• Title/Summary/Keyword: Age-related macular degeneration

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Intravitreal Anti-vascular Endothelial Growth Factor Injections to Treat Neovascular Age-related Macular Degeneration: Long-term Treatment Outcomes (삼출 나이관련황반변성에 대한 항혈관내피성장인자 유리체내주사 치료의 장기 임상 결과)

  • Park, Yu Jeong;Son, Gi Sung;Kim, Yoon Jeon;Kim, June-Gone;Yoon, Young Hee;Lee, Joo Yong
    • Journal of The Korean Ophthalmological Society
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    • v.59 no.12
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    • pp.1142-1151
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    • 2018
  • Purpose: We assessed the visual and anatomical outcomes, and the safety profile of long-term intravitreal anti-vascular endothelial growth factor (VEGF) injections (aflibercept, ranibizumab, and bevacizumab) given to treat neovascular age-related macular degeneration (NAMD). Methods: We analyzed medical records collected over 7 years of treatment-naive NAMD patients who received outpatient clinic-based intravitreal anti-VEGF injections. All were treated employing either "treat-and-extend" or "as needed" protocols at the discretion of the retinal specialist. The number of injections, adverse events associated with injection, and measures of visual acuity (VA), central foveal thickness (CFT), and intraocular pressure (IOP) were recorded. Results: Overall, we assessed 196 eyes of 196 patients (average age $68.6{\pm}9.6years$; 77 females). Patients received an average of $17.3{\pm}13.5$ injections over $78.0{\pm}16.5months$ of clinical follow-up. The initial mean VA (logMAR) was $0.75{\pm}0.58$ and the CFT was $349.7{\pm}152.6{\mu}m$. Both parameters exhibited maximal improvements at the 6-month visit (p < 0.05). However, the clinical outcomes worsened over the 7-year clinical course; the best-corrected visual acuity (BCVA) was $0.91{\pm}0.78$ and the CFT was $284.5{\pm}105.8{\mu}m$ at 7 years. The BCVA at 7 years was significantly correlated with the initial BCVA. IOP-related events increased 11-fold and anterior chamber reactions increased 3-fold over the years, but no significant complications such as endophthalmitis were recorded. Conclusions: The use of intravitreal anti-VEGF agents was associated with initial visual improvements over 6 months but did not prevent the worsening of NAMD over 5 years. The BCVA at the initial visit was a strong predictor of the final BCVA. A more intensive injection schedule might improve long-term outcomes.

Complement regulation: physiology and disease relevance

  • Cho, Heeyeon
    • Clinical and Experimental Pediatrics
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    • v.58 no.7
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    • pp.239-244
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    • 2015
  • The complement system is part of the innate immune response and as such defends against invading pathogens, removes immune complexes and damaged self-cells, aids organ regeneration, confers neuroprotection, and engages with the adaptive immune response via T and B cells. Complement activation can either benefit or harm the host organism; thus, the complement system must maintain a balance between activation on foreign or modified self surfaces and inhibition on intact host cells. Complement regulators are essential for maintaining this balance and are classified as soluble regulators, such as factor H, and membrane-bound regulators. Defective complement regulators can damage the host cell and result in the accumulation of immunological debris. Moreover, defective regulators are associated with several autoimmune diseases such as atypical hemolytic uremic syndrome, dense deposit disease, age-related macular degeneration, and systemic lupus erythematosus. Therefore, understanding the molecular mechanisms by which the complement system is regulated is important for the development of novel therapies for complement-associated diseases.

Human Apolipoprotein E2 Transgenic Mice Show Lipid Accumulation in Retinal Pigment Epithelium and Altered Expression of VEGF and bFGF in the Eyes

