Hemodialysis international. International Symposium on Home Hemodialysis, 2016
Introduction Aspirin is an effective antiplatelet drug for preventing cardiovascular events in hi... more Introduction Aspirin is an effective antiplatelet drug for preventing cardiovascular events in high-risk subjects. However, for patients with chronic kidney disease and undergoing hemodialysis (HD), its preventive efficacy remains controversial. The present study aimed to determine whether aspirin therapy reduces the risk of cardiovascular disease (CVD) and all-cause mortality in patients on HD. Methods We conducted a 5-y prospective cohort study involving patients on HD. Major exposure variables included prescription of aspirin (100 mg/d) and no aspirin (nonaspirin). The primary outcomes included all-cause death, cardiovascular events, hemorrhage, and ischemic stroke. The secondary outcome included bleeding events defined by the requirement of hospitalization. Findings In this study, 406 patients on regular HD were involved during a 5-y follow-up. Among these, 152 and 254 propensity-matched patients were enrolled in the aspirin and nonaspirin cohort, respectively. The cumulative su...
The Journal of investigative dermatology, Jan 21, 2015
Phosphatase of regenerating liver-3 (PRL-3) has been reported to play a critical role in metastat... more Phosphatase of regenerating liver-3 (PRL-3) has been reported to play a critical role in metastatic progression of cancers. Here, we investigate how PRL-3 increases the malignant degree of melanoma cells. The expression of PRL-3 increased gradually during the malignant progression of melanoma. The phosphorylation of Akt was elevated in highly malignant melanoma cells, which was accompanied by a decrease in nuclear PTEN. The phosphorylation of NHERF1 in the serine site was regulated by PRL-3 and showed cytoplasmic translocation upon dephosphorylation, which resulted in a decrease in nuclear PTEN. The co-translocation of NHERF1 and PTEN from the nucleus to the cytoplasm was observed during the malignant progression of melanoma cells. Tumor growth was inhibited significantly and the survival was prolonged upon knockdown of cytoplasmic NHERF1 in B16BL6 cells prior to the inoculation into mice. Taken together, to our knowledge previously unreported, we have identified NHERF1 as a potenti...
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS), 2014
To explore the changes in the body weight and height of Menkes disease (MNK) patients treated wit... more To explore the changes in the body weight and height of Menkes disease (MNK) patients treated with long-term copper-histidine. A survey involving a retrospective review of medical records or summaries of MNK patients was conducted. Patients were 44 males born after 1994, and their feeding method and genetic analysis of the ATP7A gene were reviewed. We compared the data of body weight and height from birth until 6 years between classical MNK patients and the general population obtained from national data and between patients who received early treatment and patients who received late treatment. Although five patients who received early treatment reached some developmental milestones, the body weight and height did not differ from patients who received late treatment in the mode of oral nutrition, and were lower in comparison to the national data (<3 percentile). We reported changes in the body weight and height of MNK patients who received early and late treatment. Although early ...
Pediatrics international : official journal of the Japan Pediatric Society, 2010
Residual dried blood spots (DBS) remaining after routine newborn screening (NBS) tests are candid... more Residual dried blood spots (DBS) remaining after routine newborn screening (NBS) tests are candidate specimens for extended uses such as quality assurance and the development of new technology. A trial of NBS using tandem mass-spectrometry was launched in 2004 in Japan. The aim of the present study was to analyze the attitudes of the public, patient families, and medical professionals toward the extended use and long-term storage of residual DBS, and to construct a standardized informational brochure. A questionnaire was sent to randomly selected members of the public, members of the Japanese Phenylketonuria (PKU) Association, medical staff of a general hospital, staff of a children's hospital, obstetricians and gynecologists, pediatricians and NBS personnel. Associated responses, which were given in a free comment format, were analyzed by text mining. The awareness ratio of NBS was low in the public (26.6%), but despite this, when a brief explanatory note on NBS was provided, 7...
Pediatrics international : official journal of the Japan Pediatric Society, 2000
Human rotaviruses are the major etiologic agents of diarrhea in infants and young children under ... more Human rotaviruses are the major etiologic agents of diarrhea in infants and young children under 2 years of age worldwide. Rotavirus diarrhea is a life-threatening disease for children; many efforts are made to reduce the morbidity and mortality in Asia. To date many natural compounds and some Western medicines have exhibited their antirotavirus effects in clinical studies, in animal experiments and in vitro. Compared with antirotavirus agents in the USA and Europe, natural compounds have been identified as ideal candidates for antirotaviral drugs in Asia because they are cheaper and effective, have no side-effect and no toxicity. We have attempted to reveal the antirotavirus mechanism of some natural compounds. We found that cacao pigment, tea extract and pine seed shell extract inhibit rotavirus adsorption to cells while cacao pigment may also inhibit rotavirus reproduction in vitro. The usage of antirotavirus agents in Asia demonstrated that additional effective approaches to con...
