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Background: As an essential trace element, copper has been considered to play an important role in lipid metabolism. However, the associations of serum copper with lipid concentration and dyslipidemia are still controversial., Methods: We used the 2011-2014 National Health and Nutrition Examination Survey to examine the relationship between serum copper and lipid concentration among participants aged 20 years and older. Multivariate linear regression was conducted to estimate the differences in the level of total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol. Logistic regression was conducted to examine the association between serum copper and the risk of dyslipidemia., Results: A total of 2,678 subjects were eligible for our analyses. The multivariable adjusted average differences (95% CIs) comparing the highest to the lowest copper tertile were 8.42 (1.45-15.38) mg/dL for TC, and 2.96 (0.02-5.90) mg/dL for HDL cholesterol. Compared with the lowest tertile of serum copper, participants had significantly higher risks of High-TC dyslipidemia (OR 1.46; 95% CI 1.02-2.08) in tertile 3 and High-LDL cholesterol dyslipidemia (OR 1.48; 95% CI 1.03-2.14) in tertile 2 after adjusting for covariates. In the stratified analyses, we found that the copper-dyslipidemia association was statistically significant in women and subjects younger than 45 years of age., Conclusion: High serum copper was associated with elevated serum concentrations of TC and HDL cholesterol, and was associated with increased risks of High-TC and High-LDL cholesterol dyslipidemia. However, the real association between serum copper and serum lipids should be verified in larger prospective cohort studies in -future., (© 2018 S. Karger AG, Basel.)

Background: Alzheimer disease (AD) is a progressive neurodegenerative disease with a complex multifactorial etiology. Here, we aim to identify a biomarker pool comprised of genetic variants and blood biomarkers as predictor of AD risk., Methods: We performed a case-control study involving 108 cases and 159 non-demented healthy controls to examine the association of multiple biomarkers with AD risk., Results: The APOE genotyping revealed that ε4 allele frequency was significantly high (p value = 0.0001, OR = 2.66, 95% CI 1.58-4.46) in AD as compared to controls, whereas ε2 (p = 0.0430, OR = 0.29, CI 0.07-1.10) was overrepresented in controls. In biochemical assays, significant differences in levels of total copper, free copper, zinc, copper/zinc ratio, iron, epidermal growth factor receptor (EGFR), leptin, and albumin were also observed. The AD risk score (ADRS) as a linear combination of 6 candidate markers involving age, education status, APOE ε4 allele, levels of iron, Cu/Zn ratio, and EGFR was created using stepwise linear discriminant analysis. The area under the ROC curve of the ADRS panel for predicting AD risk was significantly high (AUC = 0.84, p < 0.0001, 95% CI 0.78-0.89, sensitivity = 70.0%, specificity = 83.8%) compared to individual parameters., Conclusion: These findings support the multifactorial etiology of AD and demonstrate the ability of a panel involving 6 biomarkers to discriminate AD cases from non-demented healthy controls., (© 2017 S. Karger AG, Basel.)

Background: The objective of the present study was to determine concentrations of zinc (Zn), copper (Cu), iron (Fe), selenium (Se) in blood plasma and manganese (Mn) in the whole blood in patients with long-term home parenteral nutrition (HPN) in comparison to the control group., Patients and Methods: We examined 68 patients (16 men and 52 women) aged from 28 to 68 years on a long-term HPN lasting from 4 to 96 months. The short bowel syndrome was an indication for HPN. The daily doses of Zn, Cu, Fe, Se and Mn in the last 3 months were determined., Results: No significant differences in blood plasma were found for Zn, Cu and Fe in patients with HPN and in the control group (p > 0.05). The concentration of Mn in whole blood was significantly increased in HPN patients (p < 0.0001), while Se concentration in these patients was significantly decreased (p < 0.005). The concentration of Mn in the whole blood of 16 patients with cholestasis was significantly increased compared to the patients without cholestasis (p < 0.001). The Cu concentration was increased with no statistical significance., Conclusion: In long-term HPN, the status of trace elements in the patients has to be continually monitored and the daily substitution doses of these elements have to be flexibly adjusted. Dosing schedule needs to be adjusted especially in cases of cholestatic hepatopathy. A discussion about the optimal daily dose of Mn in patients on HPN is appropriate. For clinical practice, the availability of a substitution mixture of trace elements lacking Mn would be advantageous., (© 2016 S. Karger AG, Basel.)

The oxidant-stress (OS) has an essential role to play in the pathogenesis and progression of many diseases. OS is the outcome when the level of free-radical-formation is increased or protective-antioxidant-mechanisms are compromised. Its value is expected to increase, although its emerging roles have not been conclusive in different studies. The objective of this study was to explore the level of zinc, copper, and antioxidant in response to obesity-related-stress by measuring superoxide-dismutase (SOD) levels as a key antioxidant-enzyme in 706 individuals with/without obesity. Anthropometric/biochemical parameters including total-cholesterol (TC), fasting-blood-glucose, high-density-lipoprotein (HDL), low-density-lipoprotein, and triglycerides were determined. The activity of SOD was measured followed by the measurement of Cu and Zn levels. Obese subjects had a significantly higher level of body mass index (BMI) and TC, while the level of HDL was lower in the obese group, as compared to the related values in control subjects. The level of Zn was significantly decreased in the obese group, while the level of Cu and Cu/Zn ratio increased. Additionally, we observed that the SOD level was less in obese subjects when compared to that in the non-obese subjects. In addition to the complications of high BMI, low level of Zn and SOD in obesity can be considered a risk factor, resulting in a reduced antioxidant response, supporting the need for identifying a suitable treatment option for this group., (© 2016 S. Karger AG, Basel.)

Background: In phenylketonuria (PKU), phenylalanine-free L-amino acid supplements are the major source of dietary micronutrients., Methods: Four hundred fifty-two retrospective annual/bi-annual non-fasting blood samples for nutritional markers (plasma zinc, selenium, and serum folate) from 78 subjects aged 1-16 years (median number of blood samples: 6, range 1-14) were analysed over 12 years. Longitudinal blood result data were available for 51 subjects (65%). The dietary intake from supplements was calculated., Results: The median intakes of all of the micronutrients studied were >200% of the reference nutrient intakes (RNI). There was no statistical correlation between dietary intake and nutritional markers outside of the normal reference range (RR) except for selenium, but there was a correlation between a lower plasma zinc, plasma selenium and haemoglobin status and better blood phenylalanine control in 1- to 4-year-old children. On at least one occasion, the individual plasma concentrations of zinc (71%, n = 54/76) and selenium (21%, n = 16/75) were below the RR; however, the concentrations of selenium (41%, n = 31/75) and serum folate (83%, n = 34/41) were also above the RR. Dietary intakes exceeded the upper tolerable intakes for zinc and copper (32%, n = 25) and folate (65%, n = 51). Individual longitudinal data demonstrated little change in micronutrient status over time., Conclusions: In PKU, biochemical micronutrient deficiencies are common despite micronutrient intakes above the RNI. Further study of the nutritional profiling of L-amino acid supplements in PKU is needed., (© 2014 S. Karger AG, Basel.)

