Publications by authors named "Rintaro Tsukahara"

10 Publications

  • Page 1 of 1

Polarization-Sensitive Optical Coherence Tomographic Documentation of Choroidal Melanin Loss in Chronic Vogt-Koyanagi-Harada Disease.

Invest Ophthalmol Vis Sci 2017 09;58(11):4467-4476

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

Purpose: Vogt-Koyanagi-Harada (VKH) disease is a systemic autoimmune disorder that affects organs with melanocytes. The sunset glow fundus (SGF) in VKH disease was evaluated with polarization-sensitive optical coherence tomography (PS-OCT).

Methods: The study involved 28 eyes from 14 patients with chronic VKH disease, 21 eyes from 21 age-matched controls, and 22 eyes from 22 high-myopic patients with a tessellated fundus. VKH eyes were grouped into sunset or non-sunset groups on the basis of color fundus images. The presence of melanin in the choroid was determined by using the degree of polarization uniformity (DOPU) obtained by PS-OCT. The sunset glow index (SGI) was calculated by using color fundus images. Presence of an SGF was evaluated by using DOPU, SGI, subfoveal choroidal thicknesses, near-infrared images, and autofluorescence images at 488 nm (SW-AF) and 785 nm (NIR-AF).

Results: There were 16 eyes in the sunset group and 12 eyes in the non-sunset group. For all eyes in the sunset group, the disappearance of choroidal melanin was clearly detected with PS-OCT. Percentage areas of low DOPU in the choroidal interstitial stroma of the sunset group were significantly lower than those of other groups and showed no overlap with other groups. The distribution of choroidal thicknesses and SGI in the sunset group substantially overlapped with other groups. The subjective analyses of the sunset and non-sunset groups, using near infrared, SW-AF, or NIR-AF, showed substantial inconsistencies with the PS-OCT results.

Conclusions: PS-OCT provides an in vivo objective evaluation of choroidal melanin loss of the SGF in chronic VKH disease.
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http://dx.doi.org/10.1167/iovs.17-22117DOI Listing
September 2017

Focal adhesion kinase family is involved in matrix contraction by transdifferentiated Müller cells.

Exp Eye Res 2017 11 15;164:90-94. Epub 2017 Aug 15.

Department of Ophthalmology and Visual Sciences, University of Louisville, 301 E Muhammad Ali Blvd., Louisville, KY 40202, USA. Electronic address:

Transdifferentiated Müller cells that adopt a fibroblastic/myofibroblastic phenotype have been identified in epiretinal membranes (ERMs) in several ocular disorders, and have been implicated to play a role in the formation and/or the contraction of ERMs. We have previously demonstrated that dasatinib, a dual inhibitor of Src-family kinases and Abl kinase, can prevent matrix contraction by transdifferentiated Müller cells. In this study, we examined molecules involved in matrix contraction downstream of primary dasatinib targets. Tyrosine phosphorylation of focal adhesion kinase (FAK) family members FAK and PYK2 was significantly reduced by dasatinib, and select inhibitors for these kinases PF431396, which inhibits both FAK and PYK2, and PF573228, which only inhibits FAK and not PYK2, significantly reduced matrix contraction by transdifferentiated Müller cells. Dasatinib and PF431396 significantly reduced phosphorylation of Hic-5, a protein implicated to play a role in focal adhesions and cell signaling. Our data shows that FAK family members are involved in matrix contraction by transdifferentiated Müller cells, and also implicates that Hic-5 is situated downstream of the FAK family within the signaling pathway.
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http://dx.doi.org/10.1016/j.exer.2017.08.010DOI Listing
November 2017

Evaluation of intraretinal migration of retinal pigment epithelial cells in age-related macular degeneration using polarimetric imaging.

Sci Rep 2017 06 9;7(1):3150. Epub 2017 Jun 9.

Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan.

The purpose of the present study was to evaluate the intraretinal migration of the retinal pigment epithelium (RPE) cells in age-related macular degeneration (AMD) using polarimetry. We evaluated 155 eyes at various AMD stages. Depolarized light images were computed using a polarization-sensitive scanning laser ophthalmoscope (PS-SLO), and the degree of polarization uniformity was calculated using polarization-sensitive optical coherence tomography (OCT). Each polarimetry image was compared with the corresponding autofluorescence (AF) images at 488 nm (SW-AF) and at 787 nm (NIR-AF). Intraretinal RPE migration was defined by the presence of depolarization at intraretinal hyperreflective foci on PS-SLO and PS-OCT images, and by the presence of hyper-AF on both NIR-AF and SW-AF images. RPE migration was detected in 52 of 155 eyes (33.5%) and was observed in drusenoid pigment epithelial detachment (PED) and serous PED with significantly higher frequencies than in other groups (P = 0.015). The volume of the migrated RPE cluster in serous PED was significantly correlated with the volume of the PED (R = 0.26; P = 0.011). Overall, our results showed that intraretinal RPE migrations occurred in various AMD stages, and that they occurred more commonly in eyes with serous and drusenoid PED.
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http://dx.doi.org/10.1038/s41598-017-03529-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466639PMC
June 2017

Dasatinib affects focal adhesion and myosin regulation to inhibit matrix contraction by Müller cells.