ABSTRACT BiFeO(3), BiFe(0.9)Ti(0.1)O(3) and BiFe(0.9)Ti(0.0)O(3) ceramics were prepared by solid ... more ABSTRACT BiFeO(3), BiFe(0.9)Ti(0.1)O(3) and BiFe(0.9)Ti(0.0)O(3) ceramics were prepared by solid state reactions and were compared in electrical and dielectric properties. The resistivity of BiFe(0.9)Ti(0.05)O(3) was 1.3 x10(12 Omega) cm, which was about two and a half orders of magnitude higher than that of BiFe03. and three times higher than that of BiFe(0.9)Ti(0.1)O(3). The dielectric loss of BiFe(0.9)Ti(0.05)O(3) was 0.1 and 0.02 at 100Hz and 1MHz, respectively. These phenomena can be explained base on the decrease of oxygen vacancies Vo and defect complexes between the ferrum vacancies VFe&quot; and oxygen vacancies Vo in the ceramics.
Erlotinib is a potent inhibitor of epidermal growth factor receptor tyrosine kinase and has been ... more Erlotinib is a potent inhibitor of epidermal growth factor receptor tyrosine kinase and has been demonstrated to treat advanced or metastatic non-small cell lung cancer to prolong survival after failure of first-line or second-line chemotherapy. However, little is known about its effects on immune system. In the present study, we aimed to investigate the immunosuppressive activity of erlotinib on T lymphocytes both in vitro and in vivo, and further explore its potential molecular mechanism. Erlotinib exerted a significant inhibition on the T cell proliferation and activation induced by concanavalin A, anti-CD3 plus anti-CD28, staphylococcal enterotoxin B or phorbol myristate acetate respectively in a concentration-dependent manner and it also inhibited the secretion of the proinflammatory cytokines such as IL-2 and IFN-γ of activated T cells. Further study showed that erlotinib caused G0/G1 arrest and suppressed the phosphorylations of c-Raf, ERK and Akt in activated T cells. Moreover, erlotinib significantly ameliorated picryl chloride-induced ear contact dermatitis in a dose-dependent manner in vivo. In summary, these findings suggest that erlotinib may cause the impairment of T-cell-mediated immune response both in vitro and in vivo through inhibiting T cell proliferation and activation, which is closely associated with its potent down-regulation of the c-Raf/ERK cascade and Akt signaling pathway.
In the present paper, we aimed to examine the novel effects of cerebroside D, a glycoceramide com... more In the present paper, we aimed to examine the novel effects of cerebroside D, a glycoceramide compound, on murine experimental colitis. Cerebroside D significantly reduced the weight loss, mortality rate and alleviated the macroscopic and microscopic appearances of colitis induced by dexran sulfate sodium. This compound also decreased the levels of TNF-α, IFN-γ and IL-1β in intestinal tissue of mice with experimental colitis in a concentration-dependent manner, accompanied with markedly increased serum level of IL-10. Cerebroside D inhibited proliferation and induced apoptosis of T cells activated by concanavalin A or anti-CD3 plus anti-CD28 antibodies. The compound did not show an effect on naive lymphocytes but prevented cells from entering S phase and G2/M phase during T cells activation. Moreover, the treatment of cerebroside D led to apoptosis of activated T cells with the cleavage of caspase 3, 9, 12 and PARP. These results showed multiple effects of cerebroside D against activated T cells for a novel approach to treatment of colonic inflammation.
