Retinal Responses Research Articles

The relationship between disorganitazion of the retinal inner layers and anti-vegf response in branch retinal vein occlusion

The relationship between disorganitazion of the retinal inner layers and anti-vegf response in branch retinal vein occlusion

Clinical Implications

HomeHypertensionVol. 75, No. 1Clinical Implications Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBClinical Implications Originally published11 Dec 2019https://doi.org/10.1161/HYPERTENSIONAHA.119.14339Hypertension. 2020;75:2is related toImportance of Early Diagnosis in Peripartum CardiomyopathyMicrovascular Dysfunction Is Associated With Worse Cognitive PerformanceHigh Blood Pressure in Young Adult Survivors Born Extremely Preterm or Extremely Low Birthweight in the Post Surfactant EraHigh Blood Pressure in Young Adults Born Preterm (page 211)Download figureDownload PowerPointInfants who were born extremely preterm (EP; <28 weeks’ gestation) or extremely low birthweight (ELBW; <1000 g) are now surviving into adulthood in increasing numbers. In our study, young adults born EP/ELBW in the early 1990s had substantially elevated blood pressure at 25 years of age compared with controls (>2499 g at birth), with higher proportions in the hypertensive range. Importantly, blood pressure increased more in the EP/ELBW group between 18 and 25 years compared with controls. Our findings have several important clinical implications. Health care professionals, families of EP/ELBW infants, and the survivors themselves should all be aware of the increased risk for high blood pressure in those born EP/ELBW. Taking a complete perinatal history, including gestational age and birthweight, and offering blood pressure measurements, along with advocating for a healthy lifestyle, are recommended when patients born EP/ELBW present for a health check-up. An early, simple proactive approach in the timely identification and control of high blood pressure may lead to improved long-term cardiovascular outcomes in this rapidly growing at-risk population of young adults.Microvascular Damage May Impair Cognitive Function (page 237)Download figureDownload PowerPointCognitive impairment and dementia are major health problems and their prevalence rises with the aging of the population. The mechanisms underlying cognitive impairment remain, however, incompletely understood, and may include microvascular dysfunction and damage. The microvasculature is involved in the regulation of many cerebral processes, notably neurovascular coupling, cerebral autoregulation, and blood-brain barrier permeability. Impairment of these processes may lead to neuronal dysfunction and contribute to cognitive decline. However, evidence for an association between microvascular dysfunction and worse cognitive performance is limited. We therefore used cross-sectional data from the large population-based Maastricht Study to test whether microvascular dysfunction is associated with worse cognitive function. Measures of microvascular dysfunction included magnetic resonance imaging features of cerebral small vessel disease, plasma biomarkers of microvascular dysfunction, albuminuria, flicker light-induced retinal arteriolar and venular dilation response and heat-induced skin hyperemia. These measures were summarized into a microvascular dysfunction composite score. Cognitive domains assessed were memory, processing speed, and executive function. The results showed an association between microvascular dysfunction and worse cognitive performance independent of a large set of potential confounders. These findings support the hypothesis that microvascular dysfunction contributes to the development of cognitive impairment and suggest that microvascular dysfunction may be a target for prevention strategies of cognitive impairment. Future longitudinal studies are needed to further evaluate the association of microvascular dysfunction and cognitive decline and dementia.Early Diagnosis and PPCM Recovery (page 91)Download figureDownload PowerPointPeripartum cardiomyopathy (PPCM) is an often severe form of cardiomyopathy diagnosed towards the end of pregnancy or in the months after delivery. Most women will recover, however, a significant percentage experience persistent cardiomyopathy. Hypertensive disorders of pregnancy (HDP) such as preeclampsia are one of the strongest risk factors for PPCM and share a common pathophysiological mechanism. The rapid resolution of angiogenic imbalance in preeclampsia may lead to faster recovery in women with HDP and PPCM but controversy remains on whether HDP predict a favorable outcome. Timing of diagnosis and race may confound this relationship, as black women are more likely to be diagnosed with HDP, less likely to recover, and more likely to be diagnosed later in the postpartum period. In this single-center study of 220 women with PPCM, patients with HDP were diagnosed earlier postpartum than patients without HDP, an effect that was most pronounced in nonblack patients. Hypertensive disorders of pregnancy were not associated with improved recovery rates. In contrast, early diagnosis (<1-month postpartum) was associated with improved recovery compared to women diagnosed later in the postpartum period. These findings were consistent among black and nonblack women. Notably, women diagnosed early had less severe LV dysfunction, which likely explains the association between early diagnosis and improved outcomes. Improving the early diagnosis of PPCM in at-risk women may improve clinical outcomes in traditionally underserved populations. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesImportance of Early Diagnosis in Peripartum CardiomyopathyJennifer Lewey, et al. Hypertension. 2020;75:91-97Microvascular Dysfunction Is Associated With Worse Cognitive PerformanceSytze P. Rensma, et al. Hypertension. 2020;75:237-245High Blood Pressure in Young Adult Survivors Born Extremely Preterm or Extremely Low Birthweight in the Post Surfactant EraAnjali Haikerwal, et al. Hypertension. 2020;75:211-217 January 2020Vol 75, Issue 1 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.119.14339PMID: 31825745 Originally publishedDecember 11, 2019 PDF download Advertisement

