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The Placental Growth Factor Pathway and Its Potential Role in Macular Degenerative Disease.
Cunningham, F, Van Bergen, T, Canning, P, Lengyel, I, Feyen, JHM, Stitt, AW
Current eye research. 2019;(8):813-822
Abstract
There is growing evidence that placental growth factor (PlGF) is an important player in multiple pathologies, including tumorigenesis, inflammatory disorders and degenerative retinopathies. PlGF is a member of the vascular endothelial growth factor (VEGF) family and in the retina, binding of this growth factor to specific receptors is associated with pathological angiogenesis, vascular leakage, neurodegeneration and inflammation. Although they share some receptor signalling pathways, many of the actions of PlGF are distinct from VEGF and this has revealed the enticing prospect that it could be a useful therapeutic target for treating early and late stages of diabetic retinopathy (DR) and neovascular age-related macular degeneration (AMD). Recent research suggests that modulation of PlGF could also be important in the geographic atrophy (GA) form of late AMD by protecting the outer retina and the retinal pigment epithelium (RPE). This review discusses PlGF and its signalling pathways and highlights the potential of blocking the bioactivity of this growth factor to treat irreversible visual loss due to the two main forms of AMD.
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Prevalence and causes of vision loss in North Africa and Middle East in 2015: magnitude, temporal trends and projections.
Kahloun, R, Khairallah, M, Resnikoff, S, Cicinelli, MV, Flaxman, SR, Das, A, Jonas, JB, Keeffe, JE, Kempen, JH, Leasher, J, et al
The British journal of ophthalmology. 2019;(7):863-870
Abstract
BACKGROUND To assess the prevalence and causes of vision impairment in North Africa and the Middle East (NAME) from 1990 to 2015 and to forecast projections for 2020. METHODS Based on a systematic review of medical literature, the prevalence of blindness (presenting visual acuity (PVA) <3/60 in the better eye), moderate and severe vision impairment (MSVI; PVA <6/18 but ≥3/60) and mild vision impairment (PVA <6/12 but ≥6/18) was estimated for 2015 and 2020. RESULTS The age-standardised prevalence of blindness and MSVI for all ages and genders decreased from 1990 to 2015, from 1.72 (0.53-3.13) to 0.95% (0.32%-1.71%), and from 6.66 (3.09-10.69) to 4.62% (2.21%-7.33%), respectively, with slightly higher figures for women than men. Cataract was the most common cause of blindness in 1990 and 2015, followed by uncorrected refractive error. Uncorrected refractive error was the leading cause of MSVI in the NAME region in 1990 and 2015, followed by cataract. A reduction in the proportions of blindness and MSVI due to cataract, corneal opacity and trachoma is predicted by 2020. Conversely, an increase in the proportion of blindness attributable to uncorrected refractive error, glaucoma, age-related macular degeneration and diabetic retinopathy is expected. CONCLUSIONS In 2015 cataract and uncorrected refractive error were the major causes of vision loss in the NAME region. Proportions of vision impairment from cataract, corneal opacity and trachoma are expected to decrease by 2020, and those from uncorrected refractive error, glaucoma, diabetic retinopathy and age-related macular degeneration are predicted to increase by 2020.
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Effects of Huangban Bianxing One decoction combined with ranibizumab on treating exudative age-related macular degeneration.
