Publications by authors named "Norihiro Nagai"

83 Publications

Taurine rescues mitochondria-related metabolic impairments in the patient-derived induced pluripotent stem cells and epithelial-mesenchymal transition in the retinal pigment epithelium.

Redox Biol 2021 May 28;41:101921. Epub 2021 Feb 28.

Laboratory of Retinal Cell Biology, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan; Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan; Department of Ophthalmology, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan; St. Luke's International University, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan. Electronic address:

Mitochondria participate in various metabolic pathways, and their dysregulation results in multiple disorders, including aging-related diseases. However, the metabolic changes and mechanisms of mitochondrial disorders are not fully understood. Here, we found that induced pluripotent stem cells (iPSCs) from a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) showed attenuated proliferation and survival when glycolysis was inhibited. These deficits were rescued by taurine administration. Metabolomic analyses showed that the ratio of the reduced (GSH) to oxidized glutathione (GSSG) was decreased; whereas the levels of cysteine, a substrate of GSH, and oxidative stress markers were upregulated in MELAS iPSCs. Taurine normalized these changes, suggesting that MELAS iPSCs were affected by the oxidative stress and taurine reduced its influence. We also analyzed the retinal pigment epithelium (RPE) differentiated from MELAS iPSCs by using a three-dimensional culture system and found that it showed epithelial mesenchymal transition (EMT), which was suppressed by taurine. Therefore, mitochondrial dysfunction caused metabolic changes, accumulation of oxidative stress that depleted GSH, and EMT in the RPE that could be involved in retinal pathogenesis. Because all these phenomena were sensitive to taurine treatment, we conclude that administration of taurine may be a potential new therapeutic approach for mitochondria-related retinal diseases.
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http://dx.doi.org/10.1016/j.redox.2021.101921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944050PMC
May 2021

Renin-angiotensin system impairs macrophage lipid metabolism to promote age-related macular degeneration in mouse models.

Commun Biol 2020 Dec 9;3(1):767. Epub 2020 Dec 9.

Laboratory of Retinal Cell Biology, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan.

Metabolic syndrome, a condition involving obesity and hypertension, increases the risk of aging-associated diseases such as age-related macular degeneration (AMD). Here, we demonstrated that high-fat diet (HFD)-fed mice accumulated oxidized low-density lipoprotein (ox-LDL) in macrophages through the renin-angiotensin system (RAS). The ox-LDL-loaded macrophages were responsible for visual impairment in HFD mice along with a disorder of the retinal pigment epithelium (RPE), which is required for photoreceptor outer segment renewal. RAS repressed ELAVL1, which reduced PPARγ, impeding ABCA1 induction to levels that are sufficient to excrete overloaded cholesterol within the macrophages. The ox-LDL-loaded macrophages expressed inflammatory cytokines and attacked the RPE. An antihypertensive drug, angiotensin II type 1 receptor (AT1R) blocker, resolved the decompensation of lipid metabolism in the macrophages and reversed the RPE condition and visual function in HFD mice. AT1R signaling could be a future therapeutic target for macrophage-associated aging diseases, such as AMD.
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http://dx.doi.org/10.1038/s42003-020-01483-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725839PMC
December 2020

Association between axial length and choroidal thickness in early age-related macular degeneration.

PLoS One 2020 9;15(10):e0240357. Epub 2020 Oct 9.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

The clinical course of age-related macular degeneration (AMD) is related to choroidal conditions, and can be determined by the evaluation of the central choroidal thickness (CCT). The aim of this study was to determine the association between the axial length (AL) and choroidal thickness in AMD by measuring these parameters in patients with and without AMD. Seventy eyes of 70 patients (34 men and 36 women; age, 64-88 years; mean age, 77.0 ± 6.5 years) who underwent cataract surgery from February 2015 to March 2020 at the Department of Ophthalmology, Keio University School of Medicine were retrospectively analyzed. The AMD group (29 patients, 29 eyes) included eyes with early AMD, whereas the control group (41 patients, 41 eyes) included those without ocular diseases other than cataract. Optical coherence tomography images were used to measure the CCT and the choroidal vessel diameter (CVD). The IOL Master was used to measure the AL. The results revealed that mean CCT was greater in the AMD group (238.3 ± 108.3 μm) compared with the age-matched control group (187.2 ± 66.8 μm) (p = 0.03). The CCT was negatively correlated with AL in the overall sample (r = -0.42, p = 0.001), the AMD group (r = -0.42, p = 0.02), and the control group (r = -0.42, p = 0.006). Note that all eyes with CCT > 350 μm were included in the AMD group. CCT and CVD were positively correlated in the overall sample (r = 0.76, p < 0.001) as well as in the individual groups (AMD: r = 0.82, p < 0.001; control: r = 0.76, p = 0.004). Given that CCT is an important parameter for predicting the prognosis of subfoveal diseases, routine evaluation of AL may be valuable for a better understanding of the pathogenesis of AMD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240357PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546466PMC
December 2020

Risk of newly developing visual field defect and neurodegeneration after pars plana vitrectomy for idiopathic epiretinal membrane.

Br J Ophthalmol 2020 Oct 5. Epub 2020 Oct 5.

Department of Ophthalmology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan

Background/aims: Pars plana vitrectomy (PPV) is widely performed in patients with idiopathic epiretinal membrane (iERM) to improve vision. Postoperative visual field defects (VFDs) have been previously reported. However, whether they occur when using the most recent PPV system, and the frequency of VFDs as measured by standard automated perimetry, remain poorly documented and were examined in this study.

Methods: Data of 30 eyes (30 patients; mean age, 66.1 years; 15 men) who underwent PPV for iERM during February 2016-June 2019 and had preoperative and postoperative visual field measurements using standard automated perimetry (Humphrey visual field analyser 30-2 program) were retrospectively analysed. Eyes with diseases other than iERM, including moderate-to-severe cataract or preoperative VFDs were excluded.

Results: VFD, defined by the Anderson and Patella's criteria, was found in 73.3% of the eyes 1 month after PPV. After age adjustment, internal limiting membrane (ILM) peeling was identified as a risk factor for postoperative VFD (p=0.035; 95% CI 1.173 to 92.8). Postoperative VFD was frequently observed nasally (86.4%, p=0.002), and on optical coherence tomography measurements, ganglion cell layer (GCL) thinning was found temporal to the fovea (p=0.008). Thinning of the superior and inferior retinal nerve fibre layers and of the GCL temporal to the fovea were significant in eyes after ILM peeling (all p<0.05).

