B-wave Amplitude Research Articles

Beneficial Effect of Sirolimus-Pretreated Mesenchymal Stem Cell Implantation on Diabetic Retinopathy in Rats.

Diabetic retinopathy (DR) is a vision-threatening complication that affects virtually all diabetic patients. Various treatments have been attempted, but they have many side effects and limitations. Alternatively, stem cell therapy is being actively researched, but it faces challenges due to a low cell survival rate. In this study, stem cells were pretreated with sirolimus, which is known to promote cell differentiation and enhance the survival rate. Additionally, the subconjunctival route was employed to reduce complications following intravitreal injections. Diabetes mellitus was induced by intraperitoneal injection of 55 mg/kg of streptozotocin (STZ), and DR was confirmed at 10 weeks after DM induction through electroretinogram (ERG). The rats were divided into four groups: intact control group (INT), diabetic retinopathy group (DR), DR group with subconjunctival MSC injection (DR-MSC), and DR group with subconjunctival sirolimus-pretreated MSC injection (DR-MSC-S). The effects of transplantation were evaluated using ERG and histological examinations. The ERG results showed that the DR-MSC-S group did not significantly differ from the INT in b-wave amplitude and exhibited significantly higher values than the DR-MSC and DR groups (p < 0.01). The flicker amplitude results showed that the DR-MSC and DR-MSC-S groups had significantly higher values than the DR group (p < 0.01). Histological examination revealed that the retinal layers were thinner in the DR-induced groups compared to the INT group, with the DR-MSC-S group showing the thickest retinal layers among them. Subconjunctival injection of sirolimus-pretreated MSCs can enhance retinal function and mitigate histological changes in the STZ-induced DR rat model.

Genotypic and phenotypic diversity in X-linked retinoschisis: Findings from a South Indian patient cohort.

Retinoschisis is a distinctive condition characterized by intraretinal layer clefts, primarily associated with X-linked recessive inheritance due to RS1 gene mutations. This study aims to uncover the RS1 mutation spectrum in a cohort of 22 X-linked retinoschisis cases from South India and emphasizes the genotypic and phenotypic associations within patients harboring only RS1 mutations. A total of 22 probands were suspected of having X-linked retinoschisis. All study subjects underwent ophthalmic investigations, including assessments of visual acuity, fundus examination, optical coherence tomography (OCT), and electroretinogram (ERG). RS1 gene screening was conducted using Sanger sequencing, and the pathogenicity of the variants was assessed through Sorting Intolerant from Tolerant (SIFT) and PolyPhen-2 in silico tools. The study found that the probands had an average visual acuity of 0.79 ± 0.39 log of minimum angle of resolution (logMAR), ranging from 0.17 to 1.77. During fundus examination, the probands exhibited a characteristic spoke wheel-like pattern in the macular region. Furthermore, OCT analysis revealed distinct alterations in the inner retinal microstructure, and ERG results consistently showed a reduction in b-wave amplitude. Eventually, Sanger sequencing results showed hemizygous mutations in the RS1 gene in only 12 probands, including a novel missense mutation in the RS1 gene's signal sequence. This study provides valuable insights into the spectrum of RS1 mutations in X-linked retinoschisis probands from South India. It reveals distinct genotypic-phenotypic associations and highlights the clinical manifestations associated with the disease pathogenesis.

Paediatric norms for photopic electroretinogram testing based on a large cohort of Chinese preschool children

ObjectiveFull-field electroretinogram (ffERG) is an objective test to determine the electroretinal activities in response to light stimulation for investigating retinal physiology and diagnosing retinal diseases. This study aimed to establish...

