Papers - IKEDA Yasuhiro
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Murakami Y., Funatsu J., Nakatake S., Fujiwara K., Tachibana T., Koyanagi Y., Hisatomi T., Yoshida S., Sonoda S., Sakamoto T., Sonoda K., Ikeda Y.
Investigative Ophthalmology and Visual Science 59 ( 2 ) 1134 - 1143 2018.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Investigative Ophthalmology and Visual Science
© 2018 The Authors. PURPOSE. To investigate the relationships between foveal blood flow as measured by laser speckle flowgraphy (LSFG), the retinal-choroidal structure in enhanced depth imaging– optical coherence tomography (EDI-OCT), and central visual function in patients with retinitis pigmentosa (RP). METHODS. We studied 52 consecutive typical RP patients ≤50 years old and 21 age- and sex-matched controls. The mean blur rate (MBR), which represents the blood flow volume, was calculated in a 2.4-mm2 area centered on the fovea by LSFG. Subfoveal horizontal EDI-OCT images were recorded, and the choroidal area, choroidal hyporeflective area, and choroidal hyperreflective area were analyzed in the central 2.4-mm-wide region. The central foveal thickness (CFT), subfoveal choroidal thickness (SCT), and ellipsoid zone (EZ) width were also measured. Visual acuity (VA) and retinal sensitivity (Humphrey 10-2 program) were measured in the RP patients. RESULTS. The MBR, choroidal area, hyporeflective area, hyperreflective area, and SCT were significantly decreased in the RP patients (all P < 0.001, versus controls). Spearman’s rank testing demonstrated no significant correlation between the MBR and the choroidal structural parameters in the RP patients. Decreased MBR was significantly associated with reductions in VA, retinal sensitivity, CFT, and EZ width (all P < 0.05). The choroidal structural parameters did not correlate with central visual function, and the choroidal area, hyperreflective area, and SCT were inversely associated with CFT (all P < 0.05). CONCLUSIONS. These results demonstrated the divergence between the choroidal structure and blood function, and suggest that decreased choroidal flow, rather than the structural alteration, is closely associated with foveal degeneration in RP.
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Discovery of a cynomolgus monkey family with retinitis pigmentosa Reviewed
Ikeda Y., Nishiguchi K., Miya F., Shimozawa N., Funatsu J., Nakatake S., Fujiwara K., Tachibana T., Murakami Y., Hisatomi T., Yoshida S., Yasutomi Y., Tsunoda T., Nakazawa T., Ishibashi T., Sonoda K.
Investigative Ophthalmology and Visual Science 59 ( 2 ) 826 - 830 2018.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Investigative Ophthalmology and Visual Science
© 2018 The Authors. PURPOSE. To accelerate the development of new therapies, an inherited retinal degeneration model in a nonhuman primate would be useful to confirm the efficacy in preclinical studies. In this study, we describe the discovery of retinitis pigmentosa in a cynomolgus monkey (Macaca fascicularis) pedigree. METHODS. First, screening with fundus photography was performed on 1443 monkeys at the Tsukuba Primate Research Center. Ophthalmic examinations, such as indirect ophthalmoscopy, ERGs using RETeval, and optic coherent tomography (OCT) measurement, were then performed to confirm diagnosis. RESULTS. Retinal degeneration with cystoid macular edema was observed in both eyes of one 14-year-old female monkey. In her examinations, the full-field ERGs were nonrecordable and the outer layer of the retina in the parafoveal area was not visible on OCT imaging. Moreover, less frequent pigmentary retinal anomalies also were observed in her 3-year-old nephew. His full-field ERGs were almost nonrecordable and the outer layer was not visible in the peripheral retina. His father was her cousin (the son of her mother’s older brother) and his mother was her younger half-sibling sister with a different father. CONCLUSIONS. The hereditary nature is highly probable (autosomal recessive inheritance suspected). However, whole-exome analysis performed identified no pathogenic mutations in these monkeys.
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Quantifying metamorphopsia with M-CHARTS in patients with idiopathic macular hole Reviewed
Wada I., Yoshida S., Kobayashi Y., Zhou Y., Ishikawa K., Nakao S., Hisatomi T., Ikeda Y., Ishibashi T., Sonoda K.