Возрастная динамика функционального состояния сетчатки у мышей с наследственной дегенерацией фоторецепторов

C3H mice with a mutation in the Pde6b gene are a standard model object for studying inherited retinal pathologies. These animals lack the function of rod-specific phosphodiesterase, which leads to the photoreceptors’ death and complete vision loss by 4 weeks of age. It was also shown that in C3H mice, originating from Charles River Laboratories - the C3H/Crl strain - there is an additional mutation in the Gpr179 gene, which leads to disruption of the ON-bipolar retinal cell transduction cascade. Despite the wide distribution of C3H/Crl mice as research objects, a detailed study of their process of photoreceptor degeneration and its features has never been performed yet. Our work aimed to investigate the age-related dynamics of morphological and functional changes occurring in the retinas of C3H/Crl mice in early life. Wild-type mice, the C57Bl/6J strain, were taken as a control group. To assess the functional state of the retina, we used the in vivo electroretinography method; morphological analysis was performed on histological preparations of eye tissues. Our study has shown that retinal responses to light stimulation of C3H/Crl mice lack the contribution of rods and ON-bipolar cells during the entire measurement period, starting from the 18th day of life, while cone-derived response disappears by the 25th day. The number of photoreceptors and neurons of the retinal inner nuclear layer in C3H/Crl mice retina is reduced, and by the 25th day of life, photoreceptor degeneration proceeds. At the same time, it was shown that the response amplitude and sensitivity of wild-type mice retina do not undergo significant changes during early life. Our data make it possible to make an insight into the development of retinal pathology in C3H/Crl strain.

CoPP-Induced-Induced HO-1 Overexpression Alleviates Photoreceptor Degeneration With Rapid Dynamics: A Therapeutic Molecular Against Retinopathy.

Retinitis pigmentosa (RP) causes progressive photoreceptor degeneration in the retina. The N-methyl-N-nitrosourea (MNU)-administered mouse is used as a chemically induced RP model with rapid progression rate. This study was designed to study heme oxygenase-1 (HO-1) expression in the MNU-administered mice, and to explore the therapeutic effects of cobalt protoporphyrin (CoPP). The HO-1 expression in the retina of MNU-administered mice was analyzed. CoPP was injected intravenously into the MNU-administered mice. Subsequently, the CoPP-treated mice were subjected to functional and morphologic examinations. HO-1 was involved in the MNU-induced photoreceptor degeneration. CoPP treatment enhanced retinal HO-1 expression in the MNU-administered mice. Electroretinogram (ERG) examination and behavioral tests showed that CoPP treatment improved the retinal responsiveness of MNU-administered mice. Histologic analysis and optical coherence tomography (OCT) examination showed that retinal architecture of the CoPP-treated mice was more intact than that of the MNU+vehicle group. Cone photoreceptors in the MNU-administered mice were rescued efficiently by CoPP treatment. Furthermore, multielectrode array (MEA) recording showed that CoPP treatment mitigated the spontaneous firing response, enhanced the light-induced firing response, and preserved the basic configurations of visual signal pathway in the MNU-administered mice. Mechanism studies suggested that CoPP afforded these therapeutic effects by modulating the apoptosis cascades and alleviating the oxidative stress in degenerative retinas. CoPP alleviated photoreceptor degeneration and rectified the signaling abnormities in MNU-administered mice. CoPP may serve as a potential medication against degenerative retinopathy.

Global-flash mfERG responses to local differences in spherical and astigmatic defocus across the human retina.

