toddlers' linear growth. In children with low intakes of animal product foods, breast feeding was positively associated with linear growth at 15 months (p 0.05). There was a 0.5 cm/3 months difference in linear growth between weaned toddlers and those who consumed the average number (6.3/day) of breast feeds. Linear growth was further positively associated with intake of animal product foods in children with low intakes of complementary foods. The negative association between diarrhea and linear growth did not occur in children with high intakes of complementary foods. When the household diet is of poor quality, breast feeding is an especially important source of energy, protein, and micronutrients in toddlers and should be continued beyond 12 months of age in conjunction with the provision of complementary foods. Breast milk not only added to the total diet of these young children, but also potentiated the beneficial effects of complementary foods consumed by increasing their growth promotion capacity.

[n-3 polyunsaturated fatty acids, heart rate variability and ventricular arrhythmias in post-AMI-patients. A clinical controlled trial]. / n-3 polyumaettede fedtsyrer, hjertefrekvensvariabilitet og ventrikulaere arytmier hos post-AMI-patienter. Et klinisk kontrolleret studie.

There is evidence for an antiarrhythmic effect of n-3 polyunsaturated fatty acids (n-3 PUFA) in animals. The aim of the present study was to investigate the effect of dietary n-3 PUFA on ventricular arrhythmias and heart rate variability (HRV) in patients with a previous myocardial infarction. Fifty-five patients were randomized to receive either 5.2 g of n-3 PUFA daily for 12 weeks or placebo in a double blind, placebo-controlled study. Prior to randomization a 24-hour Holter recording was obtained, and this was repeated at the end of the study. The major end-points were the number of ventricular extrasystoles (VE)/24 hours and the 24-hour HRV. A non-significant decrease in VE/24 hours was found in both the n-3 PUFA group and among controls after dietary supplementation, whereas HRV significantly increased after n-3 PUFA compared to both baseline values (p = 0.04) and to controls (p = 0.01). The present study therefore supports the hypothesis that n-3 PUFA may have an anti-arrhythmic effect in humans.

Fish consumption, n-3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction.

To elucidate a possible antiarrhythmic effect of long-chained n-3 polyunsaturated fatty acids, heart rate variability was assessed in 52 patients with a previous myocardial infarction and left ventricular dysfunction. The content of n-3 polyunsaturated fatty acids in platelets was closely associated with the patient's fish-consuming habits, and a significant positive correlation was observed between the n-3 fatty acid docosahexaenoic acid and heart rate variability.

The novel atypical antipsychotic olanzapine, but not the CCK-B antagonist LY288513, blocks apomorphine-induced disruption of pre-pulse inhibition.

Pre-pulse inhibition (PPI) of the acoustic startle response is the diminution of the startle response when the startle stimulus is preceded by a weaker, non-startle-eliciting stimulus. Deficits in PPI occur in animals following the administration of apomorphine and in schizophrenic patients. In this study, we examined the ability of the novel atypical antipsychotic olanzapine and the cholecystokinin (CCK)-B antagonist LY288513 to reverse the apomorphine-induced disruption of pre-pulse inhibition. Olanzapine (3.0 and 5.0 mg/kg, i.p.), but not LY288513 (1.0-100 mg/kg, p.o.), blocked apomorphine-induced disruption of PPI. These results indicate that olanzapine, but not LY288513, has dopamine antagonist properties in vivo and predict that olanzapine, but not LY288513, will have antipsychotic activity in man.

Adherence to iron supplementation during pregnancy in Tanzania: determinants and hematologic consequences.

Limited adherence to iron supplementation is thought to be a major reason for the low effectiveness of anemia-prevention programs. In rural Tanzania, women at 21-26 wk of gestation were randomly given either 120 mg of a conventional (Con) iron supplement or 50 mg of a gastric-delivery-system (GDS) iron supplement for 12 wk. Adherence was assessed by using a pill bottle equipped with an electronic counting device. Adherence in the GDS group was 61% compared with 42% for the Con group. In both groups, women experiencing side effects had about one-third lower adherence. Fewer side effects were observed in the GDS group. In a subgroup of women with a low initial hemoglobin concentration (< or = 120 g/L), the response to the iron supplements suggested that both of the applied doses were unnecessarily high for adequate hematologic response in a population with a marginal hemoglobin concentration. The GDS group appeared to require a dose one-fourth as high as that of the Con group for an equal effect on improving hemoglobin to normal concentrations.

