start-ver=1.4 cd-journal=joma no-vol=14 cd-vols= no-issue=2 article-no= start-page=205 end-page=220 dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20221029 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Suramin prevents the development of diabetic kidney disease by inhibiting NLRP3 inflammasome activation in KK-Ay mice en-subtitle= kn-subtitle= en-abstract= kn-abstract=Aims/Introduction Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes produce IL-18 upon being activated by various stimuli via the P2 receptors. Previously, we showed that serum and urine IL-18 levels are positively associated with albuminuria in patients with type 2 diabetes, indicating the involvement of inflammasome activation in the pathogenesis of diabetic kidney disease (DKD). In the present study, we investigated whether the administration of suramin, a nonselective antagonist of the P2 receptors, protects diabetic KK.Cg-A(y)/TaJcl (KK-Ay) mice against DKD progression. Materials and Methods Suramin or saline was administered i.p. to KK-Ay and C57BL/6J mice once every 2 weeks for a period of 8 weeks. Mouse mesangial cells (MMCs) were stimulated with ATP in the presence or absence of suramin. Results Suramin treatment significantly suppressed the increase in the urinary albumin-to-creatinine ratio, glomerular hypertrophy, mesangial matrix expansion, and glomerular fibrosis in KK-Ay mice. Suramin also suppressed the upregulation of NLRP3 inflammasome-related genes and proteins in the renal cortex of KK-Ay mice. P2X4 and P2X7 receptors were significantly upregulated in the isolated glomeruli of KK-Ay mice and mainly distributed in the glomerular mesangial cells of KK-Ay mice. Although neither ATP nor suramin affected NLRP3 expression in MMCs, suramin inhibited ATP-induced NLRP3 complex formation and the downstream expression of caspase-1 and IL-18 in MMCs. Conclusions These results suggest that the NLRP3 inflammasome is activated in a diabetic kidney and that inhibition of the NLRP3 inflammasome with suramin protects against the progression of early stage DKD. en-copyright= kn-copyright= en-aut-name=OdaKaori en-aut-sei=Oda en-aut-mei=Kaori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MiyamotoSatoshi en-aut-sei=Miyamoto en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KoderaRyo en-aut-sei=Kodera en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WadaJun en-aut-sei=Wada en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ShikataKenichi en-aut-sei=Shikata en-aut-mei=Kenichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=3 en-affil=Osafune Clinic kn-affil= affil-num=4 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism kn-affil= affil-num=5 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= en-keyword=Diabetic kidney disease kn-keyword=Diabetic kidney disease en-keyword=Inflammasomes kn-keyword=Inflammasomes en-keyword=Suramin kn-keyword=Suramin END start-ver=1.4 cd-journal=joma no-vol=11 cd-vols= no-issue=2 article-no= start-page=325 end-page=332 dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20200517 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Prevalence of albuminuria and renal dysfunction, and related clinical factors in Japanese patients with diabetes: The Japan Diabetes Complication and its Prevention prospective study 5 en-subtitle= kn-subtitle= en-abstract= kn-abstract=Aims/Introduction
To clarify the prevalence of albuminuria and renal dysfunction, and related factors in Japanese patients with diabetes, we analyzed the baseline data of the Japan Diabetes Complication and its Prevention prospective study.
Materials and Methods
We used the data of 355 patients with type 1 diabetes and 5,194 patients with type 2 diabetes to evaluate the prevalence of albuminuria and renal dysfunction, and related factors. A binomial logistic regression analysis was used to investigate independent contributing factors for estimated glomerular filtration rate <60 mL/min/1.73 m2 or albuminuria.
