Selenium supplementation in rheumatoid arthritis investigated in a double blind, placebo-controlled trial.

INTRODUCTION: Selenium is an essential trace element with antioxidant properties. Trials with selenium have been conducted in rheumatoid arthritis (RA) to correct impaired selenium status and increase defences against deleterious oxidant species. AIM OF THE STUDY: To investigate in a double blind multi-centric placebo-controlled study the effects of selenium supplementation in RA. METHODS: Fifty five patients with moderate RA received during 90 days either capsules containing selenium-enriched yeast (200 microg/d) or a placebo. RESULTS: The visual analog scale, the Ritchie index, the number of swollen and painful joints, and morning stiffness significantly decreased with time in both groups (p<0.001), but no difference between groups could be identified. When examining the quality of life a significant (p<0.01) improvement in arm movements and health feeling was evidenced in selenium-treated patients. CONCLUSION: Selenium treatment did not show clinical benefit on RA. Interestingly, the improval in both groups demonstrated a placebo effect of the intervention trial.

Zinc supplementation increases bone alkaline phosphatase in healthy men.

Zinc takes part in the metabolism of bone as a constituent of the matrix and as an activator of several metallo-enzymes. Animal in vitro and in vivo studies strongly suggest that zinc supplementation could stimulate bone formation and inhibit bone resorption but data in humans remain rare. The biological effects of 50 mg zinc given orally as gluconate in 20 healthy male volunteers were investigated in a 12 weeks double-blind placebo-controlled randomized trial. To investigate bone turnover, total alkaline phosphatases activity (ALP), bone specific alkaline phosphatase activity (BAPE) and BAP mass (BAP-M) concentration were measured as parameters of bone formation while urine calcium and C-terminal collagen peptide were determined as parameters of bone resorption. Samples were obtained in fasting subjects at baseline and after 6 and 12 weeks. In zinc treated subjects, a significant increase was observed at least after 12 weeks in total ALP (p < 0.01), BAP-M (p < 0.05) and BAP-E (p < 0.02). These parameters did not significantly change in the placebo group. Urine zinc/creatinine ratio significantly increased after 6 (p < 0.03) and 12 weeks (p < 0.04) in the zinc-treated group and was significantly different from the placebo group (p < 0.002). There was no significant effect of zinc supplementation on parameters of bone resorption. In conclusion, zinc supplementation at supraphysiological doses increased parameters of bone formation in healthy men while parameters of bone resorption remained unchanged.

Quantitative ultrasound and dual X-ray absorptiometry measurements of the calcaneus in patients on maintenance hemodialysis.

It has been suggested that quantitative ultrasound measurements (QUS), which reflect mainly bone density, could be influenced by bone micro-architecture. The aim of the study was to assess whether the relationship of QUS to dual X-ray absorptiometry (DXA) would reflect abnormalities of bone structure observed in renal osteodystrophy. QUS and bone mineral density of the calcaneus (BMDc) were measured by DXA in 30 patients on maintenance hemodialysis and 34 age- and gender-matched controls. QUS parameters and BMDc were significantly lower in hemodialysis patients than in controls (speed of sound [SOS] and broadband ultrasound attenuation [BUA], p = 0. 030; stiffness, p = 0.003; BMDc, p = 0.006). Bone measurements were not correlated with serum parathyroid hormone (PTH). The regression lines of SOS, BUA, and stiffness to BMDc were not significantly different from that of the controls. When dividing the patients into two subgroups according to their median PTH (203 pg/mL), the slopes of the regression lines of BUA to BMDc were significantly different between these two subgroups (p = 0.052). The slope of the subgroup with PTH

A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly.

