Metal-induced autoimmunity in neurological disorders: A review of current understanding and future directions.

Autoimmunity is a multifaceted disorder influenced by both genetic and environmental factors, and metal exposure has been implicated as a potential catalyst, especially in autoimmune diseases affecting the central nervous system. Notably, metals like mercury, lead, and aluminum exhibit well-established neurotoxic effects, yet the precise mechanisms by which they elicit autoimmune responses in susceptible individuals remain unclear. Recent studies propose that metal-induced autoimmunity may arise from direct toxic effects on immune cells and tissues, coupled with indirect impacts on the gut microbiome and the blood-brain barrier. These effects can activate self-reactive T cells, prompting the production of autoantibodies, inflammatory responses, and tissue damage. Diagnosing metal-induced autoimmunity proves challenging due to nonspecific symptoms and a lack of reliable biomarkers. Treatment typically involves chelation therapy to eliminate excess metals and immunomodulatory agents to suppress autoimmune responses. Prevention strategies include lifestyle adjustments to reduce metal exposure and avoiding occupational and environmental risks. Prognosis is generally favorable with proper treatment; however, untreated cases may lead to autoimmune disorder progression and irreversible organ damage, particularly in the brain. Future research aims to identify genetic and environmental risk factors, enhance diagnostic precision, and explore novel treatment approaches for improved prevention and management of this intricate and debilitating disease.

Health risk indices and zooplankton-based assessment of a tropical rainforest river contaminated with iron, lead, cadmium, and chromium.

Oil exploration's devastation on health and the environment may far outweigh its economic benefits. An oil spill occurred at Egbokodo River in Delta State, Nigeria, thereby polluting the land and water bodies. The study was therefore aimed at evaluating the impacts of iron, lead, cadmium, and chromium on the zooplankton community structure of Egbokodo River and the potential health risks. Zooplankton and surface water samples were collected to investigate the concentrations of trace metals and zooplankton abundance. The associated carcinogenic and non-carcinogenic effects of the metals in the water were analyzed. Trace metal concentrations in the surface water were determined using atomic absorption spectroscopy (Philips model PU 9100) and zooplankton samples were collected using a hydrobios plankton net (mesh size 25 µm). Total petroleum hydrocarbons (TPH) and oil and grease (OG) were determined using Agilent 7890B gas chromatography coupled to flame ionization detector (GC-FID) and volumetric analysis respectively. The trend of the abundance of zooplanktons cross the river was 18 individuals (Station A) < 100 individuals (Station B) < 155 individuals (Station C). Cyclopoida proved to be the most resilient to the impacts of the oil spill. On a taxa basis, the order of abundance among Calanoida, Cyclopoida, Cladoceran, and Harpacticoida was Station C > Station B > Station A, except in Amphipoda where Station B > Station C > Station A was observed. Iron and lead posed significant carcinogenic risks that are liable to be inflicted by the ingestion of the water. The cumulative non-carcinogenic health risk in the male was the only significant (> 1) among the age groups. Total petroleum hydrocarbons (TPH), oil and grease (OG), iron, and lead had notable impacts on the general abundance of zooplankton in the aquatic habitat. The dominance of the Cyclopoida in the river buttressed the impact of the oil spill which warrants a prompt remediation measure. The pollution had notable ecological impacts on the zooplankton community structure of the aquatic habitat. The adults in the nearby human populations are liable to elicit carcinogenic health challenges associated with lead and iron ingestion. The males are at risk of non-carcinogenic illnesses which are associated with the combined toxicity effects of all the metals. The study suggests that the pollution in Egbokodo River was validated by the dominance of the Cyclopoida in the aquatic habitat. The study confers bioindicator reputation on the Cyclopoida for future biomonitoring studies.

Effect of the duration of use of aluminum cookware on its metal leachability and cytogenotoxicity in Allium cepa assay.