Clinical Ophthalmology 11 1719 - 1726 2017.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Clinical Ophthalmology
© 2017 Wada et al. Purpose: The purpose of this study was to determine the degree of metamorphopsia using M-CHARTS™ in patients with idiopathic macular hole before and after pars plana vitrectomy and internal limiting membrane (ILM) peeling. Patients and methods: The records of 22 eyes of 22 patients with a full-thickness macular hole who underwent pars plana vitrectomy and ILM peeling were reviewed. All patients underwent a complete ophthalmic examination including spectral-domain optical coherence tomography (OCT). Horizontal metamorphopsia (MH) and vertical metamorphopsia (MV) scores were determined using M-CHARTS at the same time. The time course of changes in metamorphopsia and the relationship between best-corrected visual acuity (BCVA) and OCT parameters were assessed. Results: Sealing of the macular hole was noted in all eyes after surgery. BCVA improved significantly from 1 month after surgery (P,0.001). The MV score was significantly higher than the MH score before surgery (P,0.05) and improved significantly from 1 month after surgery (P,0.03). The MH score improved significantly at 6 months after surgery (P,0.001). The postoperative MV and MH scores became closer to one another from 1 month after surgery. Moreover, the MV score was higher than the MH score at all postoperative assessments. There was a significant correlation between the MV and MH scores at all follow-up assessments. There was no significant correlation between BCVA and the MV or MH score at any follow-up assessment. Conclusion: The satisfaction of the patients with macular hole after surgery cannot be necessarily measured by BCVA alone, because M-scores were not correlated to BCVA in postoperative evaluation. Therefore, evaluation of the MV and MH scores can be an independent treatment outcome in addition to BCVA.
DOI： 10.2147/OPTH.S144981
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Yoshida S., Kobayashi Y., Nakao S., Sassa Y., Hisatomi T., Ikeda Y., Oshima Y., Kono T., Ishibashi T., Sonoda K.
Clinical Ophthalmology 11 1697 - 1705 2017.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Clinical Ophthalmology
© 2017 Yoshida et al. Background: Pars plana vitrectomy is the only treatment for advanced proliferative diabetic retinopathy (PDR). However, vitrectomy is not always successful despite current progress in vitreoretinal surgical techniques. The aim of our study was to investigate whether the vitreal concentrations of MCP-1, IL-6, IL-8, and VEGF are elevated after unsuccessful vitrectomy in patients with PDR and to investigate whether the altered levels of these cytokines are associated with the cause for the reoperation. Patients and methods: Vitreous samples were collected from 263 eyes of 233 patients: PDR (n=129 eyes), proliferative vitreoretinopathy (PVR; n=24 eyes) and nondiabetic controls (n=110 eyes) prior to vitrectomy. Vitreous samples were also collected from 14 eyes of 14 patients with PDR before vitrectomy and from the same 14 eyes before a second vitrectomy for reoperation. The levels of MCP-1, IL-6, IL-8, and VEGF were measured by flow cytometry using a cytometric bead array (CBA) assay. Results: The mean concentrations of vitreal MCP-1, IL-6, IL-8, and VEGF were significantly higher in patients with PDR and PVR (P,0.01). There were significantly high correlations among the concentrations of MCP-1, IL-6, and IL-8, whereas the correlation of VEGF with the other 3 cytokines was lower. Among the 14 patients who required reoperation, the mean vitreal concentrations of MCP-1, IL-6, and IL-8 were higher than that at the time of the initial vitrectomy (P,0.01). At the time of the reoperation vitrectomy, the mean vitreous level of MCP-1, IL-6, and IL-8 in eyes with fibrous proliferation was higher than in those without fibrous proliferation (P,0.05). In contrast, VEGF in eyes with neovascular glaucoma (NVG) or anterior hyaloidal fibrovascular proliferation (AHFVP) was higher than in the eyes without NVG and AHFVP (P,0.05). Conclusion: The elevated levels of MCP-1, IL-6, and IL-8 may be the cause of the postoperative fibrous proliferation. In contrast, VEGF may be the cause of the neovascularization after unsuccessful vitrectomy in the eyes of PDR patients.
DOI： 10.2147/OPTH.S141821
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Kaizu Y., Nakao S., Yoshida S., Hayami T., Arima M., Yamaguchi M., Wada I., Hisatomi T., Ikeda Y., Ishibashi T., Sonoda K.
