Cobalt exposure and pulmonary function reduction in chronic obstructive pulmonary disease patients: the mediating role of club cell secretory protein.

BACKGROUND: Cobalt (Co) is a metal which is widely used in the industrial production. The previous studies found the toxic effects of environmental Co exposure on multiple organs. However, the correlation of blood Co concentration with lung function was inconsistent in patients with chronic obstructive pulmonary disease (COPD). METHODS: All 771 stable COPD patients were recruited. Peripheral blood and clinical information were collected. The levels of blood Co and serum CC16 were measured. RESULTS: Cross-sectional study suggested that the level of blood Co was inversely and dose-dependently related to lung function parameters. Each 1 ppm elevation of blood Co was related to 0.598 L decline in FVC, 0.465 L decline in FEV1, 6.540% decline in FEV1/FVC%, and 14.013% decline in FEV1%, respectively. Moreover, higher age, enrolled in winter, current-smoking, higher smoking amount, and inhaled corticosteroids prominently exacerbated the negative correlation between blood Co and lung function. Besides, serum CC16 content was gradually reduced with blood Co elevation in COPD patients. Besides, serum CC16 was positively correlated with lung function, and inversely related to blood Co. Additionally, decreased CC16 substantially mediated 11.45% and 6.37% Co-triggered downregulations in FEV1 and FEV1%, respectively. CONCLUSION: Blood Co elevation is closely related to the reductions of pulmonary function and serum CC16. CC16 exerts a significantly mediating role of Co-related to pulmonary function decrease among COPD patients.

Metal Ion Release in Cancer Patients Following Megaprosthesis Salvage Surgery.

BACKGROUND: Megaprostheses contain many more modular components than conventional total hip and knee arthroplasty, which may lead to higher serum levels of metal ions. The aim of this study was to determine serum concentrations of titanium, chromium, and cobalt ions in cancer patients after limb salvage surgery with a megaprosthesis. METHODS: A retrospective, descriptive cohort analysis consisting of patients who underwent cancer-related limb salvage surgery with a megaprosthesis at our hospital between 2010 and 2020 was conducted. Baseline and follow-up data were extracted from clinical and surgical records. Blood samples were prospectively obtained. Descriptive statistics were used for the analysis. RESULTS: A total of 71 patients underwent limb salvage surgery during the study period. Of these, 22 (10 women, 12 men) were included in the study. The mean age was 52 years (range, 21 to 80). Most cases (n = 16; 72.7%) involved the femur. Most patients (n = 14, 63.6%) underwent total knee megaprosthesis surgery. Implant revision surgery was required in 45% of cases (n = 10), with a mean interval of 4.32 years between the initial and revision surgeries. The mean follow-up time after revision surgery was 4.05 years. High levels of chromium were observed in 22.7% of patients (n = 5). High cobalt levels were found in 68.2% (n = 15) of patients, with toxic levels in 9.1% (n = 2). Titanium levels were high in 77.3% (n = 17) of cases and toxic in 22.7% (n = 5). Postoperative chemotherapy was significantly associated with titanium levels (P = .017). No correlation was observed between metal ion levels and time from primary or revision surgery or time from the first to revision surgery. CONCLUSIONS: This study shows that cancer-related limb salvage surgery with megaprosthesis is associated with metal ion levels that exceed established safe thresholds. Compared to conventional hip arthroplasty, a higher proportion of the patients in this cohort presented elevated levels of metal ions. LEVEL OF EVIDENCE: III.

Accumulation of blood chromium and cobalt in the participants with metal objects: findings from the 2015 to 2018 National Health and Nutrition Examination Survey (NHANES).

BACKGROUND: Chromium (Cr) and cobalt (Co) are the essential elements for producing metal implants, but might have potential health issues. The research on the correlation between metal implants and blood Cr and Co on a large population is still limited. METHODS: National Health and Nutrition Examination Survey (NHANES) is a program of studies designed to assess the health status of Americans began in the early 1960s. The study was based on the NHANES database from two data collection years (2015-2016 and 2017-2018). The exposure variable of this study was whether the participants had metal objects in the body or not. The outcome variables were blood concentrations of Cr and Co. Age, body mass index, sex, race/ethnicity, income to poverty ratio, tap water behavior, shellfish/fish/tuna/salmon eating habits, level of education, smoking behavior, marital status, blood hemoglobin, and data collection years were included as confounding variables. RESULTS: A total of 4412 participants, aged 40 years or older, were included in this analysis, consisting of the without metal objects group (n = 3150) and the metal objects group (n = 1262). Metal objects was positively correlated to the accumulation of blood Cr (ß = 0.072, 95% CI: 0.043-0.102, p < 0.001) and blood Co (ß = 0.079, 95% CI: 0.049-0.109, p < 0.001). However, the positive correlation of metal objects with blood Cr was only presented in women (ß = 0.112, 95% CI: 0.074-0.151, p < 0.001), but not in men. Meanwhile, the positive relationship between metal objects and blood Cr/Co was not observed in the Asian subgroup. CONCLUSIONS: Blood Cr and Co concentrations were statistically higher in people with metal objects, but with race and sex differences. LEVEL OF EVIDENCE: Level IV, cross-sectional study.