Luo, D, Deng, T, Yuan, W, Deng, H, Meng, H, Jin, M
Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan. 2019;(6):892-901
Abstract
OBJECTIVE To evaluate the clinical efficacy and safety of Chinese medicine formula Huangban Bianxing One decoction (HBOD) combined with ranibizumab for treating exudative age-related macular degeneration (AMD) patients. METHODS Totally 75 cases with exudative AMD (75 eyes) were enrolled in this study and randomly divided into two groups to receive either HBOD with ranibizumab or only ranibizumab. Early treatment diabetic retinopathy study (ETDRS) letters for the best corrected visual acuity, center macular thickness (CMT), height of the lesion, fundus hemorrhage area, fundus fluorescein leakage area as the main outcomes and safety indexes were estimated and compared before and after treatment for 3 or 6 months. RESULTS Comparing with the before treatment, ETDRS letter scores of both groups after treatment at month 3 obtained a greater improvement (P < 0.05), but the significant improvement only existed in the HBOD+ranibizumab group at month 6 (P < 0.01), and better than the ranibizumab group (P < 0.05). At month 3, the CMT and lesion height of both groups were significantly lower than those before treatment (P < 0.01 or P < 0.05) and the HBOD + ranibizumab group had a similar result at month 6 (P < 0.01). The hemorrhage area and fluorescein leakage area of the HBOD+ranibizumab group were also significantly reduced and also smaller than those of the ranibizumab group at month 6 (P < 0.01 or P < 0.05). During treatment, no significant adverse events relating to HBOD or ranibizumab treatment were elucidated. CONCLUSION HBOD combined with ranibizumab can improve visual acuity and reduce hemorrhage and fluorescein leakage of patients with exudative AMD. These results also indicated that HBOD may function as an effective and safe adjuvant drug for exudative AMD.
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The Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration: Results from the Randomized Phase 2 Ladder Clinical Trial.
Campochiaro, PA, Marcus, DM, Awh, CC, Regillo, C, Adamis, AP, Bantseev, V, Chiang, Y, Ehrlich, JS, Erickson, S, Hanley, WD, et al
Ophthalmology. 2019;(8):1141-1154
Abstract
PURPOSE To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) treatment. DESIGN Phase 2, multicenter, randomized, active treatment-controlled clinical trial. PARTICIPANTS Patients diagnosed with nAMD within 9 months who had received 2 or more prior anti-vascular endothelial growth factor intravitreal injections and were responsive to treatment. METHODS Patients were randomized 3:3:3:2 to receive the PDS filled with ranibizumab 10 mg/ml, 40 mg/ml, 100 mg/ml, or monthly intravitreal ranibizumab 0.5-mg injections. MAIN OUTCOME MEASURES Time to first implant refill assessed when the last enrolled patient completed the month 9 visit (primary efficacy end point), improvement in best-corrected visual acuity (BCVA) and central foveal thickness (CFT), and safety. RESULTS The primary analysis population was 220 patients, with 58, 62, 59, and 41 patients in the PDS 10-mg/ml, PDS 40-mg/ml, PDS 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg arms, respectively. Median time to first implant refill was 8.7, 13.0, and 15.0 months in the PDS 10-mg/ml, PDS 40-mg/ml, and PDS 100-mg/ml arms, respectively. At month 9, the adjusted mean BCVA change from baseline was ‒3.2 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, ‒0.5 ETDRS letters, +5.0 ETDRS letters, and +3.9 ETDRS letters in the PDS 10-mg/ml, PDS 40-mg/ml, PDS 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg arms, respectively. At month 9, the adjusted mean CFT change from baseline was similar in the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg arms. The optimized PDS implant insertion and refill procedures were generally well tolerated. After surgical procedure optimization, postoperative vitreous hemorrhage rate was 4.5% (7/157; 1 event classified as serious). There was no evidence of implant clogging. CONCLUSIONS In the phase 2 Ladder trial, the PDS was generally well tolerated and demonstrated a dose response across multiple end points in patients with nAMD. The PDS 100-mg/ml arm showed visual and anatomic outcomes comparable with monthly intravitreal ranibizumab 0.5-mg injections but with a reduced total number of ranibizumab treatments. The PDS has the potential to reduce treatment burden in nAMD while maintaining vision.
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Treatment of exudative age-related macular degeneration with aflibercept combined with pranoprofen eye drops or nutraceutical support with omega-3: A randomized trial.
