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We report a 40-year-old man who presented with multiple bone pseudofractures after about 20 years from the onset of Wilson's disease (WD). At age 36, he first noticed pain in his left shoulder. At age 39, he had multiple chest pain. On neurologic examinations, dysarthria and dysphagia due to pseudobulbar palsy, rigidity and tremor on right upper lim were observed. WD was confirmed because of low levels of plasma cupper and ceruloplasmin in addition to ATP7B gene mutation. The chest X-ray revealed multiple fractures of the several ribs. We diagnosed osteomalacia due to Fanconi's syndrome because of hypophosphatemia and the impairment of renal tubules for WD. After administration of vitamin D, there happened no new bone pseudofractures. Although bone pseudofractures accompanied by Wilson's disease generally happen in childhood, we should be aware of this symptom even in adulthood.

We report a 39-year-old woman with slowly progressive spastic gait and paresthesia in the lower extremities. Cervical spinal MRI revealed high intensity in the dorsal column from vertebrae C2 to C7. Laboratory findings showed normal vitamin B12 and low serum copper level. By lifestyle history taking, we noticed her extreme unbalanced diet of having 15-20 oysters everyday over 5 years. Then we considered that zinc excess caused copper deficiency myelopathy. We needed to pay attention to copper and zinc level if the patient has a symptom resembling subacute combined degeneration of spinal cord with normal serum vitamin B12.

A 64-year-old man underwent kidney transplantation for progressive chronic renal failure which had developed 8 years after allogeneic bone marrow transplantation for acute myeloid leukemia. Because of post-operative complications, he had been placed on intravenous hyperalimentation. Three months after the transplantation, anemia rapidly progressed (hemoglobin, 7.9 g/dl). The proportion of reticulocytes was 0.2%, but white blood cell and platelet counts remained within normal ranges. Serum iron, vitamin B12, and folate levels were normal. Bone marrow examination showed the presence of ringed sideroblasts and cytoplasmic vacuoles in a fraction of erythroid cells. Megakaryocytes were adequate in number with normal morphology. Although the findings were consistent with refractory anemia with ringed sideroblasts according to the WHO classification, cytoplasmic vacuolations were also observed in myeloid cells, suggesting copper deficiency. Indeed, serum copper and ceruloplasmin levels were found to be low (33 μg/dl and 11 mg/dl, respectively), and oral copper supplementation at a daily dose of 1 mg was initiated. There was a prompt increase in reticulocytes, and the hemoglobin level was normalized within one month, in response to this regimen. In progressive anemia cases with ringed sideroblasts in the bone marrow, copper deficiency should be considered in the differential diagnosis.

Objective: Ketogenic diets tend to cause trace mineral deficiencies. Ketonformula is a foumula for a ketogenic diet developed by Meiji Co Ltd in Japan. No reports are available on the trace mineral deficiencies associated with a use of Ketonformula., Methods: We monitored the serum levels of selenium, zinc and copper as well as the amount of the daily intake of these minerals before and at 6 months after the initiation of the ketogenic diet with Ketonformula in six patients with intractable epilepsy associated with severe motor and intellectual disabilities., Result: The median serum selenium concentration decreased from 7.0 (range, 6.5-12.3) microg/dl to 6.2 (5.4-10.9) microg/dl as a result of the 6-month-treatment with Ketonformula (p < 0.05, Wilcoxon signed-rank test). The median daily selenium intake decreased from 17.8 (15.0-27.0) microg/day at the baseline to 5.5 (5.0-22.0) microg/day after 6 months on the diet (p < 0.05). The median serum zinc concentration increased slightly (from 66.0 (46.0-84.0) microg/dl to 68.0 (46.0-71.0) microg/dl), but the difference was not significant. The median daily zinc intake, however, significantly decreased from 4.2 (3.7-6.0) mg/day to 2.2 (2.0-3.0) mg/day (p < 0.05). The median serum copper concentration also showed no significant decrease (from 134.5 (119.0-168.0) microg/dl to 126.0 (86.0-183.0) microg/dl). The median daily copper intakes, however, decreased significantly from 0.80 (0.35-1.30) mg/day to 0.30 (0.26-0.40) mg/day (p < 0.05)., Conclusions: The decline of the serum selenium concentrations and daily enteral intakes of selenium, zinc, and copper after 6 months on Ketonformula suggested that patients on this ketogenic formula needs close monitoring as well as supplementation of these trace minerals.

