pH-sensitive molybdenum (Mo)-based polyoxometalate nanoclusters have therapeutic efficacy in inflammatory bowel disease by counteracting ferroptosis.

Current therapeutic drugs for ulcerative colitis (UC) remained inadequate due to drug dependence and unacceptable adverse events. Reactive oxygen species (ROS) played a critical role in the occurrence and development of UC, which most likely benefited from treatment in scavenging ROS. In this study, we developed a pH-sensitive molybdenum-based polyoxometalate (POM) nanocluster, which might contribute to site specific colonic delivery and enhance systemic efficacy of UC treatment. Our results demonstrated that POM displayed robust ROS scavenging ability in vitro. POM could significantly alleviate the enteric symptoms and inflammatory indicators in DSS-induced UC mouse models. Flow cytometry showed an effective diminishment of macrophages, neutrophils and T cells infiltration after POM administration in UC models. Also, for the first time, we demonstrated that POM interfered with metabolic pathway associated to oxidative stress and partially improved the abnormal production of intestinal metabolites in UC to some extent. Benefiting from the ROS scavenging ability, POM attenuated ferroptosis in DSS induced UC, as evidenced by increase of GSH, down-expression of GPX4 and improvement in mitochondrial morphological changes. Meanwhile, there were no side effects on normal tissues. Thus, our powerful therapeutic effects pioneered the application of POM for safer and more effective POM-based UC therapy.

A systematic review and meta-analysis of the hyperuricemia risk from certain metals.

The relationship between exposure to certain metals and the risk of hyperuricemia (HUA) has biological plausibility, yet prior studies have presented inconsistent findings. We aim to clarify the relationship between exposure to certain metals and HUA using a systematic review and meta-analysis approach. We searched the Web of Science, Embase, MEDLINE, Pubmed, Corchrane and China National Knowledge Infrastructure databases from inception through December, 2021 in order to identify studies that assessed the relationships between metals and the risk of HUA. Data were pooled by random-effects models and expressed as pooled odds ratios (OR) and 95% confidence intervals (CIs). The risk of bias was assessed using a tool from Agency for Healthcare Research and Quality (AHRQ). Twenty eligible articles (nineteen cross-sectional studies and one cohort) were included in our analysis, involving 63,283 participants in total. The studies showed that arsenic (pooled OR = 1.702, 95% CI: 1.44, 2.011; n = 6, I2 = 29.5%), calcium (pooled OR = 1.765, 1.111, 2.804; 4, 82.3%), cadmium (pooled OR = 1.199,1.020, 1.410; 11, 38.5%) and lead (pooled OR = 1.564,1.205, 2.030; 11, 72.9%) exposure were, all linked to an increased risk of HUA. Exposure to molybdenum (pooled OR = 0.804, 0.724, 0.975, 3, 0%) was linked to a decreased risk of HUA, however. Exposure to arsenic, calcium, cadmium and lead is associated with an increased risk of HUA. Molybdenum exposure was associated with a decreased prevalence of HUA; however, aluminum, cobalt, copper, iron, magnesium, manganese, mercury, selenium, thallium and zinc are not associated with HUA risk. Further experimental studies are warranted to decipher the mechanisms by which exposure to the above metals affect HUA risk. The findings reinforced the importance of metals in the HUA risk, and provided a reference for legislation to prevent HUA and protect people's health.

In vivo assessment of molybdenum and cadmium co-induced the mRNA levels of heat shock proteins, inflammatory cytokines and apoptosis in shaoxing duck (Anas platyrhyncha) testicles.