Much remains unknown regarding extrathyroidal congenital malformations (ECMs) in patients with pr... more Much remains unknown regarding extrathyroidal congenital malformations (ECMs) in patients with primary congenital hypothyroidism (PCH) and Down syndrome (DS). Here, we investigated the frequency of ECMs in patients with PCH, particularly among patients with or without DS. In a retrospective review of questionnaires based on medical records, ECMs were identified in 1520 patients with PCH and were compared with congenital malformations among nationwide live births or liveborn infants with DS. The ECMs in PCH patients with or without DS were then analyzed. The statistical analysis was based on the Poisson distribution. Ethnicity, sex, and familial and seasonal factors were also observed in relation to the ECMs. The incidences of ECMs (222/1520, 14.6%) and DS (86/1520, 5.7%) were significantly higher among the PCH patients than among the general population. Among the 127 PCH patients without chromosomal abnormalities, 101 had a single ECM and 26 had multiple ECMs. Unlike previously reported American and Egyptian patients with PCH, a significantly higher incidence of cardiovascular malformations was observed in the Japanese PCH patients, and a female predominance was also observed, except in patients with multiple ECMs. Regarding the PCH patients with DS, a significantly higher, male-predominant incidence of duodenal atresia was observed, compared with data for liveborn infants with DS, whereas a male-predominant, significantly higher incidence of gastrointestinal malformations and a female-predominant, significantly higher incidence of cardiovascular malformations were found compared with data among PCH patients without DS. Moreover, urogenital and orofacial ECMs were absent among the PCH patients with DS. Regarding PCH patients without DS, a male-predominant, significantly higher incidence of urogenital malformations and a female-predominant, significantly higher incidence of cardiovascular and nervous malformations were found, compared with data for nationwide live births. In PCH patients with DS and in PCH patients with a single ECM, both familial and seasonal factors existed, while in PCH patients with multiple ECMs, only familial factors were observed. The incidence of ECMs in PCH patients was significantly higher than in the normal population, and ethnic-, sex-, and DS-related differences were observed. Genetic and environmental factors were also identified in PCH patients with ECMs.
Seasonality in the incidence of congenital hypothyroidism (CH) has been reported in several count... more Seasonality in the incidence of congenital hypothyroidism (CH) has been reported in several countries. The objective of this study was to examine whether seasonality was also observable in Japan and whether this seasonality affected genders differently. Confirmed primary CH cases (n = 1586) occurring between 1994 and 2003 were examined through a retrospective review of the nationwide follow-up system at the Aiiku Maternal and Child Health Center, Tokyo, Japan. The number of live births in Japan was obtained from the country&amp;amp;amp;amp;#39;s vital statistics. Monthly incidence of CH was analyzed using time series analysis. The relationship between monthly incidence and ambient temperature was also investigated. The sex ratio (female/male) was 1.25 for CH, against a background ratio of 0.95 for overall live births in Japan. Monthly CH incidence showed an upward time trend and clear seasonality among both males and females, but with different patterns between the two genders: from January to December, males had one peak while females had two peaks, which continued for a longer period than males had. A significant statistical correlation was found between the incidence and temperature (p &amp;amp;amp;amp;lt; 0.001). In Japan, the monthly incidence of primary CH cases exhibits temperature-associated seasonality, gender-specific patterns, and an upward time trend.
To investigate the time trend and geographic distribution of treated patients with congenital hyp... more To investigate the time trend and geographic distribution of treated patients with congenital hypothyroidism (CH) and explore their possible relationship to the availability of endocrinologists in Japan. The 2-source capture-recapture method was used to estimate the total number of patients. The ratio of the total estimated number of patients with CH to the number of endocrinologists and Spearman correlation coefficients were calculated. Curve fitting for changes in incidence or prevalence was estimated. The incidence and prevalence of CH exhibited upward trends, with linear slopes of increase during the period 1994-2002. A statistically significant positive correlation was observed between the prevalence of CH and the ratio of the number of patients with CH to the number of endocrinologists in the 10 regions studied. The prevalence of CH was significantly higher in the regions with a higher ratio of patients with CH to endocrinologists, and also in younger patients. A shortage of endocrinologists may be one reason for the upward trend in the incidence and prevalence of treated patients with CH.