Emmetropisation is essentially a visually guided, within-eye process. We investigated differences in global-flash multifocal electroretinogram (gmfERG) responses to naturally occurring differences in spherical and astigmatic defocus across the retina, which might provide a basis for guiding eye growth. Experiment 1: The gmfERG responses (direct, DC, and induced, IC, amplitudes and latencies) recorded simultaneously from six retinal areas (15° eccentricity, spaced at 60°, areas 3.2°2 ) were correlated with the uncorrected retinal defocus measured at the six corresponding retinal locations in 20 adults with foveal refractive errors (-4.75 to +1.25D). No correcting lenses were used to avoid introduction of lens-induced aberrations and magnification. Experiment 2 investigated the effect of superimposing astigmatic defocus (+2.00/-4.00D Jackson Cross Cylinder presented at four orientations) on gmfERG responses. Experiment 1: DC and IC response amplitudes were greater in retinal regions naturally exposed to more hyperopic spherical defocus (DC: rho=0.26, p=0.005; IC: rho=0.29, p=0.001), but response latencies were unaffected by sign or magnitude of spherical defocus (DC: p=0.34; IC: p=0.40). Response amplitudes and latencies were unaffected by astigmatic defocus. Experiment 2: Rotating the JCC axis to four different orientations had no effect on the gmfERG responses (DC amplitude, p=0.39; DC latency, p=0.10; IC amplitude, p=0.51; IC latency, p=0.64). The gmfERG responses from discrete retinal areas varied with the sign and magnitude of local spherical defocus, but we found no evidence that retinal responses were affected by astigmatic defocus. Therefore, local astigmatism is unlikely to provide cues for controlling eye growth, whereas differences in response to spherical defocus between different retinal regions could potentially provide cues for controlling eye growth in emmetropisation.

Label-free tracking of single blood cells in the retinal immune response

Label-free tracking of single blood cells in the retinal immune response

Microvascular Dysfunction Is Associated With Worse Cognitive Performance: The Maastricht Study.

Microvascular dysfunction may be associated with worse cognitive performance. Most previous studies did not adjust for important confounders, evaluated only individual measures of microvascular dysfunction, and showed inconsistent results. We evaluated the association between a comprehensive set of measures of microvascular dysfunction and cognitive performance in the population-based Maastricht Study. We used cross-sectional data including 3011 participants (age 59.5±8.2; 48.9% women; 26.5% type 2 diabetes mellitus [oversampled by design]). Measures of microvascular dysfunction included magnetic resonance imaging features of cerebral small vessel disease, plasma biomarkers of microvascular dysfunction, albuminuria, flicker light-induced retinal arteriolar and venular dilation response and heat-induced skin hyperemia. These measures were summarized into a microvascular dysfunction composite score. Cognitive domains assessed were memory, processing speed, and executive function. A cognitive function score was calculated as the sum of the scores on these 3 cognitive domains. The microvascular dysfunction score was associated with a worse cognitive function score (standardized β, -0.087 [95% CI, -0.127 to -0.047]), independent of age, education level, sex, type 2 diabetes mellitus, smoking, alcohol use, hypertension, total/HDL (high-density lipoprotein) cholesterol ratio, triglycerides, lipid-modifying medication, prior cardiovascular disease, depression and plasma biomarkers of low-grade inflammation. The fully adjusted β-coefficient of the association between the microvascular dysfunction score and the cognitive function score was equivalent to 2 (range, 1-3) years of aging for each SD higher microvascular dysfunction score. The microvascular dysfunction score was associated with worse memory and processing speed but not with worse executive function. The present study shows that microvascular dysfunction is associated with worse cognitive performance.

Multidisciplinary Study Based on Clinical, Electrophysiological and Psycological Evaluations Combined with Advanced Neuroimaging in Gaucher Disease Patients