FGF1ΔHBS ameliorates retinal inflammation via suppressing TSPO signal in a type 2 diabetes mouse model

Translocator protein (18 kDa) (TSPO) plays an important role in retinal neuroinflammation in the early stage of diabetic retinopathy (DR). Studies have found that a FGF1 variant (FGF1ΔHBS) with reduced proliferative potency exerts excellent anti-inflammatory effects and potential therapeutic value for diabetic complications. In this study, intravitreal injection of FGF1ΔHBS was administrated every week for one month in db/db mice, which are genetically predisposed to develop type 2 diabetes mellitus and early retinopathy. Changes in retinal function and structure in the animal models were detected by electrophysiology (ERG) and optical tomography coherence (OCT). TSPO expression and retinal inflammation were analyzed by immunofluorescence, Western blot and real-time qPCR. In the retina of T2D (db/db) mice, FGF1 was significantly down-regulated while FGFR1 was up-regulated (both p < 0.05). TSPO and retinal inflammatory factors were all up-regulated. TSPO and FGFR1 were mainly co-stained in the inner retina. After FGF1ΔHBS treatment, ERG showed that the total amplitude of dark-adapted b-wave and oscillating potentials (Ops) was significantly improved, and OCT showed that the thickness of the retina around the optical nerve head was significantly preserved in T2D mice (all p < 0.05). The TSPO signal was significantly suppressed by FGF1ΔHBS. The activation of NF-κB p65 and the expression of inflammatory factors such as TNF-α, IL-1β, IL-6, COX-2, MIP-1α, and iNOS were all significantly down-regulated (all p < 0.05). Collectively, our current data demonstrated that intravitreal FGF1ΔHBS treatment can effectively inhibit retinal inflammation via suppressing TSPO signal and to preserve retinal function and structure in a T2D mouse model.

The Effect of S-Allyl L-Cysteine on Retinal Ischemia: The Contributions of MCP-1 and PKM2 in the Underlying Medicinal Properties.

Retinal ischemia plays a vital role in vision-threatening retinal ischemic disorders, such as diabetic retinopathy, age-related macular degeneration, glaucoma, etc. The aim of this study was to investigate the effects of S-allyl L-cysteine (SAC) and its associated therapeutic mechanism. Oxidative stress was induced by administration of 500 μM H2O2 for 24 h; SAC demonstrated a dose-dependent neuroprotective effect with significant cell viability effects at 100 μM, and it concurrently downregulated angiogenesis factor PKM2 and inflammatory biomarker MCP-1. In a Wistar rat model of high intraocular pressure (HIOP)-induced retinal ischemia and reperfusion (I/R), post-administration of 100 μM SAC counteracted the ischemic-associated reduction of ERG b-wave amplitude and fluorogold-labeled RGC reduction. This study supports that SAC could protect against retinal ischemia through its anti-oxidative, anti-angiogenic, anti-inflammatory, and neuroprotective properties.

Cone dystrophy with supernormal rod response – A rare case report

Cone dystrophy with supernormal rod response (CDSRR), also known as potassium channel subfamily V, member 2 (KCNV2) retinopathy, is a rare autosomal recessive cone rod dystrophy, which derives its name from its characteristic full-field electroretinography (ERG) features and the causative gene mutation (KCNV2 gene). It is one of the rare eye retinal dystrophies where ERG is pathognomonic and directly carries the genetic imprint of the condition. Here, we discuss the case of a 9-year-old Indian child with history of diminution of vision in both eyes. Full-field ERG showed a characteristic response of supranormal scotopic b-wave amplitude at high luminance intensities along with broadened trough of the a-wave with late negative component with reduced and delayed photopic response suggestive of CDSRR.

