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The angopoietin/tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Ang/Tie) pathway is an emerging key regulator in vascular development and maintenance. Its relevance to clinicians and basic scientists as a potential therapeutic target in retinal and choroidal vascular diseases is highlighted by recent preclinical and clinical evidence. The Ang/Tie pathway plays an important role in the regulation of vascular stability, in angiogenesis under physiological and pathological conditions, as well as in inflammation. Under physiological conditions, angiopoietin-1 (Ang-1) binds to and phosphorylates the Tie2 receptor, leading to downstream signalling that promotes cell survival and vascular stability. Angiopoietin-2 (Ang-2) is upregulated under pathological conditions and acts as a context-dependent agonist/antagonist of the Ang-1/Tie2 axis, causing vascular destabilisation and sensitising blood vessels to the effects of vascular endothelial growth factor-A (VEGF-A). Ang-2 and VEGF-A synergistically drive vascular leakage, neovascularisation and inflammation, key components of retinal vascular diseases. Preclinical evidence suggests that modulating the Ang/Tie pathway restores vascular stabilisation and reduces inflammation. This review discusses how targeting the Ang/Tie pathway or applying Ang-2/VEGF-A combination therapy may be a valuable therapeutic strategy for restoring vascular stability and reducing inflammation in the treatment of retinal and choroidal vascular diseases.摘要: 本篇文章是关于不同照明条件对原发性开角型青光眼 (POAG) 患者视力和生活质量影响的研究的系统回顾。研究对CINAHL, MEDLINE, PsycARTICLES, PsycINFO, Embase and Ovid Nursing Database六个数据库进行系统文献检索, 截止发表日期为2019年4月。检索内容包括诊断为POAG的患者, 在变换照明设备/光照水平或炫光的情况下评估人群的视功能和生活质量。两名研究者独立筛选符合标准的受试者。从实验设计, 入选者标准, 结果与结论中挑选合格的研究并提取数据。入选研究的质量经过了严格的评估。在8437项研究中, 共有56项研究符合入选标准。在POAG患者中调查光照对以下因素的影响: 生活质量 (18/56),心理物理学干预 (16/56), 功能性视力 (10/56), 日常活动 (10/56) 和定性发现 (2/56)。POAG会影响患者的低亮度对比敏感度, 炫光症状, 暗适应的时间和程度。在视觉生活质量调查问卷中, 根据POAG患者反馈, 照明设备, 炫光和暗适应的问题较其它问题更多见。这些问题随着进行性视野的缺失而严重, 与同年龄对照组相比(AMC), POAG患者在发病的早期在低亮度和不同亮度切换的环境中会面临更多的困难, 这对之前POAG患者早期阶段没有症状的认知进行了挑战。但是, 基于性能方面的研究很少显示POAG参与者和AMC在模拟非最佳照明条件下日常活动方面有显着差异。 需要对较大的样本进行进一步研究, 以优化环境照明和面向任务的照明, 以支持患者适应POAG。未来亟待大样本的研究为POAG患者提供优化环境和适合工作的照明。.

PURPOSE To provide a concise overview for ophthalmologists and practicing retina specialists of available clinical evidence of manipulating the angiopoietin/tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains (Tie) pathway and its potential as a therapeutic target in retinal vascular diseases. METHODS A literature search for articles on the angiopoietin/Tie pathway and molecules targeting this pathway that have reached Phase 2 or 3 trials was undertaken on PubMed, Association for Research in Vision and Ophthalmology meeting abstracts (2014-2019), and ClinicalTrials.gov databases. Additional information on identified pipeline drugs was obtained from publicly available information on company websites. RESULTS The PubMed and Association for Research in Vision and Ophthalmology meeting abstract search yielded 462 results, of which 251 publications not relevant to the scope of the review were excluded. Of the 141 trials related to the angiopoietin/Tie pathway on ClinicalTrials.gov, seven trials focusing on diseases covered in this review were selected. Vision/anatomic outcomes from key clinical trials on molecules targeting the angiopoietin/Tie pathway in patients with retinal vascular diseases are discussed. CONCLUSION Initial clinical evidence suggests a potential benefit of targeting the angiopoietin/Tie pathway and vascular endothelial growth factor-A over anti-vascular endothelial growth factor-A monotherapy alone, in part due to of the synergistic nature of the pathways.