Aluminum cookware are widely used in many parts of the world. Data is increasing on the leaching of toxic metals from aluminum cookware into food and drink. In the present study, cytogenotoxicity of water boiled in three different aluminum pots (new, 3-year-old, and 6-year-old) in onion root tip's dividing cells was evaluated using the Allium cepa assay. The concentrations of Pb, As, Cd, Cu, Ni, and Al in the samples were also analyzed. Onion bulbs were grown in the boiled water samples, while tap water served as the control. Cytological and genetic analyses were carried out after 48 h, while analysis of inhibition of root length was carried out after 72 h. The results showed a significant (p < 0.05) cell proliferation and root growth inhibition compared with the control, which is dependent on the duration of use of the aluminum pots. The boiled water samples also caused modification of the root morphology as well as chromosomal aberrations which include sticky chromosomes, anaphase bridge, and disturbed spindle. The highest cytogenotoxicity was observed in the 6-year-old aluminum pot and the least in the new aluminum pot. Pb, As, Cd, Cu, Ni, and Al analyzed in the samples, with the highest concentrations in the 6-year-old aluminum pot, were believed to be responsible for the cytogenotoxicity observed in the A. cepa assay. The data of this study are indications that the aluminum pot-boiled water contains substances with the potential to be cytotoxic and cause mutations in somatic cells of A. cepa.

Ability of selenium species to inhibit metal-induced Aß aggregation involved in the development of Alzheimer's disease.

Extracellular accumulation of amyloid beta peptide (Aß) is believed to be one of the main factors responsible for neurodegeneration in Alzheimer's disease (AD). Metals could induce Aß aggregation, by their redox activity or binding properties to amyloid ß fibrils, leading to their accumulation and deposition outside neurons. For this reason, metal chelation may have an acknowledged part to play in AD prevention and treatment. In the current work, the role of different selenium species, including selenium nanoparticles, in Aß aggregation, was studied by evaluating their metal-chelating properties and their ability both to inhibit metal-induced Aß1-42 aggregation fibrils and to disaggregate them once formed. Transition biometals such as Fe(II), Cu(II), and Zn(II) at 50 µM were selected to establish the in vitro models. The DPPH assay was used to determine the antioxidant capacity of the evaluated selenium species. Selenium nanoparticles stabilized with chitosan (Ch-SeNPs) and with both chitosan and chlorogenic acid polyphenol (CGA@ChSeNPs) showed the highest antioxidant properties with EC50 of 0.9 and 0.07 mM, respectively. UV-Vis and d1(UV-Vis) spectra also revealed that selenium species, in particular selenomethionine (SeMet), were able to interact with metals. Regarding Aß1-42 incubation experiments, Fe(II), Cu(II), and Zn(II) induced Aß aggregation, in a similar way to most of the evaluated selenium species. However, Ch-SeNPs produced a high inhibition of metal-induced Aß aggregation, as well as a high disaggregation capacity of Aß fibrils in both the presence and absence of biometals, in addition to reducing the length and width (20% of reduction in the presence of Zn(II)) of the generated Aß fibrils. Graphical abstract.

The management of embedded metal fragment patients and the role of chelation Therapy: A workshop of the Department of Veterans Affairs-Walter Reed National Medical Center.

Exposure to retained metal fragments from war-related injuries can result in increased systemic metal concentrations, thereby posing potential health risks to target organs far from the site of injury. Given the large number of veterans who have retained fragments and the lack of clear guidance on how to medically manage these individuals, the Department of Veterans Affairs (VA) convened a meeting of chelation experts and clinicians who care for embedded fragment patients to discuss current practices and provide medical management guidance. Based on this group's clinical expertise and review of published literature, the evidence presented suggests that, at least in the case of lead fragments, short-term chelation therapy may be beneficial for embedded fragment patients experiencing acute symptoms associated with metal toxicity; however, in the absence of clinical symptoms or significantly elevated blood lead concentrations (greater than 80 µg/dL), chelation therapy may offer little to no benefit for individuals with retained fragments and pose greater risks due to remobilization of metals stored in bone and other soft tissues. The combination of periodic biomonitoring to assess metal body burden, longitudinal fragment imaging, and selective fragment removal when metal concentrations approach critical injury thresholds offers a more conservative management approach to caring for patients with embedded fragments.

