Symptoms and differential diagnosis of patients fearing mercury toxicity from amalgam fillings.
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Clinical signs, somatic symptoms reported by patients, and mercury excretion in urine were studied for 348 patients selected by odontologists or internists as amalgam-free referents, or as subjects with unexplained clinical findings or who were self-selected due to their fear of mercury intoxication from their amalgam fillings. Sixty patients were excluded because other explanations could be given for their complaints. The age distribution was bimodal, with peaks between 30 and 35 years and between 45 and 50 years. Mercury was determined in a morning urine sample and 30 minutes after the injection of 300 mg of 2,3 dimercapto-1-propane sulfonic acid (DMPS), a mercury-chelating agent. The patients were followed for 1-3 years. Among the patients there were 26 who had had their amalgam fillings removed and who, at the time of the follow-up, were subjectively cured. When the patients were classified according to the excretion of mercury after the DMPS challenge, those who belonged to the upper quartile had an odds ratio of 7.2 (95% confidence interval 3.1-15.2) for becoming cured after amalgam removal. The symptoms of the cured patients had been predominantly mental. No consistent clinical picture could, however, be found among the other patients, as various types of mental and physical distress were reported. (+info)
Involvement of tyrosine phosphorylation in inhibition of fMLP-induced PLD activation by N-acetyl-L-cysteine in differentiated HL60 cells.
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N-acetyl-L-cysteine (NAC), which is known as a multipotential agent; an antioxidant, a thiol reagent, or a tyrosine kinase inhibitor, inhibited N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced phospholipase D (PLD) activation in HL60 cells in a concentration-dependent manner (IC50 = 2 mM). Its inhibitory mechanism was examined in this study to gain insight into the regulation of PLD activity. NAC had no direct effect on membrane PLD activity in an in vitro assay system. fMLP-induced formation of inositol phosphates via phospholipase C (PLC) was not affected by the drug, suggesting that the receptor-G protein coupling was not inhibited. H2O2, which is known to induce PLD activation in several types of cells, failed to activate PLD in HL60 cells. Pretreatment of 3-amino-1,2,4-triazole (ATZ), a catalase inhibitor, did not enhance fMLP-induced PLD activation. NAC inhibited fMLP-induced tyrosine phosphorylation of several protein bands (42, 44, 64, and 138 kDa) in a concentration-dependent manner. The temporal and concentration-dependent inhibitory profiles for tyrosine phosphorylation of 64- and 138-kDa proteins were well correlated with PLD activation. However, thiol reagents, 1 mM 2,3-dimercapto-l-propanol (2,3-DMP), 1 mM dithiothreitol (DTT), and 2 mM cysteine also did not suppress protein tyrosine phosphorylation or PBut formation by fMLP. Wortmannin, a selective phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, inhibited these two tyrosine phosphorylation bands. These results suggest that NAC inhibits fMLP-induced PLD activation through blockage of protein tyrosine phosphorylation, which is located at the downstream of PI-3 kinase. (+info)
Characterization of lipid DNA interactions. I. Destabilization of bound lipids and DNA dissociation.
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We have recently described a method for preparing lipid-based DNA particles (LDPs) that form spontaneously when detergent-solubilized cationic lipids are mixed with DNA. LDPs have the potential to be developed as carriers for use in gene therapy. More importantly, the lipid-DNA interactions that give rise to particle formation can be studied to gain a better understanding of factors that govern lipid binding and lipid dissociation. In this study the stability of lipid-DNA interactions was evaluated by measurement of DNA protection (binding of the DNA intercalating dye TO-PRO-1 and sensitivity to DNase I) and membrane destabilization (lipid mixing reactions measured by fluorescence resonance energy transfer techniques) after the addition of anionic liposomes. Lipid-based DNA transfer systems were prepared with pInexCAT v.2.0, a 4.49-kb plasmid expression vector that contains the marker gene for chloramphenicol acetyltransferase (CAT). LDPs were prepared using N-N-dioleoyl-N,N-dimethylammonium chloride (DODAC) and either 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) or 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). For comparison, liposome/DNA aggregates (LDAs) were also prepared by using preformed DODAC/DOPE (1:1 mole ratio) and DODAC/DOPC (1:1 mole ratio) liposomes. The addition of anionic liposomes to the lipid-based DNA formulations initiated rapid membrane destabilization as measured by the resonance energy transfer lipid-mixing assay. It is suggested that lipid mixing is a reflection of processes (contact, dehydration, packing defects) that lead to formulation disassembly and DNA release. This destabilization reaction was associated with an increase in DNA sensitivity to DNase I, and anionic membrane-mediated destabilization was not dependent on the incorporation of DOPE. These results are interpreted in terms of factors that regulate the disassembly of lipid-based DNA formulations. (+info)
Mechanisms of action of 2,3-dimercaptopropane-1-sulfonate and the transport, disposition, and toxicity of inorganic mercury in isolated perfused segments of rabbit proximal tubules.
