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Objective: Lung adenocarcinoma (LA), the most prevalent type of lung cancer, is associated with a high mortality rate, especially among patients with cancer previously infected with coronavirus disease (COVID-19). Therefore, this study aimed to explore the mechanisms by which COVID-19 exacerbates LA progression in a clinical setting., Methods: The experiment involved collecting serum samples from three groups: a healthy control group (Con, n = 20), a lung adenocarcinoma group (LA, n = 30), and a group of lung adenocarcinoma patients with first-time COVID-19 infection (C-LA, n = 58). Metabolites were analyzed using liquid chromatography-mass spectrometry, and differentially expressed metabolites were identified through bioinformatics analysis. The concentrations of glutathione (GSH), reactive oxygen species (ROS), and copper ions (Cu 2+ ) in the serum of patients in the Con and C-LA groups were measured. Mitochondrial morphological changes in monocytes and lymphocytes were observed using electron microscopy., Results: Metabolomic analysis revealed 142 distinct metabolites, among which glutamine (Gln) expression was significantly decreased in the C-LA group. Compared to the Con group, the C-LA group showed a significant decrease in GSH and a notable increase in ROS and Cu 2+ . Further research revealed that the mitochondria of monocytes and lymphocytes in the C-LA group exhibited corresponding alterations indicative of cuproptosis., Conclusions: SARS-CoV-2 infection may reduce Gln levels, leading to reduced GSH levels, copper overload, and increased death of immune cells, which may further exacerbate rapid tumor development. Thus, glutamine regulation plays an important role in LA progression in patients with COVID-19 and represents a potential therapeutic target., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Selenoproteins regulate pathways controlling neurodevelopment, e.g., redox signaling and thyroid hormone metabolism. However, studies investigating maternal selenium in relation to child neurodevelopmental disorders are scarce., Methods: 719 mother-child pairs from the prospective population-based Odense Child Cohort study in Denmark were included. Three selenium biomarkers, i.e. concentrations of serum selenium, selenoprotein P (SELENOP), and activity of glutathione peroxidase 3 (GPX3), along with serum copper, zinc and iron were measured in early third trimester (at 28.9+/-0.8 weeks of pregnancy). ADHD and ASD traits in children were assessed systematically using the established Child Behaviour Checklist at 5 years of age, based on a Danish reference cohort with cut-off at 90th percentile. Multivariable regression models adjusted for biologically relevant confounders were applied., Results: 155 of 719 (21.6 %) children had ASD traits and 59 of 719 (8.2 %) children had traits of ADHD at 5 years of age. In crude and adjusted models, all three selenium biomarkers associated inversely with ADHD traits. For ADHD, fully adjusted OR for 10 μg/L increment in selenium was 0.76 (95 % CI 0.60, 0.94), for one mg/L increment in SELENOP was 0.73 (0.56, 0.95), and for 10 U/L increment in GPx3 was 0.93 (0.87,1.00). Maternal total selenium was inversely associated with child ASD traits, OR per 10 μg/L increment was 0.85 (0.74, 0,98). SELENOP and GPx3 were not associated with ASD traits. The associations were specific to selenium, as other trace elements such as copper, zinc, or iron were not associated with the outcomes., Conclusions: The results provide coherent evidence for selenium deficiency as a risk factor for ADHD and ASD traits in an environment with borderline supply, the causality of which should be elucidated in a randomized controlled trial., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate risk factors for dysgeusia after tonsillectomy., Methods: A retrospective survey of medical records identified 318 patients (163 male and 155 female subjects aged 12-75 years, average 41.7±16.1 years) who underwent tonsillectomy., Results: Thirty three patients (10.4%) and seven patients (2.2%) reported suffering from dysgeusia three and six months after tonsillectomy, respectively. Average age, serum level of Zn and operation time were not significantly different between positive and negative findings of dysgeusia. Women with positive findings of dysgeusia (72.7%) was significantly higher than men (27.3%) (Odds ratio: 3.276, 95% CI: 1.441-7.450, p<0.005). A chi-square test of independence was calculated comparing the frequency of dysgeusia in under 60 years old group (13-59 years-old) and 60 years old and over group (60-75 years-old). A significant interaction was found (χ2 (1)=5.238. p<0.05)., Conclusions: Women and under 60 years old patients had a significantly higher rate of dysgeusia after tonsillectomy. It is recommended that patients are informed of the potential postoperative complication of dysgeusia., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Age-related macular degeneration (AMD), the main cause of irreversible blindness in people over 60 years of age, is an eye disease that evolves with loss of central vision. Although AMD manifests itself in the eye, blood is continuously flowing through the macular region, such that potential alterations in this region could be reflected in the composition of whole blood or plasma/serum. Therefore, the potential clinical relevance of analysis of serum samples was assessed because of the low degree of invasiveness of blood sampling. 40 initial samples (20 from controls and 20 from patients with the dry form of AMD) have been analysed in this work to investigate the possible occurrence of homeostatic alterations of essential mineral elements caused by the disease. Both major (Na, Mg, P and K) and trace (Fe, Cu and Zn) essential mineral elements were determined in blood serum using single-collector ICP-mass spectrometry. Also, the isotopic composition of Cu (an element proposed to be directly involved in the onset of AMD) was determined using multi-collector ICP-mass spectrometry. Unexpected light Cu isotopic compositions in three individuals assumed as controls, resulted in a re-evaluation of their clinical information and a later exclusion due to pathologies initially not accounted for. In this pilot study, a significant alteration in the δ 65 Cu value has been found between the two final cohorts (AMD patients: n = 20; controls n = 17), with lower δ 65 Cu values (i.e. an enrichment in the light 63 Cu isotope) in the case of AMD. Also, higher serum concentrations of the elements P and Zn were established in AMD at a systemic level., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: There is paucity of studies on predictors of seizures in Wilson disease with neurological manifestation (WDNM), and none has evaluated the role of copper (Cu) induced oxidative stress, proinflammatory and excitotoxicity in the genesis of seizure., Objectives: To report frequency, refractoriness, and outcome of seizure in WDNM. We also evaluate role of Cu induced oxidative stress, excitotoxicity and cytokines in predicting seizures., Methods: The diagnosis of WDNM was based on clinical, MRI, KF ring and 24 h urinary Cu. Detailed clinical examination including severity of WD, occurrence of seizure, seizure semiology, antiepileptic drug (AED) and breakthrough seizures were noted. Cranial MRI and electroencephalography findings were noted. Serum free-Cu, oxidative stress markers (glutathione, total antioxidant capacity, malondialdehyde), glutamate and cytokines (interleukin 6, 8 and 10 and tumour necrosis factor α) were measured by atomic absorption spectrophotometer, spectrophotometer, fluorometer and flow cytometer respectively, and correlated with seizures. Patients were treated with zinc with or without penicillamine, and those with epilepsy received second-generation antiepileptic drugs (AEDs)., Results: Out of 110 patients with WDNM, 16(14.5%) had seizures; focal in 11(68.7%) and generalized in 5(31.3%). Patients with seizure had higher serum free-Cu (35.87 ± 1.34 vs 31.72 ± 0.68; P = 0.02), severe dystonia (P = 0.04), and more frequent cortical (100% vs 6.4%; P < 0.01) and subcortical (81.3% vs 20.2%; P < 0.01) lesions on MRI compared to those without seizure. Oxidative stress markers (glutathione, total antioxidant capacity, malondialdehyde), cytokines and glutamate were elevated in WDNM compared to controls. On multivariate logistic regression analysis, cortical involvement (OR = 105.49; 95%CI = 8.74-1272.39; P < 0.01) and number of MRI lesions (OR = 1.99; 95% CI = 1.11-3.57; P = 0.02) were independent predictors of seizure. The seizures were controlled with single and dual AEDs in seven patients each, and two patients needed three AEDs. All the patients had seizure remission for a median follow up of 66(24-180) months., Conclusion: About one-sixth WDNM patients have seizures especially in those with cortical and extensive MRI lesions. Seizures are easily controlled by AEDs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The effect of maternal copper (Cu) level on the risk of spontaneous preterm birth (SPB) remains debate. Therefore, we conducted a prospective nested case-control study in Shanxi Province to investigate the relationship between maternal serum Cu concentration and SPB risk, as well as the potential mediation effect of lipid metabolism., Method: From an overall cohort of 4229 women, 147 women affected by SPB at 20-36 gestational weeks (cases) and 381 women who delivered at ≥37 gestational weeks (controls) were included in our nested case-control study. Maternal blood samples were collected during 4-22 gestational weeks, and the concentrations of Cu, total cholesterol (TC), and triglycerides (TG) were measured. Information on maternal social demographic characteristics were collected using questionnaires. Unconditional logistic regression models were used to estimate the associations of Cu, TC or TG levels with SPB risk. Linear regressions were used to assess the relationships between concentrations of Cu and TC or TG., Results: Serum Cu concentrations in the case group (median: 184 μg/dL) were significantly higher than those in the control group (median: 166 μg/dL, p < 0.0001). Compared to the lowest serum Cu levels, the odds ratios associated with SPB increased to 2.02 (95% confidence interval [CI]: 1.07, 3.82), 3.10 (1.54, 6.22) and 4.18 (2.11, 8.27) in the second, third and fourth quartile respectively, after adjusting for sampling time, maternal age, pre-pregnancy BMI, education, occupation, parity, spontaneous abortion history, folic acid use, medication use, pre-pregnancy passive smoking status, child gender and fasting status. Plasma concentrations of TC and TG were positively associated with SPB risk in a dose-dependent manner. However, when stratified by sampling time, the above-mentioned relationships were significant in the first trimester but not in the second. In addition, plasma concentrations of TC and TG were positively correlated with serum Cu concentrations., Conclusions: High maternal Cu level in the first trimester may increase the risk of SPB, by potentially increasing plasma concentrations of TC and TG., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: While metals have been implicated in the pathophysiology of Parkinson's disease (PD), the clinical evidence is scarce. Further, the contribution of metals for the risk or clinical presentation of PD remains to be explored., Methods: To investigate the associations between the level of metals in blood serum and PD risk or clinical presentation, including sex-related differences, we studied 325 PD patients and age- and sex-matched 304 controls. We collected clinical data of the PD patients, including age at onset, PD duration, levodopa-equivalent dose (LED), Hoehn and Yahr stage (H-Y stage), presence of motor fluctuation, levodopa-induced dyskinesia (LID), freezing of gait, hallucination, and Mini-Mental State Examination (MMSE) score. Iron, copper, and zinc levels in serum were assayed by inductively coupled plasma mass spectrometry. Statistical analyses were performed to determine the sex-related differences in metal levels., Results: Among the three metal elements tested, serum copper levels showed significant correlations with PD risk or clinical presentation. Higher copper levels were associated with a decreased PD risk. Higher copper or lower iron levels were associated with the risk of LID in women. Serum copper levels were negatively correlated with MMSE scores in PD patients., Conclusions: This clinical study suggests significant associations between serum metal levels and PD risk or essential clinical features, demonstrating the possible roles of metals in PD pathogenesis or symptom development., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: NSTEMI is a type of myocardial infarction (MI) causing partial but progressive occlusion of cardiac coronary vessels. The aim of this study was to investigate rs1137101 polymorphism of soluble leptin receptor (sLEPR) as well as circulatory selenium and copper levels in NSTEMI patients and their usefulness in analyzing susceptibility to NSTEMI., Methods: We collected sera and whole blood of 80 NSTEMI patients and 80 healthy individuals using cTnI levels plus electrocardiography as the "gold standard". Polymorphism analysis was done after DNA extraction by high-resolution melt PCR, selenium and copper levels by atomic absorption spectrophotometry, and sLEPR by ELISA., Results and Discution: There was Hardy-Weinberg (HWE) equilibrium for both patient and control loci (χ2 = 0.368434509 and 0.341447368, respectively). The frequencies of A/A, A/G, and G/G genotypes were 18 (22%), 37 (46%), and 25 (31%) for patients, and 30 (38%), 36 (45%), and 14 (18%) for healthy controls, respectively. The frequencies of A and G alleles were 73 (46%) and 87 (54%) for patients and 96 (60%) and 64 (40%) for control groups. There was correlation between allele G and sLEPR level and Body Mass Index (BMI). Selenium levels were lower in patient group than control group (66.307 ± 11.013 against 87.488 ± 11.839 μg/L; p < 0.001) but copper concentrations were higher (1.8105 ± 0.358 against 1.366 ± 0.454 mg/L; p < 0.001). sLEPR levels were also higher in patient than control group (30.568 ± 3.290 against 23.740 ± 5.457 ng/dL; p < .001). Low selenium and high copper concentration had positive diagnostic value for disease., Conclusion: We find for the first time that there is a significant association between rs1137101 polymorphism and susceptibility to NSTEMI. There is also statistically meaningful association between decrease in serum selenium and increase in serum copper levels with susceptibility to NSTEMI., (Copyright © 2018 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Lead (Pb) is a neurotoxic heavy metal, but the mechanism of its neurotoxicity is not clearly understood. Expression of metallothioneins (MTs) is induced in response to heavy metal exposure as a protective mechanism against heavy metal toxicity. There are several isoforms of MTs (MT-1 to 4), of which MT-3 is the neuron specific isoform, which also has neurite growth inhibitory effects. Whereas, the induction of MT-1 and 2 in response to Pb has been reported, the effect of Pb on the expression of MT-3 in the brain has not been documented. This study aimed at investigating the effect of Pb exposure on the expression of MT-3 in the cerebrum and hippocampus. Wistar rat pups were exposed to Pb via their dams' drinking water (0.2% lead acetate in deionized water) from postnatal day (PND) 0 to 21 and directly via drinking water until PND30. Expression of MT-3 was measured by Western blot and quantitative RT-PCR. MT-3 localization was done by immunohistochemistry. Divalent metal ions were analysed by atomic absorption spectrophotometry. Levels of Pb in blood and cerebrum were significantly increased, while that of copper (Cu), zinc (Zn) and manganese (Mn) were significantly decreased in the Pb-exposed rats at both PND21 and PND30. MT-3 protein was significantly increased in the cerebrum (by 2.5-fold) and in hippocampus (1.4 to 3.2-fold) in both PND21 and PND30 Pb-exposed rats over controls. MT-3 gene expression also increased in the cerebrum (by 42%), and in the hippocampus (by 65% and 43% in the PND21 and PND30 rats, respectively), in the Pb-exposed rats over controls, but the increase was statistically significant (p < 0.05) only in the PND30 rats. Pb exposure significantly increased (p < 0.05) percentage of MT-3 immunoreactive cells in Cornu Ammonis and dentate gyrus regions in the PND21 rats, and in the Cornu Ammonis 1, dentate gyrus and cortex regions in the PND30 rats. Our data thus provide convincing evidence that exposure to low levels of Pb during preweaning period increases the expression of MT-3 in the brain of rats., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: The concentration of nutritionally important minerals in circulation is under tight homeostatic control, however, physical activity and aging influence their body stores and nutritional requirement. The aim of this study was to evaluate the effect of both physical activity and age on plasma concentrations of copper, zinc, iron, and magnesium., Methods: Stratified cluster sampling was used for selection of study participants (N = 360) belonging to three physical activity groups: sedentary, moderately active, and highly active on the basis of their physical activity levels as 1.53, 1.8, and 2.3, respectively. They were also divided into six different age groups (18-20, 21-25, 26-30, 31-35, 36-40, and 41-45 y). We assessed nutritional status by determining their body composition using bioelectrical impedance method and measuring intake levels. Fasting blood samples were taken to separate plasma for analysis of copper, zinc, magnesium, and iron., Results: There was a major difference (P < 0.001) in the mean value of plasma copper, zinc, magnesium, and iron for the three activity groups. The plasma copper and iron concentrations were higher in the moderately active group (copper: 1.59 ± 0.05 mg/L, iron: 0.79 ± 0.22 mg/L) whereas zinc concentration was higher in the sedentary group (2.37 ± 0.29 mg/L). Both the highly and moderately active groups had higher plasma magnesium levels compared with the sedentary group. Plasma copper, zinc, magnesium, and iron levels also were influenced by age in a different pattern with respect to physical activity., Conclusion: Physical activity-related energy expenditure and age play a remarkable role in deciphering the plasma mineral levels in the healthy individuals., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Altered function of platelets can lead to cardiovascular complications in numerous disorders. Various studies aimed to investigate mechanisms triggering platelets activation cascade show a significant role of reactive oxygen species (ROS) in this matter. Moreover, ROS are known causal factor of oxidative stress that can result in DNA, lipid and protein damage. This review aims to comprehensively present the variety of methods that are potentially useful in assessment of platelets redox balance, such as intracellular concentration of particular ROS, activity of antioxidant enzymes, reduced/oxidized glutathione ratio, level of lipid peroxidation, Cu/Zn ratio, and molecular oxygen consumption. They may help to establish the platelet-related etiological factors in different disorders and to evaluate the antiplatelet therapies. The advantages and limitations of these methods are also discussed. The present paper highlights that clinicians may benefit from implementation of such tools and further encourages developing interdisciplinary evidence-based practice., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Dried blood spots (DBS) is a unique matrix that offers advantages compared to conventional blood collection making it increasingly popular in large population studies. We here describe development and validation of a method to determine multiple elements in DBS., Methods: Elements were extracted from punches and analyzed using inductively coupled plasma-mass spectrometry (ICP-MS). The method was evaluated with quality controls with defined element concentration and blood spiked with elements to assess accuracy and imprecision. DBS element concentrations were compared with concentrations in venous blood. Samples with different hematocrit were spotted onto filter paper to assess hematocrit effect., Results: The established method was precise and accurate for measurement of most elements in DBS. There was a significant but relatively weak correlation between measurement of the elements Mg, K, Fe, Cu, Zn, As and Se in DBS and venous whole blood. Hematocrit influenced the DBS element measurement, especially for K, Fe and Zn., Conclusion: Trace elements can be measured with high accuracy and low imprecision in DBS, but contribution of signal from the filter paper influences measurement of some elements present at low concentrations. Simultaneous measurement of K and Fe in DBS extracts may be used to estimate sample hematocrit., (Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Objective: Dietary habits and adequate intake of antioxidants in the diet-for example, copper (Cu) and zinc (Zn)-may be an environmental factor in the occurrence of multiple sclerosis (MS). The aim of this study was to estimate the influence of dietary habits on the concentration of Cu, Zn in the serum, and the effect of Cu-to-Zn ratio on the ability status of patients with relapsing-remitting MS., Methods: This was an observational case-control study that included 101 individuals with MS and 68 healthy individuals (controls). Food frequency questionnaires were used to collect dietary data. Serum concentrations of Cu and Zn were determined by the electrothermal and flame atomic absorption spectrometry method, respectively. The ratio of Cu to Zn was calculated and compared with the Expanded Disability Status Scale of patients., Results: The concentration of Zn was significantly lower in the serum of individuals with MS (0.776 ± 0.195 mg/L) than in the control group (0.992 ± 0.315 mg/L). The ratio of Cu to Zn was higher in the examined patients (1.347 ± 0.806) than in the healthy volunteers (1.012 ± 0.458). Lower ability status (P < 0.05) was revealed in patients with an abnormal ratio of Cu to Zn, particularly, in cerebellar function, pyramidal tracts, and emotional conditions. Selected dietary habits have a significant influence on Cu and Zn concentration in the serum of patients with MS., Conclusions: Lower serum concentrations of Zn and higher ratio of Cu to Zn in patients with MS can suggest a relationship between MS and oxidative stress. Products that are a source of Zn should be included in the diet, which can improve the clinical condition of people with MS., (Copyright © 2017 Elsevier Inc. All rights reserved.)

