Seiya Okuda

Kurume University, Куруме, Fukuoka, Japan

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Publications (229)873.93 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Diabetic patients with severe chronic kidney disease (CKD) not treated with dialysis falsely show low levels of HbA1c and GA due to renal anemia and proteinuria, respectively. Recently, we reported that serum albumin-adjusted GA (adjGA) accurately reflects mean plasma glucose (PG) in these patients. It is considered that GA reflects not only mean PG but also glycemic excursion; therefore, in the present study we investigated whether adjGA reflects glycemic excursion in these patients.
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    ABSTRACT: Advanced glycation end products (AGEs) and their receptor (RAGE) have a role in diabetic nephropathy. We have recently found that linagliptin, an inhibitor of dipeptidyl peptidase-4 (DPP-4), could inhibit renal damage in type 1 diabetic rats by suppressing the AGE-RAGE axis. However, it remains unclear whether DPP-4 deficiency could also have beneficial effects on experimental diabetic nephropathy. To address the issue, we rendered wild-type F344/NSlc and DPP-4-deficient F344/DuCrl/Crlj rats diabetic by injection of streptozotocin, and then investigated whether DPP-4 deficiency could block the activation of AGE-RAGE axis in the diabetic kidneys and resultantly ameliorate renal injury in streptozotocin-induced diabetic rats. Compared with control rats at 9 and 11 weeks old, body weight and heart rates were significantly lower, while fasting blood glucose was higher in wild-type and DPP-4-deficient diabetic rats at the same age. There was no significant difference of body weight, fasting blood glucose and lipid parameters between the two diabetic rat strains. AGEs, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nitrotyrosine levels in the kidney, renal gene expression of RAGE and intercellular adhesion molecule-1, glomerular area, urinary excretion of 8-OHdG and albumin, and the ratio of renal to body weight were increased in wild-type diabetic rats at 9 and/or 11 weeks old compared with age-matched control rats, all of which except for urinary 8-OHdG levels at 11 weeks old were significantly suppressed in DPP-4-deficient diabetic rats. Our present study suggests that DPP-4 deficiency could exert beneficial actions on type 1 diabetic nephropathy partly by blocking the AGE-RAGE axis. DPP-4 might be a novel therapeutic target for preventing diabetic nephropathy.Laboratory Investigation advance online publication, 2 March 2015; doi:10.1038/labinvest.2015.35.
    Laboratory Investigation 03/2015; 95(5). DOI:10.1038/labinvest.2015.35 · 3.83 Impact Factor
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    ABSTRACT: Food or supplement-derived L-carnitine is changed to trimethylamine (TMA) by interstinal microbiota, which is further metabolized to trimethylamine-N-oxide (TMAO), being involved in the promotion of atherosclerosis in animal models. Meanwhile, carnitine deficiency has played a role in accelerated atherosclerosis in hemodialysis (HD) patients. However, effects of oral L-carnitine supplementation on circulating levels of TMAO and markers of vascular injury and oxidative stress in patients on HD remain unclear. In this study, we addressed the issue. Thirty-one HD patients with carnitine deficiency were treated with oral L-carnitine (900mg/day) for 6 months. At baseline and after treatment, clinical variables including circulating levels of carnitine fractions, TMA, TMAO, advanced glycation end products (AGE), soluble forms of intracellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and malondialdehyde (MDA) were measured. Oral L-carnitine supplementation significantly increased total, free, and acyl carnitine, and plasma TMA and TMAO levels, whereas it decreased markers of vascular injury and oxidative stress such as sICAM-1, sVCAM-1, and MDA levels. TMA and TMAO levels at baseline were correlated with each other, and free carnitine was independently associated with TMAO levels. Further, change in AGE values from baseline ([INCREMENT]AGE) was positively correlated with [INCREMENT]sICAM-1 (p=0.043), and was a sole independent determinant of [INCREMENT]sICAM-1 (R2=0.133, p=0.043). The present study demonstrated that although oral L-carnitine supplementation was associated with increased TMAO levels, it might be beneficial on vascular injury in patients on HD. Vasculoprotective properties of L-carnitine supplementation in HD patients might be ascribed partly to its inhibitory actions on AGE.