Exploring the association of metal mixture in blood to the kidney function and tumor necrosis factor alpha using machine learning methods.

This research aimed to approach relationships between metal mixture in blood and kidney function, tumor necrosis factor alpha (TNF-α) by machine learning. Metals levels were measured by Inductively Couple Plasma Mass Spectrometry in blood from 421 participants. We applied K Nearest Neighbor (KNN), Naive Bayes classifier (NB), Support Vector Machines (SVM), random forest (RF), Gradient Boosting Decision Tree (GBDT), Categorical boosting (CatBoost), eXtreme Gradient Boosting (XGBoost), Whale Optimization-based XGBoost (WXGBoost) to identify the effect of plasma metals, TNF-α, and estimated glomerular filtration rate (eGFR by CKD-EPI equation). We conducted not only toxic metals, lead (Pb), arsenic (As), cadmium (Cd) but also included trace essential metals, selenium (Se), copper (Cu), zinc (Zn), cobalt (Co), to predict the interaction of TNF-α, TNF-α/white blood count, and eGFR. The high average TNF-α level group was observed among subjects with higher Pb, As, Cd, Cu, and Zn levels in blood. No associations were shown between the low and high TNF-α level group in blood Se and Co levels. Those with lower eGFR group had high Pb, As, Cd, Co, Cu, and Zn levels. The crucial predictor of TNF-α level in metals was blood Pb, and then Cd, As, Cu, Se, Zn and Co. The machine learning revealed that As was the major role among predictors of eGFR after feature selection. The levels of kidney function and TNF-α were modified by co-exposure metals. We were able to acquire highest accuracy of over 85% in the multi-metals exposure model. The higher Pb and Zn levels had strongest interaction with declined eGFR. In addition, As and Cd had synergistic with prediction model of TNF-α. We explored the potential of machine learning approaches for predicting health outcomes with multi-metal exposure. XGBoost model added SHAP could give an explicit explanation of individualized and precision risk prediction and insight of the interaction of key features in the multi-metal exposure.

Plasma Concentrations of Trace Elements Selenium and Cobalt During and After Coronary Artery Bypass Grafting Surgery.

Trace elements selenium (Se) and cobalt (Co) are essential in the human body, and a correlation between Se and cardiac surgery has been suggested. We investigated the plasma concentrations of Se and Co during and after coronary artery bypass grafting (CABG) surgery under cardiopulmonary bypass (CPB). From December 2019 to January 2020, preoperative plasma samples from isolated first-time CABG patients (n=20; 10 males, 10 females) were prospectively collected post-anesthesia and before CPB (T1), 45 min after CPB started (T2), 90 min after CPB started (T3), and postoperative days 1 (T4), and day 4 (T5). The plasma concentrations of Se and Co were measured. The Se concentration was significantly decreased at T2 (105.24±4.08 vs. 68.56±2.42 µg/L, p<0.001) and T3 (105.24±4.08 vs. 80.41±3.40 µg/L, p<0.001). The Co concentration was significantly decreased at T4 (0.35±0.19 vs. 0.26±0.13 µg/L, p<0.01) and T5 (0.35±0.19 vs. 0.23±0.11 µg/L, p<0.001). Five patients developed atrial fibrillation (AF); there was no other operative mortality or major morbidity. This is the first report of alterations of plasma Se and Co concentrations during and after CABG surgery. Our results may indicate that Se supplementation before or during CABG and Co supplementation after CABG may become necessary for patients undergoing CABG.

[Determination of cobalt in plasma blood samples by the ICP-MS method after oral intake of dietary supplements containing low doses of cobalt].

Salts of inorganic cobalt (Со) prevent the degradation of the alpha subunit of the hypoxia-inducible factor (HIF), imitating the state of hypoxia in the body and increasing the production of the endogenous hormone erythropoietin (EPO), and are used as doping substances that increase blood oxygen capacity and endurance, which give competitive advantages in sports. Currently, a large number of dietary supplements, including Co-containing ones, are offered on free sale. Their uncontrolled intake can affect not only the professional career of athletes, but also their health, due to the fact that this trace element and its salts are the strongest inorganic poisons and carcinogens. Despite this, their availability on the pharmaceutical market, a noticeable effect of erythropoiesis stimulation and a convenient oral form of administration lead to the need for their detection in modern doping control. The purpose of this research was to develop an approach to differentiate cobalt from vitamin B12, present in the body in its natural state, from the intake of cobalt salts by quantifying and comparing blood levels of vitamin B12 and total cobalt. Methods. The study involved 9 healthy volunteers (women and men) aged 25 to 45 years, leading an active lifestyle. Three of them took 2500 µg/day of cobalamin for 20 days (comparison group), three - dietary supplement containing cobalt asparaginate (100 µg/day in terms of pure cobalt), and the rest - dietary supplements with cobalt sulfate heptahydrate (100 µg/day in terms of pure cobalt) (administration groups) at the same time after meals. Blood samples were taken at baseline and on days 5, 9, 14 and 20. The concentrations of total cobalt in blood plasma samples of volunteers were measured by inductively coupled plasma mass-spectrometry (ICP-MS), the levels of cobalamin were determined on a Cobas 6000 immunochemical analyzer using the Elecsys Vitamin B12 II Assay ELISA kits. Results. It was found that oral intake of of cobalamin at a therapeutic dose significantly exceeding the recommended daily intake (3 µg), there was a regular slight increase in the blood concentration of total cobalt (1.1 times). At the same time intake of dietary supplements containing cobalt in the form of sulfate or asparaginate (about 100 µg per day in terms of pure cobalt) was accompanied by 4-6.7 fold increase in the concentration of total cobalt while unchanged vitamin B12 plasma concentration was observed. The detection of such changes can reliably indicate the use of prohibited salts and, of course, will be in demand for anti-doping control. Conclusion. Long-term monitoring of vitamin B12 and total cobalt levels, similar to hematological module of the Athlete Biological Passport program, will unambiguously detect possible abuse of cobalt salts and can be an additional evidence of the presence of these doping substances to other analytical methods, such as a combination of liquid chromatography and ICP-MS (LC-ICP-MS).

