Susumu Ishida

Hokkaido University, Sapporo, Hokkaidō, Japan

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Publications (348)877.08 Total impact

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    ABSTRACT: Leber's hereditary optic neuropathy (LHON) refers to an optic nerve dysfunction due to mutations in the mitochondrial DNA, resulting in visual loss by apoptosis of retinal ganglion cells (RGC). In 20% of LHON cases, their fundus examination looks entirely normal at early stage. There are some reports regarding the circumpapillary retinal nerve fiber layer (cpRNFL) and the ganglion cell analysis around the macula in LHON patients and carriers by using optical coherence tomography. A 40-year-old female complained of acute visual loss in both eyes. Her best-corrected visual acuity was 0.3 in the right eye and 0.2 in the left eye at the initial visit. Goldmann perimetry revealed bilateral central scotomas. Fundus examination and fluorescein angiography findings were normal, but decreased retinal inner layer thickness was detected around the macular area on spectral domain optical coherence tomography (SD-OCT). One month later, her visual acuity deteriorated to counting fingers in both eyes, and the thinning area of retinal inner layer spread rapidly. Suspected progressive RGC loss led us to check the possibility of LHON, with which the patient was diagnosed due to a positive result for the mitochondrial DNA (mtDNA) 11778 mutation. The ganglion cell complex (GCC) and cpRNFL thicknesses were observed for 24 months by using SD-OCT. The GCC thickness plunged sharply within 3 months followed by gradual decline until 6 months, thereafter showing a plateau up to 24 months. On the cpRNFL map, the temporal quadrant also showed the earliest thinning as seen in the macular area of the GCC map. The thicknesses of the superior, nasal, and inferior quadrants decreased gradually, keeping their normal ranges up to 6 months. SD-OCT was a useful tool in the diagnosis and follow-up of LHON. The macular GCC thickness map may detect the earliest morphological changes in LHON, as well as the temporal area of cpRNFL, before funduscopic examination reveals optic nerve atrophy.
    BMC Ophthalmology 12/2015; 15(1):15. DOI:10.1186/s12886-015-0015-1 · 1.08 Impact Factor
  • Atsuhiro Kanda, Kousuke Noda, Susumu Ishida
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    ABSTRACT: Aerobic glucose metabolism is indispensable for metabolically active cells; however, the regulatory mechanism of efficient energy generation in the highly evolved mammalian retina remains incompletely understood. Here, we revealed an unsuspected role for (pro)renin receptor, also known as ATP6AP2, in energy metabolism. Immunoprecipitation and mass spectrometry analyses identified pyruvate dehydrogenase (PDH) complex as Atp6ap2-interacting proteins in the mouse retina. Yeast two-hybrid assays demonstrated direct molecular binding between ATP6AP2 and the PDH E1 β subunit (PDHB). Pdhb immunoreactivity co-localized with Atp6ap2 in multiple retinal layers including the retinal pigment epithelium (RPE). ATP6AP2 knockdown in RPE cells reduced PDH activity, showing a predilection to anaerobic glycolysis. ATP6AP2 protected PDHB from phosphorylation, thus controlling its protein stability. Downregulated PDH activity due to ATP6AP2 knockdown inhibited glucose-stimulated oxidative stress in RPE cells. Our present data unraveled the novel function of ATP6AP2/(P)RR as a PDHB stabilizer, contributing to aerobic glucose metabolism together with oxidative stress. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
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    ABSTRACT: To investigate the relationship between circulation hemodynamics and morphology in the choroid during systemic corticosteroid therapy for patients with Vogt-Koyanagi-Harada (VKH) disease. This retrospective case series includes 18 eyes of nine patients with VKH disease (two men and seven women; average age, 40.8 years) who received systemic corticosteroid therapy. Laser speckle flowgraphy (LSFG) and enhanced-depth imaging optical coherence tomography (EDI-OCT) were performed before treatment and at 1 week and 1 and 3 months after treatment. The average values of the mean blur rate (MBR) at the macula and the central choroidal thickness (CCT) were compared at each stage. The changing rates of the average MBR significantly increased at all examinations after the start of treatment compared with the pre-treatment value with resolution of serous retinal detachment (SRD) (P = 0.0002 for all). The CCT decreased significantly at all examinations after the start of treatment compared with the pre-treatment value (P = 0.0002 for all). Changes in MBR and CCT during the 3-month follow-up period correlated significantly (R = -0.5913, P = 0.0097). The best-corrected visual acuity at pre-treatment correlated significantly with the changing rate of the MBR from 0 to 3 months (R = 0.5944, P = 0.0093) but not with CCT. Our data suggest that circulatory disturbances and increased thickness of the choroid relate to the pathogenesis of VKH disease with link mutually. LSFG is useful as an index for evaluating the choroiditis activity of VKH disease as well as EDI-OCT.