The LQT1 locus (KCNQ1) has been correlated with the most common form of inherited long QT (LQT) syndrome. LQT patients suffer from syncopal episodes and high risk of sudden death. The KCNQ1 gene encodes KvLQT1 alpha-subunits, which together with auxiliary IsK (KCNE1, minK) subunits form IK(s) K(+) channels. Mutant KvLQT1 subunits may be associated either with an autosomal dominant form of inherited LQT, Romano-Ward syndrome, or an autosomal recessive form, Jervell and Lange-Nielsen syndrome (JLNS). We have identified a small domain between residues 589 and 620 in the KvLQT1 C-terminus, which may function as an assembly domain for KvLQT1 subunits. KvLQT1 C-termini do not assemble and KvLQT1 subunits do not express functional K(+) channels without this domain. We showed that a JLN deletion-insertion mutation at KvLQT1 residue 544 eliminates important parts of the C-terminal assembly domain. Therefore, JLN mutants may be defective in KvLQT1 subunit assembly. The results provide a molecular basis for the clinical observation that heterozygous JLN carriers show slight cardiac dysfunctions and that the severe JLNS phenotype is characterized by the absence of KvLQT1 channel.

[New NSAIDS: COX-1, COX-2, what about them?]. / Nouveaux AINS: COX-1, COX-2, que faut-il penser?

Non steroidal antiinflammatory (NSAID) drugs are the most widely prescribed drugs against pain and inflammation. Problems of tolerance, particularly gastrointestinal toxicity, limit their use. The central mechanism of NSAID action is the reduction of prostaglandin production from arachidonic acid through cyclooxygenase inhibition. Although such a mechanism was already described 25 years ago, the recent discovery of two isoforms of cyclooxygenase, the cyclooxygenase 1 (COX-1) constitutively expressed in most tissues and the cyclooxygenase 2 (COX-2), inducible, has prompted research in developing new NSAID that would be safer whilst maintaining their efficacy. Nevertheless, their long term efficacy and safety need to be demonstrated in clinical practice. There are still unsolved questions, especially about the physiological role of COX-2.

Comparative study of the intestinal absorption of three salts of calcium in young and elderly women.

A daily ingestion of 1000 to 1500 mg elemental calcium associated with vitamin D supplement is presently considered to be the adequate and least expensive therapy for senile osteoporosis. There exists only scarce data about calcium absorption with available calcium salts in elderly patients. We have compared the digestive absorption of calcium (Ca) citrate in soluble and solid form and calcium gluconolactate-carbonate in 15 young and 20 elderly, healthy women using the oral calcium loading test. The subjects were divided into two groups. In the first group, the absorption of solid Ca citrate (1000 mg Ca element) was compared to the absorption of Ca gluconolactate-carbonate (1000 mg Ca element) both in young (n = 7) and elderly women (n = 10). In the second group, the absorption of soluble Ca citrate (1000 mg Ca element) was compared to the absorption of Ca gluconolactate-carbonate (1000 mg Ca element) in young (n = 8) and elderly (n = 10) women. In the preload phase, basal calciuria was increased in elderly women (p < 0.01) although basal calcemia was similar in young and elderly women. After oral administration of the calcium salts, an increase in plasma Ca was observed in both groups which was greater for soluble Ca citrate and Ca gluconolactate than for solid Ca citrate. In young women, the increase in plasma calcium was significantly higher with soluble Ca citrate compared to Ca gluconolactate (p < 0.05). In elderly women, the postload calciuria was significantly higher for soluble Ca citrate (p < 0.05) and Ca gluconolactate (p < 0.05) compared to solid Ca citrate. A similar pattern was observed in young women, although it was not significant. In conclusion, an oral load of 1000 mg soluble Ca citrate and Ca gluconolactate-carbonate induces significant biochemical changes suggesting a better digestive absorption compared to Ca citrate in solid form, both in young and elderly women. We did not observe different response, between young and old patients.

Trace element status and inflammation parameters during chronic indomethacin treatment in adjuvant arthritic rats.