Exp Eye Res 2015 Oct 1;139:90-6. Epub 2015 Aug 1.

Department of Ophthalmology and Visual Sciences, University of Louisville, 301 E. Muhammad Ali Blvd., Louisville, KY 40202, USA; Department of Biochemistry and Molecular Genetics, University of Louisville, 319 Abraham Flexner Way, Louisville, KY 40202, USA. Electronic address:

Epiretinal membrane (ERM) contraction is associated with a variety of ocular diseases that cause macular dysfunction. Trans-differentiated Müller cells have been identified in ERMs, and have been implicated to be involved in the contractile process. In this study, we tested the effect of dasatinib, an FDA-approved tyrosine kinase inhibitor, on matrix contraction caused by Müller cells, and examined molecular mechanism of action. Type I collagen matrix contraction assays were used to examine the effect of drugs on matrix contraction by trans-differentiated Müller cells. Fluophore-conjugated phalloidin was used for the detection of actin cytoskeleton, and Western-blot analyses were carried out to examine protein expression and phosphorylation status. Dasatinib inhibited collagen matrix contraction by trans-differentiated Müller cells that was associated with decreased cell spreading and reduction of actomyosin stress fibers. Concomitantly, dasatinib-treated Müller cells had reduced phosphorylation of Src family kinase, paxillin, as well as myosin II light chain. Specific inhibitors of Rho/ROCK and myosin II confirmed the critical role played by this pathway in Müller cell contraction. Our data demonstrate that dasatinib significantly reduced matrix contraction by Müller cells via inhibition of focal adhesion, as well as actomyosin contraction.
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http://dx.doi.org/10.1016/j.exer.2015.07.019DOI Listing
October 2015

Role of retinal pigment epithelial cell β-catenin signaling in experimental proliferative vitreoretinopathy.

Am J Pathol 2014 May 18;184(5):1419-28. Epub 2014 Mar 18.

Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky; Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky. Electronic address:

Proliferative vitreoretinopathy is caused by the contraction of fibrotic membranes on the epiretinal surface of the neurosensory retina, resulting in a traction retinal detachment and loss of visual acuity. Retinal pigment epithelial (RPE) cells play an important role in formation of such fibrotic, contractile membranes. We investigated the role of Wnt/β-catenin signaling, a pathway implicated in several fibrotic diseases, in RPE cells in proliferative vitreoretinopathy. In vitro culture of swine RPE sheets resulted in nuclear translocation of β-catenin in dedifferentiated RPE cells. FH535, a specific inhibitor of β-catenin signaling, reduced the outgrowth of cultured RPE sheets and prevented dedifferentiated RPE cell proliferation and migration. It also inhibited formation of contractile membranes by dedifferentiated RPE cells on collagen I matrices. Expression and function of the β-catenin signaling target connexin-43 were down-regulated by FH535, and functional blockade of connexins with carbenoxolone also prevented the in vitro formation of fibrotic, contractile membranes. Intravitreal injection of FH535 in swine also inhibited formation of dense, contractile membranes on the epiretinal surface and prevented development of traction retinal detachment. These findings demonstrate that β-catenin signaling is involved in formation of contractile membranes by dedifferentiated RPE cells and suggest that adjunctive treatment targeting this pathway could be useful in preventing proliferative vitreoretinopathy.
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http://dx.doi.org/10.1016/j.ajpath.2014.01.022DOI Listing
May 2014

Biological activity is the likely origin of the intersection between the photoreceptor inner and outer segments of the rat retina as determined by optical coherence tomography.

Clin Ophthalmol 2011 22;5:1649-53. Epub 2011 Nov 22.

Department of Ophthalmology, Tokyo Medical University Hospital, Tokyo, Japan.

Background: Recent research on macular diseases has prompted investigations into the condition of the intersection between the photoreceptor inner and outer segments (IS/OS) and the relationship with retinal photoreceptor abnormalities. Although the origin of the IS/OS in optical coherence tomography (OCT) images is unclear, it may be related to either the cellular activity of the photoreceptors or the structure of the OS disks. To address this question, we compared the IS/OS status in OCT images of rat retinas before and after euthanasia.

Methods: OCT images were taken before and after euthanasia in four eyes of two Brown Norway rats. After the OCT images were taken, the rats were used for histopathological studies to confirm that retinal structures were intact.

Results: Before euthanasia, the IS/OS and external limiting membrane (ELM) line were clearly identifiable on the OCT images. However, after euthanasia, neither the IS/OS nor the ELM line was evident in three out of four eyes, and a faint IS/OS and an ELM line were identified in one eye. Histopathological analysis did not show any abnormalities in the retina in any of the four eyes.