Metals and Mechanisms of Carcinogenesis.

Metal exposure is pervasive and not limited to sporadic poisoning events or toxic waste sites. Hundreds of millions of people around the globe are affected by chronic metal exposure, which is associated with serious health concerns, including cancer, as demonstrated in a variety of studies at the molecular, systemic, and epidemiologic levels. Metal-induced toxicity and carcinogenicity are sophisticated and complex in nature. This review provides a broad context and holistic view of currently available studies on the mechanisms of metal-induced carcinogenesis. Specifically, we focus on the five most prevalent carcinogenic metals, arsenic, nickel, cadmium, chromium, and beryllium, and their potential to drive carcinogenesis in humans. A comprehensive understanding of the mechanisms behind the development of metal-induced cancer can provide valuable insights for therapeutic intervention involving molecular targets in metal-induced carcinogenesis.

Direct and indirect effects of chemical contaminants on the behaviour, ecology and evolution of wildlife.

Chemical contaminants (e.g. metals, pesticides, pharmaceuticals) are changing ecosystems via effects on wildlife. Indeed, recent work explicitly performed under environmentally realistic conditions reveals that chemical contaminants can have both direct and indirect effects at multiple levels of organization by influencing animal behaviour. Altered behaviour reflects multiple physiological changes and links individual- to population-level processes, thereby representing a sensitive tool for holistically assessing impacts of environmentally relevant contaminant concentrations. Here, we show that even if direct effects of contaminants on behavioural responses are reasonably well documented, there are significant knowledge gaps in understanding both the plasticity (i.e. individual variation) and evolution of contaminant-induced behavioural changes. We explore implications of multi-level processes by developing a conceptual framework that integrates direct and indirect effects on behaviour under environmentally realistic contexts. Our framework illustrates how sublethal behavioural effects of contaminants can be both negative and positive, varying dynamically within the same individuals and populations. This is because linkages within communities will act indirectly to alter and even magnify contaminant-induced effects. Given the increasing pressure on wildlife and ecosystems from chemical pollution, we argue there is a need to incorporate existing knowledge in ecology and evolution to improve ecological hazard and risk assessments.

Multielemental Analysis of Tobacco Plant and Tobacco Products by TXRF.

The aim of this research is to develop a fast analytical method for multielemental analysis of the tobacco plant Virginia tobacco (cultivated in Poland) and tobacco products (cigarettes, cigars, cigarillos, snuff and two kinds of properly crafted tobacco such as a shisha and cigarette tobacco) distributed in Polish markets by means of a low-power benchtop total reflection X-ray fluorescence (TXRF) system. For this purpose, a set of certified tobacco materials and real samples was employed. In leaves and stalks of V. tobacco and tobacco products, a concentration of 18 elements (P, S, Cl, K, Ca, Ti, Cr, Mn, Fe, Ni, Cu, Zn, As, Se, Br, Rb, Sr and Pb) was determined. Analyzing elemental composition of tobacco plants, one can see that concentrations of S, Ca, Ti, Mn, Zn, Sr and Pb are higher in leaves, whereas the concentrations of P, Cl, K, Fe Cu and Br are higher in stalks; the levels of Cr, Ni, As and Rb are comparable in both these parts of the tobacco plant. All of the parameters affecting sample preparation and TXRF measurements conditions were carefully evaluated. The accuracy and precision of the TXRF measurements were verified using an internal standardization approach for quantification.

Three cases of metallosis associated with spine instrumentation.