An innovative dual dispersive ionic liquid based on ultrasound assisted microextraction (UDIL-μE), for the enrichment of trace levels of copper ion (Cu 2+ ), in serum (blood) of patients suffering from different neurological disorders. The enriched metal ions were subjected to flame atomic absorption spectrometry (FAAS). In the UDIL-μE method, the extraction solvent, ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate [C 4 mim][PF 6 ], was dispersed into the aqueous samples using an ultrasonic bath. The(PAN) 1-(2-pyridylazo)-2-naphthol was used as ligand for the complexation of Cu ion in IL (as extracting solvent). The various variables such as sonication time, pH, concentration of complexing agent, time and rate of centrifugation, IL volume that affect the extraction process were optimized. The enhancement factor (EF) and detection limit (LOD) was found under favorable condition was 31 and 0.36μgL -1 , respectively. Reliability of the proposed method was checked by relative standard deviation (%RSD), which was found to be <5%. The accuracy of developed procedure was assured by using certified reference material (CRM) of blood serum. The developed procedure was applied successfully to the analysis of concentration of Cu ion in blood serum of different neurological disorders subjects and referents of same age group. It was observed that the levels of Cu ion was two folds higher in serum samples of neurological disorders patients as related to normal referents of same age group., (Copyright © 2016. Published by Elsevier B.V.)