Adverse Local Tissue Reactions are Common in Asymptomatic Individuals After Hip Resurfacing Arthroplasty: Interim Report from a Prospective Longitudinal Study.

BACKGROUND: The evaluation of the natural history prevalence of adverse local tissue reactions (ALTRs) using MRI has focused only on metal-on-metal (MoM) bearing surfaces without comparison to nonMoM bearing surfaces. QUESTIONS/PURPOSES: To determine (1) the longitudinal changes and differences in blood metal ion levels in patients with hip resurfacing arthroplasty (HRA), ceramic-on-ceramic (CoC) THA, and metal-on-polyethylene (MoP) THA compared with those undergoing ceramic-on-polyethylene (CoP) THA; (2) how the longitudinal change of synovial reaction classification in patients with HRA, CoC THA, and MoP THA compares with those undergoing CoP THA, and whether there is an association between the presence of an ALTR or metallosis on MRI with corresponding patient-reported outcomes, or the presence of capsular dehiscence; and (3) differences in blood metal ion levels between patients undergoing HRA with an ALTR or metallosis on MRI and those with HRA without these conditions. METHODS: Between March 2014 and February 2019, 22,723 patients underwent primary HRA and THA at one center. Patients received an HRA based on their desired athletic level after surgery and the presence of normal acetabular and proximal femoral bone morphology without osteopenia or osteoporosis. Two percent (342 of 22,723) of patients were contacted to participate, and 71% (243 of 342 hips in 206 patients) were enrolled for analysis at baseline. The patients underwent arthroplasty for degenerative joint disease, and 25 patients withdrew over the course of the study. We included patients who were more than 1 year postarthroplasty. All participants had an MRI examination and blood serum ion testing and completed a Hip Disability and Osteoarthritis Outcome Score survey annually for four years (baseline, year 1, year 2, year 3). Morphologic and susceptibility-reduced MR images were evaluated by a single radiologist not involved in the care of patients for the presence and classification of synovitis (Gwet AC1: 0.65 to 0.97), synovial thickness, and volume (coefficient of repeatability: 1.8 cm3). Linear mixed-effects models were used to compare the mean synovial thickness, synovial volume, and Hip Disability and Osteoarthritis Outcome Score subscales between bearing surfaces at each timepoint and within each bearing surface over time. Marginal Cox proportional hazards models were used to compare the time to and the risk of developing ALTR only, metallosis only, and ALTR or metallosis between bearing surfaces. All models were adjusted for age, sex, BMI, and length of implantation based on known confounders for hip arthroplasty. Adjustment for multiple comparisons was performed using the Dunnett-Hsu method. RESULTS: Patients with unilateral HRA had higher cobalt and chromium serum ion levels (baseline: 1.8 ± 0.8 ppb, year 1: 2.0 ± 1.5 ppb, year 2: 2.1 ± 1.2 ppb, year 3: 1.6 ± 0.7 ppb) than those with unilateral CoP bearings (baseline: 0.0 ± 0.1 ppb, year 1: 0.1 ± 0.3 ppb, year 2: 0.0 ± 0.2 ppb, year 3: 0.0 ± 0.0 ppb) at all timepoints (p < 0.001 for each time point). More patients who received an HRA developed ALTR or metallosis on MRI than did patients with CoP bearings (hazard ratio 4.8 [95% confidence interval 1.2 to 18.4]; p = 0.02). There was no association between the longitudinal change of synovial reaction to ALTR or metallosis on MRI with patient-reported outcomes. In addition, there was no association between the presence of dehiscence at baseline and the subsequent development of ALTR or metallosis, as seen on MRI. There were elevated cobalt (4.7 ± 3.5 ppb) and chromium (4.7 ± 2.6 ppb) serum levels in patients with unilateral HRA who had an ALTR or metallosis present on MRI at year 1 compared with patients without an ALTR or metallosis on MRI (cobalt: 1.8 ± 1.0 ppb, mean difference 4.7 ppb [95% CI 3.3 to 6.0]; p < 0.001; chromium: 2.3 ± 0.5 ppb, mean difference 3.6 ppb [95% CI 2.2 to 5.0]; p < 0.001) as well as for chromium at year 3 (3.9 ± 2.4 ppb versus 2.2 ± 1.1 ppb, mean difference 1.3 ppb [95% CI 0.3 to 2.4]; p = 0.01). CONCLUSION: We found a higher proportion of ALTR or metallosis on MRI in patients with HRA compared with patients with CoP, even when patient self-assessed symptomatology of those with an ALTR or metallosis on MRI was not different than the absence of these features. MRI detected ALTRs in high-function patients, emphasizing that an annual clinical assessment dependent on survey or blood ion testing alone may not detect soft tissue complications. The results of this study are in line with prior consensus recommendations of using MRI as part of a routine follow-up protocol for this patient population. LEVEL OF EVIDENCE: Level III, therapeutic study.

