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This study aimed (1) to assess serum trace elements concentrations and hematological parameters, (2) to evaluate the sex differences in the associations between serum trace elements levels and hematological parameters, and (3) to identify the associations between serum trace elements concentrations and risk of anemia among Japanese community dwellers. This is a community-based cross-sectional study that utilized the data of the 2014 Iwaki Health Promotion Project. Participants were 1176 community dwellers (>18 years) residing in the Iwaki District, Aomori Prefecture, Japan. We assessed the data of serum trace elements concentrations of cadmium (Cd), cobalt (Co), copper (Cu), selenium (Se), zinc (Zn), and iron (Fe) as well as the hematological parameters of red blood cells (RBC) counts, hemoglobin, packed cells volume (PCV), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH). Serum concentrations of Zn (871.5 μg/L vs. 900.1 μg/L) and Fe (946.8 μg/L vs. 1096.1 μg/L) were significantly lower in females than in males, while serum concentrations of Co (0.4 μg/L vs. 0.3 μg/L) and Cu (1062.4 μg/L vs. 965.3 μg/L) were significantly higher in females. By multivariate linear regression, serum Se concentration was significantly, positively associated with PCV (β = 1.04; 95% confidence interval (CI): 0.17, 1.92; p = 0.016) among the study participants. Serum Zn also had positive associations with hemoglobin (β = 0.42; 95% CI: 0.07, 0.77; p = 0.020), PCV (β = 1.79; 95% CI: 0.78, 2.81; p < 0.001), and RBCs count (β = 15.56; 95% CI: 7.31, 31.69; p = 0.002). On the other hand, serum Co concentration was negatively associated with the hematological parameters, particularly in females. Moreover, serum Zn concentration had a decreased risk of anemia (lowest vs. highest quartiles: odds ratio (OR) = 0.42; 95% CI: 0.23, 0.76; p = 0.005) while higher Co concentrations had an increased risk of anemia (lowest vs. highest quartiles: OR = 1.95; 95% CI: 1.04, 3.67; p = 0.037). However, no significant association was found between serum Cu level and hematological parameters. There were substantial sex differences in serum trace elements, implying that trace elements metabolism differed between males and females. Zn can play a protective role in the development of anemia. Surprisingly, increased Co concentration increased the risk of anemia among our study population, which called for further studies to confirm and to consider for speciation analysis.

Background: Cortical gray matter (GM) and white matter (WM) deterioration are signals of neurodegeneration and increased dementia risk; however, their specific etiologies in dementia-free aging is unclear., Objective: The objective of this study was to examine potentially modifiable risk factors of GM and WM degeneration in a well-characterized cohort of dementia-free elderly., Methods: 96 Okinawan elderly participants (age 83.6) from the Keys to Optimal Cognitive Aging Project (KOCOA) underwent MRI and cognitive evaluation. Serum markers of inflammation (interleukin-6 (IL-6), high sensitivity C-reactive protein), cerebrovascular disease (systolic blood pressure (SBP) 140+, hemoglobin A1C (HgbA1C), total cholesterol), and essential minerals (copper (Cu), magnesium, and calcium) were examined in relation to mean cortical thickness (MCT) and white matter hyperintensities (WMH), adjusting for age and gender. Voxel-based morphometry (VBM) analyses identified relationships between regional GM density and the above markers., Results: Decreased MCT was associated with SBP 140 + (p = 0.029) and increased serum IL-6 (p = 0.036), HgbA1C (p = 0.002), and Cu (p = 0.025). In VBM analyses, increased IL-6, HgbA1C, and Cu were associated with decreased GM density in temporal lobe regions. HgbA1C (p = 0.004) was associated with greater WMH volume., Conclusions: Peripheral markers of Cu, CVD risk, and inflammation are associated with MRI-markers of decreased brain health in dementia-free Okinawan elderly, with regional cortical thinning in areas involved in early accumulation of Alzheimer's disease pathology. Results identify potentially modifiable biomarkers as targets in the prevention of dementia in older individuals.

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.)