Aim: The purpose of this study was to examine the effects of copper supplementation on lipid profiles in elderly patients with copper deficiency., Methods: Nine long-term bed-ridden, patients (5 men and 4 women, mean age 83.3+/-8.7 years old) with severe copper deficiency, who had a serum copper of 15 microg/dL or less (normal range 70-140 microg/dL), had their diets supplemented with copper sulfate (3 mg/day) over 12 weeks in addition to their diet of only one kind of enteral food with a low concentration of copper. Copper, ceruloplasmin, total cholesterol (TC), triacylglycerides (TG), HDL-cholesterol (HDL-C), c-reactive protein (CRP), creatinine (Cr), zinc (Zn) and albumin (Alb) in the serum were measured before, 4 weeks and 12 weeks after copper supplementation., Results: Serum copper and ceruloplasmin were significantly increased at 4 weeks after copper supplementation. TG was significantly increased at 4 weeks after copper supplementation, but at 12 weeks the increase of TG was not significant. TC, HDL-C, CRP, Cr, Zn and Alb were not changed by copper supplementation., Conclusion: TG was transiently increased by copper supplementation in elderly patients with copper deficiency. TC and HDL-C were not changed by copper supplementation.

Objectives: First, we observed that copper and histidine levels were increased in the sera of undernourished women. The objective of this study was to clarify the reason for the increase in copper and histidine. Furthermore, we tried to determine the compound(s) to which the increased copper was binding, and examined the effect of the increased copper and histidine on lipid peroxidation., Methods: We investigated young women's diets and took blood samples, and the contents of histidine in the sera were determined by HPLC. The contents of copper were determined by flameless atomic absorption spectroscopy. The subjects were classified into three groups according to the concentration of histidine in the sera. The contents of copper and lipid peroxide in the sera were compared among the high histidine group and the other groups. We also examined the ability of the complexes to prevent LDL oxidation induced by copper, using an in vitro assay., Results: The contents of lipid peroxide were lower in the high histidine group than in the other groups. Furthermore, the complexes of histidine and copper inhibited the formation of peroxidized lipids in an in vitro assay., Conclusions: These results indicate that histidine masks copper, reducing oxidation reaction. They also suggest that the complexes are suited for plasma antioxidation, preventing oxidative modification of lipids in the sera of undernourished women. The increased histidine appeared to be an effective trap for active oxygen.

Copper deficiency (normal serum copper level: 78-136 micrograms/dl) has been reported in patients with long-term enteral nutrition, caused by a copper deficit in enteral nutrition. Occasionally, this leads to anemia and leukopenia. We used Hershey's pure cocoa that is rich in copper (content 3.8 mg/cocoa 100 g) for copper deficiency. A total of 86 (40 men and 46 women, mean age 69 years) patients on enteral nutrition were studied. The primary diseases were cerebral vascular disease in 71 patients, neurological disease in 5 and others in 10. Those who showed serum copper levels of 20 micrograms/dl or less (N = 8) were given 30-45 g of cocoa (copper content 1.14-1.71 mg) per day for about 40 days. Among them, two patients could not continue because of vomiting and diarrhea and were excluded from this study. Mean serum copper levels increased from 8.7 +/- 6.2 to 99.0 +/- 25.4 micrograms/dl (N = 6). Those who showed serum copper levels 20-77 mg/dl (N = 31) were given 10 g of cocoa (copper content 0.38 mg) per day for about 40 days. When mean serum copper levels increased from 50.5 +/- 19.3 to 89.0 +/- 12.9 micrograms/dl with cocoa administration, anemia and neutropenia caused by copper deficiency showed a tendency to improve. After completing the study period, cocoa was reduced to 5 g (copper content 0.19 mg) per day in 23 patients. The mean serum copper levels increased from 90.7 +/- 10.4 to 100.6 +/- 17.1 micrograms/dl for about 100 days. Recently, the amount of daily copper requirement for adults has been reported to be 1.28-2.5 mg per day. We showed that 10 g of cocoa (0.6 mg total copper: 0.38 mg in cocoa and 0.22 mg in other nutrients) is sufficient to treat copper deficiency, and 5 g of cocoa (0.37 mg total copper: 0.19 mg in cocoa and 0.18 mg in other nutrients) is enough to maintain the normal level of serum copper in patients with long-term enteral nutrition.