Sex differences in the link between blood cobalt concentrations and insulin resistance in adults without diabetes.

BACKGROUND: Little is known about the effects of environmental cobalt exposure on insulin resistance (IR) in the general adult population. We investigated the association between cobalt concentration and IR. METHODS: A total of 1281 subjects aged more than 20 years with complete blood cobalt data were identified from the National Health and Nutrition Examination Survey (NHANES) 2015-2016 cycle. Blood cobalt levels were analyzed for their association with IR among all populations and subgroups by sex. Regression coefficients and 95% confidence intervals (CIs) of blood cobalt concentrations in association with fasting glucose, insulin and homeostatic model assessment of insulin resistance (HOMA-IR) were estimated using multivariate linear regression after adjusting for age, sex, ethnicity, alcohol consumption, body mass index, education level, and household income. A multivariate generalized linear regression analysis was further carried out to explore the association between cobalt exposure and IR. RESULTS: A negative association between blood cobalt concentration (coefficient = - 0.125, 95% CI - 0.234, - 0.015; P = 0.026) and HOMA-IR in female adults in the age- and sex-adjusted model was observed. However, no associations with HOMA-IR, fasting glucose, or insulin were found in the overall population. In the generalized linear models, participants with the lowest cobalt levels had a 2.74% (95% CI 0.04%, 5.50%) increase in HOMA-IR (P for trend = 0.031) compared with subjects with the highest cobalt levels. Restricted cubic spline regression suggested that a non-linear relationship may exist between blood cobalt and HOMA-IR. CONCLUSIONS: These results provide epidemiological evidence that low levels of blood cobalt are negatively associated with HOMA-IR in female adults.

Gross trunnion failure in metal on polyethylene total hip arthroplasty-a systematic review of literature.

BACKGROUND: Multiple cases of dissociation of the head from the neck termed as gross trunnion failure (GTF) in total hip replacement have been described. Very little quantitative data is available for patient and implant factors associated and predisposing to this complication. STUDY PURPOSE: To systematically review and analyze all studies which have gross trunnion failure in case of metal on polyethylene (MoP) total hip replacement. METHODS: PubMed database was searched. We also performed a secondary search by pearling bibliography of all full text articles obtained. Predefined inclusion and exclusion criteria were used for abstract screening by two independent observers. A total 46 cases met our inclusion criteria. These were included in the final analysis and data was pooled. RESULTS: Till date, 46 cases of GTF in MoP THR have been reported. The mean age at time of revision was 70.13 years (range 50 to 89 years). The mean time to revision surgery was 8.24 years (range 4.7 to 14 years). 91.4% cases were male. BMI was ≥ 25 in 38/41 cases and ≥ 30 in 21/41 cases. Pain (95.5%) and difficulty or inability to walk (97.7%) were the most common symptoms. A total of 19/44 cases described varying sounds like click, clunk, and pop before dislocation. Accolade TMZF/TMZF plus was the most common stem used in 34/46 cases. The stem neck angle was 127 degrees in 97% cases (32/33 cases). A positive neck offset of 4 mm or more was used in 91.1% cases (40/44 cases). The head size ≥ 36 mm in approximately 90% cases. The head material was cobalt chromium in all 45 cases, where data was available. Among the intra-operative findings, the most common findings were metallosis (41/44), black or brow coloured synovial fluid (21/44), pseudotumour (19/44), synovial hypertrophy (18/44), damage to the abductor musculature (17/44), proximal femoral osteolysis (5/44 cases), and heterotrophic ossification (2/44 cases). Histopathological analysis was available in 11 cases and was suggestive of fibrous tissue with chronic cellular infiltrate in all cases. The serum cobalt and chromium concentrations were raised above normal in 86.4% (19/22) and 21.7% cases (5/23) respectively. CONCLUSIONS: Gross trunnion failure may not be as uncommon as was previously thought. A number potential associations and predisposing factors of this complication have been highlighted in this review. But due to small sample size and weak level of evidence, further studies are needed in this field.

Bowing-head sign: rare but detectable in pre-catastrophic hip implant failure.

