Significant decrease of von Willebrand factor and plasminogen activator inhibitor-1 by providing supplementation with selenium and coenzyme Q10 to an elderly population with a low selenium status.

PURPOSE: Endothelial dysfunction and inflammation are conditions which fuel atherosclerosis and ischaemic heart disease. We have previously reported reduced cardiovascular (CV) mortality following supplementation with selenium and coenzyme Q10 to 443 elderly individuals with low selenium status (mean 67 µg/L) for 4 years. Here, we wanted to evaluate a possible association between the supplementation and the plasma concentrations of the von Willebrand factor (vWf), and the plasminogen activator inhibitor-1 (PAI-1), as they, besides other functions, are also strongly associated with endothelial function. METHODS: In this sub-study, 308 individuals (active substance: 157, placebo: 151) were included. Blood samples were drawn after 6 and 36 months and vWf and PAI-1 were determined in plasma by ELISA. Changes in concentrations of the biomarkers were evaluated by the use of T tests, repeated measures of variance, and ANCOVA analyses. RESULTS: The active treatment group presented a lower level of vWf after 36 months compared with the placebo group (1.08 U/mL vs. 5.10 U/mL; p = 0.0007). The results were validated through the repeated measures of variance evaluation. The PAI-1 levels showed an equally significant decrease in the active group (26.2 ng/mL vs. 49.2 ng/mL; p = 0.0002) and were also validated through repeated measures of variance evaluation. CONCLUSION: In this sub-study on elderly receiving selenium and coenzyme Q10, or placebo we found significantly lower levels of vWf and PAI-1 in the active treatment group as compared to the placebo group. We interpret this as a better endothelial function because of the intervention, which accords with a previous finding of reduced CV mortality.

Selenoprotein P increases upon selenium and coenzyme Q10 supplementation and is associated with telomere length, quality of life and reduced inflammation and mortality.

BACKGROUND: Selenoprotein P (SELENOP) transports selenium to extrahepatic tissues and is a biomarker of selenium status. Low soil selenium leads to low dietary selenium intake. A consequence is an increased risk of cardiovascular disease. OBJECTIVE: To investigate clinical aspects associated with SELENOP deficiency, including biomarkers of inflammation, quality of life, and mortality within 12 years, and the effect of dietary selenium and coenzyme Q10 supplementation on SELENOP. METHODS: SELENOP was determined at inclusion and after four years of supplementation in 403 elderly community-living participants low in selenium receiving selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day), or placebo. Pre-intervention, the average serum selenium level was 67 µg/L. T-tests, repeated measures of variance, Cox proportional regressions analyses, Kaplan-Meier graphs and ANCOVA analyses were applied. Associations with biomarkers of inflammation, telomere length, quality of life and mortality were investigated. Benchmark modelling was used to determine the serum selenium concentration at which the saturation levels of SELENOP and GPx3 was achieved. Comparison with GPx3 and serum selenium to identify increased mortality risk was performed, and the effect of supplementation on SELENOP levels were evaluated. RESULTS: Inverse associations were observed between the level of SELENOP at inclusion and biomarkers for inflammation. At follow-up, shorter telomere lengths were seen in those with low levels of SELENOP at inclusion, whereas high levels of SELENOP were associated with better quality of life and decreased mortality. SELENOP had increased prognostic power compared to GPx3 and selenium. Saturation of SELENOP was achieved at a serum selenium level of 146 µg/L, and for GPx3 at 99 µg/L. Supplementation induced higher levels of SELENOP. CONCLUSION: Significant associations between SELENOP and inflammation, length of telomeres, quality of life, and mortality were observed. Thus, selenium supplementation improved SELENOP expression, thereby facilitating systemic selenium bioavailability and resulting in the observed positive health effects.

Relatively high mortality risk in elderly Swedish subjects with low selenium status.