Cadmium (Cd) and high dietary intake of molybdenum (Mo) can lead to adverse reactions on animals, but the combined impacts of Mo and Cd on testicle are not clear. To investigate the co-induced toxic effects of Mo and Cd in duck testicles on the mRNA levels of heat shock proteins (HSPs), inflammatory cytokines, and apoptosis. A total of sixty 11-day-old male Shaoxing ducks (Anas platyrhyncha) were randomly divided into 6 groups and testicles were collected on day 120. The mRNA levels of HSPs (HSP60, HSP70, HSP90), inflammatory cytokines (TNF-α, NF-κB, COX-2), and apoptosis genes (Bcl-2, Bak-1, Caspase-3) were determined by real-time quantitative polymerase chain reaction (RT-qPCR), meanwhile the changes of ultrastructural were evaluated. The results showed HSPs mRNA levels were increased in high Mo and Cd groups, however, they were decreased in high dose Mo and Cd co-treated group. In all treatment groups, the mRNA levels of Bak-1 and Caspase-3 were upregulated, and Bcl-2 mRNA level was downregulated, especially in combination groups. The TNF-α, NF-κB, and COX-2 expression in co-exposure groups were higher than those in single groups. Furthermore, the ultrastructural changes showed nuclear deformation, mitochondria hyperplasia and cristaes rupture, and vacuolation in combination groups. Changes of all above factors indicated a possible synergistic relationship between the two elements, and the high expression of HSPs and inflammatory cytokines may play a role in the resistance of testicles toxicity induced by Mo or Cd or both.

Comparative effectiveness of common therapies for Wilson disease: A systematic review and meta-analysis of controlled studies.

BACKGROUND & AIMS: Wilson disease (WD) is a rare disorder of copper metabolism. The objective of this systematic review was to determine the comparative effectiveness and safety of common treatments of WD. METHODS: We included WD patients of any age or stage and the study drugs D-penicillamine, zinc salts, trientine and tetrathiomolybdate. The control could be placebo, no treatment or any other treatment. We included prospective, retrospective, randomized and non-randomized studies. We searched Medline and Embase via Ovid, the Cochrane Central Register of Controlled Trials, and screened reference lists of included articles. Where possible, we applied random-effects meta-analyses. RESULTS: The 23 included studies reported on 2055 patients and mostly compared D-penicillamine to no treatment, zinc, trientine or succimer. One study compared tetrathiomolybdate and trientine. Post-decoppering maintenance therapy was addressed in one study only. Eleven of 23 studies were of low quality. When compared to no treatment, D-penicillamine was associated with a lower mortality (odds ratio 0.013; 95% CI 0.0010 to 0.17). When compared to zinc, there was no association with mortality (odds ratio 0.73; 95% CI 0.16 to 3.40) and prevention or amelioration of clinical symptoms (odds ratio 0.84; 95% CI 0.48 to 1.48). Conversely, D-penicillamine may have a greater impact on side effects and treatment discontinuations than zinc. CONCLUSIONS: There are some indications that zinc is safer than D-penicillamine therapy while being similarly effective in preventing or reducing hepatic or neurological WD symptoms. Study quality was low warranting cautious interpretation of our findings.

Ammonium tetrathiomolybdate treatment of copper-associated hepatopathy in dogs.

BACKGROUND: Copper-associated hepatopathy (CAH) is a common cause of liver disease in dogs. Although d-penicillamine can be an effective treatment, some dogs fail treatment or develop adverse effects. Ammonium tetrathiomolybdate (TTM) has been used to treat pathologic copper accumulation in other species, but its therapeutic potential for CAH is unknown. OBJECTIVES: To investigate short-term safety and efficacy of TTM for treatment of CAH. ANIMALS: Ten dogs with CAH. METHODS: Prospective study. All dogs were treated with TTM PO for 6 weeks, and hepatic biopsies were performed after the treatment course. Dog experiencing initial decreases in hepatic copper concentrations ([Cu]H ) received 6 additional weeks of TTM treatment and underwent 1 additional biopsy. Physical and laboratory examinations were performed every 2 weeks for study duration. RESULTS: Eight of 10 dogs had decreases in [Cu]H . Compared to baseline (median, 1606 µg/g; range, 572-5158 µg/g), [Cu]H were decreased at 6 weeks (1033 µg/g, 450-2975 µg/g; P = .04) and 12 weeks (931 µg/g, 218-1677 µg/g; P = .02). Hepatic molybdenum concentrations increased >50-fold (P < 0.001). Changes in histologic scores and hematologic and biochemical test results were variable and not significantly different from baseline. One dog developed presumed immune-mediated anemia and thrombocytopenia, but it was unclear if this was related to TTM administration. CONCLUSIONS AND CLINICAL IMPORTANCE: Results suggest that TTM can effectively decrease [Cu]H in some dogs with CAH. Larger studies are needed to determine the overall safety and efficacy of TTM for treating CAH and how it compares with current treatments.