Gaucher Disease (GD) is an autosomal recessive metabolic disorder due to glucocerebrosidase deficit. There are three main clinical phenotypes: type I (GD1: non-neuronopathic form), characterized by a visceral involvement that can mimic a hematologic disease; type II (GD2: acute neuropathic form) and type III (GD3) characterized by a slower and progressive neurological involvement. Hematologists have often involved in diagnosis and management of the GD1 patients. Increasing data and our experience show that patients with GD1 may present manifestations of Parkinson's disease or Parkinsonism symptoms (tremor, bradykinesia and rigidity), frequently combined with cognitive impairment and behavioral alterations. The aim of this study is to deeply investigate the neurological and neuropsychiatric aspects in GD1 patients in order to identify clinical and subclinical neurological manifestations, including cognitive impairment and behavioral alterations in this category of patients. This observational, monocentric, and prospective study is planned to enroll 22 GD patients (19 GD1 patients and 3 GD3 patients with or without active neurological signs) aged &gt;12 years. Neurological assessments include: clinical evaluation including Severity Scoring Tool Unified Parkinson's Disease Rating scale and Epworth Sleepiness scale, psycho-diagnostic tests and psychiatric evaluation using cognitive test battery and two psychiatric (BPRS) and psychological (CBA 2.0) questionnaires, Somatosensory and Motors Evoked Potentials, Electroencephalography (EEG) and magnetic resonance (MR) 3Tesla, at baseline, after 12 months and 24 months. Preliminary results concerning the baseline evaluation of first cohort of patients are here reported. Since June 2019, 11 patients (10 GD1 and 1 symptomatic GD3) have been enrolled. Neurological impairment according to the major features (Gaucher severity score tool) was found in 4/11 patients: signs of Parkinson disease in 1 GD1 patient, motoneuron disease in 1 GD3 patients, abnormalities in ocular motility and psycho-cognitive disturbances in 2 GD1 patients. Minor features of a neurological impairment was found as follows: bradykinesia in 5 GD1 patients, excessive daytime sleepiness in 5 GD1 patients, and saccadic slowness in 1 GD1 patient. EEG revealed focal or diffuse slow waves in 6 patien patients (5 GD1 and 1 GD3). Cognitive and psychological evaluations revealed the presence of significant psychiatric symptoms such as depression, anxiety, and physical concerns. Six patients (5 GD1and 1 GD3) surprisingly had sensorineural hearing loss. Auditory Brainstem Response revealed abnormal disyncrony-like morphology and central speech processing in noise in 3 GD1 and in 4 (3 GD1 and 1 GD3) patients, respectively. Ophthalmological evaluation highlighted a normal visus and intraocular pressure in all patients. Moderate alterations of the fundus were present in 2 patients (1 GD1 and 1 GD3) and superficial corneal dystrophies in 3 (2 GD1 and 1 GD3) patients. An increased latency and moderate reduction in the amplitudes of optic nerve function were found in all tested patients. The retinal responses to the Electroretinogram exam were of excellent quality in all but one GD1 patient, who showed slightly reduced responses. The spectral domain-optical coherence tomography (SD-OCT) examination showed posterior pole alterations in 3 patients (2 GD1 and 1 GD3) and borderline nerve fiber layers of the optic nerve (RNFL) in 3 (2 GD1 and 1 GD3) cases. Our clinical study represents quite an innovative one, since neurological investigations are focused on GD2 and GD3 phenotypes. Neurological involvement with different phenotypical aspects were also found in GD1 patients. Sensorineural hearing loss and central alteration of auditory processing were present in higher incidence compared to the unaffected population. Psychological data din't show significant cognitive impairments, but pointed out some psychiatric aspects, such as anxiety, depression and somatic concerns. MR 3Tesla can be an important tool to better understand these data. Evaluation of the remaining cohort of patients and longer follow-up could confirm that neurological involvement is not exclusive of the type 3 GD. Disclosures No relevant conflicts of interest to declare.

Apolipoprotein E Deficiency Causes Endothelial Dysfunction in the Mouse Retina.

Objective Atherogenic lipoproteins may impair vascular reactivity consecutively causing tissue damage in multiple organs via abnormal perfusion and excessive reactive oxygen species generation. We tested the hypothesis that chronic hypercholesterolemia causes endothelial dysfunction and cell loss in the retina. Methods Twelve-month-old apolipoprotein E-deficient (ApoE-/-) mice and age-matched wild-type controls were used in this study (n = 8 per genotype for each experiment). Intraocular pressure, blood pressure, and ocular perfusion pressure were determined. Retinal arteriole responses were studied in vitro, and reactive oxygen and nitrogen species were quantified in the retinal and optic nerve cryosections. The expression of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and the NADPH oxidase isoforms, NOX1, NOX2, and NOX4, were determined in retinal cryosections by immunofluorescence microscopy. Pro- and antioxidant redox genes were quantified in retinal explants by PCR. Moreover, cell number in the retinal ganglion cell layer and axon number in the optic nerve was calculated. Results Responses to the endothelium-dependent vasodilator, acetylcholine, were markedly impaired in retinal arterioles of ApoE-/- mice (P < 0.01). LOX-1 (P = 0.0007) and NOX2 (P = 0.0027) expressions as well as levels of reactive oxygen species (P = 0.0022) were increased in blood vessels but not in other retinal structures. In contrast, reactive nitrogen species were barely detectable in both mouse genotypes. Messenger RNA for HIF-1α, VEGF-A, NOX1, and NOX2, but also for various antioxidant redox genes was elevated in the retina of ApoE-/- mice. Total cell number in the retinal ganglion cell layer did not differ between ApoE-/- and wild-type mice (P = 0.2171). Also, axon number in the optic nerve did not differ between ApoE-/- and wild-type mice (P = 0.6435). Conclusion Apolipoprotein E deficiency induces oxidative stress and endothelial dysfunction in retinal arterioles, which may trigger hypoxia in the retinal tissue. Oxidative stress in nonvascular retinal tissue appears to be prevented by the upregulation of antioxidant redox enzymes, resulting in neuron preservation.