BACKGROUND/OBJECTIVES: The daily dietary intake of selenium (Se), an essential trace element, is still low in Sweden in spite of decades of nutritional information campaigns and the effect of this on the public health is presently not well known. The objective of this study was to determine the serum Se levels in an elderly Swedish population and to analyze whether a low Se status had any influence on mortality. SUBJECTS/METHODS: Six-hundred sixty-eight (n=668) elderly participants were invited from a municipality and evaluated in an observational study. Individuals were followed for 6.8 years and Se levels were re-evaluated in 98 individuals after 48 months. Clinical examination of all individuals included functional classification, echocardiography, electrocardiogram and serum Se measurement. All mortality was registered and endpoints of mortality were assessed by Kaplan-Meier plots, and Cox proportional hazard ratios adjusted for potential confounding factors were calculated. RESULTS: The mean serum Se level of the study population (n=668) was 67.1 µg/l, corresponding to relatively low Se intake. After adjustment for male gender, smoking, ischemic heart disease, diabetes, chronic obstructive pulmonary disease and impaired heart function, persons with serum Se in the lowest quartile had 43% (95% confidence interval (CI): 1.02-2.00) and 56% (95% CI: 1.03-2.36) increased risk for all-cause and cardiovascular mortality, respectively. The result was not driven by inflammatory effects on Se concentration in serum. CONCLUSION: The mean serum Se concentration in an elderly Swedish population was 67.1 µg/l, which is below the physiological saturation level for several selenoprotein enzymes. This result may suggest the value of modest Se supplementation in order to improve the health of the Swedish population.

Organ distribution and cellular uptake of methyl mercury in the rat as influenced by the intra- and extracellular glutathione concentration.

Intravenous administration of CH3HgCl (4 mumol/Kg) premixed with glutathione or cysteine (8 mumole/kg) to female rats caused a rapid uptake of mercury in the kidney and a depressed content in the liver and blood as compared to CH3HgCl given alone. GSH depletion in the tissues, produced by injection of diethylmaleate, DEM (3.9 mmole/kg) did not influence the kidney uptake of mercury from administered (CH3Hg+-GSH, whereas the uptake of injected CH3HgCl was depressed. Both GSH and cysteine (8 mumole/kg) promoted the biliary excretion of methyl mercury. In suspensions of rat erythrocytes and isolated hepatocytes, additions of GSH reduced the cellular uptake of CH3Hg+ from the medium, whereas this was increased in the hepatocytes by adding cysteine or methionine. Cysteine addition slightly reduced the uptake of CH3Hg+ in the erythrocytes. GSH-depletion as obtained by DEM pretreatment of the cells, reduced the Ch3Hg+ uptake into hepatocytes by 40%, in contrast to only a negligible effect on the erythrocytes. Our results support previous reports that a physiological CH3Hg+-GSH-complexation takes place intracellularly, at least in liver cells. Our results are furthermore consistent with the assumption that biliary excreted CH3Hg+-GSH, which can be reabsorbed, only to a limited extent is taken up by the liver, whereas this GSH-complexation and reabsorption is of importance for the Ch3Hg+-uptake in the kidneys.

Prediagnostic serum selenium in a case-control study of thyroid cancer.

Sera from 43 persons who developed thyroid cancer on an average 4.8 years after blood sampling were compared with sera from controls. Three controls per case matched for sex, age, place of residence and year of blood sampling, with regard to serum selenium and serum copper. Cases were significantly lower in serum selenium than controls, and the estimated odds ratio of thyroid cancer increased from 1 for levels greater than or equal to 1.65 mumol/l, to 6.1 for levels 1.26-1.64 mumol/l, to 7.7 for levels less than or equal to 1.25 mumol/l. When time from blood sampling to diagnosis of the case was considered, it could be shown that the protective effect of high serum selenium concentrations was restricted to the last (less than 7) years prior to the diagnosis of thyroid cancer. The serum selenium concentration of cases tended to decrease relative to controls the shorter time was from blood sampling to the diagnosis. There was no difference between cases and controls with regard to serum copper.

Serum selenium levels in liver diseases.

A possible pathogenetic role of selenium deficiency in alcoholic cirrhosis of the liver has previously been discussed. In the present study serum selenium was analyzed in 5 groups of liver diseases. The method used for selenium determination was electrothermal atomic absorption, after thermal stabilization of selenium compounds by addition of nickel nitrate. The selenium level of a reference group of healthy Norwegian adults (n = 40) was 1.53 +/- 0.25 mumol/l. The serum concentrations of selenium in patients suffering from alcoholic cirrhosis, chronic active hepatitis and chronic persistent hepatitis were lowered to 40-80 per cent of those of the reference group. In alcoholic cirrhosis and chronic active hepatitis the decreased serum selenium concentrations were significantly correlated to decreased levels of albumin and prealbumin.

Hepatobiliary transport and organ distribution of silver in the rat as influenced by selenite.