Investigative Ophthalmology and Visual Science 58 ( 11 ) 4889 - 4897 2017.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Investigative Ophthalmology and Visual Science
© 2017 The Authors. PURPOSE. Our purpose is to evaluate the spatial bias of macular capillary dropout accompanying diabetic retinopathy (DR) using optical coherence tomography angiography (OCTA). METHODS. This study included 47 patients with diabetes and 29 healthy individuals who underwent OCTA. Retinal capillary flow density (FD) of 2.6 × 2.6 or 5.2 × 5.2 mm foveal area as well as the four divided areas (superior, inferior, temporal, nasal) without a foveal avascular zone (FAZ) at the superficial capillary plexus and deep capillary plexus (DCP) were measured respectively using ImageJ and NI Vision. Spatial biases of FD (orientation bias ratio and hierarchical bias ratio) and the correlation between FAZ and FD were examined. RESULTS. OCTA showed focal capillary dropout in DR patients. The orientation bias of FD was significantly higher in NPDR compared to NDR in the DCP (P = 0.03). The hierarchical bias of FD was significantly shifted to a DCP dominance with progression of DR (P < 0.01). In addition, the FD and FAZ area were significantly inversely correlated in both plexus in DR patients but not in healthy subjects (P < 0.01). CONCLUSIONS. Area-divided OCTA quantification shows the appearance of spatial biases of macular capillary dropout with the onset of DR, suggesting that DR-related macular capillary dropout occurs locally and randomly. Future studies are necessary to determine the clinical relevance of the spatial pattern of capillary dropout in DR.
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Kaizu Y., Nakao S., Wada I., Yamaguchi M., Fujiwara K., Yoshida S., Hisatomi T., Ikeda Y., Hayami T., Ishibashi T., Sonoda K.
Translational Vision Science and Technology 6 ( 5 ) 2017.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Translational Vision Science and Technology
© 2017, The Authors. Purpose: Retinal vascular networks are observed as a layered structure residing in a nerve fiber layer and an inner nuclear layer of the retina. This study aimed to evaluate reflectance confocal adaptive optics scanning laser ophthalmoscopy (AO-SLO) for imaging of the layered retinal vascular networks. Methods: This study included 16 eyes of 16 healthy cases. On the fovea, 2.8-and 3.0 mm2-areas were imaged using a prototype AO-SLO and optical coherence tomography angiography (OCTA), respectively. AO-SLO images focused on the nerve fiber and photoreceptor layers were recorded in the area. Two different vessel images (capillary networks in the superficial layer and in all layers) were generated to examine if the deep capillary network could be distinguished. We compared AO-SLO with OCTA in imaging of the layered retinal vascular networks. Results: Sufficient images of capillary networks for analysis could be generated when the motion contrast was enhanced with AO-SLO movies in seven cases (43.8%). The deep capillary network could be distinguished in the merged image. Vascular depiction performance in AO-SLO was significantly better than in OCTA at both 0.5-and 1.0-mm areas from the fovea (P < 0.05). Conclusions: Retinal vascular imaging using AO-SLO might be a useful adjunct to OCTA as a supportive method to evaluate the retina in healthy patients and patients with disease. Translational Relevance: In cases requiring accurate and detailed retinal vasculature observation, AO-SLO might be useful for evaluating retinal vascular lesions as a supportive imaging method of OCTA.
DOI： 10.1167/tvst.6.5.2
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INCOMPLETE REPAIR of RETINAL STRUCTURE after VITRECTOMY with INTERNAL LIMITING MEMBRANE PEELING Reviewed
Hisatomi T., Tachibana T., Notomi S., Nakatake S., Fujiwara K., Murakami Y., Ikeda Y., Yoshida S., Enaida H., Murata T., Sakamoto T., Sonoda K., Ishibashi T.