Semeraro, F, Gambicordi, E, Cancarini, A, Morescalchi, F, Costagliola, C, Russo, A
British journal of clinical pharmacology. 2019;(5):908-913
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Abstract
AIMS: The aim of this study was to determine whether a combination of intravitreal aflibercept (IVA) and pranoprofen eyedrops or nutraceutical support provides additional benefit over IVA monotherapy for the treatment of choroidal neovascularization (CNV) in age-related macular degeneration. METHODS This was a prospective, randomized, pilot study in 60 patients with treatment-naïve CNV. Patients were randomized 1:1:1 into three groups: aflibercept monotherapy (AM), aflibercept plus pranoprofen (AP) or aflibercept plus nutraceutical (AN) tablets containing multivitamin antioxidant and mineral supplementation plus omega-3. RESULTS At 12 months, all groups showed significant improvement in both best-corrected visual acuity (BCVA) and central retinal thickness (CRT). The mean BCVA change from baseline to 12 months was -0.26 ± 0.06 LogMAR, -0.30 ± 0.06 LogMAR and -0.24 ± 0.04 LogMAR in the AM, AP and AN groups, respectively. The mean CRT change from baseline to 12 months was -76.9 ± 10.9 μm, -129 ± 19.9 μm and -105 ± 11.6 μm in the AM, AP and AN groups, respectively. The AN group required one less IVA injection than the AM group. CONCLUSIONS Compared with AM, both combination groups acted synergistically, although no significant benefits in BCVA were found over AM. Nutraceutical support with omega-3 leads to a reduced need for IVA.
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An evidence-based approach to the routine use of optical coherence tomography.
Ly, A, Phu, J, Katalinic, P, Kalloniatis, M
Clinical & experimental optometry. 2019;(3):242-259
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Optical coherence tomography is an imaging technology that has revolutionised the detection, assessment and management of ocular disease. It is now a mainstream technology in clinical practice and is performed by non-specialised personnel in some settings. This article provides a clinical perspective on the implications of that movement and describes best practice using multimodal imaging and an evidence-based approach. Practical, illustrative guides on the interpretation of optical coherence tomography are provided for three major diseases of the ocular fundus, in which optical coherence tomography is often crucial to management: age-related macular degeneration, diabetic retinopathy and glaucoma. Topics discussed include: cross-sectional and longitudinal signs in ocular disease, so-called 'red-green' disease whereby clinicians rely on machine/statistical comparisons for diagnosis in managing treatment-naïve patients, and the utility of optical coherence tomography angiography and machine learning.
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Mechanisms enhancing the protective functions of macular xanthophylls in the retina during oxidative stress.
Widomska, J, Subczynski, WK
Experimental eye research. 2019;:238-246
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Macular xanthophylls (MXs) are distinguished from other dietary carotenoids by their high membrane solubility and preferential transmembrane orientation. Additionally, these properties enhance the chemical and physical stability of MXs in the eye retina, and maximize their protective activities. The effectiveness of MXs' protection is also enhanced by their selective accumulation in the most vulnerable domains of retinal membranes. The retina is protected by MXs mainly through blue-light filtration, quenching of the excited triplet states of potent photosensitizers, and physical quenching of singlet oxygen. To perform these physical, photo-related actions, the structure of MXs should remain intact. However, the conjugated double-bond structure of MXs makes them highly chemically reactive and susceptible to oxidation. Chemical quenching of singlet oxygen and scavenging of free radicals destroy their intact structure and consume MXs. Consequently, their physical actions, which are critical to the protection of retina, are diminished. Thus, it is timely and important to identify mechanisms whereby the chemical destruction (bleaching) of MXs in retinal membranes can be reduced. It was shown that nitroxide free radicals (spin labels) located in membranes protect MXs against destruction, and their effect is especially pronounced during the light-induced formation of singlet oxygen. That should extend and enhance their positive action in the retina through physical processes. In this review, we will discuss possible applications of this new strategy during ophthalmological procedures, which can cause acute bleaching of MXs and damage the retina through oxidative processes.
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Investigation of the relationship between macular pigment levels and rod-mediated dark adaptation in intermediate age-related macular degeneration.