    Journal of Cardiovascular Pharmacology 01/2015; DOI:10.1097/FJC.0000000000000197 · 2.11 Impact Factor
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    ABSTRACT: Corresponding author at: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
    Thrombosis Research 01/2015; 135(4). DOI:10.1016/j.thromres.2015.01.023 · 2.43 Impact Factor
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    ABSTRACT: Diabetic patients with end-stage renal disease (ESRD) who are not on hemodialysis show low levels of HbA1c and GA due to renal anemia and proteinuria, respectively. In the present study, we examined whether serum albumin (SA)-adjusted GA (adjGA) could accurately reflect glycemic control in these patients. To examine the correlation between GA and SA (Study 1), 49 diabetic patients with ESRD not on hemodialysis were used. To evaluate the association between the glycemic control indicators and the glycemic control state (Study 2), 30 diabetic patients with ESRD were enrolled. The estimated HbA1c (eHbA1c) and the estimated GA (eGA) levels were calculated based on the mean blood glucose levels obtained from the diurnal variation. The adjGA levels were calculated from the regression formula between the SA and GA obtained from Study 1. No significant correlation was found between the measured HbA1c (mHbA1c) and eHbA1c levels. The eHbA1c (inversely) and mHbA1c/eHbA1c ratio (positively), but not mHbA1c, showed a significant correlation with Hb levels. The eGA was positively associated with the mGA and adjGA levels. Although mGA/eGA ratio was positively correlated with SA, there was no significant association between the adjGA/eGA ratio and SA, Hb and eGFR. We found for the first time that the adjustment of GA by SA could be useful to determine glycemic control in diabetic patients with ESRD not on hemodialysis. These findings suggest that adjGA might be a better indicator of glycemic control than mHbA1c and mGA in these patients. © 2015 Sage Publications, Inc.
    Annals of Clinical Biochemistry 01/2015; DOI:10.1177/0004563214568162 · 2.08 Impact Factor
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    ABSTRACT: Receptor for advanced glycation endproducts (RAGE) is a multiligand receptor of the immunoglobulin superfamily, which binds not only to advanced glycation endproducts, but also to high-mobility group box-1, S100/calgranulins, amyloid fibrils, and lipopolysaccharide. We discuss the pathophysiological role of RAGE in both diabetic and nondiabetic progressive renal diseases, and its potential use for therapeutic interventions in these devastating disorders. Although initial studies about RAGE focused on diabetic nephropathy, a number of recent findings have revealed that RAGE also actively participates in the pathogenesis of nondiabetic progressive renal diseases, including hypertensive nephropathy, obesity-related glomerulopathy, lupus nephritis, autosomal dominant polycystic kidney disease, renal amyloidosis, and septic acute kidney injury. Furthermore, blocking the RAGE by a neutralizing antibody or genetic deletion of RAGE was found to prevent the development and progression of various renal disorders. The interaction of several RAGE ligands with RAGE plays a role in a broad range of progressive kidney diseases. The blockade of the various RAGE ligands-RAGE interactions might be a novel therapeutic strategy for preventing the development and progression of numerous progressive kidney diseases.