Background and Aims: The aim of this study was to assess the micronutrient status of children receiving prolonged enteral nutrition., Methods: This cross-sectional single-center study included all 64 children (median age 6.8 years) receiving enteral nutrition providing >50% of daily energy intake for more than 6 months (median duration of enteral nutrition 43 months). The characteristics of the patients and mode of enteral nutrition were recorded. The concentrations of iron, zinc, copper, selenium and vitamins A, D, E and C were measured in plasma., Results: Twelve children (19%) had iron deficiency. A high 25-hydroxyvitamin D concentration was recorded in 20% of the children, but none had associated hypercalcemia. Fifty-two children (81%) had low zinc concentrations in both plasma and erythrocytes. Plasma zinc, calcium, phosphorus and vitamin D concentrations were significantly lower in children receiving fiber supplementation. Abnormal micronutrient concentrations were found more frequently in the children receiving fiber supplementation. No other predisposing factors were associated with micronutrient deficiencies., Conclusion: Long-term enteral nutrition can lead to micronutrient deficiencies in children, whose micronutrient concentrations may require regular checking. Fiber supplementation might reduce the bioavailability of zinc, calcium, phosphorus and vitamin D., (Copyright © 2013 S. Karger AG, Basel.)

Zinc is one of the essential trace elements required by the human body as it is present in more than a hundred specific enzymes and serves as an important structural ion in transcription factors. Around one third of the world population lives in countries with a high prevalence of zinc deficiency. Food fortification with zinc seems to be an attractive public health strategy and a number of programs have been initiated, especially in developing countries. We conducted a systematic review to assess the efficacy of zinc fortification. A total of 11 studies with 771 participants were included in our analysis. Zinc fortification was associated with significant improvements in plasma zinc concentrations [standard mean difference (SMD) 1.28, 95% CI 0.56, 2.01] which is a functional indicator of zinc status. Significant improvement was observed for height velocity (SMD 0.52, 95% CI 0.01, 1.04); however, this finding was weak and based on a restricted analysis. Further subgroup analysis showed significant improvement in height velocity among very-low-birth-weight infants (SMD 0.70, 95% CI 0.02, 1.37), while for healthy newborns, the impact was insignificant. Zinc fortification had insignificant impacts on serum alkaline levels, serum copper levels, hemoglobin and weight gain. Although the findings highlight that zinc fortification is associated with an increased serum concentration of the micronutrient, overall evidence of the effectiveness of this approach is limited. Data on pregnant and lactating women is scarce. Large-scale fortification programs with robust impact assessment should be initiated to cover larger populations in all age groups. Mass fortification of zinc may be a cost-effective strategy to overcome zinc deficiency., (Copyright © 2013 S. Karger AG, Basel.)

Introduction: Many epidemiological and experimental studies report a strong role of chemical carcinogens in the etiology of bladder cancer. However, involvement of trace elements in the tumorigenesis of transitional cell carcinoma of the bladder has been poorly investigated. The aim of this study was to examine the relationship between zinc, copper and bladder cancer., Materials and Methods: Zinc and copper concentration and Cu/Zn ratio in two 36-sample series of bladder cancer tissue and sera from patients with this neoplasm were matched with those of the control group. The amount of trace elements in every tissue sample was determined using atomic absorption spectrometry. This was correlated with tumor stage., Results: While the copper concentrations reached statistically higher values in the bladder cancer tissue, the zinc levels in the sera and bladder tissue of the patients with this carcinoma were substantially lower as compared to those of the control group. The serum Cu/Zn ratio was significantly higher in the bladder cancer group and this increase was greater in the patients with muscle-invasive neoplasm., Conclusions: The results obtained suggest a relationship between trace elements and the bladder cancer., (Copyright © 2012 S. Karger AG, Basel.)

Gastrojejunal bypass surgery may be complicated by nutritional deficiencies, including trace elements. Copper, which is absorbed in the duodenum and proximal jejunum, is poorly absorbed when a significant portion of the proximal small intestine is bypassed. However, despite this theoretical risk of hypocupremia in the gastrojejunal bypass patient, reports of symptomatic copper deficiency are very rare, and even then the deficiency is often potentiated by an accelerant, such as concomitant zinc ingestion. We report a case of hypocupremia resulting in hematologic abnormalities and myeloneuropathy after gastrojejunal bypass surgery for morbid obesity. It stresses the importance of recognizing nutritional deficiencies, particularly copper deficiency, because of the possible and serious sequelae of bone marrow suppression and myeloneuropathy. The early recognition and treatment of the symptoms of hypocupremia is emphasized to avoid these long-term sequelae. With the rapidly growing number of patients undergoing gastrojejunal bypass surgery for morbid obesity, the index of suspicion for hypocupremia must be heightened., (Copyright © 2010 S. Karger AG, Basel.)

Objective: This study aimed to establish reference ranges of serum concentrations of copper, zinc, retinol, alpha-tocopherol, copper:caeruloplasmin and copper:zinc ratios in a group of healthy Omani men and women., Materials and Methods: Assay techniques employed were atomic absorption spectrophotometry (copper and zinc), reverse-phase high-pressure liquid chromatography with isocratic elution (retinol and alpha-tocopherol), immunonephelometry (caeruloplasmin) and spectrophotometry (albumin and cholesterol)., Results: The mean +/- SD (microM) obtained for copper, zinc, retinol, and alpha-tocopherol were 15.9 +/- 3.0, 14.2 +/- 2.0, 1.45 +/- 0.39 and 16.9 +/- 4.4, respectively. The mean +/- SD for copper:zinc and copper:caeruloplasmin ratios were 1.15 +/- 0.30 micromol/mmol and 6.99 +/- 0.84 micromol/g, respectively. Significantly higher (p < 0.0001) copper and caeruloplasmin concentrations, copper:zinc and copper:caeruloplasmin ratios and lower zinc, retinol, alpha-tocopherol, cholesterol concentrations and alpha-tocopherol:cholesterol ratio were present in women compared to men. Age appeared to be associated with copper and retinol concentrations, and copper:caeruloplasmin ratios in women; in men, the association was mostly moderate with caeruloplasmin, alpha-tocopherol, cholesterol concentrations and alpha-tocopherol:cholesterol ratios. Smokers had decreased albumin (p = 0.002), zinc (p = 0.023) concentrations, and copper:caeruloplasmin ratios (p = 0.002), increased alpha-tocopherol concentrations (p = 0.016) and alpha-tocopherol:cholesterol ratios (p = 0.021) compared with non-smokers. Deficiency incidence was < or =5% for all investigated parameters., Conclusions: Reference ranges of micronutrient concentrations and micromineral ratios were established for Omani subjects. The mean values of several micronutrients were lower than those reported for other populations and some showed gender effects., ((c) 2008 S. Karger AG, Basel)

