Diseases caused by metal allergy are usually contact dermatitis. But as causes, ground metal, a clasp, a metallic beauty implement, metal button on jeans are sometimes passed by and also not a few cheilitis, stomatitis, lichen planus, dyshidrotic eczema, pustulosis palmaris et plantaris, nummular eczema, pseudo-atopic dermatitis which result from metal included in food and dental metal are reported. The knowledge of the number of skin cancers caused by arsenic is more prevaling than ever. At present, a proposition that arsenic is a poisonous material is established, and therapy by already been given up. However, it is about thirty years since arsenic was given up. When We come to think of the period of the exposure of arsenic, the thirty years keep the possibility that skin cancer may outbreak. Good notice should be taken of arsenic as one of the carcinogens.

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Amyotrophic lateral sclerosis (ALS) is characteristic of selective degeneration of the upper and lower motor neurons. The correct pathogenesis of this fatal disease is unknown. Several possible mechanism of motor neuron degeneration is postulated in ALS. In particular, gene mutation of Cu/Zn superoxide dismutase (SOD) is discovered in a part of familial ALS patients. The evidence suggests a major possibility that trace elements, such as Cu and Zn, may have toxic effects on motor neurons. We review shortly the relationship between several trace elements and ALS. We hope that neurotoxic studies of metals and other trace elements could contribute to further therapeutic potential and strategy in ALS.

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The trace elements play important roles in the human brain. The knowledge on the trace elements and neuropsychiatric disorders were comprehensively reviewed. These include iron, zinc, copper, iodine, lithium, aluminum, manganese, lead and mercury. Some metals have toxic actions on nerve cells and neurobehavioral functioning. The toxic actions could be expressed either as developmental effects or as an increased risk of neurodegenerative diseases in old age. Redox metals, which were iron, copper, and zinc in the brain, play many important roles in maintenance of cellular function.

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Iron deficiency is the most common cause of anemia. Zinc, copper, manganese, molybdenum, and cobalt are also related to anemia. The body of an adult man stores approximately 4500 mg of iron. About 60% of this iron is in the form of hemoglobin, 20% is in the storage form of iron, 7% to 8% is contained in myoglobin in the muscle, and 12% to 13% is stored in iron-containing enzymes. The average amount of iron lost daily has been estimated to be approximately 1.0 mg in normal individuals. These losses are balanced by ingesting an equivalent amount of iron from the diet. Because of increasing iron needs of infants and adolescents during growth, and blood loss during menstruation in females, these patient groups may suffer from lack of iron, especially if they ingest inadequate amounts of iron from their meals. Pica is one of the symptomes of iron deficiency anemia. Pacophagia is one of clinical manifestation of pica which is characterized by eating ice. Measuring serum zinc before and after iron treatment in patients with iron deficiency anemia, we observed decrease of zinc concentration in patients with pica whereas normal zinc concentration in patients without pica. However there was no significance between two groups. Zinc deficiency leads to pathological signs related to impaired function of plasma membrane proteins such as erythrocyte plasma membrane. This impaired function causes hemolytic anemia. On the contrary, the excess of zinc also leads to anemia because suppression of iron absorption occur. Hypochromic microcytic anemia has been observed in copper deficiency. Since the activity of cytochrome oxidase, which contains copper, decrease in this condition, iron will not be mounted in heme followed by anemia because of failure of iron reduction. Ceruloplasmin, which also have copper, make iron to combine with transferrin by converting ferrous iron to ferric iron through oxidative process. Therefore, lack of ceruloplasmin cause anemia similar to that in iron deficiency.