Results
The prevalence of microalbuminuria and macroalbuminuria was 15.2% (54/355) and 3.1% (11/355) in type 1 diabetes patients, and 25.0% (1,298/5,194) and 5.1% (265/5,194) in type 2 diabetes patients, respectively. The proportion of renal dysfunction (estimated glomerular filtration rate <60 mL/min/1.73 m2) was 9.9% (35/355) in type 1 diabetes patients, and 15.3% (797/5,194) in type 2 diabetes patients. The proportion of patients with renal dysfunction with normoalbuminuria was 7.3% (26/355) for type 1 diabetes patients, and 9.0% (467/5,194) for type 2 diabetes patients. The factors related to albuminuria in type 2 diabetes patients were glycated hemoglobin, hypertension, age, duration of diabetes, body mass index and estimated glomerular filtration rate. In contrast, factors to related renal dysfunction were age, duration of diabetes, dyslipidemia, hypertension, body mass index, male sex and albuminuria.
Conclusions
We showed the recent prevalence of albuminuria and renal dysfunction, and related factors in Japanese type 1 and type 2 diabetes patients using the baseline data of the Japan Diabetes Complication and its Prevention prospective study. The current results suggest that renal disease in patients with type 2 diabetes is heterogeneous, and different mechanisms might be involved in albuminuria and deterioration of renal function. en-copyright= kn-copyright= en-aut-name=ShikataKenichi en-aut-sei=Shikata en-aut-mei=Kenichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KoderaRyo en-aut-sei=Kodera en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=UtsunomiyaKazunori en-aut-sei=Utsunomiya en-aut-mei=Kazunori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KoyaDaisuke en-aut-sei=Koya en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NishimuraRimei en-aut-sei=Nishimura en-aut-mei=Rimei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MiyamotoSatoshi en-aut-sei=Miyamoto en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=TajimaNaoko en-aut-sei=Tajima en-aut-mei=Naoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=the JDCP study group en-aut-sei=the JDCP study group en-aut-mei= kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=2 en-affil=The Japan Diabetes Society kn-affil= affil-num=3 en-affil=The Japan Diabetes Society kn-affil= affil-num=4 en-affil=The Japan Diabetes Society kn-affil= affil-num=5 en-affil=The Japan Diabetes Society kn-affil= affil-num=6 en-affil=Center for Innovative Clinical Medicine, Okayama University Hospital kn-affil= affil-num=7 en-affil=The Japan Diabetes Society kn-affil= affil-num=8 en-affil= kn-affil= en-keyword=Diabetic nephropathy kn-keyword=Diabetic nephropathy en-keyword=Diabetic kidney disease kn-keyword=Diabetic kidney disease en-keyword=Japan Diabetes Complication and its Prevention study kn-keyword=Japan Diabetes Complication and its Prevention study END start-ver=1.4 cd-journal=joma no-vol=68 cd-vols= no-issue=4 article-no= start-page=235 end-page=241 dt-received= dt-revised= dt-accepted= dt-pub-year=2014 dt-pub=201408 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Factors Associated with Remission and/or Regression of Microalbuminuria in Type 2 Diabetes Mellitus en-subtitle= kn-subtitle= en-abstract= kn-abstract=The aim of this study was to clarify the factors associated with the remission and/or regression of microalbuminuria in Japanese patients with type 2 diabetes mellitus. We retrospectively analyzed the data of 130 patients with type 2 diabetes mellitus with microalbuminuria for 2-6 years (3.39±1.31 years). Remission was defined as improving from microalbuminuria to normoalbuminuria using the albumin/creatinine