WTX101 - an investigational drug for the treatment of Wilson disease.

INTRODUCTION: Wilson disease (WD) is a genetic disorder in which excess toxic copper accumulates in the liver, brain, and other tissues leading to severe and life-threatening symptoms. Copper overload can be assessed as non-ceruloplasmin-bound copper non-ceruloplasmin-bound copper (NCC) in blood. Current therapies are limited by efficacy, safety concerns, and multiple-daily dosing. Areas covered: This article reviews the literature on WTX101 (bis-choline tetrathiomolybdate), an oral first-in-class copper-protein-binding agent in development for the treatment of WD. Expert opinion: In a proof-of-concept phase II trial, once-daily WTX101 over 24 weeks rapidly lowered NCC levels and this was accompanied by improved neurological status without apparent initial drug-induced paradoxical worsening, reduced disability, stable liver function, with a favorable safety profile. WTX101 directly removes excess copper from intracellular hepatic copper stores and also forms an inert tripartite complex with copper and albumin in the circulation and promotes biliary copper excretion. These mechanisms may explain the rapid biochemical and clinical improvements observed. A phase III trial of WTX101 is ongoing and results are eagerly awaited to confirm if WTX101 can improve the treatment of this devastating disease.

Comparison of trace mineral repletion strategies in feedlot steers to overcome diets containing high concentrations of sulfur and molybdenum.

To compare trace mineral (TM) repletion in feedlot steers after depletion by S and Mo, 72 Red Angus steers blocked by BW (253 ± 14 kg) were assigned (6 steers per pen, fed via GrowSafe bunks) to corn silage depletion diets (depletion, DEP) supplemented with NRC (1996) recommended concentrations of Cu, Mn, Se, and Zn (CON) or supplemented with 0.3% S (CaSO4), 2 mg of Mo/kg dry matter (DM), and no added Cu, Mn, Zn, or Se (antagonist, ANT). Three 62 d TM repletion strategies (repletion, REP) were applied within DEP diets on day 89: 1) Multimin90 injection (contains Cu, Mn, Se, Zn) and 100% of recommended Cu, Mn, Zn, and Se from inorganic sources (ITM), 2) saline injection and 150% of recommended TM from inorganic sources (ING), or 3) saline injection and 150% of recommended TM provided as 25% organic and 75% inorganic sources (BLEND). Subcutaneous injections were given at 1 mL/68 kg BW. Inorganic sources were Cu, Mn, and Zn SO4, and sodium selenite, and organic sources were Availa Cu, Mn and Zn, and SelPlex Se. Repletion period liver and blood were collected on day -10, 14, 28, and 42 and data were analyzed as a 2 × 3 factorial (n = 12 steers per treatment) using Proc Glimmix of SAS with plasma and liver analytes analyzed as repeated measures. Liver Cu, Se, and Mn were decreased (P < 0.01) by ANT during DEP. There were no DEP × REP × day interactions in liver TM (P ≥ 0.18). A DEP × day effect was noted for liver Cu (P < 0.01) and Mn (P = 0.07), where ANT Cu increased linearly from day 0 to day 42, CON Cu was slightly increased on day 14 and day 28, and ANT Mn was lesser than CON Mn on all days except day 42. There were REP × day effects on liver Cu (P < 0.01) and Se (P < 0.01) where status was improved by ITM by day 14, increased in BLEND by day 28, and not different by day 42. Liver Se concentrations were lesser (P < 0.01) in ANT vs. CON throughout repletion. Liver Zn was greater (P < 0.01) on day 0 than day 14, 28, and 42, and concentrations were greater on day 42 than day 28. Glutathione peroxidase activity tended to be lesser (P = 0.07) on day 14 relative to other days. Manganese superoxide dismutase activity was lesser (P < 0.01) on day 14 and 28 compared to day 0 and 42, and tended to be lesser (P = 0.06) in ANT than CON during repletion. Final body weight (BW) and average daily gain (ADG) were not affected by treatment (P ≥ 0.60), and ANT decreased dry matter intake (DMI) (P = 0.04) and improved G:F (P < 0.01) during repletion. All repletion strategies were effective at increasing TM status of steers, and ITM had the most rapid recovery of Cu and Se status, followed by BLEND, and ING.