Menkes disease (MD) is a neurodegenerative disorder characterized by a copper deficiency in the b... more Menkes disease (MD) is a neurodegenerative disorder characterized by a copper deficiency in the brain. It is caused by the defective intestinal absorption of copper resulting from a deficiency of a copper-transporting ATPase, ATP7A. This gives rise to an accumulation of copper in the intestine. The copper deficiency in the brain of MD patients cannot be improved by copper injections, because the administered copper accumulates at the blood-brain barrier and is not transported across to the neurons. To resolve this problem, we investigated the effect of a combination therapy of copper and sodium diethyldithiocarbamate (DEDTC), a lypophilic chelator, in an animal model of MD, the macular mouse. Four-week-old macular mice treated with 50 mug of CuCl2 on the 7th day after birth were used. Experimental mice were given a subcutaneous injection of CuCl2 (4 microg) and an intraperitoneal injection of DEDTC (0.2 mg/g body weight) twice a week for 4 weeks and then sacrificed. Copper concentrations and cytochrome-c oxidase activity in the brains of treated mice were higher than those of control macular mice, which received only copper or saline. The ratios of brain noradrenaline to dopamine and of adrenaline to dopamine were also increased by the treatment, suggesting that the activity of dopamine beta-hydroxylase, a copper-dependent enzyme, was improved by the treatment. Liver and renal function tests showed no abnormalities in the treated mice, although copper concentrations in the kidneys of treated mice were higher than those of control macular mice. These results suggest that DEDTC facilitates the passage of copper across the blood-brain barrier and that the combination therapy of copper and DEDTC may be an effective treatment for the neurological disturbances suffered by patients with MD.
Menkes disease (MNK) is a lethal, X-linked recessive disorder of copper metabolism dominated by n... more 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.
Menkes disease (MNK) is an X-linked recessive disorder. Incidence of live-born infants with MNK i... more Menkes disease (MNK) is an X-linked recessive disorder. Incidence of live-born infants with MNK is 2.8 per million live births in Japan. The aim of this study was to observe congenital malformations (CMs) in MNK patients. Subjects comprised 35 Japanese male patients with classical MNK who received copper histidine treatment. Patient clinical data were obtained anonymously from medical records or medical record summaries by pediatrician&amp;amp;#39;s retrospective review through a survey. We observed 21 different CMs in 14 patients. Eight of these had a single CM, while six had multiple CMs. The most frequent CM was higher arched palate with other CMs found in five patients. There was no relationship between CMs and mutations in the ATP7A gene. Using Mann-Whitney U tests, age at death was also significantly lower in MNK patients with CMs (P&amp;amp;lt;0.05), compared to those without CMs, even though there was no significant difference of age onset, age at diagnosis and age at start of treatment with copper histidine between both groups of patients. Sudden death occurred in three MNK patients with CMs only: two with congenital heart disease, and one with microphallus.
Hemodialysis international. International Symposium on Home Hemodialysis, 2016
Introduction Aspirin is an effective antiplatelet drug for preventing cardiovascular events in hi... more Introduction Aspirin is an effective antiplatelet drug for preventing cardiovascular events in high-risk subjects. However, for patients with chronic kidney disease and undergoing hemodialysis (HD), its preventive efficacy remains controversial. The present study aimed to determine whether aspirin therapy reduces the risk of cardiovascular disease (CVD) and all-cause mortality in patients on HD. Methods We conducted a 5-y prospective cohort study involving patients on HD. Major exposure variables included prescription of aspirin (100 mg/d) and no aspirin (nonaspirin). The primary outcomes included all-cause death, cardiovascular events, hemorrhage, and ischemic stroke. The secondary outcome included bleeding events defined by the requirement of hospitalization. Findings In this study, 406 patients on regular HD were involved during a 5-y follow-up. Among these, 152 and 254 propensity-matched patients were enrolled in the aspirin and nonaspirin cohort, respectively. The cumulative su...
The Journal of investigative dermatology, Jan 21, 2015
Phosphatase of regenerating liver-3 (PRL-3) has been reported to play a critical role in metastat... more Phosphatase of regenerating liver-3 (PRL-3) has been reported to play a critical role in metastatic progression of cancers. Here, we investigate how PRL-3 increases the malignant degree of melanoma cells. The expression of PRL-3 increased gradually during the malignant progression of melanoma. The phosphorylation of Akt was elevated in highly malignant melanoma cells, which was accompanied by a decrease in nuclear PTEN. The phosphorylation of NHERF1 in the serine site was regulated by PRL-3 and showed cytoplasmic translocation upon dephosphorylation, which resulted in a decrease in nuclear PTEN. The co-translocation of NHERF1 and PTEN from the nucleus to the cytoplasm was observed during the malignant progression of melanoma cells. Tumor growth was inhibited significantly and the survival was prolonged upon knockdown of cytoplasmic NHERF1 in B16BL6 cells prior to the inoculation into mice. Taken together, to our knowledge previously unreported, we have identified NHERF1 as a potenti...