ratio (ACR), and regression of microalbuminuria was defined as a decrease in ACR of 50% or more from baseline. Progression of microalbuminuria was defined as progressing from microalbuminuria to overt proteinuria during the follow-up period. Among 130 patients with type 2 diabetes mellitus with microalbuminuria, 57 and 13 patients were defined as having remission and regression, respectively, while 26 patients progressed to overt proteinuria. Sex (female), higher HDL cholesterol and lower HbA1c were determinant factors associated with remission/regression of microalbuminuria by logistic regression analysis. Lower systolic blood pressure (SBP) was also correlated with remission/regression, but not at a significant level. These results suggest that proper control of blood glucose, BP and lipid profiles may be associated with remission and/or regression of type 2 diabetes mellitus with microalbuminuria in clinical practice. en-copyright= kn-copyright= en-aut-name=OnoTetsuichiro en-aut-sei=Ono en-aut-mei=Tetsuichiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ShikataKenichi en-aut-sei=Shikata en-aut-mei=Kenichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ObikaMikako en-aut-sei=Obika en-aut-mei=Mikako kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MiyatakeNobuyuki en-aut-sei=Miyatake en-aut-mei=Nobuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KoderaRyo en-aut-sei=Kodera en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HirotaDaisyo en-aut-sei=Hirota en-aut-mei=Daisyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=WadaJun en-aut-sei=Wada en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KataokaHitomi en-aut-sei=Kataoka en-aut-mei=Hitomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=OgawaDaisuke en-aut-sei=Ogawa en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MakinoHirofumi en-aut-sei=Makino en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil= kn-affil=Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=2 en-affil= kn-affil=Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=3 en-affil= kn-affil=Center for Graduate Medical Education, Okayama University affil-num=4 en-affil= kn-affil=Department of Hygiene, Faculty of Medicine, Kagawa University affil-num=5 en-affil= kn-affil=Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=6 en-affil= kn-affil=Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=7 en-affil= kn-affil=Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=8 en-affil= kn-affil=Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences affil-num=9 en-affil= kn-affil=Diabetic Nephropathy, Okayama University affil-num=10 en-affil= kn-affil=Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences en-keyword=microalbuminuria kn-keyword=microalbuminuria en-keyword=type 2 diabetes mellitus kn-keyword=type 2 diabetes mellitus en-keyword=remission kn-keyword=remission en-keyword=regression kn-keyword=regression END start-ver=1.4 cd-journal=joma no-vol=126 cd-vols= no-issue=1 article-no= start-page=1 end-page=6 dt-received= dt-revised= dt-accepted= dt-pub-year=2014 dt-pub=20140401 dt-online= en-article= kn-article= en-subject= kn-subject= en-title=Cholecystokinin plays a novel protective role in diabetic kidney through anti-inflammatory actions on macrophages kn-title=糖尿病の腎臓においてcholecystokininはマクロファージに対する抗炎症作用を介した新規の保護効果を発揮する en-subtitle= kn-subtitle= en-abstract= kn-abstract= en-copyright= kn-copyright= en-aut-name=MiyamotoSatoshi en-aut-sei=Miyamoto en-aut-mei=Satoshi kn-aut-name=宮本聡 kn-aut-sei=宮本 kn-aut-mei=聡 aut-affil-num=1 ORCID= en-aut-name=ShikataKenichi en-aut-sei=Shikata en-aut-mei=Kenichi kn-aut-name=四方賢一 