  • Lee, Sung-Joon;Kim, Jeong-Hun;Kim, Jin-Hyoung;Chung, Mi-Ja;Wen, Qingcheng;Chung, Hum;Kim, Kyu-Won;Yu, Young-Suk
    • Journal of Microbiology and Biotechnology
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    • v.17 no.6
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    • pp.1024-1030
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    • 2007
  • We investigated the human apolipoprotein E2 (apoE2) transgenic mouse as an animal model system for age-related macular degeneration (AMD). Transgenic mice expressing human apoE2 and C57BL/6J mice were fed normal chow or a high-fat diet for 4 weeks. Eyes were collected from the mice and lipid deposits in retinal pigment epithelium (RPE) were assessed using electron microscopy. The expressions of apoE, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and pigment-epithelium derived factor (PEDF), which are molecular markers for angiogenesis, were assessed with immunohistochemistry. Eyes from apoE2 mice, regardless of diet, contained lipid accumulation in RPE under electron microscopy, whereas control C57BL/6J eyes did not. Lipid accumulation was found predominantly in the RPE and the Bruch's membrane and increased in the eyes of apoE2 mice after one month of a high-fat diet ($8{\pm}2\;per\;50{\mu}m^2$ for normal chow and $11{\pm}2\;per\;50\;{\mu}m^2,\;p<0.05)$. ApoE expression was similar in the apoE2 and control mice; however, VEGF and bFGF were overexpressed in the retinal pigment epithelium of apoE2 eyes compared with control eyes, and PEDF expression was slightly decreased. These expression patterns of VEGF, bFGF, and PEDF suggest angiogenesis is progressing in apoE2 eyes. In conclusion, the eyes of apoE2 mice develop typical lipid accumulations, a common characteristic of AMD, making them a suitable animal model for AMD. The expression profile of VEGF and bFGF on the retinal pigment epithelium suggests that apoE2 may induce neovascularization by altering angiogenic cytokines.

Application of genome engineering for treatment of retinal diseases

  • Jo, Dong Hyun;Kim, Jeong Hun
    • BMB Reports
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    • v.51 no.7
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    • pp.315-316
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    • 2018
  • Genome engineering with clustered regularly interspaced short palindromic repeats (CRISPR) system can be used as a tool to correct pathological mutations or modulate gene expression levels associated with pathogenesis of human diseases. Owing to well-established local administration methods including intravitreal and subretinal injection, it is relatively easy to administer therapeutic genome engineering machinery to ocular tissues for treating retinal diseases. In this context, we have investigated the potential of in vivo genome engineering as a therapeutic approach in the form of ribonucleoprotein or CRISPR packaged in viral vectors. Major issues in therapeutic application of genome engineering include specificity and efficacy according to types of CRISPR system. In addition to previous platforms based on ribonucleoprotein and CRISPR-associated protein 9 derived from Campylobacter jejuni, we evaluated the therapeutic effects of a CRISPR RNA-guided endonuclease derived from Lachnospiraceae bacterium ND2006 (LbCpf1) in regulating pathological angiogenesis in an animal model of wet-type age-related macular degeneration. LbCpf1 targeting Vegfa or Hif1a effectively disrupted the expression of genes in ocular tissues, resulting in suppression of choroidal neovascularization. It was also notable that there were no significant off-target effects in vivo.

The Effect of Brown Tinted or UV-A blocking Ophthalmic Lens Against the Photooxidation of A2E, a Lipofuscin in Retina (망막 내 노인성 형광색소의 광산화에 미치는 Brown 착색렌즈와 UV-A 차단 안경렌즈의 영향)

  • Park, Sang-Il
    • Journal of Korean Ophthalmic Optics Society
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    • v.17 no.1
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    • pp.91-97
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    • 2012
  • Purpose: This purpose of study is to investigate the effect of UV-A-blocking or brown-tinted ophthalmic lens against A2E photooxidation which known as one of the etiologies of AMD(Age-related macular degenaration). Methods: The photooxidation of A2E, synthetic product of two molecules of all-trans-retinal and ethanolamine, was induced by the exposure to blue light (420~470 nm, $94mW/cm^2$) for 3 minutes. The inhibitory effect of UVblocking or brown-tinted ophthalmic lens against A2E photooxidation was evaluated by UV absorbance and HPLC analysis of remained A2E after the exposure to blue light. Results: UV-blocking ophthalmic lens could not inhibit A2E photooxidation induced by blue light irradiation. There was no difference in A2E photooxidation in the presence of brown-tinted ophthalmic lens to block 15% of visible ray, however, those lenses blocking 55% or 86% of visible ray showed the inhibitory effect of A2E photooxidation as 9.98% and 16.55%, respectively. By HPLC analysis, the amount of residual A2E which was not blocked by any lens was $199.29{\pm}26.53{\mu}M$, however, the inhibitory effect against A2E photooxidation was shown in the presence of brown-tinted lens. The remained A2Es were $264.58{\pm}31.91{\mu}M$ and $402.93{\pm}28.68{\mu}M$ in brown-tinted lenses of 55% and 86% blocking visible ray, respectively. However, there was no inhibitory effect against A2E photooxidation in the case of UV-blocking lens by HPLC analysis. Conclusions: In this study, brown-tinted ophthalmic lens was confirmed to have the inhibitory effect against the photooxidation of A2E, a causing substance of AMD onset.