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS), 2014
To explore the changes in the body weight and height of Menkes disease (MNK) patients treated wit... more To explore the changes in the body weight and height of Menkes disease (MNK) patients treated with long-term copper-histidine. A survey involving a retrospective review of medical records or summaries of MNK patients was conducted. Patients were 44 males born after 1994, and their feeding method and genetic analysis of the ATP7A gene were reviewed. We compared the data of body weight and height from birth until 6 years between classical MNK patients and the general population obtained from national data and between patients who received early treatment and patients who received late treatment. Although five patients who received early treatment reached some developmental milestones, the body weight and height did not differ from patients who received late treatment in the mode of oral nutrition, and were lower in comparison to the national data (<3 percentile). We reported changes in the body weight and height of MNK patients who received early and late treatment. Although early ...
Pediatrics international : official journal of the Japan Pediatric Society, 2010
Residual dried blood spots (DBS) remaining after routine newborn screening (NBS) tests are candid... more Residual dried blood spots (DBS) remaining after routine newborn screening (NBS) tests are candidate specimens for extended uses such as quality assurance and the development of new technology. A trial of NBS using tandem mass-spectrometry was launched in 2004 in Japan. The aim of the present study was to analyze the attitudes of the public, patient families, and medical professionals toward the extended use and long-term storage of residual DBS, and to construct a standardized informational brochure. A questionnaire was sent to randomly selected members of the public, members of the Japanese Phenylketonuria (PKU) Association, medical staff of a general hospital, staff of a children's hospital, obstetricians and gynecologists, pediatricians and NBS personnel. Associated responses, which were given in a free comment format, were analyzed by text mining. The awareness ratio of NBS was low in the public (26.6%), but despite this, when a brief explanatory note on NBS was provided, 7...
Pediatrics international : official journal of the Japan Pediatric Society, 2000
Human rotaviruses are the major etiologic agents of diarrhea in infants and young children under ... more Human rotaviruses are the major etiologic agents of diarrhea in infants and young children under 2 years of age worldwide. Rotavirus diarrhea is a life-threatening disease for children; many efforts are made to reduce the morbidity and mortality in Asia. To date many natural compounds and some Western medicines have exhibited their antirotavirus effects in clinical studies, in animal experiments and in vitro. Compared with antirotavirus agents in the USA and Europe, natural compounds have been identified as ideal candidates for antirotaviral drugs in Asia because they are cheaper and effective, have no side-effect and no toxicity. We have attempted to reveal the antirotavirus mechanism of some natural compounds. We found that cacao pigment, tea extract and pine seed shell extract inhibit rotavirus adsorption to cells while cacao pigment may also inhibit rotavirus reproduction in vitro. The usage of antirotavirus agents in Asia demonstrated that additional effective approaches to con...
ABSTRACT BiFeO(3), BiFe(0.9)Ti(0.1)O(3) and BiFe(0.9)Ti(0.0)O(3) ceramics were prepared by solid ... more ABSTRACT BiFeO(3), BiFe(0.9)Ti(0.1)O(3) and BiFe(0.9)Ti(0.0)O(3) ceramics were prepared by solid state reactions and were compared in electrical and dielectric properties. The resistivity of BiFe(0.9)Ti(0.05)O(3) was 1.3 x10(12 Omega) cm, which was about two and a half orders of magnitude higher than that of BiFe03. and three times higher than that of BiFe(0.9)Ti(0.1)O(3). The dielectric loss of BiFe(0.9)Ti(0.05)O(3) was 0.1 and 0.02 at 100Hz and 1MHz, respectively. These phenomena can be explained base on the decrease of oxygen vacancies Vo and defect complexes between the ferrum vacancies VFe&quot; and oxygen vacancies Vo in the ceramics.
Erlotinib is a potent inhibitor of epidermal growth factor receptor tyrosine kinase and has been ... more Erlotinib is a potent inhibitor of epidermal growth factor receptor tyrosine kinase and has been demonstrated to treat advanced or metastatic non-small cell lung cancer to prolong survival after failure of first-line or second-line chemotherapy. However, little is known about its effects on immune system. In the present study, we aimed to investigate the immunosuppressive activity of erlotinib on T lymphocytes both in vitro and in vivo, and further explore its potential molecular mechanism. Erlotinib exerted a significant inhibition on the T cell proliferation and activation induced by concanavalin A, anti-CD3 plus anti-CD28, staphylococcal enterotoxin B or phorbol myristate acetate respectively in a concentration-dependent manner and it also inhibited the secretion of the proinflammatory cytokines such as IL-2 and IFN-γ of activated T cells. Further study showed that erlotinib caused G0/G1 arrest and suppressed the phosphorylations of c-Raf, ERK and Akt in activated T cells. Moreover, erlotinib significantly ameliorated picryl chloride-induced ear contact dermatitis in a dose-dependent manner in vivo. In summary, these findings suggest that erlotinib may cause the impairment of T-cell-mediated immune response both in vitro and in vivo through inhibiting T cell proliferation and activation, which is closely associated with its potent down-regulation of the c-Raf/ERK cascade and Akt signaling pathway.
