Publications by authors named "Chikako Hara"

34 Publications

Long-term outcomes of intravitreal activated protein C injection for ischemic central retinal vein occlusion: an extension trial.

Graefes Arch Clin Exp Ophthalmol 2021 Apr 24. Epub 2021 Apr 24.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

Purpose: Our previous 1-year pilot study evaluated the efficacy of intravitreally injected activated protein C (APC) in 10 eyes with ischemic central retinal vein occlusion (CRVO). The reperfusion of the areas of retinal nonperfusion (RNP) exceeded 50% of the baseline in five (50%) eyes 1 year after the APC injection. The current study evaluated the long-term efficacy and safety of intravitreal APC.

Methods: The 10 eyes in the pilot study were included in this study. Other treatments were administered at the physicians' discretion after the pilot study. We evaluated visual acuity (VA), central retinal thickness (CRT) and perfusion status, and adverse events and severity over the long term.

Results: The median follow-up was 60 months (range, 48-68 months). Compared with baseline, the post-treatment VA improved significantly (P < 0.001) from 1.39 to 1.06 logarithm of the minimum angle of resolution. The CRT improved significantly (P < 0.001) from 1090 to 195 μm at the last visit. The RNP areas decreased from an average 29.7 disc areas (DAs) at baseline to an average 16.5 DAs at the last examination (mean, 40 ± 6.5 months after the first APC treatment). No adverse events were related to intravitreal APC.

Conclusion: No complications were associated with intravitreal APC, the clinical course improved, and improved RNP was maintained for the long term, suggesting that intravitreal APC may be an alternative treatment for CRVO.
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http://dx.doi.org/10.1007/s00417-021-05072-9DOI Listing
April 2021

Association of disorganization of retinal inner layers with optical coherence tomography angiography features in branch retinal vein occlusion.

Graefes Arch Clin Exp Ophthalmol 2021 Apr 16. Epub 2021 Apr 16.

Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, E-7, Suita, Osaka, 565-0871, Japan.

Purpose: To examine the associations between the disorganization of the retinal inner layers (DRIL) and optical coherence tomography angiography characteristics and visual acuity (VA) outcomes in eyes with macular edema secondary to branch retinal vein occlusion (BRVO).

Methods: In this single-center cross-sectional cohort study, the data of 43 patients with macular edema secondary to BRVO that received pro re nata anti-vascular endothelial growth factor therapy were analyzed. B-scan and en face angiographic images were obtained by swept-source-based wide-field optical coherence tomography angiography performed at a single visit 1 month after the anti-vascular endothelial growth factor therapy session and evaluated. Correlations between the vascular indices in macula-centered 3 × 3 and 12 × 12 mm areas and B-scan parameters, such as DRIL length and VA, were examined.

Results: The mean DRIL length (Rs = 0.588, p < 0.001) and the proportion of scans with DRIL out of five scans (Rs = 0.507, p = 0.001) were significantly correlated with the final best-corrected VA in patients with BRVO. DRIL length was associated with vascular density (VD) and vascular length in the macula (Rs =  - 0.425, p = 0.006 and Rs =  - 0.382, p = 0.013, respectively), but not with VD and vascular length in the larger areas (12 × 12 mm). Multilinear regression analysis revealed that the extent of macular edema (p = 0.0016) and VD in the 3 × 3 mm area (p = 0.004) was significantly associated with the DRIL development.

Conclusion: DRIL severity was correlated with VA and associated with the peri-macular perfusion status in eyes with BRVO. Macular edema and macular perfusion affected DRIL severity. These findings would help understand the pathogenesis of DRIL in eyes with BRVO.
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http://dx.doi.org/10.1007/s00417-021-05168-2DOI Listing
April 2021

Flow pattern and perforating vessels in three different phases of myopic choroidal neovascularization seen by swept-source optical coherence tomography angiography.

Graefes Arch Clin Exp Ophthalmol 2021 Mar 9. Epub 2021 Mar 9.

Department of Ophthalmology, Osaka University Medical School, 2-2 Yamadaoka, 565-0871, Suita, Osaka, Japan.

Purpose: To compare the choroidal neovascularization (CNV) flow patterns and the relationship between perforating vessels (PVs) and CNV in the three different stages of networks in myopic CNV (mCNV) using swept-source optical coherence tomography angiography (SS-OCTA).

Methods: This retrospective study included 28 eyes with mCNV that was divided into three phases (active, scar, and atrophic) and observed by SS-OCTA. SS-OCTA findings, with special focus on the relationship between the PVs and CNV, were compared among the three phases.

Results: Overall, the CNV signal was detected in 31 of the 34 areas of CNV (91%); in the active, scar, and atrophic phases, respectively, CNV signals were detected in eight of eight areas of CNV (100%), 10 of 11 areas of CNV (91%), and 13 of 15 areas of CNV (86%). Two signal patterns were observed in each phase, i.e., dense and loop; in the atrophic phase, seven eyes were unclassifiable. The ratio between the dense and loop patterns did not differ significantly among the phases. In 30 of 34 areas of CNV for which clear images were obtained, the PVs and CNV were connected directly or indirectly in 19 area of CNV, and in five areas of CNV, trunk-like vessels were connected to the PVs within the CNV. The numbers of foveal or parafoveal CNVs accompanied by PVs were significantly (p=0.0048) greater than those of the extrafoveal CNV.

Conclusions: OCTA provides detailed observation of mCNV and the relationship between CNV and PVs. Although the CNV signal pattern does not differ depending on the degree of atrophy, there are cases in which only the trunk-like vessels connect to the PVs within the CNV in the atrophic phase without CNV flow signal.
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http://dx.doi.org/10.1007/s00417-021-05134-yDOI Listing
March 2021

Structural En Face OCT Angiography Image of Avulsed Retinal Vessels and Vitreal Neovascularization.

Ophthalmol Retina 2020 Dec;4(12):1157

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

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http://dx.doi.org/10.1016/j.oret.2020.05.010DOI Listing
December 2020

HLA-Matched Allogeneic iPS Cells-Derived RPE Transplantation for Macular Degeneration.

J Clin Med 2020 Jul 13;9(7). Epub 2020 Jul 13.

Tomey Corporation, Nagoya 451-0051, Japan.