Epidemiological studies evaluating the associations between serum copper and ratios of Cu/Zn and the preeclampsia (PE) risk in Asian population have produced inconsistent results. Therefore, we conducted a meta-analysis to summarize the relationships. We hypothesize that higher serum copper and ratios of Cu/Zn may increase the PE risk. A systematic literature search was performed in PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure (CNKI), VIP (Database of Chinese Scientific and Technical Periodicals) and Wangfang databases for relevant studies up to November 2016. Pooled standardized mean difference (SMD) was calculated with random effects model. The results showed that PE patients had a higher serum copper level [SMD (95% CI): 1.05 (0.34, 1.77), Z=2.88, P for Z=0.004; I 2 =96.9%, P for I 2 <0.0001] compared with healthy pregnancy controls. In subgroup analyses, a higher serum copper level in PE patients was observed in case-control studies [SMD (95% CI): 1.39 (0.44, 2.34)]. No significant difference was found between PE patients and healthy pregnancy controls for ratios of Cu/Zn [(SMD (95% CI): 0.26 (-0.77, 1.29), Z=0.49, P for Z=0.625; I 2 =95.8%, P for I 2 <0.0001)]. In conclusion, our meta-analysis indicates that a higher serum copper level is associated with an increased risk of PE. Further studies are needed to confirm these results in future research., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In the present study, twenty four adult male albino rats were classified into four groups. The control group received normal diet and water; the second group was treated daily with oral dose of Ginkgo biloba (200 mg/kg body weight [b.wt]) for 3 mo; the third group was treated daily with oral dose of aluminum chloride (10 mg/kg b.wt) for 3 mo; and the fourth group was treated with both Ginkgo biloba and aluminum chloride (200 and 10 mg/kg b.wt, respectively) using a stomach tube for 3 mo. The results showed that administration of AlCl 3 to rats induced significant increase (P < 0.05) in thiobarbituric acid reactive substance and decrease (P < 0.05) in glutathione, catalase, and superoxide dismutase in brain and testis homogenates. The data also showed significant decrease (P < 0.05) in noradrenaline, dopamine, and serotonin (5-HT) levels in brain tissue. The rats administered AlCl 3 showed significant decrease (P < 0.05) in serum zinc (Zn) and copper (Cu), significant increase (P < 0.05) in serum iron (Fe), and non-significant decrease in magnesium (Mg). Furthermore, significant increase (P < 0.05) in serum alkaline phosphatase and acid phosphatase and significant decrease (P < 0.05) in testosterone were recorded. The histologic examination showed some degenerative changes in both brain and testis tissues while significant improvement in biochemical and histologic changes were observed in the aluminum chloride plus Ginkgo biloba group. It could be concluded that the protective effect of Ginkgo biloba may be attributed to its antioxidant properties., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Several trace elements are essential for immunity and wound healing, particularly after major burns. Continuous renal replacement therapy (CRRT), which is used to treat renal failure, causes significant trace elements losses. The aim of the present review is to update the current literature and draw attention to this type of complication, as copper deficiency is rarely suspected and diagnosed in clinical conditions and may occur in chronic critically ill patients., Methods: This is an emblematic case report and review of literature., Results: Major copper and selenium deficiencies were documented in a patient with major burns complicated by renal failure. The main cause was effluent loss during prolonged CRRT. The copper deficit resulted in life-threatening bradycardia and the alteration of lipid metabolism with severe hypertriglyceridemia. The published data are scarce, but trace element losses with effluent have been previously documented, as has the affect of copper deficiency on cardiac rhythm., Conclusion: The literature regarding the specific requirements for chronically critically ill patients is limited. During prolonged CRRT, copper and selenium levels decrease and probably should be monitored during prolonged therapy. Research in this area is required., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In this study, Cyprinus carpio was exposed to 0.25mgL(-1) copper as either copper sulfate (CuSO4) or copper oxide nanoparticles (nano-Cu), and 25mgL(-1) copper as nano-Cu for 14days. CuSO4 and high concentration of nano-Cu led to a significant increase in plasma total copper levels. Plasma free copper levels increased significantly in all copper-exposed treatments. Except for low concentration of nano-Cu after 7 and 14days, copper exposure generally led to a significant decrease in plasma ceruloplasmin levels. Plasma iron levels increased significantly in CuSO4 (all times) and nano-Cu (7th and 14th days) treatments. A significant elevation in plasma total iron binding capacity (TIBC) was observed after 3days in the fish exposed to low concentration nano-Cu, and after 14days in all copper-exposed treatments. Transferrin saturation (TSA) ratio showed significant increase in CuSO4 (3rd and 7th days) and the high concentration nano-Cu (7th day) treatments. Decrease in plasma chloride (7th and 14th days) and sodium (14th days) was observed in CuSO4 treatment. In conclusion, the results suggest that ionic copper is mainly absorbed via fish gill, whereas, nano-copper are more likely absorbed via gut. Also, data suggest that ionic copper has more adverse effects on the examined plasma biochemical characteristics compared to the equivalent nano-copper concentration, which may be due to the lower copper absorption by fish in the nano-copper suspension., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: Humans and other living organisms require small quantities of trace elements throughout life. Both insufficient and excessive intakes of trace elements can have negative consequences. However, there is little information on serum level of trace elements in different populations. This study examines serum levels of trace elements in Ethiopian, Japanese, and Vietnamese women., Methods: Random samples of healthy women who were referred for routine hospital laboratory examinations in the cities of Hanoi, Sapporo, and Gondar were invited to participate in the study. Serum levels of magnesium, zinc, copper, iron, selenium, and calcium were determined using an inductively coupled plasma mass spectrometer. Furthermore, body mass index of each study participant was determined., Results: The mean ± SD serum concentrations of zinc (μg/dL), copper (μg/dL), iron (μg/dL), selenium (μg/dL) and calcium (mg/dL), respectively, were 76.51 ± 39.16, 152.20 ± 55.37, 385.68 ± 217.95, 9.15 ± 4.21, and 14.18 ± 3.91 in Ethiopian women; 111.49 ± 52.92, 105.86 ± 26.02, 155.09 ± 94.83, 14.11 ± 3.41, and 11.66 ± 2.51 in Vietnamese women; and 60.69 ± 9.76, 107 ± 156, 268 ± 128, 8.33 ± 3.65, and 11.18 ± 0.68 in Japanese participants. Ethiopian women had significantly higher level of serum calcium than Vietnamese and Japanese women (both P < 0.05). Although the mean calcium concentration in Vietnamese women was higher than in women from Japan, the difference was not statistically significant (P > 0.05). Furthermore, compared with Japanese women, Ethiopian women had significantly high iron and copper concentrations (P < 0.05). Serum selenium and zinc levels were higher in Vietnamese than Ethiopian women., Conclusion: The study revealed a remarkable difference in serum concentrations of trace elements in women from different countries, implying differences in trace elements in the food or soil., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Diabetes impairs copper (Cu) regulation, causing elevated serum Cu and urinary Cu excretion in patients with established cardiovascular disease; it also causes cardiomyopathy and chronic cardiac impairment linked to defective Cu homeostasis in rats. However, the mechanisms that link impaired Cu regulation to cardiac dysfunction in diabetes are incompletely understood. Chronic treatment with triethylenetetramine (TETA), a Cu²⁺-selective chelator, improves cardiac function in diabetic patients, and in rats with heart disease; the latter displayed ∼3-fold elevations in free Cu²⁺ in the coronary effluent when TETA was infused into their coronary arteries. To further study the nature of defective cardiac Cu regulation in diabetes, we employed an isolated-perfused, working-heart model in which we infused micromolar doses of Cu²⁺ into the coronary arteries and measured acute effects on cardiac function in diabetic and non-diabetic-control rats. Infusion of CuCl₂ solutions caused acute dose-dependent cardiac dysfunction in normal hearts. Several measures of baseline cardiac function were impaired in diabetic hearts, and these defects were exacerbated by low-micromolar Cu²⁺ infusion. The response to infused Cu²⁺ was augmented in diabetic hearts, which became defective at lower infusion levels and underwent complete pump failure (cardiac output = 0 ml/min) more often (P < 0.0001) at concentrations that only moderately impaired function of control hearts. To our knowledge, this is the first report describing the acute effects on cardiac function of pathophysiological elevations in coronary Cu²⁺. The effects of Cu²⁺ infusion occur within minutes in both control and diabetic hearts, which suggests that they are not due to remodelling. Heightened sensitivity to the acute effects of small elevations in Cu²⁺ could contribute substantively to impaired cardiac function in patients with diabetes and is thus identified as a new mechanism of heart disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