Background: Transthyretin (TTR), a sensitive indicator of malnutrition and inflammation, has been shown to be associated with mortality in elderly population., Methods: We examined relationships between serum TTR and a range of risk factors for mortality in 185 free-living elderly women. Blood was drawn between breakfast and lunch., Results: TTR was correlated negatively with age (r=-0.30, p<0.001). After controlling for age, TTR was negatively associated with log high-sensitivity CRP (hsCRP) and serum copper. It was positively associated with albumin, serum iron and hemoglobin. In addition, TTR was positively correlated with systolic and diastolic blood pressure and postprandial triglyceride (TG). In multiple regression analysis for TTR as a dependent variable, hemoglobin (standardized β, 0.244), serum copper (standardized β, -0.134), postprandial TG (standardized β, 0.223) and log hsCRP (standardized β, -0.190) emerged as determinants of TTR independently of age, albumin, serum iron, systolic and diastolic blood pressure, and explained 22.8% of TTR variability., Conclusions: Subclinical low-grade inflammation, elevated serum copper and decreased hemoglobin were associated with decreased serum TTR in community-living elderly Japanese women and may represent important confounders of the relationship between low TTR and mortality in the elderly. The positive association of TTR with postprandial TG warrants further investigation.

Background: Associations of copper (Cu) and zinc (Zn) serum levels with risk factors for cardiovascular disease (CVD) have not been extensively studied in elderly Asian people., Methods: Relationships to CVD risk factors were examined in 202 freely-living elderly Japanese women., Results: By univariate analysis, log high-sensitivity C-reactive protein (hsCRP) and non-HDL cholesterol were associated with serum Cu concentrations. An independent predictor of Cu was log hsCRP. Serum Zn concentrations decreased with age. After adjustment for age, serum albumin, HDL cholesterol and red blood cell (RBC) were positively and serum insulin and log hsCRP were inversely associated with serum Zn. In stepwise multiple regression analysis (model 1), serum albumin and HDL cholesterol were associated with serum Zn. In analysis excluding albumin from model 1 (model 2), independent determinants were log hsCRP (inverse) and the total number of RBC. In analysis including serum creatinine in model 2, creatinine has emerged as a determinant in addition to log hsCRP and RBC number. In analysis including estimated glomerular filtration rate (eGFR) instead of creatinine and excluding age in model 2, eGFR has emerged as a determinant of serum Zn in addition to log hsCRP and RBC number., Conclusions: Systemic low-grade inflammation may contribute to elevated serum Cu and decreased serum Zn concentrations in the elderly, and may represent an important confounder of the relationship between the serum trace elements and mortality in this population.

The aim of the present study is to investigate the taste acuity in Japanese young women in relation to their micronutrient status. Thirty-eight healthy young women (mean age; 21.3, range; 19-27 years) were enrolled. Gustatory thresholds were estimated for four basic tastes: sweet (sucrose), salty (sodium chloride), sour (tartaric acid), and bitter (quinine hydrochloride) by a filter-paper disk method. Various concentrations at each taste were serially scored from disc number 1 (lowest) to number 5 (highest). The lowest concentration at which the quality of the taste was correctly identified was defined as the recognition threshold. The mean of three measurements for each test on three different days was calculated. We divided our participants into normal taste and hypogeusia groups based on the mean threshold disc numbers, <=3.5 and >3.5, respectively, according to previous literature using the same method. We also measured serum concentrations and dietary intakes of micronutrients including zinc, iron, copper, and selenium. The numbers of participants belonging to the hypogeusia group were 24 (63.2%) for sweet, 19 (50.0%) for sour, 17 (44.7%) for bitter, and 16 (42.1%) for salty taste. Although the hypogeusia group exhibited significantly lower serum iron concentrations, except for the salty taste, the other three micronutrients concentrations did not show any association with the four taste acuities. Dietary micronutrient intake did not show any association with the four taste acuities. This study indicates that in addition to zinc status, iron status should be considered in the study of taste acuity.