Recently, catastrophic failure (i.e., dissociation between the metal femoral head and stem due to stem neck deformation) after total hip arthroplasty (THA) has been reported. Early detection of this complication is very important, because it is accompanied by an increased cobalt concentration in the body, which might influence systemic conditions such as heart failure and immune system diseases. However, early detection of stem neck deformation is considered as difficult. In most cases in the literatures, the diagnosis was made at the time of acute dissociation. We report a case of early detection of stem neck deformation with the 'Bowing-head sign' before acute dissociation. The patient is a 71-year old woman complained of a clicking sensation in the right hip during regular follow-up after THA with a 32-mm cobalt/chromium head with polyethylene insert for osteoarthritis performed 7 years previously. The plain radiograph showed that the angle between the metal femoral head and the axis of the stem neck was not perpendicular ('Bowing-head sign'). Dynamic evaluation under fluoroscopy showed movement of the stem neck in the metal femoral head with hip abduction and adduction. Laboratory data showed abnormal serum cobalt (6.3 µg/L, normal < 1 µg/L) and chromium (3.8 µg/L, normal < 5 µg/L) levels. Considering those radiographic findings, deformation of the stem neck due to trunnionosis was diagnosed, and elective revision surgery was performed without any complications. Plain radiographs after THA should be assessed with attention to this complication, 'Bowing-head sign' must not be overlooked.

Repeated cobalt and chromium ion measurements in patients with bilateral large-diameter head metal-on-metal ReCap-M2A-Magnum total hip replacement.

Background and purpose - Whole-blood (WB) chromium (Cr) and cobalt (Co) measurements are vital in the follow-up of metal-on-metal total hip replacement (MoM THR) patients. We examined whether there is a substantial change in repeated WB, Co, and Cr levels in patients with bilateral ReCap-M2A-Magnum THR. We also specified the number of patients exceeding the safe upper limit (SUL) of WB Co and Cr in the repeated measurement.Patients and methods - We identified 141 patients with bilateral ReCap-M2A-Magnum THR operated in our institution. 61 patients had repeated WB metal ion measurements with bilateral MoM implants still in situ in the second measurement. The mean time elapsing from the first measurement (initial measurement) to the second (control measurement) was 1.9 years (SD = 0.6, range 0.2-3.5). We used earlier established SUL levels for bilateral implants by Van Der Straeten et al. (2013).Results - The median (range) Co and Cr values decreased in the repeated measurement from 2.7 (0.6-25) to 2.1 (0.5-21) and 2.6 (0.8-14) to 2.1 (0.5-18) respectively. In 13% of the patients Co levels exceeded the SUL in the initial measurement and the proportion remained constant, at 13%, in the repeated measurement. In 5% of the patients, Cr levels were above SUL in the initial measurement and an equal 5% in the control measurement.Interpretation - Repeated WB metal ion levels did not increase in patients with bilateral ReCap-M2A-Magnum THR with a mean 1.9-year measurement interval. Long-term development of WB metal ion levels is still unclear in these patients.

No association between blood count levels and whole-blood cobalt and chromium levels in 1,900 patients with metal-on-metal hip arthroplasty.

Background and purpose - The accelerated wear of poorly functioning metal-on-metal (MoM) hip implants may cause elevated whole-blood cobalt (Co) and chromium (Cr) levels. Hematological and endocrinological changes have been described as the most sensitive adverse effects due to Co exposure. We studied whether there is an association between whole-blood Co/Cr levels and leukocyte, hemoglobin, or platelet levels. Patients and methods - We analyzed whole-blood Co and Cr values and complete blood counts (including leukocytes, hemoglobin, platelets) from 1,900 patients with MoM hips. The mean age at the time of whole-blood metal ion measurements was 67 years (SD 10). The mean time from primary surgery to whole-blood metal ion measurement was 8.2 years (SD 3.0). The mean interval between postoperative blood counts and metal ion measurements was 0.2 months (SD 2.7). Results - The median Co value was 1.9 µg/L (0.2-225), Cr 1.6 µg/L (0.2-125), mean leukocyte count 6.7 × 109/L (SD 1.9), hemoglobin value 143 g/L (SD 13), and platelet count 277 × 109/L (SD 70). We did not observe clinically significant correlations between whole-blood Co/Cr and leukocyte, hemoglobin, or platelet counts. Interpretation - Elevated whole-blood Co and Cr values are unlikely to explain abnormal blood counts in patients with MoM hips and the reason for possible abnormal blood counts should be sought elsewhere.

Suitability of MDA, 8-OHdG and wild-type p53 as genotoxic biomarkers in metal (Co, Ni and Cr) exposed dental technicians: a cross-sectional study.

BACKGROUND: High concentrations of Co, Ni, and Cr in the blood serum of dental technicians are strongly associated with free radical formation. It has highly reactive properties that can cause further oxidation of molecule in the vicinity. PURPOSE: This study intended to investigate whether the Dental Technician occupational exposure of Co, Ni and Cr, could contribute to the high incidence of cancer. METHODS: This was a cross-sectional study to dental technicians, performed after acccepting ethical clearance. Blood was sampled in 3 examinations for Co, Ni, Cr using Atomic Absorbance Spectrophotometry (AAS), MDA was examined with TBARS test, also 8 OHdG and wildtype p53 proteins determined by ELISA method. RESULTS: Comparative statistical analysis, showing a significant difference (p < 0.05) between levels of Co, Ni, and Cr in exposed groups to the control group. But, not all variables was proven to be positively correlated, only with Cr, and Co, and negatively correlated with wild-type p53. CONCLUSION: MDA,8-OHdG and wildtype p53 can be used as genotoxic biomarkers in the metal exposed group, since they can accurately reflect the degree of Oxidative damage.