The characteristic trait of metallosis is the presence of tissue staining. Analyzing explanted revision hardware from spine surgeries and performing ICPMS/AES analysis on removed tissue samples, a clinically relevant definition for metallosis may be developed. Results of the analysis identified hardware fretting wear and corrosion, and ICP-MS/AES analysis identified elevated metal ion concentrations in all cases. This supports the hypothesis that corrosion may be linked to poor health outcomes and potential need for revision surgery. Using failure analysis methods, corrosion products from orthopedic spine implants can be identified to begin to characterize metallosis in a clinically relevant manner. Failure analysis for patients undergoing revision spine surgery for other causes. Using failure analysis methods we conducted a retrieval analysis of explanted hardware and tissue. Implant failure with surrounding tissue metal staining is a current issue in the field of orthopedics. Specifically in spine, this issue is under reported and over looked as a clinically significant finding. Metallosis is most commonly used to describe the presence of tissue staining however this is not a clinically relevant definition. There is a need for further research to provide a better understanding of metallosis leading to better patient outcomes. Patients were screened for this study during a radiological review prior to surgery. All explanted hardware was documented and inspected for signs of wear and corrosion using non-destructive testing. A tissue sample that is normally removed and discarded was collected for ICP-MS/AES analysis. The presence of fretting corrosion, galling and corrosion fatigue was found on all explanted hardware. Cr levels are significantly higher than what was previously published as normal in muscle 0.03 µg/g. One case was a 4 order of magnitude elevation with the other 2 approximately 2 orders of magnitude increase. Titanium and Co concentrations are also significantly increased. The Ca to P ratio for all samples is approximately 1.7:1 suggesting some form of apatitic crystal present due to drying of the tissues. In all cases, the Al, Mo, V, Co, content in surrounding tissue is significantly elevated >10× above "normal," 8.4 ± 4.8; 1.61 ± 1.41; 0.06 ± 0.03; 1.35 ± 1.97 µg/g respectively. A "normal" reference titanium level could only be found for whole blood, 0.00072 ± 0.1412 µ/g. Iron and Ni measurements are within typical values presented in previous studies. No single mechanism for the release of metal ion in a patient is clear. Evidence suggests a tribocorrosive process due to both wear and environmental factors. Specific biologic mechanisms, such as the possible presence of bacteria may affect the fretting and corrosion of spinal instrumentation must be explored in conjunction with thorough review of patient outcomes. Such an effort can potentially reduce patient readmission and increase successful patient outcomes.

Somatoform and neurocognitive syndromes after HPV immunization are not associated to cell-mediated hypersensitivity to aluminum.

Vaccines against human papilloma virus (HPV) have been demonstrated to be very effective to prevent infection-related neoplasms. However, several reports describing heterogeneous post-vaccination phenomena have been published in last few years. The spectrum of these disorders includes both immune-mediated neurological diseases and neuropsychiatric functional disorders. Some researchers speculated about a genetic predisposition, but others hypothesized a role of adjuvants, including some metals and, particularly, aluminum. Here, we tested sixteen young girls developing somatoform and neurocognitive syndromes after the HPV immunization, through MELISA® test, detecting cell-mediated hypersensitivity to several metals. We found no association between these neurocognitive disorders and the results provided by this test; importantly, no patients showed hypersensitivity to aluminum, which is the inorganic adjuvant included in HPV vaccines. Thus, if aluminum played a role in the pathophysiology of musculoskeletal and neurocognitive disturbances occurring in some young girls after HPV immunization, that should recognize other mechanisms than the activation of aluminum-specific lymphocytes.

Mining and Environmental Health Disparities in Native American Communities.

PURPOSE OF REVIEW: More than a century of hard rock mining has left a legacy of >160,000 abandoned mines in the Western USA that are home to the majority of Native American lands. This article describes how abrogation of treaty rights, ineffective policies, lack of infrastructure, and a lack of research in Native communities converge to create chronic exposure, ill-defined risks, and tribal health concerns. RECENT FINDINGS: Recent results show that Native Americans living near abandoned uranium mines have an increased likelihood for kidney disease and hypertension, and an increased likelihood of developing multiple chronic diseases linked to their proximity to the mine waste and activities bringing them in contact with the waste. Biomonitoring confirms higher than expected exposure to uranium and associated metals in the waste in adults, neonates, and children in these communities. These sites will not be cleaned up for many generations making it critical to understand and prioritize exposure-toxicity relationships in Native populations to appropriately allocate limited resources to protect health. Recent initiatives, in partnership with Native communities, recognize these needs and support development of tribal research capacity to ensure that research respectful of tribal culture and policies can address concerns in the future. In addition, recognition of the risks posed by these abandoned sites should inform policy change to protect community health in the future.