Bile from rats injected with 110mAgNO3 (1 micromol/kg) were fractionated on Sephadex G-15 revealing binding of silver to one high molecular weight substance and one low molecular weight substance eluting corresponding to the void volume and glutathione (GSH) respectively. Fractionation of AgNO3 and GSH mixed in vitro gave rise to a polynuclear complex and a 1 : 1 complex of Ag+-GSH which both eluted corresponding to silver in bile. Depletion of GSH in the liver by diethylmaleate (3.9 mmol/kg) caused a parallel decrease in the biliary excretion of both silver and reduced GSH. These findings support the hypothesis that silver is excreted into bile by a GSH-dependent mechanism most likely using GSH as a carrier molecule. Selenite (1 micromol/kg) inhibited the biliary excretion of silver while AgNO3 (1 mumol/kg) did not influence the excretion of selenium into bile. Pretreatment with selenite (1 micromol/kg) also caused a retention of silver (AgNO3, 1 micromol/kg) in the blood, kidney and brain. The liver content of silver was decreased and the organ to plasma ratio of silver was unchanged for erythrocytes, but decreased for the brain, kidney and liver, respectively. The effects caused by selenite are attributed to the formation of Ag2Se complexes which are nearly water insoluble and probably unavailable for biliary excretion. Selenium metabolites (GSSeSG, GSSeH) which are excreted into bile are probably not available for complexing with Ag+.

Uptake of chromium by rat liver mitochondria.

Isolated rat liver mitochondria rapidly accumulate chromate (1.2 microM 51CrO4(2-)) to about 0.25-0.30 nmol Cr/mg protein. The relative uptake decreases with increasing chromate doses. Chromate uptake decreases when pH is raised from 7.0 to 7.5.N-ethylmaleimide (0.25 mM) and butylmalonate (5 mM) inhibit chromate uptake to 70% and 30% of control values, respectively, whereas mersalyl (40 nmol/mg protein) causes an inhibition of greater than 95%. Both sulphate and phosphate decrease mitochondrial chromate uptake, the former being more effective in lower doses (5 mM). These results indicate that transport of chromate is mediated both on the dicarboxylate and the phosphate carrier. The extensive mitochondrial chromium accumulation can be explained by trapping of chromium, probably by reduction of chromate to the trivalent form, within the mitochondria. Release of chromium after chromate loading was seen after 15 min. Added after chromate loading, mersalyl partly prevents this release. Trivalent chromium as 51CrCl3 is taken up to a much lower degree than hexavalent chromium as 51CrO4(2-). The presence of glutathione (5 mM) reduces the uptake both of 51Cr-III and 51Cr-VI, indicating extramitochondrial reduction of Cr-VI to Cr-III and subsequent binding to GSH.

Evaluation of methyl mercury chelating agents using red blood cells and isolated hepatocytes.

The relative efficacy of thiol-containing mercurial scavengers was assayed by using cellular suspensions of erythrocytes or isolated hepatocytes. The blood cells incubated in a buffer (pH 7.4) containing 1 mM glucose (10% hematocrit) were exposed to 5 microM methyl mercuric chloride. In the absence of extracellular thiols the red blood cells took up more than 90% of methyl mercury from the surrounding medium during 5--10 min. This uptake was almost completely inhibited by dimercaptosuccinic acid (DMSA) (1 mM) and the same chelant could rapidly remove 80% of the mercury from 'pre-loaded' erythrocytes. Hepatocytes prepared according to the method of Seglen [11] in a suspension of 10(6) cells/ml in a buffer containing 5 mM glucose and 5 mg/ml of bovine serum albumin were also exposed to methyl mercuric chloride (4 microM). Almost 50% of the mercurial was taken up by the cells slowly during the incubation period of 240 min. DMSA (1 mM) almost completely blocked the methyl mercury binding by the hepatocytes. 2-Mercaptopropionylglycin (Thiola) or mercaptosuccinic acid (MSA) was almost as effective mercurial scavengers as DMSA in hepatocytes and in red blood cells. Diethyldithiocarbamate (DDC) and dimercaptopropanol (BAL) were considerably less effective than DMSA to inhibit the mercurial binding to hepatocytes. Experiments in vivo have shown that DMSA is a better mercurial chelator than Thiola or MSA, whereas DDC and BAL may both be considered to be inapplicable in methyl mercury poisonings. Our cellular assay provides preliminary information of the efficiency of chelating thiols and may serve as a useful first approximation when planning further experiments.

Prophylactic iron supplementation in pregnant women in Norway.