Metaheuristic Optimisation Algorithms for Tuning a Bioinspired Retinal Model.

A significant challenge in neuroscience is understanding how visual information is encoded in the retina. Such knowledge is extremely important for the purpose of designing bioinspired sensors and artificial retinal systems that will, in so far as may be possible, be capable of mimicking vertebrate retinal behaviour. In this study, we report the tuning of a reliable computational bioinspired retinal model with various algorithms to improve the mimicry of the model. Its main contribution is two-fold. First, given the multi-objective nature of the problem, an automatic multi-objective optimisation strategy is proposed through the use of four biological-based metrics, which are used to adjust the retinal model for accurate prediction of retinal ganglion cell responses. Second, a subset of population-based search heuristics—genetic algorithms (SPEA2, NSGA-II and NSGA-III), particle swarm optimisation (PSO) and differential evolution (DE)—are explored to identify the best algorithm for fine-tuning the retinal model, by comparing performance across a hypervolume metric. Nonparametric statistical tests are used to perform a rigorous comparison between all the metaheuristics. The best results were achieved with the PSO algorithm on the basis of the largest hypervolume that was achieved, well-distributed elements and high numbers on the Pareto front.

Abnormal Photic Entrainment to Phase-Delaying Stimuli in the R6/2 Mouse Model of Huntington's Disease, despite Retinal Responsiveness to Light.

The circadian clock located in the suprachiasmatic nucleus (SCN) in mammals entrains to ambient light via the retinal photoreceptors. This allows behavioral rhythms to change in synchrony with seasonal and daily changes in light period. Circadian rhythmicity is progressively disrupted in Huntington's disease (HD) and in HD mouse models such as the transgenic R6/2 line. Although retinal afferent inputs to the SCN are disrupted in R6/2 mice at late stages, they can respond to changes in light/dark cycles, as seen in jet lag and 23 h/d paradigms. To investigate photic entrainment and SCN function in R6/2 mice at different stages of disease, we first assessed the effect on locomotor activity of exposure to a 15 min light pulse given at different times of the day. We then placed the mice under five non-standard light conditions. These were light cycle regimes (T-cycles) of T21 (10.5 h light/dark), T22 (11 h light/dark), T26 (13 h light/dark), constant light, or constant dark. We found a progressive impairment in photic synchronization in R6/2 mice when the stimuli required the SCN to lengthen rhythms (phase-delaying light pulse, T26, or constant light), but normal synchronization to stimuli that required the SCN to shorten rhythms (phase-advancing light pulse and T22). Despite the behavioral abnormalities, we found that Per1 and c-fos gene expression remained photo-inducible in SCN of R6/2 mice. Both the endogenous drift of the R6/2 mouse SCN to shorter periods and its inability to adapt to phase-delaying changes will contribute to the HD circadian dysfunction.

Proteome and Secretome Dynamics of Human Retinal Pigment Epithelium in Response to Reactive Oxygen Species

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries, and is characterized by slow retinal degeneration linked to chronic reactive oxygen species (ROS) in the retinal pigmented epithelium (RPE). The molecular mechanisms leading to RPE dysfunction in response to ROS are unclear. Here, human stem cell-derived RPE samples were stressed with ROS for 1 or 3 weeks, and both intracellular and secreted proteomes were quantified by mass spectrometry. ROS increased glycolytic proteins but decreased mitochondrial complex I subunits, as well as membrane proteins required for endocytosis. RPE secreted over 1,000 proteins, many of which changed significantly due to ROS. Notably, secreted APOE is decreased 4-fold, and urotensin-II, the strongest known vasoconstrictor, doubled. Furthermore, secreted TGF-beta is increased, and its cognate signaler BMP1 decreased in the secretome. Together, our results paint a detailed molecular picture of the retinal stress response in space and time.