The efficacy and safety of transcorneal electrical stimulation for patients with retinitis pigmentosa: a systematic review and meta-analysis

Retinitis pigmentosa (RP) is a heterogeneous group of genetically inherited degenerative disorders characterized by progressive loss of peripheral vision. Tran&amp;apos;s corneal electrical stimulation (TES) has been proposed as a treatment for various ocular conditions, but its mechanism remains uncertain. This systematic review and meta-analysis aimed to assess the safety and efficacy of trans-corneal electrical stimulation (TcES) as a treatment for RP by comprehensively examining the available literature in medical databases. The literature of the related studies was retrieved from five databases including central, midline, scopus, directory of open access journals, and clinicalTrials.gov. All of the selected scholarly databases were extensively searched online for articles that were published between January 2019 and July 2023. TES was found to be safe for RP patients, with positive effects on the visual field area (VFA) and scotopic b-wave amplitude. It significantly attenuated the annual decline in the visual field hence effectively doubling its half-life from 10 to 20 years. No significant side effects were observed during TES. TES offers a promising treatment option for RP, with potential benefits in slowing disease progression and preserving vision. The OkuStim system and TES present an affordable and adaptable approach, with opportunities for patient self-administration. However, further studies with larger sample sizes and longer durations are needed to confirm these findings and optimize treatment parameters.

Analysis of the results of retinal peptides application in different ages of Campbell rats with Retinitis Pigmentosa

The work concerns studying electrophysiological parameters and, based on histological studies, morphological parameters of the retina in different age groups of Campbell rats with Retinitis Pigmentosa (RP) before and after Retinalamin treatment. 50 Campbell rats, as an experimental model of inherited RP, were used in the study. Rats were divided into two age groups, with 25 rats in each. Group I consisted of newborns up to 3 weeks, and Group II consisted of adults aged 3.5 ± 0.3 months. Retinalamin injections were given parabulbarly to all animals for 10 days. The total bioelectrical activity of the a, b, and c waves and the average value of the b-wave amplitude were studied using the electroretinography (ERG) method. Also, the thickness of the outer nuclear layer of retinal pigment epithelium cells was studied in a histological examination. Studies were conducted before the start of Retinalamin injections and in dynamics after 10 and 30 days. According to the ERG results, a decrease in the total bioelectrical activity of the rat retina and the average b-wave amplitude were already observed in 19-day-old rats. A statistically significant increase in these indicators was observed in both groups after 10 and 30 days of Retinalamin injections. Histological analysis of retinal preparations also revealed positive changes after the peptide administrations. An improvement in morphological structures and thickening of the outer nuclear layer of retinal pigment epithelial cells were noted in both groups. More significant positive dynamics were in Group I of newborn rats. Conclusion. Retinalamin treatment in newborn and adult Campbell rats with retinitis pigmentosa stabilized the processes developing in the retina. At the same time, the maximum positive effect was manifested in newborn rats.

Neuroprotective properties of Na+/H+-exchanger isoform-1 inhibitor in experimental POAG

Introduction: Worldwide glaucoma is the leading cause of irreversible vision loss. The processes associated with the loss of retinal ganglion cells are multifactorial and have much in common with neurodegenerative diseases. Therefore the search for means to prevent the death of retinal neurons is an important task of modern pharmacology. Materials and Methods: The study was conducted on male Wistar rats. Glaucoma was modeled by injecting a 1% solution of hyaluronic acid into the anterior chamber of the eye. The IOP level was recorded on the 0th, 63rd and 73rd days of the experiment. The effectiveness of the drugs was evaluated based on the results of ophthalmoscopy, electroretinography, followed by the determination of gene expression. Results and Discussion: In the group with RU-1355 correction, the fundus picture improved; the index in the group was 18.0% lower compared to the model. The introduction of the RU-1355 compound provided an increase in the a-wave amplitude by 18.1%, and b-wave amplitude by 39.0% relative to the group with pathology. The most pronounced effect was observed on the expression level of BDNF, Bcl-2, Caspase 3 and NF-κB p65, which indicates that the compound has the capacity to influence the slowdown of the apoptosis process through an increase in the neurotrophic factor and the anti-apoptotic factor Bcl-2. Conclusion: RU-1355 has neuroprotective properties, which was expressed by a decrease in ophthalmoscopic manifestations, preservation of the b-wave amplitude of the electroretinogram and the influence on gene expression of factors involved in apoptosis and neuroprotection. Based on the pharmacological activity of the RU-1355 compound in relation to POAG, further study of its action against other retinal diseases is promising.