Coronary stent restenosis and the association with allergy to metal content of 316L stainless steel.

BACKGROUND: Most intra-coronary stents in use are made of 316 L stainless steel, which contains nickel, chromate and molybdenum. Whether inflammatory and allergic reactions to metals contribute to in-stent restenosis is still a matter of debate. AIM: The aim of this study was to ascertain the relationship between metal allergy and the occurrence of in-stent restenosis. METHODS: Ninety-nine adult patients who underwent two cardiac catheterisations, up to two years apart, were included in the study. Seventy patients had patent stents at the second angiogram (patent stent group) and 29 were found to have in-stent restenosis (restenosis group). All patients underwent patch testing with the relevant metals and the 316L stainless steel plate. RESULTS: Twenty-eight (28.3%) patients were found to have an allergy to at least one metal. There was no significant difference in the prevalence of metal allergy between the patent stent group and the restenosis group (28.6 and 27.6%, respectively; p = 0.921). CONCLUSIONS: Our data do not support the theory that contact allergy plays a role in the pathogenesis of in-stent restenosis.

Potential presence of metals in patients treated with metal-metal coupling prostheses for hip arthroplasty at 7 and 10 years of follow-up.

BACKGROUND: Beginning in 2008, metal-on-metal prostheses have been in the spotlight owing to much higher revision rates than expected. Adverse local tissue reactions have been well described in the literature as potential complications. METHODS: Between 2012 and 2013, 13 patients with metal-on-metal total hip replacements were evaluated clinically and radiologically and with laboratory samples. The same tests were repeated between 2015 and 2016 on eight patients to assess any changes. In the laboratory assessment, we searched for chromium, cobalt, molybdenum, and nickel in blood and urine samples over 24 h. RESULTS: Clinical assessment has shown good score in all patients except one. On a second examination, between 2015 and 2016, all patients obtained results similar to those obtained in the first assessment, except a patient, who reported a recent fall. In the radiological assessment between 2012 and 2013, results were optimal, apart from a case of aseptic mobilization. The patients reassessed 3 years after the first examination showed radiological results similar to those previously obtained, apart from a patient, who showed signals of mobilization. Metal levels found in their blood decreased in most cases after 3 years. Urine levels of nickel increased in five subjects, and chromium levels increased in four, but levels of cobalt and molybdenum decreased in four patients. CONCLUSION: It could be hypothesized that the decreasing trend of metal ion levels is associated with a stable wear status. On the contrary, a progressive increase in metal ion levels must be considered as early proof of implant loosening.

Hypersensitivity to material and environmental burden as a possible cause of late complications of cardiac implantable electronic devices.

Aims: To evaluate whether patients with late complications of pacemakers or implantable cardioverter-defibrillators have hypersensitivity reactions to some of the materials used in generators or in electrodes, or to environmental metal burden. Methods and results: The cohort consisted of 20 men and 4 women (mean age: 62.3 ± 17.2 years) who had a history of late complications of implanted devices. The control group involved 25 men and 8 women (mean age: 64.6 ± 14.0 years) who had comparable devices, but no history of late complications. Lymphocyte transformation test was used to evaluate hypersensitivity to eight metal pollutants (antimony, manganese, mercury, molybdenum, nickel, platinum, tin, and titanium) selected by results of questionnaires on environmental burden, and by material analysis of generators and electrode surfaces. Exposures to metal pollutants were approximately the same in patients and in controls. Titanium alloy used in generators contained at least 99.32% of titanium and trace levels of other metals; higher levels of tin and platinum were detected in electrode surfaces. Hypersensitivity reactions to mercury and tin were significantly more frequent in patients than in controls (patients and controls: mercury: 68.2 and 31.1%, respectively; P = 0.022; tin: 25.0 and 3.2%, respectively; P = 0.035). In contrast, hypersensitivity to manganese was significantly more frequent in controls than in patients (patients and controls: 13.6 and 50.0%, respectively; P = 0.008). Conclusion: Our findings suggest a possible relation between hypersensitivity to metals used in implantable devices or to environmental metal burden and the occurrence of their late complications.