In the present study 67 non-anaemic women were randomly allocated to either 100 mg or 15 mg iron daily at about the 10. week of pregnancy. At about week 18, 30 and 36 of pregnancy, as well as 6 weeks after delivery, hemoglobin and the serum concentrations of ferritin, vitamin B12, folates, Zn, Cu and Se were monitored. Dietary allowances of other minerals and vitamins are also increased in pregnancy, and the 15 mg iron tablet was enriched with Zn (10 mg), Cu (2 mg), Se (50 microg), vitamin B12 (3 microg), and folate (0.1 mg). Neither ferritin, nor Cu, Zn or Se concentrations differed statistically significantly between the treatment groups during pregnancy. Ferritin and Zn appeared to decrease approximately parallel to the hemodilution, whereas Cu concentrations increased from a non-pregnant reference mean of 18 micromol Cu/L to a maximum mean of nearly 33 micromol Cu/L during pregnancy. Se decreased concomitantly to about 1.0 micromol Se/L. Serum folate (around 15 micromol/L) was essentially unaffected by pregnancy in the group given multivitamin/mineral supplementation, whereas the mean concentration fell below 10 micromol/L in the group supplemented with 100 mg iron daily. Our results indicate that supplementation of 15 mg Fe daily during pregnancy results in a small reduction of hemoglobin. It is suggested that additional supplementation with folate might be of importance to maintain the serum folate concentration during pregnancy.

Thyroid hypofunction in Down's syndrome: is it related to oxidative stress?

Oxidative stress affecting the thyroxin biosynthesis might explain the proneness of patients with Down's syndrome (DS) (trisomia 21) to develop hypothyroidism. Thyroideal cells are exposed to endogenous H2O2 that acts as a cofactor for the iodination of thyroxin precursors. The gland has high levels of selenium-containing proteins, including peroxide-detoxicating enzyme proteins. The object of the present study was to explore the hypothesis of a role of an imbalance between toxic oxygen production and protective metalloenzymes during the development of thyroid hypofunction in DS patients. We analyzed serum levels of thyroid hormones and trace metals in 38 institutionalized adults with DS, using mentally retarded subjects matched for age, sex, and behavioral function as controls. The DS patients had significantly lower mean values of free thyroxin (fT4) and increased TSH (thyroid stimulating hormone), as compared to the controls. They had lower serum selenium than the controls. A positive correlation was observed between serum concentrations of fT4 and selenium in the DS patients (r = 0.393, p < 0.05). No significant differences were found between the fT4 or the TSH concentrations in the patients with and without circulating antithyroid autoantibodies. Our results support the suggestion that thyroid hypofunction in patients with Down's syndrome in some way is linked to the low serum levels of selenium found in these patients. It is suggested that selenium-containing proteins are involved in thyroid hormonal synthesis, by protecting biosynthetic processes against the toxicity of free oxygen radicals.

Selenium concentrations in the human thyroid gland.

Recently, we found that prediagnostic serum selenium concentration was significantly lower for cases developing thyroid cancer (n = 43) than for controls. We assumed that redistribution of serum selenium into the affected tissue took place in the prediagnostic period. The present study was carried out to determine the physiological concentration of selenium in the thyroid, since very few data are available in the literature. The concentrations of selenium in the thyroid (n = 45) and liver samples from Norwegians who had died because of acute illness or accidents were determined by hydride generation atomic absorption spectrometry. The mean selenium concentration was found to be 0.72 +/- 0.44 microgram/g in the thyroid and 0.45 +/- 0.11 microgram/g in the liver tissue. The surprisingly high concentration of selenium in apparently normal thyroids indicates that selenium has important functions in this organ. The remarkably broad range, together with the observation that no significant correlation exists between thyroid and liver concentrations, suggest that factors other than the selenium status are important determinants for the selenium concentration in the thyroid gland. This observation is consistent with our hypothesis that in carcinogenesis, prediagnostic processes influence the serum-/thyroid-ratio of selenium.

Long-term effect of fibre supplement and reduced energy intake on body weight and blood lipids in overweight subjects.

A weight-reducing potential has been ascribed to high dietary fibre intake. To investigate the practical reliability of this hypothesis, fifty-three moderately overweight females (BMI > 27.5 kg/m2) on reduced energy intake (1200 kcal/day) were treated for 24 weeks with a fibre supplement on a randomly, double-blind, placebo-controlled basis. The fibre was administered as an initial dose of 6 g and a maintenance dose of 4 g. Body weight and blood pressure were recorded weekly during the first 3 months and thereafter every second week. Blood samples were drawn at start and at end of the study. Initial body weights were 75.6 +/- 1.6 kg in the fibre group versus 75.5 +/- 1.6 kg in the placebo group. After treatment, mean weight loss in the fibre group was 8.0 kg versus 5.8 kg in the placebo group (p < 0.05). Systolic and diastolic blood pressures were significantly reduced in both groups without differences between the groups. Serum concentrations of cholesterol, triglycerides and uric acid were significantly reduced in the group with reduced energy intake, whereas no additional effect was observed when fibre was supplemented. Serum concentrations of potassium and sodium did not change significantly. The results suggest that a dietary fibre supplement in combination with a hypocaloric diet is of value as an adjunct in the management of overweight.