Diabetic Müller-Glial-Cell-Specific Il6ra Knockout Mice Exhibit Accelerated Retinal Functional Decline and Thinning of the Inner Nuclear Layer.

Interleukin-6 (IL-6) is implicated in the pathology of diabetic retinopathy (DR). IL-6 trans-signaling via soluble IL-6 receptor (IL-6R) is primarily responsible for its pro-inflammatory functions, whereas cis-signaling via membrane-bound IL-6R is anti-inflammatory. Using a Müller-glial-cell-specific Il6ra-/- mouse, we examined how loss of IL-6 cis-signaling in Müller glial cells (MGCs) affected retinal thinning and electroretinography (ERG) response over 9months of diabetes. Diabetes was induced in wildtype and knockout mice with streptozotocin (40mg/kg, daily for 5days). Spectral domain optical coherence tomography (SD-OCT), ERG, and fundoscopy/fluorescein angiography (FA) were assessed at 2, 6, and 9months of diabetes. MGCs and bipolar neurons were examined in retinal tissue sections by immunofluorescence. Diabetic MGC Il6ra-/- mice had significantly thinner retinas than diabetic wildtype mice at 2 (-7.6µm), 6 (-12.0µm), and 9months (-5.0µm) of diabetes, as well as significant thinning of the inner nuclear layer (INL). Diabetic MGC Il6ra-/- mice also showed a reduction in scotopic B-wave amplitude and B-wave/A-wave ratio earlier than wildtype diabetic mice. In retinal sections, we found a decrease in bipolar neuronal marker PKCα only in diabetic MGC Il6ra-/- mice, which was significantly lower than both controls and diabetic wildtype mice. Glutamine synthetase, a Müller cell marker, was reduced in both wildtype and MGC Il6ra-/- diabetic mice compared to their respective controls. IL-6 cis-signaling in MGCs contributes to maintenance of the INL in diabetes, and loss of the IL-6 receptor reduces MGC-mediated neuroprotection of bipolar neurons in the diabetic retina.

Defect of TIMP4 Is Associated with High Myopia and Participates in Rat Ocular Development in a Dose-Dependent Manner.

Thinning of the sclera happens in myopia eyes owing to extracellular matrix (ECM) remodeling, but the initiators of the ECM remodeling in myopia are mainly unknown. The matrix metalloproteinase (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs) regulate the homeostasis of the ECM. However, genetic studies of the MMPs and TIMPs in the occurrence of myopia are poor and limited. This study systematically investigated the association between twenty-nine genes of the TIMPs and MMPs families and early-onset high myopia (eoHM) based on whole exome sequencing data. Two TIMP4 heterozygous loss-of-function (LoF) variants, c.528C>A in six patients and c.234_235insAA in one patient, were statistically enriched in 928 eoHM probands compared to that in 5469 non-high myopia control (p = 3.7 × 10-5) and that in the general population (p = 2.78 × 10-9). Consequently, the Timp4 gene editing rat was further evaluated to explore the possible role of Timp4 on ocular and myopia development. A series of ocular morphology abnormalities in a dose-dependent manner (Timp4-/- < Timp4+/- < Timp4+/+) were observed in a rat model, including the decline in the retinal thickness, the elongation in the axial length, more vulnerable to the form deprivation model, morphology changes in sclera collagen bundles, and the decrease in collagen contents of the sclera and retina. Electroretinogram revealed that the b-wave amplitudes of Timp4 defect rats were significantly reduced, consistent with the shorter length of the bipolar axons detected by HE and IF staining. Heterozygous LoF variants in the TIMP4 are associated with early onset high myopia, and the Timp4 defect disturbs ocular development by influencing the morphology and function of the ocular tissue.