Retina 37 ( 8 ) 1523 - 1528 2017.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Retina
Purpose: To examine retinal changes after vitrectomy with internal limiting membrane (ILM) peeling, we used a cynomolgus monkey model and focused on surgical damages of ILM peeling for long observational period of 3 years. Methods: Vitrectomy was performed followed by ILM peeling similar to clinical settings in humans. Ultrastructural changes of the retina were investigated by light, transmission, and scanning electron microscopy at 3 months and 3 years after ILM peeling. Results: Ultrastructural study showed that the ILM peeled area was still clearly recognized after 3 years. The Müller cell processes covered most of the retina; however, the nerve fiber layer was partly uncovered and exposed to the vitreous space. The arcuate linear nerve fiber bundles were observed as comparable with dissociated optic nerve fiber layer appearance. Small round retinal surface defects were also observed around macula, resembling the dimple sign. Forceps-related retinal thinning was also found on the edge of ILM peeling, where we started peeling with fine forceps. Conclusion: The ultrastructural studies showed that most of ILM peeling area was covered with glial cells during wound healing processes. Retinal changes were found comparable with dissociated optic nerve fiber layer appearance or dimple sign, which were clinically observed with optical coherence tomography.
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Comparación de la efectividad de ranibizumab intravítreo para el tratamiento del edema macular diabético en ojos vitrectomizados y no vitrectomizados. Reviewed
Koyanagi Y, Yoshida S, Kobayashi Y, Kubo Y, Yamaguchi M, Nakama T, Nakao S, Ikeda Y, Ohshima Y, Ishibashi T, Sonoda K.
Ophthalmologica. 2017.7
Language：English Publishing type：Research paper (scientific journal)
DOI： 10.1159/000477513
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Risk factors for posterior subcapsular cataract in retinitis pigmentosa Reviewed
Fujiwara K., Ikeda Y., Murakami Y., Funatsu J., Nakatake S., Tachibana T., Yoshida N., Nakao S., Hisatomi T., Yoshida S., Yoshitomi T., Ishibashi T., Sonoda K.
Investigative Ophthalmology and Visual Science 58 ( 5 ) 2534 - 2537 2017.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Investigative Ophthalmology and Visual Science
© 2017 The Authors. PURPOSE. Posterior subcapsular cataract (PSC) is a frequent complication in patients with retinitis pigmentosa (RP). The risk factors for PSC formation in RP are largely unknown. The purpose of this study was to investigate the risk factors for PSC. METHODS. We retrospectively studied a total of 322 eyes of 173 patients who were diagnosed with typical RP. We considered the following possible risk factors for PSC: age, sex, hypertension, diabetes mellitus, high myopia, asthma, history of steroid intake, and aqueous flare. Aqueous flare values were measured consecutively in 2012 and 2013 using a laser flare cell meter. The lens including PSC was examined with a slit lamp after dilation with tropicamide 1% and phenylephrine 2.5%. RESULTS. The geometric mean values of aqueous flare and mean values of visual acuity were significantly higher for the RP patients with PSC compared to those without PSC (P = 0.0003, P = 0.0004, respectively). When the aqueous flare values were assessed continuously, each 1-log-transformed increase in flare levels was associated with an elevation of the likelihood of having PSC after multivariable adjustment (odds ratio: 1.71; 95% confidence interval: 1.05-2.77). There were no significant associations of the other possible risk factors with PSC. CONCLUSIONS. Our analysis demonstrated that elevated aqueous flare is a significant risk factor for PSC formation. This result might provide insights into the association of inflammation and the pathogenesis of PSC formation in RP.
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Nakama T., Yoshida S., Ishikawa K., Kubo Y., Kobayashi Y., Zhou Y., Nakao S., Hisatomi T., Ikeda Y., Takao K., Yoshikawa K., Matsuda A., Ono J., Ohta S., Izuhara K., Kudo A., Sonoda K., Ishibashi T.
Molecular Therapy - Nucleic Acids 6 279 - 289 2017.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Molecular Therapy - Nucleic Acids
© 2017 Retinal neovascularization (NV) due to retinal ischemia remains one of the principal causes of vision impairment in patients with ischemic retinal diseases. We recently reported that periostin (POSTN) may play a role in the development of preretinal fibrovascular membranes, but its role in retinal NV has not been determined. The purpose of this study was to examine the expression of POSTN in the ischemic retinas of a mouse model of oxygen-induced retinal NV. We also studied the function of POSTN on retinal NV using Postn KO mice and human retinal endothelial cells (HRECs) in culture. In addition, we used a novel RNAi agent, NK0144, which targets POSTN to determine its effect on the development of retinal NV. Our results showed that the expression of POSTN was increased in the vascular endothelial cells, pericytes, and M2 macrophages in ischemic retinas. POSTN promoted the ischemia-induced retinal NV by Akt phosphorylation through integrin αvβ3. NK0144 had a greater inhibitory effect than canonical double-stranded siRNA on preretinal pathological NV in vivo and in vitro. These findings suggest a causal relationship between POSTN and retinal NV, and indicate a potential therapeutic role of intravitreal injection of NK0144 for retinal neovascular diseases.