kn-aut-sei=四方 kn-aut-mei=賢一 aut-affil-num=2 ORCID= en-aut-name=MiyasakaKyoko en-aut-sei=Miyasaka en-aut-mei=Kyoko kn-aut-name=宮坂京子 kn-aut-sei=宮坂 kn-aut-mei=京子 aut-affil-num=3 ORCID= en-aut-name=OkadaShinichi en-aut-sei=Okada en-aut-mei=Shinichi kn-aut-name=岡田震一 kn-aut-sei=岡田 kn-aut-mei=震一 aut-affil-num=4 ORCID= en-aut-name=SasakiMotofumi en-aut-sei=Sasaki en-aut-mei=Motofumi kn-aut-name=佐々木基史 kn-aut-sei=佐々木 kn-aut-mei=基史 aut-affil-num=5 ORCID= en-aut-name=KoderaRyo en-aut-sei=Kodera en-aut-mei=Ryo kn-aut-name=小寺亮 kn-aut-sei=小寺 kn-aut-mei=亮 aut-affil-num=6 ORCID= en-aut-name=HirotaDaisho en-aut-sei=Hirota en-aut-mei=Daisho kn-aut-name=廣田大昌 kn-aut-sei=廣田 kn-aut-mei=大昌 aut-affil-num=7 ORCID= en-aut-name=KajitaniNobuo en-aut-sei=Kajitani en-aut-mei=Nobuo kn-aut-name=梶谷展生 kn-aut-sei=梶谷 kn-aut-mei=展生 aut-affil-num=8 ORCID= en-aut-name=TakatsukaTetsuharu en-aut-sei=Takatsuka en-aut-mei=Tetsuharu kn-aut-name=高塚哲全 kn-aut-sei=高塚 kn-aut-mei=哲全 aut-affil-num=9 ORCID= en-aut-name=Kataoka UsuiHitomi en-aut-sei=Kataoka Usui en-aut-mei=Hitomi kn-aut-name=片岡仁美 kn-aut-sei=片岡 kn-aut-mei=仁美 aut-affil-num=10 ORCID= en-aut-name=NishishitaShingo en-aut-sei=Nishishita en-aut-mei=Shingo kn-aut-name=西下伸吾 kn-aut-sei=西下 kn-aut-mei=伸吾 aut-affil-num=11 ORCID= en-aut-name=Horiguchi SatoChikage en-aut-sei=Horiguchi Sato en-aut-mei=Chikage kn-aut-name=堀口千景 kn-aut-sei=堀口 kn-aut-mei=千景 aut-affil-num=12 ORCID= en-aut-name=FunakoshiAkihiro en-aut-sei=Funakoshi en-aut-mei=Akihiro kn-aut-name=船越顕博 kn-aut-sei=船越 kn-aut-mei=顕博 aut-affil-num=13 ORCID= en-aut-name=NishimoriHisakazu en-aut-sei=Nishimori en-aut-mei=Hisakazu kn-aut-name=西森久和 kn-aut-sei=西森 kn-aut-mei=久和 aut-affil-num=14 ORCID= en-aut-name=UchidaHaruhito Adam en-aut-sei=Uchida en-aut-mei=Haruhito Adam kn-aut-name=内田治仁 kn-aut-sei=内田 kn-aut-mei=治仁 aut-affil-num=15 ORCID= en-aut-name=OgawaDaisuke en-aut-sei=Ogawa en-aut-mei=Daisuke kn-aut-name=小川大輔 kn-aut-sei=小川 kn-aut-mei=大輔 aut-affil-num=16 ORCID= en-aut-name=MakinoHirofumi en-aut-sei=Makino en-aut-mei=Hirofumi kn-aut-name=槇野博史 kn-aut-sei=槇野 kn-aut-mei=博史 aut-affil-num=17 ORCID= affil-num=1 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科　腎・免疫・内分泌代謝内科学 affil-num=2 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科　腎・免疫・内分泌代謝内科学 affil-num=3 en-affil= kn-affil=東京家政大学　栄養学科 affil-num=4 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科　腎・免疫・内分泌代謝内科学 affil-num=5 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科　腎・免疫・内分泌代謝内科学 affil-num=6 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科　腎・免疫・内分泌代謝内科学 affil-num=7 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科　腎・免疫・内分泌代謝内科学 affil-num=8 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科　腎・免疫・内分泌代謝内科学 affil-num=9 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科　腎・免疫・内分泌代謝内科学 affil-num=10 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科　腎・免疫・内分泌代謝内科学 affil-num=11 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科　腎・免疫・内分泌代謝内科学 affil-num=12 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科　腎・免疫・内分泌代謝内科学 affil-num=13 en-affil= kn-affil=国立病院機構九州がんセンター　消化器肝胆膵内科 affil-num=14 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科　血液・腫瘍・呼吸器内科学 affil-num=15 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科　腎・免疫・内分泌代謝内科学 affil-num=16 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科　腎・免疫・内分泌代謝内科学 affil-num=17 en-affil= kn-affil=岡山大学大学院医歯薬学総合研究科　腎・免疫・内分泌代謝内科学 en-keyword=cholecystokinin kn-keyword=cholecystokinin en-keyword=糖尿病性腎症 kn-keyword=糖尿病性腎症 en-keyword=抗炎症作用 kn-keyword=抗炎症作用 en-keyword=腎保護効果 kn-keyword=腎保護効果 END start-ver=1.4 cd-journal=joma no-vol=16 cd-vols= no-issue=5 article-no= start-page=739 end-page=748 