Essential Role of XBP1 in Maintaining Photoreceptor Synaptic Integrity in Early Diabetic Retinopathy.

Diabetic retinopathy (DR) is a leading cause of blindness in working-age adults characterized by retinal dysfunction and neurovascular degeneration. We previously reported that deletion of X-box binding protein 1 (XBP1) leads to accelerated retinal neurodegeneration in diabetes; however, the mechanisms remain elusive. The goal of this study is to determine the role of XBP1 in the regulation of photoreceptor synaptic integrity in early DR. Diabetes was induced by streptozotocin in retina-specific XBP1 conditional knockout (cKO) or wild-type (WT) mice to generate diabetic cKO (cKO/DM) or WT/DM mice for comparison with nondiabetic cKO (cKO/NDM) and WT/NDM mice. Retinal morphology, structure, and function were assessed by immunohistochemistry, optical coherence tomography, and electroretinogram (ERG) after 3months of diabetes. The synapses between photoreceptors and bipolar cells were examined by confocal microscopy, and synaptic integrity was quantified using the QUANTOS algorithm. We found a thinning of the outer nuclear layer and a decline in the b-wave amplitude in dark- and light-adapted ERG in cKO/DM mice compared to all other groups. In line with these changes, cKO mice showed increased loss of synaptic integrity compared to WT mice, regardless of diabetes status. In searching for candidate molecules responsible for the loss of photoreceptor synaptic integrity in diabetic and XBP1-deficient retinas, we found decreased mRNA and protein levels of DLG4/PSD-95 in cKO/DM retina compared to WT/DM. These findings suggest that XBP1 is a crucial regulator in maintaining synaptic integrity and retinal function, possibly through regulation of synaptic scaffold proteins.

GSK840 Alleviates Retinal Neuronal Injury by Inhibiting RIPK3/MLKL-Mediated RGC Necroptosis After Ischemia/Reperfusion.

This study aimed to explore the impact of GSK840 on retinal neuronal injury after retinal ischemia/reperfusion (IR) and its associated mechanism. We established an in vivo mouse model of IR and an in vitro model of oxygen and glucose deprivation/reoxygenation (OGDR) in primary mouse retinal ganglion cells (RGCs). GSK840, a small-molecule compound, was used to specifically inhibit RIPK3/MLKL-dependent necroptosis. Retinal structure and function evaluation was performed by using hematoxylin and eosin staining, optical coherence tomography, and electroretinography. Propidium Iodide (PI) staining was used for detection of necroptotic cell death, whereas Western blot analysis and immunofluorescence were used to assess necroptosis-related proteins and inner retinal neurons. RIPK3/MLKL-dependent necroptosis was rapidly activated in RGCs following retinal IR or OGDR. GSK840 helped maintain relatively normal inner retinal structure and thickness by preserving inner retinal neurons, particularly RGCs. Meanwhile, GSK840 ameliorated IR-induced visual dysfunction, as evidenced by the improved amplitudes of photopic negative response, a-wave, b-wave, and oscillatory potentials. And GSK840 treatment significantly reduced the population of PI+ RGCs after injury. Mechanistically, GSK840 ameliorated RGC necroptosis by inhibiting the RIPK3/MLKL pathway. GSK840 exerts protective effects against retinal neuronal injury after IR by inhibiting RIPK3/MLKL-mediated RGC necroptosis. GSK840 may represent a protective strategy for RGC degeneration in ischemic retinopathy.

