Longitudinal and regional association between dietary factors and prevalence of Crohn's disease in Japan.

Although a Western diet has been identified as a risk factor for Crohn's disease (CD), there is still controversy surrounding the specific foods that may contribute to the development of the disease. In this study, we examined the association between food intake and the prevalence of CD in Japan, as Japanese patients with CD are known to have limited genetic involvement. We identified changes in food intake associated with an increase in the number of patients with CD by analyzing the per capita consumption of food types from 1981 to 2014. Additionally, we examined the association between CD prevalence and food intake in each prefecture. Finally, the relationship between food intake and estimated age at CD onset was also investigated. Between 1981 and 2014, we observed Increased consumption of meat, eggs, milk and dairy products, oil, and potatoes and decreased consumption of grains, beans, vegetables, fruit, fish, sugar, and seaweed. The annual incidence of CD increased by 1388% over the same period. We found that meat consumption was significantly associated with CD prevalence (ß = 0.503, p = 0.0003), while a significant negative correlation was observed between CD prevalence and fruit and vegetable consumption (fruit, ß = 0.464, p = 0.0012; vegetables, ß = 0.404, p = 0.0023). Furthermore, we estimated that the peak consumption of more meat and less fruit and vegetables and the peak age of CD onset occurred within the age range of 20-24 years. Our study identified a clear correlation between the consumption of meat, fruits, and vegetables and the prevalence of CD in Japan. Additionally, we found an association between meat, fruit, and vegetable consumption and the age at CD onset.

Selenium Associates With Response to Erythropoiesis-Stimulating Agents in Hemodialysis Patients.

Introduction: Impaired response to erythropoiesis-stimulating agents (ESAs) is associated with increased mortality in patients with end-stage kidney disease. However, the underlying mechanisms are not fully elucidated. Accumulating data reveal that selenium (Se), a trace element, plays a key role in stress erythropoiesis and erythrocyte homeostasis. We evaluated the relationship between serum Se levels and the response to ESAs in hemodialysis patients. Methods: In this cross-sectional study, we determined serum Se levels in 173 hemodialysis patients. We analyzed the association of serum Se with ESA responsiveness, as defined by ESA resistance index. Results: Of the study participants, 50% had lower Se levels than the population-based reference values. We found that serum Se levels were significantly and inversely correlated with erythropoiesis resistance index (ERI) but not transferrin saturation (TSAT) or ferritin levels. Multiple regression analyses confirmed the association between Se levels and ESA hyporesponsiveness, independently of other known factors, such as iron status, being female, and dialysis vintage (ß = -0.11, P < 0.001). When patients were divided according to Se levels and iron status, both low serum Se (<10.5 µg/dl) and iron deficiency significantly affected the response to ESA. Conversely, serum Se levels were significantly different among groups when patients were divided according to ERI quartiles. The association of low serum Se with ESA hyporesponsiveness persisted after adjustment of confounding variables. Conclusion: Serum Se levels are associated with the response to ESAs and can predict ESA resistance independently of iron status in Japanese hemodialysis patients. These data open the possibility to test whether Se supplementation reduces ESA demand.

Early clinical signs and treatment of Menkes disease.

Menkes disease (MD) is an X-linked recessive disorder caused by mutations in ATP7A. Patients with MD exhibit severe neurological and connective tissue disorders due to copper deficiency and typically die before 3 years of age. Early treatment with copper injections during the neonatal period, before the occurrence of neurological symptoms, can alleviate neurological disturbances to some degree. We investigated whether early symptoms can help in the early diagnosis of MD. Abnormal hair growth, prolonged jaundice, and feeding difficulties were observed during the neonatal period in 20 of 69, 16 of 67, and 3 of 18 patients, respectively. Only three patients visited a physician during the neonatal period; MD diagnosis was not made at that point. The mean age at diagnosis was 8.7 months. Seven patients, who were diagnosed in the prenatal stage or soon after birth, as they had a family history of MD, received early treatment. No diagnosis was made based on early symptoms, highlighting the difficulty in diagnosing MD based on symptoms observed during the neonatal period. Patients who received early treatment lived longer than their elderly relatives with MD. Three patients could walk and did not have seizures. Therefore, effective newborn screening for MD should be prioritized.

