Susumu Ishida

Hokkaido University, Sapporo, Hokkaidō, Japan

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Publications (349)790.72 Total impact

  • [Show abstract] [Hide abstract]
    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;
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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 & visual science. 12/2014;
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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.
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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;
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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;
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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 & visual science. 07/2014;
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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.].
    Ophthalmic surgery, lasers & imaging retina. 07/2014;
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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.
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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. · 0.24 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. · 1.44 Impact Factor
  • Ocular immunology and inflammation 05/2014; · 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; · 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; · 3.43 Impact Factor
  • Ocular immunology and inflammation 04/2014; · 0.72 Impact Factor
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    ABSTRACT: Human adenovirus species D (HAdV-D), which is composed of clinically and epidemiologically important pathogens worldwide, contains more taxonomic "types" than any other species of the genus Mastadenovirus, although the mechanisms accounting for the high level of diversity remain to be disclosed. Recent studies of known and new types of HAdV-D have indicated that intertypic recombination between distant types contributes to the increasing diversity of the species. However, such findings raise the question as to how homologous recombination events occur between diversified types since homologous recombination is suppressed as nucleotide sequences diverge. In order to address this question, we investigated the distribution of the recombination boundaries in comparison with the landscape of intergenomic sequence conservation assessed according to the synonymous substitution rate (dS). The results revealed that specific genomic segments are conserved between even the most distantly related genomes; we call these segments "universally conserved segments" (UCSs). These findings suggest that UCSs facilitate homologous recombination, resulting in intergenomic segmental exchanges of UCS-flanking genomic regions as recombination modules. With the aid of such a mechanism, the haploid genomes of HAdV-Ds may have been reshuffled, resulting in chimeric genomes out of diversified repertoires in the HAdV-D population analogous to the MHC region reshuffled via crossing over in vertebrates. In addition, some HAdVs with chimeric genomes may have had the opportunity to avoid host immune responses thereby causing epidemics.
    Gene 04/2014; · 2.20 Impact Factor
  • Acta ophthalmologica 04/2014; · 2.44 Impact Factor
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    ABSTRACT: Specific cross-reacting autoimmunity against recoverin or collapsin response mediator protein (CRMP)-5 is known to cause cancer-associated retinopathy or paraneoplastic optic neuropathy, respectively. We report a rare case with small cell lung carcinoma developing bilateral neuroretinitis and unilateral focal outer retinitis positive for these antibodies. A 67-year-old man developed bilateral neuroretinitis and foveal exudation in the right eye. Optical coherence tomography showed a dome-shaped hyperreflective lesion extending from inner nuclear layer to the photoreceptor layer at the fovea in the right eye. Single-flash electroretinography showed normal a-waves in both eyes and slightly reduced b-wave in the left eye. Results of serological screening tests for infection were within normal limits. The patient's optic disc swelling and macular exudation rapidly improved after oral administration of prednisolone. Systemic screening detected lung small cell carcinoma and systemic chemotherapy was initiated. Immunoblot analyses using the patient's serum detected autoantibodies against recoverin, CRMP-5, and alpha-enolase, but not carbonic anhydrase II. Neuroretinitis once resolved after almost remission of carcinoma on imaging but it recurred following the recurrence of carcinoma. The development of neuroretinitis in this cancer patient with antiretinal and anti-optic nerve antibodies depended largely on the cancer activity, suggesting the possible involvement of paraneoplastic mechanisms. Patients with paraneoplastic optic neuropathy and retinopathy are likely to develop autoimmune responses against several antigens, thus leading to various ophthalmic involvements.
    BMC Ophthalmology 01/2014; 14(1):5. · 1.44 Impact Factor
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    ABSTRACT: Echinochrome is a pigment present in the shells and spines of sea urchins. It has been reported to have several biologic protective effects, including in experimental models of myocardial ischemia/reperfusion injury, for which the proposed mechanisms are scavenging reactive oxygen species (ROS) and chelating iron. Endotoxin-induced uveitis (EIU) is an animal model of acute anterior segment intraocular inflammation that is induced by the injection of lipopolysaccharide (LPS). In this study, the therapeutic effect of echinochrome was examined in uveitis using the EIU model. EIU was induced in Lewis rats via 200 μg subcutaneous injections of LPS from Escherichia coli. Echinochrome was administered intravenously in 10, 1, or 0.1 mg/kg doses suspended in PBS (controls were injected with PBS only). Twenty-four hours after LPS injection, the number of infiltrating cells and the protein concentration in aqueous humor were determined. Aqueous tumor necrosis factor α (TNF-α) concentration was quantified with enzyme-linked immunosorbent assay, eyes were stained with nuclear factor (NF) κB antibodies, and ROS production was determined by dihydroethidium staining in fresh frozen samples. The number of inflammatory aqueous cells and protein levels were lower in the groups treated with 10 and 1 mg/kg of echinochrome than in the untreated LPS group (p<0.01). Treatment with 10 and 1 mg/kg of echinochrome significantly reduced TNF-α concentrations in aqueous humor (p<0.01). The numbers of NFκB-positive cells and ROS signals were also reduced by echinochrome administration (p<0.05). Echinochrome ameliorated intraocular inflammation caused by EIU by reducing ROS production, thereby also decreasing the expression of NFκB and TNF-α. As a natural pigment, echinochrome may therefore be a promising candidate for the safe treatment of intraocular inflammation. The use of sea urchin shells and spines in health foods and medical products is thus both economically and environmentally meaningful.
    Molecular vision 01/2014; 20:171-7. · 1.99 Impact Factor

Publication Stats

4k Citations
790.72 Total Impact Points


  • 2009–2014
    • Hokkaido University
      • Department of Ophthalmology
      Sapporo, Hokkaidō, Japan
  • 1999–2013
    • Keio University
      • • Department of Ophthalmology
      • • Department of Pathology
      Tokyo, Tokyo-to, Japan
  • 2012
    • Health Sciences University of Hokkaido
      Tōbetsu, Hokkaidō, Japan
    • Teikyo University Hospital
      Edo, Tōkyō, Japan
  • 2011
    • Teine Keijinkai Hospital
      Sapporo, Hokkaidō, Japan
    • Fukushima Medical University
      • Department of Microbiology
      Hukusima, Fukushima, Japan
  • 2002–2011
    • Japan Atomic Energy Agency
      • Nuclear Science and Engineering Directorate
      Muramatsu, Niigata, Japan
  • 2010
    • Kyorin University
      • Kyorin Eye Center
      Edo, Tōkyō, Japan
    • Hokkaido University Hospital
      • Division of Ophthalmology
      Sapporo-shi, Hokkaido, Japan
  • 1995–2010
    • Osaka Medical College
      • First Department of Internal Medicine
      Takatsuki, Osaka-fu, Japan
  • 2007
    • University of Tsukuba
      • Department of Ophthalmology
      Tsukuba, Ibaraki-ken, Japan
  • 2003–2004
    • Harvard Medical School
      Boston, Massachusetts, United States
    • Massachusetts Eye and Ear Infirmary
      • Department of Ophthalmology
      Boston, MA, United States
  • 2001
    • Hitachi Cable, Ltd.
      Edo, Tōkyō, Japan
    • Academia Sinica
      • Institute of Physics
      T’ai-pei, Taipei, Taiwan
  • 1997
    • The University of Tokyo
      Tōkyō, Japan