Immune attacks are key issues for cell transplantation. To assess the safety and the immune reactions after iPS cells-derived retinal pigment epithelium (iPS-RPE) transplantation, we transplanted HLA homozygote iPS-RPE cells established at an iPS bank in HLA-matched patients with exudative age-related macular degeneration. In addition, local steroids without immunosuppressive medications were administered. We monitored immune rejections by routine ocular examinations as well as by lymphocytes-graft cells immune reaction (LGIR) tests using graft RPE and the patient's blood cells. In all five of the cases that underwent iPS-RPE transplantation, the presence of graft cells was indicated by clumps or an area of increased pigmentation at 6 months, which became stable with no further abnormal growth in the graft during the 1-year observation period. Adverse events observed included corneal erosion, epiretinal membrane, retinal edema due to epiretinal membrane, elevated intraocular pressure, endophthalmitis, and mild immune rejection in the eye. In the one case exhibiting positive LGIR tests along with a slight fluid recurrence, we administrated local steroid therapy that subsequently resolved the suspected immune attacks. Although the cell delivery strategy must be further optimized, the present results suggest that it is possible to achieve stable survival and safety of iPS-RPE cell transplantation for a year.
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http://dx.doi.org/10.3390/jcm9072217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408794PMC
July 2020

Identification of as a susceptibility gene for neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

Br J Ophthalmol 2020 Mar 9. Epub 2020 Mar 9.

Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China

Purpose: The endothelial and cell-specific angiopoietin-Tie pathway plays an important regulatory role in angiogenesis. In this study, we investigated the associations of the () gene with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV), using haplotype-tagging single-nucleotide polymorphisms (SNPs) analysis.

Methods: This study involved totally 2343 subjects, including a Hong Kong Chinese cohort (214 nAMD patients, 236 PCV patients and 433 control subjects), a Shantou Chinese cohort (189 nAMD patients, 187 PCV patients and 531 control subjects) and an Osaka Japanese cohort (192 nAMD patients, 204 PCV patients and 157 control subjects). Thirty haplotype-tagging SNPs in were genotyped in the Hong Kong cohort using TaqMan technology. Two SNPs (rs625767 and rs2273717) showing association in the Hong Kong cohort were genotyped in the Shantou and Osaka cohorts. The SNP-disease association of individual and pooled cohorts were analysed.

Results: Two SNPs (rs625767 and rs2273717) showed suggestive association with both nAMD and PCV in the Hong Kong cohort. In the meta-analysis involving all the three cohorts, rs625767 showed significant associations with nAMD (p=0.01; OR=0.82, 95% CI 0.70 to 0.96; I=0%), PCV (p=0.02; OR=0.83, 95% CI 0.71 to 0.97; I=27%) and pooled nAMD and PCV (p=0.002; OR=0.82, 95% CI 0.72 to 0.93; I=0%), with low inter-cohort heterogeneities.

Conclusion: This study revealed as a novel susceptibility gene for nAMD and PCV in Japanese and Chinese. Further studies in other populations are warranted to confirm its role.
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http://dx.doi.org/10.1136/bjophthalmol-2019-315746DOI Listing
March 2020

Five-year follow-up of fundus autofluorescence and retinal sensitivity in the fellow eye in exudative age-related macular degeneration in Japan.

PLoS One 2020 6;15(3):e0229694. Epub 2020 Mar 6.

Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

Purpose: To assess the 5-year change in abnormal fundus autofluorescence (FAF) patterns and retinal sensitivity in the fellow eye of Japanese patients with unilateral exudative age-related macular degeneration (AMD).

Methods: Patients with unilateral exudative AMD who developed abnormal FAF in the fellow eyes were enrolled. FAF imaging and microperimetry were performed at baseline and follow-ups. FAF findings were classified into 8 patterns based on the International Fundus Autofluorescence Classification Group to assess retinal sensitivity. Forty-five points covering the central 12 degrees on microperimetry were superimposed onto the FAF images. Each point was classified depending on the distance from the abnormal FAF. "Close" was defined as the portion within 1 degree from the border of any abnormal FAF, and "Distant" was defined as the portion over 1 degree from the border of abnormal FAF. To investigate the association between the retinal sensitivity and distance from the abnormal FAF, hierarchical linear mixed-effect models were used with the distance, time and time squared from baseline (months), and angle (degrees) as fixed effects. Differences among patients, eyes, and test point locations were considered successively nested random effects.

Results: We studied 66 fellow eyes with abnormal FAF. Twenty-seven eyes were followed-up during the 5 years. In the 13 of 27 eyes (48%), the abnormal FAF patterns had changed during the 5 years. We found retinal sensitivity was associated significantly with the distance from the abnormal FAF ("Distant": p<0.001, time2 from baseline: p<0.001, angle: p<0.001). The mean retinal sensitivity of the "Close" tended to deteriorate after the third year and eventually showed the similar sensitivity as the portion within the abnormal FAF.

Conclusion: FAF patterns can change about half during the 5 years and the retinal sensitivity near abnormal FAF tends to deteriorate after the third year.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229694PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059919PMC
June 2020

Tachyphylaxis during treatment of exudative age-related macular degeneration with aflibercept.

Graefes Arch Clin Exp Ophthalmol 2019 Nov 3;257(11):2559-2569. Epub 2019 Sep 3.

Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Purpose: At present, the standard treatment of neovascular age-related macular degeneration (AMD) is the repeated administration of antivascular endothelial growth factor (VEGF) agents. However, we often encounter patients who develop tachyphylaxis for anti-VEGF agents. In this study, we investigated the characteristics of patients who developed tachyphylaxis on repeated intravitreal aflibercept (IVA) injections for neovascular AMD and the frequency of tachyphylaxis.

Methods: Three hundred thirteen eyes (313 patients) with treatment-naïve AMD who achieved resolution soon after starting IVA and were followed up for ≥ 12 months were enrolled in this retrospective, interventional, consecutive case series. The eyes were investigated for tachyphylaxis to aflibercept. Tachyphylaxis was defined as absence of any improvement (more than 100 μm) in or worsening of CRT within 1 month after more than two repeated monthly IVA injections when the exudative change remained.