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    ABSTRACT: To describe a level of vascular endothelial growth factor (VEGF) in the subretinal fluid obtained from a case with vasoproliferative retinal tumors (VPRTs). A 30-year-old male patient presented with VPRTs subsequent to long-standing rhegmatogenous retinal detachment. The patient was treated with encircling scleral buckling, cryopexy, and intravitreal bevacizumab injection. The protein level of VEGF in the subretinal fluid was measured and compared with those in the subretinal fluid obtained from patients with rhegmatogenous retinal detachment. Vascular endothelial growth factor level in the subretinal fluid from a patient with VPRTs was 12,997.9 pg/mL, whereas the mean VEGF concentration in the subretinal fluid from 4 patients with rhegmatogenous retinal detachment was 2.1 ± 2.8 pg/mL. The current data provide the evidence that VEGF production has increased in eyes with VPRTs and anti-VEGF therapy is theoretically effective for the treatment of VPRTs.
    Retinal Cases & Brief Reports 12/2014; DOI:10.1097/ICB.0000000000000124
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    ABSTRACT: Purpose: Extranodal marginal zone B-cell lymphoma (EMZL) is the most common subtype of conjunctival lymphoma though its molecular mechanisms of pathogenesis are largely unknown. Here, we attempted to explore the association of the renin-angiotensin system (RAS) and (pro)renin receptor [(P)RR] in the pathogenesis of conjunctival lymphoma. Methods: Surgically removed conjunctiva EMZL samples were used for gene expression, immunohistochemical and immunofluorescence analyses of (P)RR and RAS components. Human B-lymphoblast IM-9 cells were treated with prorenin or angiotensin II (Ang II), and gene expression levels were analyzed using real-time qPCR. In addition, immunofluorescence analysis of EMZL samples was used to evaluate the in vivo expression of those molecules. Results: Gene expression and immunohistochemical analyses revealed the expression of all RAS components, including (P)RR and angiotensin II type 1 receptor (AT1R), in EMZL tissues. Double-labeling analyses demonstrated that, both (P)RR and AT1R were detected in cells positive for CD20, a marker for B-cells, where they co-localized with prorenin and angiotensinogen, respectively. Prorenin stimulation of human B-lymphoblast IM-9 cells increased mRNA expression levels of fibroblast growth factor 2 (FGF2), while angiotensin II treatment upregulated the expression levels of basigin (BSG), matrix metallopeptidase (MMP)2, 9 and 14, which were abolished by (P)RR and AT1R blockades, respectively. Immunofluorescence analyses of clinical samples showed co-localizations of (P)RR and AT1R with the products of these upregulated genes. Conclusions: The present study suggests that activation of (P)RR and AT1R is associated with the pathogenesis of conjunctival EMZL by stimulating the production of FGF2 and MMPs. Copyright © 2014 by Association for Research in Vision and Ophthalmology.
