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 Investigative Ophthalmology & Visual ScienceJournal Prestige (SJR): 2.058 Citation Impact (citeScore): 3Number of Followers: 35      Subscription journal ISSN (Print) 0146-0404 Published by ARVO  [1 journal]
• Longitudinal Evaluation of Changes in Retinal Architecture Using Optical
Coherence Tomography in Achromatopsia

Abstract: Purpose This prospective study investigates longitudinal changes in retinal structure in patients with achromatopsia (ACHM) using optical coherence tomography (OCT). Methods Seventeen patients (five adults, 12 children) with genetically confirmed CNGA3- or CNGB3-associated ACHM underwent ocular examination and OCT over a follow-up period of between 2 and 9.33 years (mean = 5.7 years). Foveal tomograms were qualitatively graded and were segmented for quantitative analysis: central macular thickness (CMt), outer nuclear layer thickness (ONLt), and size of the foveal hyporeflective zone (vertical HRZ thickness: HRZt and horizontal HRZ width: HRZw) were measured. Data were analyzed using linear mixed regression models. Both age and visit were included into the models, to explore the possibility that the rate of disease progression depends on patient age. Results Fifteen of 17 patients (88%) showed longitudinal changes in retinal structure over the follow-up period. The most common patterns of progression was development of ellipsoid zone (EZ) disruption and HRZ. There was a significant increase in HRZt (P = 0.01) and HRZw (P = 0.001) between visits and no significant change in CMt and ONLt. Retinal parameters showed no difference in changes by genetic mutation (CNGA3 (n = 11), CNGB3 (n = 6)). Conclusions This study demonstrates clear longitudinal changes in foveal structure mainly in children, but also in adults with ACHM, over a long follow-up period. The longitudinal foveal changes suggest that treatment at an earlier age should be favored.
PubDate: Fri, 05 Aug 2022 14:30:51 GMT

• Branched Chain Amino Acids Promote ATP Production Via Translocation of
Glucose Transporters

Abstract: Purpose We have previously shown that maintenance of ATP levels is a promising strategy for preventing neuronal cell death, and that branched chain amino acids (BCAAs) enhanced cellular ATP levels in cultured cells and antagonized cell death. BCAAs attenuated photoreceptor degeneration and retinal ganglion cell death in rodent models of retinal degeneration or glaucoma. This study aimed to elucidate the mechanisms through which BCAAs enhance ATP production. Methods Intracellular ATP concentration was measured in HeLa cells under glycolysis and citric acid cycle inhibited conditions. Next, glucose uptake was quantified in HeLa cells and in 661W retinal photoreceptor-derived cells under glycolysis inhibition, endoplasmic reticulum stress, and glucose transporters (GLUTs) inhibited conditions, by measuring the fluorescence of fluorescently labeled deoxy-glucose analog using flow cytometry. Then, the intracellular behavior of GLUT1 and GLUT3 were observed in HeLa or 661W cells transfected with enhanced green fluorescent protein-GLUTs. Results BCAAs recovered intracellular ATP levels during glycolysis inhibition and during citric acid cycle inhibition. BCAAs significantly increased glucose uptake and recovered decreased glucose uptake induced by endoplasmic reticulum stress or glycolysis inhibition. However, BCAAs were unable to increase intracellular ATP levels or glucose uptake when GLUTs were inhibited. Fluorescence microscopy revealed that supplementation of BCAAs enhanced the translocation of GLUTs proteins to the plasma membrane over time. Conclusions BCAAs increase ATP production by promoting glucose uptake through promotion of glucose transporters translocation to the plasma membrane. These results may help expand the clinical application of BCAAs in retinal neurodegenerative diseases, such as glaucoma and retinal degeneration.
PubDate: Fri, 05 Aug 2022 14:30:51 GMT

• Consequences of a Rare Complement Factor H Variant for Age-Related Macular
Degeneration in the Amish