[Hypersensitivity reactions to implantable cardiac pacemakers and defibrillators]. / Unverträglichkeitsreaktionen auf implantierbare Herzschrittmacher und Defibrillatoren.

Nowadays, for modern electrotherapy of cardiac arrhythmias different pacemaker systems are used. Antibradycardia pacing systems (e. g. single-chamber, two-chamber, three-chamber systems, frequency-adapted pacemaker) can be distinguished from antitachycardia pacing systems like implantable or portable cardioverter defibrillators and combined antibradycardia/antitachycardia systems. Cutaneous reactions overlying a pacemaker or defibrillator are often termed "pacemaker dermatitis". In terms of the differential diagnostic workup, these cutaneous reactions can have various causes. After exclusion of infection by analyzing clinical and laboratory-chemical results, "pressure dermatitis" or the often clinically asymptomatic "reticular telangiectatic erythema" (synonym "postimplantation erythema") must be considered. Histological examination of the affected skin can contribute to the diagnosis. In case of suspected contact hypersensitivity to implant material, allergological exploration should be realized. In addition to patch testing with commercially available contact allergens, product-related material metal alloy discs are often available from the pacemaker manufacturer for epicutaneous testing. Due to the lack of additional benefit compared to standardized patch testing, a clear recommendation for such metal alloy discs cannot be given. In selected cases of suspected hypersensitivity reaction, sensitization can eventually be analyzed by the lymphocyte transformation test. Positive reactions must always be critically interpreted taking into consideration the corresponding clinical signs. Depending on the cause, cutaneous reactions are occasionally self-limiting. In many cases, however, removal of the pacemaker is inevitable.

A Risk Assessment Tool for the Virtual Screening of Metal Oxide Nanoparticles through Enalos InSilicoNano Platform.

The increasing use of Nanoparticles (NPs) in a wide range of applications has led to a rising concern on the possible toxicological effects that this use may have on human health and the environment. Since experimental toxicity evaluation for the different types of NPs already available, is often expensive and time consuming, several computational approaches are proposed for the risk assessment of NPs. In this work, we have developed a predictive classification model for the toxicological assessment of iron oxide NPs with different core, coating and surface modification based on a number of different properties including size, relaxivities, zeta potential and type of coating. The model was fully validated based on several validation measurements and was released online via Enalos InSilicoNano Platform (http://enalos.insilicotox.com/QNAR_IronOxide_Toxicity/). The developed web service gives the interested user the opportunity to insert the indicated properties and get a toxicity prediction accompanied by an indication of its reliability based on the domain of applicability. This newly introduced web service complements our previously reported efforts to extract important information from available datasets and develop user friendly applications for the toxicity assessment of NPs.

Metal pollutants and cardiovascular disease: mechanisms and consequences of exposure.

INTRODUCTION: There is epidemiological evidence that metal contaminants may play a role in the development of atherosclerosis and its complications. Moreover, a recent clinical trial of a metal chelator had a surprisingly positive result in reducing cardiovascular events in a secondary prevention population, strengthening the link between metal exposure and cardiovascular disease (CVD). This is, therefore, an opportune moment to review evidence that exposure to metal pollutants, such as arsenic, lead, cadmium, and mercury, is a significant risk factor for CVD. METHODS: We reviewed the English-speaking medical literature to assess and present the epidemiological evidence that 4 metals having no role in the human body (xenobiotic), mercury, lead, cadmium, and arsenic, have epidemiologic and mechanistic links to atherosclerosis and CVD. Moreover, we briefly review how the results of the Trial to Assess Chelation Therapy (TACT) strengthen the link between atherosclerosis and xenobiotic metal contamination in humans. CONCLUSIONS: There is strong evidence that xenobiotic metal contamination is linked to atherosclerotic disease and is a modifiable risk factor.