    Investigative Ophthalmology &amp Visual Science 12/2014; 56(1). DOI:10.1167/iovs.14-15743 · 3.66 Impact Factor
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    ABSTRACT: The mechanism underlying focal choroidal excavation (FCE) remains largely unknown. We evaluated the sequential progression of FCE generation using enhanced depth imaging optical coherence tomography (EDI-OCT) in a patient with multiple evanescent white dot syndrome (MEWDS). A 37-year-old woman suffered MEWDS in the right eye. EDI-OCT showed the loss of photoreceptor inner segment/outer segment junction line, detachment between the retinal pigment epithelium (RPE) and Bruch's membrane, and dome-shaped, moderately reflective, focal photoreceptor-layer lesions corresponding to perifoveal white dots. The region with pigment epithelium detachment involved RPE/Bruch's membrane ruptures. After 1 month, almost all white dots spontaneously resolved together with improvements of the perifoveal OCT findings. Interestingly, perifoveal region developed a conforming-type FCE. An abnormal hyper-reflective lesion on OCT, regarded as fibrosis formation, simultaneously appeared within the choroid below the FCE and subsequently increased in size. These results suggest that the RPE/Bruch's membrane disruption due to chorioretinal abnormalities and subsequent intrachoroidal scar formation play a role in the pathogenesis on an acquired FCE.
    BMC Ophthalmology 11/2014; 14(1):135. DOI:10.1186/1471-2415-14-135 · 1.08 Impact Factor
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    ABSTRACT: On the basis of angiographic features, it is suggested that choroidal circulation disturbance may be involved in the pathogenesis of multiple evanescent white dot syndrome (MEWDS). The aim of this study is to quantitatively evaluate changes in choroidal circulation hemodynamics using laser speckle flowgraphy (LSFG) in patients with MEWDS.
    Albrecht von Graæes Archiv für Ophthalmologie 10/2014; DOI:10.1007/s00417-014-2831-z · 2.33 Impact Factor
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    ABSTRACT: AGEs are permanently modified macromolecule derivatives that form through nonenzymatic glycation of amino groups of proteins. Glycer-AGEs are highly toxic and play an important role in the pathogenesis of chronic inflammatory diseases. However, the contribution of glycer-AGEs to the pathogenesis of uveitis is unclear. In this study, we measured serum levels of glycer-AGEs in 100 patients with endogenous uveitis (22 with HLA-B27-associated uveitis, 20 with VKH disease, 14 with Behçet's disease, and 44 with sarcoidosis) and 33 healthy volunteers. We then examined the effect of the AGE inhibitor in a mouse model of human endogenous uveitis (EAU) by continuous oral administration of pyridoxamine at 200 or 400 mg/kg/day. Regardless of the etiology, serum glycer-AGE levels were significantly higher in patients with uveitis than in healthy subjects. Treatment with 400 mg/kg pyridoxamine significantly reduced the clinical and histological severity of EAU and was accompanied by a significant decrease in serum and retinal glycer-AGE levels and suppression of translocation of NF-κB p65 into the nucleus of retinal cells. Serum glycer-AGE levels may therefore serve as a biomarker of human uveitis, as well as systemic inflammation, and may contribute to the progression of uveitis, including diabetic iritis, via the activation of NF-κB.
    Journal of Leukocyte Biology 09/2014; 96(6). DOI:10.1189/jlb.3A0513-288RRR · 4.30 Impact Factor
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    ABSTRACT: To evaluate the efficacy and safety of intravitreal injections of pegaptanib sodium in subjects with diabetic macular edema (DME).
    Nippon Ganka Gakkai zasshi 09/2014; 118(9):773-82.
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    ABSTRACT: Genistein is a dietary-derived flavonoid abundantly present in soybeans and known to possess various biological effects including anti-inflammation and anti-angiogenic activity. To investigate the effects of genistein on intraocular neovascularization, we used an animal model of laser-induced choroidal neovascularization (CNV). Male C57BL/6J mice were treated in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. CNV was induced by laser photocoagulation. The animals were fed a mixture diet containing 0.5% genistein or a control diet ad libitum for 7 days before laser photocoagulation and the treatment was continued until the end of the study. Seven days after laser injury, the size of CNV lesions was quantified. Retinal pigment epithelium (RPE)-choroid complex was also harvested 1 or 3 days after laser injury and the level of monocyte chemoattractant protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, and matrix metalloproteinase (MMP)-9 were measured by enzyme-linked immunosorbent assay. Expression levels of Ets-1 and F4/80 were examined by real-time PCR. A significant decrease in CNV size was observed in animals treated with genistein (15441.9±1511.8 μm(2)) compared to control mice (21074.0±1940.7μm(2), P<.05). Genistein significantly reduced the protein level of MCP-1, ICAM-1, and MMP-9 in the RPE-choroid complex (P<.05). In addition, genistein suppressed the expression levels of Ets-1 and F4/80 (P<.05). The current data indicate the anti-angiogenic property of genistein during CNV formation.