A novel compound heterozygous PEX1 variant in Heimler syndrome

Heimler syndrome (HS) is a rare autosomal recessive hereditary disease that is caused by biallelic variants in peroxisomal biogenic factor 1 gene (PEX1), peroxisomal biogenic factor 6 gene (PEX6) or peroxisomal biogenic factor 26 gene (PEX26), resulting in intracellular peroxisomal dysfunction (PBDs). We report a patient with HS with a new compound heterozygous PEX1 variant. Exon sequencing was used to screen pathologic variants in the patient. Retinal characteristics and serum metabolome alterations were evaluated. Scanning laser ophthalmoscope showed a large area of retinal choroidal atrophy at the posterior pole of the retina, with scattered patchy subretinal pigmentation. Optical coherence tomography showed fovea atrophy accompanied by retinal retinoschisis in the right eye and macular retinoschisis and edema in the left eye. The electroretinogram showed obviously reduced amplitudes of a-waves and b-waves under photopic and scotopic conditions in both eyes. Visual field tests showed a reduced central visual field in both eyes. Exon sequencing identified the compound heterozygous variant including c.2966T > C and c.1670+1G > T of the PEX1 gene, with the latter being novel. Nontargeted determination of total lipid metabolites and targeted determination of medium- and long-chain fatty acids in the serum of the patient and his healthy sibling were tested. This study identified a new compound heterozygous PEX1 variant, expanding our understanding of phenotypes in HS.

Diabetes-Induced Changes of the Rat ERG in Relation to Hyperglycemia and Acidosis

Purpose To understand the mechanism of changes in the c-wave of the electroretinogram (ERG) in diabetic rats, and to explore how glucose manipulations affect the c-wave. Methods Vitreal ERGs were recorded in control and diabetic Long-Evans rats, 3–60 weeks after IP vehicle or streptozotocin. A few experiments were performed on Brown Norway rats. Voltage responses to current pulses were used to measure the transepithelial resistance of the retinal pigment epithelium (RPE). Results During development of diabetes the b-wave amplitude progressively decreased to about half of the initial amplitude after a year. In contrast, the c-wave was strongly affected from the very beginning (3 weeks) of diabetes. In control rats, the c-wave was cornea-positive at lower illuminations but was cornea-negative at higher (photopic) illumination. In diabetics, the whole amplitude-intensity curve was shifted toward negativity. The magnitude of this shift was markedly affected by acute glucose manipulations in diabetics but not in controls. Increased blood glucose made the c-wave more negative, and decreased blood glucose with insulin had the opposite effect. Experimentally induced acidification of the retina had a small effect that was different from diabetes, shifting the c-wave toward positivity, slightly in controls and more noticeably in diabetics. One reason for the significant negativity of the diabetic ERG was a decrease of the cornea-positive response of the RPE due to a decrease of the transepithelial resistance. Conclusions The ERG c-wave is more negative in diabetics than in control animals, and is far more sensitive to changes in blood glucose. The increased negativity is largely if not entirely due to changes in the transepithelial resistance of the RPE, an electrical analog of the breakdown of the blood-retinal barrier observed in other studies. The sensitivity of the c-wave to glucose in diabetics may also be due to changes in transepithelial resistance.

Inhibition of retinal ischemia-reperfusion injury in rats by inhalation of low-concentration hydrogen gas.

To investigate the inhibitory effect of hydrogen gas inhalation on retinal ischemia reperfusion (I/R) injury using a rat model. Six-week-old male Sprague-Dawley rats were used. A 27G needle connected by a tube to a saline bottle placed 200cm above the eye was inserted into the anterior eye chamber to create a rat retinal I/R model. In the ischemia-plus-hydrogen-gas group (H2( +) group), the ischemia time was set to 90min, and 1.8% hydrogen was added to the air delivered by the anesthesia mask simultaneously with the start of ischemia. In the non-hydrogen-treatment ischemia group (H2( -) group), I/R injury was created similarly, but only air was inhaled. ERGs were measured; after removal of the eyes, the retina was examined for histological, immunostaining, and molecular biological analyses. The mean thickness of the inner retinal layer in the H2( +) group was 107.2 ± 16.0μm (n = 5), significantly greater than that in the H2( -) group (60.8 ± 6.7μm). Immunostaining for Iba1 in the H2( -) group showed increased numbers of microglia and microglial infiltration into the subretinal space, while there was no increase in microglia in the H2( +) group. B-wave amplitudes in the H2( +) group were significantly higher than in the H2( -) group. In the membrane antibody array, levels of interleukin-6, monocyte chemotactic protein 1, and tumor necrosis factor alpha were significantly lower in the H2( +) group than in the H2( -) group. Inhalation of 1.8% hydrogen gas inhibited the induction of inflammation, morphological/structural changes, and glial cell increase caused by retinal I/R injury.