Conclusion: ILM peeling may cause inner retinal degeneration and lead to the development of VFDs after PPV, which should be further examined.
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http://dx.doi.org/10.1136/bjophthalmol-2020-317478DOI Listing
October 2020

Hyperreflective Material in Optical Coherence Tomography Images of Eyes with Myopic Choroidal Neovascularization May Affect the Visual Outcome.

J Clin Med 2020 Jul 27;9(8). Epub 2020 Jul 27.

Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

The visual outcome of myopic choroidal neovascularization (CNV) after anti-vascular endothelial growth factor (anti-VEGF) therapy varies among individuals. We retrospectively analyzed the data of 24 eyes (24 patients) with treatment-naïve myopic CNV who underwent anti-VEGF monotherapy following a pro-re-nata regimen at the Division of Medical Retina Clinic, Department of Ophthalmology, Keio University Hospital between May 2014 and December 2017. The mean age was 70.6 ± 2.1 years, and 16 (66.7%) patients were female. Overall, the mean best-corrected visual acuity (BCVA) improved ( = 0.034), and the mean height of the hyperreflective material (HRM), involving the CNV lesion recorded by optical coherence tomography, decreased ( < 0.01) 12 months after the initial treatment. Fifteen eyes (62.5%) achieved a BCVA of better than 0.10 in LogMAR at 12 months; they had a better BCVA ( = 0.015) and lower HRM intensity ( = 0.033) at baseline than the others. Remarkably, the BCVA improved ( < 0.05) and the HRM height ( < 0.01) decreased only in eyes with a final BCVA better than 0.10 as early as 1 month after the initial treatment, which was still present at 12 months. The HRM height and intensity, not only the BCVA, would be valuable in evaluating the prognosis of myopic CNV after anti-VEGF therapy, although further study is required.
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http://dx.doi.org/10.3390/jcm9082394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466026PMC
July 2020

Progress of macular atrophy during 30 months' follow-up in a patient with spinocerebellar ataxia type1 (SCA1).

Doc Ophthalmol 2021 Feb 9;142(1):87-98. Epub 2020 Jul 9.

Department of Ophthalmology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

Purpose: To report the 30-months' course of macular dystrophy in a patient with genetically confirmed spinocerebellar ataxia type1 (SCA1).

Methods: Detailed ophthalmological examinations including best-corrected visual acuity (BCVA), perimetry, multimodal fundus imaging, and electrophysiological recordings were performed on a 52-year-old woman with SCA1. The number of CAG sequence repeats of the candidate gene was verified.

Results: The baseline decimal BCVA was 0.2 OD and 0.3 OS. Goldman perimetry showed relative central scotomas and slight enlargements of Mariotte blind spot bilaterally. Ophthalmoscopy revealed no abnormalities in the macula and optic disk. Fundus autofluorescence (FAF) showed a circular hyperautofluorescence and round-shaped hypoautofluorescence in the macula. Optical coherence tomography (OCT) showed a loss of the interdigitation zone and ellipsoid zone (EZ) in the macula. Full-field scotopic and photopic Full-field electroretinograms (ERGs) were normal, and multifocal ERGs were decreased in the central area. After 30 months, the BCVA had not changed, but the FAF showed a spark-like hypoautofluorescence in the macula. The abnormal area of the EZ had expanded toward the periphery, and the rate of EZ loss was 199.7%/year OD and 206.8%/year OS. Genetic examinations revealed an increase in the number of heterozygous CAG repeats in the ATXN1 gene, and the CAG repeat number of the mutant allele ranged from 43 to 48.

Conclusions: The full-field scotopic and photopic ERGs were normal. The mfERGs were significantly smaller in the central region. OCT demonstrated bilateral photoreceptor atrophy in the macula, and the rate of EZ loss was more rapid than in other macular dystrophies. Spark-like hypoautofluorescence appeared during the course of the disease process which might be a specific feature of SCA1-related retinopathy.
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http://dx.doi.org/10.1007/s10633-020-09782-zDOI Listing
February 2021

Ocular and Systemic Effects of Antioxidative Supplement Use in Young and Healthy Adults: Real-World Cross-Sectional Data.

Antioxidants (Basel) 2020 Jun 3;9(6). Epub 2020 Jun 3.

Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

Randomized controlled studies have shown that antioxidative supplements are effective in suppressing the progression of age-related macular degeneration and visual display terminal syndrome. However, effects of their general use in the real-world and by young and healthy individuals have not been well documented. We analyzed 27 participants who were under 35 years of age and had no diagnosed diseases. Mean functional visual acuity (FVA) score and visual maintenance ratio, which represent quick recognition of a target, both measured using FVA system, were better (both < 0.01) in subjects who had had regular antioxidative supplement intake for more than 2 months (11 participants) compared with those who had not. Systemic data, i.e., total cholesterol, hemoglobin A1c (HbA1c), and high-sensitivity C-reactive protein (hs-CRP) levels, which correspond to chronic low-grade inflammation, were lower (all < 0.05) in the former. Overall, hs-CRP levels had a correlation with total cholesterol ( < 0.05) and a trend of correlation with HbA1c ( = 0.054) levels. Thus, current real-world data showed that young, healthy participants who had a regular intake of antioxidative supplements had better visual acuity and systemic levels of metabolic and low-grade inflammation markers. This study will help promote future research into the effects of general antioxidative supplement use.
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http://dx.doi.org/10.3390/antiox9060487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346213PMC
June 2020

The Area and Number of Intraretinal Cystoid Spaces Predict the Visual Outcome after Ranibizumab Monotherapy in Diabetic Macular Edema.

J Clin Med 2020 May 8;9(5). Epub 2020 May 8.