Isolated neutropenia caused by copper deficiency due to jejunal feeding and excessive zinc intake: A case report.

BACKGROUND: Percutaneous endoscopic gastrostomy with jejunal extension (PEG-J) is often used to treat patients with neurological impairment and difficulty in swallowing. However, these patients often develop copper deficiency. This report describes a case of isolated neutropenia, which is a rare manifestation of copper deficiency. CASE SUMMARY: Our patient was a 19-year-old boy with neurological impairment and gastroesophageal reflux. He received PEG-J feeding, including an enteral supplement containing copper and zinc. However, as his serum zinc level was low (53 µg/dL) at the age of 19 years and 2 mo, we changed to a zinc-rich supplement containing 22 mg/d of zinc and 1.0 mg/d of copper. The supplement comprised a mixture of isocal 1.0 junior (5 packs/d), Tezon [2 packs (250 mL)/d], and cocoa powder. Seven months later, he had neutropenia (606/mm3) with a serum copper level of 16 µg/dL. There were no other manifestations of copper deficiency, including anemia. Copper deficiency and neutropenia both improved following the administration of cocoa powder and Tezon. CONCLUSION: In patients receiving long-term PEG-J feeds, white blood cell counts, hemoglobin, and serum levels of copper and zinc should be regularly monitored.

The Association of Body Image Self-Discrepancy With Female Gender, Calorie-Restricted Diet, and Psychological Symptoms Among Healthy Junior High School Students in Japan.

Background: Body image self-discrepancy reflects a preference for weight loss regardless of normal body size and is a distorted cognition that may be a precursor to eating disorders. The aim of this study was to investigate factors associated with body image self-discrepancy among healthy junior high school students in Japan. Method: This cross-sectional study was conducted at one junior high school in Saitama, Japan, in December 2016. After excluding obese participants (defined as 20% above their ideal weight), 304 students (mean age, 13.9years; n=181 girls, 59.5%) who fell into underweight (n=22, 7.2%) and normal weight categories were selected. Body image self-discrepancy was measured using the Contour Drawing Rating Scale which includes eight separate figures representing body sizes. We then calculated the difference by subtracting ideal from current body sizes and defined body image self-discrepancy if the difference >1. Results: Girls constituted 92% (n=49) of the 53 students with body image self-discrepancy. In all students, multivariable stepwise models demonstrated that female gender (OR, 6.92, 95% CI: 2.33-20.51), a calorie-restricted diet (OR, 5.18, 95% CI: 2.22-12.05), and psychological symptoms (OR, 1.47, 95% CI: 1.15-1.87) were significantly associated with an increased risk of body image self-discrepancy. Specifically for girls, an increased risk of body image self-discrepancy was associated with calorie-restricted suppers and psychological symptoms. Conclusion: Body image self-discrepancy among healthy adolescents in Japan was found to be closely linked to being a girl, having a calorie-restricted diet, and having psychological symptoms.

Pharmacokinetics of CuGTSM, a Novel Drug Candidate, in a Mouse Model of Menkes Disease.