    Current Opinion in Nephrology and Hypertension 01/2015; 24(1):54-60. DOI:10.1097/MNH.0000000000000091 · 4.24 Impact Factor
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    ABSTRACT: Advanced glycation endproducts (AGEs) and their receptor (RAGE) play a role in vascular complications in diabetes. We have previously shown that 17β-estradiol at 10 nmol/l, a nearly identical plasma concentration to that during mid-pregnancy, up-regulates RAGE expression in endothelial cells. The finding might suggest the involvement of 17β-estradiol in the deterioration of vascular complications in diabetes during pregnancy. However, the effects of the selective estrogen receptor modulator, bazedoxifene, on oxidative and inflammatory reactions in AGEs-exposed endothelial cells remain unknown. In this study, we addressed the issue. Ten nmol/l 17β-estradiol increased RAGE and monocyte chemoattractant protein-1 (MCP-1) gene and protein expression in human umbilical vein endothelial cells (HUVECs), both of which were blocked by 10 nmol/l bazedoxifene. Bazedoxifene at 10 nmol/l also significantly inhibited the AGEs-induced superoxide generation, RAGE and MCP-1 gene and protein expression in HUVECs. The present study suggests that blockade of the AGEs–RAGE axis by bazedoxifene might be a novel therapeutic target for preventing vascular damage in diabetes, especially in postmenopausal women.
    Climacteric 10/2014; 18(3). DOI:10.3109/13697137.2014.958073 · 2.24 Impact Factor
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    ABSTRACT: Carnitine deficiency may contribute to cardiovascular disease (CVD) in patients with hemodialysis (HD). Dyslipidemia plays a role in CVD and its prevalence is also high in HD patients. We examined here the effects of switching from oral administration (PO) to intravenous (IV) injection of l-carnitine on lipid metabolism in patients with HD. Nine HD patients who had received l-carnitine orally (900 mg/day) for 1 year were enrolled in this study. We examined whether lipid parameters were improved by switching to IV injection therapy of 1000 mg l-carnitine. IV injection of l-carnitine for 1 week significantly increased total, free and acyl carnitine levels both before and after HD. Switching to IV injection therapy for 1 and 4 weeks decreased serum free fatty acid (FFA) (322 ± 104 versus 261 ± 124 µmol/L) and increased high-density lipoprotein-cholesterol levels (1.46 ± 0.49 versus 1.63 ± 0.62 mmol/L), respectively. Change in FFA values from the baseline (ΔFFA) was positively correlated with the Δacyl/free carnitine ratio (r (2) = 0.553, P = 0.022). This study demonstrated that switching to IV l-carnitine therapy from oral supplementation improved lipid profiles, thus supporting the clinical utility of IV administration of l-carnitine for the treatment of patients on HD.
    10/2014; 7(5):470-4. DOI:10.1093/ckj/sfu082
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    ABSTRACT: There are very little data available regarding nephrotic syndrome (NS) in elderly (aged ≥65 years) Japanese. The aim of this study was to examine the causes and outcomes of NS in elderly patients who underwent renal biopsies between 2007 and 2010.
    Clinical and Experimental Nephrology 09/2014; DOI:10.1007/s10157-014-1022-x · 1.71 Impact Factor
  • International Journal of Cardiology 08/2014; 176(3). DOI:10.1016/j.ijcard.2014.07.299 · 6.18 Impact Factor
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    ABSTRACT: Advanced glycation end products (AGEs) decrease adiponectin expression and suppress insulin signaling in cultured adipocytes through the interaction with a receptor for AGEs (RAGE) via oxidative stress generation. We have recently found that high-affinity DNA aptamer directed against AGE (AGE-aptamer) prevents the progression of experimental diabetic nephropathy by blocking the harmful actions of AGEs in the kidney. This study examined the effects of AGE-aptamer on adipocyte remodeling, AGE-RAGE-oxidative stress axis, and adiponectin expression in fructose-fed rats. Although AGE-aptamer treatment by an osmotic mini pump for 8 weeks did not affect serum insulin levels, it significantly decreased average fasting blood glucose and had a tendency to inhibit body weight gain in fructose-fed rats. Furthermore, AGE-aptamer significantly suppressed the increase in adipocyte size and prevented the elevation in AGEs, RAGE, and an oxidative stress marker, 8-hydroxydeoxyguanosine (8-OHdG), levels in adipose tissues of fructose-fed rats at 14-week-old, while it restored the decrease in adiponectin mRNA levels. Our present study suggests that AGE-aptamer could improve glycemic control and prevent adipocyte remodeling in fructose-fed rats partly by suppressing the AGE-RAGE-mediated oxidative stress generation. AGE-aptamer might be a novel therapeutic strategy for fructose-induced metabolic derangements.