Zebrafish are Resistant to Staphylococcus aureus Endophthalmitis.

Gram-positive bacteria remain the leading cause of endophthalmitis, a blinding infectious disease of the eye. Murine models have been widely used for understanding the pathogenesis of bacterial endophthalmitis. In this study, we sought to develop an alternative zebrafish (Danio rerio) model for Staphylococcus aureus and compare the disease pathobiology to a murine model. Endophthalmitis was induced in zebrafish and C57BL/6 mice through the intravitreal injection of S. aureus. Disease progression was monitored by assessing corneal haze, opacity, bacterial burden, and retinal histology. Our results demonstrated that, unlike the murine models, zebrafish maintained ocular integrity, corneal transparency, and retinal architecture. We found that the zebrafish was capable of clearing S. aureus from the eye via transport through retinal vessels and the optic nerve and by mounting a monocyte/macrophage response beginning at 8 hour post-infection (hpi). The bacterial burden increased up to 8 hpi and significantly decreased thereafter. An assessment of the innate retinal response revealed the induced expression of Il-1β and Il-6 transcripts. Collectively, our study shows that unlike the murine model, zebrafish do not develop endophthalmitis and rapidly clear the pathogen. Hence, a better understanding of the zebrafish protective ocular innate response may provide new insights into the pathobiology of bacterial endophthalmitis.

VEGF-Trap is a potent modulator of vasoregenerative responses and protects dopaminergic amacrine network integrity in degenerative ischemic neovascular retinopathy.

Retinal hypoxia triggers abnormal vessel growth and microvascular hyper-permeability in ischemic retinopathies. Whereas vascular endothelial growth factor A (VEGF-A) inhibitors significantly hinder disease progression, their benefits to retinal neurons remain poorly understood. Similar to humans, oxygen-induced retinopathy (OIR) mice exhibit severe retinal microvascular malformations and profound neuronal dysfunction. OIR mice are thus a phenocopy of human retinopathy of prematurity, and a proxy for investigating advanced stages of proliferative diabetic retinopathy. Hence, the OIR model offers an excellent platform for assessing morpho-functional responses of the ischemic retina to anti-angiogenic therapies. Using this model, we investigated the retinal responses to VEGF-Trap (Aflibercept), an anti-angiogenic agent recognizing ligands of VEGF receptors 1 and 2 that possesses regulatory approval for the treatment of neovascular age-related macular degeneration, macular edema secondary to retinal vein occlusion and diabetic macular edema. Our results indicate that Aflibercept not only reduces the severity of retinal microvascular aberrations but also significantly improves neuroretinal function. Aflibercept administration significantly enhanced light-responsiveness, as revealed by electroretinographic examinations, and led to increased numbers of dopaminergic amacrine cells. Additionally, retinal transcriptional profiling revealed the concerted regulation of both angiogenic and neuronal targets, including transcripts encoding subunits of transmitter receptors relevant to amacrine cell function. Thus, Aflibercept represents a promising therapeutic alternative for the treatment of further progressive ischemic retinal neurovasculopathies beyond the set of disease conditions for which it has regulatory approval. Cover Image for this issue: doi: 10.1111/jnc.14743.

Intraocular VEGF deprivation induces degeneration and fibrogenic response in retina.

VEGF is a critical driver of ocular neovascularization under disease conditions. Current therapeutic strategies rely on intraocular delivery of VEGF-antagonizing reagents, which results in sustained suppression of pathogenic vascularization. Although significant advancement has been achieved in VEGF antagonism, substantial adverse effects have been reported in retrospective clinical studies. To study mechanisms for VEGF antagonism-associated adverse effects in visual system, we intravitreally delivered recombinant adeno-associated virus-mediated expression of soluble Fms-related tyrosine kinase-1 (rAAV.sFLT-1), the extracellular domain of VEGF receptor, and analyzed the morphology and functions of retinal tissue. Here, we confirmed that intraocular VEGF antagonism induced retinal degeneration and gliosis. The functional deficit in retinal response to visual stimulation was also demonstrated in rAAV.sFLT-1-treated eyes by electroretinogram. Moreover, high-throughput RNA sequencing analysis suggests that VEGF antagonism activates retinal degeneration, inflammation, and other adverse effects. Taken together, our findings have shed light on pathogenic mechanisms for VEGF antagonism-associated adverse effects and potential therapeutic targets.-Xiao, M., Liu, Y., Wang, L., Liang, J., Wang, T., Zhai, Y., Wang, Y., Liu, S., Liu, W., Luo, X., Wang, F., Sun, X. Intraocular VEGF deprivation induces degeneration and fibrogenic response in retina.