PURPOSE: Menkes disease is a rare hereditary disease in which systemic deficiency of copper due to mutation of the ATP7A gene causes severe neurodegenerative disorders. The present parenteral drugs have limited efficacy, so there is a need for an efficacious drug that can be administered orally. This study focused on glyoxal-bis (N(4)-methylthiosemicarbazonato)-copper(II (CuGTSM), which has shown efficacy in macular mice, a murine model of Menkes disease, and examined its pharmacokinetics. In addition, nanosized CuGTSM (nCuGTSM) was prepared, and the effects of nanosizing on CuGTSM pharmacokinetics were investigated. METHODS: CuGTSM or nCuGTSM (10 mg/kg) was administered orally to male macular mice or C3H/HeNCrl mice (control), and plasma was obtained by serial blood sampling. Plasma concentrations of CuGTSM and GTSM were measured by LC-MS/MS and pharmacokinetic parameters were calculated. RESULTS: When CuGTSM was administered orally, CuGTSM and GTSM were both detected in the plasma of both mouse strains. When nCuGTSM was administered, the Cmax was markedly higher, and the mean residence time was longer than when CuGTSM was administered for both CuGTSM and GTSM in both mouse strains. With macular mice, the AUC ratio (GTSM/CuGTSM) was markedly higher and the plasma CuGTSM concentration was lower than with C3H/HeNCrl mice when either CuGTSM or nCuGTSM was administered. CONCLUSION: Absorption of orally administered CuGTSM was confirmed in macular mice, and the nano-formulation improved the absorption and retention of CuGTSM in the body. However, the plasma concentration of CuGTSM was lower in macular mice than in control mice, suggesting easier dissociation of CuGTSM.

Longitudinal Glycaemic Profiles during Remission in 6q24-Related Transient Neonatal Diabetes Mellitus.

INTRODUCTION: Transient neonatal diabetes mellitus (TNDM) is a rare condition that is characterized by the presence of diabetes mellitus during the first 6 months of life and remission by 18 months of age. It usually relapses at a median age of 14 years. Hyperinsulinaemic hypoglycaemia is a relatively common complication during remission. Although ß-cell function is reported to be impaired at relapse, the clinical course of glycaemic profiles during remission in patients with TNDM remains largely unknown. CASE PRESENTATION: Longitudinal glycaemic profiles were investigated annually from remission (185 days) to relapse (14.5 years) in a patient with TNDM due to paternal 6q24 duplication using the oral glucose tolerance test (glucose intake: 1.75 g/kg to a maximum of 75 g). The patient's ß-cell function and insulin sensitivity were assessed by calculating the insulinogenic index, homeostasis model assessment of ß-cell function (HOMA-ß), homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index, and Matsuda index. Early insulin response to glucose intake was impaired throughout remission, whereas fasting insulin and ß-cell function by HOMA-ß gradually increased in the first few years since remission, followed by a gradual decline in function. In contrast, HOMA-IR fluctuated and peaked at 6.5 years of age. CONCLUSION: This is the first report of annual longitudinal glycaemic profiles in a patient with 6q24-related TNDM during remission. We identified fluctuations in ß-cell function and insulin resistance during remission.

Copper and zinc concentrations in the breast milk of mothers undergoing treatment for Wilson's disease: a prospective study.

Objective: To evaluate the concentrations of copper and zinc in the breast milk of mothers undergoing treatment for Wilson's disease (WD) and clarify whether they can safely breast feed their infants. Design: This was an observational and prospective study in an individual-based case series. Setting: Breast milk samples were collected from participants across Japan from 2007 to 2018 at the Department of Pediatrics, Teikyo University in Tokyo. This was a primary-care level study. Clinical data were collected from the participants' physicians. Patients: Eighteen Japanese mothers with WD who were treated with trientine, penicillamine or zinc, and 25 healthy mothers as controls, were enrolled. Main outcome measures: Whey exacted from the milk was used to evaluate the distribution of copper by high-performance liquid chromatography-inductively coupled plasma mass spectrometry. Copper and zinc concentrations in the breast milk samples were analysed by atomic absorption spectrometry. Results: Copper distribution was normal in the breast milk of mothers with WD treated with trientine, penicillamine or zinc. No peak was detected for trientine-bound or penicillamine-bound copper. The mean copper concentrations in the mature breast milk of patients treated with trientine, penicillamine and zinc were 29.6, 26 and 38 µg/dL, respectively, and were within the normal range compared with the value in healthy controls (33 µg/dL). Likewise, mean zinc concentrations were normal in the mature breast milk of patients treated with trientine and penicillamine (153 and 134 µg/dL, respectively vs 160 µg/dL in healthy controls). Zinc concentrations in the breast milk of mothers treated with zinc were significantly higher than those in control milk. All infants were born normally, breast fed by mothers undergoing treatment and exhibited normal development. Conclusions: Our results suggest that mothers with WD can safely breast feed their infants, even if they are receiving treatment for WD.