    Hormone and Metabolic Research 08/2014; 47(04). DOI:10.1055/s-0034-1385904 · 2.04 Impact Factor
  • Atherosclerosis 08/2014; 235(2):e241-e242. DOI:10.1016/j.atherosclerosis.2014.05.720 · 3.97 Impact Factor
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    ABSTRACT: Preclinical studies in rodent models of chronic liver fibrosis have shown that transplantation of peripheral blood (PB) CD34(+) cells leads to hepatic regeneration and a reduction of liver fibrosis by suppressing hepatic stellate cell activity and increasing matrix metalloproteinase activity. The aim of this study was to examine the safety and clinical efficacy of intrahepatic transplantation of autologous granulocyte-colony stimulating factor (G-CSF)-mobilized PB-CD34(+) cells in patients with decompensated liver cirrhosis. PB-CD34(+) cells were isolated from G-CSF-mobilized apheresis products. Ten patients were treated with G-CSF-mobilized PB-CD34(+) cells (treatment group) and 7 patients were treated with standard medical therapy. For mobilization, patients in the treatment group received subcutaneous injections of 10 μg G-CSF /kg/day for 5 days. The cells were then injected at three different doses (5×10(5) , 1×10(6) and 2×10(6) cells/kg) through the hepatic artery. Thereafter, all patients were followed-up for 24 months. G-CSF treatment and leukapheresis were well tolerated and no serious adverse events were observed. Patients in the treatment group had a significant but transient splenomegaly. After 24 weeks, serum albumin was significantly increased in patients who had received middle- or high-doses of CD34(+) cells compared to baseline. Doppler-US showed a significant increase in hepatic blood flow velocity and blood flow volume after CD34(+) cell therapy. The hepatic vein pressure gradient decreased in 2 patients who received high-dose CD34(+) cells at week 16. CD34(+) cell therapy is feasible, safe and effective in slowing the decline of hepatic reserve function.
    Journal of Gastroenterology and Hepatology 04/2014; 29(10). DOI:10.1111/jgh.12622 · 3.63 Impact Factor
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    ABSTRACT: Abstract Late-onset hypogonadism (LOH) and depression contribute to cardiovascular disease (CVD) in male hemodialysis (HD) patients. Carnitine deficiency is frequently observed in HD patients, playing a role in CVD. We examined whether carnitine deficiency was independently associated with LOH and depression in these patients. Twenty-six male HD patients underwent determinations of serum levels of free carnitine and testosterone. Status of LOH and depression were evaluated by questionnaires using aging male symptoms' (AMS) scale and self-rating depression scale (SDS), respectively. Free carnitine and testosterone levels in male HD patients were significantly lower than those in age-matched healthy male subjects. Linear regression analysis showed that AMS scale was positively associated with SDS. Univariate regression analysis revealed that total carnitine (inversely), free carnitine (inversely) and HD duration were correlated with AMS scale. Multiple stepwise regression analysis revealed that free carnitine was an independent determinant of AMS scale. Furthermore, free carnitine was also independently correlated with SDS in male HD patients. This study demonstrated that decreased free carnitine levels were independently associated with AMS scale and SDS in male HD patients. The observations suggest that decreased free carnitine levels could be a marker and therapeutic target of LOH and depression in uremic men with HD.
