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Ions released from metal implants have been associated with adverse tissue reactions and are therefore a major concern. Studies with macrophages have shown that cobalt, chromium, and nickel ions can activate the NLRP3 inflammasome, a multiprotein complex responsible for the activation of caspase-1 (a proteolytic enzyme converting pro-interleukin [IL]-1β to mature IL-1β). However, the mechanism(s) of inflammasome activation by metal ions remain largely unknown. The objectives of the present study were to determine if, in macrophages: 1. caspase-1 activation and IL-1β release induced by metal ions are oxidative stress-dependent; and 2. IL-1β release induced by metal ions is NF-κB signaling pathway-dependent. Lipopolysaccharide (LPS)-primed murine bone marrow-derived macrophages (BMDM) were exposed to Co2+ (6-48 ppm), Cr3+ (100-500 ppm), or Ni2+ (12-96 ppm), in the presence or absence of a caspase-1 inhibitor (Z-WEHD-FMK), an antioxidant (L-ascorbic acid [L-AA]), or an NF-κB inhibitor (JSH-23). Culture supernatants were analyzed for caspase-1 by western blotting and/or IL-1β release by ELISA. Immunoblotting revealed the presence of caspase-1 (p20 subunit) in supernatants of BMDM incubated with Cr3+, but not with Ni2+ or Co2+. When L-AA (2 mM) was present with Cr3+, the caspase-1 p20 subunit was undetectable and IL-1β release decreased down to the level of the negative control, thereby demonstrating that caspase-1 activation and IL-1β release induced by Cr3+ was oxidative stress-dependent. ELISA demonstrated that Cr3+ induced the highest release of IL-1β, while Co2+ had no or limited effects. In the presence of Ni2+, the addition of L-AA (2 mM) also decreased IL-1β release, below the level of the negative control, suggesting that IL-1β release induced by Ni2+ was also oxidative stress-dependent. Finally, when present during both priming with LPS and activation with Cr3+, JSH-23 blocked IL-1β release, demonstrating NF-κB involvement. Overall, this study showed that while both Cr3+ and Ni2+ may be inducing inflammasome activation, Cr3+ is likely a more potent activator, acting through oxidative stress and the NF-κB signaling pathway., Competing Interests: The authors have declared that no competing interests exist.

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., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: We aimed to assess the early outcome following revision arthroplasty for failed metal-on-metal (MoM) total hip replacements (THR) due to adverse reaction to metal debris (ARMD)., Methods: We reviewed 106 consecutive revision arthroplasties. Case notes and radiological investigations were reviewed to assess the complications. Oxford Hip Score (OHS) and Euroqol (EQ-5D-3L) scores were used to assess the functional outcome and improvement of quality of life., Results: At a mean follow-up of 20 months (12-48 months), the mean OHS was 28.7. Pain improved in 61% patients. A majority of patients were in level 2 for all the EQ-5D-3L dimensions. The overall complication rate was 16%. Survivorship free from further revision for any cause was 94.3% at 48 months. There was no correlation between pre-revision blood metal ions and the final outcome., Conclusions: Revision surgery for failed MoM hip replacement due to ARMD is associated with a relatively higher rate of complications and risk of chronic pain. There is poor correlation between serum metal ions and development of ARMD and outcome following revision surgery.

Autoimmune nephritis triggered by metallic ions was assessed in a Long-Evans rat model. The parameters evaluated included antinuclear autoantibody production, kidney damage mediated by immune complexes detected by immunofluorescence, and renal function tested by retention of nitrogen waste products and proteinuria. To accomplish our goal, the animals were treated with the following ionic metals: HgCl2, CuSO4, AgNO3, and Pb(NO3)2. A group without ionic metals was used as the control. The results of the present investigation demonstrated that metallic ions triggered antinuclear antibody production in 60% of animals, some of them with anti-DNA specificity. Furthermore, all animals treated with heavy metals developed toxic glomerulonephritis with immune complex deposition along the mesangium and membranes. These phenomena were accompanied by proteinuria and increased concentrations of urea. Based on these results, we conclude that metallic ions may induce experimental autoimmune nephritis.

Increased wear leads to elevated systemic and local metal ion concentrations for patients treated with metal-on-metal bearings. The local metal ion content in the close environment of the joint replacement (e.g. joint aspirate or tissue) is several times higher compared to the systemic metal content (e.g. in blood or serum). As a result of increased metal ion levels, local and systemic effects, such as osteolysis, pseudotumors, sensitization or in rare cases toxicity may occur. Although the definition of a specific threshold to define clinical problems is difficult due to a lack of sensitivity, the systemic metal concentration is frequently measured clinically. Currently a threshold for cobalt and chromium between 4 µg/l and 7 µg/l is under debate. Very high levels (≥ 20 µg/l) or a steady increase over time should be a warning sign; however, metal ion levels should not be interpreted as a single diagnostic tool but rather in the entire context of the clinical, radiological and cross-sectional imaging, metal artefact reduction sequence (MARS) magnetic resonance imaging (MRI), ultrasound and computed tomography (CT) findings.

It was hypothesized that relative mass relationships among select constituent metals and iron (Fe3+) govern the pulmonary immunotoxic potential of any PM(2.5) sample, as these determine the extent to which Fe3+ binding by transferrin is affected (resulting in altered alveolar macrophage [AM] Fe status and subsequent antibacterial function). Iron response protein (IRP) binding activity is a useful indirect measurement of changes in Fe status, as reductions in cell Fe levels lead to increases in IRP binding. However, AM IRP activity can be affected by an increased presence of nitric oxide generated by inducible nitric oxide synthase (iNOS). This study sought to determine if any changes in AM IRP activity induced by PM(2.5) constituents V, Mn, or Al were independent from effects of the metals on cell NO formation. NR8383 rat AM were exposed to Fe3+ alone or combined with V, Mn, or Al at metal:Fe ratios representative of those in PM(2.5) collected in New York City, Los Angeles, and Seattle during fall 2001. Cells were then assessed for changes in IRP activity and iNOS expression. Phosphorylated extracellular signal-regulated kinase (ERK) 1 and 2 levels were also measured since activated ERKs are involved in signaling pathways that lead to increased iNOS expression. The results indicate that V and Al, and to a lesser extent Mn, altered IRP activity, though the effects were not consistently concentration dependent. Furthermore, while V and Mn treatments did not induce iNOS expression, Al did. These results confirmed our hypothesis that certain metals associated with PM(2.5) might alter the pulmonary immunocompetence of exposed hosts by affecting the Fe status of AM, a major class of deep lung defense cells.

In this study 67 workmen exposed to ions of heavy metals have been investigated because of their fertility. Concentrations of the noxious substances and their metabolites in blood and urine have been estimated and spermiograms were performed. The investigations demonstrated that a correlation exists between the concentrations of noxious substances in the place of employment, in the blood, and in the ejaculate, besides of zinc. An increased number of pathological spermiograms could be established especially in cases with an exceed of maximum permitted concentrations in the place of employment.