Response Latency Tuning by Retinal Circuits Modulates Signal Efficiency

In the visual system, retinal ganglion cells (RGCs) of various subtypes encode preprocessed photoreceptor signals into a spike output which is then transmitted towards the brain through parallel feature pathways. Spike timing determines how each feature signal contributes to the output of downstream neurons in visual brain centers, thereby influencing efficiency in visual perception. In this study, we demonstrate a marked population-wide variability in RGC response latency that is independent of trial-to-trial variability and recording approach. RGC response latencies to simple visual stimuli vary considerably in a heterogenous cell population but remain reliable when RGCs of a single subtype are compared. This subtype specificity, however, vanishes when the retinal circuitry is bypassed via direct RGC electrical stimulation. This suggests that latency is primarily determined by the signaling speed through retinal pathways that provide subtype specific inputs to RGCs. In addition, response latency is significantly altered when GABA inhibition or gap junction signaling is disturbed, which further supports the key role of retinal microcircuits in latency tuning. Finally, modulation of stimulus parameters affects individual RGC response delays considerably. Based on these findings, we hypothesize that retinal microcircuits fine-tune RGC response latency, which in turn determines the context-dependent weighing of each signal and its contribution to visual perception.

Retinal vessel caliber and caliber responses in true normotensive black and white adults: The African-PREDICT study

PurposeGlobally, a detrimental shift in cardiovascular disease risk factors and a higher mortality level are reported in some black populations. The retinal microvasculature provides early insight into the pathogenesis of systemic vascular diseases, but it is unclear whether retinal vessel calibers and acute retinal vessel functional responses differ between young healthy black and white adults. MethodsWe included 112 black and 143 white healthy normotensive adults (20–30 years). Retinal vessel calibers (central retinal artery and vein equivalent (CRAE and CRVE)) were calculated from retinal images and vessel caliber responses to flicker light induced provocation (FLIP) were determined. Additionally, ambulatory blood pressure (BP), anthropometry and blood samples were collected. ResultsThe groups displayed similar 24 h BP profiles and anthropometry (all p > .24). Black participants demonstrated a smaller CRAE (158 ± 11 vs. 164 ± 11 MU, p < .001) compared to the white group, whereas CRVE was similar (p = .57). In response to FLIP, artery maximal dilation was greater in the black vs. white group (5.6 ± 2.1 vs. 3.3 ± 1.8%; p < .001). ConclusionsAlready at a young age, healthy black adults showed narrower retinal arteries relative to the white population. Follow-up studies are underway to show if this will be related to increased risk for hypertension development. The reason for the larger vessel dilation responses to FLIP in the black population is unclear and warrants further investigation.

Electoretinographic evidence of retinal ganglion cell-dependent function in schizophrenia

Schizophrenia is a complex disorder that is diagnosed mainly with clinical observation and evaluation. Recent studies suggest that many people with schizophrenia have abnormalities in the function of the N-methyl-d-aspartate receptor (NMDAR). The retina is part of the central nervous system and expresses the NMDAR, raising the possibility of the early detection of NMDAR-related schizophrenia by detecting differences in retinal function. As a first-step, we used two non-invasive outpatient tests of retinal function, the photopic negative response (PhNR) of the light-adapted flash-electroretinogram (PhNR-fERG) and the pattern ERG (PERG), to test individuals with schizophrenia and controls to determine if there were measurable differences between the two populations. The PhNR-fERG showed that males with schizophrenia had a significant increase in the variability of the overall response, which was not seen in the females with schizophrenia. Additionally at the brightest flash strength, there were significant increases in the PhNR amplitude in people with schizophrenia that were maximal in controls. Our results show measurable dysfunction of retinal ganglion cells (RGCs) in schizophrenia using the PhNR-fERG, with a good deal of variability in the retinal responses of people with schizophrenia. The PhNR-fERG holds promise as a method to identify individuals more at risk for developing schizophrenia, and may help understand heterogeneity in etiology and response to treatment.