A 59-year-old man who complained of binocular vertical diplopia after an exploratory laparotomy, complicated by cardiorespiratory arrest during anesthetic induction, was found to have Collier's sign, anisocoria, complete paralysis of upward vertical gaze associated with convergence-retraction nystagmus on attempted upgaze and skew deviation with hypertropia in the left eye without ptosis, and an absent Bielschowsky sign. Magnetic resonance imaging of the brain showed a small lesion in the left paramedian midbrain compatible with microvascular ischemic sequelae. This patient was diagnosed with Parinaud's syndrome (dorsal midbrain syndrome) associated with a vertical strabismus from an unilateral vascular ischemic paramedian midbrain lesion.

The retina consists of organized layers of photoreceptors, interneurons, glia, epithelial cells, and endothelial cells. The economic model of supply and demand used to appropriately determine cost is highly applicable to the retina, in which the extreme metabolic demands of phototransduction are met by precisely localized and designed vascular networks. Proper development and maintenance of these networks is critical to normal visual function; dysregulation is characteristic of several devastating human diseases, including but not limited to age-related macular degeneration and diabetic retinopathy. In this article, we focus on the lessons learned from the study of retinal vascular development and how these lessons can be used to better maintain adult vascular networks and prevent retinal diseases. We then outline the vasculotrophic contributions from neurons, retinal pigment epithelium (RPE) cells, and glia (specifically microglia) before we shift our focus to pathology to provide molecular contexts for neovascular retinal diseases. Finally, we conclude with a discussion that applies what we have learned about how retinal cells interact with the vasculature to identify and validate therapeutic approaches for neurovascular disease of the retina.

Purpose: To evaluate ganglion cell layer (GCL) and ganglion cell complex (GCC) thickness manually by spectral-domain optical coherence tomography in subjects with early and intermediate age-related macular degeneration (AMD) in 12 locations on the horizontal meridian. Methods: A total of 450 eyes (specifically, 246 eyes classified as having early/intermediate AMD plus 204 control eyes) were studied. Mann-Whitney U and Kruskal-Wallis tests were used to compare values between the healthy controls and the AMD group and also between the subgroups under study. Diagnostic performance was also compared calculating the areas under the receiver operating characteristic curve. Results: The manual layer segmentation showed clear boundaries between the GCL and the GCC. It was in the temporal GCC that more changes were found. Conclusions: The GCC, especially in the temporal region, allowed the discrimination of differences between various subgroups that have faint variations as well as between early AMD and the first signs of aging.