Age- and gender-specific reference intervals for total homocysteine and methylmalonic acid in plasma before and after vitamin supplementation.

We present reference intervals for total homocysteine and methylmalonic acid in plasma based on samples from 126 women (ages 20-85 years, median 49 years) and 109 men (ages 20-84 years, median 50 years). The central 0.95 interval for methylmalonic acid was 0.08-0.28 micromol/L. Supplementation with cyanocobalamin caused a nonsignificant decrease in methylmalonic acid. Supplementation with folic acid caused a decrease in homocysteine concentrations, with data analysis identifying two significantly different clusters: 182 subjects with the lowest initial concentrations (7.76 +/- 1.54 micromol/L, mean +/- SD) and the smallest decrease (1.26 +/- 0.96 micromol/L), and 53 subjects with the highest initial concentrations (12.33 +/- 2.04 micromol/L) and greatest decrease (4.14 +/- 1.32 micromol/L). We argue in favor of the age- and gender-specific central 0.95 intervals obtained for the 182 subjects before being supplemented with folic acid: 4.6-8.1 micromol/L for subjects at <30 years; 4.5-7.9 micromol/L for women, ages 30-59 years; 6.3-11.2 micromol/L for men, ages 30-59 years; and 5.8-11.9 micromol/L for subjects at >60 years.

Combination therapy with metoprolol and nifedipine versus monotherapy in patients with stable angina pectoris. Results of the International Multicenter Angina Exercise (IMAGE) Study.

OBJECTIVES: This study was designed to investigate whether combination therapy with metoprolol and nifedipine provides a greater anti-ischemic effect than does monotherapy in individual patients with stable angina pectoris. BACKGROUND: Combination therapy with a beta-adrenergic blocking agent (which reduces myocardial oxygen consumption) and a dihydropyridine calcium antagonist (which increases coronary blood flow) is a logical approach to the treatment of stable angina pectoris. However, it is not clear whether, in individual patients, this combined therapy is more effective than monotherapy. METHODS: Two hundred eighty patients with stable angina pectoris were enrolled in a double-blind trial in 25 European centers. Patients were randomized (week 0) to metoprolol (controlled release, 200 mg once daily) or nifedipine (Retard, 20 mg twice daily) for 6 weeks; placebo or the alternative drug was then added for a further 4 weeks. Exercise tests were performed at weeks 0, 6 and 10. RESULTS: At week 6, both metoprolol and nifedipine increased the mean exercise time to 1-mm ST segment depression in comparison with week 0 (both p < 0.01); metoprolol was more effective than nifedipine (p < 0.05). At week 10, the groups randomized to combination therapy had a further increase in time to 1-mm ST segment depression (p < 0.05 vs. placebo). Analysis of the results in individual patients revealed that 7 (11%) of 63 patients adding nifedipine to metoprolol and 17 (29%) of 59 patients (p < 0.0001) adding metoprolol to nifedipine showed an increase in exercise tolerance that was greater than the 90th percentile of the distribution of the changes observed in the corresponding monotherapy + placebo groups. However, among these patients, an additive effect was observed only in 1 (14%) of the 7 patients treated with metoprolol + nifedipine and in 4 (24%) of the 17 treated with nifedipine + metoprolol. CONCLUSIONS: The mean additive anti-ischemic effect shown by combination therapy with metoprolol and nifedipine in patients with stable angina pectoris is not the result of an additive effect in individual patients. Rather, it may be attributed to the recruitment by the second drug of patients not responding to monotherapy.

Nicotine withdrawal leads to increased firing rates of midbrain dopamine neurons.

In order to explore the neurophysiology of nicotine withdrawal, we examined the activity of substantia nigra (A9) and ventral tegmental area (A10) dopamine cells in rats undergoing withdrawal from chronic exposure to nicotine. Animals were exposed to nicotine (6 mg kg-1 day-1 base) via s.c. implanted osmotic minipumps. After 12 days the pumps were removed and the animals allowed to go through spontaneous withdrawal. Rats were anesthetized on various days of the procedure and single-unit recordings were made from A9 and A10 dopamine cells. Chronic administration of nicotine led to a decreased firing rate of A10, but not A9, dopamine cells. Upon withdrawal from the chronic exposure to nicotine, the firing rates of A10 dopamine cells returned to control levels, while the firing rate of A9 dopamine cells significantly increased above control levels. This increased dopamine neuronal activity may play a role in some behavioural symptoms of nicotine withdrawal.