Background: Metabolic syndrome is a clinical disorder that is becoming more prevalent in Spain. The syndrome encompasses a set of metabolic disorders such as type-2 diabetes mellitus, hypertension, dyslipidemia, and obesity, which may be associated with variations in serum levels and poor delivery of certain mineral elements., Methods: This study attempted to ascertain whether metabolic syndrome might be linked to alterations in serum levels of the mineral elements magnesium, copper, zinc, chromium, and nickel in a population of 92 diabetic subjects, some suffering from certain conditions associated with the metabolic syndrome, and 72 control subjects (Hospital Príncipe de Asturias, Alcalá de Henares, Spain)., Results: The results indicated that as a group the alterations implicated in metabolic syndrome were indeed associated with variations in blood levels of the mineral elements considered, though statistically significant differences were recorded only in the case of copper. Still, trends in mineral levels for each of the separate components contributing to the syndrome tended to increase., Conclusion: Metabolic complications appear to be associated with alterations in the levels of some minerals, especially copper., ((c) 2007 S. Karger AG, Basel.)

Aim: To assess the effects of dehydration, conventional in-bottle sterilization, and ultrahigh-temperature (UHT) sterilization, involved in the production of infant formulas, on the copper bioavailability in rats at two stages., Methods: Two-week-old suckling rats were fed a reconstituted powder (P1) and an in-bottle-sterilized liquid infant formula (SC1) in a drinking bottle for 7 days. Weanling rats were fed P1, SC1, another powder (P2), and a liquid UHT formula (UHT2) complemented with a standard rat diet. Intake, body weight, and percentage copper absorption were calculated, and whole-body, serum, liver, skin, and erythrocyte copper concentrations were determined., Results: Food intake, body weight, and copper intake were reduced in suckling rats consuming SC1, but the percentage copper absorption increased, and whole-body and tissue copper concentrations were unaffected, except for the erythrocyte copper concentration which was significantly higher as compared with pups fed P1. In weanling rats, the only difference observed was the significantly higher liver copper concentration in animals fed the diet containing P1 as compared with the diets containing SC1 and UHT2., Conclusions: Consuming the SC1 formula induced high erythrocyte copper levels in suckling rats, whereas the equivalent dehydrated formula (P1) induced elevated liver copper concentrations in weanling rats. This is associated with the different Maillard reaction products resulting from the processing of each infant formula and with the developmental stage of the animals.

Background: Myelodysplastic syndrome (MDS) is an iron overload condition. Copper deficiency itself might induce dysplastic changes and iron overload. The relationship between the iron and copper metabolism is analyzed in MDS patients., Methods: Copper, iron and ceruloplasmin levels were established, and transferrin saturation determination and HFE mutation analysis were performed in 32 MDS patients., Results: Eleven of 32 MDS patients were copper deficient. A decreased copper level occurred together with a significantly elevated iron level and transferrin saturation and in 45% HFE gene mutation. In the normal copper group, twice as many patients had a decreased rather than an elevated iron content and carried the wild-type HFE gene rather than the mutant., Conclusions: Copper deficiency is a frequent finding in MDS. It is desirable to include copper level determination in the initial workup of MDS., (Copyright 2006 S. Karger AG, Basel.)

Objective: Preclinical studies suggest antiangiogenesis strategies may be effective in the treatment of prostate cancer. In tumor models, the copper-chelating agent tetrathiomolybdate (TM) has been shown to be antiangiogenic. We evaluated the antitumor activity of TM in patients with hormone-refractory prostate cancer (HRPC)., Methods: Nineteen patients with asymptomatic HRPC enrolled. Copper depletion was monitored using serum ceruloplasmin levels. Once the target ceruloplasmin level of 5-15 mg/dl was attained, patients underwent staging evaluation. Patients were reassessed every 12 weeks, and TM was continued until they developed evidence of disease progression or intolerable toxicity. Prostate-specific antigen and levels of vascular endothelial growth factor, basic fibroblast growth factor, interleukin (IL)-6 and IL-8 were measured at study entry, at the time of copper depletion, and monthly while on therapy., Results: Seventeen of 19 patients achieved copper deficiency on TM therapy. Of the 16 evaluable patients, 14 developed progressive disease, 1 discontinued therapy because of toxicity and 1 patient opted to discontinue therapy because of rising prostate-specific antigen level without objective evidence of progressive disease. Levels of vascular endothelial growth factor, IL-6 and IL-8, but not basic fibroblast growth factor, were elevated when compared to normal controls prior to TM therapy, but there was no significant change during therapy. There was no correlation between prostate-specific antigen and levels of angiogenesis factors., Conclusions: Copper depletion with TM did not delay disease progression in patients with asymptomatic metastatic HRPC.

It has previously been reported that men with developmental stuttering showed reduced concentration of copper in the blood, and a negative correlation between the copper level and the severity of stuttering. Disorders of copper metabolism may result in dysfunction of the basal ganglia system and dystonia, a motor disorder sharing some traits of stuttering. It has been shown that copper ions affect the dopamine and the GABA systems. With this background we investigated the plasma level of copper, the copper binding protein ceruloplasmin, and the estimated level of free copper in stuttering adults. Sixteen men with developmental stuttering were compared with 16 men without speech problems. The samples were assayed in one batch in a pseudorandom and counterbalanced order. No significant differences were found between stuttering men and the control group in any of the biological variables, and no negative correlation between copper and the general severity of stuttering was shown. On the contrary, an explorative analysis resulted in a positive correlation between high plasma copper and superfluous muscular activity during stuttering (r=0.51, p=0.04). This result indicates that there is no relation between developmental stuttering and low plasma copper in the main population of stuttering adults., (Copyright (c) 2005 S. Karger AG, Basel.)