The relationship between metabolic abnormalities of trace elements and insulin resistance has been established. Recent studies have revealed that insulin resistance is associated with autoimmune responses. The purpose of this study was to examine the correlation between zinc or copper metabolism and insulin resistance in patients with primary biliary cirrhosis (PBC). Sixteen patients with PBC were divided into two groups: early and advanced stage disease. The overall value of the homeostasis model assessment of insulin resistance (HOMA-IR) in patients with advanced stage PBC was significantly higher than that in patients with early stage PBC, although the mean value in advanced stage PBC was significantly lower than that in hepatitis C virus (HCV)-related liver cirrhosis. There was an inverse correlation between serum zinc concentrations and HOMA-IR values in patients with PBC, while we found no correlation between serum copper levels and HOMA-IR values. HOMA-IR values were inversely associated with peripheral platelet counts, indicating the relationship between insulin resistance and hepatic fibrosis. These results suggest that zinc deficiency plays important roles of insulin resistance and subsequent hepatic fibrosis in patients with PBC, although insulin resistance in advanced stage PBC was significantly milder than that in HCV-related liver cirrhosis.

Objective: Because of an increasing number of case reports of copper deficiency associated with long-term tube feeding nutrition in Japan, we identified patients with copper deficiency associated with long-term tube feeding and described the prevalence, clinical data and cocoa treatment for these patients., Materials and Methods: We conducted a retrospective study to identify patients who were referred from long-term care institutions and had copper deficiency associated with tube feeding. We reviewed all serum copper concentration data during a 6-year period. We also compared admission and post-treatment peripheral blood counts., Results: Among 210 consecutive admissions with nutritional tube feeding from long-term care institutions (N=210), we identified 13 (6.2%) patients with copper deficiency (aged 46-91; 12 women). All patients had anemia, while most had neutropenia. The range of serum copper concentrations of these patients was 0.1-2.4 microg/L (normal; 6.8-12.8 microg/L). Their feeding formulas revealed a low copper content (5 to 12 microg per 100 kcal of each formula). Cocoa powder was used as the treatment. With cocoa supplements, the blood leukocyte count and hemoglobin significantly improved in all patients. Median leukocyte counts were 1,800 /mm(3)at admission and 6,300/mm(3) at follow-up (p=0.001). Median hemoglobin were 7.0 g/dl at admission and 10.3 g/dl at follow-up (p=0.001). Two patients developed transient tachycardia as a possible adverse effect of cocoa., Conclusion: We identified many cases with copper deficiency associated with tube feeding in Okinawa, Japan. Cocoa supplement appeared to be a safe and effective treatment. Increasing the copper content of Japanese tube feeding formulas should be considered for its prevention.

Menkes disease (MNK) is a lethal, X-linked recessive disorder of copper metabolism dominated by neurodegenerative symptoms and connective tissue disturbances. The incidence of MNK in Asia is not known. Most patients die by the age of 3 years if adequate treatment is not carried out. Early parenteral administration of copper can prevent the neurological disturbances and lead to a better outcome. In the present study, a survey on MNK in Japan was performed. There were in total 53 live-born Japanese patients with MNK collected from 1990 to 2003, including two females. The incidence of live-born MNK patients between 1992 and 2002 was 2.8 per million live births (95% confidence interval (CI): 1.8 to 3.7), 4.9 per million male live births (95% CI: 3.2 to 6.6). One-third of the patients were born before 37 weeks or weighing less than 2500 g. Seventeen per cent were born both before 37 gestational weeks and weighing less than 2500 g. These proportions were higher than those in Japanese live-birth babies according to a nationwide estimate. The hair on these Japanese patients appeared not only as white or grey but also brown and blond. We also found that many signs had been noted before the patient was brought to a hospital with typical symptoms. These signs may be a clue to early diagnosis of MNK.