    The Aging Male 03/2014; DOI:10.3109/13685538.2014.888053 · 1.85 Impact Factor
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    ABSTRACT: Oxidative stress and smoking contribute to endothelial dysfunction. Iron might also play a role in oxidative stress generation and endothelial dysfunction. However, the involvement of iron in smoking-induced endothelial dysfunction in healthy smokers remains unclear. Therefore, we examined here whether (1) intravenous iron infusion impaired endothelial function evaluated by flow-mediated vasodilatation (FMD) in non-smokers, and (2) deferoxamine, a potent iron chelator, ameliorated endothelial dysfunction in healthy smokers. Eight healthy young male non-smokers (23±4 years old) received intravenous injection of saccharated ferric oxide (0.7 mg/kg body weight), while 10 age-matched healthy male smokers received deferoxamine mesylate (8.3 mg/kg body weight). At baseline, 5 and 20 minutes after treatment with iron or deferoxamine, biochemical variables were measured, including serum iron and marondialdehyde (MDA), a marker of lipid oxidation, and endothelial function was simultaneously evaluated by FMD. Compared with non-smokers, FMD was significantly lower in smokers. Iron and MDA levels were significantly increased, whereas FMD was impaired by iron infusion in non-smokers. Conversely, deferoxamine treatment significantly decreased iron and MDA levels and restored the decreased FMD in smokers. Baseline serum iron and MDA levels in all 18 subjects (non-smokers and smokers) were correlated with each other. There was a significant inverse correlation between the changes in MDA values and FMD from baseline in 18 men. Endothelium-independent vasodilation by glyceryl trinitrate was unaltered by either treatment. Our present study suggests that iron-evoked oxidative stress might play a role in endothelial dysfunction in healthy smokers.
    PLoS ONE 02/2014; 9(2):e89433. DOI:10.1371/journal.pone.0089433 · 3.53 Impact Factor
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    Yosuke Nakayama, Seiji Ueda, Seiya Okuda
    Circulation Journal 02/2014; 78(3). DOI:10.1253/circj.CJ-14-0058 · 3.69 Impact Factor
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    ABSTRACT: Advanced glycation end products (AGE)-receptor for AGE (RAGE) axis and renin-angiotensin system (RAS) play a role in diabetic nephropathy (DN). Matrix metalloproteinase-2 (MMP-2) activation also contributes to DN. However, the pathological interaction among AGE-RAGE, RAS and MMP-2 in DN remains unknown. We examined here the involvement of AGE and RAS in MMP-2 activation in streptozotocin (STZ)-induced diabetic rats and in AGE-exposed rat renal proximal tubular cells (RPTCs).
    Diabetology and Metabolic Syndrome 01/2014; 6(1):86. DOI:10.1186/1758-5996-6-86 · 2.50 Impact Factor
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    ABSTRACT: 【Background and Aim】Carnitine deficiency may contribute to erythropoietin-resistant anemia and malnutrition, which could lead to impaired quality of life in patients with hemodialysis (HD). We examined here the effects of oral L-carnitine supplementation on renal anemia and malnutrition in HD patients. We also investigated whether switching from oral administration of L-carnitine to intravenous injection could affect serum carnitine levels in these patients.【Methods】One hundred and two HD patients (total carnitine levels<50μmol/L) were enrolled and randomized to either oral administration of L-carnitine (900 mg/day) (N=51) or control (N=51). After 6 months, anemia and clinical variables, including serum levels of carnitine, were measured. Three months after administration, serum carnitine levels were examined just before and after the HD session. Furthermore, oral L-carnitine administration was switched to intravenous injection (500 or 1,000 mg), and serum carnitine levels were examined.【Results】Oral L-carnitine supplementation for 6 months (n=23) significantly increased hematocrit, LDL-cholesterol, triglycerides, and all carnitine levels, while AST and ALT levels, and acyl/free carnitine ratio were decreased. Switching to intravenous injection therapy (1,000 mg) for 1 week dramatically increased all serum carnitine levels just before and after and 10 min after the injection. There was no change of carnitine levels by switching to 500 mg intravenous injection.【Conclusion】The present study demonstrated that oral L-carnitine supplementation might improve renal anemia and malnutrition in HD patients. Switching to intravenous injection may be beneficial as a result of increase in carnitine levels, improvement of adherence, cost-benefit, and reducing the production of trimethylamine-N oxide (TMAO).