PARP1 Impedes SIRT1-Mediated Autophagy during Degeneration of the Retinal Pigment Epithelium under Oxidative Stress

  • Jang, Ki-Hong;Hwang, Yeseong;Kim, Eunhee
    • Molecules and Cells
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    • v.43 no.7
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    • pp.632-644
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    • 2020
  • The molecular mechanism underlying autophagy impairment in the retinal pigment epithelium (RPE) in dry age-related macular degeneration (AMD) is not yet clear. Based on the causative role of poly(ADP-ribose) polymerase 1 (PARP1) in RPE necrosis, this study examined whether PARP1 is involved in the autophagy impairment observed during dry AMD pathogenesis. We found that autophagy was downregulated following H2O2-induced PARP1 activation in ARPE-19 cells and olaparib, PARP1 inhibitor, preserved the autophagy process upon H2O2 exposure in ARPE-19 cells. These findings imply that PARP1 participates in the autophagy impairment upon oxidative stress in ARPE-19 cells. Furthermore, PARP1 inhibited autolysosome formation but did not affect autophagosome formation in H2O2-exposed ARPE-19 cells, demonstrating that PARP1 is responsible for impairment of late-stage autophagy in particular. Because PARP1 consumes NAD+ while exerting its catalytic activity, we investigated whether PARP1 impedes autophagy mediated by sirtuin1 (SIRT1), which uses NAD+ as its cofactor. A NAD+ precursor restored autophagy and protected mitochondria in ARPE-19 cells by preserving SIRT1 activity upon H2O2. Moreover, olaparib failed to restore autophagy in SIRT1-depleted ARPE-19 cells, indicating that PARP1 inhibits autophagy through SIRT1 inhibition. Next, we further examined whether PARP1-induced autophagy impairment occurs in the retinas of dry AMD model mice. Histological analyses revealed that olaparib treatment protected mouse retinas against sodium iodate (SI) insult, but not in retinas cotreated with SI and wortmannin, an autophagy inhibitor. Collectively, our data demonstrate that PARP1-dependent inhibition of SIRT1 activity impedes autophagic survival of RPE cells, leading to retinal degeneration during dry AMD pathogenesis.

The Bcl-2/Bcl-xL Inhibitor ABT-263 Attenuates Retinal Degeneration by Selectively Inducing Apoptosis in Senescent Retinal Pigment Epithelial Cells

  • Wonseon Ryu;Chul-Woo Park;Junghoon Kim;Hyungwoo Lee;Hyewon Chung
    • Molecules and Cells
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    • v.46 no.7
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    • pp.420-429
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    • 2023
  • Age-related macular degeneration (AMD) is one of the leading causes of blindness in elderly individuals. However, the currently used intravitreal injections of anti-vascular endothelial growth factor are invasive, and repetitive injections are also accompanied by a risk of intraocular infection. The pathogenic mechanism of AMD is still not completely understood, but a multifactorial mechanism that combines genetic predisposition and environmental factors, including cellular senescence, has been suggested. Cellular senescence refers to the accumulation of cells that stop dividing due to the presence of free radicals and DNA damage. Characteristics of senescent cells include nuclear hypertrophy, increased levels of cell cycle inhibitors such as p16 and p21, and resistance to apoptosis. Senolytic drugs remove senescent cells by targeting the main characteristics of these cells. One of the senolytic drugs, ABT-263, which inhibits the antiapoptotic functions of Bcl-2 and Bcl-xL, may be a new treatment for AMD patients because it targets senescent retinal pigment epithelium (RPE) cells. We proved that it selectively kills doxorubicin (Dox)-induced senescent ARPE-19 cells by activating apoptosis. By removing senescent cells, the expression of inflammatory cytokines was reduced, and the proliferation of the remaining cells was increased. When ABT-263 was orally administered to the mouse model of senescent RPE cells induced by Dox, we confirmed that senescent RPE cells were selectively removed and retinal degeneration was alleviated. Therefore, we suggest that ABT-263, which removes senescent RPE cells through its senolytic effect, has the potential to be the first orally administered senolytic drug for the treatment of AMD.