Oral indomethacin administration (2 mg/kg/d) was investigated in rats with adjuvant arthritis up to a period of 5 wk. Baseline low serum zinc levels in arthritic rats increased rapidly from the first week of indomethacin treatment (started 1 or 2 wk after disease induction), whereas baseline high serum copper decreased after 1-2 wk. After 3-4 wk of treatment, serum zinc levels returned to control values, but serum copper was somewhat higher in arthritic animals having received indomethacin 2 wk after disease induction than in controls. Clinical indices of inflammation simultaneously improved to reach control values at the end of the trial. Biological indicators of inflammation also improved, but did not reach control levels. Serum zinc correlated negatively with plasma fibrinogen (r = -0.69, p < 0.0005) and serum copper correlated positively with serum ceruloplasmin (r = 0.92, p < 0.0005) both in indomethacin-treated and untreated arthritic rats. Contrary to long-term glucocorticoid administration that was previously reported to maintain or aggravate hypozincemia, indomethacin treatment normalized perturbed zinc and copper status in arthritic animals.

Effects of zinc supplementation on the phagocytic functions of polymorphonuclears in patients with inflammatory rheumatic diseases.

The phagocytosis of blood polymorphonuclear cells (PMNs) was measured by cytofluorometry in 22 patients with inflammatory rheumatic diseases before and after a 60-day treatment with 45 mg zinc daily or a placebo, and the values were compared with those obtained in a group of healthy subjects. Plasma zinc was lower than controls before supplementation and phagocytosis assessed by the percentage of PMNs exhibiting phagocytic activity was significantly impaired. Zinc supplementation increased the percentage of phagocytic PMNs and the mean phagocytic activity, particularly in subjects with initial low phagocytosis. The impairment of PMN phagocytosis could therefore be corrected by zinc supplementation, but the clinical consequence of this stimulant effect remains unknown.

Zinc distribution in blood components, inflammatory status, and clinical indexes of disease activity during zinc supplementation in inflammatory rheumatic diseases.

The effects of zinc supplementation on zinc status and on clinical and biological indicators of inflammation were investigated in 18 patients with chronic inflammatory rheumatic diseases and in 9 healthy control subjects. Patients with mild and recent onset disease were assigned to a 60-d trial to receive either 45 mg Zn (as gluconate)/d or a placebo, while control subjects received the zinc supplement. Baseline mean plasma zinc of the patients was low whereas mononuclear cell zinc content was elevated, suggesting a redistribution of the element related to the inflammatory process rather than to a zinc-deficient state. Zinc supplementation increased plasma zinc to a similar extent in patients and in control subjects, which suggested no impairment of zinc intestinal absorption as a result of the inflammatory process. On the contrary, erythrocyte and leukocyte zinc concentrations were not modified in the two groups examined. No beneficial effect of zinc treatment could be demonstrated on either clinical or inflammation indexes.

Effects of acute prednisolone administration on plasma and liver copper in rats with adjuvant arthritis.

Several studies in animals and humans have shown that copper metabolism could be affected by inflammation or by corticosteroids. The relative importance of these two factors, often imbedded in clinical practice, was assessed by investigating the effects of acute prednisolone administration (30 mg/kg, ip) on healthy and adjuvant arthritis rats. Plasma copper levels were significantly higher in arthritic rats compared to healthy animals, whereas there was a slight, but nonsignificant increase in liver copper. Acute prednisolone administration in healthy rats resulted in a significant increase in plasma copper (10-15%) as early as 4 h after corticosteroid administration, which was maintained for 12 h. In arthritic rats, the response was much higher (25-40%), but somewhat delayed and shorter. Liver copper was not clearly modified by prednisolone treatment in both groups. This time-controlled study showed that acute prednisolone administration increased plasma copper in both healthy and arthritic rats, but in different ways, indicating that inflammation and corticosteroids may act synergistically.

Effects of acute and chronic prednisolone treatment on serum zinc levels in rats with adjuvant arthritis.