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We studied trace metals (copper, iron, zinc) in patients with hepatocellular carcinoma (HCC) with special reference to carcinogenesis. 1. High signal intensity on T1-weighted images in magnetic resonance imaging, suggestive of HCC, was due to excessive accumulation of copper within the tumor. 2. Hepatic copper content increased with progression of hepatic fibrosis (p<0.05). However, hepatic iron and zinc contents did not show a significant difference between grades of fibrosis. 3. In patients with grade F3 or F4 fibrosis, copper content in the liver parenchyma was higher in the presence of HCC than in its absence (p<0.05). Multiple regression analysis showed that the only factor significantly associated with the coexistence of HCC in HCV-positive patients with chronic liver disease was the copper level in the liver parenchyma. Thus, hepatic copper overload may contribute to the development of HCC in HCV-positive patients with chronic hepatitis or cirrhosis. 4. Accumulation of copper in small HCC, in which copper was present as Cu-MT or Zn, Cu-MT, was greater than that in the surrounding liver parenchyma. 5. Content of 8-hydroxydeoxyguanosine was higher in HCC and its surrounding liver parenchyma than normal liver parenchyma (p<0.05). Thus, copper accumulation and the presence of MT in the liver may be related to carcinogenesis of HCC.

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慢性C型肝疾患の病態や予後に、微量元素がどのような影響を与えているかについてprospectiveに検索した。対象は、C型慢性肝炎(CH)87例、肝硬変(LC)15例およびasymptomatic hepatitis C virus(HCV)carrier5例である。さらに原発性肝細胞癌(HCC)と診断された121例である。これらの対象例について、外来受診時に血中亜鉛濃度、血中フェリチン濃度を測定した。血清フェリチン濃度は、HCC群およびLC群が有意にCH群に比較して高値を呈した。また血清フェリチン値は男女ともに血清AST値と有意な相関関係を認めた。またALT値が80IU/L以上の例は、80IU/L未満の例に比較して血清フェリチン濃度は有意に高値を呈した。経過中に血清フェリチン濃度が低下した群は、上昇ないしは不変群に比較してAST値ないしALT値共に明らかに低下した。一方血清フェリチン濃度が上昇ないし不変群では、AST値ないしALT値は上昇した。血清亜鉛濃度は、HCC群およびLC群が有意にCH群に比較して低値であった。血清亜鉛濃度は、アルブミン濃度および血小板数と有意な相関関係が認められた。血清亜鉛濃度が低下ないしは不変群は上昇群に比較して、AST値ないしALT値共に明らかに上昇した。一方血清亜鉛濃度が低下ないし不変群はAST値ないしALT値は明らかに低下した。C型慢性肝炎では、これらの微量元素の補充ないし減量を計る治療法により、その長期予後の改善が可能であることが示唆された。

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We measured the toxic metal contents in 5846 hair samples from infant to elderly to estimate their exposure levels. The geometric means of hair mercury levels in male adults showed age-related increase from 2.4 μg/g at high-teens up to a peak of 5.9 μg/g at 50's, and then decreased with further aging. In children, at the age of 4-15 years, a small peak of 3.1 μg/g was observed. The hair mercury levels in female were significantly lower than those in male. A similar, age-related accumulation profile with gender difference was also observed with arsenic in hair. The mean arsenic levels in male age-dependently increased up to 98 ng/g at the 80's elderly, with a small peak of 66 ng/g at the age of 10-15 years. A similar, but lower age-related accumulation pattern was observed in female. Cadmium and lead showed another type of accumulation profile: the highest levels were observed in the infants aged 1-3 years both for male and female, with neither marked age-dependency nor gender difference. Aluminium also exhibited a similar accumulation profile with the highest levels at infants and young children, as well as cadmium and lead. These findings indicate that the toxic metals are classified to two types based on their accumulation profiles, and some elements having high accumulation in infants and children, namely cadmium, lead and aluminium, should be reconsidered and surveyed as risky metal to the young generation.

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It has been revealed that pigmentation based on the oxidative polymerization of 3,4-dihydroxyphenylalanine (dopa) by the action of a copper-containing enzyme, tyrosinase, is suppressed by free oxalic acid and its salts (oxalates) as well as by sodium benzenesulfinate (NaBS) and sodium p-toluenesulfinate (NaTS). The results of this investigation on the inhibition mechanisms suggested that oxalates non-competitively inhibit the activity of tyrosinase due to the formation of a chelate linkage with the functional copper ions in the enzyme molecule and that the two aromatic sulfinates react with dopaquinone formed by the enzymatic oxidation of dopa to afford their stable derivatives which are no longer transformed and polymerized.