Trace element levels in mature breast milk of recently lactating Japanese women.

BACKGROUND: Many trace elements are essential for infant growth and development during early life. Their concentrations in breast milk vary depending on social and economic factors. Nonetheless, the present available values in Japan were derived from lactating mothers approximately 15 years ago. METHODS: Healthy mothers who gave birth to a single infant after 37 weeks of gestation at Teikyo University Hospital were recruited between July 2016 and December 2017. They were encouraged to collect breast milk samples and a self-administered food frequency questionnaire at 1 and 3 months postpartum. Anthropometric data for the mothers and their infants were also collected. Overall, 79 subjects were analyzed after excluding subjects with inadequate data in the food frequency questionnaire, insufficient breast milk samples, and medication that could affect dietary intakes. Trace element concentrations were determined by inductively coupled plasma mass spectrometry, and their correlation with several factors were investigated. RESULTS: Trace element concentrations were widely distributed as previously reported. Median concentrations of Cr, Mn, Fe, Cu, Zn, Se, and Mo were 0.8, 0.8, 98, 50, 272, 2.2, and 0.7 µg/dL at 1 month postpartum and 0.6, 0.7, 55, 33, 177, 2.1, and 0.7 µg/dL at 3 months postpartum, respectively. There were no correlations between trace element concentrations and either mothers' intakes or infants' growth. In contrast, there were significant correlations between several trace elements and macronutrients in addition to inter-element correlations among almost all trace elements. CONCLUSIONS: Trace element concentrations in mature breast milk were determined from recently lactating mothers in Japan.

[The impact of support from medical professionals on families' decision-making during end-of-life care].

Families are involved in decision-making regarding end-of-life (EOL) care in Japan. However, how support from medical professionals toward families' decision-making affects families' satisfaction with EOL care has not been adequately studied. We aimed to examine the impact of support from medical professionals considering the care recipients' preferences on families' overall satisfaction with EOL care and the mediating effect of fulfilling care recipients' preferences.We administered self-report questionnaires through home-nursing providers to bereaved families (n=753), who lost loved ones between April 2015 and March 2016. Analyses were conducted with 237 of these bereaved families whose loved ones had been ≥65 years old, and had no missing values in key variables. We asked whether the families had received any support from medical professionals in determining the care recipients' EOL preferences, in discussing how to honor the care recipients' own interests, and in supporting the families' decision-making. We also collected data measuring the overall satisfaction with EOL care, families' perceptions that the care recipients' preferences were honored during EOL care, and demographic characteristics of care recipients and caregivers.Data from 58 male and 179 female family members were analyzed. The average age was 65.8 (standard deviation [SD]=11.9) years. Care recipients were 113 men and 124 women, and their average age was 83.0 (SD=9.1) years old at the time of death. A path analysis revealed that support for families from medical professionals was related to families' satisfaction with EOL care through the mediating factor of fulfilling care recipients' preferences.Support from medical professionals considering care recipients' preferences will help families' involvement in EOL decision-making.

Japan's Practical Guidelines for Zinc Deficiency with a Particular Focus on Taste Disorders, Inflammatory Bowel Disease, and Liver Cirrhosis.