Synergism of mechanisms underlying early-stage changes in retina function in male hyperglycemic db/db mice in the absence and presence of chemically-induced dyslipidemia

The study was designed to quantify retina function in a spontaneous mutation mouse model of diabetes, in which sustained dyslipidemia was induced chemically. The goal of the study was to identify if dyslipidemia in the presence of hyperglycemia resulted in either a synergistic, or a merely additive, exacerbation of retinal and visual dysfunctions in diabetes. Two cohorts of mice, male C57BL/6 and C57BL/KsJ-db/db mice were divided into two groups each. One group of each strain received the triblock copolymer, poloxamer 407 (P-407), administered by intraperitoneal injection (“WT P-407” and “db/db P-407” groups) with saline as a control in the remaining two groups (“WT” and “db/db” groups). Blood glucose, total cholesterol (TC) and total triglyceride (TG) levels were quantified using enzyme-based colorimetric assays. Retina function was measured using electroretinography (ERG) and visual acuity was determined by behaviorally assessing parameters of the optomotor reflex. TC and TG levels were normal in both saline controls (WT) and db/db mice but were significantly elevated in the WT P-407 group (p < 0.01 for TC; p < 0.001 for TG), while levels of the same lipids were further elevated in the db/db P-407 group when compared to the WT P-407 group levels (p < 0.001 for both TC and TG). Behavioral assessment of the optomotor reflex indicated reduced visual acuity for the db/db P-407 group when compared to either the WT P-407 or the db/db groups (p < 0.001, p < 0.0001). ERG measurements of scotopic retina function showed a significant decline in the scotopic b-wave amplitude of the WT P-407 animals (p < 0.01) and a further reduction for the db/db P-407 group when compared to controls (p < 0.0001). Very significant, strong correlations between scotopic b-wave amplitude and implicit time to TC (r = − 0.8376, p = < 0.0001 and r = 0.7069, p = 0.0022, respectively) and TG levels (r = − 0.8554, p = < 0.0001 and r = 0.7150, p = 0.0019, respectively) were found. Dyslipidemia in the presence of hyperglycemia synergistically exacerbated the severity of retinal dysfunction in diabetes. P-407 administration significantly elevated plasma TC and TG levels in male wild-type (WT) and diabetic mice (db/db), but the resulting hyperlipidemia was more significantly pronounced in the diabetic mice. While elevated plasma lipid and blood glucose levels were individually correlated with a decline in retinal function, the combination of both exacerbated retinal dysfunction. This model of combined hyperglycemia and dyslipidemia can be used to dissect individual contributions of features of the metabolic syndrome to the pathogenesis of retinal dysfunction in diabetes.

A natural history study of autosomal dominant GUCY2D-associated cone–rod dystrophy