A total of 507 residents (232 males and 275 females) of a rural area of Hokkaido, Japan, were enrolled in the present follow-up study as the follow-up cohort. We investigated the relationship between mortality rates from cancer or all causes and blood levels of SOD activity and Zn/Cu ratio, and serum levels of SOD activity and lipid peroxides (TBARS), by following up our subjects over the course of 18 years. The hazard ratios of lowest blood levels of SOD activity and Zn/Cu ratios to mortality rates from cancer were 1.36 (95% C.I.: 0.59-3.10) and 1.97 (95% C.I.: 0.84-4.63), and those to mortality rates from all causes were 1.31 (95%C.I: 0.76-2.27) and 1.99 (95%C.I.: 1.14-3.46), respectively, in comparison with subjects with highest values for these factors. Hazard ratios of lowest serum levels of SOD activity and TBARS to mortality rates from cancer were 2.68 (95%C.I.: 1.05-6.82) and 0.71 (95%C.I.: 0.31-1.67), and those to mortality rates from all causes were 1.55 (95% C.I., 0.90-2.66) and 0.88 (95%C.I.: 0.51-1.50), respectively. The results of this follow-up study indicate that high serum SOD activity is associated with protective effects against mortality from cancer, and that high blood Zn/Cu ratio is associated with low mortality from other causes. In contrast, serum TBARS levels do not appear to be a biomarker for the risk of death from cancer.

The gene ATP7B responsible for Wilson's disease (WD) produces a protein which is predicted to be a copper-binding P-type ATPase, homologous to the Menkes disease gene (ATP7A). Various mutations of ATP7B have been identified. This study aimed to detect disease-causing mutations, to clarify their frequency and distribution, to determine whether genotype correlates with phenotype, and to determine the rate of abnormal findings in heterozygotes for the WD gene. We analyzed 41 unrelated Japanese WD families, including 47 patients. Twenty-one mutations, including nine novel ones, were identified. 2871delC (15.9%), 1708-5T-->G (11. 0%), and Arg778Leu (13.4%) were the most common mutations. 2871delC was detected mainly in eastern Japan and 1708-5T-->G in western Japan. The homozygotes for the 1708-5T-->G, 2871delC, or Arg778Leu mutations did not show a correlation with their phenotypes. Ceruloplasmin and copper levels were abnormally low in 28.6% and 35. 0% of heterozygotes, respectively. When patients and their families are screened for WD, a high rate of abnormal laboratory data in heterozygotes must be taken into account., (Copyright 2000 Wiley-Liss, Inc.)

Blood and urine samples from cloisonne ware workers were assayed for Pb, Cr, Cd, Mn, Sb, Co and Cu for biological monitoring. Mean blood Pb levels were 47.8 +/- 27.3 micrograms/dl (111-13.3 micrograms/dl) for 49 cloisonne glaze workers, and 0.97 +/- 0.47 microgram/dl (2.4-0.6 microgram/dl) for 62 normal subjects. There was a distinct difference between the 2 groups, and slight differences (p < 0.01) in mean Cr, Cd and Mn levels. There was a distinct difference in mean urinary Pb level between the 2 groups, and slight differences (p < 0.01) in mean Cr, Cd and Mn levels. The correlation coefficient, r, between blood Pb and Cd levels was 0.631 (p < 0.01) for 132 subjects consisting of cloisonne ware workers and normal subjects. r between blood Pb and blood Cr levels was 0.501 (p < 0.01), and that between blood and urinary Pb levels, 0.794 (p < 0.01). The above assays showed that glaze workers at cloisonne plants suffer severe exposure to lead and slight exposure to Cd and Cr.

To evaluate the changes in zinc and copper concentrations in breast milk and maternal blood during lactation, milk and blood samples were obtained from 80 lactating women during the period between 2 and 201 days of lactation. Zinc and copper concentrations were measured by atomic absorption spectrophotometry. Breast milk zinc and copper concentrations markedly decreased during the first few weeks of lactation and gradually declined for the remaining period. Mean values of milk zinc and copper levels were 1.76 and 0.29 micrograms/ml, respectively, between 15 and 84 days after parturition and were 0.76 and 0.19 microgram/ml between 85 and 201 days of lactation. Calculated daily intakes of these minerals for infants from breast milk were markedly lower than those of US Recommended Dietary Allowances. Plasma zinc levels of lactating mothers increased as lactation progressed, whereas erythrocyte zinc and plasma copper concentrations decreased. Plasma zinc and copper and erythrocyte zinc values returned to normal approximately three months after parturition.

