A major key to the diagnosis of Wilson’s disease is recognition of the possibility that this diagnosis is a possibility in a given patient. The rare patient with neurologic Wilson’s tends to be hidden among much more common patients with essential tremor, Parkinson’s disease, and other neurologic conditions. The rare patient with hepatic Wilson’s tends to be hidden among much more common patients with viral hepatitis, chronic active hepatitis, alcoholic cirrhosis, and other liver disease. And, of course, patients with initial psychiatric disease only are rarely recognized. Kayser-Fleischer ring examination and 24-hour urine copper assays are excellent screening tools. Liver biopsy with quantitative measurement of copper is still the gold standard for diagnosis. Modern anticopper treatment involves use of different drugs for different presentations and stages of the disease. We recommend tetrathiomolybdate plus zinc for initial therapy of neurologic Wilson’s, trientine plus zinc for initial therapy of hepatic Wilson’s, and zinc alone for maintenance therapy, the presymptomatic patient, and the pregnant patient.
The final part of this review discusses new findings in which copper-lowering therapy with tetrathiomolybdate is remarkably effective in treating or preventing inflammatory and fibrotic damage in animal models of lung and liver injury. The postulated mechanism is inhibition of overexpressed and dysregulated profibrotic and proinflammatory cytokines.

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Dietary Reference Intakes (DRIs) were introduced in the 6th revised Recommended Dietary Allowances (RDAs), including the tolerable upper intake level (UL). In the present paper, clinically important trace elements, such as iron, zinc and selenium were described in the standpoint of RDAs. Iron deficiency anemia in adolescence has been interestingly thought in relating with Helicobacter pylori infection. Therefore antibiotic therapy is need for this anemia accompanying with iron supplementation. Zinc deficiency is often reported with or without skin manifestation, but recently much attention is attracted in association of runner’s hemoglobinuria.

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Knowledge of dietary element intakes is important from the standpoint of radiation protection, nutrition, and medical monitoring. It is also of interest to know the relationships for both radioactive and non-radioactive nuclides (stable elements) in food chains. Therefore, the dietary intakes of both radioactive and non-radioactive nuclides have been analyzed since early 1980s for the radiation purpose. There are several procedures for assessing individual food intake, e.g. selective studies of individual food, market basket studies (MBS), duplicate portion studies, model dish studies, and 24-hour dietary recall and food record methods. The MBS is now recommended as one of the best methods. A single or multiple methods are chosen to obtain reliable results based on the purpose, subjects etc, of the study being expected because each method has both merits and demerits. Recently, highly sophisticated instruments such as inductively coupled plasma mass spectrometry (ICP-MS), inductively coupled plasma atomic emission spectrometry (ICP-AES) and so on, have become valuable instrumental methods for trace element detection because of their low detection limits, high precision, wide dynamic range, and capability for multi-element analyses. In this review, eighteen stable elements and five radioactive nuclides in eighteen food categories were determined using a market basket study to clarify the food pathways of each element in Japanese subjects. The daily intakes of them for Japanese were also estimated. Dietary intake studies by using eighteen or more food categories should be an effective procedure to resolve critical foods and critical pathways for Japanese.

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In Japan, Recommend Dietary Allowance (RDA) and Dietary Reference Intake (DRI) of trace elements were first specified in 1999. More than 4, 000 human milk samples were collected during 1998 and 1999 from Japanese lactating women at different postpartum and were individually analyzed for composition of nutrients including trace minerals. The latest data on zinc, copper, and selenium concentrations was summarized. The daily intake status of the trace elements by breast- and bottle-fed infants was investigated in reference to the 6th edition of RDA and DRI for Japanese nation.

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Today’s concept of dietary supplement of trace elements is introduced. Although requirements of some elements such as iodine and selenium were established based on the scientific studies against the deficiencies of these elements in human, those of some other elements have not been established. More studies are needed to reveal the need and quantity of dietary supplement of trace elements.