Abstract: Purpose Genetic variants in the complement factor H gene (CFH) have been consistently implicated in age-related macular degeneration (AMD) risk. However, their functional effects are not fully characterized. We previously identified a rare, AMD-associated variant in CFH (P503A, rs570523689) in 19 Amish individuals, but its functional consequences were not investigated. Methods We performed genotyping for CFH P503A in 1326 Amish individuals to identify additional risk allele carriers. We examined differences for age at AMD diagnosis between carriers and noncarriers. In blood samples from risk allele carriers and noncarriers, we quantified (i) CFH RNA expression, (ii) CFH protein expression, and (iii) C-reactive protein (CRP) expression. Potential changes to the CFH protein structure were interrogated computationally with Phyre2 and Chimera software programs. Results We identified 39 additional carriers from Amish communities in Ohio and Indiana. On average, carriers were younger than noncarriers at AMD diagnosis, but this difference was not significant. CFH transcript and protein levels in blood samples from Amish carriers and noncarriers were also not significantly different. CRP levels were also comparable in plasma samples from carriers and noncarriers. Computational protein modeling showed slight changes in the CFH protein conformation that were predicted to alter interactions between the CFH 503 residue and other neighboring residues. Conclusions In total, we have identified 58 risk allele carriers for CFH P503A in the Ohio and Indiana Amish. Although we did not detect significant differences in age at AMD diagnosis or expression levels of CFH in blood samples from carriers and noncarriers, we observed modest structural changes to the CFH protein through in silico modeling. Based on our functional and computational observations, we hypothesize that CFH P503A may affect CFH binding or function rather than expression, which would require additional research to confirm.
PubDate: Fri, 05 Aug 2022 14:30:51 GMT

• Hypolacrimia and Alacrimia as Diagnostic Features for Genetic or
Congenital Conditions

Abstract: As part of the lacrimal apparatus, the lacrimal gland participates in the maintenance of a healthy eye surface by producing the aqueous part of the tear film. Alacrimia and hypolacrimia, which are relatively rare during childhood or young adulthood, have their origin in a number of mechanisms which include agenesia, aplasia, hypoplasia, or incorrect maturation of the gland. Moreover, impaired innervation of the gland and/or the cornea and alterations of protein secretion pathways can lead to a defective tear film. In most conditions leading to alacrimia or hypolacrimia, however, the altered tear film is only one of numerous defects that arise and therefore is commonly disregarded. Here, we have systematically reviewed all of those genetic conditions or congenital disorders that have alacrimia or hypolacrimia as a feature. Where it is known, we describe the mechanism of the defect in question. It has been possible to clearly establish the physiopathology of only a minority of these conditions. As hypolacrimia and alacrimia are rare features, this review could be used as a tool in clinical genetics to perform a quick diagnosis, necessary for appropriate care and counseling.
PubDate: Thu, 04 Aug 2022 14:24:08 GMT

• Ciliary Neurotrophic Factor Derived From Astrocytes Protects Retinal
Ganglion Cells Through PI3K/AKT, JAK/STAT, and MAPK/ERK Pathways

Abstract: Purpose The purpose of this study was to investigate the roles of ciliary neurotrophic factor (CNTF) on the protective effects of astrocytes on retinal ganglion cells (RGCs). Methods Primary RGCs were isolated from neonatal rats. Oxidative stress was induced, and the effects of co-culture with astrocytes and CNTF treatment on RGCs were evaluated. The pathways commonly altered by astrocytes and CNTF were investigated. Effects of each pathway were investigated using pathway inhibitors against PI3K/AKT, JAK/STAT, and MAPK/ERK. RNA sequencing was performed to identify the genes upregulated and downregulated by CNTF treatment. Results Astrocytes improved the viability and increased β3-tubulin expression in RGCs. The concentration of CNTF increased in the RGC-astrocyte co-culture medium. The protective effects of astrocytes were abolished by neutralization with the anti-CNTF antibody; thus, CNTF may play an important role in the effects mediated by astrocytes. Furthermore, CNTF treatment alone enhanced the viability and β3-tubulin expression of RGCs and increased the population of viable RGCs under oxidative stress. The PI3K/AKT pathway was associated with both RGC viability and β3-tubulin expression. However, the JAK/STAT pathway increased the viability of RGCs, whereas the MAPK/ERK pathway was associated with β3-tubulin expression. RNA sequencing revealed the CNTF-upregulated genes associated with response to DNA damage and downregulated genes associated with photoreceptor cell differentiation. Conclusions Our data revealed protective effects of astrocyte-derived CNTF on RGCs. In addition, we showed that multiple pathways exert these protective effects and identified the novel genes involved. These results may be helpful in developing treatments for RGC injury.
PubDate: Thu, 04 Aug 2022 14:24:08 GMT

• Phenotypic Expression of CFH Rare Variants in Age-Related Macular
Degeneration Patients in the Coimbra Eye Study