Good midterm results after Birmingham hip resurfacing and total hip arthroplasty.

The aim of this study is to determine the functional outcome and midterm survival rates of the Birmingham Hip Resurfacing and Birmingham Total Hip Arthroplasty. This retrospective, observational study included 150 surgeries (46 resurfacing procedures and 104 arthroplasty procedures) performed in 127 patients from 2005 to 2012. The Resurfacing and Arthroplasty study groups were evaluated with clinical (Harris Hip Score and Hip Disability and Osteoarthritis Outcome Score) and radiological follow-up. Cobalt and chromium levels were measured via blood samples. No revisions were required in either study group. Femoral stem osteolysis was observed in three patients in the Arthroplasty group. No osteolysis was observed in the Resurfacing group. Significantly higher clinical scores were observed in the Resurfacing group (p=0.04 and p=0.04, respectively). The average level of metal ions were similar in both groups. Both groups showed excellent midterm clinical and radiographic results with 100 percent survival rates. Additional follow-up is required to monitor future changes in blood metal ion levels.

Comparison of the neurotoxicity associated with cobalt nanoparticles and cobalt chloride in Wistar rats.

Cobalt nanoparticles (CoNPs) have been widely used in industry given their physical, chemical and magnetic properties; however, CoNPs may cause neurological symptoms and diseases in human, yet their mechanisms of toxicity remain unknown. Here, we used male Wistar rats to investigate differences in the toxic effects associated with CoNPs and CoCl2. Upon exposure to CoCl2, and 96 nm or 123 nm CoNPs at the same concentration, the Co2+ content in CoCl2 group was significantly higher than that in either the CoNPs groups in brain tissues and blood, but lower in liver. Significant neural damage was observed in both hippocampus and cortex of the temporal lobe. Increase malondialdehyde (MDA) content and CASPASE 9 protein level were associated both with CoCl2 and CoNPs treatments, consistent with lipid perioxidation and apoptosis. Heme oxygenase-1 and (NF-E2) p45-related factor-2 protein levels were elevated in response to 96 nm CoNPs exposure. In PC12 cells, NRF2 downregulation led to reduced cell viability and increased apoptotic rate. In conclusion, both CoNPs and CoCl2 cause adverse neural effects, with nanoparticles showing greater neurotoxic potency. In addition, NRF2 protects neural cells from damage induced by CoCl2 and CoNPs by activating downstream antioxidant responses.

Modular implant design affects metal ion release following metal-on-metal hip arthroplasty: a retrospective study on 75 cases.

Metal-on-Metal (MoM) total hip arthroplasty (THA) has been associated to wear and metal-ions release, controversially related to a variety of clinical complications. Little is known about the relevant design-dependent parameters involved in this process. The present study investigated the correlation between metal ion release in blood and revision rate as a function of: (i) specific MoM implant modular design parameters, (i.e. acetabular cup and femoral head diameters, taper adapter material and size, femoral neck material and modularity and stem size); (ii) MoM bilaterality. Co and Cr ions concentration levels in blood of 75 patients were retrospectively-evaluated with a mean follow-up of 4.8 years (range: 1.8-6.3). Patients were divided in a unilateral and a bilateral group. Statistical analysis was performed to find any significant difference related to acetabular cup diameter, femoral head diameter, taper adapter material/size, neck material/size and stem size. The bilateral MoM group had 4-times higher metal ion levels in blood than the unilateral one (p=0.017 only Cr), related to a higher revision rate (30% vs 20%): differences were 10-times higher particularly with a 48 mm femoral head diameter (p=0.012) and a Ti-alloy neck (p=0.041). Within the monolateral group using a shorter taper adapter and a shorter neutrally-oriented neck demonstrated higher ion levels (p=0.038 only Cr and p=0.008 only Co, respectively). The aforementioned design-features and MoM bilaterality are important risk-factors for metal-ion release in modular MoM THA.

Ischemia-Modified Albumin Expression: Is there a Difference between Male and Female Subjects?

BACKGROUND: Ischemia-modified albumin (IMA) derives from naive albumin, modified in the binding region of bivalent ions, as cobalt and iron. The cobalt, released from some types of hip prosthesis seems to be metabolized differently in males and females but the iron ion is more prevalent than cobalt and is detectable in the healthy population. Our aim was to verify if there are any gender- and age-related differences in IMA concentrations and if IMA correlates with cobalt and iron-related proteins. METHODS: IMA, albumin, iron, ferritin, transferrin, and cobalt were measured in 50 men and 50 women divided into two age/fertility-homogeneous groups. RESULTS: Men < 45-years-old showed a statistically significant lower IMA concentration than men ≥ 45 and fertile and menopausal women. Considering all the population studied, IMA does not seem to be correlated with age and is distributed differently by gender; also, Co distribution was different between males and females. CONCLUSIONS: IMA did not correlate with cobalt, iron, ferritin, and transferrin in any group, except for fertile women where IMA presented a statistically significant correlation with serum iron values. Minor expression of IMA in young males together with the results obtained on serum iron in fertile females, could explain the higher accumulation of circulating Co in women compared to men and their different cobalt metabolism.