Background: Oxidative stress is one of the leading causes of cardiovascular morbidity and mortality in chronic kidney disease. Although it is clear that many metabolic abnormalities improve, the effects of kidney transplantation on oxidative state are obscure., Methods: Twenty-three kidney transplant patients were included in the study. Eleven patients (mean age 27.9+/- 9.1 years) were treated with cyclosporine A (CsA) whereas 12 patients (mean age 22.4 +/- 3.4 years) were treated with tacrolimus. Twenty-three healthy subjects served as controls. None of the patients or controls suffered from diabetes mellitus or an acute infection at the time of the study. Plasma malondialdehyde (MDA), plasma selenium (Se), erythrocyte glutathione peroxidase (GSH-Px), erythrocyte superoxide dismutase (SOD), erythrocyte Zn (EZn), and erythrocyte Cu (ECu) levels were studied before and in the 1st, 3rd, 7th, 14th and 28th days after the transplantation., Results: The GSH-Px, SOD, ECu, EZn and selenium levels were lower and MDA levels were higher in patients than controls before transplantation (p < 0.001 for all). MDA levels decreased and SOD, GSH-Px, ECu, EZn levels increased in parallel to the decrement of serum creatinine levels following the renal transplantation. No difference was found among the patients regarding the treatment regime., Conclusion: The study data suggest that the improvement in oxidative state parameters begins at the first day of renal transplantation and continues at the 28th posttransplant day in living donor transplantations.

The present study sought to determine whether supplementation of dietary antioxidant ascorbic acid with glutathione (GSH) could ameliorate the age-related increased oxidative stress and changes in hormonal, lipid and copper (Cu) as well as zinc (Zn) levels in 18-month-old rats. The present study demonstrated that supplementation of vitamin C (30 mg) + GSH 100 mg/kg b.w. significantly reduced the concentration of thiobarbituric acid-reactive substances in liver and testes in old male rats as compared with nonsupplemented ones, indicating lower oxidative stress. In addition, testicular GSH was increased but not hepatic GSH. Also, cholesterol and triglycerides were decreased in the serum of supplemented rats. Furthermore, she serum testosterone level was increased in the same supplemented rats. However, the present results show that the thyroid hormones, T3 and T4, were not influenced. Lastly, the concentration of Cu in serum, liver, brain and testes was increased in supplemented old rats. Zn concentration was also increased in the same organs but not in the liver. According to the present study, the supplementation of antioxidants could play an important role in the modulation of the oxidative damage and changes associated with age., (Copyright 2002 S. Karger AG, Basel)

As heavy metal ions may be implicated in the formation of senile plaques in Alzheimer-afflicted brains, treatment with clioquinol was tested in 20 patients with Alzheimer's disease. Clioquinol is a chelator that crosses the blood-brain barrier and has greater affinity for zinc and copper ions than for calcium and magnesium ions. Treatment was given for 21 days at doses of 20 mg/day to 10 patients and 80 mg/day to another 10 patients. The study was blind to the dosages but included no controls. Cerebrospinal fluid (CSF) investigations revealed a significant increase at day 7 and a decrease at day 21 in Tau protein and growth-associated protein (GAP43). These proteins are increased in Alzheimer's disease and considered as rather stable markers. The initial increase may indicate a temporary cytotoxicity to the brain and/or an increased release into the CSF from stores in the tissue, possibly from senile plaques where the proteins are accumulated. The levels of CSF-Tau protein correlated positively and significantly with the serum levels of copper and also with the serum copper/zinc ratio. Clinical ratings showed slight improvement after 3 weeks treatment with clioquinol in this open study., (Copyright 2001 S. Karger AG, Basel)

Background/aims: The aim of this study was to examine the relationship between the degree of urinary copper excretion and stages of diabetic nephropathy., Methods: Copper, ceruloplasmin and albumin concentrations were measured in serum and urine samples from 41 type 2 diabetic outpatients with different stages of nephropathy and from 10 healthy controls. The copper/albumin and copper/ceruloplasmin ratios in serum and urine were determined. Furthermore, we examined whether free copper ions are dissociated from ceruloplasmin under various pH conditions., Results: Urinary copper concentrations significantly increased only in macroalbuminuric patients. The copper/ceruloplasmin and copper/albumin ratios in urine were consistently greater than those in serum which were not different between patients and healthy controls except the copper/albumin ratio in macroalbuminuric patients. The ratios in urine decreased in parallel with the progression of nephropathy. Copper was found to be released from ceruloplasmin under acidic conditions., Conclusion: Urinary copper excretion in healthy controls may be the result of dissociation from the albumin-copper complex of serum during its passage through the kidney. In diabetic patients with advanced nephropathy, urinary copper excretion may be due to dissociations from both copper-albumin and ceruloplasmin-copper complexes filtered through the damaged glomerulus. Overloading of urinary copper to damaged renal tubules may play some roles in the progression of nephropathy in patients with advanced nephropathy., (Copyright 2001 S. Karger AG, Basel.)

The aims of this study were to examine the late components of the auditory event-related potentials (AERPs), i.e. N(100), P(200) and P(300), in recently detoxified alcohol-dependent patients compared to normal controls and to investigate whether there is a relationship between alterations in these AERPs and signs of activation of the inflammatory response system (IRS). The study subjects consisted of 14 healthy volunteers and 14 recently detoxified alcohol-dependent patients. All subjects performed a two-tone auditory discrimination task, using a standard "oddball" paradigm. The alcohol-dependent patients had their blood sampled to examine IRS markers, such as erythrocyte sedimentation rate (ESR), serum copper concentrations and the number of leukocytes. The P(300) latency was significantly greater in recently detoxified alcohol-dependent patients than in normal controls. There were significant correlations between the P(300) latency and the ESR (r = 0.84, p = 0.009), serum copper concentrations (r = 0.73, p = 0.01) and number of monocytes (r = 0.71, p = 0.006). It is concluded that the P(300) latency is prolonged in detoxified, chronic alcohol-dependent patients and is positively related to indicators of IRS activation. It is hypothesized that activation of the IRS may play a role in the delayed P(300) latency in recently detoxified, alcohol-dependent patients., (Copyright 2001 S. Karger AG, Basel)

Increased free-radical production leading to oxidative stress may contribute to the development of cardiovascular complications in haemodialysis patients. The ferroxidase activity of caeruloplasmin forms an important component of antioxidant defences in body fluids. The aim of this study was to assess ferroxidase activity in haemodialysis patients. Venous blood was collected from 83 haemodialysis patients immediately prior to and after dialysis and from 52 healthy controls. Immunoreactive caeruloplasmin was measured by rate nephelometry, and ferroxidase activity determined by measuring loading of ferrous iron onto iron-free transferrin. A significant reduction in ferroxidase activity was observed in dialysis patients when compared with controls (37 +/- 1.20 and 46 +/- 1.14 mU/l, respectively; p < 0.001). Following dialysis, ferroxidase activity rose significantly to 41 +/- 1.16 mU/l, with a significant difference still remaining between control and patient ferroxidase activity (p < 0.005). Immunoreactive caeruloplasmin was found to be similar in all groups (before dialysis 0.40 +/- 0.07 g/l, after dialysis 0.39 +/- 0.07 g/l, control 0.42 +/- 0.09 g/l: p = NS). A significant difference in caeruloplasmin-specific activity was therefore observed between predialysis, postdialysis and control samples (97 +/- 2.31, 105 +/- 1.74 and 112 +/- 1.51 mU/g; p < 0.001, p < 0.01, respectively). Ferroxidase activity of caeruloplasmin is impaired in renal failure. Inhibition of caeruloplasmin ferroxidase activity in dialysis patients may contribute to increased oxidative stress in these patients., (Copyright 2000 S. Karger AG, Basel)