PurposeTo describe the natural history of autosomal dominant (AD) GUCY2D-associated cone–rod dystrophies (CRDs), and evaluate associated structural and functional biomarkers.MethodsRetrospective analysis was conducted on 16 patients with AD GUCY2D-CRDs across two sites. Assessments included central macular thickness (CMT) and length of disruption to the ellipsoid zone (EZ) via optical coherence tomography (OCT), electroretinography (ERG) parameters, best corrected visual acuity (BCVA), and fundus autofluorescence (FAF).ResultsAt first visit, with a mean age of 30 years (range 5–70 years), 12 patients had a BCVA below Australian driving standard (LogMAR ≥ 0.3 bilaterally), and 1 patient was legally blind (LogMAR ≥ 1). Longitudinal analysis demonstrated a deterioration of LogMAR by − 0.019 per year (p < 0.001). This accompanied a reduction in CMT of − 1.4 µm per year (p < 0.0001), lengthened EZ disruption by 42 µm per year (p = < 0.0001) and increased area of FAF by 0.05 mm2 per year (p = 0.027). Similarly, cone function decreased with increasing age, as demonstrated by decreasing b-wave amplitude of the light-adapted 30 Hz flicker and fused flicker (p = 0.005 and p = 0.018, respectively). Reduction in CMT and increased EZ disruption on OCT were associated with functional changes including poorer BCVA and decreased cone function on ERG.ConclusionWe have described the natural long-term decline in vision and cone function associated with mutations in GUCY2D and identified a set of functional and structural biomarkers that may be useful as outcome parameters for future therapeutic clinical trials.

Group comparisons of the individual electroretinogram time trajectories for the ascending limb of the b-wave using a raw and registered time series

ObjectivesThe electroretinogram is a clinical test commonly used in the diagnosis of retinal disorders with the peak time and amplitude of the a- and b-waves used as the main indicators of retinal function. However, subtle changes that affect the shape of the electroretinogram waveform may occur in the early stages of disease or in conditions that have a neurodevelopmental or neurodegenerative origin. In such cases, we introduce a statistical approach to mathematically model the shape of the electroretinogram waveform that may aid clinicians and researchers using the electroretinogram or other biological signal recordings to identify morphological features in the waveforms that may not be captured by the time or time–frequency domains of the waveforms. We present a statistical graphics-based analysis of the ascending limb of the b-wave (AL-b) of the electroretinogram in children with and without a diagnosis of autism spectrum disorder (ASD) with a narrative explanation of the statistical approach to illustrate how different features of the waveform based on location and scale derived from raw and registered time series can reveal subtle differences between the groups.ResultsAnalysis of the raw time trajectories confirmed findings of previous studies with a reduced and delayed b-wave amplitude in ASD. However, when the individual time trajectories were registered then group differences were visible in the mean amplitude at registered time ~ 0.6 suggesting a novel method to differentiate groups using registration of the ERG waveform.

Prevention of Inflammation, Neovascularization, and Retinal Dysfunction by Kinin B1 Receptor Antagonism in a Mouse Model of Age-Related Macular Degeneration.

The kallikrein-kinin system (KKS) contributes to vascular inflammation and neovascularization in age-related macular degeneration (AMD), particularly via the kinin B1 receptor (B1R). The aim of the present study was to determine the protective effects of the topical administration of the B1R antagonist (R-954) on inflammation, neovascularization, and retinal dysfunction in a murine model of neovascular AMD. Choroidal neovascularization (CNV) was induced in C57BL6 mice using an argon laser. A treatment with ocular drops of R-954 (100 μg/15 μL, twice daily in both eyes), or vehicle, was started immediately on day 0, for 7, 14, or 21 days. CNV, invasive microglia, and B1R immunoreactive glial cells, as well as electroretinography alterations, were observed within the retina and choroid of the CNV group but not in the control group. The staining of B1R was abolished by R-954 treatment as well as the proliferation of microglia. R-954 treatment prevented the CNV development (volume: 20 ± 2 vs. 152 ± 5 × 104 µm3 in R-954 vs. saline treatment). R-954 also significantly decreased photoreceptor and bipolar cell dysfunction (a-wave amplitude: -47 ± 20 vs. -34 ± 14 µV and b-wave amplitude: 101 ± 27 vs. 64 ± 17 µV in R-954 vs. saline treatment, day 7) as well as angiogenesis tufts in the retina. These results suggest that self-administration of R-954 by eye-drop treatment could be a promising therapy in AMD to preserve retinal health and vision.