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Lithium content of the ocean fish has been investigated for estimating the intake of lithium, which was known as an element being used to a medicine (lithium carbonate) for the remedy of manic-depressive psychosis. In this study, fish (184 samples) was classified commercially into three types; raw fish (n=95), dry fish (n=70) and canned fish (n=19). Lithium content was determined by flame photometry after the decomposition of a fish sample (∼ 2g) with the mixture of nitric and perchloric acids. In the raw fish, lithium content was obviously higher in a sardine group (264 ± 186 ng/g in the range of 67 ∼ 934 ng/g, n=51) than in the other fish group (38 ± 28 ng/g in the range of 11 ∼ 86 ng/g, n=44, at wet-weight basis). Especially in the sardine group, the content was higher in anchovy (407 ± 167 ng/g, n=25) than in others (e. g., big-eye sardine; 85 ± 12 ng/g, n=11 and Japanese pilchard; 157 ± 43 ng/g, n=6, at wet-weight basis). In addition to the sardine group (anchovy, pilchard, sardine and blue sprat) rich lithium was found in the head (40 ∼ 66% of total lithium), compared with the eyes (0.1 ∼ 1%), internal organ (1 ∼ 9%), body (10 ∼ 33%) and back bone (15 ∼ 36%) of the fish. On the other hand, in dry fish, lithium was rich in the anchovy of “Niboshi” (5390 ng/g, as mean, n=30, at dry-weight basis) among dry sardine; manufactured as “Niboshi”, “Tazukuri”, “Maruboshi”, “Namaboshi” and “Chirimen” named for depending on their different drying-treatments in Japan. Lithium content of raw anchovy, 407 ± 167 ng/g (n=25) at wet-weight basis, was converted to 1770 ± 727 ng/g (n=25) at dry-weight basis, and the value was close to 2440 ± 657 ng/g (n=9) of dry anchovy as “Tazukuri” at dry-weight basis. The lithium content of canned sardine soaked with oil (sardine fillet: 246 ± 135 ng/g, n=15, at wet-weight basis) was close to that with water (sardine fillet: 123 ± 62 ng/g, n=3, at wet-weight basis), and was almost equal to that of raw sardine group (264 ± 186 ng/g, n=51, at wet-weight basis). It was concluded that anchovy and sardine, regardless of raw, dry or canned fish and of different ocean of the fish collected, were good material for the intake of lithium.

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In this study, we examined whether arsenic has any toxicological effects on the differentiation of human peripheral blood monocytes into macrophages by macrophage colony stimulating factor (M-CSF) in vitro compared with that of other trace elements (metallic compounds), and found that trivalent inorganic arsenite sensitively inhibited the M-CSF-induced in vitro maturation of monocytes into macrophages at very low concentrations, nM levels, although other metallic compounds, including chromium, selenium, cadmium, mercury, zinc, nickel, copper, cobalt, manganese and other human pentavalent arsenic metabolites, such as inorganic arsenate, monomethylarsonic acid and dimethylarsinic acid showed cytolethality in monocytes at μ-mM levels [1]. This work may have implications in arsenic-induced chronic inflammatory poisoning in humans.

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In order to make clear the relationship between the surface properties of a dental implant and biocompatibility, trace elements on the titanium surface of the implant extracted from a rat bone were examined. A cpTi bullet, as a prototype, of 1.1 mm diameter and 3.5 mm length had a flat surface on its cylindrical side. The flat area was sandblasted by glassy particle and cleaned by argon sputtering. The surfaces of the implants extracted from the femur of Wistar rats were cleaned ultrasonically and examined by X-ray photoelectron spectroscopy (XPS). The detected main elements were Ti, O, C, and N. Ti peaks arise from the base material and the others indicate presence of bio-molecules including proteins. Trace elements, such as P, Ca and Si, were also detected. However, the Ca/P ratios were very small compared to those of calcium phosphate compounds, such as calcium diphosphate. This fact indicates that calcium phosphate compounds, including hydroxyapatite, don’t form on the titanium implant in rat bone.

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A simple method for preconcentration and determination of trace boron has been developed by the conversion of common anion-exchange resins with a chelating agent, beryllon-II, and the proposed method has been successfully applied to the determination of boron in human urine samples. Beryllon-II-immobilized resin is useful for selective collection of boron in neutral pH region. The concentration of collected boron is determined by introducing the boron-sorbed resin as water-resin suspension into inductively coupled plasma-atomic emission spectroscopy(ICP-AES) apparatus without stripping procedure.