Laboratory of Retinal Cell Biology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

Visual outcomes in diabetic macular edema (DME) after anti-vascular endothelial growth factor therapy vary across individuals. We retrospectively reviewed the clinical records for 46 treatment-naive eyes of 46 patients with DME who underwent intravitreal ranibizumab (IVR) monotherapy with a pro re nata regimen for 12 months. Overall, mean best-corrected visual acuity (BCVA) improved. Multivariate analyses adjusted for age and baseline BCVA showed that the area ratio, compared with the retinal area, and the number of intraretinal cystoid spaces evaluated on OCT (optical coherence tomography) images at baseline positively correlated with LogMAR BCVA and the extents of ellipsoid zone and external limiting membrane disruption at 12 months, and negatively correlated with central retinal thickness at the time of edema resolution. Therefore, a high area ratio and large number of intraretinal cystoid spaces resulted in a disorganized outer retinal structure at 12 months, a thin and atrophic retina after edema resolution, and a worse visual outcome. The area ratio and number of intraretinal cystoid spaces on initial OCT images were predictors of the visual outcome after IVR therapy in DME irrespective of baseline age and BCVA. The factors were related to retinal neurodegenerative changes in DME and could help in obtaining proper informed consent before treatment.
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http://dx.doi.org/10.3390/jcm9051391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290842PMC
May 2020

Macular Pigment Optical Density and Photoreceptor Outer Segment Length as Predisease Biomarkers for Age-Related Macular Degeneration.

J Clin Med 2020 May 5;9(5). Epub 2020 May 5.

Laboratory of Retinal Cell Biology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

To explore predisease biomarkers, which may help screen for the risk of age-related macular degeneration (AMD) at very early stages, macular pigment optical density (MPOD) and photoreceptor outer segment (PROS) length were analyzed. Thirty late AMD fellow eyes, which are at high risk and represent the predisease condition of AMD, were evaluated and compared with 30 age-matched control eyes without retinal diseases; there was no early AMD involvement in the AMD fellow eyes. MPOD was measured using MPS2 (M.E. Technica Co. Ltd., Tokyo, Japan), and PROS length was measured based on optical coherence tomography images. MPOD levels and PROS length in the AMD fellow eyes were significantly lower and shorter, respectively, than in control eyes. MPOD and PROS length were positively correlated in control eyes (R = 0.386; = 0.035) but not in AMD fellow eyes. Twenty (67%) AMD fellow eyes met the criteria of MPOD < 0.65 and/or PROS length < 35 μm, while only five (17%) control eyes did. After adjusting for age and sex, AMD fellow eyes more frequently satisfied the definition ( < 0.001; 95% confidence interval, 3.50-60.4; odds ratio, 14.6). The combination of MPOD and PROS length may be a useful biomarker for screening predisease AMD patients, although further studies are required in this regard.
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http://dx.doi.org/10.3390/jcm9051347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290696PMC
May 2020

Correlation between Macular Pigment Optical Density and Neural Thickness and Volume of the Retina.

Nutrients 2020 Mar 25;12(4). Epub 2020 Mar 25.

Laboratory of Retinal Cell Biology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

Macular pigment (MP), which is composed of lutein/zeaxanthin/mezo-zeaxanthin, is concentrated in the central part of the retina, the macula. It protects the macula by absorbing short-wavelength light and suppressing oxidative stress. To evaluate whether MP levels are related to retinal neural protection and resulting health, we analyzed the association between the MP optical density (MPOD), and the macular thickness and volumes. Forty-three eyes of 43 healthy adult volunteers (21 men and 22 women; age: 22-48 (average 31.4 ± 1.1) years) were analyzed. Highly myopic eyes (<-6 diopters) were excluded. MPOD was measured using MPS2®, and the neural retinal thickness and volume were measured using optical coherence tomography. The mean MPOD was 0.589 ± 0.024, and it positively correlated with the central retinal thickness ( = 0.017, R = 0.360) and retinal volume of the fovea (1-mm diameter around the fovea; = 0.029, R = 0.332), parafovea (1-3-mm diameter; = 0.002, R = 0.458), and macula (6-mm diameter; = 0.003, R = 0.447). In the macular area (diameter: 6 mm), MPOD was correlated with the retinal neural volume of the ganglion cell layer ( = 0.037, R = 0.320), inner plexiform layer ( = 0.029, R = 0.333), and outer nuclear layer ( = 0.020, R = 0.353). Thus, MPOD may help in estimating neural health. Further studies should determine the impact of MP levels on neuroprotection.
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http://dx.doi.org/10.3390/nu12040888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230595PMC
March 2020

Neuroprotective and vision-protective effect of preserving ATP levels by AMPK activator.

FASEB J 2020 04 24;34(4):5016-5026. Epub 2020 Feb 24.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

Progression of blinding diseases, such as age-related macular degeneration, is accelerated by light exposure. However, no particular intervention is applied to the photostress. Here, we report neuroprotective effects of the adenosine monophosphate (AMP)-activated protein kinase (AMPK) activator, 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), on light-induced visual function impairment, photoreceptor disorders and death in mice. Increase in retinal ATP levels in response to photostress was transient, because oxygen consumption rate (OCR) and cytochrome c oxidase (CcO) activity were reduced under photostress. However, AICAR treatment preserved OCR, CcO activity, and high levels of retinal ATP after light exposure. AMPK knockdown in the photoreceptor-derived cell line revealed that AMPK targeted CcO activity. Further, our data indicated that photostress reduced mitochondrial respiratory function and ATP levels, while AICAR treatment promoted neuronal survival and retained visual function, stabilizing ATP levels through preserved CcO activity. The current study has provided proof of concept for providing cells with sufficient energy to promote cell survival in the presence of cellular stress. This is in contrast to the previous reports which primarily investigated therapeutic approaches to suppress stress signals. Hence, stabilization of the ATP supply may serve as a novel therapeutic approach to support tissue survival under stress and prevent neurodegeneration.
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http://dx.doi.org/10.1096/fj.201902387RRDOI Listing
April 2020

Effect of axial length and age on the visual outcome of patients with idiopathic epiretinal membrane after pars plana vitrectomy.