Three bed-ridden patients who had had only one kind of enteral nutrition without sufficient copper element during a few years showed very low levels of serum copper. Two of them also had leukopenia. The abnormal findings disappeared after the feeding nutrients rich in copper element. The leukopenia may have been due to copper deficiency rather than zinc deficiency. We confirmed that long-term parenteral nutrition must contain trace elements, for example copper.

Effects of a newly developed angiogenesis inhibitor, TNP-470 (AGM-1470) alone and in combination with cisplatinum on tumor-bearing rats were investigated. Wistar-King A male rats were subcutaneously inoculated with 10(7) cultured syngeneic liver cancer cells that had been induced by oral intake of 3'-methyl-4-dimethylaminoazobenzen, and were used as tumor-bearing rats. Tumor sizes and changes in serum copper levels were measured after administration of TNP-470. Administration of TNP-470 (5, 10, 20 or 30mg/kg, s.c., daily for 7 days) inhibited tumor growth in a dose-dependent manner. The suppressive effects were the same in the rats which were administered TNP-470 (20mg/kg, s.c., daily for 7 days) and cisplatinum (0.5 mg/kg, s.c., daily for 7 days) simultaneously, and rats administered cisplatinum (0.5mg/kg, s.c., daily for 7 days) following TNP-470 (20mg/kg, s.c., daily for 7 days). These inhibitory effects were almost the same as that of cisplatinum (0.5mg/kg, s.c., daily for 7 days) alone. While, administration of TNP-470 (20mg/kg, s.c., daily for 7 days) following cisplatinum treatment (0.5 mg/kg, s.c., daily) showed markedly higher anti-tumor effects, compared with these groups. Administration of TNP-470 caused elevation of serum copper levels in normal rats as well as tumor-bearing rats with the same degree. Serum copper levels remained normal after discontinuation of TNP-470 in normal rats, while in tumor-bearing rats, it decreased during the first week and re-elevated in 2 to 3 weeks after discontinuation of TNP-470. This re-elevation of serum copper levels was related to rapid tumor growth after discontinuation of TNP-470. Furthermore, there was also a positive correlation between serum copper levels and capillary density in the tumor. In conclusion, TNP-470 had anti-tumor effect in a dose-dependent manner against a rat liver cancer, with markedly higher effects when it was administered following cisplatinum. Serum copper levels after discontinuation of TNP-470 treatment might indicate re-proliferation of the capillaries in the tumor tissue.

Serum zinc and copper were measured in 47 patients undergoing pulmonary operation. They were divided into two groups according to the extent of the operation. Group A consisted of 32 patients with lung cancer, in whom lobectomy with lymphadenectomy was performed through the postero-lateral thoracotomy. Group B consisted of 15 patients with benign pulmonary lesion or metastatic pulmonary tumor, in whom wedge resection was performed through the axillary thoracotomy. In Group A, the serum zinc concentration most decreased 6 hours after surgery. It returned to normal level in 5-7 days and to the preoperative level within 14 days. In Group B, the maximal fall in serum zinc was at 3 hours after operation. Restoration to normal level was at 2nd postoperative day and to the preoperative level was at 5th postoperative day. The differences in serum zinc between two groups were significant (p < 0.05) from just after operation to 4th postoperative day. The degree of maximal decrease in serum zinc in Group A was more than that in Group B. Blood loss, operation time and pulmonary function did not influenced the change of serum zinc concentration in our series. These results show that degree and duration of reduction in serum zinc depends on the surgical trauma. On the other hand, no significant difference in serum copper levels was observed between two groups. The influence of pre- and post-operative pneumonia on serum zinc concentrations were followed in 3 patients. Fall and rise in serum zinc levels coincided with manifestation of and recovery from pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS)