Occipital horn syndrome (OHS; Ehlers-Danlos syndrome type IX) belongs to the category of the copper metabolism disorders and is at present being investigated biochemically as is Menkes disease. We report a case of OHS in a 34-year-old male, which we believe to be the first Japanese case. He had been noted to have psychomotor retardation since his early childhood and now presents severe psychomotor retardation and muscle atrophy. He shows characteristic facial appearance, hyperelasticity of the skin, joint subluxation and generalized muscular atrophy. Laboratory investigations revealed a low serum copper and ceruloplasmin level as well as intestinal non-absorption of copper. Radiologic imagings showed occipital exostoses and bladder diverticula. The activity of lysyl oxidase, a copper-dependent enzyme involved in cross-link formation in collagen, was decreased in a skin-biopsied specimen. Electronmicroscopic investigation of a muscle biopsy showed irregularity of the myofibrillar network and accumulation of the concentric laminated bodies in the subsarcolemmal regions.

This study showed differences in plasma and erythrocyte copper concentrations in children and adults. All determinations were performed with a flameless atomic absorption spectrophotometer. The mean plasma copper level at 1 month of age was significantly lower than in adults. After 1 month of age the mean concentration in plasma increased to its peak value at 2 to 5 yr of age, then decreased gradually with age. At 7 months to 10 yr of age, the copper levels in plasma were significantly higher than in adults. The erythrocyte copper levels at 1 month to 1 yr of age were significantly higher than in adults. The copper content of erythrocytes was highest at 2 to 6 months of age and then decreased gradually. The copper concentration of erythrocytes may reflect more accurately liver and total body copper levels than does the plasma copper level. There is less possibility of copper contamination in erythrocytes than in hair. Therefore, the measurement of erythrocyte copper concentration may well be a helpful index of the total copper status.

Zinc deficiency was observed in two infants receiving total parenteral alimentation for chronic diarrhea. An acrodermatitis enteropathica-like rash occurred in both of the infants. Staphylococcus aureus was cultured from the rash. Treatment with zinc resulted in rapid cure of the rash and a subsidence of other signs consistent with zinc deficiency.

To investigate the interrelation of heavy metals and the influence on next generation, total mercury and methylmercury, lead, cadmium, manganese, copper, zinc, and iron were determined in the maternal blood, placenta, umbilical cord, and umbilical cord blood. Samples were collected at delivery from 231 pregnant women who were living in the city of Nagoya, located in the central district of Japan, during 1974 and 1978. Total mercury and methylmercury, cadmium, and iron were higher in cord blood than in maternal blood, whereas copper and zinc were lower. Significant positive correlations were observed between maternal and cord blood with regard to total mercury and methylmercury, lead, cadmium, and manganese contents. Significant correlations were also observed between many pairs of metals, particularly in umbilical cord and its blood.

Serum zinc and copper concentrations of 156 healthy children (6-12 years old) were measured by the atomic absorption spectrophotometric method. The average serum zinc concentration was 92 +/- 13 mug/100 ml (mean +/- S.D.) with a range of 62-127 mug/100 ml. No statistically significant age or sex differences were found in serum zinc levels. The mean serum copper level was 109 +/- 17 mug/100 ml with a range of 70-164 mug/100 ml. Average serum copper concentration in younger age groups (6-9 years old) was higher than that in older age groups (10-12 years old). The highest value of mean serum copper level was observed in the group of 8-year-old children. No sex differences in serum copper levels were found in all the age groups.

The serum zinc and copper concentrations were measured in 45 healthy Japanese infants with age ranging from 5 days to 12 months. At one month of age there was a significant decrease in serum zinc concentration, and this low level persisted until 6 months of age when a significant increase in serum zinc concentration was observed. Serum zinc concentrations remained relatively stable between 6 and 12 months of age. The concentration of serum copper in newborn infants was significantly lower than in healthy children (age: 6 to 12 years), but had risen by 5 months of age to the same levels. There were no significant differences in serum zinc and copper concentrations between male and female infants. However, there was a tendency for serum zinc levels in exclusively breastfed infants to be higher than those in bottlefed infants at 3 months of age and for serum copper levels in exclusively or partially breastfed infants to be higher than those in bottlefed infants at one month of age.