In the present paper, we aimed to examine the novel effects of cerebroside D, a glycoceramide com... more In the present paper, we aimed to examine the novel effects of cerebroside D, a glycoceramide compound, on murine experimental colitis. Cerebroside D significantly reduced the weight loss, mortality rate and alleviated the macroscopic and microscopic appearances of colitis induced by dexran sulfate sodium. This compound also decreased the levels of TNF-α, IFN-γ and IL-1β in intestinal tissue of mice with experimental colitis in a concentration-dependent manner, accompanied with markedly increased serum level of IL-10. Cerebroside D inhibited proliferation and induced apoptosis of T cells activated by concanavalin A or anti-CD3 plus anti-CD28 antibodies. The compound did not show an effect on naive lymphocytes but prevented cells from entering S phase and G2/M phase during T cells activation. Moreover, the treatment of cerebroside D led to apoptosis of activated T cells with the cleavage of caspase 3, 9, 12 and PARP. These results showed multiple effects of cerebroside D against activated T cells for a novel approach to treatment of colonic inflammation.
Much remains unknown regarding extrathyroidal congenital malformations (ECMs) in patients with pr... more Much remains unknown regarding extrathyroidal congenital malformations (ECMs) in patients with primary congenital hypothyroidism (PCH) and Down syndrome (DS). Here, we investigated the frequency of ECMs in patients with PCH, particularly among patients with or without DS. In a retrospective review of questionnaires based on medical records, ECMs were identified in 1520 patients with PCH and were compared with congenital malformations among nationwide live births or liveborn infants with DS. The ECMs in PCH patients with or without DS were then analyzed. The statistical analysis was based on the Poisson distribution. Ethnicity, sex, and familial and seasonal factors were also observed in relation to the ECMs. The incidences of ECMs (222/1520, 14.6%) and DS (86/1520, 5.7%) were significantly higher among the PCH patients than among the general population. Among the 127 PCH patients without chromosomal abnormalities, 101 had a single ECM and 26 had multiple ECMs. Unlike previously reported American and Egyptian patients with PCH, a significantly higher incidence of cardiovascular malformations was observed in the Japanese PCH patients, and a female predominance was also observed, except in patients with multiple ECMs. Regarding the PCH patients with DS, a significantly higher, male-predominant incidence of duodenal atresia was observed, compared with data for liveborn infants with DS, whereas a male-predominant, significantly higher incidence of gastrointestinal malformations and a female-predominant, significantly higher incidence of cardiovascular malformations were found compared with data among PCH patients without DS. Moreover, urogenital and orofacial ECMs were absent among the PCH patients with DS. Regarding PCH patients without DS, a male-predominant, significantly higher incidence of urogenital malformations and a female-predominant, significantly higher incidence of cardiovascular and nervous malformations were found, compared with data for nationwide live births. In PCH patients with DS and in PCH patients with a single ECM, both familial and seasonal factors existed, while in PCH patients with multiple ECMs, only familial factors were observed. The incidence of ECMs in PCH patients was significantly higher than in the normal population, and ethnic-, sex-, and DS-related differences were observed. Genetic and environmental factors were also identified in PCH patients with ECMs.