Sci Rep 2019 12 13;9(1):19056. Epub 2019 Dec 13.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

We evaluated predictive factors for visual outcomes in patients with idiopathic epiretinal membrane (iERM) after pars plana vitrectomy (PPV). Clinical records for 114 eyes (114 patients, mean age: 70.6 years) with iERM treated by PPV between March 2012 and March 2018 were retrospectively reviewed. Overall, the mean postoperative best-corrected visual acuity (BCVA) and central retinal thickness measured by optical coherence tomography improved as early as 1 month after surgery, and further improved until 3 months (P < 0.01). Multiple linear regression analyses adjusted for the preoperative BCVA showed that older age (B, 0.010; 95% confidence interval, 0.003 to 0.016; P = 0.003) and a shorter axial length (AL; B, -0.059; 95% confidence interval, -0.099 to -0.019; P = 0.005) predicted worse postoperative BCVA. The Mann-Whitney U test showed that the postoperative BCVA was worse in eyes with AL < 23.6 mm than in eyes with AL ≥ 23.6 mm (P = 0.037), and in patients aged ≥69 years than in patients aged <69 years (P = 0.024). The findings may help in evaluating surgical indications for each patient to obtain satisfactory outcomes, irrespective of the preoperative BCVA.
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http://dx.doi.org/10.1038/s41598-019-55544-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911110PMC
December 2019

Dynamic changes in neural retinal images during the development of a lamellar macular hole: A case report.

Medicine (Baltimore) 2019 Dec;98(49):e18297

Department of Ophthalmology, Keio University, School of Medicine, Shinjukuku, Tokyo, Japan.

Rationale: Lamellar macular hole (LMH) comprises a partial-thickness defect of the macula, the central part of the neural retina. Classification of LMHs into degenerative and tractional types has been proposed based on macular morphology observed on optical coherence tomography (OCT) imaging. Although LMHs are assumed to develop from aborted full-thickness macular holes, the clinical course of LMH development is not fully understood.

Patient Concerns: A 67-year-old man noticed slight changes in his central vision, and exhibited gradual change in macular morphology.

Diagnosis: The patient was first diagnosed with macular hole, which closed spontaneously. He then developed an LMH.

Interventions: The patient was placed under observation.

Outcomes: The patient first exhibited a macular hole, which resolved spontaneously. However, the tractional force at the surface of the macula became more severe, thereby causing retinoschisis-like appearance, which is the characteristic finding of a tractional LMH. The same eye then developed a lamellar hole-associated epiretinal proliferation (LHEP)-like structure, which is often observed in a degenerative LMH; importantly, the retinoschisis-like appearance persisted. Finally, the macula formed a typical degenerative LMH, characterized by intraretinal cavitation with persistent LHEP and disappearance of the retinoschisis-like structure.

Lessons: The present report shows dynamic changes of neural retinal morphology during development of an LMH: a tractional LMH developed initially; it then transformed into a degenerative LMH, which comprises a neurodegenerative disease. The findings in this report may help to understand the pathogenesis of LMHs and to elucidate the neurodegenerative disease process in various fields.
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http://dx.doi.org/10.1097/MD.0000000000018297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919539PMC
December 2019

Spatial-sweep steady-state pattern electroretinography can detect subtle differences in visual function among healthy adults.

Sci Rep 2019 12 2;9(1):18119. Epub 2019 Dec 2.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

We aimed to establish a highly sensitive method for measuring visual function using spatial-sweep steady-state pattern electroretinography (swpPERG). Overall, 35 eyes of 35 healthy adults (18 men; mean age, 32.3 years) were examined using swpPERG, and the data were recorded using spatial-patterned and contrast-reversed stimuli of size 1 (thickest) to 6. Data were converted into frequency-domain using a Fourier transform and expressed by signal-to-noise ratio (SNR). The number of participants who showed SNR ≥ 1 was significantly lesser at stimulus sizes 5 and 6 compared with those at greater stimulus sizes. Among the data with SNR ≥ 1, SNRs were negatively correlated with age at stimulus size 5 (r = -0.500, P = 0.029), and positively correlated with macular volume evaluated by optical coherence tomography (OCT) within a 6-mm circle diameter from the fovea of the retinal nerve fibre layer at size 4 (r = 0.409, P = 0.025) and of the ganglion cell layer at size 5 (r = 0.567, P = 0.011). We found that SNRs of swpPERG, recorded using the EvokeDx system, were correlated with age and macular morphology in participants without diagnosed eye diseases. The system detected subtle differences in retinal function, which may help in early disease diagnosis and visual evaluation in neuroprotective interventions in the future.
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http://dx.doi.org/10.1038/s41598-019-54606-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889279PMC
December 2019

Dietary Spirulina Supplementation Protects Visual Function From Photostress by Suppressing Retinal Neurodegeneration in Mice.

Transl Vis Sci Technol 2019 Nov 20;8(6):20. Epub 2019 Nov 20.

Laboratory of Retinal Cell Biology, Keio University School of Medicine, Tokyo, Japan.

Purpose: We investigated whether daily consumption of Spirulina, an antioxidant generating cyanobacterial nutritional supplement, would suppress photostress-induced retinal damage and prevent vision loss in mice.

Methods: Six-week-old male BALB/cAJcl mice were allowed constant access to either a standard or Spirulina-supplemented diet (20% Spirulina) that included the antioxidants, β-carotene and zeaxanthin, and proteins for 4 weeks. Following dark adaptation, mice were exposed to 3000-lux white light for 1 hour and returned to their cages. Visual function was analyzed by electroretinogram, and retinal histology by hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated, deoxyuridine triphosphate nick-end labeling (TUNEL) assay, and immunohistochemistry. Retinal expression of proteins, reactive oxygen species (ROS), and mRNAs were measured using immunoblot analysis, enzyme-linked immunosorbent assay (ELISA), 2',7'-dichlorofluorescein-diacetate, or ROS Brite 700 Dyes, and real-time reverse-transcription polymerase chain reaction, respectively.

Results: Light-induced visual function impairment was suppressed by constant Spirulina intake. Thinning of the photoreceptor layer and outer segments, photoreceptor cell death, decreased rhodopsin protein, and induction of glial fibrillary acidic protein were ameliorated in the Spirulina-intake group. Increased retinal ROS levels after light exposure were reduced by Spirulina supplementation. Light-induced superoxide dismutase 2 and heme oxygenase-1 mRNAs in the retina, and Nrf2 activation in the photoreceptor cells, were preserved with Spirulina supplementation, despite reduced ROS levels, suggesting two pathways for suppressing ROS, scavenging and induction of endogenous antioxidative enzymes. Light-induced MCP-1 retinal mRNA and proteins were also suppressed by Spirulina.