In a randomized clinical trial of calorie restriction (CR), we demonstrated that important cardiovascular disease (CVD) biomarkers were favorably influenced by CR alone and in conjunction with physical exercise. The aim of this study was to examine the effects of CR with or without exercise on copper bound to ceruloplasmin (CuCp), a well-known biomarker for CVD, in overweight men and women enrolled in the CALERIE phase 1 study. Forty-six individuals were randomized to one of four groups for 6 months: control, healthy weight maintenance; CR, 25% CR from baseline energy requirements; CR+exercise, 12.5% CR and 12.5% through aerobic exercise; and low-calorie diet, low-calorie diet until 15% reduction in body weight followed by weight maintenance diet. CuCp was determined in fasting blood samples by a high-performance liquid chromatography-inductively coupled plasma mass spectrometry methodology and compared with changes in body composition and markers of CVD. After 6 months, CR combined with exercise induced a decrease in plasma concentration of CuCp. CuCp was inversely correlated with insulin sensitivity at baseline and after 6 months of intervention. A cluster analysis showed that the percent change of weight after 6 months of intervention was the most important variable that could discriminate the intervention groups. The percent change of CuCp was the only other variable selected by the analysis. Decreased CuCp in overweight subjects by CR combined with exercise suggests a positive effect of this intervention on metabolic health. Further studies to explain the relationship between weight loss and CuCp and its relevance for cardiovascular health are needed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