Zinc deficiency is common in Japan, yet awareness on this disorder is lacking. The Japanese Society of Clinical Nutrition recently issued the Japan's Practical Guideline for Zinc Deficiency 2018 setting forth criteria for diagnosing zinc deficiency, i.e., (a) one or more symptoms of zinc deficiency or low serum alkaline phosphatase, (b) ruling out other diseases, (c) low serum zinc, and (d) alleviation of symptoms upon zinc administration. Serum zinc <60 µg/dL and 60-80 µg/dL indicate zinc deficiency and marginal deficiency, respectively. Zinc deficiency symptoms vary and include dermatitis and taste disorders among others. Zinc administration improves taste in 50-82% of patients suffering from taste disorders (a common symptom of zinc deficiency). Effects of zinc administration do not appear immediately, and therapy should be continued for at least three months. Zinc deficiency often accompanies various diseases and conditions. Here, we focus on inflammatory bowel diseases and liver cirrhosis. As zinc deficiency enhances intestinal inflammation via macrophage activation, we discuss the pathological mechanism for inflammation and zinc deficiency in the context of IBD. Zinc deficiency can also lead to a nitrogen metabolic disorder in patients with liver cirrhosis. Zinc supplementation can improve not only the ammonia metabolism, but also the protein metabolism. We also discuss directions for future studies of zinc deficiency.

Policy statement of enteral nutrition for preterm and very low birthweight infants.

For preterm and very low birthweight infants, the mother's own milk is the best nutrition. Based on the latest information for mothers who give birth to preterm and very low birthweight infants, medical staff should encourage and assist mothers to pump or express and provide their own milk whenever possible. If the supply of maternal milk is insufficient even though they receive adequate support, or the mother's own milk cannot be given to her infant for any reason, donor human milk should be used. Donors who donate their breast milk need to meet the Guideline of the Japan Human Milk Bank Association. Donor human milk should be provided according to the medical needs of preterm and very low birthweight infants, regardless of their family's financial status. In the future, it will be necessary to create a system to supply an exclusive human milk-based diet (EHMD), consisting of human milk with the addition of a human milk-derived human milk fortifier, to preterm and very low birthweight infants.

Effects of Zinc Acetate on Serum Zinc Concentrations in Chronic Liver Diseases: a Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial and a Dose Adjustment Trial.

The essential trace element zinc maintains liver functions. Liver diseases can alter overall zinc concentrations, and hypozincemia is associated with various hepatic pathologies. Modulating systemic zinc through dietary supplementation is potentially useful for liver diseases. We evaluated the usefulness of zinc (NPC-02; acetate formulation) supplementation. We conducted two NPC-02 studies on zinc-deficient patients (serum zinc < 70 µg/dL). Study 1: double-blind, randomized, placebo-controlled trial on 57 subjects with chronic liver diseases comparing serum zinc in patients given NPC-02 (NPC-02 group) versus placebo (Placebo group). Study 2: dose adjustment study on 43 subjects with/without liver diseases to determine proportions maintaining serum zinc target (≥ 80 µg/dL but < 200 µg/dL). In study 1, NPC-02 subjects had higher serum zinc concentrations at week 8 than Placebo subjects (83.2 ± 20.2 and 61.3 ± 12.0, respectively; P < 0.0001), and more NPC-02 than Placebo subjects achieved the serum zinc target (15/27 vs. 1/26). In study 2, the NPC-02-induced serum zinc increase was dose-dependent in subjects both with and without liver diseases (r = 0.5143, P = 0.0022 and r = 0.5753, P = 0.0005, respectively). Interestingly, there was a marginally positive correlation between serum zinc and albumin levels in subjects with but not in those without liver diseases (r = 0.4028, P = 0.0631 and r = 0.1360, P = 0.5567, respectively). NPC-02 dose-dependently increases serum zinc in hypozincemic patients, regardless of liver disease. NPC-02 is a potentially effective therapy for liver cirrhosis, in which zinc deficiency is common. Clinical trial registry number: NCT02337569, NCT02321865.

Maternal Undernutrition and Breast Milk Macronutrient Content Are Not Associated with Weight in Breastfed Infants at 1 and 3 Months after Delivery.