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Kobayashi Y., Yoshida S., Zhou Y., Nakama T., Ishikawa K., Kubo Y., Arima M., Nakao S., Hisatomi T., Ikeda Y., Matsuda A., Sonoda K., Ishibashi T.
Laboratory Investigation 96 ( 11 ) 1178 - 1188 2016.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Laboratory Investigation
Tenascin-C is expressed in choroidal neovascular (CNV) membranes in eyes with age-related macular degeneration (AMD). However, its role in the pathogenesis of CNV remains to be elucidated. Here we investigated the role of tenascin-C in CNV formation. In immunofluorescence analyses, tenascin-C co-stained with α-SMA, pan-cytokeratin, CD31, CD34, and integrin α V in the CNV membranes of patients with AMD and a mouse model of laser-induced CNV. A marked increase in the expression of tenascin-C mRNA and protein was observed 3 days after laser photocoagulation in the mouse CNV model. Tenascin-C was also shown to promote proliferation and inhibit adhesion of human retinal pigment epithelial (hRPE) cells in vitro. Moreover, tenascin-C promoted proliferation, adhesion, migration, and tube formation in human microvascular endothelial cells (HMVECs); these functions were, however, blocked by cilengitide, an integrin α V inhibitor. Exposure to TGF-β2 increased tenascin-C expression in hRPE cells. Conditioned media harvested from TGF-β2-treated hRPE cell cultures enhanced HMVEC proliferation and tube formation, which were inhibited by pretreatment with tenascin-C siRNA. The CNV volume was significantly reduced in tenascin-C knockout mice and tenascin-C siRNA-injected mice. These findings suggest that tenascin-C is secreted by transdifferentiated RPE cells and promotes the development of CNV via integrin α V in a paracrine manner. Therefore, tenascin-C could be a potential therapeutic target for the inhibition of CNV development associated with AMD.
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Changes in chorioretinal blood flow velocity and cerebral blood flow after carotid endarterectomy Reviewed
Enaida H., Nagata S., Takeda A., Nakao S., Ikeda Y., Ishibashi T.
Japanese Journal of Ophthalmology 60 ( 6 ) 459 - 465 2016.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Ophthalmology
© 2016, Japanese Ophthalmological Society. Purpose: To investigate the changes in chorioretinal blood flow velocity and cerebral blood after carotid endarterectomy (CEA). Methods: Nine patients with moderate to severe internal carotid artery stenosis underwent CEA. Chorioretinal blood flow velocity was measured by laser speckle flowgraphy (LSFG), while cerebral blood flow (CBF) was measured by single-photon emission computed tomography (SPECT), on the affected side both before and after CEA. LSFG was evaluated in five areas to determine mean blur rate, while CBF was calculated from regional CBF and cerebrovascular reactivity (CVR), at the middle cerebral artery (MCA) region of each patient. Results: Five cases showed an increase (mean 3.49 %, range −29.82 to 35.59 %) of average chorioretinal blood flow velocity using LSFG after CEA. A particularly averaged increase in chorioretinal blood flow was observed in the macular area compared with other areas. Similarly, there was an increase in CBF at rest (mean 11.46 %, range −14.51 to 74.14 %) observed using SPECT after surgery. Improvement of CVR was confirmed in four cases. All general and visual symptoms disappeared after CEA. Severe adverse effects, including hyperperfusion syndrome, were not observed in any cases. Conclusions: LSFG may be useful for the analysis of chorioretinal blood flow changes after CEA.
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Yamaguchi M., Nakao S., Kaizu Y., Kobayashi Y., Nakama T., Arima M., Yoshida S., Oshima Y., Takeda A., Ikeda Y., Mukai S., Ishibashi T., Sonoda K.