In the cuprizone model of demyelination, the neurotoxin cuprizone is fed to mice to induce a reproducible pattern of demyelination in the brain. Cuprizone is a copper chelator and it has been hypothesized that it induces a copper deficiency in the brain, which leads to demyelination. To test this hypothesis and investigate the possible role of other transition metals in the model, we fed C57Bl/6 mice a standard dose of cuprizone (0.2% dry chemical to dry food weight) for 6 weeks then measured levels of copper, manganese, iron, and zinc in regions of the brain and visceral organs. As expected, this treatment induced demyelination in the mice. We found, however, that while the treatment significantly reduced copper concentrations in the blood and liver in treated animals, there was no significant difference in concentrations in brain regions relative to control. Interestingly, cuprizone disrupted concentrations of the other transition metals in the visceral organs, with the most notable changes being decreased manganese and increased iron in the liver. In the brain, manganese concentrations were also significantly reduced in the cerebellum and striatum. These data suggest a possible role of manganese deficiency in the brain in the cuprizone model., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Preeclampsia (PE) affects approximately 5% of all pregnancies, but is increased several-fold in women with pre-gestational type 1 diabetes mellitus (T1DM). Increased oxidative stress and altered maternal plasma trace elements that modulate the antioxidant system have been implicated in PE. In non-diabetic women, increased plasma copper and iron and decreased manganese, selenium, and zinc have been associated with PE in cross-sectional studies. In a longitudinal study, we hypothesized that plasma levels of trace elements differ between T1DM women with vs. without subsequent PE. Samples were collected during the first (gestation 12.2 ± 1.9 weeks, [mean ± SD]), second (21.6 ± 1.5 weeks), and third (31.5 ± 1.7 weeks) trimesters of pregnancy, all before the onset of PE. We compared 23 T1DM women who subsequently developed PE with 24 T1DM women who remained normotensive; and we included 19 non-diabetic (non-DM) normotensive pregnant women as reference controls. Trace elements were measured using inductively coupled plasma mass spectroscopy. In T1DM women with subsequent PE vs normotensive, only plasma zinc was significantly higher at the first trimester, while copper:zinc and copper:high-density lipoprotein cholesterol ratios were higher throughout gestation (all P < .05). These findings persisted after adjustment for covariates. Higher copper:zinc ratios may contribute to oxidative stress in T1DM women who develop PE. Ratios of pro- to anti-oxidant factors may predict risk for PE in diabetic pregnancies more effectively than individual trace element levels., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Preeclampsia is a pregnancy-specific condition affecting 2-7% of women and a leading cause of perinatal and maternal morbidity and mortality. Deficiencies of specific micronutrient antioxidant activities associated with copper, selenium, zinc, and manganese have previously been linked to preeclampsia at the time of disease. Our aims were to investigate whether maternal plasma micronutrient concentrations and related antioxidant enzyme activities are altered before preeclampsia onset and to examine the dependence on genetic variations in these antioxidant enzymes. Predisease plasma samples (15±1 weeks׳ gestation) were obtained from women enrolled in the international Screening for Pregnancy Endpoints (SCOPE) study who subsequently developed preeclampsia (n=244) and from age- and BMI-matched normotensive controls (n=472). Micronutrient concentrations were measured by inductively coupled plasma mass spectrometry; associated antioxidant enzyme activities, selenoprotein-P, ceruloplasmin concentration and activity, antioxidant capacity, and markers of oxidative stress were measured by colorimetric assays. Sixty-four tag-single-nucleotide polymorphisms (SNPs) within genes encoding the antioxidant enzymes and selenoprotein-P were genotyped using allele-specific competitive PCR. Plasma copper and ceruloplasmin concentrations were modestly but significantly elevated in women who subsequently developed preeclampsia (both P<0.001) compared to controls (median (IQR), copper, 1957.4 (1787, 2177.5) vs 1850.0 (1663.5, 2051.5) µg/L; ceruloplasmin, 2.5 (1.4, 3.2) vs 2.2 (1.2, 3.0) µg/ml). There were no differences in other micronutrients or enzymes between groups. No relationship was observed between genotype for SNPs and antioxidant enzyme activity. This analysis of a prospective cohort study reports maternal micronutrient concentrations in combination with associated antioxidant enzymes and SNPs in their encoding genes in women at 15 weeks׳ gestation that subsequently developed preeclampsia. The modest elevation in copper may contribute to oxidative stress, later in pregnancy, in those women that go on to develop preeclampsia. The lack of evidence to support the hypothesis that functional SNPs influence antioxidant enzyme activity in pregnant women argues against a role for these genes in the etiology of preeclampsia., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