Several studies in animals and humans have independently demonstrated that zinc metabolism is significantly affected either by inflammation or by glucocorticoid administration. The relative importance of these two factors was assessed in this study by the investigation of the effects on serum zinc concentrations of acute and chronic prednisolone treatments in adjuvant arthritis rats and in healthy controls animals. Acute steroid administration (3 mg/kg, i.p.) caused a rapid drop in serum zinc followed by a quick recovery, regardless to the fact that these concentrations were normal (healthy animals) or already reduced by the inflammatory process. However, the modification occurred faster in inflamed animals. Chronic steroid administration (0.58 to 0.78 mg/kg/day during 1 to 4 weeks) had a more complex effect. A previous experiment in healthy rats demonstrated that such a treatment only induced a slight decrease in serum zinc. In adjuvant arthritis animals, the early steroid treatment of the induced process promoted a further decrease in serum zinc level while a delayed treatment did not result in additional changes.

Effects of selenium supplementation on immune parameters in gut failure patients on home parenteral nutrition.

The relationships between some parameters of the immune response and selenium were investigated in five patients receiving home parenteral nutrition for short-bowel syndrome. They were first submitted to a relative depletion by providing 20 micrograms selenium/day as L-selenomethionine for 1 mo. Then, daily selenium intake was raised to 200 micrograms for 2-4 mo. On entering the study, the patients presented a relatively good health status, and immunological parameters were at the lowest limit of the normal range. Four patients rapidly responded to the 200-micrograms supplementation by a continuous increase in their plasma selenium levels, whereas the fifth patient showed a moderate and late increase. At the end of the trial, there was an improvement in the lymphocyte response to pokeweed and phytohemagglutinin mitogens in four patients and to CD3 in three patients. The response to two of three antigens (Candidin, Varidase) tested was also enhanced in the same patients, but the response to the third antigen (tetanus toxoid) was uniformly low in all patients. The only patient showing essentially no immune improvement after selenium supplementation was the one with a low and delayed increase in plasma selenium. This study supports a role for selenium in the maintenance of an optimal immune response in humans.

Lymphocyte response is enhanced by supplementation of elderly subjects with selenium-enriched yeast.

The effect of selenium supplementation on plasma selenium concentrations and lymphocyte-proliferation responses to mitogens was investigated in 22 elderly institutionalized subjects. Subjects were assigned to a 6-mo trial with either 100 micrograms Se/d (as selenium-enriched yeast) or a placebo. Plasma selenium concentrations of the selenium-supplemented group increased from 0.84 +/- 0.26 to 1.55 +/- 0.33 mumol/L (mean +/- SD) after 2 mo and the values plateaued thereafter. The mean response of lymphocytes to mitogens in elderly subjects tended to be lower than responses in healthy adults, although responses remained within the 5-95% confidence-interval limit for healthy adults. During selenium supplementation the proliferative response to pokeweed mitogen increased significantly (+79% of baseline concentrations after 4 mo, P less than 0.01) and reached the upper limit of the usual range for adults after 6 mo (+138%, P less than 0.001). In accordance with previous studies in animals and in vitro, this investigation demonstrates for the first time immunostimulatory properties of selenium-enriched yeast in elderly humans.

Selenium in rheumatic diseases.

Selenium is involved in several important biochemical pathways relevant to rheumatic diseases. Experimental and clinical studies suggest that selenium modulates the inflammatory and immune responses. Patients suffering from inflammatory rheumatic diseases often have low selenium levels, but this finding does not correlate with disease severity. Selenium supplementation needs stricter selection criteria and better ascertainment of dose to obtain a stimulatory or inhibitory effect relevant to the disease state. Prevention of marginal selenium deficiency by moderate supplementation might enhance host defense mechanisms.

Choice of parameter for expressing bone mineralization.