Conclusions: Spirulina ingestion protected retinal photoreceptors from photostress in the retina.

Translational Relevance: Spirulina has potential as a nutrient supplement to prevent vision loss related to oxidative damage in the future.
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http://dx.doi.org/10.1167/tvst.8.6.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871545PMC
November 2019

Predicting recurrences of macular edema due to branch retinal vein occlusion during anti-vascular endothelial growth factor therapy.

Graefes Arch Clin Exp Ophthalmol 2020 Jan 15;258(1):49-56. Epub 2019 Nov 15.

Laboratory of Retinal Cell Biology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Purpose: To determine the predictive factors for recurrent macular edema due to branch retinal vein occlusion (BRVO) during intravitreal ranibizumab (IVR) monotherapy.

Methods: Clinical records were retrospectively reviewed for 65 patients (mean age 66.5 years, 65 eyes) who were diagnosed with macular edema due to BRVO and treated with IVR monotherapy for 12 months at the Medical Retina Division, Department of Ophthalmology, Keio University Hospital between October 2013 and August 2017. Best-corrected visual acuity (BCVA), fundus findings, and sectional optical coherence tomography (OCT) images were analyzed.

Results: Overall BCVA and central retinal thickness (CRT) improved (all p < 0.01). BCVA at 12 months was significantly worse in patients with recurrent macular edema (40 eyes [61.5%]) (p < 0.01) than in those without, while CRT decreased and was comparable in both groups at 12 months. Logistic regression analyses showed association of recurrence with disorganization of the retinal inner layer (DRIL) temporal to the fovea at baseline (odds ratio = 7.74; 95% confidence interval 1.62-37.08, p = 0.01), after adjusting for age, gender, and initial CRT.

Conclusion: Recurrent macular edema due to BRVO affects visual outcome and is associated with initial DRIL temporal to the fovea, evaluated using OCT sectional images before treatments. DRIL may facilitate determination of follow-up schedules in clinical practice.
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http://dx.doi.org/10.1007/s00417-019-04495-9DOI Listing
January 2020

Ultra-Widefield Retinal Imaging for Analyzing the Association Between Types of Pathological Myopia and Posterior Staphyloma.

J Clin Med 2019 Sep 20;8(10). Epub 2019 Sep 20.

Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

High myopia may develop to pathologic myopia, which brings severe visual impairment; however, the etiology is not fully understood. We, therefore, investigated the relationship between the presence of posterior staphyloma and posterior ocular disorders by assessing the patients with high myopia. A retrospective study was performed for the patients, who have more than 26 mm of the axial length and of whom fundus photography was taken with an ultra-widefield retinal imaging system. The objectives were 138 cases encompassing 229 eyes. In 138 cases, 91 were bilateral and 47 were unilateral. The averages ± SD of axial length of bilateral and unilateral were 28.8 ± 2.2 mm, 27.3 ± 1.2 mm, respectively, showing statistically significant difference. The number of eyes with and without posterior staphyloma were 107 (46.7%) and 122 (53.3%), respectively. Retinal detachment and retinal breaks are more observed in cases without posterior staphyloma ( = 0.017). Myopic choroidal neovascularization (mCNV) ( = 0.002), chorioretinal atrophy ( < 0.001), retinoschisis ( < 0.001), and optic neuropathy ( = 0.038) are more often seen in cases with posterior staphyloma. In conclusion, the prevalence rates of myopic choroidal neovascularization, retinal choroidal atrophy, and optic neuropathy were significantly higher with posterior staphyloma. The rate of periocular disorders such as retinal detachment was significantly higher without posterior staphyloma. These results indicate associations between types of pathological myopia and presence or absence of posterior staphyloma analyzed by ultra-widefield retinal imaging.
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http://dx.doi.org/10.3390/jcm8101505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832756PMC
September 2019

Suppression of Blue Light at Night Ameliorates Metabolic Abnormalities by Controlling Circadian Rhythms.

Invest Ophthalmol Vis Sci 2019 09;60(12):3786-3793

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

Purpose: Light-emitting diodes that emit high-intensity blue light are associated with blue-light hazard. Here, we report that blue light disturbs circadian rhythms by interfering with the clock gene in the suprachiasmatic nucleus (SCN) and that suppression of blue light at night ameliorates metabolic abnormalities by controlling circadian rhythms.

Methods: C57BL/6J mice were exposed to 10-lux light for 30 minutes at Zeitgeber time 14 for light pulse with blue light or blue-light cut light to induce phase shift of circadian rhythms. Phase shift, clock gene expression in SCN, and metabolic parameters were analyzed. In the clinical study, healthy participants wore blue-light shield eyewear for 2 to 3 hours before bed. Anthropometric data analyses, laboratory tests, and sleep quality questionnaires were performed before and after the study.

Results: In mice, phase shift induced with a blue-light cut light pulse was significantly shorter than that induced with a white light pulse. The phase of Per2 expression in the SCN was also delayed after a white light pulse. Moreover, blood glucose levels 48 hours after the white light pulse were higher than those after the blue-cut light pulse. Irs2 expression in the liver was decreased with white light but significantly recovered with the blue-cut light pulse. In a clinical study, after 1 month of wearing blue-light shield eyeglasses, there were improvements in fasting plasma glucose levels, insulin resistance, and sleep quality.

Conclusions: Our results suggest that suppression of blue light at night effectively maintains circadian rhythms and metabolism.
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http://dx.doi.org/10.1167/iovs.19-27195DOI Listing
September 2019

Dynamic changes in choroidal conditions during anti-vascular endothelial growth factor therapy in polypoidal choroidal vasculopathy.

Sci Rep 2019 08 6;9(1):11389. Epub 2019 Aug 6.

Laboratory of Retinal Cell Biology, Keio University, School of Medicine, Tokyo, Japan.