The concentration of calcium (Ca), cobalt (Co), copper (Cu), iron (Fe), magnesium (Mg), manganese (Mn) and selenium (Se) in plasma of 76 nonagenarians (mean age, 89.0±6.3 years), 64 centenarians (mean age, 101±1 years) and 24 middle-aged subjects as controls (mean age 61.2±1.1 years), was determined by sector field inductively coupled plasma mass spectrometry. All the subjects lived in Sardinia, an Italian island, that has the higher prevalence of centenarians than in other European countries. A comparison among the three classes of age showed a significant depletion of Ca, Co, Fe, Mn and Se (all p<0.001) in nonagenarians and centenarians with respect to controls. In particular, the geometric mean (GM) values of Ca, Co, Fe, Mn and Se were: 94.1 μg/ml, 0.46 ng/ml, 1314 ng/ml, 2.47 ng/ml and 111 ng/ml in controls; 87.6 μg/ml, 0.22 ng/ml, 815 ng/ml, 1.07 ng/ml and 88.9 ng/ml in nonagenarians; 87.0 μg/ml, 0.29 ng/ml, 713 ng/ml, 1.27 ng/ml and 81.9 ng/ml in centenarians. The highest inverse relationship with age was observed for Fe (p<0.001; ρ=-0.352) and Se (p<0.001; ρ=-0.417). This trend was also observed when data were sorted by gender. On the other hand, Cu and Mg levels in plasma remained substantially unchanged during aging. As regards Cu, it was significantly higher in females than in males in controls (GM, 1294 ng/ml vs. 1077 ng/ml; p=0.012), in nonagenarians (GM, 1216 ng/ml vs. 1081 ng/ml; p=0.011) as well as in centenarians (GM, 1226 ng/ml vs. 1152 ng/ml; p=0.045) and in hypertensive subjects with respect to healthy people (GM, 1215 ng/ml vs. 1129 ng/ml; p=0.021). These data can be used to enhance knowledge and support the research on: i) metals involved in aging in areas with high rates of human longevity; ii) variables (gender, lifestyle habits and health status) as critical determinants in aging; and iii) mineral intake and supplementation at older age affecting the healthy aging., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: Copper (Cu) is widely used in industry for the manufacture of a vast range of goods including Cu-intrauterine devices (IUDs), electronic products, agrochemicals, and many others. It is also one of the trace elements essential to human health in the right measure and is used as a parenteral supplement in patients unable to ingest food. Elevated Cu levels have been found in the plasma of women using Cu-IUDs and in farmers working with Cu-based pesticides. However, possible alterations due to Cu overload in the brain have been poorly studied. Therefore, the aim of this study was to investigate the effects of Cu administration on rat brain in Cu-sufficient and Cu-deficient animals fed on semi-synthetic diets with different doses of Cu (7 or 35 ppm)., Methods: We aimed to investigate the effects of Cu administration using two routes of administration: oral and intraperitoneal (IP). Male Wistar rats were feeding (one month) a complete (7 ppm) or a deficient (traces) Cu diets subdivided into three categories oral-, intraperitoneal- (or both) supplemented with copper carbonate (7 to 35 ppm). Cu content in plasma, brain zones (cortex and hippocampus), antioxidant enzyme activities, and protease systems involved in programmed cell death were determined., Results: The results show that Cu levels and the concentration of Cu in plasma and brain were dose-dependent and administration route-dependent and demonstrated a prooxidative effect in plasma and brain homogenates. Oxidative stress biomarkers and antioxidative enzyme activity both increased under Cu overload, these effects being more noticeable when Cu was administered IP. Concomitantly, brain lipids from cortex and hippocampus were strongly modified, reflecting Cu-induced prooxidative damage. A significant increase in the activities of calpain (milli- and micro-) and caspase-3 activity also was observed as a function of dose and administration route., Conclusion: The findings of this study could be important in evaluating the role of Cu in brain metabolism and neuronal survival., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: We evaluated changes in the status of iron, zinc, and copper in non-anemic Peruvian infants who were receiving daily supplements of 10 mg of iron and 0.5 mg of copper with or without 10 mg of zinc from 6 to 18 mo of age., Methods: Overall, 251 infants were randomized to receive one of two daily supplements. Venous blood draws at 6, 12, and 18 mo of age were taken to characterize hemoglobin, plasma ferritin, zinc, and copper concentrations. The urinary excretion of zinc was also measured at each time point. Repeated measures analysis of variance was used to evaluate changes over time and by supplement type., Results: Both hemoglobin and copper concentrations increased significantly and plasma ferritin decreased from 6 to 12 mo of age (P < 0.05). Mean plasma zinc concentrations in the zinc treatment group were maintained over time, whereas zinc concentrations in the control group declined; differences by treatment were found at 12 and 18 mo of age (P < 0.05). Urinary zinc concentration was increased in the zinc group at 12 mo only. There was evidence that zinc treatment improved the hemoglobin level at 18 mo of age (P = 0.09). Compliance with supplementation was high, with 81% of the intended dose consumed over the 12-mo period., Conclusions: Daily mineral supplementation over the course of 1 y appears to be feasible and acceptable in this population. A combined supplement can improve the status of iron, zinc, and copper in infants at the same time., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to investigate the blood copper (Cu), zinc (Zn), calcium (Ca), magnesium (Mg), iron (Fe), lead (Pb), and cadmium (Cd) concentrations in women of ≤12 (group I), 13-20 (group II), 21-27 (group III), 28-35 (group IV), and 36-42 (group V) weeks of gestation and compare them with those in nonpregnant women., Design and Methods: The cross-sectional study was performed in 2380 pregnant women [group I (n = 550); group II (n = 552); group III (n = 600); group IV (n = 553); and group V (n = 125)] and 552 nonpregnant women as controls. Blood seven element concentrations, including Cu, Zn, Ca, Mg, Fe, Pd, and Cd, were determined by atomic absorption spectrometry (AAS)., Results: Compared with the nonpregnant women group, the concentrations of Cu, Zn, Ca, Mg, Fe, Pb, and Cd at ≤12, 13-20, 21-27, 28-35, and 36-42 weeks of gestation, on the whole, were significantly different. Blood Cu, Mg, Ca, Fe, Pb, and Cd concentrations were correlated with weeks of gestation (P<0.05). The gestational age-specific reference intervals were established for Cu, Zn, Ca, Mg, Fe, Pd, and Cd., Conclusions: The established reference intervals for Cu, Zn, Ca, Mg, and Fe can provide important guidance for the reasonable supplementation of essential elements in pregnancy. And the reference intervals for Pd and Cd can play an important part in the surveillance and diagnosis of environmental overexposure., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of the study is to evaluate the distribution and correlation of toxic and essential elements in whole blood from 0- to 6-year-old children from Jinan, China., Design and Methods: Levels of toxic and essential elements found in the whole blood of 1110 children were analyzed using an atomic absorption spectrometer. Distributions and correlations of trace elements in different age groups were analyzed and compared., Results: The overall mean blood lead (Pb) and cadmium (Cd) levels (49.42±20.16 and 1.47±1.08μg/L, respectively) were relatively stable among different age groups. The prevalence of Pb and Cd intoxication in all children was 1.4% and 0.4%, respectively. Calcium (Ca) levels decreased gradually with age, with an overall concentration of 1.82±0.15mmol/L. Whole levels of copper (Cu) and magnesium (Mg) were 17.79±4.22μmol/L and 1.52±0.14mmol/L, respectively. While 7.6% of all children showed Cu levels below the normal threshold, the levels of Mg were stable in different age groups. Though the overall mean blood zinc (Zn) and iron (Fe) concentrations (59.59±15.15μmol/L and 7.39±0.74mmol/L, respectively) gradually increased with age and the overall deficiency levels (59.8% and 59.5%, respectively) decreased with age, Zn and Fe deficiencies were still very common. Significant positive correlations were found when comparing Cu to Zn, Ca, Mg, and Fe; Zn to Mg and Fe; and Mg to Ca and Fe. Additionally, minor positive correlations were found when comparing Pb to Zn and Fe., Conclusion: The degree of Pb and Cd intoxication in all the children studied was low; however, Pb and Cd exposure was still evident. The importance of Ca deficiency and supplementation is well recognized, but the severity of Fe and Zn deficiency is not as well documented., (Copyright © 2013 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Objective: To study the antioxidant activity of melatonin in diabetes in relation to the regulation and levels of plasma copper (Cu), zinc (Zn), iron (Fe), manganese (Mn), and selenium (Se) in Zucker diabetic fatty (ZDF) and lean (ZL) rats., Methods: At 6 wk of age, both ZDF (n = 30) and ZL (n = 30) animals were subdivided into three groups: control (C) (n = 10), vehicle (V) (n = 10), and melatonin-treated (M) (10 mg/kg/d; n = 10) rats for a 6-wk period. At the end of treatment period, plasma mineral levels were measured by flame (Cu, Zn, and Fe), electrothermal (Mn), and hydride generation (Se) atomic absorption spectrometry., Results: ZDF rats had significantly higher Cu, Fe, and Mn plasma levels than did ZL rats (P < 0.05). No significant differences were found between control and vehicle groups (P > 0.05). Melatonin treatment did not influence plasma levels of these antioxidant minerals (Cu, Zn, Fe, and Mn) in ZDF groups (M-ZDF versus C-ZDF group) and ZL (M-ZL versus C-ZL group) rats with the exception of Zn, whose mean plasma level was lower in the M-ZL versus C-ZL group. However, plasma Se levels increased significantly (P < 0.05) after melatonin supplementation in both groups (M-ZDF and M-ZL)., Conclusion: The higher mean plasma Cu, Fe, and Mn levels in the ZDF group are related to the enhanced oxidative stress in diabetes and obesity. Melatonin administration significantly enhanced plasma Se levels in both groups (M-ZDF and M-ZL). This is the first study to report that melatonin treatment increases plasma Se levels., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Iron supplementation is commonly recommended for infants; however, there are some reports that it causes oxidative damage. The aim of this study was to investigate the potential effects of iron supplementation at 4 mo of age, for a period of 2 mo, on lipid peroxidation and free radical scavenging enzymes., Methods: Twenty-seven healthy 4-mo-old infants chosen randomly and given iron supplementation (ferrous sulfate, 10 mg of elemental iron per day) constituted the study group and 26 healthy 4-mo-old infants who were chosen randomly and not given iron supplementation constituted the control group. Weight, height, head circumference, complete blood cell count, serum ferritin level and intraerythrocytic zinc, iron, copper, malondialdehyde, catalase, superoxide dismutase, and glutathione peroxidase levels were measured in the two groups at 4 and 6 mo of life., Results: Compared with controls at 6 mo of age, no significant differences were observed for intraerythrocytic zinc (0.5 ± 0.1 versus 0.6 ± 0.2 μg/mL, P > 0.05), copper (0.2 ± 0.1 versus 0.2 ± 0.2 μg/mL, P > 0.05), iron (130.8 ± 10.9 versus 127.4 ± 11.1 μg/mL, P > 0.05), malondialdehyde (21.4 ± 3.5 versus 22.4 ± 2.3 nmol/g of hemoglobin, P > 0.05), catalase (135.4 ± 23.9 versus 135.1 ± 23.3 MU/g of hemoglobin, P > 0.05), superoxide dismutase (1736.4 ± 141.1 versus 1701.3 ± 103.9 U/g of hemoglobin, P > 0.05), and glutathione peroxidase (8.9 ± 1.6 versus 8.4 ± 1.6 U/g of hemoglobin, P > 0.05) levels., Conclusion: Our study indicates that the supplemental use of elemental iron 10 mg/d for a period of 2 mo in healthy iron-replete infants did not cause lipid peroxidation or an impairment of antioxidant status., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Copper levels are elevated in cancer patients compared to normal subjects. However, few studies have investigated the relationship between copper and hematological malignancies., Methods: 84 patients with hematological diseases were studied, along with 50 healthy individuals. Copper was measured by flame atomic absorption spectrometry. The patients were classified to 2 homogeneous groups, acute and chronic hematological neoplasms, respectively. For the patients with acute hematological malignancies, relapse and remission were investigated in relation to serum copper levels. For chronic hematological neoplasms, serum copper was connected either with stable or progressive disease. Zeta-chain-associated protein kinase 70 (ZAP70) and CD38 expression, along with the unmutated VH immunoglobulin genes (IgVH) status were also determined for the 22 chronic lymphocytic leukemia (CLL) patients., Results: 54 patients with relapse or progressive disease had elevated copper levels (mean value 1.8 mg/l), whereas 30 patients either in remission or in stable disease had normal copper levels (mean value 1.01 mg/l) (normal range 0.8-1.3mg/l)., Conclusion: Hence, our study indicates that serum elevated copper levels are associated with hematological malignancies either in relapse or in disease progression, whereas normal copper levels are linked with hematological neoplasms in remission or in stable disease. Furthermore, we report for the first time an association between high serum copper levels and several adverse prognostic markers in CLL, such as increased expression of ZAP70 and CD38, along with elevated percentage of unmutated IgVH., (Copyright © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Serum Cu levels rise with age and high Cu/Zn ratios are linked with multiple-cause mortality in the elderly. The relationships of these parameters to measures of musculoskeletal health and frailty have not yet been analyzed. We used inductively coupled mass spectrometry to assess serum levels of Cu and Zn and probed for relationships between serum Cu levels and the Cu/Zn ratio with specific measures of bone, physical and overall health in a cohort of 144 frail elderly men. Subjects were divided into quintiles based on serum metal levels and comparisons for functional measures were made between the reference (middle) group and the low and high groups. Subjects' serum metal values were normally distributed. We found significant correlations between high Cu/Zn ratios and deficits in femoral bone mineral density, measures of speed and strength, muscle mass and hematocrit. High Cu/Zn ratios were also correlated with decreased triglycerides and increased reliance on ADL assistance. This study identifies specific deficits associated with high Cu/Zn ratios that span multiple organ systems and supports earlier studies indicating that serum Cu levels and the Cu/Zn ratio may serve as useful predictive biomarkers for poor health in the elderly., (Copyright © 2012. Published by Elsevier Inc.)