Multifunctional 8-hydroxyquinoline-appended cyclodextrins as new inhibitors of metal-induced protein aggregation.

Mounting evidence suggests a pivotal role of metal imbalances in protein misfolding and amyloid diseases. As such, metal ions represent a promising therapeutic target. In this context, the synthesis of chelators that also contain complementary functionalities to combat the multifactorial nature of neurodegenerative diseases is a highly topical issue. We report two new 8-hydroxyquinoline-appended cyclodextrins and highlight their multifunctional properties, including their Cu(II) and Zn(II) binding abilities, and capacity to act as antioxidants and metal-induced antiaggregants. In particular, the latter property has been applied in the development of an effective assay that exploits the formation of amyloid fibrils when ß-lactoglobulin A is heated in the presence of metal ions.

Allergological and toxicological aspects in a multiple chemical sensitivity cohort.

BACKGROUND: Multiple chemical sensitivity (MCS) is a chronic condition characterized by an exaggerated response to toxicants. We ascertained the prevalence of allergy to metals and toxicological aspects in MCS patients. METHODS: We conducted a retrospective review of medical records of 41 patients with MCS. We performed patch testing (n = 21) for dental series and did lymphocyte transformation test (n = 18) for metals. We measured mercury in samples of blood (n = 19), urine (n = 19), saliva (n = 20), and scalp hair (n = 17) to investigate the association between mercury levels and cases of MCS. RESULTS: The prevalence of metal immune hypersensitivity in a subset of 26 patients was 92.3 percent. Elevations of mercury occurred in 81.2 percent (26 of 32). The mean (±SD) in blood concentrations of mercury was 7.6 ± 13.6 µg/L; mean in urine was 1.9 ± 2.5 µg/L; mean in scalp hair was 2.2 ± 2.5 µg/g; mean in saliva was 38.1 ± 52.1 µg/L. Subgroup analyses showed that elevation of mercury levels in biological matrices were associated with mercury amalgams in patients with MCS (22 patients), compared with controls (8 patients) (odds ratio 11 : 95 percent confidence interval 1.5 to 81.6; P = 0.023). CONCLUSIONS: Our data show an increased prevalence of metal allergy and elevation of mercury levels in bioindicators among patients with MCS.

The relevance of metals in the pathophysiology of neurodegeneration, pathological considerations.

Neurodegenerative disorders are featured by a variety of pathological conditions that share similar critical processes, such as oxidative stress, free radical activity, proteinaceous aggregations, mitochondrial dysfunctions, and energy failure. They are mediated or triggered by an imbalance of metal ions leading to changes of critical biological systems and initiating a cascade of events finally leading to neurodegeneration and cell death. Their causes are multifactorial, and although the source of the shift in oxidative homeostasis is still unclear, current evidence points to changes in the balance of redox transition metals, especially iron, copper, and other trace metals. They are present at elevated levels in Alzheimer disease, Parkinson disease, multisystem atrophy, etc., while in other neurodegenerative disorders, copper, zinc, aluminum, and manganese are involved. This chapter will review the recent advances of the role of metals in the pathogenesis and pathophysiology of major neurodegenerative diseases and discuss the use of chelating agents as potential therapies for metal-related disorders.

Maternal exposure to metals--concentrations and predictors of exposure.

A variety of metals are important for biological function but have also been shown to impact health at elevated concentrations, whereas others have no known biological function. Pregnant women are a vulnerable population and measures to reduce exposure in this group are important. We undertook a study of maternal exposure to the metals, aluminium, arsenic, copper, cobalt, chromium, lithium, manganese, nickel, selenium, tin, uranium and zinc in 173 participants across Western Australia. Each participant provided a whole blood and urine sample, as well as drinking water, residential soil and dust samples and completed a questionnaire. In general the concentrations of metals in all samples were low with the notable exception of uranium (blood U mean 0.07 µg/L, range <0.01-0.25 µg/L; urinary U mean 0.018 µg/g creatinine, range <0.01-0.199 µg/g creatinine). Factors that influenced biological concentrations were consumption of fish which increased urinary arsenic concentrations, hobbies (including mechanics and welding) which increased blood manganese concentrations and iron/folic acid supplement use which was associated with decreased concentrations of aluminium and nickel in urine and manganese in blood. Environmental concentrations of aluminium, copper and lithium were found to influence biological concentrations, but this was not the case for other environmental metals concentrations. Further work is underway to explore the influence of diet on biological metals concentrations in more detail. The high concentrations of uranium require further investigation.