Results: Twenty-eight (8.9%) of the 313 eyes developed tachyphylaxis (occult with no classic, n = 14; polypoidal choroidal vasculopathy, n = 14) at an annual rate of about 3%. The mean number of IVA injections was 10.5 ± 7.8, and the mean interval until tachyphylaxis was 20.9 ± 14.0 months. There was a significant difference in the AMD subtypes between the group with tachyphylaxis and the group without it (p = 0.0029). Occult with no classic type and polypoidal choroidal vasculopathy were the only AMD subtypes in the eyes with tachyphylaxis. In the analysis of the eyes that had occult with no classic or polypoidal choroidal vasculopathy, only intraretinal edema was significantly less common (p = 0.042). A combination of photodynamic therapy and aflibercept was effective in 13 (87%) of 15 eyes with tachyphylaxis, and switching to intravitreal ranibizumab was effective in 5 (56%) of 9 eyes.

Conclusions: Tachyphylaxis occurs after repeated IVA injections in a minority of patients with AMD for a long term and is more likely to occur in eyes with lesions beneath the retinal pigment epithelium and no intraretinal edema. Treatment of AMD should be performed keeping this fact in mind, while considering the consecutive treatment.
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http://dx.doi.org/10.1007/s00417-019-04456-2DOI Listing
November 2019

Time course of swept-source optical coherence tomography angiography findings after photodynamic therapy and aflibercept in eyes with age-related macular degeneration.

Am J Ophthalmol Case Rep 2019 Sep 1;15:100485. Epub 2019 Jun 1.

Department of Ophthalmology, Osaka University Medical School, Osaka, Japan.

Purpose: To report swept-source optical coherence tomography angiography (SS-OCTA) findings after full-fluence photodynamic therapy (PDT) and aflibercept intravitreal injection (IVA) for age-related macular degeneration (AMD).

Methods: Five eyes of five patients with AMD treated with PDT and IVA were include into the study. We retrospectively reviewed the data obtained from the five patients using SS-OCTA before and after treatment. Three eyes had type 1 choroidal neovascularization (CNV) and two eyes had polypoidal choroidal vasculopathy.

Results: Before treatment, the CNV signals detected in all cases, decreased in three eyes and were not detected completely in two eyes at 1 months after treatment. The areas indicating CNV increased over time, but they did not increase to the baseline level. No CNV signal was detected in one eye during follow-up. In all cases, the exudation unchanged or resolved without additional IVA; the exudation recurred in two cases. In one eye, the CNV signal and the exudation occurred simultaneously; however, there was no association in another eye. A feeder vessel, from which the CNV signal seemed to originate, was seen in one of the five eyes.

Conclusion And Importance: SS-OCTA is useful to monitor the morphology of CNV after PDT and IVA, indicating that the remodeling of the choroidal vasculature occurs gradually after treatment. The presence or absence of the CNV signal might indicate CNV activity.
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http://dx.doi.org/10.1016/j.ajoc.2019.100485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556523PMC
September 2019

Quantitative evaluation of visual function in patients with cornea verticillata associated with Fabry disease.

Acta Ophthalmol 2019 Dec 24;97(8):e1098-e1104. Epub 2019 May 24.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

Purpose: To evaluate the visual function of patients with cornea verticillata associated with Fabry disease through quantitative evaluations of contrast sensitivity function and straylight.

Methods: We enrolled 28 eyes of 14 patients with Fabry disease (mean age, 37.1 ± 17.2  years) and 20 eyes of 20 age-matched healthy controls. Comprehensive ophthalmological examinations were performed and contrast sensitivity and letter contrast sensitivity were measured for all patients, following which the area under the log contrast sensitivity function (AULCSF) was calculated. Straylight was quantified using a straylight metre. Furthermore, subgroup analysis was performed according to the whorl-like pattern of cornea verticillata (mild and typical groups).

Results: All 28 eyes showed cornea verticillata. Visual acuity and letter contrast sensitivity values were the same for normal eyes and those with Fabry disease. AULCSF differed by 0.15 log[s] between the eyes with Fabry disease and the control eyes (p < 0.001), while straylight differed by 0.45 log[s] between the two groups (p < 0.001). Subgroup analysis based on the whorl-like pattern of cornea verticillata showed that AULCSF and straylight differed by 0.11 log[s] and 0.08 log[s], respectively, between the typical and mild groups (p = 0.036 and p = 0.147, respectively).

Conclusion: Although cornea verticillata associated with Fabry disease does not affect the visual acuity and letter contrast sensitivity, more comprehensive testing of visual function by the inclusion of straylight and grating contrast sensitivity measurements shows clear functional deficits in these patients.
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http://dx.doi.org/10.1111/aos.14143DOI Listing
December 2019

Activated Protein C for Ischemic Central Retinal Vein Occlusion: One-Year Results.

Ophthalmol Retina 2019 01 25;3(1):93-94. Epub 2018 Jul 25.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

Intravitreally administered activated protein C in 10 eyes with ischemic central retinal vein occlusion significantly improved macular edema; in 5 eyes, the reperfusion of the retinal nonperfused areas exceeded 50% of baseline.
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http://dx.doi.org/10.1016/j.oret.2018.07.012DOI Listing
January 2019

Evaluation of retinal nonperfusion in branch retinal vein occlusion using wide-field optical coherence tomography angiography.

Acta Ophthalmol 2019 Sep 22;97(6):e913-e918. Epub 2019 Mar 22.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Yamadaoka, Japan.

Purpose: To characterize wide-field optical coherence tomography angiography (OCTA) features of retinal nonperfusion in eyes with branch retinal vein occlusion (BRVO).

Methods: Automated scanning of five 12 × 12-mm areas of swept-source OCTA and wide-field fluorescein angiography (FA) images was performed in a consecutive case series of 27 eyes in 27 patients with BRVO in this institutional cross-sectional study. The correlation between the areas of retinal nonperfusion detected by both examinations was assessed. Panoramic images obtained in five 12 × 12-mm OCTA scans in eyes with retinal nonperfusion were binarized or skeletonized, and the associations between vascular parameters such as vascular density (VD) and vascular length (VL) with the wide-field FA characteristics were evaluated.