Scientific Reports 6 2016.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
Histological studies from autopsy specimens have characterized hard exudates as a composition of lipid-laden macrophages or noncellular materials including lipid and proteinaceous substances (hyaline substances). However, the characteristics of hard exudates in living patients have not been examined due to insufficient resolution of existing equipment. In this study, we used adaptive optics scanning laser ophthalmoscopy (AO-SLO) to examine the characteristics of hard exudates in patients with retinal vascular diseases. High resolution imaging using AO-SLO enables morphological classification of retinal hard exudates into two types, which could not be distinguished either on fundus examination or by spectral domain optical coherence tomography (SD-OCT). One, termed a round type, consisted of an accumulation of spherical particles (average diameter of particles: 26.9 ± 4.4 μm). The other, termed an irregular type, comprised an irregularly shaped hyper-reflective deposition. The retinal thickness in regions with round hard exudates was significantly greater than the thickness in regions with irregular hard exudates (P = 0.01 â †'0.02). This differentiation of retinal hard exudates in patients by AO-SLO may help in understanding the pathogenesis and clinical prognosis of retinal vascular diseases.
DOI： 10.1038/srep33574
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Koyanagi Y., Yoshida S., Kobayashi Y., Kubo Y., Yamaguchi M., Nakama T., Nakao S., Ikeda Y., Ohshima Y., Ishibashi T., Sonoda K.
Ophthalmologica 236 ( 2 ) 67 - 73 2016.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Ophthalmologica
© 2016 S. Karger AG, Basel. Copyright: All rights reserved. Purpose: To compare the effectiveness of intravitreal ranibizumab (IVR) for diabetic macular edema (DME) between eyes with and without previous vitrectomy. Procedures: We prospectively assessed the best-corrected visual acuity (BCVA) and central macular thickness (CMT) after IVR for 6 months. Results: There were no significant differences in the baseline BCVA and CMT between both groups. In the nonvitrectomized group (n = 15), the mean changes of BCVA and CMT from baseline to month 6 were significant (p < 0.01). In the vitrectomized group (n = 10), the improvement appeared to be slower, and the mean BCVA improvement was not significant (p = 0.5), although the mean CMT decrease was significant (p < 0.05). There were no significant differences in the mean changes of BCVA and CMT between both groups at 6 months. Conclusions: The difference in the effectiveness of IVR between both groups was not significant. IVR can be a treatment option even for vitrectomized DME eyes.
DOI： 10.1159/000446992
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Association between aqueous flare and epiretinal membrane in retinitis pigmentosa Reviewed
Fujiwara K., Ikeda Y., Murakami Y., Nakatake S., Tachibana T., Yoshida N., Nakao S., Hisatomi T., Yoshida S., Yoshitomi T., Sonoda K., Ishibashi T.
Investigative Ophthalmology and Visual Science 57 ( 10 ) 4282 - 4286 2016.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Investigative Ophthalmology and Visual Science
© 2016, Association for Research in Vision and Ophthalmology Inc. All rights reserved. PURPOSE. Epiretinal membrane (ERM) is a frequent macular complication in patients with retinitis pigmentosa (RP). The etiology of ERM formation in RP is largely unknown. The purpose of this study was to investigate the association between aqueous flare, a surrogate index of intraocular inflammation, and ERM secondary to RP. METHODS. We retrospectively studied a total of 206 eyes of 117 patients who were diagnosed with typical RP. Aqueous flare values were measured consecutively in 2012 and 2013 using a laser flare cell meter. Spectral-domain optical coherence tomography images and fundus photographs taken on the same day of the aqueous flare measurements were analyzed for ERM detection. RESULTS. The mean values of aqueous flare, age, and frequency of male sex were significantly higher in the RP patients with ERM compared with the RP patients without ERM (P < 0.0001, P = 0.007, and P = 0.004, respectively). After adjustment for age and sex, the eyes in the highest quartile of aqueous flare had significantly higher odds of having ERM than those in the lowest quartile (odds ratio [OR], 2.68; 95% confidence interval [CI], 1.04-6.93), and the linear trend across flare levels was significant (P = 0.005). In addition, each 1-log-transformed increase in flare values was associated with an elevation of the likelihood of having ERM (OR, 2.59; 95% CI, 1.33-5.06). CONCLUSIONS. Our analysis demonstrated that elevated aqueous flare is associated with ERM secondary to RP, suggesting that inflammation may be implicated in the pathogenesis of ERM formation in RP.