dt-received= dt-revised= dt-accepted= dt-pub-year=2012 dt-pub=201210 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Phenotypic change of macrophages in the progression of diabetic nephropathy; sialoadhesin-positive activated macrophages are increased in diabetic kidney en-subtitle= kn-subtitle= en-abstract= kn-abstract=Inflammatory process is involved in pathogenesis of diabetic nephropathy, although the activation and phenotypic change of macrophages in diabetic kidney has remained unclear. Sialoadhesin is a macrophage adhesion molecule containing 17 extracellular immunoglobulin-like domains, and is an I-type lectin which binds to sialic acid ligands expressed on hematopoietic cells. The aim of this study is to clarify the activation and phenotypic change of macrophages in the progression of diabetic nephropathy. We examined the expression of surface markers for pan-macrophages, resident macrophages, sialoadhesin, major histocompatibility complex class II and alpha-smooth muscle actin in the glomeruli of diabetic rats using immunohistochemistry at 0, 1, 4, 12, and 24 weeks after induction of diabetes by streptozotocin. Expression of type IV collagen and the change of mesangial matrix area were also measured. The mechanism for up-regulated expression of sialoadhesin on macrophages was evaluated in vitro. The number of macrophages was increased in diabetic glomeruli at 1 month after induction of diabetes and the increased number was maintained until 6 months. On the other hand, sialoadhesin-positive macrophages were increased during the late stage of diabetes concomitantly with the increase of alpha-smooth muscle actin-positive mesangial cells, mesangial matrix area and type IV collagen. Gene expression of sialoadhesin was induced by stimulation with interleukin (IL)-1 beta and tumor necrosis factor-alpha but not with IL-4, transforming growth factor-beta and high glucose in cultured human macrophages. The present findings suggest that sialoadhesin-positive macrophages may contribute to the progression of diabetic nephropathy. en-copyright= kn-copyright= en-aut-name=NagaseRyo en-aut-sei=Nagase en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KajitaniNobuo en-aut-sei=Kajitani en-aut-mei=Nobuo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ShikataKenichi en-aut-sei=Shikata en-aut-mei=Kenichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OgawaDaisuke en-aut-sei=Ogawa en-aut-mei=Daisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KoderaRyo en-aut-sei=Kodera en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OkadaShinichi en-aut-sei=Okada en-aut-mei=Shinichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KidoYuichi en-aut-sei=Kido en-aut-mei=Yuichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=MakinoHirofumi en-aut-sei=Makino en-aut-mei=Hirofumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil= kn-affil=Okayama Univ, Dept Med & Clin Sci, Grad Sch Med Dent & Pharmaceut Sci affil-num=2 en-affil= kn-affil=Okayama Univ, Dept Med & Clin Sci, Grad Sch Med Dent & Pharmaceut Sci affil-num=3 en-affil= kn-affil=Okayama Univ, Dept Med & Clin Sci, Grad Sch Med Dent & Pharmaceut Sci affil-num=4 en-affil= kn-affil=Okayama Univ, Dept Med & Clin Sci, Grad Sch Med Dent & Pharmaceut Sci affil-num=5 en-affil= kn-affil=Okayama Univ, Dept Med & Clin Sci, Grad Sch Med Dent & Pharmaceut Sci affil-num=6 en-affil= kn-affil=Okayama Univ, Dept Med & Clin Sci, Grad Sch Med Dent & Pharmaceut Sci affil-num=7 en-affil= kn-affil=Okayama Univ, Dept Med & Clin Sci, Grad Sch Med Dent & Pharmaceut Sci affil-num=8 en-affil= kn-affil=Okayama Univ, Dept Med & Clin Sci, Grad Sch Med Dent & Pharmaceut Sci END