Results: The mean area of retinal nonperfusion in the OCTA images was 81.0 ± 66.8 mm (range, 0.0-188.8). The mean areas of retinal nonperfusion in FA and the total FA images were, respectively, 84.7 ± 72.5 mm (range, 0.0-221.9) and 184.1 ± 167.7 mm (range, 0.0-515.0). The mean VD was 27.6 ± 3.5% (range, 19.6-33.7), and the mean VL was 12.4 ± 8.5% (range, 5.4-31.3). Separate regression analyses of the areas of retinal nonperfusion in FA (p = 0.0004, R  = 0.4627) and the total FA (p = 0.0008, R  = 0.4214) images showed a significant association with the VL.

Conclusions: OCTA images based on wide-field technologies can quantitatively evaluate retinal nonperfusion in eyes with BRVO.
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http://dx.doi.org/10.1111/aos.14087DOI Listing
September 2019

Fundus autofluorescence and retinal sensitivity in fellow eyes of age-related macular degeneration in Japan.

PLoS One 2019 28;14(2):e0213161. Epub 2019 Feb 28.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

Purpose: Abnormal fundus autofluorescence (FAF) potentially precedes onset of late age-related macular degeneration (AMD) in Caucasian patients. Many differences exist between Asian and Caucasian patients regarding AMD types and severity, gender, and genetic backgrounds. We investigated the characteristics of abnormal FAF and retinal sensitivity in the fellow eyes of Japanese patients with unilateral neovascular AMD.

Methods: Sixty-six patients with unilateral neovascular AMD and abnormal FAF in the fellow eye were enrolled in this multicenter, prospective, observational study. The best-corrected visual acuity, fundus photographs, FAF images, and retinal sensitivity on microperimetry were measured periodically for 12 months. The FAF images were classified into eight patterns based on the International Fundus Autofluorescence Classification Group. The points measured by microperimetry were superimposed onto the FAF images and fundus photographs and classified as "within," "close," and "distant," based on the distance from the abnormal FAF and other findings. The relationship between the location of the baseline abnormal FAF and retinal sensitivity was investigated.

Results: In Japanese patients, patchy (33.3%) and focally increased (30.3%) patterns predominated in the abnormal FAF. Intermediate-to-large drusen was associated predominantly with hyperfluorescence and hypofluorescence. Neovascular AMD developed within 1 year in six (9.1%) eyes, the mean baseline retinal sensitivity of which was 12.8 ± 4.7 dB, significantly (p<0.002) lower than the other eyes. In 44 of the other 60 eyes, microperimetry was measurable at baseline and month 12 and the mean retinal sensitivity improved significantly from 13.5 ± 4.4 to 13.9 ± 4.8 dB (p<0.001), possibly associated with lifestyle changes (e.g., smoking cessation, antioxidant and zinc supplementation). The mean retinal sensitivities of points within and close to the abnormal FAF were 9.9 and 11.7 dB, respectively, which were significantly lower than the 14.0 dB of the points distant from the abnormal FAF.

Conclusion: In Japanese patients, patchy and focally increased patterns predominated in the abnormal FAF. The retinal sensitivity was lower close to/within the abnormal FAF. FAF and microperimetry are useful to assess macular function before development of neovascular AMD or geographic atrophy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213161PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394952PMC
December 2019

Retinal Microvasculature and Visual Acuity after Intravitreal Aflibercept in Diabetic Macular Edema: An Optical Coherence Tomography Angiography Study.

Sci Rep 2019 02 7;9(1):1561. Epub 2019 Feb 7.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Japan.

We investigated changes in retinal vascular area and the foveal avascular zone (FAZ) after intravitreal aflibercept in diabetic macular edema (DME) and the association of these changes with visual outcomes. The retinal vascular area in the superficial capillary plexus (SCP) and the deep capillary plexus (DCP) and the FAZ area were measured using optical coherence tomography angiography (OCTA) in 23 eyes of 23 patients with DME, before and after intravitreal aflibercept. Overall, there was no significant change in retinal vascular area or FAZ. Better BCVA after treatment was significantly associated with larger retinal vascular area in the SCP and the DCP, both at baseline (R = 0.512, P < 0.001 and R = 0.361, P = 0.002, respectively) and after intravitreal aflibercept (R = 0.717, P < 0.001 and R = 0.618, P < 0.001, respectively). MAs were observed in the DCP in 20 eyes (87%), but only detected in four eyes (17%) in the SCP before treatment. The number of eyes with MAs in the DCP significantly decreased to 13 (57%) after treatment (P = 0.049). The persistence of DME was associated with persistent MAs (P = 0.019) and less visual gain (P = 0.031) following treatment. Thus, preserving retinal perfusion and the resolution of MAs are associated with better vision and resolution of the DME after intravitreal aflibercept.
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http://dx.doi.org/10.1038/s41598-018-38248-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367399PMC
February 2019

Effect of intravitreal injection of aflibercept or ranibizumab on chorioretinal atrophy in myopic choroidal neovascularization.

Graefes Arch Clin Exp Ophthalmol 2019 Apr 14;257(4):749-757. Epub 2019 Jan 14.

Department of Ophthalmology, Osaka University Medical School, Osaka, Japan.

Purpose: To compare chorioretinal atrophy (CRA) progression in myopic choroidal neovascularization (mCNV) between intravitreal injections of ranibizumab (IVR) and aflibercept (IVA) in the eyes with mCNV.

Methods: Thirty eyes (28 patients) with treatment-naïve mCNV were included in this study. IVR or IVA was administered for up to 1 year. The best-corrected visual acuity (BCVA) was measured, and fundus photographs and fundus autofluorescence were obtained before and 1, 3, 6, and 12 months after the initial treatment. The clinical characteristics including the macular choroidal thickness in various areas and CRA progression were compared between the drugs. The clinical characteristics and macular choroidal thicknesses were compared between eyes with and without CRA progression.

Results: The BCVA improved significantly (p < 0.05 for all comparisons) from 0.44 to 0.26, 0.19, 0.20, and 0.17 after 1, 3, 6, and 12 months, respectively. CRA progressed in 12 (40%) eyes over 1 year. The CRA progression did not differ significantly between aflibercept and ranibizumab. The foveal choroid was significantly (p = 0.0043) thinner in aflibercept-treated eyes compared with ranibizumab-treated eyes at 1 year. Subfoveal CNV tended to cause CRA progression more frequently at 1 year, although this did not reach significance.