    The Journal of Nutritional Biochemistry 07/2014; 25(11). DOI:10.1016/j.jnutbio.2014.06.004 · 4.59 Impact Factor
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    ABSTRACT: Purpose: To study the retinal degeneration caused by decreased proteasomal activity in β5t transgenic (β5t-Tg) mice, an animal model of senescence acceleration. Methods: β5t-Tg mice and age-matched littermate control (WT) mice were used. Proteasomal activities and protein level of poly-ubiquitinated protein in retinal extracts were quantified. Fundus images of β5t-Tg mice were taken and their features were assessed. For histological evaluation, the thicknesses of inner nuclear layer (INL), outer nuclear layer (ONL) and photoreceptor outer segment were measured. For functional analysis, electroretinogram (ERG) was recorded under scotopic and photopic illumination conditions. Immunofluorescence (IF) staining and TdT-mediated dUTP nick end labeling (TUNEL) were performed to investigate the mechanism of photoreceptor degeneration. Results: Chymotrypsin-like activity was partially suppressed in retinal tissues of β5t-Tg mice. Retinal degenerative changes with arterial attenuation were present in β5t-Tg, but not in WT mice. INL thickness showed no significant change between β5t-Tg and WT mice at 1, 3, 6 and 9 months-of-age. By contrast, thicknesses of ONL and outer segment in β5t-Tg mice were significantly decreased at 3, 6 and 9 months compared with those in WT mice. ERGs showed decrease of scotopic a-wave amplitude in β5t-Tg mice. The number of TUNEL-positive cells in ONL were significantly increased in β5t-Tg mice and co-localized with apoptosis-inducing factor, but not with cleaved caspase-3 and cleaved caspase-9, indicating that the photoreceptor cell death was induced via a caspase-independent pathway. Conclusions: The current data showed that impaired proteasomal function causes photoreceptor degeneration.
    Investigative Ophthalmology &amp Visual Science 07/2014; DOI:10.1167/iovs.13-13272 · 3.66 Impact Factor
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    ABSTRACT: A case of retinoschisis associated with peripapillary intrachoroidal cavitation (ICC) was successfully treated with pars plana vitrectomy. A 70-year-old woman developed macular elevation and peripapillary ICC in her right eye. Optical coherence tomography revealed retinoschisis with retinal detachment in the macula. A microhole was observed within the myopic conus. A narrow passage was observed linking the ICC with the schisis cavity, complicated by a peripapillary epiretinal membrane tissue adjacent to the passage. The patient underwent vitrectomy with removal of the membrane tissue. Complete regression of the retinoschisis was observed with closure of the connection channel between the ICC and schisis cavity. These findings suggest that the communication channel between the vitreous and schisis cavities was formed due to the traction exerted by the membrane tissue on the ICC that had generated a connecting path to the schisis cavity. [Ophthalmic Surg Lasers Imaging Retina. 2014;45:xxx-xxx.].