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Interleukin-12 inhibits pathological neovascularization in mouse model of oxygen-induced retinopathy Reviewed
Zhou Y., Yoshida S., Kubo Y., Kobayashi Y., Nakama T., Yamaguchi M., Ishikawa K., Nakao S., Ikeda Y., Ishibashi T., Sonoda K.
Scientific Reports 6 2016.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
Hypoxia-induced retinal neovascularization is a major pathological condition in many vision-threatening diseases. In the present study, we determined whether interleukin (IL)-12, a cytokine that regulates angiogenesis, plays a role in the neovascularization in a mouse model of oxygen-induced retinopathy (OIR). We found that the expressions of the mRNAs of both IL-12p35 and IL-12p40 were significantly reduced in the OIR retinas compared to that of the room air-raised control. The sizes of the avascular areas and neovascular tufts were larger in IL-12p40 knock-out (KO) mice than that in wild type (WT) mice. In addition, an intravitreal injection of recombinant IL-12 reduced both avascular areas and neovascular tufts. IL-12 injection enhanced the expressions of interferon-gamma (IFN-γ) and other downstream chemokines. In an in vitro system, IL-12 had no significant effect on tube formation of human retinal microvascular endothelial cells (HRECs). Moreover, a blockade of IFN-γ suppressed the inhibitory effect of IL-12 on pathological neovascularization. These results suggest that IL-12 plays important roles in inhibiting pathological retinal neovascularization.
DOI： 10.1038/srep28140
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Kobayashi Y., Yoshida S., Zhou Y., Nakama T., Ishikawa K., Arima M., Nakao S., Sassa Y., Takeda A., Hisatomi T., Ikeda Y., Matsuda A., Sonoda K., Ishibashi T.
Molecular Vision 22 436 - 445 2016.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Molecular Vision
© 2016 Molecular Vision. Purpose: We previously demonstrated that tenascin-C was highly expressed in the fibrovascular membranes (FVMs) of patients with proliferative diabetic retinopathy (PDR). However, its role in the pathogenesis of FVMs has not been determined. The purpose of this study was to investigate what role tenascin-C plays in the formation and angiogenesis of FVMs. Methods: The level of tenascin-C was determined by sandwich enzyme-linked immunosorbent assay in the vitreous samples collected from patients with PDR and with a macular hole as control. The locations of tenascin-C, α- smooth muscle actin (SMA), CD34, glial fibrillary acidic protein (GFAP), and integrin αV in the FVMs from PDR patients were determined by immunohistochemistry. We also measured the in vitro expression of the mRNA and protein of tenascin-C in vascular smooth muscle cells (VSMCs) stimulated by interleukin (IL)-13. The effects of tenascin-C on cell proliferation, migration, and tube formation were determined in human retinal endothelial cells (HRECs) in culture. Results: The mean vitreous levels of tenascin-C were significantly higher in patients with PDR than in patients with a macular hole (p<0.001). Double immunofluorescence analyses of FVMs from PDR patients showed that tenascin-C co-stained FVMs with α-SMA, CD34, and integrin αV but not with GFAP. In addition, IL-13 treatment increased both the expression and secretion of tenascin-C by VSMCs in a dose-dependent manner. Tenascin-C exposure promoted proliferation, migration, and tube formation in HRECs. Tenascin-C neutralizing antibody significantly blocked the tube formation by HRECs exposed to VSMC-IL-13-conditioned medium. Conclusions: Our findings suggest that tenascin-C is secreted from VSMCs and promotes angiogenesis in the FVMs associated with PDR.
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MUTYH promotes oxidative microglial activation and inherited retinal degeneration Reviewed
Nakatake S., Murakami Y., Ikeda Y., Morioka N., Tachibana T., Fujiwara K., Yoshida N., Notomi S., Hisatomi T., Yoshida S., Ishibashi T., Nakabeppu Y., Sonoda K.H.