Conclusions: IVA to treat mCNV caused more severe thinning of the foveal choroid than ranibizumab; however, no significant difference was seen in CRA progression between the drugs and the choroidal thickness should not be associated with CRA progression. The CNV location may predict CRA progression after anti-vascular endothelial growth factor therapy for mCNV.
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http://dx.doi.org/10.1007/s00417-018-04214-wDOI Listing
April 2019

The impact of spot size, spacing, pattern, duration and intensity of burns on the photocoagulation index in a geometric simulation of pan-retinal laser photocoagulation.

Acta Ophthalmol 2019 Jun 3;97(4):e551-e558. Epub 2018 Dec 3.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Japan.

Purpose: To evaluate the impact of spot size, spacing, pattern, duration and intensity of burns on the photocoagulation index, using a geometric simulation of pan-retinal laser photocoagulation.

Methods: Simulations of full-scattered pan-retinal laser photocoagulation were performed on a retinal map, using a geometry-based method. Simulations consisted of 300-, 400- or 500-μm diameter equidistant spots on the retina with 1.0-spot width spacing, as well as 400-μm diameter spots on the retina in an equidistant pattern or grid pattern, with 1.0-, 0.75-, 0.50-, 0.25- or 0-spot width spacing. For each simulation, we calculated the ratio of the total photocoagulated retinal area to the whole retina, termed the photocoagulation index. We recalculated the photocoagulation indexes using the expansion ratios of photocoagulated lesions by different duration and intensity of burns from a previous study.

Results: The photocoagulation indexes of the simulated pan-retinal laser photocoagulation with 300-, 400- and 500-μm diameter spots were 20.8%, 20.6% and 21.0%, respectively. The photocoagulation indexes of the 1.0-, 0.75-, 0.50-, 0.25- and 0-spot width spacing configurations of pan-retinal laser photocoagulation burns for the equidistant pattern were 20.6%, 27.1%, 36.7%, 53.2% and 83.1%, respectively, and those for the grid pattern were 17.9%, 23.5%, 31.8%, 46.1% and 72.0%, respectively. The photocoagulation indexes obtained with the equidistant and grid patterns changed (range, 1.7-84.7% and 1.5-73.4%, respectively) when the duration or burn intensity of the pan-retinal photocoagulation was changed.

Conclusion: This geometric simulation method could evaluate the impact of a range of conditions on the photocoagulation index.
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http://dx.doi.org/10.1111/aos.13939DOI Listing
June 2019

Characteristics of patients with neovascular age-related macular degeneration who are non-responders to intravitreal aflibercept.

Br J Ophthalmol 2018 Jun 15. Epub 2018 Jun 15.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Japan.

Purpose: To investigate the frequency and patient characteristics that influence anatomic response of intravitreal aflibercept in treatment-naïve neovascular age-related macular degeneration (AMD).

Design: Retrospective, interventional, consecutive case series.

Methods: Three hundred and sixty-five eyes of 365 patients with AMD who underwent 3 monthly intravitreal aflibercept treatments with follow-up for at least 12 months were investigated. Treatment response was evaluated as follows. Responders were defined as those with complete resolution of exudation, including intraretinal oedema, subretinal fluid and pigment epithelial detachment, or more than a 100 µm decrease of central retinal thickness at 3 months compared with baseline. Non-responders were defined as patients exhibiting an increase in exudation or a decreased central retinal thickness of less than 100 µm.

Results: Nineteen (5.2%) of 365 eyes were identified as non-responders. The remaining were responders to intravitreal aflibercept. The non-responders group was significantly associated with choroidal vascular hyperpermeability on indocyanine green angiography and lower frequency of subretinal hyper-reflective materials on optical coherence tomography. The central choroidal thickness at baseline and after 3 monthly injections tended to be thicker in the non-responder group than the responder group, although the differences did not meet statistical significance (p=0.066 and p=0.051, respectively). Additional treatments with either intravitreal ranibizumab or PDT in combination with aflibercept were effective in 15 (79%) of 19 non-responders.

Conclusion: Intravitreal aflibercept is effective for treating eye pathology in most naïve AMD cases. However, non-responsiveness may occur in small subgroup of patients with choroidal vascular hyperpermeability.
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http://dx.doi.org/10.1136/bjophthalmol-2018-312275DOI Listing
June 2018

Modification of Dentofacial Growth Associated with Goldenhar Syndrome.

Acta Med Okayama 2017 Oct;71(5):437-443

Department of Orthodontics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.

The rare developmental defect, Goldenhar syndrome is characterized by complex craniofacial and dentofacial anomalies. Here we describe the successful orthodontic treatment of a 5-year-old Japanese Goldenhar syndrome patient with mild facial asymmetry, right microtia, right-side hearing loss, and tongue-thrusting by a modification of dentofacial growth using a non-surgical orthopedic treatment approach. Improvement of the vertical discrepancies on the affected side and canted occlusal plane as well as mandibular deviation were achieved with a functional orthopaedic approach. Stable and acceptable occlusion were obtained over the 32-month post-retention period. A non-surgical orthodontic treatment approach offers satisfactory facial aesthetic outcomes in Goldenhar syndrome.
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http://dx.doi.org/10.18926/AMO/55443DOI Listing
October 2017

A prospective multicenter study on genome wide associations to ranibizumab treatment outcome for age-related macular degeneration.

Sci Rep 2017 08 23;7(1):9196. Epub 2017 Aug 23.

Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, 606-8507, Japan.

We conducted a genome-wide association study (GWAS) on the outcome of anti-VEGF treatment for exudative age-related macular degeneration (AMD) in a prospective cohort. Four hundred and sixty-one treatment-naïve AMD patients were recruited at 13 clinical centers and all patients were treated with 3 monthly injections of ranibizumab followed by pro re nata regimen treatment for one year. Genomic DNA was collected from all patients for a 2-stage GWAS on achieving dry macula after the initial treatment, the requirement for an additional treatment, and visual acuity changes during the 12-month observation period. In addition, we evaluated 9 single-nucleotide polymorphisms (SNPs) in 8 previously reported AMD-related genes for their associations with treatment outcome. The discovery stage with 256 patients evaluated 8,480,849 SNPs, but no SNPs showed genome-wide level significance in association with treatment outcomes. Although SNPs with P-values of <5 × 10 were evaluated in replication samples of 205 patients, no SNP was significantly associated with treatment outcomes. Among AMD-susceptibility genes, rs10490924 in ARMS2/HTRA1 was significantly associated with additional treatment requirement in the discovery stage (P = 0.0023), and pooled analysis with the replication stage further confirmed this association (P = 0.0013). ARMS2/HTRA1 polymorphism might be able to predict the frequency of injection after initial ranibizumab treatment.
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http://dx.doi.org/10.1038/s41598-017-09632-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569099PMC
August 2017

A Multicenter Randomized Controlled Study of Antioxidant Supplementation with Lutein for Chronic Central Serous Chorioretinopathy.