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We have investigated the daily nutritional intakes of young women(subjects). The sera of subjects were separated to under molecular weight 50,000 (mw<50,000) and more than 50,000 (mw>50,000) by filter. The copper concentrations in mw<50,000 fraction from subjects under 1600kcal/day intake (low intakes) were significantly higher than those from standard intakes in sera. The copper-dependence oxidation of low-density lipoproteins (LDL) has been reported in many articles, so we studied the lipid peroxides of LDL. A significant increase of the content of thiobarbituric acid reaction substances (TBARS), as used for index of the lipid peroxides, were observed in sera of low intakes. We also observed that lipid peroxides in sera of low intakes were decreased when the concentrations of histidine were increased. So, we studied LDL oxidation of copper at various ratios of the histidine/copper in vitro. The LDL oxidation by the copper might be blocked by chelating of histidine to the copper in mw<50,000. It's appeared to be a more effective peroxyl radical trap. Meanwhile, low concentration of lipid peroxide was observed even though low concentration of histidine in sera of standard intakes. The concentration of glycine was low in sera of standard intakes but high in low intakes. Cu(II) was coordinated by two moles of histidine which has three coordinate functional groups and was coordinated by two moles of glycine which has two coordinate functional groups. The inhibitory effect of histidine and glycine on Cu(II) induced LDL oxidation was examined in vitro. LDL oxidation may be blocked by the chelating of histidine, but not blocked by the chelating of glycine. These results indicated that the increased of glycine in sera of low intakes may make the formation of Cu(II)- glycine chelate and its chelate promote lipid peroxidation in vivo.

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Many aged-patients with zinc deficiency were found in our clinic in autumn of 2002, complaining of impaired taste, nausea, anorexia, delayed healing of decubitus, behavior abnormality, or others. The typical cases and their clinical features were presented. The reasons why we could find so many patients are not clear. To guess the reasons, we tried to survey the population level of serum zinc concentration (Zn) of the peoples living in the same rural region, called Kita-mimaki village. From April through November, 2003, we could examined Zn of 1431 peoples consisting of 590 males (average age: 44.8 year-old, range: 6-93) and 841 females (average: 47.2, range: 6-96). RESULTS: 1) Level of Zn showed the tendency to decrease gradually in a day. The average Zn of the subjects whose blood sampled in the morning was higher than that in the afternoon. 2) Mean value ± SD of Zn in the adults of 20-39 year-old(yo), that of 60-69yo and that of 80-94yo were 81.5 ± 13.6, 76.6 ± 9.3 and 65.0 ± 10.6 μg/dl respectively. Significant decrease in Zn was found in the aged comparing with young adults. 3) Mean value of Zn in the young aged 20-39yo was significantly (p<0.01) less in female than that in male. 4) In the adults aged 20-69yo and blood sampling done in the morning, mean value ± SD of Zn was 78.9 ± 11.6 μg/dl. This value was 10 μg/dl lower than a reported value of healthy adults, that is 87.5 ± 11.2 μg/dl. CONCLUSION: 1) Serum zinc concentration (Zn) seemed to show daily variation, depending on time of blood sampling and the interval between mealtime and sampling time. Zn also depends on age and gender of a subject. We must give a careful attention to “Lower value of Zn is not the same as zinc deficiency”, because lots of factors affect the concentration. 2) No mass examinations as a population level were not found except NHANES II which was published about 25 years ago. Comparing our results with the data about zinc in NHANES II, zinc deficiency is coming a more important clinical entity than before especially in an aged society. Zinc deficiency must be discussed nation-wide, because it might be derived from decreased zinc in soil, poorer zinc content of foods, additives in daily foods, medical drugs and so on.

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