Seasonality in the incidence of congenital hypothyroidism (CH) has been reported in several count... more Seasonality in the incidence of congenital hypothyroidism (CH) has been reported in several countries. The objective of this study was to examine whether seasonality was also observable in Japan and whether this seasonality affected genders differently. Confirmed primary CH cases (n = 1586) occurring between 1994 and 2003 were examined through a retrospective review of the nationwide follow-up system at the Aiiku Maternal and Child Health Center, Tokyo, Japan. The number of live births in Japan was obtained from the country&amp;amp;amp;amp;#39;s vital statistics. Monthly incidence of CH was analyzed using time series analysis. The relationship between monthly incidence and ambient temperature was also investigated. The sex ratio (female/male) was 1.25 for CH, against a background ratio of 0.95 for overall live births in Japan. Monthly CH incidence showed an upward time trend and clear seasonality among both males and females, but with different patterns between the two genders: from January to December, males had one peak while females had two peaks, which continued for a longer period than males had. A significant statistical correlation was found between the incidence and temperature (p &amp;amp;amp;amp;lt; 0.001). In Japan, the monthly incidence of primary CH cases exhibits temperature-associated seasonality, gender-specific patterns, and an upward time trend.
To investigate the time trend and geographic distribution of treated patients with congenital hyp... more To investigate the time trend and geographic distribution of treated patients with congenital hypothyroidism (CH) and explore their possible relationship to the availability of endocrinologists in Japan. The 2-source capture-recapture method was used to estimate the total number of patients. The ratio of the total estimated number of patients with CH to the number of endocrinologists and Spearman correlation coefficients were calculated. Curve fitting for changes in incidence or prevalence was estimated. The incidence and prevalence of CH exhibited upward trends, with linear slopes of increase during the period 1994-2002. A statistically significant positive correlation was observed between the prevalence of CH and the ratio of the number of patients with CH to the number of endocrinologists in the 10 regions studied. The prevalence of CH was significantly higher in the regions with a higher ratio of patients with CH to endocrinologists, and also in younger patients. A shortage of endocrinologists may be one reason for the upward trend in the incidence and prevalence of treated patients with CH.
Menkes disease (MD) is a neurodegenerative disorder characterized by a copper deficiency in the b... more Menkes disease (MD) is a neurodegenerative disorder characterized by a copper deficiency in the brain. It is caused by the defective intestinal absorption of copper resulting from a deficiency of a copper-transporting ATPase, ATP7A. This gives rise to an accumulation of copper in the intestine. The copper deficiency in the brain of MD patients cannot be improved by copper injections, because the administered copper accumulates at the blood-brain barrier and is not transported across to the neurons. To resolve this problem, we investigated the effect of a combination therapy of copper and sodium diethyldithiocarbamate (DEDTC), a lypophilic chelator, in an animal model of MD, the macular mouse. Four-week-old macular mice treated with 50 mug of CuCl2 on the 7th day after birth were used. Experimental mice were given a subcutaneous injection of CuCl2 (4 microg) and an intraperitoneal injection of DEDTC (0.2 mg/g body weight) twice a week for 4 weeks and then sacrificed. Copper concentrations and cytochrome-c oxidase activity in the brains of treated mice were higher than those of control macular mice, which received only copper or saline. The ratios of brain noradrenaline to dopamine and of adrenaline to dopamine were also increased by the treatment, suggesting that the activity of dopamine beta-hydroxylase, a copper-dependent enzyme, was improved by the treatment. Liver and renal function tests showed no abnormalities in the treated mice, although copper concentrations in the kidneys of treated mice were higher than those of control macular mice. These results suggest that DEDTC facilitates the passage of copper across the blood-brain barrier and that the combination therapy of copper and DEDTC may be an effective treatment for the neurological disturbances suffered by patients with MD.
Menkes disease (MNK) is a lethal, X-linked recessive disorder of copper metabolism dominated by n... more 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.
Menkes disease (MNK) is an X-linked recessive disorder. Incidence of live-born infants with MNK i... more Menkes disease (MNK) is an X-linked recessive disorder. Incidence of live-born infants with MNK is 2.8 per million live births in Japan. The aim of this study was to observe congenital malformations (CMs) in MNK patients. Subjects comprised 35 Japanese male patients with classical MNK who received copper histidine treatment. Patient clinical data were obtained anonymously from medical records or medical record summaries by pediatrician&amp;amp;#39;s retrospective review through a survey. We observed 21 different CMs in 14 patients. Eight of these had a single CM, while six had multiple CMs. The most frequent CM was higher arched palate with other CMs found in five patients. There was no relationship between CMs and mutations in the ATP7A gene. Using Mann-Whitney U tests, age at death was also significantly lower in MNK patients with CMs (P&amp;amp;lt;0.05), compared to those without CMs, even though there was no significant difference of age onset, age at diagnosis and age at start of treatment with copper histidine between both groups of patients. Sudden death occurred in three MNK patients with CMs only: two with congenital heart disease, and one with microphallus.
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