Biocompatibility evaluation and corrosion resistance of tungsten added Co-30Cr-4Mo-1Ni alloy.

Biomaterials are continuously being developed to overcome the drawbacks of existing materials and provide improved function in artificial organs. Currently Co-Cr based alloys are used in many medical applications such as hip and knee implants which still require modification to better perform. In this article, therefore, the influence of tungsten allying element on electrochemical corrosion resistance and biocompatibility behaviour of a recently developed Co-30Cr-4Mo-1Ni alloy composition were investigated. The tungsten modified alloys were prepared by using a high temperature vertical vacuum casting technique at five different weight percentages (0-4wt.% tungsten). The electrochemical corrosion behaviour of all the samples under NaCl solution was studied by using potentiodynamic scan method. The corrosion characteristics were investigated in terms of corrosion potential (Ecorr) and corrosion current density (Icorr). From the results of the analysis, it was observed that out of all samples, an alloy with 2wt.% of tungsten in composition (i.e. Co-30Cr-4Mo-1Ni-2W) exhibited better corrosion resistance. Furthermore, histopathological evaluations in subcutaneous tissue were performed in rats according to the standard ISO 10993 to examine the biocompatibility of the prepared samples. The results showed no evidence of inflammatory cell migration, no epidermal necrosis, no vacuolar degeneration of basal cell, no adnexal atrophy and vesicle formation of any samples. The obtained findings indicate that Co-30Cr-4Mo-1Ni-2W can be used in biomedical applications including femoral component of hip and knee implants.

Bis-choline tetrathiomolybdate in patients with Wilson's disease: an open-label, multicentre, phase 2 study.

BACKGROUND: Wilson's disease is a genetic disorder in which copper accumulates in the liver, brain, and other tissues. Therapies are limited by efficacy, safety concerns, and multiple daily dosing. Bis-choline tetrathiomolybdate (WTX101) is an oral first-in-class copper-protein-binding molecule that targets hepatic intracellular copper and reduces plasma non-ceruloplasmin-bound copper (NCC) by forming tripartite complexes with albumin and increasing biliary copper excretion. We aimed to assess the efficacy and safety of WTX101 in the initial or early treatment of patients with Wilson's disease. METHODS: We did this open-label, phase 2 study at 11 hospitals in the USA and Europe. We enrolled patients (≥18 years) with Wilson's disease who were untreated or had received no more than 24 months of treatment with chelators or zinc, had a Leipzig score of 4 or more, and had NCC concentrations above the lower limit of the normal reference range (≥0·8 µmol/L). Eligible patients received WTX101 monotherapy at a starting dose of 15-60 mg/day on the basis of baseline NCC concentrations for the first 4-8 weeks, with response-guided individualised dosing for the remaining weeks up to week 24. Investigators, other hospital personnel, and patients were aware of the identity of the treatment. The primary endpoint was change in baseline NCC concentrations corrected for copper in tetrathiomolybdate-copper-albumin complexes (NCCcorrected) at 24 weeks, with treatment success defined as achievement or maintenance of normalised NCCcorrected (≤2·3 µmol/L [upper limit of normal]) or achievement of at least a 25% reduction in NCCcorrected from baseline at 24 weeks. This study is registered with ClinicalTrials.gov, number NCT02273596. FINDINGS: Between Nov 24, 2014, and April 27, 2016, 28 patients were enrolled and received WTX101; 22 (79%) patients completed the study up to week 24. At 24 weeks, 20 (71%, 95% CI 51·3-86·8; p<0·0001) of 28 patients met the criteria for treatment success: 16 (57%) treated with WTX101 either achieved or maintained normalised NCCcorrected concentrations and 4 (14%) had at least a 25% reduction from baseline NCCcorrected. Mean NCCcorrected was reduced by 72% from baseline to week 24 (least squares mean difference -2·4 µmol/L [SE 0·4], 95% CI -3·2 to -1·6; p<0·0001). No cases of paradoxical drug-related neurological worsening were recorded. Liver function was stable in all patients, although reversible increased concentrations of asymptomatic alanine or aspartate aminotransferase, or γ-glutamyltransferase, without increased bilirubin, occurred in 11 (39%) of 28 patients who received at least 30 mg/day. 11 serious adverse events were reported in seven (25%) patients and included psychiatric disorders (six events in four patients), gait disturbance (one event), elevated liver aminotransferases (two events in two patients, one with agranulocytosis), and decline in neurological functioning (one event, likely due to natural disease progression although causality could not be ruled out). The seven serious adverse events categorised as psychiatric disorders and as gait disturbance were assessed as unlikely to be related to the study drug, whereas the remaining four events were possibly or probably related. INTERPRETATION: Our findings indicate that WTX101 might be a promising new therapeutic approach for Wilson's disease, with a unique mode of action. In view of its once-daily dose and favourable safety profile, WTX101 could improve the treatment of patients with this debilitating condition. FUNDING: Wilson Therapeutics AB.