We defined the relationships between initial choroidal conditions and their dynamics and exudative changes during anti-vascular endothelial growth factor (anti-VEGF) therapy in polypoidal choroidal vasculopathy (PCV). One hundred treatment-naïve eyes of 100 patients with PCV treated for 24 months at Keio University Hospital with intravitreal ranibizumab or aflibercept monotherapy (three injections and PRN thereafter) were retrospectively analyzed. Wet macula risk after three induction injections, which affected visual prognosis, was predicted by initial pachyvessels in the choroid (foveal greatest vertical choroidal vessel diameter [CVD] ≥180 μm) and pachychoroid (central choroidal thickness [CCT] ≥220 μm) recorded by optical coherence tomography. The risk for recurrent exudative change was greater in the pachyvessel groups irrespective of presence or absence of pachychoroid. Mean CVD and CCT decreased with anti-VEGF therapy when achieving a dry macula, suggesting that exudative changes are regulated by VEGF. Mean CVD and CCT at remission were greater in patients with initial pachyvessels and pachychoroid than in those without; the basal levels of CVD and CCT most likely represent VEGF-unrelated conditions. CVD increase preceded CCT increase and recurrent exudative changes, suggesting that the VEGF-related CVD increase may regulate CCT and exudative change; and that CVD may be a biomarker of exudative change.
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http://dx.doi.org/10.1038/s41598-019-47738-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684594PMC
August 2019

Aquaporin 4 Suppresses Neural Hyperactivity and Synaptic Fatigue and Fine-Tunes Neurotransmission to Regulate Visual Function in the Mouse Retina.

Mol Neurobiol 2019 Dec 12;56(12):8124-8135. Epub 2019 Jun 12.

Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan.

The bidirectional water channel aquaporin 4 (AQP4) is abundantly expressed in the neural tissue. The advantages and disadvantages of AQP4 neural tissue deficiency under pathological conditions, such as inflammation, and relationship with neural diseases, such as Alzheimer's disease, have been previously reported. However, the physiological functions of AQP4 are not fully understood. Here, we evaluated the role of AQP4 in the mouse retina using Aqp4 knockout (KO) mice. Aqp4 was expressed in Müller glial cells surrounding the synaptic area between photoreceptors and bipolar cells. Both scotopic and photopic electroretinograms showed hyperactive visual responses in KO mice, gradually progressing with age. Moreover, the amplitude reduction after frequent stimuli and synaptic fatigue was more severe in KO mice. Glutamine synthetase, glutamate aspartate transporter, synaptophysin, and the inward potassium channel Kir2.1, but not Kir4.1, were downregulated in KO retinas. KIR2.1 colocalized with AQP4 in Müller glial cells at the synaptic area, and its expression was affected by Aqp4 levels in primary Müller glial cell cultures. Intraocular injection of potassium in wild-type mice led to visual function hyperactivity, as observed in Aqp4 KO mice. Mitochondria molecules, such as Pgc1α and CoxIV, were downregulated, while apoptotic markers were upregulated in KO retinas. AQP4 may fine-tune synaptic activity, most likely by regulating potassium metabolism, at least in part, via collaborating with KIR2.1, and possibly indirectly regulating glutamate kinetics, to inhibit neural hyperactivity and synaptic fatigue which finally affect mitochondria and cause neurodegeneration.
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http://dx.doi.org/10.1007/s12035-019-01661-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834759PMC
December 2019

QD laser eyewear as a visual field aid in a visual field defect model.

Sci Rep 2019 01 30;9(1):1010. Epub 2019 Jan 30.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

Visual field defects interfere with free actions and influence the quality of life of patients with retinitis pigmentosa; the prevalence of this disease is increasing in aging societies. Patients with progressive disease may require visual aids; however, no such devices are currently available. We utilized a retinal projection eyewear system, QD laser eyewear, which includes a projector inside the spectacle frame, to draw the image taken by a connected portable camera with a wide field lens. The images are projected onto the retina using a Maxwellian view optical system, which is not influenced by refractive error or the amount of incident light. Goldmann perimetry and figure recognition tests with the QD laser eyewear showed increased visual field areas and angles, and shortened the time for recognition of the number of figures in a sheet, in a limited visual field model that we developed by using a pin-hole system to simulate the tunnel vision of retinitis pigmentosa in 19 healthy adults. The device supported the quality of vision. Additionally, the visual field defect model used in healthy adults was useful for validating the device in the development stage of the study, to clarify both advantages and future goals for improving the device.
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http://dx.doi.org/10.1038/s41598-018-37744-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353865PMC
January 2019

Retinal inflammation diagnosed as an idiopathic macular hole with multiple recurrences and spontaneous closures: A case report.

Medicine (Baltimore) 2019 Jan;98(4):e14230

Department of Ophthalmology, Keio University, School of Medicine, 35 Shinanomachi, Shinjukuku.

Rationale: An idiopathic macular hole that causes substantial reduction in central visual acuity is believed to involve no obvious underlying diseases; thus, it is suspected to form due to the presence of idiopathic tractional forces at the vitreoretinal interface. Importantly, it is effectively treated with pars plana vitrectomy (PPV), which removes the mechanical forces. However, while it is exceedingly rare, a macular hole can develop in eyes after PPV; fresh or postoperative macular holes can close spontaneously without surgical removal of traction. Thus, another mechanism might be involved, although it remains obscure.

Patients Concerns: A 67-year-old woman experienced 4 episodes of distorted and/or blurred vision.

Diagnosis: She was diagnosed with recurrent macular hole formation.

Interventions: For each episode, she either underwent surgery or was placed under observation.

Outcomes: The macular hole was twice closed with PPV and twice without. The 2nd PPV procedure, which was performed at the time of 2nd recurrence, confirmed the absence of the epiretinal membrane and internal limiting membrane that cause tractional forces at the vitreoretinal interface in the macular area. At the time of the 3rd recurrence, fluorescein angiographies (FAs) revealed the presence of mild and diffuse inflammation throughout the peripheral retina, although there were no other findings indicative of ocular inflammation during the general eye examination conducted for every episode of macular hole formation. After the initiation of topical steroid treatment, inflammation (as recorded on FA) was reduced, and the macular hole subsequently closed. Development and resolution of perifoveal cystoid change and retinal protrusion were observed in every episode in optical coherence tomography (OCT) images. A bridging element in an OCT image was observed during the 4th closure of the macular hole.

Lessons: Dynamic changes in FA and OCT images unraveled the pathogenesis of a macular hole that was originally diagnosed as idiopathic; mild inflammation was involved. The FA is typically not used for the diagnosis and management of macular hole formation; however, its use in this case helped determine a new mechanism in an otherwise idiopathic disease.
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http://dx.doi.org/10.1097/MD.0000000000014230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358394PMC
January 2019

Optic neuropathy causing vertical unilateral hemianopsia after pars plana vitrectomy for a macular hole: A case report.