Copper concentration in blood plasma is used mainly as an indicator for alimentary copper supply. This has some limitations because copper concentration in plasma fluctuates with age, exercise and health status and does not increase after a meal nor decrease during short-term fasting. The Austrian Study on Nutritional Status (ASNS) provides data on nutrient intake and corresponding plasma concentrations, permitting to evaluate the suitability of copper plasma concentration as a marker of copper intake. Copper intake and intake of relevant nutrients and food groups were evaluated from 7-day weighed food records from 2,400 preschool and schoolchildren between 4 and 19 years of age. Blood samples were collected from a subgroup of 1,400 of these children. The copper concentration in plasma was measured by graphite furnace atomic absorption spectrometry. Correlations between plasma concentrations and intake of nutrients and food groups were calculated using a stepwise linear regression model. The results showed that the determination of copper plasma concentrations are inadequate to predict copper intake from dietary records. A better indicator for copper supply may be the evaluation of those food items, which are the predominant sources of copper intake at the population level. The highest influence on copper plasma concentration was found for the intake of meat, representing not only the most important food group for copper supply but also the most important food group for fat and protein supply. The individual copper status can only be estimated accurately when information on characteristic enzyme activities under control of additional factors of influence or even body stores of copper are available., (Copyright 2000 S. Karger AG, Basel)

Caffeine consumption has been implicated in the development of cardiovascular disease. Therefore, in the present study, litters of rats were combined upon birth, and 8 pups were randomly assigned to each dam. Dams with pups were divided into 2 groups: group 1 received a 20% protein diet as a control, and group 2 received the 20% protein diet supplemented with caffeine (4 mg/100 g body weight). Pups from both groups were killed on days 11 and 15. Transmission electron microscopy revealed swollen, disrupted, degenerating mitochondria and intracellular edema in the hearts of rats in the caffeine groups when compared with those of the controls. Plasma Cu concentration was significantly decreased. These results indicate that early exposure to caffeine through maternal milk adversely affects cardiac mitochondria of rat pups and may be associated with decreased plasma Cu levels. It is unclear whether these results apply to the human infant. Interspecies extrapolation from rat to human must be made with caution.

The copper-containing enzyme superoxide dismutase (SOD) is a key enzyme in suppressing the amounts of superoxide anion radicals. Ceruloplasmin, the copper-transporting protein in plasma, also possesses an important redox capacity. In this study the levels of copper and ceruloplasmin as well as SOD-activity and ceruloplasmin oxidative activity were analyzed in order to throw some light on possible defects in copper mechanisms in patients diagnosed with Alzheimer's disease (AD). The study included 44 patients with AD and their healthy age- and gender-matched controls. No difference of significance was seen when comparing the copper or ceruloplasmin concentration in plasma of AD patients to that of their paired controls. The SOD activity in red blood cells was significantly lower in the patients than in their controls (p = 0.019). The ceruloplasmin oxidative activity in plasma of Alzheimer's patients was greatly reduced as compared to that of age- and gender-matched controls and the difference was highly significant (p = 0.0005). Ceruloplasmin activity and SOD activity were not found to be intrinsically correlated. It was postulated that reduced oxidative activity of ceruloplasmin in plasma might be either a cause or a consequence of AD and that reduced SOD activity might further add to the oxidative disturbances in AD due to defective ceruloplasmin activity.

A 56-year-old Japanese man was diagnosed as having hereditary ceruloplasmin deficiency. His ceruloplasmin concentration was below the lower limit of detection. Serum copper and iron concentrations were below normal, but the ferritin concentration was highly elevated. An ophthalmoscopic examination showed retinal degeneration with yellowish discoloration of the fundus in both eyes. Fluorescein angiography demonstrated a dark choroid in the posterior pole. Geographic areas of window defects were seen in the midperipheral fundus. The retinal degeneration in this patient was thought to be caused by the cellular iron deposition that occurred as a result of ceruloplasmin deficiency.

Trace elements constitute important prosthetic groups in a number of antioxidant enzymes which neutralize free radicals generated during inflammatory conditions such as colitis. However, the status of trace elements in colitis remains to be found. In the present study the concentrations of zinc, copper, manganese and selenium in the colon, liver and serum of rats with acetic acid (HAc)- or trinitrobenzenesulfonic acid (TNBS)-induced colitis were measured using atomic absorption spectrophotometer. Myeloperoxidase and glutathione peroxidase activities were measured spectrophotometrically. Our results show that the selenium concentration was significantly decreased by 33 and 37.5% in the colon and 69 and 78% in liver by HAc and TNBS treatment, respectively. Similarly the zinc concentration in the colon was decreased by 21 and 28% by HAc- and TNBS-induced colitis as compared to the controls, but manganese and copper, remained unaltered. The serum concentrations of copper, zinc and selenium also remained unaltered during colitis. The weight of HAc-treated rats did not decrease while there was a significant weight loss in the TNBS-treated rats. Myeloperoxidase activity was increased, whereas glutathione peroxidase activity was significantly decreased in the colon inflamed by HAc or TNBS as compared to the controls. These findings suggest that colitis induces a reduction in the tissue levels of trace elements which is independent of the way colitis is induced. Our findings of a reduction in Se and glutathione peroxidase activity together suggest that the reduction in the trace element concentrations is not due to dietary factors or malabsorption. The decrease may severely affect the antioxidant potential of the colon and therefore is a putative factor for the progression of disease.

In Morocco, malnutrition is a public health problem. Indeed, 25% of 6- to 60-month-old children suffer from malnutrition. Imbalance between antioxidant protection and prooxidant stress has been reported to accurately predict the survival of malnourished children. Therefore, we determined blood antioxidant vitamins (retinol, alpha-tocopherol and carotenoids), trace elements (serum zinc, copper and selenium) and enzymes (erythrocyte Se glutathione peroxydase and Cu-Zn superoxide dismutase) as well as blood oxidative stress index [ferritine, thiobarbituric-acid reactants (TBARS)] in 21 children suffering from severe malnutrition, 15 children suffering from mild malnutrition and in 20 healthy control children. Selenium, retionol, alpha-tocopherol and carotenoids were significantly decreased in malnourished children. These decreases were related to the severity of malnutrition. Moreover, the percentage of vitamin and trace element concentrations under deficient cutoff were high in malnourished children. On the contrary, TBARS, ferritin and prognostic inflammatory and nutritional index (PINI) were significantly increased in malnourished children. Except for TBARS, these increases were related to the severity of malnutrition. On the other hand, blood retional, alpha-tocopherol, beta-carotene and selenium were negatively related to alpha 1-acid glycoprotein. Blood beta-cryptoxanthin, lycopene, carotenes and copper were positively related to weight. Finally, blood lutein/zeaxanthin and copper were positively related to height. These results confirm the imbalance between antioxidant protective factors and oxidative stress index in malnourished children. Moreover, the decrease in antioxidant protective factors is related to inflammation or stature. These results suggest that antioxidant micronutrient supplementation of the refeeding diet could be required in the nutritional rehabilitation of malnourished children.