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Mechanisms by which the dithiol chelating agent 2, 3-dimercaptopropane-1-sulfonate (DMPS) significantly alters the renal tubular transport, accumulation, and toxicity of inorganic mercury were studied in isolated perfused pars recta (S2) segments of proximal tubules of rabbits. Addition of 200 microM DMPS to the bath provided complete protection from the toxic effects of 20 microM inorganic mercury in the lumen. The protection was linked to decreased uptake and accumulation of mercury. Additional data indicated that, when DMPS and inorganic mercury were coperfused through the lumen, very little inorganic mercury was taken up from the lumen. We also obtained data indicating that DMPS is transported by the organic anion transport system and that this transport is linked to the therapeutic effects of DMPS. Interestingly, very little inorganic mercury was taken up and no cellular pathological changes were detected when inorganic mercury and DMPS were added to the bath. We also tested the hypothesis that DMPS can extract cellular mercury while being transported from the bath into the luminal compartment. Our findings showed that, when DMPS was applied to the basolateral membranes of S2 segments after they had been exposed to mercuric conjugates of glutathione of the laminal membrane, the tubular content of mercury was greatly reduced and the rates of disappearance of mercury from the lumen changed from positive values to markedly negative values. We conclude that inorganic mercury is extracted from proximal tubular cells by a transport process involving the movement of DMPS from the bathing compartment to the luminal compartment. (+info)
Mobilization of mercury and arsenic in humans by sodium 2,3-dimercapto-1-propane sulfonate (DMPS).
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Sodium 2,3-dimercapto-1-propane sulfonate (DMPS, Dimaval) is a water-soluble chelating agent that can be given by mouth or systemically and has been used to treat metal intoxication since the 1960s in the former Soviet Union and since 1978 in Germany. To better approximate the body burdens of Hg and As in humans, DMPS-Hg andDMPS-As challenge tests have been developed. The tests involve collecting an overnight urine, administering 300 mg DMPS at zero time, collecting the urine from 0 to 6 hr, and determining the urinary Hg before and after DMPS is given. The challenge test, when applied to normal college student volunteers with and without amalgam restorations in their mouths, indicated that two-thirds of the Hg excreted in the urine after DMPS administration originated in their dental amalgams. In addition, there was a positive linear correlation between the amalgam score (a measure of amalgam surface) and urinary Hg after the challenge test. When the DMPS-Hg challenge test was used to study dental personnel occupationally exposed to Hg, the urinary excretion of Hg was 88, 49, and 35 times greater after DMPS administration than before administration in 10 dental technicians, 5 dentists, and 13 nondental personnel, respectively. DMPS also was used to measure the body burden of humans with a history of drinking water containing 600 microgram As/liter. DMPS administration resulted in a tripling of the monomethylarsonic acid percentage and a halving of the dimethylarsinic acid percentage as related to total urinary As. Because South American animals studied were deficient in arsenite methyltransferase, a hypothesis is presented that arsenite and arsenite methyltransferase may have had a role in the evolution of some South American animals. (+info)
DMPS (2,3-dimercaptopropane-1-sulfonate, dimaval) decreases the body burden of mercury in humans exposed to mercurous chloride.
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DMPS (2,3-dimercaptopropane-1-sulfonate, Na salt), when used as a challenge test for mercury in workers involved in the production of a calomel skin-bleaching lotion and in direct contact with mercurous chloride, elevated urine levels of mercury. A DMPS treatment regimen was devised and initiated. Three days after the challenge test, DMPS was administered p.o. (400 mg per day) for 8 days, followed by a no-treatment period of five days. A new cycle of DMPS treatment for 7 days was initiated and followed by 5 days without treatment. A third period of treatment was begun for 6 days, followed by a 5-day no-treatment period. The urinary mercury greatly increased during those periods when DMPS was administered (1754, 314, and 173 microgram/24 h for the periods 1, 2 and 3, compared with 106, 48 and 53 microgram/24 h on the corresponding no-treatment periods). One of the workers presented signs of drug intolerance and was discharged after receiving the first cycle of treatment. DMPS treatment was effective in lowering the body burden of mercury and in decreasing the urinary mercury concentration to normal levels. (+info)
Dynamics and ordering in mixed model membranes of dimyristoylphosphatidylcholine and dimyristoylphosphatidylserine: a 250-GHz electron spin resonance study using cholestane.
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We report here on a 250-GHz electron spin resonance (ESR) study of macroscopically aligned model membranes composed of mixtures of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylserine (DMPS), utilizing the nixtroxide-labeled cholesterol analog cholestane (CSL). Two clearly resolved spectral components, distinct in both their ordering and dynamics, are resolved. The major component in membranes composed mostly of DMPC shows typical characteristics, with the long axis of CSL parallel to the bilayer normal with slow (10(6) +info)
Contributions to maxima in protein kinase C activation.
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In many lipid systems, the activity of protein kinase C (PKC) exhibits a peak followed by a decline as the mol % of one component is increased. In these systems, an increase in one lipid component is always at the expense of another or accompanied by a change in total lipid concentration. Here we report that in saturated phosphatidylserine (PS)/phosphatidylcholine (PC)/diacylglycerol (DAG) mixtures, increasing PS or DAG at the expense of PC revealed an optimal mol % PS, dependent on mol % DAG, with higher mol % PS diminishing activity. The decrease at high mol % PS is probably not attributable simply to more gel-phase lipid due to the higher melting temperature of saturated PS versus PC because a similar peak in activity occurred in unsaturated lipid systems. Increasing the total lipid concentration at suboptimal mol % PS provided the same activity as higher mol % PS at lower total lipid concentration. However, at optimal mol % PS, activity increased and then decreased as a function of total lipid concentration. PKC autophosphorylation also exhibited an optimum as a function of mol % PS, and increasing the PKC concentration increased the mol % PS at which activity decreased, both for autophosphorylation and for heterologous phosphorylation. Formation of two-dimensional crystals of PKC on lipid monolayers also exhibited a peak as a function of mol % PS, and the unit cell size of the crystals formed shifts from 50 x 50 A at low mol % PS to 75 x 75 A at higher PS. Collectively, these data suggest the existence of optimal lipid compositions for PKC activation, with increased quantity of these domains serving to dilute out enzyme-substrate aggregates and/or enzyme-enzyme aggregates on the lipid surface. (+info)