Ophthalmologica 2017 8;237(3):159-166. Epub 2017 Feb 8.

Division of Ophthalmology, Department of Visual Sciences, Nihon University School of Medicine, Tokyo, Japan.

Purpose: To investigate functional and morphological changes in patients with chronic central serous chorioretinopathy after supplementation with antioxidants containing lutein or a placebo.

Procedures: One hundred eyes of 100 patients were randomly divided into 2 groups, one taking tablets with lutein plus other antioxidants and the other taking a placebo for 6 months. Best-corrected visual acuity (BCVA) and the subfoveal fluid height on optical coherence tomography were measured.

Results: Seventy-nine patients (37 in the supplementation and 42 in the placebo group) completed the 6-month follow-up. In the supplementation group, mean BCVA showed significant improvement (p = 0.003), while there was no significant change in the placebo group (p = 0.589). The mean subfoveal fluid height was significantly reduced, by 28.6%, in the supplementation group (p = 0.028), in contrast to 3.3% in the placebo group (p = 0.898).

Conclusions: Antioxidant supplementation significantly reduced subfoveal fluid height. The impacts of antioxidant supplementation on BCVA remain to be elucidated in future studies.
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http://dx.doi.org/10.1159/000455807DOI Listing
September 2017

Factors Associated With Corneal Deformation Responses Measured With a Dynamic Scheimpflug Analyzer.

Invest Ophthalmol Vis Sci 2017 01;58(1):538-544

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

Purpose: The purpose of this study was to clarify correlations between corneal deformation parameters measured with a dynamic Scheimpflug analyzer and baseline factors such as axial length, intraocular pressure (IOP), age, central corneal thickness (CCT), and corneal curvature.

Methods: Ninety-six eyes of 96 healthy subjects (mean 55.2 ± 16.1 years of age) were examined using a dynamic Scheimpflug analyzer. Eighteen of 35 deformation parameters were selected for analyses based on measurement reliability and clinical relevance. The associations between corneal deformation parameters and axial length, IOP, age, CCT, and average corneal power were evaluated using multivariate regression analyses.

Results: Deformation parameters were correlated significantly with axial length (n = 13), IOP (n = 13), age (n = 8), and CCT (n = 6) in the multivariate models. Longer axial length corresponded with greater corneal deformability, less viscous damping, and less movement of the entire eye. Higher IOP was associated with greater corneal resistance and less movement of the entire eye. Older age was associated with less corneal deformability and greater movement of the entire eye. Corneal curvature was correlated significantly with only three deformation parameters.

Conclusions: This study clarified the substantial impact of axial length, age, and IOP on the biomechanical responses of the cornea and the entire eye. In contrast, corneal curvature did not affect most of the deformation parameters. The current results confirmed the importance of corneal biomechanics, especially in eyes with longer axial length and in older subjects.
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http://dx.doi.org/10.1167/iovs.16-21045DOI Listing
January 2017

Simulation of panretinal laser photocoagulation using geometric methods for calculating the photocoagulation index.

Eur J Ophthalmol 2017 Mar 13;27(2):205-209. Epub 2016 Sep 13.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita - Japan.

Purpose: To establish geometrically based methods for simulating panretinal laser photocoagulation (PRP) for the photocoagulation index.

Methods: A formula for calculating the curved surface area of a spherical dome was used for the simulation. If the radius of the dome is c and the height of the dome is h, then the curved surface area (S) of the dome is S = π (c2 + h2). We calculated the area of the whole retina using this formula and the anatomical dimensions of the standard eyeball. To simulate PRP with a 400-μm spot on the retina with 1-spot spacing, we drew 400-μm-diameter circles, separated by 400 μm, on a retinal map. We calculated the ratio of the total retinal photocoagulated area to the whole retina, termed the photocoagulation index, in order to investigate the impact of the extent of the photocoagulated area and the pulse duration on PRP.

Results: The whole retinal area was 1,092 mm2. The numbers of spots in the scattered and full-scattered PRP were 1,222 and 1,814, respectively. The photocoagulation index was 14.1% and 20.9% for scattered and full-scattered PRP, respectively. These values changed to 14.3% (5.6%) and 21.3% (8.3%), respectively, for PRP with a 100-ms pulse or a 20-ms pulse.

Conclusions: This method will be useful for investigating the impact of various PRP parameters (duration, spacing, intensity of burns, extent of photocoagulated area, etc.) on the photocoagulation index.
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http://dx.doi.org/10.5301/ejo.5000865DOI Listing
March 2017

Involvement of multiple CCN family members in platelets that support regeneration of joint tissues.

Mod Rheumatol 2016 Nov 21;26(6):940-949. Epub 2016 Apr 21.

a Department of Biochemistry and Molecular Dentistry , and.

Objectives: Platelet-rich plasma (PRP) has been widely used to enhance the regeneration of damaged joint tissues, such as osteoarthritic and rheumatoid arthritic cartilage. The aim of this study is to clarify the involvement of all of the CCN family proteins that are crucially associated with joint tissue regeneration.

Methods: Cyr61-CTGF-NOV (CCN) family proteins in human platelets and megakaryocytic cells were comprehensively analyzed by Western blotting analysis. Production of CCN family proteins in megakaryocytes in vivo was confirmed by immunofluorescence analysis of mouse bone marrow cells. Effects of CCN family proteins found in platelets on chondrocytes were evaluated by using human chondrocytic HCS-2/8 cells.

Results: Inclusion of CCN2, a mesenchymal tissue regenerator, was confirmed. Of note, CCN3, which counteracts CCN2, was newly found to be encapsulated in platelets. Interestingly, these two family members were not detectable in megakaryocytic cells, but their external origins were suggested. Furthermore, we found for the first time CCN5 and CCN1 that inhibits ADAMTS4 in both platelets and megakaryocytes. Finally, application of a CCN family cocktail mimicking platelets onto HCS-2/8 cells enhanced their chondrocytic phenotype.