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 reports the contents of Zn and Cu in the breast milk and serum of postpartum mothers, 17 primiparas and 20 multiparas, at one week and at one month after delivery. Results were as follows. 1. The mean content of Zn in the breast milk was 5.44 micrograms/ml at 1 week after delivery, and it decreased significantly (p less than 0.01) to 2.73 micrograms/ml at 1 month after delivery. 2. The mean content of Zn in serum was 0.66 microgram/ml at 1 week, and it increased significantly (p less than 0.01) to 0.84 microgram/ml, close to the normal level, at 1 month. 3. The milk Zn level at 1 week after delivery was about 8 times as high as the Zn in serum. There was a significant (p less than 0.05) negative correlation in Zn contents between milk and serum at 1 week after delivery, and there was no significant correlation in Zn contents between milk and serum at 1 month after delivery. 4. The mean content of Cu in breast milk was 0.55 microgram/ml at 1 week after delivery, and it decreased to 0.44 microgram/ml at 1 month after delivery. 5. The mean content of Cu in serum was 2.14 micrograms/ml at 1 week after delivery, and it decreased significantly (p less than 0.01) to 1.35 micrograms/ml, close to the normal level, at 1 month after delivery. 6. Concerning the Cu contents of milk and serum, there was not a significant correlation at 1 week after delivery, but a significant (p less than 0.05) positive correlation was found at 1 month after delivery.

Recently, the study of the physiological role of the essential trace elements is being emphasized. Some environmental and disease factors has been demonstrated to perturb trace element homeostasis. A number of recent studies have described alterations in serum copper levels (SCLs) and serum zinc levels (SZLs) in human cancer patients and the relationship between the magnitude of their perturbation and disease activity. This report describes SCLs, SZLs and SCL/SZL ratios in patients with malignant neoplasms of the urogenital tract at various clinical stages and the relationship of the levels of these trace elements to disease activity. According to SCLs before treatment, patients with renal cell carcinoma appeared to be separated into two groups, normal SCL group and higher SCL group. In the higher SCL group, patients generally displayed increased erythrocyte sedimentation rate, CRP, alpha 2 globulin, beta 2 microglobulin, ferritin and CEA. In this group, SCL was a useful index of disease activity. In the normal SCL group, SCLs remained within normal limit even in patients with advanced disease. In renal cell carcinoma, SZLs did not reflect disease activity. In transitional cell carcinoma of the upper urinary tract, patients with metastasis had significantly elevated SCLs and significantly decreased SZLs, compared with normal controls or patients without metastasis. In transitional cell carcinoma of the bladder, no distinct relationships were observed between these trace elements and extent of malignancy. But there was a trend toward increasing SCLs and decreasing SZLs with progressing stage and SCL/SZL ratios fairly reflect stage of disease. Patients with prostatic cancer had nearly normal SCLs and SZLs, although there were a few exceptions. Testicular cancer patients with distant metastasis had significantly elevated SCLs and initially high SCLs decreased in patients responding to therapy and increased again in relapse. SZLs and, hence, SCL/SZL ratios had no relationship to activity of testicular cancer. Currently there is no satisfactory way of following the progress of malignancies of the urogenital tract except prostatic cancer with elevated acid phosphatase and non-seminomatous testicular tumors until the secondary tumor can be detected radiographically. Our study suggests that these trace element might be a useful indicator of disease activity of some of the urogenital malignancies.

SA96 in combination with indomethacin or prednisolone was investigated for their effects on the adjuvant arthritis in Lewis rats. SA96 given orally at a dose of 10 mg/kg inhibited the inflammation of adjuvant treated foot and untreated foot and the increase of serum Cu concentration which followed the development of adjuvant arthritis, but 2 mg/kg had no effect. Indomethacin given orally at a dose of 0.1 mg/kg or prednisolone given orally at a dose of 0.4 mg/kg also inhibited the adjuvant arthritis. Prednisolone suppressed the decrease of A/G ratio. Indomethacin and prednisolone, however, had no effects on the increase of serum Cu concentration. SA96 at a dose of 10 mg/kg in combination with indomethacin was more effective than the treatment of each drug alone on inflammation of adjuvant treated and untreated foot, serum Cu concentration, erythrocyte sedimentation rate and A/G ratio. The combination of SA96 at a dose of 2 mg/kg or 10 mg/kg with prednisolone had similar synergistic effects towards the adjuvant arthritis in rats.

Serum copper levels, serum zinc levels, and serum Cu:Zn ratios were evaluated in 100 patients with gastric cancer. The following conclusions were drawn from the results: Serum copper levels and the serum Cu:Zn ratio were elevated, while serum zinc levels were decreased, reflecting the progress of the disease. Since serum zinc levels varied more remarkably, it was suggested that this value was more useful than serum copper levels as an indicator of tumor activity. Serum copper and zinc levels were independent of the presence of liver metastasis and of the histological types. It was shown that the serum copper levels correlated (significantly) to the survival time (p less than 0.005).