Are Serum Metal Ion Levels a Concern at Mid-term Followup of Revision Knee Arthroplasty With a Metal-on-metal Hinge Design?

BACKGROUND: Elevated serum levels of chromium and cobalt ions in metal-on-metal (MoM) bearing surfaces is a well-known phenomenon in THA. However, few studies have addressed this issue in complex primary and revision knee arthroplasty using a MoM hinged mechanism, and no study, to our knowledge, has investigated knees with MoM hinges in patients without megaprostheses (tumor prostheses). QUESTIONS/PURPOSES: We analyzed a series of patients who received MoM hinged revision knee prostheses and asked: (1) What are the serum metal ion levels at short-term followup? (2) Is there any correlation between metal ion levels and the Knee Society Score (KSS) at this followup? METHODS: Between 2013 and 2017, we performed 198 revision knee arthroplasties, of which 32 (17.7%) were performed with a latest-generation MoM hinge knee design. In addition, three complex primary TKAs utilizing the same design were included in this study. The device features a metal-on-polyethylene bearing with a MoM hinge. During that period, our general indications for using a hinge were single-stage and two-stage revision surgeries, revisions with large bone defects, and primary TKA with > 20° mechanical malalignment or collateral ligament insufficiency. Of the 35 patients who received this device, 23 patients (65% of the overall group who received this implant; 11 males, 12 females) were available for followup at a median of 28 months (range, 13-61 months), and the remaining 12 (35%) patients were lost to followup. Our rationale for reporting before the more typical 2-year minimum was the finding of elevated serum ion levels with unclear clinical significance. Median age at the time of surgery was 68 years (range, 52-84 years). None of the patients included in the study had other implants with MoM bearings. Serum ion levels of chromium (III) and cobalt were assessed using mass spectrometry. Ion levels > 5 ppb were considered elevated. Clinical outcome was assessed using the original KSS. RESULTS: Median chromium serum level was 6.3 ppb (range, 0.6-31.9 ppb) and median cobalt serum level was 10.5 (range, 1.0-47.5 ppb). Of the 23 patients, 16 had elevated serum ion levels. There was a moderate correlation between KSS and both chromium (p = 0.029, r = 0.445) and cobalt (p = 0.012, r = 0.502) levels. CONCLUSIONS: Elevated metal ion levels and radiolucent lines are common after surgery with this MoM hinge design at short-term followup, and we believe this finding is of great concern. Although no patient has yet been revised, these patients will be closely monitored. We recommend that serum ion analysis become a routine part of followup after any hinge TKA in an attempt to better understand the potential consequences of this phenomenon. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Revisions of Modular Metal-on-metal THA Have a High Risk of Early Complications.

BACKGROUND: The risk of early complications is high after monoblock acetabular metal-on-metal (MoM) THA revisions. However, there is a paucity of evidence regarding clinical complications after isolated head-liner exchange of modular MoM THA. QUESTIONS/PURPOSES: The purposes of this study were (1) to describe the frequency of early complications after an isolated head-liner exchange revision of modular MoM THA; and (2) to determine whether patients who experienced complications or dislocation after head-liner exchanges had higher serum chromium (Cr) or cobalt (Co) ion levels than those who did not. METHODS: A review of our institution's total joint registry retrospectively identified 53 patients who underwent 54 liner exchange revisions of a modular acetabular MoM THA. The study period was from April 2008 to April 2016 at a single tertiary care center. During this period, isolated head-liner exchanges (rather than more extensive revisions) were performed in patients if they did not have evidence of loosening of the acetabular or femoral components. Reasons for revision surgery included pain, mechanical symptoms, radiographic evidence of osteolysis, elevated serum metal ions, and MRI abnormalities with 40 of the 54 hips having pain or mechanical symptoms and 38 of 54 hips having multiple reasons for revision before surgery. Patients were excluded if they did not meet the minimum postrevision followup or had the modular liner exchange secondary to infection. All revisions were from a single manufacturer with one head-liner exchange of a MoM THA from another manufacturer excluded during the study period. The mean time from index MoM THA to modular exchange was 96 (SD ± 36) months. Because the focus of this study was early complications, we had a minimum 90-day followup duration for inclusion. Mean followup after revision was 15 months (SD ± 12); a total of 56% (30 of 54) had followup of at least 12 months' duration. Complications (dislocation, infection) and reoperations were obtained by chart review performed by individuals other than the treating physician(s). Serum metal ion levels were obtained before head-liner exchange. The median serum Cr and Co levels were 6 µg/L (range, 0-76 µg/L) and 12 µg/L (range, 0-163 µg/L), respectively. RESULTS: Of the 54 revision THAs, 15 (28%) developed complications. Nine (17%) occurred within 90 days of the revision surgery and 11 (20%) resulted in reoperation. The most common complication was dislocation (12 of 54 [22%]) with recurrent dislocation noted in eight of these 12 patients. All patients with recurrent dislocation continued to dislocate and underwent repeat revision. Patients with dislocation had higher median serum Cr and Co ion levels than those without dislocation (Cr: 24 [range, 11-76] versus 4 [range, 0-70], p = 0.001 [95% confidence interval {CI}, 10-57]; Co: 41 [range, 6-163] versus 8 [range, 0-133], p = 0.016 [95% CI, 6-141]). Three (6%) of the 54 patients underwent repeat surgery for deep space infection. CONCLUSIONS: Complications and reoperations are common after modular head-liner exchange in the setting of a failed MoM THA. Our study likely underestimates the frequency of complications and revisions because the followup period in this report was relatively short. Dislocation is the most common complication and elevated serum metal ion levels may be a predictor of dislocation. These findings are concerning and surgeons should be aware of the high complication risk associated with this procedure. LEVEL OF EVIDENCE: Level IV, therapeutic study.