Conclusions: Multiple inclusion of CCN1, 2 and 3 in platelets was clarified, which supports the harmonized regenerative potential of PRP in joint therapeutics.
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http://dx.doi.org/10.3109/14397595.2016.1155255DOI Listing
November 2016

ONE-YEAR RESULTS OF INTRAVITREAL AFLIBERCEPT FOR POLYPOIDAL CHOROIDAL VASCULOPATHY.

Retina 2016 Jan;36(1):37-45

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

Purpose: To evaluate the 1-year results of intravitreal aflibercept injections for polypoidal choroidal vasculopathy based on indocyanine green angiography findings.

Methods: Twenty-nine eyes with treatment-naive polypoidal choroidal vasculopathy treated with intravitreal aflibercept injections and followed longer than 1 year were retrospectively reviewed. The best-corrected visual acuity, optical coherence tomography findings, and polypoidal lesions in indocyanine green angiography were evaluated.

Results: The mean number of injections through 1 year was 3.9 ± 1.9 (range: 1-8). Fourteen eyes (48%) were received no additional injections because of no recurrence of exudative change after the first loading dose. The mean best-corrected visual acuity levels at 6 months and 1 year significantly improved, and the mean central retinal thickness significantly decreased at all observation points from the baseline. At 3 months, the polypoidal lesions completely resolved in 19 (66%) eyes. At 1 year, the complete resolution of polypoidal lesions was seen in 4 of 10 eyes with persistent polypoidal lesions at 3 months. However, polypoidal lesions recurred at 1 year in 5 of 19 eyes (26%) with complete resolution of polypoidal lesions at 3 months.

Conclusion: Aflibercept is effective for the eyes with treatment-naive polypoidal choroidal vasculopathy to achieve the resolution of polypoidal lesions. The authors need to carefully observe the eyes after confirming complete resolution of polypoidal lesion because of recurrent polyps seen in one-quarter of the study eyes.
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http://dx.doi.org/10.1097/IAE.0000000000000767DOI Listing
January 2016

En-face high-penetration optical coherence tomography imaging in polypoidal choroidal vasculopathy.

Br J Ophthalmol 2015 Jan 8;99(1):29-35. Epub 2014 Aug 8.

Department of Ophthalmology, Osaka University Medical School Room E7, Suita, Osaka, Japan.

Aim: To observe the choroidal microstructure in polypoidal choroidal vasculopathy (PCV) using high-penetration optical coherence tomography (HP-OCT) with a long-wavelength light source that visualises tissue beneath the retinal pigment epithelium (RPE) and deep choroid, and to compare the findings with those of indocyanine green angiography (ICGA).

Methods: In this retrospective, non-invasive, observational case series, 19 eyes (18 patients) with PCV were observed using HP-OCT (swept source, 100 000 A-scans/s, 1060 nm wavelength) and ICGA. The HP-OCT scan protocol was a 3×3-mm or 6×6-mm square containing 256×256 or 512×128 A-scans. The choroidal thickness (CT) was measured using HP-OCT.

Results: ICGA showed 43 polypoidal lesions in 14 eyes and a vascular network in 17 eyes. HP-OCT showed 41 of the 43 polypoidal lesions visualised by ICGA as RPE rings with inner reflectivity and 15 eyes with a vascular network. Six eyes with RPE rings with inner reflectivity on HP-OCT were not visualised on ICGA images. The choroidal vascular network was dilated in 14 (33%) of 43 polypoidal lesions and 22 (47%) of 47 polypoidal lesions on ICGA and HP-OCT images, respectively. The mean CT at the fovea was 250 μm. The CT at the dilated choroidal vessels beneath the polypoidal lesions was significantly (p = 0.0095) thicker than that of the undilated choroidal vessels beneath the polypoidal lesions.

Conclusions: HP-OCT can visualise choroidal vascular abnormalities in eyes with PCV and should be useful for understanding the pathogenesis of these abnormalities.
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http://dx.doi.org/10.1136/bjophthalmol-2013-304658DOI Listing
January 2015

Effects of a lutein supplement on the plasma lutein concentration and macular pigment in patients with central serous chorioretinopathy.

Invest Ophthalmol Vis Sci 2014 Jul 29;55(8):5238-44. Epub 2014 Jul 29.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

Purpose: To investigate the effects of lutein supplementation on plasma lutein concentrations and the macular pigment optical density (MPOD) in central serous chorioretinopathy (CSC).

Methods: In this double-masked placebo-controlled study, 20 patients received lutein 20 mg/d and 19 received placebo. The plasma lutein concentration and MPOD using autofluorescence spectrometry (density unit, DU) were measured at baseline and 1 and 4 months.

Results: The mean plasma lutein concentrations and MPOD values in the lutein and control groups, respectively, were 91.5 and 78.2 ng/mL and 0.444 and 0.437 DU at baseline; 204.9 and 79.3 ng/mL and 0.460 and 0.442 DU at 1 month; and 228.0 and 78.4 ng/mL and 0.441 and 0.421 DU at 4 months. The plasma concentration in the lutein group was significantly higher than in controls at 1 and 4 months (P < 0.0001 for both comparisons); however, the MPOD values did not differ significantly between groups at 1 (P = 0.479) or 4 months (P = 0.883). In patients with a plasma lutein concentration below the mean level in 20 age-matched healthy subjects (mean 105.3 ng/mL; n = 13 in lutein group, n = 15 in control group), the control MPOD values significantly (P = 0.0430) decreased at 4 months (mean baseline, 0.437 DU; 4 months, 0.404 DU). The MPOD in the lutein group remained at the baseline level (mean baseline, 0.426 DU; 4 months, 0.438 DU) (P = 0.6542).

Conclusions: The MPOD did not increase in patients with CSC with short-term lutein supplementation; however, among patients with low plasma lutein, supplemental lutein prevented a decline in MPOD that was observed in control subjects (www.umin.ac.jp/ctr number, UMIN000005849).
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http://dx.doi.org/10.1167/iovs.14-14470DOI Listing
July 2014

Characteristics of central serous chorioretinopathy complicated by focal choroidal excavation.