Objectives: We evaluated the relationship of the plasma copper/zinc (Cu/Zn) ratio with nutritional status, inflammation, oxidative stress, and immune function in peritoneal dialysis patients., Design and Methods: Clinical and laboratory parameters were measured in patients (n=45) and age- and sex-matched healthy individuals (n=30)., Results: There were significant negative correlations of the Cu/Zn ratio with nutrition-related parameters (body mass index [BMI], creatinine, hemoglobin, and albumin) and antioxidant (vitamin C and E) levels and positive correlations of the Cu/Zn ratio with the levels of high sensitivity C-reactive protein (hs-CRP) and oxidation products (malondialdehyde [MDA] and protein carbonyl). The Cu/Zn ratio was negatively correlated with the percentages of B- and T-lymphocyte subsets and the ratio of CD4/CD8 antigens., Conclusions: In peritoneal dialysis patients, elevated Cu/Zn ratios are associated with malnutrition, increased oxidative stress, inflammation, and disrupted immune status., (Copyright © 2010. Published by Elsevier Inc.)

Objectives: We measured concentrations of lead (Pb), manganese (Mn), chromium (Cr), and copper (Cu) in umbilical cord whole blood and examined sources of environmental Pb exposures in a predominantly African-American population., Methods: Between April and July 2006, we collected reproductive histories, questionnaires, and blood samples from 102 women, aged 16-45 years, who delivered at a Memphis, TN hospital., Results: The prevalence of preeclampsia and low birth weight infancy in the study population was 11% and 10%, respectively. Twenty-eight percent of mothers reported living near a potential Pb-contaminated area, while 43% lived in a residence built before 1978. Geometric mean (GM) concentrations for umbilical cord blood in the study population were 1.3, 3.5, 9.0, and 52.0 microg/dL for Pb, Mn, Cr, and Cu, respectively. Six neonates had cord blood Pb (CBL) concentrations above 10 microg/dL, while 20 had CBL concentrations > or =2 microg/dL. GM umbilical CBL levels were higher in neonates born to women living near a potential Pb-contaminated area (2.2 vs. 1.1 microg/dL) and those with friends, family or household members exposed to lead products (1.6 vs. 1.1 microg/dL). Some evidence of an exposure-response relationship was also detected between all four metal concentrations and an increasing number of maternal lead exposures. After adjustment for confounding, proximity to a Pb-contaminated area was the strongest environmental determinant of CBL levels among neonates with CBL concentrations of > or =2 microg/dL (odds ratio=5.1; 95% CI=1.6, 16.7)., Conclusions: Metal concentrations were elevated in this population, and CBL levels were associated with proximity to Pb-contaminated areas., (Published by Elsevier Ltd.)

Objectives: In rats a significant increase of the copper biliary excretion is produced by valproic acid administration, however, a conclusive study on the possible appearance of copper deficiency in humans during treatment with this drug has still not been carried out., Design and Methods: In 101 adult epileptic patients treated in monotherapy (n=75) and polytherapy (n=26) with valproic acid, and 50 healthy controls, were determined serum copper, immunoreactive ceruloplasmin and its oxidase activity against o-dianisidine, in order to calculate the specific oxidase activity (activity per unit mass of enzyme protein) and copper/ceruloplasmin ratio., Results: Specific oxidase activity of ceruloplasmin and copper/ceruloplasmin ratio were significantly lower in the groups of patients treated with valproic acid than in the controls. Significant correlations were obtained between both biochemical variables (p<0001). In 38% of the patients treated in mono or polytherapy, the specific oxidase activities of ceruloplasmin were smaller than the estimated lower limit of reference., Conclusions: These results, possible due to a diminished copper content of the circulating ceruloplasmin, suggest that marginal or moderate copper deficiency may have a substantial prevalence among patients treated with valproic acid., (Copyright (c) 2010. Published by Elsevier Inc.)

Objective: To assess homocysteine, folic acid and vitamin B12, trace element levels and oxidant/antioxidant status in Down syndrome (DS) mothers and children., Design and Methods: 42 mothers with previous history of bearing DS baby with karyotypically confirmed full trisomy 21 were included. 48 healthy mothers with their healthy children were considered as control. Serum B12, folic acid, total homocysteine (tHcy), vitamins E and C, TBARS and trace elements were estimated., Results: DS mothers showed higher levels of tHCy, lower levels of folic acid and vitamin B12 than controls. tHCy and folic acid concentrations were significantly decreased, while vitamin B12 exhibited a slight decrease in DS children versus control. Vitamins E and C, zinc and copper levels were markedly reduced in DS mothers. By contrast, TBARS showed significant elevation in them. Furthermore, DS children had severe reduction of vitamin C and zinc levels relative to healthy children. However, vitamin E showed slight reduction and TBARS displayed a slight rise in DS children., Conclusion: Abnormal folic acid-homocysteine metabolism is a potent marker to identify women at risk for having DS child and it also exposes them to oxidant/antioxidant imbalance., (2010 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

We report two patients, both with a history of gastric surgery, who presented with progressive optic neuropathy and myelopathy. The patients' symptoms were initially attributed to vitamin B12 deficiency and/or neuromyelitis optica; however, after the neurologic deficits continued to progress with the use of conventional treatments, further evaluation was initiated, and a severe copper deficiency was revealed. Copper deficiency is a rare cause of progressive optic neuropathy and myelopathy and should be considered in the differential diagnosis. It is crucial to elicit a history of gastric surgery or other risk factors for hypocupremia in those patients undergoing an evaluation for subacute or chronically progressive optic neuropathy or myelopathy., (Copyright 2010 Elsevier Inc. All rights reserved.)

Neurodegeneration of the central and peripheral nervous system associated with hypocupremia and hyperzincinemia has been widely recognized but the origin of high zinc remained unknown. Denture cream has been recently suggested as one possible source of zinc, but the frequency with which denture fixative alone accounts for this syndrome is unknown. We analyzed the origin of excessive zinc in eleven patients with a progressive myelopolyneuropathy and unexplained hypocupremia with hyperzincinemia. These patients had a detailed clinical assessment, determination of zinc and copper levels, and analyzed use of denture cream with the estimates of daily zinc exposure. We identified denture cream as a source of excessive zinc in 100% patients in our cohort. They all had a history of ill-fitting dentures requiring large amounts of denture cream, resulting in significant zinc exposure. Their copper and zinc normalized after stopping denture cream, further confirming that this is the source of high zinc. Inappropriate use of denture cream appears to be the sole source of excessive zinc in these patients.

Objective: We investigated the prevalence of anemia and deficiency in trace elements in adolescent girls living in rural Vietnam., Methods: Two hundred forty-five adolescent girls 11-17 y of age from three schools in rural province of Ha Nam, Vietnam, were assessed., Results: The prevalence of anemia was 20.4%. The incidences of low serum selenium (Se), zinc, and copper in subjects were 15.9%, 26.5%, and 4.1%, respectively. The parameter significantly associated with anemia was the low serum levels of Se and vice versa (odds ratio [OR] 5.36, 95% confidence interval [CI] 2.57-11.18, P < 0.0001). Other risk factors for anemia were a body mass index <17.00 kg/m(2) (OR 2.72, 95% CI 1.37-5.37, P = 0.004) and years of age (OR 1.35, 95% CI 1.14-1.59, P < 0.001). A body mass index <17.00 kg/m(2) (OR 2.65, 95% CI 1.25-5.61, P = 0.011) was also found to be a risk factor for low serum Se., Conclusion: The findings of the present study demonstrate that low serum Se is independently associated with anemia in adolescent girls living in rural Vietnam. Interventions are required to gain insight into the potential role of Se on prevention and control of anemia.