The effect of metal ions released from different dental implant-abutment couples on osteoblast function and secretion of bone resorbing mediators.

OBJECTIVES: The etiology of the reduced marginal bone loss observed around platform-switched implant-abutment connections is not clear but could be related to the release of variable amounts of corrosion products. The present study evaluated the effect of different concentrations of metal ions released from different implant abutment couples on osteoblastic cell viability, apoptosis and expression of genes related to bone resorption. METHODS: Osteoblastic cells were exposed to five conditions of culture media prepared containing metal ions (titanium, aluminum, vanadium, cobalt, chromium and molybdenum) in different concentrations representing the amounts released from platform-matched and platform-switched implant-abutment couples as a result of an earlier accelerated corrosion experiment. Cell viability was evaluated over 21days using the Alamar Blue assay. Induction of apoptosis was measured after 24h of exposure using flow cytometry. Expression of interleukin-6, interleukin-8, cyclooxygenase-2, caspase-8, osteoprotegerin and receptor activator of nuclear factor kappa-B ligand (RANKL) by osteoblastic cells were analysed after exposure for 1, 3 and 21days using real-time quantitative polymerase chain reaction assay RESULTS: Metal ions in concentrations representing the platform-matched groups led to a reduction in cell viability (P<0.01) up to 7days of exposure. Stimulated cells showed higher rates of early apoptosis (P<0.01) compared to non-treated cells. Metal ions up-regulated the expression of interleukin-6, interleukin-8, cyclooxygenase-2 and RANKL in a dose dependent manner after 1day of exposure (P<0.05). The up-regulation was more pronounced in the groups containing the corrosion products of platform-matched implant-abutment couples. CONCLUSION: Osteoblastic cell viability, apoptosis, and regulation of bone resorbing mediators were significantly altered in the presence of metal ions. The change in cytokine levels expressed was directly proportional to the metal ion concentration. CLINICAL SIGNIFICANCE: The observed biological responses to decreased amounts of metal ions released from platform-switched implant-abutment couples compared to platform-matched couples may partly explain the positive radiographic findings in respect to crestal bone level when utilising the "platform-switching" concept, which highlights the possible role of corrosion products in the mediation of crestal bone loss around dental implants.

Novel perspectives on Wilson disease treatment.

Wilson disease is an autosomal-recessive copper overload disorder causing hepatic and neurologic symptoms. Commonly used medical therapy shows satisfactory results with regard to hepatic disease but only limited effects in neurologically affected patients. In recent years several new therapy options have been developed, showing promising results that might improve the management of Wilson disease in the near future. Optimization of treatment regimens depending on biochemical response pattern seems worthwhile, especially in the decoppering phase of therapy. The chelator tetrathiomolybdate (TTM) is a promising therapy option, currently under clinical investigation. TTM is a fast-acting and very potent chelator and appears to be associated with early neurologic deterioration after initiation of therapy to a lower extent than the drugs currently used. Treatment with nonchelating drugs characterized by alternative modes of action is under investigation, but restricted to animal or in vitro studies to date. This includes basic research studies demonstrating proof of principle for successful cell or gene therapy in Wilson disease in order to restore sufficient biliary copper excretion, even before the onset of disease.

Titanium ions form particles that activate and execute interleukin-1ß release from lipopolysaccharide-primed macrophages.