JCI Insight 1 ( 15 ) 2016
Language：English Publishing type：Research paper (scientific journal) Publisher：JCI Insight
© 2016 American Society for Clinical Investigation. All rights reserved. Oxidative stress is implicated in various neurodegenerative disorders, including retinitis pigmentosa (RP), an inherited disease that causes blindness. The biological and cellular mechanisms by which oxidative stress mediates neuronal cell death are largely unknown. In a mouse model of RP (rd10 mice), we show that oxidative DNA damage activates microglia through MutY homolog–mediated (MUYTH-mediated) base excision repair (BER), thereby exacerbating retinal inflammation and degeneration. In the early stage of retinal degeneration, oxidative DNA damage accumulated in the microglia and caused single-strand breaks (SSBs) and poly(ADP-ribose) polymerase activation. In contrast, Mutyh deficiency in rd10 mice prevented SSB formation in microglia, which in turn suppressed microglial activation and photoreceptor cell death. Moreover, Mutyh-deficient primary microglial cells attenuated the polarization to the inflammatory and cytotoxic phenotype under oxidative stress. Thus, MUTYH-mediated BER in oxidative microglial activation may be a novel target to dampen the disease progression in RP and other neurodegenerative disorders that are associated with oxidative stress.
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Correlation between macular blood flow and central visual sensitivity in retinitis pigmentosa Reviewed
Murakami Y., Ikeda Y., Akiyama M., Fujiwara K., Yoshida N., Nakatake S., Notomi S., Nabeshima T., Hisatomi T., Enaida H., Ishibashi T.
Acta Ophthalmologica 93 ( 8 ) e644 - e648 2015.12
Language：English Publishing type：Research paper (scientific journal) Publisher：Acta Ophthalmologica
© 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd. Purpose To investigate the changes in macular blood flow and the correlation between those changes and central visual function in patients with retinitis pigmentosa (RP). Methods The mean blur rate (MBR), a quantitative blurring index of the laser speckle pattern that represents retinal and choroidal blood flow, was measured by laser speckle flowgraphy. Mean blur rate values in the macular area were compared between 70 patients with RP and 28 control subjects. The relationships between MBR on the one hand and, on the other, visual acuity (VA), mean deviation (MD) and averaged macular sensitivity of static perimetry tests (Humphrey Filed Analyzer, the central 10-2 program) were analysed in patients with RP. Results Macular MBR was decreased to 75% in patients with RP compared with control subjects (p < 0.0001, Student's t-test). Spearman's rank testing showed that macular MBR was significantly correlated with VA (r = -0.261, p = 0.0299), MD values (r = 0.438, p = 0.0002) and averaged macular sensitivity at the central 4 and 12 points of static perimetry tests (r = 0.426 and 0.442, p = 0.0003 and 0.0002, respectively). Multivariable-adjusted analysis confirmed that MBR was independently associated with MD (p = 0.0002) and macular sensitivity at the central 4 and 12 points (p < 0.0001 and 0.0002, respectively). Conclusions Decreased macular blood flow was associated with reduced macular visual sensitivity in patients with RP. Although the cause-effect relationships remain to be elucidated, these findings suggest that vascular defects may be involved in the pathogenesis of RP such as central vision loss.
DOI： 10.1111/aos.12693
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Vitreous cysts in patients with retinitis pigmentosa Reviewed
Yoshida N., Ikeda Y., Murakami Y., Nakatake S., Tachibana T., Notomi S., Hisatomi T., Ishibashi T.
Japanese Journal of Ophthalmology 59 ( 6 ) 373 - 377 2015.11
Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Ophthalmology
© 2015, Japanese Ophthalmological Society. Purpose: To determine the prevalence of vitreous cysts in patients with retinitis pigmentosa (RP). Methods: We retrospectively reviewed the charts of 435 consecutive patients diagnosed as having typical RP. Results: Vitreous cysts were diagnosed in 37 eyes of 28 patients with RP (13 males and 15 females; mean age 47.0 ± 19.8 years; range 15–79 years), for an overall prevalence of 6.4 %. The cysts were observed bilaterally in nine of the patients (32.1 %). Among these 28 patients, 11 (39.3 %) were younger than 40 years. In all, 81.8 % of the vitreous cysts were detected around the optic nerve head. Conclusions: We demonstrated that the prevalence of vitreous cysts was 6.4 % in patients with RP. These cysts were considered to be asymptomatic.