The aim of our study was to examine the influence of tea decoction given ad libitum for 15 days on body weight gains and on nonheme iron, copper, zinc and magnesium concentrations in the blood from a semisynthetic diet provided to healthy rats. We have also evaluated the reserves of these essential minerals in the liver, duodenum and spleen. Our findings indicate that the tea decoction significantly reduced the total body weight growth in the tea group as compared to the control group (p < 0.0001). The total body weight gains for the control and tea groups were 13.2 and 2.4%, respectively. On the other hand, our data show that the tea decoction significantly reduced nonheme iron concentration in the total blood by 31.8% (p < 0.001). Similarly, the reserve of iron stored in the liver and the duodenum declined more significantly by 57% (p < 1.10(-7) and 50.5% (p < 1.10(-6)). respectively. In contrast to the inhibitory effect on iron concentration and its stored reserve, tea decoction significantly increased zinc, copper and magnesium concentrations in the total blood. Zinc, copper and magnesium concentrations increased by 29.4 (p < 0.05), 69.0 (p < 0.001) and 48.7% (p < 0.001), respectively. Moreover, tea decoction treatment did not raise the reserve of zinc or copper significantly but it increased the reserve of magnesium stored in the liver (p < 0.05).

Beginning on the day of delivery and until the 15th or 22nd day of lactation, one group of dams received a 20% protein diet as a basal diet and one group received the basal diet supplemented with caffeine (4 mg/100 g body weight). A correlation between caffeine concentrations in the dams' plasma and milk was observed. In the caffeine group, levels of Fe and Cu in the dams' mammary glands at day 22 were decreased. Copper levels in the milk at day 15 and Fe and Zn levels in the milk at day 22 showed a significant decrease. Copper concentration in the plasma of 15-day-old pups showed a significant decrease also, but Zn and Fe concentration showed no difference between caffeine and noncaffeine control groups. The present study shows that the dams' consumption of a caffeine-containing diet influences trace elements of mammary glands, milk, and pups' plasma.

A comparison of the effects of the trace element cobalt and the protoporphyrin chelate of this metal, cobalt-protoporphyrin, on copper and zinc metabolism in male Sprague-Dawley rats was made. Following subcutaneous treatment (250 mumol/kg body weight), inorganic cobalt elicited only a moderate (25-30%) and transient (48 h) increase in plasma copper levels and a concomitant elevation (up to 2-fold) in ceruloplasmin (ferroxidase) activity. Treatment with cobalt-protoporphyrin (25 mumol/kg), however, produced substantial (2- to 3-fold) and prolonged (up to 4 weeks) increases in plasma copper levels and ceruloplasmin. This effect on ceruloplasmin was specific to cobalt-protoporphyrin, since equimolar doses (25 mumol/kg body weight) of both tin-protoporphyrin and iron-protoporphyrin did not produce changes in the levels of circulating ceruloplasmin. Both inorganic cobalt and cobalt-protoporphyrin produced an elevation in liver cytosolic zinc levels at 48 h. This zinc associated with a fraction that coelutes with authentic metallothionein standard. These differential effects of inorganic cobalt and cobalt-protoporphyrin on copper and zinc metabolism represent newly defined biological properties of this trace element and point to the importance of chemical speciation as an underlying factor in the ultimate biological actions of metals.

Dietary modifications can partly compensate for the alterations in copper homeostasis caused by distal intestinal resection, by improving biliary function. We studied the effects of resecting 50% of the distal small intestine (DSI) on copper status in rats fed three semisynthetic diets (basal diet, and basal diet with cholecalciferol or ascorbic acid). Intestinal resection significantly decreased the digestive (apparent digestibility coefficient; ADC) and metabolic utilization (balance) of copper 1 month after surgery. However, the supplementation of the basal diet with cholecalciferol attenuated the negative impact of surgery, leading to small differences in Cu ADC and Cu balance between transected and resected rats. Ascorbic acid also enhanced copper retention. Copper status was not as markedly affected by intestinal resection as digestive utilization 1 month after the operation. The beneficial effects of cholecalciferol and ascorbic acid at the digestive and metabolic levels suggest ways to lessen the impact of intestinal resection, and to avoid possible long-term postabsorptive alterations in copper distribution.

Apparently healthy elderly donors were screened according to a simple protocol that included clinical examination and the determination of hematological and biochemical values. This screening was performed to detect subclinical alterations which might interfere with immune responses and trace element status. The elderly were divided into two groups. The first group consisted of 22 (age 76 +/- 1 years) positively selected elderly (PSE), i.e. healthy subjects with no hematological and laboratory alterations, the second one comprised 13 (age 75 +/- 1 years) negatively selected elderly (NSE). Data were then compared with those obtained from 40 (age 35 +/- 2 years) healthy young controls. In both groups of elderly donors, plasma zinc levels were normal, while plasma copper concentrations were increased. Intracellular values of zinc and copper in mono- and polymorphonuclear cells from both groups of elderly were within reference limits. After in vitro activation, granulocyte chemiluminescence activity was impaired only in NSE. A decrement in the number of circulating CD3 lymphocytes and an increase in CD8d, CD57 cells were found in PSE, while NSE showed an increased number of CD3,DR cells and CD8d, CD57, CD8b,CD57 and CD16,CD56 positive cells. Our results indicate that only plasma copper levels were affected by age, whereas subclinical alterations in hematological or biochemical values appear to impair immune responses in the elderly.

Selected vitamin (A, C, E, beta-carotene) and trace element (selenium, zinc, copper) levels were estimated in the blood of 67 vegetarian nonsmokers aged 34-60 years. The average period of lacto- or lacto-ovovegetarianism was 6.2 years. The results were compared with those of 75 nonvegetarians of the same age and living in the same region. Vegetarians had significantly higher plasma levels of essential antioxidants: vitamin C, beta-carotene, and vitamin A. A significantly higher molar ratio vitamin E/cholesterol indicates a more effective protection especially of low-density lipoproteins against peroxidation. Oxidation of low-density lipoproteins represents one of the key factors in the pathogenesis of atherosclerosis. The molar ratio vitamin E/total lipids was significantly higher in plasma of vegetarians, demonstrating a more effective protection of polyunsaturated fatty acids against peroxidation. Vegetarians had significantly higher plasma levels of selenium and similar levels of zinc and copper when compared to nonvegetarians. These trace elements are important for the activity of antioxidant enzymes. The results document a beneficial effect of vegetarian nutritional habits on antioxidative parameters and thus on the reduction of cardiovascular diseases and cancer risk. Reactive products of oxygen metabolism and subsequent toxic products of lipid peroxidation play an important role in the etiology of these diseases.