This study examined whether maternal nutritional intake and breast milk macronutrient content influence the weight of breastfed infants. We investigated 129 healthy mothers with singleton babies born from July 2016 to December 2017 in a university hospital in Tokyo, Japan. Information was obtained by a self-administered food frequency questionnaire at 1 (valid response n = 92; mean age, 34 years) and 3 (n = 57) months after delivery. Breast milk was sampled at 1 and 3 months and the macronutrient contents were analyzed. The average pre-pregnancy body mass index and weight gain during pregnancy were 20.7 ± 2.6 kg/m2 and 9.6 ± 3.7 kg, respectively. At 1 month, average maternal calorie intake was 1993 ± 417 kcal/day, which was lower than the intake recommended by Japanese Dietary Reference Intakes for breastfeeding mothers. There were no significant differences with regard to maternal calorie and protein intake, and breast milk macronutrient content between breastfed infants with weight above and below the 25th percentile of its distribution at both 1 and 3 months. This study suggests that suboptimal calorie intake by breastfeeding mothers and breast milk macronutrient content were not associated with weight of their infants at 1 and 3 months after delivery.

A severe case of Menkes disease with repeated bone fracture during the neonatal period, followed by multiple arterial occlusion.

Menkes disease (MD) is a lethal infantile neurodegenerative disorder with X-linked inheritance, characterized by progressive neurodegenerative symptoms caused by pathogenic variants in the ATP7A. Early diagnosis and treatment are important, although the diagnosis is difficult prior to 2 months of age. We present an unusually severe case of MD with skull fractures at the birth and repeated fractures during the neonatal period, with further examinations leading to diagnosis. The patient died due to hemorrhagic shock, due to multiple arterial occlusion despite initiation of copper-histidine therapy in early infancy. Bone fracture at birth and multiple arterial occlusion are very rare findings in MD. This unusual and severe presentation emphasizes the importance of early diagnosis and treatment. A congenital bone fracture should be considered as a possible presentation of MD, especially in cases without birth complications.

ATP7A mutations in 66 Japanese patients with Menkes disease and carrier detection: A gene analysis.

BACKGROUND: Menkes disease (MNK; MIN 309400) is an X-linked recessive lethal disorder of copper metabolism caused by mutations in ATP7A (MIM 300011), which encodes a transmembrane copper-transporting P-type ATPase. This study assessed mutations in ATP7A in Japanese patients with MNK and their families using gene analysis. METHODS: A total of 66 patients with MNK born between 1975 and 2013 in Japan were investigated in this study. Definite diagnosis of MNK was carried out on polymerase chain reaction (PCR) amplification and direct sequencing of each exon. Genetic analysis was also performed on 39 women for carrier diagnosis, and on nine fetuses and 10 neonates for the diagnosis of MNK. RESULTS: We detected 55 different mutations, of which 20 were de novo mutations. The mutations were located around the six copper binding sites, first to third and six transmembrane domains, and the ATP binding site. Of 30 mothers, 23 (76.7%) were carriers. Approximately half of the male siblings of patients with MNK were also diagnosed with MNK. CONCLUSION: Mutations in ATP7A varied widely across patients, although approximately half of the mutations were located in exons 4, 9, 10, and 15. Approximately 23% of patients did not inherit the mutations from their mothers, but had de novo mutations. An early definite diagnosis is necessary for the early treatment of MNK, and gene analysis serves as an effective method for detecting mutations in ATP7A.

Menkes disease: Oral administration of glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) rescues the macular mouse.