Retina 2014 Jun;34(6):1216-22

*Department of Ophthalmology, Osaka University Medical School, Osaka, Japan; and †Department of Ophthalmology, Sumitomo Hospital, Osaka, Japan.

Purpose: To investigate the characteristics of central serous chorioretinopathy complicated by focal choroidal excavation (FCE) using fundus angiography and optical coherence tomography (OCT).

Methods: A retrospective single-institution study. We reviewed the charts of 7 eyes of 7 patients (5 men, 2 women; mean age, 56.9 ± 9.8 years) with central serous chorioretinopathy complicated by FCE using fundus angiography and OCT.

Results: In six of the seven eyes, the points of leakage were at the edge of FCE on OCT. All FCE lesions were hypofluorescent from early to late phase on indocyanine green angiography. All eyes had late-phase hyperfluorescence on indocyanine green angiography secondary to choroidal vascular hyperpermeability around the FCE lesion. Five fellow eyes also had choroidal vascular hyperpermeability. The mean subfoveal choroidal thicknesses by swept source high-penetration OCT were 377 μm and 333 μm in the fellow eyes, a difference that did not reach significance (P = 0.21).

Conclusion: Fundus angiography and OCT showed that choroidal circulatory disruption and atrophic retinal pigment epithelium at the FCE lesion might be related to central serous chorioretinopathy complicated by FCE.
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http://dx.doi.org/10.1097/IAE.0000000000000045DOI Listing
June 2014

Laser-induced choroidal neovascularization in mice attenuated by deficiency in the apelin-APJ system.

Invest Ophthalmol Vis Sci 2013 Jun 21;54(6):4321-9. Epub 2013 Jun 21.

Department of Ophthalmology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

Purpose: To investigate the role of the apelin-APJ system in the development of choroidal neovascularization (CNV).

Methods: Experimental CNV was induced by laser photocoagulation in wild-type (WT), apelin-deficient (apelin-KO), and apelin receptor (APJ)-deficient (APJ-KO) mice. The gene expression levels of angiogenic or inflammatory factors were determined by quantitative real-time reverse transcription-polymerase chain reaction. APJ expression in CNV lesions was examined by immunohistochemistry. The sizes of the CNV lesions in the three mouse models were measured and compared histologically using isolectin B4 staining. Macrophage recruitment was measured by flow cytometric analysis. Proliferation of endothelial cells was determined using the alamar Blue assay.

Results: Laser photocoagulation significantly increased expression of apelin and APJ in the retina-retinal pigment epithelium (RPE) complex. APJ immunoreactive cells were found in the CNV lesions and colocalized with platelet endothelial cell adhesion molecule-1, an endothelial cell marker. The sizes of the CNV lesions in apelin-KO or APJ-KO mice decreased significantly compared with those in the WT mice. Macrophages in the RPE complex of the apelin-KO mice, in which gene expression of the inflammatory factors was almost equal to that in WT mice, were recruited as a result of laser photocoagulation to the same degree as in WT mice. In addition, apelin small and interfering RNA (siRNA) suppressed proliferation of endothelial cells independently of vascular endothelial growth factor (VEGF) receptor 2 signaling, while VEGF increased expression of apelin and APJ in human umbilical vein endothelial cells.

Conclusions: The results suggested that the apelin-APJ system contributes to CNV development partially independent of the VEGF pathway.
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http://dx.doi.org/10.1167/iovs.13-11611DOI Listing
June 2013

Regulation of CCN1 via the 3'-untranslated region.

J Cell Commun Signal 2013 Aug 16;7(3):207-17. Epub 2013 May 16.

Department of Biochemistry and Molecular Dentistry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan.

The 3'-untranslated region (UTR) is known to be a critical regulator of post-transcriptional events that determine the gene expression at the RNA level. The gene CCN1 is one of the classical members of the matricellular CCN family and is involved in a number of biological processes during mammalian development. In the present study, the 600-bp 3'-UTR of CCN1 was functionally characterized. Reporter gene analysis revealed that the entire 3'-UTR profoundly repressed gene expression in cis in different types of the cells, to which both the proximal and distal-halves of the 3'-UTR segments contributed almost equally. Deletion analysis of the 3'-UTR indicated a distinct functional element in the proximal half, whereas a putative target for microRNA-181s was predicted in silico in the distal half. Of note, the repressive RNA element in the proximal half was shown to be capable of forming a stable secondary structure. However, unexpectedly, a reporter construct with a tandem repeat of the predicted miR-181 targets failed to respond to miR-181a. In addition, the other major structured element predicted in the distal half was similarly characterized. To our surprise, the second element rather enhanced the reporter gene expression in cis. These results indicate the involvement of multiple regulatory elements in the CCN1 3'-UTR and suggest the complexity of the miRNA action as well as the 3'-UTR-mediated gene regulation.
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http://dx.doi.org/10.1007/s12079-013-0202-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709046PMC
August 2013

Significance of remyelination by neural stem/progenitor cells transplanted into the injured spinal cord.

Stem Cells 2011 Dec;29(12):1983-94

Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan.

Previous reports of functional recovery from spinal cord injury (SCI) in rodents and monkeys after the delayed transplantation of neural stem/progenitor cells (NS/PCs) have raised hopes that stem cell therapy could be used to treat SCI in humans. More research is needed, however, to understand the mechanism of functional recovery. Oligodendrocytes derived from grafted NS/PCs remyelinate spared axons in the injured spinal cord. Here, we studied the extent of this remyelination's contribution to functional recovery following contusive SCI in mice. To isolate the effect of remyelination from other possible regenerative benefits of the grafted cells, NS/PCs obtained from myelin-deficient shiverer mutant mice (shi-NS/PCs) were used in this work alongside wild-type NS/PCs (wt-NS/PCs). shi-NS/PCs behaved like wt-NS/PCs in vitro and in vivo, with the exception of their myelinating potential. shi-NS/PC-derived oligodendrocytes did not express myelin basic protein in vitro and formed much thinner myelin sheaths in vivo compared with wt-NS/PC-derived oligodendrocytes. The transplantation of shi-NS/PCs promoted some locomotor and electrophysiological functional recovery but significantly less than that afforded by wt-NS/PCs. These findings establish the biological importance of remyelination by graft-derived cells for functional recovery after the transplantation of NS/PCs into the injured spinal cord.
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http://dx.doi.org/10.1002/stem.767DOI Listing
December 2011