What Is the Clinical Presentation of Adverse Local Tissue Reaction in Metal-on-metal Hip Arthroplasty? An MRI Study.

BACKGROUND: Adverse local tissue reaction (ALTR) is not only a prominent cause of metal-on-metal (MoM) implant revision, but may also compromise the result of revision surgery. Patients treated with MoM arthroplasty and subsequently revised as a result of ALTR have been shown to experience worse patient-reported outcomes, inferior survivorship, and more complications when compared with patients receiving MoM implants who were revised for reasons other than ALTR. There is conflicting evidence as to whether the presence of symptoms is associated with ALTR in patients with MoM implants. Blood metal ions are associated with ALTR, but a consensus on appropriate thresholds associated with ALTR risk is lacking. QUESTIONS/PURPOSES: (1) Was the presence of symptoms as measured by patient-reported outcome measures associated with ALTR presence and severity as noted on metal artifact reduction sequence (MARS)-MRI in patients treated with one design of MoM THA or hip resurfacing arthroplasty (HRA)? (2) Could reliable thresholds for blood metal ion levels be determined that were associated with ALTR presence on MARS-MRI? METHODS: This retrospective study presents a secondary analysis of data drawn from a prospective, international, multicenter study of the recalled Articular Surface Replacement (ASR) hip system. This larger study aims to identify risk factors for revision and provide followup guidelines for the many unrevised ASR patients. A total of 1721 patients were enrolled from 16 centers in six countries after the device was recalled and are followed annually for 5 years. In the present analysis, data from the enrollment visit (mean time from index surgery, 7.5 years; SD 3.5 years) were considered. Only patients from two centers conducting MARS-MRI on all patients regardless of clinical presentation as a standard of care were included to avoid selection bias. A total of 327 unilateral patients fulfilled our inclusion criteria (90% of those eligible). The level of symptoms was systematically determined using the Harris hip score and a visual analog scale for pain, and whole blood metal ion levels were collected from all patients. MARS-MRIs were analyzed by a single reader for ALTR presence (Anderson classification), diameter, and synovial thickness. A validation series of 35 MARS-MRIs indicated excellent intrareader reproducibility of the evaluations (intraclass correlation = 0.82) and substantial agreement (κ coefficient = 0.64) was achieved between the MARS-MRI reader and a musculoskeletal radiologist with > 10 years of experience with MARS-MRI. Binary logistic regression was used to determine variables independently associated with ALTR. Receiver operator characteristic curves were used to determine sensitive and specific cut points for cobalt and chromium. RESULTS: After controlling for confounding variables, presence of symptoms was determined to be a risk factor for ALTR (odds ratio, 2.9; p = 0.007) in patients treated with ASR MoM THA. Moreover, among patients undergoing ASR MoM THA with ALTR, synovial thickness correlated with symptomaticity (p = 0.030). For patients undergoing ASR MoM HRA, we found no association between symptoms and ALTR prevalence or severity. A cobalt cutoff of 3.2 parts per billion (ppb) was associated with increased risk of ALTR (p < 0.001; sensitivity, 68%; specificity, 71%) in ASR MoM THA. In patients with ASR MoM HRA, a cobalt threshold of 2.9 ppb was indicative of ALTR (p < 0.001; sensitivity, 79%; specificity, 69%). CONCLUSIONS: The risk factors identified in the current study may be used to stratify patients receiving MoM implants in terms of ALTR risk. We found that symptoms are associated with an increased likelihood of ALTR presence in ASR MoM THA and that cobalt ion level is associated with ALTR in ASR MoM THA as well as ASR MoM HRA. Importantly, MoM HRA followup protocols that exempt asymptomatic patients from annual followup are not justified because asymptomatic patients are no less likely to have ALTR than symptomatic patients. Blood metal ion levels may reliably be used to screen patients undergoing MoM HRA. For patients undergoing MoM THA, a combination of symptom state and blood metal ion levels may be used to determine ALTR risk. LEVEL OF EVIDENCE: Level III, diagnostic study.