Revisiting the Safety of the Corneal Collagen Crosslinking Procedure: Evaluation of the Effect of Ultraviolet A Radiation on Retinal Function and Structure.

To evaluate the effect of ultraviolet A radiation on retinal function and structure after the corneal collagen crosslinking procedure. In the present prospective, single-center cohort study 17 eyes of 17 patients who underwent collagen crosslinking (Dresden protocol) for the treatment of corneal ectasia were examined preoperatively and at 2 and 6 weeks postoperatively with multifocal electroretinogram and optical coherence tomography. The P1 amplitude density (P1-AD) of the central retinal response was documented in 5 concentric rings, with ring 1 (R1) representing the foveal response and rings 2 to 5 (R2-R5) corresponding to successive annuli of stimulation. Visual acuity, corneal densitometry at the 0 to 2 mm zone and at the 2 to 6 mm annulus, and macular thickness (MT; central, 1 mm, 3 mm, and 5 mm zones) were recorded. The preoperative values of P1-AD were R1 = 109.96 ± 28.96, R2 = 49.8 ± 14.46, R3 = 29.85 ± 8.9, R4 = 19.33 ± 6.3, and R5 = 16.39 ± 5.48 nV/deg. At 2 weeks, these values were R1 = 77.54 ± 24.47, R2 = 36.55 ± 12.53, R3 = 21.53 ± 7.71, R4 = 15.3 ± 6.13, and R5 = 13.32 ± 5.48, showing a significant reduction for R1-R4 (P ≤ 0.026). The 6-week P1-AD was R1 = 99.8 ± 31.23, R2 = 40.67 ± 16.39, R3 = 24.98 ± 7.13, R4 = 16.35 ± 4.84, and R5 = 13.76 ± 3.98, showing no significant differences compared with preoperative values (P ≥ 0.054). Corneal densitometry increased significantly at 2 weeks (P < 0.001) and remained increased at 6 weeks (P < 0.001), showing statistically insignificant correlations with 2-week P1-AD (P ≥ 0.553). The central MT increased (P = 0.787), whereas MT at 1 mm (P = 0.444), 3 mm (P = 0.039), and 5 mm (P < 0.001) zones decreased. The return of P1-AD to preoperative (physiologic) values at 6 weeks confirms the safety standards of the duration and intensity of ultraviolet A radiation, as proposed by the Dresden protocol. However, temporary postoperative retinal dysfunction cannot be excluded.

Serum Phosphate and Microvascular Function in a Population-Based Cohort.

Higher serum phosphate is associated with cardiovascular events and all-cause mortality. Explanations of this association have focused on large vessel calcification and stiffness. Studies suggest that a higher serum phosphate induces microvascular dysfunction, but relationships in humans with direct measures of microvascular function are lacking. We performed a cross-sectional analysis of 3189 community-living participants that underwent skin capillaroscopy, laser-Doppler flowmetry, and flicker light-induced retinal vessel responses. We used linear regression to assess the association between serum phosphate and each microvascular outcome. The primary outcome was skin capillary recruitment during postocclusive peak reactive hyperemia by capillaroscopy. Secondary outcomes included capillary recruitment during venous congestion, heat-induced skin hyperemic response, flicker light-induced retinal arteriolar, and venular dilation. The mean age of the cohort was 59±8 years, 48% were women, 7% had an eGFR <60 ml/min per 1.73 m2, and the mean serum phosphate concentration was 3.2±0.5 mg/dl. A 1 mg/dl higher serum phosphate was independently associated with a 5.0% lower postocclusive capillary recruitment (95% CI, -10.0% to -0.1%). Results were similar for capillary recruitment with venous congestion (-4.5%; 95% CI, -9.8% to 0.7%). A 1 mg/dl higher serum phosphate was also independently associated with a 0.23% lower retinal venular dilation in response to flicker light (95% CI, -0.44% to -0.02%). A higher serum phosphate was not associated with change in flicker light-induced retinal arteriolar dilation or heat-induced skin hyperemic response, however a higher serum phosphate was associated with a lower heat-induced skin hyperemic response among men (-149% [95% CI, -260 to -38] per 1 mg/dl higher serum phosphate) but not women (P interaction, 0.01). Higher serum phosphate concentrations, even within the normal range, are associated with microvascular dysfunction in community-living individuals. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_09_20_CJN02610319.mp3.