Because of the restricted intake of high-biologic-value protein, children with phenylketonuria (PKU) may have lower than normal plasma concentrations of copper, zinc, and selenium. The purpose of the present study was to investigate erythrocyte zinc levels and serum copper and selenium levels in children and adolescents with PKU by analyzing the relation between their diet and the laboratory profiles of these elements. The study was conducted in 32 children and adolescents with PKU, who were on a special diet. Dietary records and blood samples were collected from each subject. Erythrocyte zinc and serum selenium levels were below normal in 37.5% and 90.6% of the subjects, respectively. Plasma copper levels were normal. Metabolic formulas were the only source of 86.9% of the zinc, 65.6% of the copper, and 32.4% of the selenium. Despite this, there was no significant correlation between the zinc formula supply and erythrocyte zinc levels (rho = -0.143, P = .435) or the supply and serum levels for copper (rho = -0.117, P = .523) and selenium (rho = 0.113, P = .538). These results suggest that Brazilian patients with PKU present with low ingestion levels, low serum selenium levels, and low erythrocyte zinc levels.

Fifty-four juvenile male New Zealand white rabbits were randomly allocated to 9 groups including chow-fed rabbits without mineral supplementation, HC diet fed rabbits without mineral supplementation, HC + Cu, HC + Zn, HC + FeO, HC + Cu + Zn, HC + FeO + Cu, HC + FeO + Zn, and HC + FeO + Cu + Zn. Feeding HC diet resulted in a significant (P < .001) increase in the serum cholesterol, TG, LDL, and very LDL except HDL when compared with chow-fed rabbits. The highest serum lipid profiles were observed in the FeO rabbits without copper or zinc supplementation. A modest decrease in serum thiobarbituric acid reactant substances in rabbits given the HC + Zn was accompanied by a significant (P < .05) increase in antioxidant enzymes activities excluding superoxide dismutase that was markedly lower than those given the HC + Cu (12.83 +/- 2.13 vs 16.00 +/- 2.23 U/mL serum). Supplementation with copper alone in both the FeO and the non-FeO rabbits significantly (P < .001) enhanced serum ceruloplasmin activity in comparison with other groups, but co-supplementation of copper plus zinc in the non-FeO rabbits did not significantly (P > .05) affect ceruloplasmin activity in comparison with those treated with unsupplemented regimens. A significant decrease was found in sudanophilia area of rabbits supplemented with zinc (62.36% +/- 3.55%) compared to those given the HC + FeO, the HC + FeO + Cu, and HC without mineral supplementation; however, no significant (P > .05) difference in animals given the HC + Cu, the HC + Cu + Zn, and the HC + FeO + Zn was observed. Based on these findings, it may be suggested that the antiatherogenic effects of zinc in presence of copper, on which there is overloading of iron, is reduced under hypercholesterolemia.

Transcuprein is a high-affinity copper carrier in the plasma that is involved in the initial distribution of copper entering the blood from the digestive tract. To identify and obtain cDNA for this protein, it was purified from rat plasma by size exclusion and copper-chelate affinity chromatography, and amino acid sequences were obtained. These revealed a 190-kDa glycosylated protein identified as the macroglobulin alpha(1)-inhibitor III, the main macroglobulin of rodent blood plasma. Albumin (65 kDa) copurified in variable amounts and was concluded to be a contaminant (although it can transiently bind the macroglobulin). The main macroglobulin in human blood plasma (alpha(2)-macroglobulin), which is homologous to alpha(1)-inhibitor III, also bound copper tightly. Expression of alpha(1)I3 (transcuprein) mRNA by the liver was examined in rats with and without copper deficiency, using quantitative polymerase chain reaction methodology and Northern blot analysis. Protein expression was examined by Western blotting. Deficient rats with 40% less ceruloplasmin oxidase activity and liver copper concentrations expressed about twice as much alpha(1)I3 mRNA, but circulating levels of transcuprein did not differ. Iron deficiency, which increased liver copper concentrations by threefold, reduced transcuprein mRNA expression and circulating levels of transcuprein relative to what occurred in rats with normal or excess iron. We conclude that transcupreins are specific macroglobulins that not only carry zinc but also carry transport copper in the blood, and that their expression can be modulated by copper and iron availability.

Objectives: To compare percentage non-caeruloplasmin bound copper (%NCC) to generally accepted values., Design and Methods: Using data for 338 normal individual patients, we calculated the %NCC., Results: The %NCC ranged (median) from -59.75% to 51.98% (8.75%) respectively. The non-parametric reference interval was -23.44% to 22.99% with 43.8% of the %NCC values >10%., Conclusions: We found the %NCC to be higher than generally accepted. This may be due to uncertainty from precision, bias and specificity.

The effects of oral zinc supplementation on lipid peroxidation and the antioxidant defense system of alloxan (80-90 mg/kg)-induced diabetic rabbits were examined. Forty-five New Zealand male rabbits, 1 year old, weighing approximately 2.5 kg, were allocated randomly and equally as control, diabetic, and zinc-supplemented diabetic groups. After diabetes was induced, zinc-supplemented diabetic rabbits had 150 mg/L of zinc as zinc sulfate (ZnSO(4)) in their drinking tap water for 3 months. The feed and water consumption was higher in diabetic groups than (P<0.01) healthy rabbits. The body weight was lower in diabetic rabbits compared to control. The blood glucose levels were higher in diabetic groups than controls. The elevated plasma malondialdehyde (MDA) levels were determined in the diabetic group (P<0.01). The glutathione peroxidase (GSH-Px), catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), and ceruloplasmin levels in the diabetic group were decreased by the effect of diabetes but there was no difference between zinc-supplemented diabetic and control rabbits. Serum zinc concentrations were lower in diabetic rabbits but iron (Fe) and copper (Cu) levels in sera were not different among the groups. As a result, it was concluded that daily zinc supplementation could reduce the harmful effects of oxidative stress in diabetics.

Background: The aim of the study was to show the influence of glucose in the dialysate on the intensity of oxidative stress, activity of glutathione peroxidase (GSHPx) and concentration of selenium in patients undergoing regular hemodialysis., Methods: The study was comprised of 85 patients hemodialyzed with dialysate containing glucose [HD-g(+)] or not containing glucose [HD-g(-)], patients with chronic renal failure on conservative treatment and control group. The concentrations of the products of reaction with thiobarbituric acid (TBARS), concentration of selenium in erythrocytes and plasma, concentration of copper in erythrocytes and the activity of GSHPx were determined., Results: GSHPx had significantly higher activity in HD-g(-) group before HD than in control group. In HD-g(+) group before hemodialysis, the activity of GSHPx was significantly lower than in the control group. After HD, the activity showed a statistically significant increase. In both hemodialyzed groups, selenium concentration before hemodialysis both in plasma and erythrocytes was significantly lower, compared to control group. In the group of patients with CRF on conservative treatment, selenium concentration in RBC was significantly higher, compared to concentrations obtained in other groups except for control group. The increase of copper concentration in erythrocytes was accompanied by the increase of oxidative stress and increase of TBARS concentration. The opposite relationship was observed for selenium-its concentration was inversely correlated to copper concentration., Conclusions: In both groups of hemodialyzed patients, hemodialysis caused the increase of GSHPx in erythrocyte activity and increase of plasma and erythrocyte selenium concentration.

Objectives: This study analyzed the influence of type 2 diabetes mellitus and primary hypothyroidism on the activity of the delta-aminolevulinate dehydratase (delta-ALA-D) in human blood., Design and Methods: Delta-ALA-D enzyme activity was determined in normal (healthy) people (n=29), compensated (DMC, n=11) and non-compensated diabetic patients (NDMC, n=23), and in patients with compensated (CH, n=19) and non-compensated primary hypothyroidism (NCH, n=10). The determination of lead, copper, zinc and magnesium was performed by graphite furnace atomic absorption spectrometry., Results: This study shows that delta-ALA-D activity was decreased (P<0.05) in situations associated to hyperglycemia maintained for long periods (HbA1c high). Another finding of this study suggests that states of hypofunction of the thyroid gland, when non-compensated, increase the activity of delta-ALA-D (P<0.001). In addition, copper was elevated in HNC, zinc was diminished in DMC, HC and HNC, and magnesium was diminished in the HNC group., Conclusion: This result points out that there is a correlation among diabetes, hypothyroidism and delta-ALA-D activity.