    Nihon Toseki Igakkai Zasshi 01/2014; 47(6):367-374. DOI:10.4009/jsdt.47.367
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    ABSTRACT: The patient was a 48-year-old man hospitalized for jaundice and anemia after a 6-day history of diarrhea. Examination demonstrated hemolytic anemia, renal dysfunction, and thrombocytopenia. Typical hemolytic uremic syndrome (HUS) was suspected based on the preceding colitis; however, plasma exchange (PE) was performed because the possibility of atypical HUS (aHUS) could not be ignored, given that the patient was an adult male. After 4 days of PE, his laboratory results improved. Stool culture on admission yielded negative results for Escherichia coli serotype O157 and ADAMTS13 activity. Antinuclear antibodies were normal, and no other drugs or infections indicating HUS were detected. Four months after onset, he suffered recurrence of aHUS after colitis. As a result, aHUS was suspected and therefore, PE was performed on the day of hospitalization. We diagnosed aHUS due to a result indicating complement dysregulation on hemolytic assay testing, which detected a complement factor H abnormality. After undergoing PE and maintaining a stable condition, the interval between PEs was extended; however, on day 17 after the last PE, he suffered a recurrent aHUS attack again. He could not be weaned from PE and started showing an allergic reaction to PE treatment, thereby leading to a switch from PE to eculizumab. Since switching to eculizumab treatment, the patient has not experienced another aHUS attack and his condition remains stable.
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    ABSTRACT: Peritoneal protein loss due to high peritoneal permeability may contribute to hypoalbuminemia and early withdrawal from peritoneal dialysis (PD) therapy in end stage renal disease (ESRD) patients. We have found that pigment epithelium-derived factor (PEDF) has anti-vasopermeability properties both in cell culture and animal models by counteracting the biological actions of vascular endothelial growth factor (VEGF). However, it remains unknown which clinical variables, including dialysate VEGF and PEDF, are associated with decreased serum albumin levels and could predict early withdrawal from the PD in ESRD patients. We address these issues. Twenty-seven ESRD patients undergoing PD were enrolled. Clinical variables were measured at 6 months after commencing PD. We examined the independent correlates of serum albumin in PD patients and then prospectively investigated the predictors of withdrawal from the PD therapy over 4 years. Dialysate VEGF was associated with peritoneal solute transport rate (P = 0.002), serum albumin (inversely, P < 0.001) and dialysate PEDF levels (P < 0.001). In multiple stepwise regression analysis, age (P = 0.002) and dialysate VEGF levels (P < 0.001) were independent determinants of serum albumin levels. High VEGF (>27 pg/mL), low serum albumin (≤3.31 g/dL) and low hemoglobin (≤11.2 g/dL) were correlated with withdrawal from the PD therapy during the 4 years. The odds ratio of dialysate VEGF for early withdrawal from the PD was 6.310 (P = 0.035). The present study demonstrated that increased dialysate VEGF was associated with decreased serum albumin and early withdrawal from the PD therapy. Inhibition of peritoneal VEGF production may be a therapeutic target in PD patients.
    Therapeutic apheresis and dialysis: official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy 11/2013; 18(5). DOI:10.1111/1744-9987.12120 · 1.53 Impact Factor

Publication Stats

4k Citations
873.93 Total Impact Points

Institutions

  • 1997–2015
    • Kurume University
      • • School of Medicine
      • • Department of Internal Medicine
      • • Division of Nephrology
      • • Department of Immunology
      • • Department of Pathology
      Куруме, Fukuoka, Japan
  • 2005–2008
    • Hokuriku University
      Ishiza, Okinawa, Japan
    • IIzuka Hospital
      Иидзука, Fukuoka, Japan
  • 1994–2008
    • Kyushu University
      • Division of Internal Medicine
      Hukuoka, Fukuoka, Japan
  • 2000–2003
    • The Cardiovascular Institute
      Tōkyō, Japan
  • 1990
    • Japan Red Cross Fukuoka Hospital
      Hukuoka, Fukuoka, Japan