    07/2014; DOI:10.3928/23258160-20140617-03
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    ABSTRACT: To investigate the concentration and composition of N-glycans in plasma and vitreous samples obtained from patients with non-proliferative vitreoretinal diseases. Plasma and vitreous samples were collected from 11 patients with idiopathic macular hole (MH) and 9 patients with epiretinal membrane (ERM). The samples were pretreated for enzymatic cleaving, and subsequently glycans released from proteins were captured on BlotGlyco H beads. Sialic acids were methyl-esterified. Processed glycans were tagged with aminooxy-functionalized peptide reagent (aoWR) and released from the beads, followed by detection by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The concentration and composition of N-glycans in the samples were assessed. Concentration of N-glycans in vitreous samples (132 +/- 29 pmol/100 mu g protein) was significantly lower compared with those in plasma samples (714 +/- 29 pmol/100 mu g protein, p < 0.001). Predominant N-glycan in both plasma (39.7 +/- 1.1 %) and vitreous fluid (37.2 +/- 3.1 %) was identical, and the composition was presumed as [(Hex)2(HexNAc)2(NeuAc)2+ (Man)3(GlcNAc)2]. By contrast, the second-ranked N-glycan in vitreous samples (15.6 +/- 1.5 %) was the seventh in plasma (2.3 +/- 0.2 %). The current data provide useful information on N-glycan profile in the vitreous fluid, which is distinct from that in the plasma.
    Albrecht von Graæes Archiv für Ophthalmologie 06/2014; 252(8). DOI:10.1007/s00417-014-2671-x · 2.33 Impact Factor
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    ABSTRACT: To investigate the causes of visual impairment in Japan.
    Nippon Ganka Gakkai zasshi 06/2014; 118(6):495-501.
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    ABSTRACT: Adenosquamous carcinoma (ASC) is a rare form of malignancy which consists of two types of cell, including squamous cells and glandular-like cells. The current report presents the first known case of ASC in the conjunctiva and analyzes the histological findings. A 76-year-old female presented with right eyelid swelling in 2001. A right conjunctival tumor was noted and a biopsy was performed. Histologically, the tumor was diagnosed as a squamous cell carcinoma. The patient underwent radiotherapy, but the tumor rapidly relapsed. Subsequently, the patient underwent orbital exenteration. Histologically, the conjunctival tissues had been replaced with invasive tumor cells. A number of tumor cells demonstrated squamous differentiation with a keratinizing tendency, while other tumor cells exhibited mucin-producing activity with glandular formation. The conjunctival tumor was diagnosed as an ASC. At the time of writing, the patient is well without local recurrence or distant metastases. ASC typically exhibits aggressive biological behavior, and is associated with worse prognosis than conventional adenocarcinoma. Therefore, complete surgical excision is considered a key treatment for ASC of the conjunctiva.
    Oncology letters 06/2014; 7(6):1941-1943. DOI:10.3892/ol.2014.2008 · 0.99 Impact Factor
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    ABSTRACT: Changes in choroidal circulation hemodynamics during the course of punctate inner choroidopathy (PIC) remain unknown. The aim of this study was to quantitatively evaluate changes in choroidal blood flow velocity by using laser speckle flowgraphy (LSFG) in patients with PIC.
    BMC Ophthalmology 05/2014; 14(1):73. DOI:10.1186/1471-2415-14-73 · 1.08 Impact Factor
  • Ocular immunology and inflammation 05/2014; 22(6):1-5. DOI:10.3109/09273948.2014.916305 · 0.72 Impact Factor
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    ABSTRACT: To analyze the histopathology and expression of 8-hydroxydeoxyguanosine (OHdG), a marker of oxidative stress, in the levator aponeurosis tissues of involutional aponeurotic and congenital blepharoptosis patients, and adult subjects with no history of blepharoptosis. Fourteen and 4 levator aponeurosis tissues obtained from Asian patients with involutional and congenital blepharoptosis and 3 normal adult tissues were examined. All tissues were fixed in 4% paraformaldehyde, embedded in paraffin, and then submitted for hematoxylin and eosin staining and immunohistochemistry with anti-8-OHdG antibody. The levator aponeurosis tissues contained spindle smooth muscle fibers and striated muscles. Nuclear immunoreactivity for 8-OHdG was noted in striated and smooth muscle cells in all the tissues. The 8-OHdG-positive rate was significantly lower in congenital blepharoptosis than involutional blepharoptosis (p < 0.05). Moreover, the number of 8-OHdG-positive striated muscle cells was significantly higher in the involutional blepharoptosis than normal tissues (p < 0.05). In contrast, there was a rare positive 8-OHdG-immunoreactivity of smooth muscle cells in the aponeurotic tissues of the involutional blepharoptosis patients. Levator aponeurosis in involutional aponeurotic blepharoptosis tissues showed oxidative stress in the muscle, indicating that oxidative stress plays a potential role in the pathologic study of the disease.