Photoreceptors are the most numerous and metabolically demanding cells in the retina. Their primary nutrient source is the choriocapillaris, and both the choriocapillaris and photoreceptors require trophic and functional support from retinal pigment epithelium (RPE) cells. Defects in RPE, photoreceptors, and the choriocapillaris are characteristic of age-related macular degeneration (AMD), a common vision-threatening disease. RPE dysfunction or death is a primary event in AMD, but the combination(s) of cellular stresses that affect the function and survival of RPE are incompletely understood. Here, using mouse models in which hypoxia can be genetically triggered in RPE, we show that hypoxia-induced metabolic stress alone leads to photoreceptor atrophy. Glucose and lipid metabolism are radically altered in hypoxic RPE cells; these changes impact nutrient availability for the sensory retina and promote progressive photoreceptor degeneration. Understanding the molecular pathways that control these responses may provide important clues about AMD pathogenesis and inform future therapies. DOI: http://dx.doi.org/10.7554/eLife.14319.001, eLife digest Cells use a sugar called glucose as fuel to provide energy for many essential processes. The light-sensing cells in the eye, known as photoreceptors, need tremendous amounts of glucose, which they receive from the blood with the help of neighboring cells called retinal pigment epithelium (RPE) cells. Without a reliable supply of this sugar, the photoreceptors die and vision is lost. As we age, we are at greater risk of vision loss because RPE cells become less efficient at transporting glucose and our blood vessels shrink so that the photoreceptors may become starved of glucose. To prevent age-related vision loss, we need new strategies to keep blood vessels and RPE cells healthy. However, it was not clear exactly how RPE cells supply photoreceptors with glucose, and what happens when blood supplies are reduced. To address this question, Kurihara, Westenskow et al. used genetically modified mice to investigate how cells in the eye respond to starvation. The experiments show that when nutrients are scarce the RPE cells essentially panic, radically change their diet, and become greedy. That is to say that they double in size and begin burning fuel faster while also stockpiling extra sugar and fat for later use. In turn, the photoreceptors don’t get the energy they need and so they slowly stop working and die. Kurihara, Westenskow et al. also show that there is a rapid change in the way in which sugar and fat are processed in the eye during starvation. Learning how to prevent these changes in patients with age-related vision loss could protect their photoreceptors from starvation and death. The next step following on from this research is to design drugs to improve the supply of glucose and nutrients to the photoreceptors by repairing aging blood vessels and/or preventing RPE cells from stockpiling glucose for themselves. DOI: http://dx.doi.org/10.7554/eLife.14319.002

Fluorocarbons are lipophobic and non-polar molecules that exhibit remarkable bio-compatibility, with applications in liquid ventilation and synthetic blood. The unique properties of these compounds have also enabled mass spectrometry imaging of tissues where the fluorocarbons act as a Teflon-like coating for nanostructured surfaces to assist in desorption/ionization. Here we report fluorinated gold nanoparticles (f-AuNPs) designed to facilitate nanostructure imaging mass spectrometry. Irradiation of f-AuNPs results in the release of the fluorocarbon ligands providing a driving force for analyte desorption. The f-AuNPs allow for the mass spectrometry analysis of both lipophilic and polar (central carbon) metabolites. An important property of AuNPs is that they also act as contrast agents for X-ray microtomography and electron microscopy, a feature we have exploited by infusing f-AuNPs into tissue via fluorocarbon liquids to facilitate multi-modal (molecular and anatomical) imaging.

Wolfram syndrome type 1 is a rare, autosomal recessive, neurodegenerative disorder that is diagnosed when insulin-dependent diabetes of non-auto-immune origin and optic atrophy are concomitantly present. Wolfram syndrome is also designated by DIDMOAD that stands for its most frequent manifestations: diabetes insipidus, diabetes mellitus, optic atrophy and deafness. With disease progression, patients also commonly develop severe neurological and genito-urinary tract abnormalities. When compared to the general type 1 diabetic population, patients with Wolfram Syndrome have been reported to have a form of diabetes that is more easily controlled and with less microvascular complications, such as diabetic retinopathy. We report a case of Wolfram syndrome in a 16-year-old male patient who presented with progressive optic atrophy and severe diabetes with very challenging glycemic control despite intensive therapy since diagnosis at the age of 6. Despite inadequate metabolic control he did not develop any diabetic microvascular complications during the 10-year follow-up period. To further investigate potential causes for this metabolic idiosyncrasy, we performed genetic analyses that revealed a novel combination of homozygous sequence variants that are likely the cause of the syndrome in this family. The identified genotype included a novel sequence variant in the Wolfram syndrome type 1 gene along with a previously described one, which had initially been associated with isolated low frequency sensorineural hearing loss (LFSNHL). Interestingly, our patient did not show any abnormal findings with audiometry testing.