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Daily bromine intake in Ukrainian subjects was estimated in relation to the health effects on habitants after the Chernobyl accident. Total diets were colleted from 106 locations for children and adult males by the duplicate portion methods. Bromine was rapidly determined by inductively coupled plasma mass spectrometry (ICP-MS) after chemical separation using a combustion apparatus. Median concentration of bromine on a dry basis for Ukrainians was 6.98 μg per g. Daily bromine intake for Ukrainians was in the range of 0.49-12.5 mg per person. The median, geometric mean and standard deviation were 2.12, 2.23 and 1.84 mg per person, respectively. The yearly trend of the intake had almost no change. Regional difference would expect to exist among 10 areas of Ukraine, but no clear difference appeared in the present findings. For Japanese, the median, geometric mean and standard deviation were 10.4, 10.5 and 1.3 mg per person, respectively; the geometric mean was approximately five times higher than that of Ukrainians. The higher values of Japanese suggested environmental contamination by pesticides and other chemicals within Japan.

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Gomel oblast in Belarus is one of the areas most seriously affected by the Chernobyl nuclear power plant accident. While food contamination by radionuclides has been well studied after the accident, no reports describing intakes of stable elements could be found. This paper describes a preliminary investigation on elements intakes. Diets of adults and children in the region were analyzed by ICP-AES and ICP-MS. The daily intakes of elements for Belarusian children were estimated as follows: Ba (1.6mg); Ca (0.44g); Cd (12μg); Co (20μg); Cs (3.3μg); Cu (0.90mg); Fe (29mg); K (2.2g); Mg (0.17g); Mn (2.4mg); Na (2.1g); P (0.65g); Rb (0.83mg); Sr (1.5mg); Th (0.50μg); U (0.36μg); and Zn (5.0mg.) Although a deficiency in Zn intake was found, the intakes of radionuclides such as ²³²Th and ²³⁸U were below levels of other regions.

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Zinc is an essential trace element and crucial for numerous biological functions. In contrast, excessive zinc in the synapses plays central roles in the neurodegenerative processes following brain injury such as the transient global ischemia. We have previously demonstrated that zinc caused marked death of immortalized hypothalamic neuronal cells (GT1-7 cells) in a dose- and time-dependent manner. To investigate the molecular mechanism of zinc-induced neurotoxicity of GT1-7 cells, we applied various metal to GT1-7 cells prior to exposure to zinc, and observed the morphological and degenerative changes. Among tested, gadolinium (Gd³⁺), a widely known channel blocker, significantly blocked zinc-induced cell death in a dose-dependent manner. Aluminum (Al³⁺) also inhibited zinc neurotoxicity. Our results suggest that functions of Gd³⁺ such as the modification of calcium homeostasis are implicated in the mechanism of zinc-induced neurotoxicity.

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Selenium (Se) is an essential trace element of mammals and plays important roles in the form of selenocysteine residues in selenoproteins. Selenocysteine lyase (SCL) specifically catalyzes the decomposition of L-selenocysteine into Se and L-alanine and is proposed to function as a Se delivery protein to selenophosphate synthetase in selenoprotein biosynthesis. However, the physiological role of SCL has not been established. In this study, the expression levels of SCL in various tissues of Se-deficient/supplemented mice were studied. We also examined effect of oxidative stress or excess sodium selenite on the expression of SCL by western blot analysis. Expression levels of SCL were not significantly changed by Se status in many tissues. However, the levels of SCL in the stomach of 7 out of 8 mice fed a Se-supplemented diet were markedly lower than those of mice fed a Se-deficient diet. By the administration of 1 mg/kg sodium selenite, the expression levels of SCL were elevated in stomach of the mice fed a Se-supplemented diet. This is the first report demonstrating the possible existence of a Se-dependent regulation system for SCL.

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The mammalian metallothioneins (MT) are effectively induced in response to the various heavy metal ions. The inductions of these genes are mainly based on the transcriptional activation and the metal ions are the factors that directly promote the gene transcription. The short DNA motifs, which are called as the metal responsive elements (MREs), are identified in the promoter regions as the cis-acting elements on the 5’-flanking region of these genes. It has been performed to examine the finding of the regulational protein as the transcriptional factors of MT genes. The finding of MTF-1, which is the trans-acting factor, has been an important advance toward understanding MT gene regulation as mediated by zinc ion. However, the interaction of the transcriptional factor with the redox active metal ions, such as Cu(II) ion, on MT induction has not been understood. In this study, we constructed the plasmids which contain the MREs as multiple enhancer sequences in the pUC19. By using this plasmid the interaction of Cu(II) ion to the linear duplex oligonucleotides, which were designed to contain two MRE motifs (MRE_c and MRE_d), was investigated by the gel mobility assay for the bendig effect of Cu(II) ion to MREs.