Medicine (Baltimore) 2018 Apr;97(17):e0321

Laboratory of Retinal Cell Biology.

Introduction: Recent progress in medical technology has resulted in improved surgical outcomes of pars plana vitrectomy (PPV); with microincision systems, the incidence of procedure-related complications during surgery has been reduced. However, unpredictable visual field defects after PPV remain an unresolved issue. A few reports have shown that damage to the retinal neurofibers owing to dry-up during air/fluid exchange or retinal neurotoxicity of the dye used to visualize the internal limiting membrane (ILM), as well as unintentional removal of retinal neurofibers during ILM peeling, are responsible for such visual field disorders. In this report, we present a case of extensive visual field defect due to optic neuropathy exhibiting vertical hemianopsia after PPV.

Case Summary: A 50-year-old woman underwent PPV and cataract surgery for a macular hole and mild cataract under retrobulbar anesthesia with 3.5 mL of xylocaine. At the time of opening an infusion cannula for PPV, the intraocular lens was herniating, with an acute increase in pressure from the posterior eyeball; thus, intraocular pressure configuration level had to be decreased from the default level, whereas the other procedures including 20% SF6 injection were performed without any modification. The macular hole was closed postoperatively. However, the patient experienced nasal hemianopsia, which turned out to be optic neuropathy, as assessed via electric physiological examinations. The pattern of the visual field defect was not typical for glaucoma or anterior ischemic optic neuropathy. Her optic nerve head was pale at the temporal side soon after the surgery, and her blood pressure was low, suggesting that there may have been a congestion of the optic nerve feeder vessels because of the relatively high pressure in the orbit. The space occupancy with xylocaine and extensively stretched and plumped out eye ball with infusion during PPV may have pressed the surrounding tissue of the optic nerve and the feeder vessels.

Conclusion: PPV is safe for most patients; however, individual variations in local and/or systemic conditions may cause complications. Future studies to optimize the surgical condition for each individual patient may be warranted.
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http://dx.doi.org/10.1097/MD.0000000000010321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944518PMC
April 2018

Benefits of aflibercept treatment for age-related macular degeneration patients with good best-corrected visual acuity at baseline.

Sci Rep 2018 01 8;8(1):58. Epub 2018 Jan 8.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

Currently, age-related macular degeneration (AMD) is treated while patients exhibit good best-corrected visual acuity (BCVA). However, previous clinical trials only include patients with poor BCVA. We prospectively analyzed the benefits of intravitreal aflibercept (IVA) treatment for AMD patients exhibiting good BCVA at baseline. Twenty-nine treatment-naive AMD patients (29 eyes) with BCVA better than 0.6 (74 letters in ETDRS chart) were treated with IVA once a month for 3 months and every 2 months thereafter with no additional treatments. Improvement in mean BCVA, measured using the conventional Landolt C chart, contrast VA chart, and functional VA (FVA) system, and reductions in mean central retinal thickness (CRT), central choroidal thickness, macular volume (MV), and choroidal area on optical coherence tomography images were observed at 6 and 12 months. Improvements in contrast VA and FVA scores, in contrast to conventional BCVA, correlated with MV reduction; no VA scores correlated with a reduced CRT. The MV correlated with choroidal area after IVA. No severe adverse events occurred. IVA improved visual function, retinal condition, and quality of life evaluated by Visual Function Questionnaire, and was beneficial in these patients. The contrast VA and FVA scores and MVs, which detect subtle changes, helped demonstrate the benefits.
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http://dx.doi.org/10.1038/s41598-017-18255-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5758719PMC
January 2018

Absolute and estimated values of macular pigment optical density in young and aged Asian participants with or without age-related macular degeneration.

BMC Ophthalmol 2017 Aug 29;17(1):161. Epub 2017 Aug 29.

Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Background: Lutein and zeaxanthin are suggested micronutrient supplements to prevent the progression of age-related macular degeneration (AMD), a leading cause of blindness worldwide. To monitor the levels of lutein/zeaxanthin in the macula, macular pigment optical density (MPOD) is measured. A commercially available device (MPSII®, Elektron Technology, Switzerland), using technology based on heterochromatic flicker photometry, can measure both absolute and estimated values of MPOD. However, whether the estimated value is applicable to Asian individuals and/or AMD patients remains to be determined.

Methods: The absolute and estimated values of MPOD were measured using the MPSII® device in 77 participants with a best-corrected visual acuity (BCVA) > 0.099 (logMAR score).

Results: The studied eyes included 17 young (20-29 years) healthy, 26 aged (>50 years) healthy, 18 aged and AMD-fellow, and 16 aged AMD eyes. The mean BCVA among the groups were not significantly different. Both absolute and estimated values were measurable in all eyes of young healthy group. However, absolute values were measurable in only 57.7%, 66.7%, and 43.8%, of the aged healthy, AMD-fellow, and AMD groups, respectively, and 56.7% of the eyes included in the 3 aged groups. In contrast, the estimated value was measurable in 84.6%, 88.9% and 93.8% of the groups, respectively, and 88.3% of eyes in the pooled aged group. The estimated value was correlated with absolute value in individuals from all groups by Spearman's correlation coefficient analyses (young healthy: R = 0.885, P = 0.0001; aged healthy: R = 0.765, P = 0.001; AMD-fellow: R = 0.851, P = 0.0001; and AMD: R = 0.860, P = 0.013). Using the estimated value, significantly lower MPOD values were found in aged AMD-related eyes, which included both AMD-fellow and AMD eyes, compared with aged healthy eyes by Student's t-test (P = 0.02).

Conclusions: Absolute, in contrast to estimated, value was measurable in a limited number of aged participants; however, it was correlated with estimated value both in young and aged Asian populations with or without AMD. These results may inform future clinical studies investigating the measurement of MPOD in understanding the role of macular pigments in the pathogenesis of AMD.
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http://dx.doi.org/10.1186/s12886-017-0557-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576241PMC
August 2017

Neuroprotective effect of bilberry extract in a murine model of photo-stressed retina.

PLoS One 2017 1;12(6):e0178627. Epub 2017 Jun 1.