In this cross-sectional study, the relative importance of anthropometric factors and that of biological parameters on bone mineralization were evaluated and their practical implications inferred on the choice of the parameter to be used for the estimation of bone mineralization. A close relationship between anthropometric factors and bone mineral content (BMC) was observed and this relationship was shown to be independent of age. Furthermore, by regression analyses, anthropometric parameters appeared to explain a large part of the variance in BMC and preceded the hormonal parameters in the stepwise analysis of this model. Using bone mineral density (BMD) data, however, we observed a weaker relationship between anthropometric factors and bone mineralization and a relatively stronger relationship between steroid hormones and bone mineralization than those observed using the BMC data. Furthermore, by multiple regression analysis the hormonal factors preceded the anthropometric parameters in the stepwise analysis of the model. As strong epidemiological and clinical evidence exists on the relationship between steroid hormones and bone loss, these results constitute a supplementary argument for the use of BMD for the estimation of bone mineralization.

Effects of chronic prednisolone administration on plasma copper in rats with adjuvant arthritis.

Copper metabolism is known to be significantly affected by inflammation or by glucocorticoid administration. We have previously demonstrated that acute prednisolone administration induces a moderate but sustained increase in plasma copper in healthy rats while it induces a more pronounced but shorter increase in rats with adjuvant arthritis. In the present study we have investigated the effects of chronic prednisolone administration (around 0.65 mg/kg daily in food) in both healthy rats and rats with adjuvant arthritis at various stages of the disease. In healthy rats, a slight but significant increase of 11% was observed in plasma copper after 3 weeks of treatment. This modification was no longer apparent after 5 weeks of treatment. In arthritic rats, plasma copper was, as expected, higher than in healthy rats and reached a maximum 3 weeks after adjuvant injection. In prednisolone-treated arthritic rats, there was a sustained decrease in plasma copper starting after 2 weeks of treatment which could be correlated with an improvement of the clinical and biochemical signs of inflammation. In conclusion, chronic prednisolone treatment only slightly increases plasma copper in healthy rats while in arthritic rats plasma copper is dependent on the severity of the disease which is improved by the treatment.

[Metabolic disorders of essential trace elements related to rheumatic disorders]. / Perturbations métaboliques des oligo-éléments essentials liées aux affections rhumatismales.

Trace elements are usually considered as "alternative" therapy. The present work is devoted to the analysis of the modifications in zinc, copper and selenium status in rheumatic diseases. The effect of the usual drug treatment is further studied as well as the therapeutic opportunities in "classic" medicine.

[Usual values of selenium and glutathione peroxidase in a Belgian population]. / Valeurs usuelles du sélénium et de la glutathion peroxydase dans une population belge.

Several biological parameters for assessing selenium status have been determined in years 1985-1986 in a large Belgian population group, males and females 0 to 92 years old, representative from Brussels and surroundings. In 145 people, 20 to 79 years old, mean concentrations were: 1.06 +/- 0.15 mumol Se/l plasma, 5.0 +/- 1.1 nmol Se/g Hb in erythrocytes and 7.4 +/- 2.0 mu/g Hb for the selenodependent glutathione peroxidase activity measured in erythrocytes (mean +/- standard deviation). Values for urine selenium have a disymmetric distribution and range from 0.05 to 0.65 mumol Se/g creatinine. No difference was evidenced in this group according to sex and age. Children below 20 years and elderly above 80 years have decreased plasma and erythrocyte selenium concentrations but glutathione peroxidase is not modified. These blood selenium concentrations are lower than those determined in a similar population group in years 1980-1981, suggesting a progressive decrease in selenium intake. The concentrations of the biological parameters are not correlated together except in selenium deficient patients having plasma selenium less than 0.75 mumol/l: a significant correlation is observed between plasma selenium and erythrocyte glutathione peroxidase activity, that becomes more intense with decreasing plasma selenium. Finally, two recent investigations are described where a significant response in platelet glutathione peroxidase was obtained during a 60 days selenium supplementation with 100 to 200 micrograms selenium per day, suggesting that usual selenium intake in Belgium (50 micrograms per day) is marginally deficient.