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Male Wistar rats were given cadmium by intraperitoneal (ip) injection (1mgCd/kg). Other male Wistar rats were given Cd by oral administration at a dose of 0, 1, 2, and 5 mgCd/kg/day. All rats were slaughtered at 24 hours after Cd injection, and the testis was extracted immediately. Animals of the control group were given distilled water. Metallothionein (MT) concentration in testis was measured by the Cd-Hem method and capillary electrophoresis. Total RNA in testis was extracted, and gene expression of iso-MT (MT I, II, and III) was checked by RT-PCR.
The increased MT concentration in the oral Cd administration group was found depending on the amount of Cd intake whereas the decreased MT level was found in the Cd ip injection group. Increased gene expression of MT I and III was found depending on the increase of Cd exposure dose in both groups of the Cd injection and the oral administration of Cd. However, the decreasing tendency of MT-II was found in the Cd injection (ip) group, whereas the tendency of increase or decrease depended on Cd ingestion were not found in the oral Cd administration group. In the testis, it was considered that Cd toxicity was mitigated by MT induced by oral administration of Cd. On the other hand, as the decreased protein amount of MT was found, it was thought that the proteolysis or the translation function of MT gene in the testis was disordered by the acute Cd toxicity. Moreover, the possibility of the MT-III induction according to the increased Cd accumulation in testis by oral Cd administration was suggested from the result of mRNA expression by RT-PCR.

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Copper is an essential micronutrient with numerous cellular functions. Previous studies have demonstrated that copper deficiency in P19 embryonal carcinoma cells by using a copper depletor, bathocuproinedisulfonic acid, suppresses the retinoic acid-induced neuronal differentiation and the retinoic acid receptor-mediated transactivation. In this study, we used an immobilized metal affinity chromatography (IMAC) technique to identify novel copper-binding nuclear proteins in mouse brain. Two copper-binding proteins, polypyrimidine tract-binding protein-associated splicing factor (PSF) and NonO/p54^nrb (NonO), were identified by IMAC loaded with copper ion and mass spectrometry. In transient transfection experiments, both PSF and NonO overexpression in Neuro-2a cells resulted in significantly increased expression of a luciferase reporter gene in response to retinoic acid. Our results suggest that the possible copper binding proteins, PSF and NonO, may act as a coactivator of retinoic acid receptor-dependent transcription.

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Soybean plants (Glycine max) were grown in hydroponic culture solution and applied Cd via roots for 48 h at different growth stages: third and fourth node (V3-4), full bloom (R2), full pod (R4), full seed (R6) and beginning maturity (R7). At a period of full maturity, soybean plants were sampled and analyzed by ICP-MS to determine Cd concentrations and calculated the amount of Cd uptake.
The Cd concentration of seeds became the highest at R4 and R6 growth stages. The Cd concentrations between seeds and pods were remarkably correlated and close to the each other at every growth stages. It was suggested that Cd concentration of seeds would be estimated from that of pods.
The amount of Cd uptake increased with the progress of growth stages. But after R6, the ratio of Cd uptake in seeds to that in whole plant reduced. Hence the Cd absorbed from R4 to R6 was the most contributive to raise the Cd amount of seeds.

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Soybean plants (Glycine max) were grown in hydroponic culture solution and applied Cd via roots for 48 h at early growth stage (third and fourth node; V3-4). Soybean plants were sampled at the growth stages as follows: full bloom (R2), full pod (R4), full seed (R6), beginning maturity (R7), and full maturity (R8). The concentration and amount of Cd in each part were determined.
Cadmium absorbed by the soybean at V3-4 was transferred into stems, petioles and leaves until R2 growth stage, and the Cd remained until R4 stage in each part. After R4 stage, Cd amount in leaves decreased steeply. On the other hand, Cd amount in pods and seeds increased from R6 to R7. These results indicate that Cd accumulated in leaves was translocated to seeds at R7 stage.

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