Laboratory of Retinal Cell Biology, Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

Excessive exposure to light promotes degenerative and blinding retinal diseases such as age-related macular degeneration and retinitis pigmentosa. However, the underlying mechanisms of photo-induced retinal degeneration are not fully understood, and a generalizable preventive intervention has not been proposed. Bilberry extract is an antioxidant-rich supplement that ameliorates ocular symptoms. However, its effects on photo-stressed retinas have not been clarified. In this study, we examined the neuroprotective effects of bilberry extract against photo-stress in murine retinas. Light-induced visual function impairment recorded by scotopic and phototopic electroretinograms showing respective rod and cone photoreceptor function was attenuated by oral administration of bilberry extract through a stomach tube in Balb/c mice (750 mg/kg body weight). Bilberry extract also suppressed photo-induced apoptosis in the photoreceptor cell layer and shortening of the outer segments of rod and cone photoreceptors. Levels of photo-induced reactive oxygen species (ROS), oxidative and endoplasmic reticulum (ER) stress markers, as measured by real-time reverse transcriptase polymerase chain reaction, were reduced by bilberry extract treatment. Reduction of ROS by N-acetyl-L-cysteine, a well-known antioxidant also suppressed ER stress. Immunohistochemical analysis of activating transcription factor 4 expression showed the presence of ER stress in the retina, and at least in part, in Müller glial cells. The photo-induced disruption of tight junctions in the retinal pigment epithelium was also attenuated by bilberry extract, repressing an oxidative stress marker, although ER stress markers were not repressed. Our results suggest that bilberry extract attenuates photo-induced apoptosis and visual dysfunction most likely, and at least in part, through ROS reduction, and subsequent ER stress attenuation in the retina. This study can help understand the mechanisms of photo-stress and contribute to developing a new, potentially useful therapeutic approach using bilberry extract for preventing retinal photo-damage.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178627PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453571PMC
September 2017

Maculopapular rash after intravitreal injection of an antivascular endothelial growth factor, aflibercept, for treating age-related macular degeneration: A case report.

Medicine (Baltimore) 2017 May;96(21):e6965

Laboratory of Retinal Cell Biology Department of Ophthalmology Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.

Rationale: Aflibercept, an anti-vascular endothelial growth factor (VEGF) drug, is used for treatment of colon cancer as well as retinal diseases, including wet age-related macular degeneration (AMD). It is injected into the vitreous cavity of eyes for treatment of AMD. Although vascular suppression-including cardiovascular events-and local infection related to the injection procedure are well-known potential adverse events, pathological immune responses after intravitreal aflibercept (IVA) injection have not been described.

Patient Concerns: A 60-year-old Japanese man diagnosed with polypoidal choroidal vasculopathy (PCV), a subtype of wet AMD, was treated by anti-VEGF injection. Ten hours after the last IVA injection, he presented with systemic erythema with itching.

Diagnoses: On the basis of the palpable erythema and papules observed on the trunk and extremities, along with redness of the pharynx, the patient was diagnosed with maculopapular-type drug eruption. The findings of biopsy of erythematous skin on the back revealed lymphocyte infiltration and telangiectasia in the upper dermis, thus confirming the diagnosis.

Interventions: The patient was administered 30 mg prednisolone to resolve the immunoreaction.

Outcomes: With this treatment, the eruption turned brown, and the pharyngeal lesion and itching were resolved, and the maculopapular rash after intravitreal IVA was resolved.

Lessons: This case illustrates the importance of medical staff being aware of aflibercept-a widely used anti-VEGF drug in various fields, including retinal diseases-as a potential cause of drug allergy.
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http://dx.doi.org/10.1097/MD.0000000000006965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457872PMC
May 2017

Predictive factors of better outcomes by monotherapy of an antivascular endothelial growth factor drug, ranibizumab, for diabetic macular edema in clinical practice.

Medicine (Baltimore) 2017 Apr;96(16):e6459

aDepartment of Ophthalmology bLaboratory of Retinal Cell Biology, Keio University, School of Medicine, Tokyo, Japan.

Intravitreal ranibizumab (IVR) has been approved for treating diabetic macular edema (DME), and is used in daily clinical practice. However, the treatment efficacies of IVR monotherapy in real-world clinical settings are not well known.The medical records of 56 eyes from 38 patients who received their first IVR for DME between April 2014 and March 2015, and were retreated with IVR monotherapy as needed with no rescue treatment, such as laser photocoagulation, were retrospectively reviewed. The clinical course, best-corrected visual acuity (BCVA), and fundus findings at baseline, before the initial IVR injection, and at 12 months, were evaluated.Twenty-five eyes from 25 patients (16 men; mean age 68.7 ± 9.8 years) who received IVR in the first eye, or unilaterally, without any other treatments during follow-up were included. After 12 months, mean central retinal thickness (CRT), which includes edema, was reduced (P = .003), although mean BCVA remained unchanged. There was a negative correlation between individual changes in BCVA (r = -0.57; P = .003) and CRT (r = -0.60; P = .002) at 12 months compared with baseline values. BCVA changes were greater in individuals with a history of pan-retinal photocoagulation at baseline (P = .026). After adjusting for age and sex, CRT improvement >100 μm at 12 months was associated with a greater CRT at baseline (OR 0.87 per 10 μm [95% CI 0.72-0.97]; P = .018) according to logistic regression analyses; however, better BCVA and CRT at 12 months were associated with a better BCVA (r = 0.77; P < .001) and lower CRT (r = 0.41; P = .039) at baseline, respectively, according to linear regression analyses.IVR monotherapy suppressed DME, and the effects varied according to baseline conditions. Eyes that had poorer BCVA or greater CRT, or a history of pan-retinal photocoagulation at baseline, demonstrated greater improvement with IVR monotherapy. In contrast, to achieve better outcome values, DME eyes should be treated before the BCVA and CRT deteriorate. These findings advance our understanding of the optimal use of IVR for DME in daily clinical practice, although further study is warranted.
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http://dx.doi.org/10.1097/MD.0000000000006459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5406051PMC
April 2017

Reply.

Am J Ophthalmol 2016 09 15;169:295-296. Epub 2016 Jul 15.

Tokyo, Japan.

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http://dx.doi.org/10.1016/j.ajo.2016.06.018DOI Listing
September 2016