Short-term effects of the TNFalpha antagonist infliximab on the acute phase reaction and activities of daily life in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the short-term effects of the tumour necrosis factor alpha (TNFalpha) antagonist infliximab on the acute phase reaction and activities of daily life (ADL) in patients with rheumatoid arthritis (RA). METHODS: Fourteen patients with active RA were treated with an intravenous infusion of 200 mg infliximab. The values of the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fibrinogen, granulocyte count, lymphocyte count, platelet count and a patient questionnaire score on ADL, the Health Assessment Questionnaire (HAQ), were obtained at baseline and on days 4 and 14. The significance levels and effect sizes (ESs) of the changes from baseline were calculated. RESULTS: Changes by day 4: The ESs and significance levels were: CRP 1.7, p<0.005; lymphocyte count 1.4, p<0.005; fibrinogen 0.9, p<0.005; ESR 0.7, p<0.005; and HAQ 0.6, p<0.01. Changes by day 14: CRP 1.6, p<0.005; ESR 1.5, p<0.005; fibrinogen 1.3, p<0.005; lymphocyte count 1.0, p<0.005; granulocyte count 0.7, p<0.05; and HAQ 0.6, p<0.05. CONCLUSION: CRP, fibrinogen and ESR showed the largest ESs and were thus the most sensitive variables showing the early effect of infliximab in this study. The score on ADL (HAQ) showed less ES, but still significant short-term improvements.

Recent advance in the therapy of metal poisonings with chelating agents.

1 A survey is given of the use of chelating agents in the treatment of metal poisonings. 1 The complexing agents in established clinical use are the polyaminopolycarboxylic acid EDTA (ethylenediamine tetraacetate) and the thiols BAL (2, 3-dimercaptopropanol) and D-penicillamine. Desferrioxamine is useful in the treatment of iron overloading. 2 The theoretical foundation of the metal-ligand interaction and some general principles of value in the search for new metal antidotes are outlined. 3 Recent research has shown that 2, 3-dimercaptosuccinic acid (DMS) and 2, 3-dimercaptopropane-1-sulphonate (DMPS) are effective in mercury and arsenic poisonings. 4 DMS and DMPS are of significantly lower toxicity than BAL, and they can be administered orally or intravenously. 5 A particularly low toxicity of DMS is reported from clinical and experimental studies, and this agent may be useful against several metal poisonings including mercury, lead and gold.

Thallium-201 as an agent for myocardial imaging studies.

The increasing use of thallium-201 (201Tl) in myocardial imaging studies during the last two decades, has justified a re-examination of the metabolism of this metal compound. It was found that about 4% of an injected dose was rapidly distributed to the healthy human myocardium, which is in agreement with previous reports. Apparent similarities exist between the transport of ionic thallium and potassium through cell membranes. Upon clinical use, myocardial perfusion scintigraphy is routinely carried out after i.v. administration of the agent. It is generally accepted that the rapid myocardial extraction of circulating 201Tl, during the initial 30 min. depends upon an unimpaired blood perfusion; whereas the prolonged uptake/redistribution during the next 3 h reflects myocardial viability. In the present paper, the reliability of 201Tl scintigraphy to disclose insufficient myocardial perfusion is illustrated by the examination of biological samples from patients, that were also studied by the classical coronary angiographic technique, the two methods showed an acceptable degree of agreement.

Uptake of chromate in human red blood cells and isolated rat liver cells: the role of the anion carrier.

The transport of [51Cr]chromate into human erythrocytes and isolated rat hepatocytes has been investigated. It was found that uptake in both cell types could be inhibited by the established anion carrier inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid. The uptake was very fast, and in kinetic studies a very low Km was found for both cell types, indicating either a high affinity of chromate for the carrier, and/or, more probably, an efficient intracellular reduction and trapping of 51Cr. The transport capacity, however, was of the same magnitude as for physiological substrates, such as lactate and sulfate. The uptake was temperature dependent and the activation energy was of the same magnitude as that for the physiological substrates. The uptake could be partly inhibited by high levels (mmol l-1) of lactate, pyruvate or sulfate. The uptake rate was greatly increased at lower pH (6.0 versus 7.4) which could indicate transport of the HCrO4- form or an increased intracellular rate of CrVI reduction. The results showed efficient uptake of 51CrO4(2-) by erythrocytes and hepatocytes. They were consistent with a mechanism of uptake which involved the cell membrane anion-exchange carrier in the transport and trapping of 51Cr within the cell.