    Ophthalmic plastic and reconstructive surgery 05/2014; 30(4). DOI:10.1097/IOP.0000000000000090 · 0.69 Impact Factor
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    ABSTRACT: Purpose: To examine the expression of vascular endothelial growth factor (VEGF) in extranodal marginal zone B-cell lymphoma (EMZL) and reactive lymphoid hyperplasia (RLH) of human ocular adnexa, and analyze the correlation with the intratumoral microvessel density (MVD). Methods: Twenty-two EMZL and sixteen RLH tissues were examined in this study. Paraformaldehyde-fixed, paraffin-embedded tissue sections were processed for immunohistochemistry with antibodies against VEGF and CD20. VEGF expression was analyzed using the enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR) in the EMZL tissues. MVD was determined based on the immunoreactivity for anti-CD34 antibody. Results: VEGF immunoreactivity was detected in the cytoplasm of lymphoid cells in EMZL and RLH. ELISA and RT-PCR confirmed VEGF protein and mRNA expressions in the EMZL tissue, respectively. VEGF-immunopositive rate in B cells was significantly higher in 12 conjunctival EMZLs than 4 RLHs (p < 0.01) and 10 orbital EMZLs than 12 RLHs (p < 0.05). The MVD showed a significant positive correlation with the VEGF-immunopositive rate in conjunctival and orbital EMZLs. Conclusions: This study demonstrated increased VEGF expression in human conjunctival and orbital EMZL compared with that in RLH, suggesting that VEGF plays a significant role in the pathogenesis and tumor angiogenesis of ocular adnexal lymphoma.
    Investigative ophthalmology & visual science 05/2014; 55(6). DOI:10.1167/iovs.13-13510 · 3.43 Impact Factor
  • Ocular immunology and inflammation 04/2014; DOI:10.3109/09273948.2014.902075 · 0.72 Impact Factor

Publication Stats

5k Citations
877.08 Total Impact Points


  • 2009–2014
    • Hokkaido University
      • • Department of Ophthalmology
      • • Laboratory of Cell Biological Science
      Sapporo, Hokkaidō, Japan
  • 1999–2013
    • Keio University
      • • Department of Ophthalmology
      • • Department of Pathology
      Edo, Tōkyō, Japan
    • Korea Atomic Energy Research Institute (KAERI)
      Daiden, Daejeon, South Korea
  • 2012
    • Seoul National University Hospital
      • Department of Internal Medicine
      Sŏul, Seoul, South Korea
    • Teikyo University Hospital
      Edo, Tōkyō, Japan
    • Health Sciences University of Hokkaido
      Tōbetsu, Hokkaidō, Japan
  • 2002–2011
    • Japan Atomic Energy Agency
      • Nuclear Science and Engineering Directorate
      Muramatsu, Niigata, Japan
  • 2010
    • Hokkaido University Hospital
      • Division of Ophthalmology
      Sapporo, Hokkaidō, Japan
  • 2008
    • Tokyo Metropolitan Institute of Gerontology
      Edo, Tōkyō, Japan
  • 2003–2004
    • Harvard Medical School
      Boston, Massachusetts, United States
    • Massachusetts Eye and Ear Infirmary
      • Department of Ophthalmology
      Boston, MA, United States
  • 2001
    • Academia Sinica
      • Institute of Physics
      T’ai-pei, Taipei, Taiwan
  • 1997
    • The University of Tokyo
      Tōkyō, Japan
  • 1995
    • Osaka Medical College
      • First Department of Internal Medicine
      Takatuki, Ōsaka, Japan