Conclusion: The origin of the IS/OS identified in OCT images is likely related to the biological activities of the photoreceptor cells.
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http://dx.doi.org/10.2147/OPTH.S26661DOI Listing
January 2012

Correlation between high-resolution optical coherence tomography (OCT) images and histopathology in an N-methyl-N-nitrosourea-induced retinal degeneration rat model.

Br J Ophthalmol 2011 Aug 20;95(8):1161-5. Epub 2011 Apr 20.

Department of Ophthalmology, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.

Background: Recent research on macular diseases has prompted investigations into the condition of the intersection between the inner and outer segments (IS/OS), and its relationship with retinal photoreceptor abnormalities. Because the correlation between optical coherence tomography (OCT) images and histopathology is unclear, the authors compared them in an N-methyl-N-nitrosourea (MNU)-induced photoreceptor degeneration rat model.

Methods: MNU (60 mg/kg), which is toxic to photoreceptors, was injected in 12 Brown Norway rats. After MNU administration, three rats were used per histopathological study 3 h, 6 h, 24 h and 1 week after the injections. Two healthy rats served as controls. OCT images were taken before euthanisation.

Results: 3 h after the MNU injections, the IS and OS were oedematous, but the IS/OS borderline was recognised histopathologically, and the IS/OS was depicted on the OCT images. Six hours after injections, the OS were preserved, but the IS structures were destroyed or partially disorganised histopathologically, and the IS/OS was not observed on the OCT images. Twenty-four hours after the injections, the IS and OS were totally disorganised histopathologically, and the IS/OS was not depicted on the OCT images.

Conclusion: The IS structure might be the origin of the IS/OS on OCT images.
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http://dx.doi.org/10.1136/bjo.2010.198317DOI Listing
August 2011

Correlation between high-resolution optical coherence tomography (OCT) images and histopathology in an iodoacetic acid-induced model of retinal degeneration in rabbits.

Br J Ophthalmol 2011 Aug 28;95(8):1157-60. Epub 2010 Oct 28.

Department of Ophthalmology, Tokyo Medical University Hospital, 6-7-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.

Background: Recent research on macular disease has prompted investigation into the condition of the intersection of the inner and outer segments (IS/OS) and its relationship with retinal photoreceptor abnormalities. Because the relationship between optical coherence tomography (OCT) images and histopathology is unclear, we compared these in an iodoacetic acid (IAA)-induced model of photoreceptor degeneration in rabbits.

Methods: IAA (20 mg/kg), which is toxic to photoreceptors, was injected into six coloured rabbits. After IAA administration, nine retinas were used for histopathological study: three from rabbits surviving for 1 day and six from rabbits surviving for 4 months. Four healthy rabbit retinas served as controls. OCT images were taken before euthanasia.

Results: In the controls, OCT images revealed the IS/OS as a clear, straight line. In rabbits surviving for 1 day, the structure of the photoreceptor IS/OS was destroyed and the IS/OS boundary was not visible. In rabbits surviving for 4 months, the IS was still preserved, but the structure of the OS was destroyed or partially disorganised, and the IS/OS was observed as a wavy, broken line on the OCT images.

Conclusion: The IS/OS on the OCT images reflected the histopathology of the inner and outer segments in a photoreceptor degeneration model.
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http://dx.doi.org/10.1136/bjo.2010.186718DOI Listing
August 2011

Critical contribution of CD80 and CD86 to induction of anterior chamber-associated immune deviation.

Int Immunol 2005 May 18;17(5):523-30. Epub 2005 Mar 18.

Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.

Intraocular inoculation of antigens induces anterior chamber-associated immune deviation (ACAID), which is mediated by development of regulatory T cells in response to antigen-presenting cells (APC) pre-conditioned by intraocular transforming growth factor-beta (TGF-beta). In this study, we examined the involvement of T-cell co-stimulatory molecules in this process. To mimic the intraocular APC, thioglycollate-elicited peritoneal exudate cells (PEC) were pre-treated with TGF-beta in vitro. Expression of CD80, CD86, OX40 ligand (OX40L) and CD70 was analyzed by flow cytometry. Contribution of these molecules to co-stimulatory activity of TGF-beta-treated PEC on antigen-stimulated T-cell proliferation and cytokine production was determined by inhibition with blocking antibodies in vitro. Contribution of CD80 and CD86 to induction of ACAID was determined by the administration of blocking antibodies at intraocular antigen inoculation in vivo. TGF-beta-treated PEC expressed CD80 and CD86 but not OX40L or CD70. Antigen-stimulated T cells proliferated and produced IL-10, but not IFN-gamma, in response to co-stimulation by TGF-beta-treated PEC, which was abrogated by blocking antibodies against CD80 and CD86. Induction of regulatory cells mediating ACAID was abolished by in vivo blockade of CD80 and CD86. The present results indicated that CD80 and CD86 play a critical role in induction of ACAID, possibly by co-stimulating expansion and IL-10 production of regulatory T cells in response to TGF-beta-conditioned APC.
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http://dx.doi.org/10.1093/intimm/dxh234DOI Listing
May 2005
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