Beirne, RO, McConnell, E
Clinical & experimental optometry. 2019;(6):611-616
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BACKGROUND It has been shown that rod-mediated dark adaptation is significantly delayed in ageing, a change which is exacerbated in age-related macular degeneration (AMD). Levels of lutein and zeaxanthin, the two main constituents of macular pigment have been found in rod outer segments, indicating that the macular pigment may have an influence on rod-mediated dark adaptation. The aim of this study was to determine if rod-mediated dark adaptation is associated with central macular pigment levels in individuals with intermediate stage AMD. METHODS A cross-sectional observational study included individuals with acuity better than 6/15 Snellen and intermediate stage AMD based on graded fundus photographs using an internationally accepted grading scale. Rod-mediated dark adaptation was assessed at five degrees eccentricity in the superior retina (inferior visual field) using the rod intercept time measure from the MacuLogix AdaptDx. Macular pigment optical density was measured at 0.5 degrees eccentricity using a heterochromatic flicker photometry-based method. RESULTS Twenty-seven individuals (mean age 76.7 years) with intermediate stage AMD and 23 age-matched normal controls (mean age 74.0 years) were recruited. Rod-mediated dark adaptation was significantly delayed in intermediate stage AMD compared with healthy controls (32.9 minutes versus 10.7 minutes, p < 0.01). There was no statistically significant correlation between the rod intercept time and the level of macular pigment in those with intermediate AMD (r = -0.04, p = 0.85). CONCLUSION The results did not support the hypothesis that higher macular pigment is associated with improved rod-mediated performance or that higher levels of macular pigment protect rod-mediated function in intermediate AMD.
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A Review of Pathogenic Drivers of Age-Related Macular Degeneration, Beyond Complement, with a Focus on Potential Endpoints for Testing Therapeutic Interventions in Preclinical Studies.
Choudhary, M, Malek, G
Advances in experimental medicine and biology. 2019;:9-13
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Age-related macular degeneration (AMD) continues to be the leading cause of visual impairment for the elderly in developed countries. It is a complex, multifactorial, progressive disease with diverse molecular pathways regulating its pathogenesis. One of the cardinal features of the early clinical subtype of AMD is the accumulation of lipid- and protein-rich deposits within Bruch's membrane, called drusen, which can be visualized by fundus imaging. Currently, multiple in vitro and in vivo model systems exist, which can be used to help tease out mechanisms associated with different molecular pathways driving disease initiation and progression. Given the lack of treatments for patients suffering from the dry form of AMD, it is imperative to appreciate the different known morphological endpoints associated with the various pathogenic pathways, in order to derive further insights, for the ultimate purpose of disease modeling and development of effective therapeutic interventions.
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Automatic Anisotropic Diffusion Filtering and Graph-search Segmentation of Macular Spectral-domain Optical Coherence Tomographic (SD-OCT) Images.
Usha, A, Shajil, N, Sasikala, M
Current medical imaging reviews. 2019;(3):308-318
Abstract
BACKGROUND Optical Coherence Tomography (OCT) is a non-invasive medical imaging technique that provides high-resolution cross-sectional images of the retina. There is a need to develop algorithms for obtaining quantitative and qualitative information about the retina which are essential for assessing and managing eye conditions. METHODS This work emphasizes on an automated image processing algorithm for segmenting retinal layers. It involves preprocessing of the acquired retinal SD-OCT image (B-scan) using the proposed automatic Anisotropic diffusion filter, followed with contrast stretching to suppress intrinsic speckle noise without blurring structural edges. Graph search segmentation using Dijkstra algorithm with a combination of threshold and axial gradient as the cost function is used to segment the retinal layer boundaries. RESULTS The algorithm was performed and the average thickness of the segmented retina was computed for the 3D retinal scan (128 B-scans) of 8 subjects (4 normal and 4 abnormal) using Early Treatment Diabetic Retinopathy Screening (ETDRS) chart. CONCLUSION Segmentation was evaluated using manually segmented B-scan by an Ophthalmologist as ground truth and accuracy was found to be 99.14 ± 0.27%.