BACKGROUND AND OBJECTIVE: Peri-implantitis is a destructive inflammatory process characterized by destruction of the implant-supporting bone. Inflammasomes are large intracellular multiprotein complexes that play a central role in innate immunity by activating the release of proinflammatory cytokines. Although inflammasome activation has previously been linked to periodontal inflammation, there is still no information on a potential association with peri-implantitis. The aim of this study was to examine cytotoxic and proinflammatory effects, including inflammasome activation, of metals used in dental implants, in an in vitro model, as well as from clinical tissue samples. MATERIAL AND METHODS: Human macrophages were exposed to different metals [titanium (Ti), cobalt, chromium and molybdenum] in a cell-culture assay. Cytotoxicity was determined using the neutral red uptake assay. Cytokine secretion was quantified using an ELISA, and the expression of genes of various inflammasome components was analysed using quantitative PCR. In addition, the concentrations of interleukin-1ß (IL-1ß) and Ti in mucosal tissue samples taken in the vicinity of dental implants were determined using ELISA and inductively coupled plasma mass spectrometry, respectively. RESULTS: Ti ions in physiological solutions stimulated inflammasome activation in human macrophages and consequently IL-1ß release. This effect was further enhanced by macrophages that have been exposed to lipopolysaccharides. The proinflammatory activation caused by Ti ions disappeared after filtration (0.22 µm), which indicates an effect of particles. Ti ions alone did not stimulate transcription of the inflammasome components. The Ti levels of tissue samples obtained in the vicinity of Ti implants were sufficiently high (≥ 40 µm) to stimulate secretion of IL-1ß from human macrophages in vitro. CONCLUSION: Ti ions form particles that act as secondary stimuli for a proinflammatory reaction.

Cobalt release and complications resulting from the use of dental prostheses.

BACKGROUND: Cobalt release from dental prostheses has been shown to elicit allergic reactions in cobalt-allergic patients. It is therefore important to investigate whether these prostheses are possible sources of sensitization. OBJECTIVES: To assess (i) cobalt release from dental prostheses and (ii) allergic reactions to components of dental prostheses, and (iii) to investigate the oral mucosa for inflammation 1-5 years after insertion of the prostheses. METHOD: Clinical oral examination was conducted in 66 patients with 84 dental prostheses. Cobalt release from 84 functional (used) and 32 non-functional (new) prostheses was investigated with the cobalt spot test. Contact allergy was assessed by patch testing. Smear tests for Candida spp. were performed in patients showing signs of inflammation of the oral mucosa. The prostheses were assessed for biological and technical complications. RESULTS: None of the functional prostheses released cobalt, whereas this was observed in 24 of 32 non-functional prostheses. None of the patients had contact allergy to cobalt. Of the 66 patients, 11 showed signs of inflammation of the oral mucosa, 2 had oral candidiasis, 16 had ill-fitting prostheses, and all had insufficient oral hygiene. CONCLUSIONS: Dental prostheses released cobalt during the fabrication stages, but not 1-5 years after insertion. No allergic reactions were observed. Signs of inflammation were related to candidiasis, insufficient oral hygiene, and ill-fitting prostheses.

Biomonitoring Equivalents for molybdenum.

Molybdenum is an essential trace element for mammalian, plant, and other animal systems. The Institute of Medicine (IOM) has established an Estimated Average Requirement (EAR) to assure sufficient molybdenum intakes for human populations; however excessive exposures can cause toxicity. As a result, several agencies have established exposure guidance values to protect against molybdenum toxicity, including a Reference Dose (RfD), Tolerable Daily Intake (TDI) and a Tolerable Upper Intake Level (UL). Biomonitoring for molybdenum in blood or urine in the general population is being conducted by the Canadian Health Measures Survey (CHMS) and the U.S. National Health and Nutrition Examination Survey (NHANES). Using pharmacokinetic data from controlled human dosing studies, Biomonitoring Equivalents (BEs) were calculated for molybdenum in plasma, whole blood, and urine associated with exposure guidance values set to protect against both nutritional deficits and toxicity. The BEEAR values in plasma, whole blood and urine are 0.5, 0.45 and 22 µg/L, respectively. The BEs associated with toxicity range from 0.9 to 31 µg/L in plasma, 0.8-28 µg/L in whole blood and 200-7500 µg/L in urine. These values can be used to interpret molybdenum biomonitoring data from a nutritional and toxicity perspective.