Six antineutrophil antibody (ANA)-positive patients with copper deficiency were classified into two groups; those with (group A, n = 3) and those without (group B, n = 3) neutropenia. The percent binding of ANA for normal peripheral neutrophils was similar in both groups (83.5 +/- 7.2 vs. 79.1 +/- 10.5%). The percent binding of sera to cultured promyelocytic leukemia cells (HL-60) was increased in group A (from 3.7 +/- 3.2 to 12.2 +/- 2.3%) but not in group B (from 65.3 +/- 21.7 to 40.7 +/- 6.3%) after stimulation of HL-60 with DMSO. The stimulated HL-60 cells expressed CD 16 and CD 11b antigens. In the presence of monoclonal antibody for CD 16, the titer of ANA was nil in group A and unchanged in group B. Thus, ANA of patients with neutropenia may recognize mainly the CD 16 antigen, the Fc gamma receptor III of neutrophils.

Young mice were found to have serum copper concentrations ranging from a low of 0.291 to a high of 0.584 ppm. Old mice had serum copper concentrations ranging from 0.223 to 1.715 with 30.9% of the old animals having values greater than 0.6 ppm. The mitogen response of isolated lymphocytes from the spleens of aging mice was greatly reduced when these cells were taken from animals with naturally occurring serum copper levels in excess of 0.6 ng of copper/mg wet weight serum. The lymphocytes taken from young mice with higher serum copper concentrations, on the other hand, had increased response to mitogens. Addition of the copper protein, ceruloplasmin, to lymphocyte cultures in vitro reduced the mitogen response of purified splenic lymphocytes with the reduction being greater for cells from old animals. We suggest that excess serum copper and ceruloplasmin may be immunosuppressive, especially in older organisms.

Trace element concentrations in serum and breast milk were studied longitudinally in 197 Nigerian women from 6 months of gestation to 6 months postpartum; 99 of them received a daily iron supplement of 100 mg from 6 months of gestation to delivery. During the last 3 months of pregnancy, serum selenium declined, whereas serum zinc remained unchanged and serum copper increased. After delivery, copper concentration in maternal serum decreased, whereas serum zinc increased from delivery to 3 months postpartum and then reached a plateau. Serum selenium increased from delivery to 6 months postpartum. In breast milk, selenium and zinc decreased from 5 days to 6 months postpartum. Copper in breast milk also declined during the course of lactation but reached a plateau by 3 months postpartum. Iron concentration in breast milk remained unchanged during the study. Iron supplementation had no significant effect upon the concentrations of copper, selenium and zinc in mother serum and breast milk. In umbilical serum, iron status, copper and zinc levels were similar in the two groups, whereas, unexpectedly, selenium concentration was significantly decreased (p < 0.03) in the iron-supplemented group. Taken together, our results suggest that the beneficial effect of iron supplementation on iron deficiency was not associated with an adverse effect on copper and zinc status. On the other hand, our results suggest that Nigerian women had a marginal zinc status but an adequate selenium status.

An experimental model has been developed to investigate the effect of copper deficiency on lung maturity in the newborn rat. Three groups of female Sprague-Dawley rats were used: the copper-deficient group was fed with a copper-free diet; the control group received a copper-adequate diet, and the pair-fed group was fed with a limited copper diet. After gestation and delivery, 35% of the newborn copper-deficient group showed respiratory distress syndrome (RDS). The neonatal lungs were isolated and processed for ultrastructural and biochemical study: A greater thickness of the air-blood barrier was observed in the lungs of the copper-deficient group, however, no other differences were observed in the rest of the pulmonary structures. Quantitative differences in pulmonary surfactant were not found in the three groups. The thickness of the air-blood barrier might explain the RDS observed in the copper-deficient newborns.

The association of copper and zinc to plasma ligands was studied during the rat perinatal period. Analysis was carried out by means of column chromatography (Sephadex G-150) and atomic absorption spectrophotometry. Levels of copper were low at birth and showed a sharp increase after day 10. This increase was similar to that of ceruloplasmin activity as well as its association with copper. Zinc levels, instead, showed higher levels before birth and decreased slowly toward the adult values. Association of zinc to albumin and associated proteins showed a pattern similar to the decrease in plasma zinc levels.

Several studies have shown that plasma/serum copper and ceruloplasmin concentrations are increased in various carcinomas. We determined serum concentrations of ceruloplasmin and plasma copper concentration to evaluate the clinical usefulness of these tests in patients with cervical carcinomas. There was a significantly higher ceruloplasmin concentration in patients with cervical carcinoma compared to healthy controls. Plasma concentrations of copper were not significantly different in the two groups of subjects. The copper to ceruloplasmin ratio was lower in cancer patients than in control subjects. There was a significant increase in the serum concentrations of ceruloplasmin with increasing FIGO stage of cancer. Copper concentration in advanced tumours (FIGO stage 3) were significantly higher compared to control subjects or FIGO 1 and 2. Copper to ceruloplasmin ratio was lower in FIGO stage 2 and 3 patients compared to stage 1 or control subjects. Ceruloplasmin can also discriminate between large tumours which are inoperable and early cervical carcinomas better than copper or copper to ceruloplasmin ratio.

Wilson's disease is an autosomal recessive disorder characterized by an accumulation of a toxic amount of copper in the body. Triethylene tetramine dihydrochloride (trientine, 2HCl) is a new chelating agent that may be effective in the removal of excess copper but long-term efficacy has not yet been investigated. Here we report the use of trientine over more than 8 years in 2 patients with Wilson's disease who could not tolerate D-penicillamine. We found no significant side effect, except a decreased serum iron concentration without clinical symptoms of anemia. In annual examinations at a steady state, the serum copper levels remained below 20 micrograms/100 ml. The 24-hour urinary copper excretion was less than that found using D-penicillamine, while the basal copper excretion, after 5 days abstinence from trientine, was maintained below 100 micrograms/day. Both hepatic and neurological manifestations except bulbar symptoms were recovered without any initial deterioration.

We present a patient who developed severe anemia and neutropenia after receiving parenteral nutrition for 2.5 years. The serum levels of copper and ceruloplasmin were low, and the bone marrow showed the presence of ringed sideroblasts and vacuolated immature cells. The administration of copper chloride by bolus injection led to a rapid improvement in anemia and neutropenia. The number of progenitor cells (colony-forming unit-granulocyte-macrophage and erythrocyte) present before the copper supplementation was well preserved. It is therefore suggested that copper enzymes play an important role in the maturation of hematopoietic cells.