Oxidative stress, redox signaling, and metal chelation in anthracycline cardiotoxicity and pharmacological cardioprotection.

SIGNIFICANCE: Anthracyclines (doxorubicin, daunorubicin, or epirubicin) rank among the most effective anticancer drugs, but their clinical usefulness is hampered by the risk of cardiotoxicity. The most feared are the chronic forms of cardiotoxicity, characterized by irreversible cardiac damage and congestive heart failure. Although the pathogenesis of anthracycline cardiotoxicity seems to be complex, the pivotal role has been traditionally attributed to the iron-mediated formation of reactive oxygen species (ROS). In clinics, the bisdioxopiperazine agent dexrazoxane (ICRF-187) reduces the risk of anthracycline cardiotoxicity without a significant effect on response to chemotherapy. The prevailing concept describes dexrazoxane as a prodrug undergoing bioactivation to an iron-chelating agent ADR-925, which may inhibit anthracycline-induced ROS formation and oxidative damage to cardiomyocytes. RECENT ADVANCES: A considerable body of evidence points to mitochondria as the key targets for anthracycline cardiotoxicity, and therefore it could be also crucial for effective cardioprotection. Numerous antioxidants and several iron chelators have been tested in vitro and in vivo with variable outcomes. None of these compounds have matched or even surpassed the effectiveness of dexrazoxane in chronic anthracycline cardiotoxicity settings, despite being stronger chelators and/or antioxidants. CRITICAL ISSUES: The interpretation of many findings is complicated by the heterogeneity of experimental models and frequent employment of acute high-dose treatments with limited translatability to clinical practice. FUTURE DIRECTIONS: Dexrazoxane may be the key to the enigma of anthracycline cardiotoxicity, and therefore it warrants further investigation, including the search for alternative/complementary modes of cardioprotective action beyond simple iron chelation.

Metal ring on 4th or 5th finger markedly increases both cardiac troponin I at left ventricle and cancer-related parameters such as oncogen C-fosAb2 & integrin α5ß1[corrected] by 4-12 times. Thus these metal rings appear to promote both heart problems & cancer.

We examined patients wearing a metal ring on the left 4th finger with abnormally increased Cardiac Troponin I (which is known to increase in the presence of myocardial injury or left ventricular hypertrophy) of 5-14ng BDORT units (depending on the ring and individual) at left ventricle compared with normal value of 1ng BDORT units or less. Although shape of the ECG does not change significantly regardless of whether metal rings are on or not, when rings are on, the Bi-Digital O-Ring Test evaluation of trace of ECG revealed "Vulnerable Period of Rising Part of T-wave" of ECG waves (which correspond to the left ventricle and AV node) become abnormal with increased Cardiac Troponin I. DHEA in various parts of the body reduced significantly and maximum decrease in DHEA was found when metal ring was on the left 4th and 5th fingers. Telomere reduced with each of the 5 fingers, but the 2nd, 4th, and 5th fingers produced the maximum reduction of telomere. When metal ring was inserted onto the left 1st finger and left 2nd finger, Cardiac Troponin I did not change significantly. Additional abnormality was found when patients with cancer wore metal ring(s); namely both Cardiac Troponin I and cancer parameters, such as Integrin α5ß1[corrected] and Oncogen C-fos Ab2, increase anywhere between 4-12 times. However, when the ring was cut, creating a 1mm or longer empty space, no increase in cancer markers and Cardiac Troponin I were observed. Similar findings were found with metal bracelets.