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Challenges in studying geographic atrophy(GA) age-related macular degeneration: the potential of a new mouse model with GA-like features

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Neural Regeneration Research 2020年第5期15卷 863-864页

作者： J. Arjuna Ratnayaka andrew J. lotery Clinical and Experimental Sciences Faculty of MedicineUniversity of SouthamptonSouthamptonUK Eye Unit University Hospital Southampton NHS Foundation TrustSouthamptonUK

Loss of central vision critical to everyday activities such as reading,face-recognition and driving due to damage in the central retina (the macula) is the leading cause of irreversible blindness amongst adults in the developed *** condition,termed age-related macular degeneration (AMD),is a complex,chronic degenerative disease driven by a combination of genetic and lifestyle risk *** signs of retinal changes in people as young as 30–40 years have been reported,although these individuals appear to be ***,by the age of 65,the disease is present in ~3% of individuals,which increases dramatically to affect 1/3 of individuals by the eighth decade of *** to intermediate AMD is estimated to affect ~150 million individuals globally,with another 10 million individuals suffering from end-stage,sight-threatening *** terminal stages are broadly grouped into dry (geographic atrophy,GA) or wet (choroidal neovascular,CNV) AMD (Sarks et al.,1988;Bird et al.,2014),with similar frequencies reported in *** advances in identifying genetic risk factors,including our discoveries in this field,indicate an initial shared pathology before progressing to aforementioned late-stage ***,GA patients have no effective treatment,which may in part be due to the lack of good in vivo models for GA ***,we summarize our new findings that describe an altogether new mouse model with GA-like features which shows progressive outer retinal pathology (Ibbett et al.,2019) that can be used to gain novel insights into GA and potentially as a tool for drug development.

关键词： macula central vision degenerative disease

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Fixed bimonthly aflibercept in nave and switched neovascular age-related macular degeneration patients:one year outcomes

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International Journal of Ophthalmology(English edition) 2016年第8期9卷 1156-1162页

作者： Alasdair N Warwick Hannah H Leaver andrew J lotery Srini V Goverdhan Clinical Neurosciences Research Group Clinical and Experimental Sciences Faculty of Medicine University of Southampton Southampton Eye Unit University Hospital Southampton NHS Foundation Trust

AIM: To determine real life clinical outcomes in poorly responsive and treatment-nave neovascular age-related macular degeneration(nv AMD) patients using bimonthly fixed dosing aflibercept ***: This was a retrospective study of 165 eyes with nv AMD started on aflibercept at Southampton Eye Unit between June 2013 and June 2014. Patients were either switched from pro re nata(PRN) ranibizumab/bevacizumab due to poor response(107 eyes), or treatment- nave( 58 eyes). Patients initially received 3-monthly intravitreal aflibercept injections followed by 2-monthly fixed doses. Clinic visits were scheduled at month 0, 4, 10 and 12. Mean change in best-corrected visual acuity(BCVA) and central retinal thickness(CRT)from baseline were assessed using the Wilcoxon signedrank test. The proportion of patients maintaining BCVA(<15 letters loss) at 12 mo was also ***: Mean BCVA change at month 12 was +3.29 and +4.67 letters in the switched and nave aflibercept groups respectively(P <0.01). BCVA was maintained in 95.3% of switched and 96.6% of nave patients. CRT at month 12 showed a decrease of -6.16 μm in the switched group and -35.36 μm in the nave group(P <0.01).Patients previously treated with ranibizumab/bevacizumab had on average received 7.4 ranibizumab/bevacizumab injections over 12.6 mo, attending 10 clinic visits. The fixed dosing aflibercept regimen required an average of 7.1 injections(nave group), 7.5 injections(switched group) and 4 clinic visits per ***: Fixed bimonthly aflibercept is effective in both treatment-nave and poorly responsive nv AMD patients. Adopting a fixed dosing regimen can reduce patient burden without compromising on outcomes.