A Study on the Relationship between Eye Disease and Nutrient Intake in Korean Adults: Data from Korean National Health and Nutrition Examination Survey 2015, 2016 (한국 성인에서 안질환과 영양소 섭취와의 관련성에 관한 연구: 2015, 2016년 국민건강영양조사 자료를 이용하여)

  • Hwang, Hyo-Jeong;Shin, Kyung-Ok;Shin, Seong-Joo
    • Journal of the Korean Dietetic Association
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    • v.27 no.2
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    • pp.77-91
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    • 2021
  • This study was conducted to investigate the effect of the differences in nutrient intakes on the onset of eye disease in the ophthalmic disease group vs. the normal group. The analysis method of this study was performed by adjusting age and gender. The daily caloric intake was 1,672.1±26.4 kcal in the ophthalmic disease group which was significantly lower than the 2,041.5±13.6 kcal intake in the normal group (P=0.006). The intake of proteins (P=0.015) and carbohydrates (P=0.000) was significantly lower in the ophthalmic disease group than in the normal group. The incidence of eye diseases was found to decrease by about 0.79 (95% CI: 0.74~0.83) times as the NAR index of protein was increased, followed by 0.79 (95% CI: 0.64~0.98) times with an increase in niacin consumption. In this study, income, BMI, smoking, alcohol consumption, and quality of life were considered as the confounding variables related to eye disease, along with age and gender, but did not lead to show significant results. It was found that the ophthalmic disease group had an unbalanced nutritional intake compared to the normal group. Therefore, we conclude that nutrition education is necessary to ensurebalanced eating habits for management and prevention of degeneration after the onset of eye diseases.

Layer Segmentation of Retinal OCT Images using Deep Convolutional Encoder-Decoder Network (딥 컨볼루셔널 인코더-디코더 네트워크를 이용한 망막 OCT 영상의 층 분할)

  • Kwon, Oh-Heum;Song, Min-Gyu;Song, Ha-Joo;Kwon, Ki-Ryong
    • Journal of Korea Multimedia Society
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    • v.22 no.11
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    • pp.1269-1279
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    • 2019
  • In medical image analysis, segmentation is considered as a vital process since it partitions an image into coherent parts and extracts interesting objects from the image. In this paper, we consider automatic segmentations of OCT retinal images to find six layer boundaries using convolutional neural networks. Segmenting retinal images by layer boundaries is very important in diagnosing and predicting progress of eye diseases including diabetic retinopathy, glaucoma, and AMD (age-related macular degeneration). We applied well-known CNN architecture for general image segmentation, called Segnet, U-net, and CNN-S into this problem. We also proposed a shortest path-based algorithm for finding the layer boundaries from the outputs of Segnet and U-net. We analysed their performance on public OCT image data set. The experimental results show that the Segnet combined with the proposed shortest path-based boundary finding algorithm outperforms other two networks.

Functional Connectivity Map of Retinal Ganglion Cells for Retinal Prosthesis

  • Ye, Jang-Hee;Ryu, Sang-Baek;Kim, Kyung-Hwan;Goo, Yong-Sook
    • The Korean Journal of Physiology and Pharmacology
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    • v.12 no.6
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    • pp.307-314
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    • 2008
  • Retinal prostheses are being developed to restore vision for the blind with retinal diseases such as retinitis pigmentosa (RP) or age-related macular degeneration (AMD). Among the many issues for prosthesis development, stimulation encoding strategy is one of the most essential electrophysiological issues. The more we understand the retinal circuitry how it encodes and processes visual information, the greater it could help decide stimulation encoding strategy for retinal prosthesis. Therefore, we examined how retinal ganglion cells (RGCs) in in-vitro retinal preparation act together to encode a visual scene with multielectrode array (MEA). Simultaneous recording of many RGCs with MEA showed that nearby neurons often fired synchronously, with spike delays mostly within 1 ms range. This synchronized firing - narrow correlation - was blocked by gap junction blocker, heptanol, but not by glutamatergic synapse blocker, kynurenic acid. By tracking down all the RGC pairs which showed narrow correlation, we could harvest 40 functional connectivity maps of RGCs which showed the cell cluster firing together. We suggest that finding functional connectivity map would be useful in stimulation encoding strategy for the retinal prosthesis since stimulating the cluster of RGCs would be more efficient than separately stimulating each individual RGC.