An experimental model using rats is described, in which a state of copper deficiency was produced in pregnant dams and their offspring. In 100% of the neonates from the copper-deficient group (10/10), 20% (2/10) from the control group, and 40% (4/10) from the pair-fed group, the ductus arteriosus was found to remain patent. These figures were highly significant in statistical terms (X2 test; p less than 0.0009). The possible physiopathology of the persistence of the ductus arteriosus in copper-deficient neonates is discussed.

Plasma selenium (Se), zinc (Zn) and copper (Cu) levels and antioxidant metalloenzymes, glutathione peroxidase (GPX) and superoxide dismutase (SOD), were studied in 17 patients on maintenance hemodialysis (HD) (group I), 14 uremic patients (group II) and 14 healthy subjects (group III). Plasma Se levels and erythrocyte GPX were significantly lower in the HD group (for Se: 0.69 +/- 0.12 vs. 1.05 +/- 0.13 mumol/l in controls; for erythrocyte GPX: 34.4 +/- 6.4 vs. 49.2 +/- 9 IU/g hemoglobin in controls) and a significant correlation was found between the two parameters (r = 0.66, p less than 0.005). There was also a correlation between decreased plasma Zn and erythrocyte SOD activity (r = 0.58, p less than 0.02) and between decreased plasma Cu and erythrocyte SOD (r = 0.60, p less than 0.02). Plasma malondialdehyde levels were augmented in HD patients (5.08 +/- 0.26 vs. 2.55 +/- 0.15 mumol/l in controls and 2.79 +/- 0.40 mumol/l in the uremic group). The catalase activity was increased in HD patients (202 +/- 24 vs. 140 +/- 40 IU/mg hemoglobin in group III). A defective antioxidant activity may thus contribute to increased peroxidative damage to cells in the course of dialysis.

This study was designed to examine the teratogenic potential of copper releasing intrauterine contraceptive devices on the developing embryo. The tissues and organs of 11 whole embryos between 7 and 12 weeks of gestation were histologically examined for copper absorption after exposure to a copper intrauterine device in utero. The findings were not significantly different when compared with a control group of 7 embryos. No malformation or copper aggregates were observed in the various organs and placentas. The observations in this small sample would suggest that the copper-releasing intrauterine device has no deleterious effects on fetal development. The question remains whether malformations reported in some cases are associated with copper deposits in the tissues or with free copper ions in the fetal circulation. The implications are discussed.

Weanling male rats were fed a purified iron-adequate, a purified iron-deficient or a commercial diet for 12 weeks. At that time the rats were sacrificed, their hearts and livers were excised, and blood samples were taken. Heart and liver weights were recorded; organ tissue and serum samples were analyzed for Zn, Cu and Fe. Hemoglobin and hematocrit values were also obtained. The iron-deficient rats grew much more slowly than controls on the iron-adequate or commercial diets. The iron-deficient rats were severely anemic and had enlarged hearts (cardiomegaly). A histopathologic examination of the hearts of all animals showed that each heart of the iron-deficient rats had lesions characteristic of cardiomyopathy by dilatation, whereas none of the hearts of the iron-adequate group or the chow controls showed any lesions at all. The iron-deficient animals had only about 25% of the hepatic iron found in the iron-adequate animals but about 5 times the hepatic copper of the latter group or the chow controls. Heart iron of the iron-deficient group was 27% of the concentration found in hearts of the iron-adequate rats; heart copper was similar in all groups. Animals on the commercial stock diet accumulated significantly more iron in their hearts than did those on the purified iron-adequate diet but not in the livers. There was also a direct correlation of heart iron or heart zinc with log concentrations of dietary iron and consequently a direct correlation between heart iron and zinc concentrations.

The effects of metoclopramide (MCP) and bromocriptine (BC) on the growth of neuroblastoma (NB) cells and their influence on the plasma membrane binding of several neurotransmitters were studied. In the first part of this study, in vitro experiments were done with three human and two murine NB cell lines. Dibutyryl cyclic 3',5'-adenosine monophosphate is known to differentiate NB cells in vitro and served as a reference substance during the experiments. MCP significantly reduced the replication rate in NB cells and increased cellular differentiation by morphological as well as by functional criteria. BC, in contrast, stimulated cell replication. Similar to dibutyryl cyclic 3',5'-adenosine monophosphate, MCP increased the binding capacity of the plasma membrane for the beta-adrenergic hormones dopamine and noradrenaline. In the second part, the effects of BC and MCP upon NB tumor growth were investigated in vivo in the mouse. Significant changes in tumor growth were induced; BC promoted and MCP inhibited the NB tumor growth in a dose-dependent relationship. The findings are discussed, along with the observed accompanying changes in serum copper and in the peripheral blood count.

Maternal and cord serum calcium, copper, iron and zinc concentrations were analyzed in 20 women with a postdate pregnancy. The control group consisted of 20 parturients with delivery at term and their newborns. Serum free estriol (E3) was also determined. Maternal serum copper, zinc and E3 were statistically significantly lower, while cord serum copper and fetomaternal ratio of zinc were significantly higher in the study group than in the control group. Further, a positive correlation between E3 and maternal serum copper level (r = 0.63) was found.

Maternal and cord blood samples were collected in 60 cases with or without rupture of membranes before and at term. Serum concentrations of calcium, copper, iron and zinc were determined by proton-induced X-ray emission. Maternal and cord serum ceruloplasmin and maternal hemoglobin were also determined. Mothers with preterm delivery showed significantly lower hemoglobin values than those with delivery at term. Concentrations of calcium, iron and zinc were higher in cord than in maternal serum whereas maternal copper levels were higher than respective cord levels in all groups. The cord copper and ceruloplasmin and also their fetal/maternal ratios were significantly lower in the group with preterm premature rupture of fetal membranes (PROM) than in other groups. Maternal serum zinc and calcium were lower in preterm groups than in term groups. The study suggests a possible role of copper in preterm PROM and of zinc in the initiation of preterm labor, whereas calcium and iron do not seem to be involved in the etiology of prematurity or PROM.

The levels of copper, zinc, calcium, manganese and magnesium have been monitored in the sera of patients suffering from various types of cancer. Only serum copper appeared to be of any diagnostic significance, its levels being above the normal reported range in the breast cancer, leukaemia and Hodgkin's lymphoma patients. In the case of breast cancer, serum copper is progressively elevated according to the stage of the disease. Serum calcium levels were also significantly lower in patients with tumours of the breast, gastrointestinal tract and cervix. The results suggest that serum copper levels could be of prognostic significance in breast cancer patients receiving radiotherapy.