关键词： age-related macular degeneration ranibizumab aflibercept anti-vascular endothelial growth factor

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The complexities underlying age-related macular degeneration： could amyloid beta play an important role？

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Neural Regeneration Research 2017年第4期12卷 538-548页

作者： Savannah A. Lynn Eloise Keeling Rosie Munday Gagandeep Gabha Helen Griffiths andrew J.lotery J.Arjuna Ratnayaka Clinical and Experimental Sciences Faculty of Medicine University of Southampton Southampton United Kingdom Eye Unit University Southampton NHS Trust Southampton United Kingdom

e-related macular degeneration （AMD） causes irreversible loss of central vision for which there is no effective treatment. Incipient pathology is thought to occur in the retina for many years before AMD manifests from midlife onwards to affect a large proportion of the elderly. Although genetic as well as non-genetic/environmental risks are recognized, its complex aetiology makes it difficult to identify susceptibility, or indeed what type of AMD develops or how quickly it progresses in different individuals. Here we summarize the literature describing how the Alzheimer＇s-linked amyloid beta （Aβ） group of misfolding proteins accumulate in the retina. The discovery of this key driver of Alzheimer＇s disease in the senescent retina was unexpected and surprising, enabling an altogether different perspective of AMD. We argue that Aβ fundamentally differs from other substances which accumulate in the ageing retina, and discuss our latest findings from a mouse model in which physiological amounts of Aβ were subretinally-injected to recapitulate salient features of early AMD within a short period. Our discoveries as well as those of others suggest the pattern of Aβ accumulation and pathology in donor aged/AMD tissues are closely reproduced in mice, including late-stage AMD phenotypes, which makes them highly attractive to study dynamic aspects of Aβ-mediated retinopathy. Furthermore, we discuss our findings revealing how Aβ behaves at single-cell resolution, and consider the long-term implications for neuroretinal function. We propose Aβ as a key element in switching to a diseased retinal phenotype, which is now being used as a biomarker for latestage AMD.

关键词： amyloid beta (Aβ) retinal neurons retina mouse models age related macular degeneration(AMD)

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Long term follow-up of a family with GUCY2D dominant cone dystrophy

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International Journal of Ophthalmology(English edition) 2018年第12期11卷 1945-1950页

作者： Georgios Tsokolas Hussein Almuhtaseb Helen Griffiths Fatima Shawkat Reuben J.Pengelly Sarah Ennis andrew lotery Clinical and Experimental Sciences University of Southampton Eye Unit University Hospital Southampton Human Genetics & Genomic Medicine Faculty of Medicine University of Southampton

AIM: To describe long term follow-up in a family with GUCY2D dominant cone dystrophy. METHODS: Optical coherence tomography scans and fundus autofluorescence images were obtained. Flash and pattern electroretinograms(ERGs) and occipital pattern reversal visual evoked potentials were recorded. RESULTS: Two members of the same family(father and son) were identified to have the heterozygous R838 C mutation in the GUCY2D gene. The father presented at the age of 45 with bilateral bull’s eye maculopathy and temporal disc pallor. Over 13 y of serial follow up visits, the bull’s eye maculopathy progressed gradually into macular atrophy. Electrophysiological tests were significantly degraded suggesting poor macular function. Spectraldomain optical coherence tomography(SD-OCT) scans showed progressive loss and disruption of the ellipsoid layer at the foveal level. His son presented at the age of 16 with bilateral granular retinal pigment epithelial changes in both maculae. Electrophysiological testing was initially borderline normal but has gradually deteriorated to show reduced cone ERGs and macula function. SD-OCT demonstrated gradual macular thinning and atrophy bilaterally. Unlike his father, there was no disruption of the ellipsoid ***: Both family members exhibited gradual changes in their fundi, electrophysiological testing and multimodal imaging. Changes were milder than those observed in other mutations of the same gene.

关键词： autofluorescence electroretinogram cone dystrophy cone-rod dystrophy GUCY2D spectral-domain optical coherence tomography visual evoked potential

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杂合子GUCY2D突变的Leber先天性黑蒙患者父母的视网膜电图异常

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美国医学会眼科杂志（中文版） 2003年第3期15卷 179-179页

作者： RobertK.Koenekoop GeraldA.Fishman Alessandrolannaccone HanyEzzeldin MariaL.Ciccarelli AlfonsoBaldi JanetS.Sunness andrewJ.lotery MonicaM.Jablonski StevenJ.Pittler IreneMaumenee 孙岩秀

背景：Leber先天性黑蒙(LCA)是一种罕见的视网膜色素变性的先天类型，具有明显的基因和临床异质性。1996年以来，已经发现了该病的10种基因。未来，LCA可以通过基因和药物干预治疗，这些治疗可以是基因特异性的，对于快速基因鉴定和基... 详细信息

背景：Leber先天性黑蒙(LCA)是一种罕见的视网膜色素变性的先天类型，具有明显的基因和临床异质性。1996年以来，已经发现了该病的10种基因。未来，LCA可以通过基因和药物干预治疗，这些治疗可以是基因特异性的，对于快速基因鉴定和基因表型分析有重要意义。

关键词：杂合子 GUCY2D 基因突变 Leber先天性黑蒙父母视网膜电图异常视网膜色素变性

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