BACKGROUND: Menkes disease is a copper metabolism disorder caused by mutations in ATP7A, a copper-transporting P-type ATPase. In this study, oral copper supplementation via glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) (CuGTSM), a lipophilic copper complex, was investigated in male hemizygous macular (MoMl/y) mice, a mouse model of Menkes disease. METHODS: CuGTSM was administered by oral gavage on postnatal days 5, 8, 11, 17, 23, and 32. The copper levels in the organs and serum, copper-dependent enzyme activities in the brain, and ceruloplasmin (Cp) activity in the serum were measured at 15 days and 3 and 8 months of age. Histological analysis of the intestines and the rotarod test were also performed. RESULTS: CuGTSM treatment extended the lifespan of MoMl/y mice and partly restored the copper concentrations and cytochrome oxidase and DBH activities in the brain; however, the rotarod test showed impaired motor performance. The treatment also increased copper concentrations and Cp activity in the serum. In suckling MoMl/y mice, CuGTSM treatment transiently induced diarrhea accompanied by copper accumulation and altered villus morphology in the ileum. CONCLUSION: Oral administration of CuGTSM extended the lifespan of MoMl/y mice. Oral administration is attractive, but pharmaceutical studies are needed to reduce the adverse enteral effects.

Sexual precocity in a girl with early-onset Graves' disease.

We describe the case of a girl diagnosed with Graves' disease (GD) at 2 yr of age, who developed early puberty. Preoperative examination for craniosynostosis revealed thyrotoxicosis. While she was tall and her bone age was advanced at GD onset, her linear growth attenuated after commencement of anti-thyroid treatment. However, at approximately 6 yr of age, breast budding was recognized. Hormonal analysis revealed pubertal levels of LH response to a GnRH stimulation test and serum E2. Gonadal suppression therapy with GnRH agonist was initiated, and her adult stature slightly exceeded the genetic potential. Although accelerated growth and skeletal maturation are often reported to occur at GD onset in prepubertal patients, early puberty is unusual, and this is the first reported case of sexual precocity in a girl with GD.

Disulfiram enhanced delivery of orally administered copper into the central nervous system in Menkes disease mouse model.

INTRODUCTION: Menkes disease (MD) is an X-linked recessive disorder caused by dysfunction of a copper-transporting protein, leading to severe neurodegeneration in early childhood. We investigated whether a lipophilic copper chelator, disulfiram, could enhance copper absorption from the intestine and transport copper across the blood-brain barrier in MD model mice. METHODS: Wild type and MD model mice were pretreated with disulfiram for 30 min before oral administration of 64CuCl2. Each organ was sequentially analyzed for radioactivity with γ counting. Copper uptake into the brain parenchyma was assessed by ex vivo autoradiography. RESULTS: In wild type mice, orally administered copper was initially detected in the intestine within 2 h, reaching a maximum level in the liver (19.6 ± 3.8 percentage injected dose per gram [%ID/g]) at 6 h. In MD model mice, the copper reached the maximum level in the liver (5.3 ± 1.5 %ID/g) at 4 h, which was lower than that of wild type mice (19.0 ± 7.4 %ID/g) (P < 0.05). Pretreatment of disulfiram in MD model mice increased the copper level in the brain (0.59 ± 0.28 %ID/g) at 24 h compared with MD model mice without disulfiram (0.07 ± 0.05 %ID/g) (P < 0.05). Ex vivo autoradiography revealed that high levels of copper uptake was observed in the cerebral cortex upon disulfiram pretreatment. CONCLUSION: Our data demonstrated that disulfiram enhanced the delivery of orally administered copper into the central nervous system in MD model mice. The administration of disulfiram will enable patients to avoid unpleasant subcutaneous copper injection in the future.

[Recent Trends of Trace Element Studies in Clinical Medicine in Japan].

The deficiency or excess intake of trace elements, including zinc, copper, selenium and iodine, has often been reported. Zinc deficiency is often observed in infants fed breast milk with low zinc concentration, individuals administered chelating medicines, athletes and patients with diabetes mellitus, hepatic cirrhosis or nephrosis syndrome. Menkes disease is associated with severe copper deficiency, and there is no effective treatment. Deficiencies of selenium and iodine are observed in patients who receive special formulas of milk and enteral formula with low selenium and iodine concentrations, respectively. In contrast, neonatal transient hypothyroidism due to excess intake of iodine in pregnant women has also reported in Japan. It is expected that collaborative studies by researchers and clinicians will contribute to clarify the detail mechanism, diagnosis and treatment of these abnormalities.