Abstract: Purpose To determine the association between rare genetic variants in complement factor H (CFH) and phenotypic features in age-related macular degeneration (AMD) patients from the Coimbra Eye Study (CES). Methods AMD patients from the Incidence CES (NCT02748824) underwent ophthalmologic examination and color fundus photography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, and near-infrared imaging. Multimodal phenotypic characterization was carried out in a centralized reading center. The coding and splice-site regions of the CFH gene were sequenced through single-molecule molecular inversion probe–based next-generation sequencing in association with the EYE-RISK consortium. Variants with minor allele frequency <0.05 resulting in splice-site or protein change were selected. Differences in phenotypic features between carriers and noncarriers were analyzed using generalized estimated equations logistic regression models, considering intereye correlations. Results We included 39 eyes of 23 patients carrying rare CFH variants and 284 eyes of 188 noncarriers. Carrier status was associated with having higher drusen burden in the macula in the inner Early Treatment Diabetic Retinopathy Study circle (odds ratio [OR], 5.44 [95% confidence interval {CI}, 1.61–18.37]; P = 0.006), outer circle (OR, 4.37 [95% CI, 1.07–17.77]; P = 0.04), and full grid (OR, 4.82 [95% CI, 1.13–20.52]; P = 0.033). In SD-OCT, a lower total macular volume and lower inner retinal layers’ volume (OR, 0.449 [95% CI, 0.226–0.894]; P = 0.023; OR, 0.496 [95% CI, 0.252–0.979]; P = 0.043) and pigment epithelial detachments (PEDs) (OR, 5.24 [95% CI, 1.08–25.44]; P = 0.04) were associated with carrying a rare CFH variant. Carriers with subretinal drusenoid deposits (SDD) had the rare variant P258L in all cases except one. Conclusions We identified in our cohort phenotypic differences between carriers and noncarriers of rare variants in the CFH gene. Carriers had more severe disease, namely superior drusen burden, PEDs, and thinner retinas. The rare variant P258L may be associated with SDD. Carriers are probably at increased risk of progression.
PubDate: Thu, 04 Aug 2022 14:24:08 GMT

• A Mathematical Model of Aqueous Humor Production and Composition

Abstract: Purpose We develop a mathematical model that predicts aqueous humor (AH) production rate by the ciliary processes and aqueous composition in the posterior chamber (PC), with the aim of estimating how the aqueous production rate depends on the controlling parameters and how it can be manipulated. Methods We propose a compartmental mathematical model that considers the stromal region, ciliary epithelium, and PC. All domains contain an aqueous solution with different chemical species. We impose the concentration of all species on the stromal side and exploit the various ion channels present on the cell membrane to compute the water flux produced by osmosis, the solute concentrations in the AH and the transepithelial potential difference. Results With a feasible set of parameters, the model predictions of water flux from the stroma to the PC and of the solute concentrations in the AH are in good agreement with measurements. Key parameters which impact the aqueous production rate are identified. A relevant role is predicted to be played by cell membrane permeability to $$\text{K}^+$$ and $$\text{Cl}^-$$, by the level of transport due to the Na+-H+ exchanger and to the co-transporter of Na+/K+/2Cl−; and by carbonic anhydrase. Conclusions The mathematical model predicts the formation and composition of AH, based on the structure of the ciliary epithelium. The model provides insight into the physical processes underlying the functioning of drugs that are adopted to regulate the aqueous production. It also suggests ion channels and cell membrane properties that may be targeted to manipulate the aqueous production rate.
PubDate: Tue, 02 Aug 2022 14:26:31 GMT

• Interocular Transfer: The Dichoptic Flash-Lag Effect in Controls and
Amblyopes

Abstract: Purpose The mammalian brain can take into account the neural delays in visual information transmission from the retina to the cortex when accurately localizing the instantaneous position of moving objects by motion extrapolation. In this study, we wanted to investigate whether such extrapolation mechanism operates in a comparable fashion between the eyes in normally sighted and amblyopic observers. Methods To measure interocular extrapolation, we adapted a dichoptic version of the flash-lag effect (FLE) paradigm, in which a flashed bar is perceived to lag behind a moving bar when their two positions are physically aligned. Twelve adult subjects with amblyopia and 12 healthy controls participated in the experiment. We measured the FLE magnitude of the subjects under binocular, monocular, and dichoptic conditions. Results In controls, the FLE magnitude of binocular condition was significantly smaller than that of monocular conditions (P ≤ 0.023), but there was no difference between monocular and dichoptic conditions. Subject with amblyopia exhibited a smaller FLE magnitude in the dichoptic condition when the moving bar was presented to the amblyopic eye and the flash to the fellow eye (DA condition) compared to the opposite way around (DF condition), consistent with a delay in the processing of the amblyopic eye (P = 0.041). Conclusions Our observations confirm that trajectory extrapolation mechanisms transfer between the eyes of normal observers. However, such transfer may be impaired in amblyopia. The smaller FLE magnitude in DA compared to DF in patients with amblyopia could be due to an interocular delay in the amblyopic visual system. The observation that normal controls present a smaller FLE in binocular conditions raises the question whether a larger FLE is or is not an indicator of better motion processing and extrapolation.
PubDate: Tue, 02 Aug 2022 14:26:31 GMT

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