Clinical trials of novel therapies for choroideremia require robust and clinically meaningful visual function outcome measures. Best-corrected visual acuity (BCVA) is mostly insensitive to changes in disease state, until late stages, and hence also to potential therapeutic gains after gene therapies. While the insensitivity of BCVA as an effective outcome measure is common wisdom, its low importance has not been rigorously demonstrated in the literature. This work uses statistical techniques to rank the relative importance of potential functional outcome measures in choroideremia.

Retrospective dominance analysis was performed on data from a longitudinal interventional clinical trial performed at the Oxford Eye Hospital. Functional data from the untreated eye were analyzed and correlated with an anatomic measure of disease progression in the form of blue fundus autofluorescence area of the surviving outer retinal island. Each functional measure was then ranked in terms of variable importance.

Microperimetry was the functional measure ranking first in terms of variable importance, followed by time since baseline visit, Pelli-Robson contrast sensitivity, high spatial frequency contrast sensitivity function, and low luminance visual acuity. Early Treatment Diabetic Screening chart BCVA under standard lighting conditions was ranked lowest among the panel of test modalities.

Clinical trials in choroideremia for early and mid-stage disease would be justified in moving away from using standard BCVA as a clinical trial outcome measure as we have shown its sensitivity to be relatively low compared to microperimetry. We have also demonstrated how functional measures rank in terms of importance.

Diabetic retinopathy (DR), a microvascular complication of type 2 diabetes (T2D), results from complex interactions of genetic and environmental factors. Vascular endothelial growth factor (VEGF) and mouse model minute 2 (MDM2)are upregulated in the retina due to diabetes, which increases the risk of DR. VEGFA and MDM2 genetic variations can influence DR risk. The present case-control study was conducted to evaluate the association of VEGFA and MDM2 promoter variants with DR in a population from Punjab, Northwest India.

A total of 414 DR patients, 425 T2D patients without DR, and 402 healthy controls were screened for VEGFA -2578C/A (rs699947), VEGFA -2549I/D (rs35569394), VEGFA -7C/T (rs25648), and MDM2 rs3730485 polymorphisms using polymerase chain reaction (PCR)-based methods.

VEGFA -2549 I allele (OR = 1.35 (1.00-1.81), p = 0.043) and II genotype (OR = 1.78 (1.00-3.15), p = 0.047) were significantly associated with increased risk of DR. VEGFA -7 CT genotype conferred reduced risk of DR (OR = 0.28 (0.20-0.38); p = <0.001). VEGFA -2578 and MDM2 rs3730485 showed no significant association with DR. A-I-T (OR = 0.30 (0.20-0.44); p = <0.001) and C-D-T (OR = 0.33 (0.16-0.65); p = 0.002) haplotypes of rs699947-rs35569394-rs25648 polymorphisms showed decreased risk of DR.

I allele and II genotype of VEGFA -2549, CT genotype of VEGFA -7, and C-I-C and A-D-C haplotypes of rs699947-rs35569394-rs25648 polymorphisms were significantly associated with DR risk in a Northwest Indian population. This is the first study worldwide to report DR risk with VEGFA promoter variants together.

Purpose: Diabetic retinopathy (DR) is a microvascular retinal disease associated with chronic diabetes mellitus, characterized by the damage of blood vessels in the eye. It is projected to become the leading cause of blindness, given the increasing burden of the diabetic population worldwide. The diagnosis and management of DR pose significant challenges for physicians because of the involvement of multiple biochemical pathways and the complexity of ocular tissues. This review aims to provide a comprehensive understanding of the molecular pathways implicated in the pathogenesis of DR, including the polyo pathway, hexosamine pathway, protein kinase C (PKC), JAK/STAT signaling pathways, and the renin-angiotensin system (RAS). Methods: Academic databases such as PubMed, Scopus, Google Scholar and Web of Science was systematically searched using a carefully constructed search strategy incorporating keywords like "Diabetic Retinopathy," "Molecular Pathways," "Pharmacological Treatments," and "Clinical Trials" to identify relevant literature for the comprehensive review. Results: In addition to activating other inflammatory cascades, these pathways contribute to the generation of oxidative stress within the retina. Furthermore, it aims to explore the existing pharmacotherapy options available for the treatment of DR. In addition to conventional pharmacological therapies such as corticosteroids, antivascular endothelial growth factors, and nonsteroidal anti-inflammatory drugs (NSAIDs), this review highlights the potential of repurposed drugs, phyto-pharmaceuticals, and novel pipeline drugs currently undergoing various stages of clinical trials. Conclusion: Overall, this review serves as a technical exploration of the complex nature of DR, highlighting both established and emerging molecular pathways implicated in its pathogenesis. Furthermore, it delves into the available pharmacological treatments, as well as the promising repurposed drugs, phyto-pharmaceuticals, and novel drugs currently being evaluated in clinical trials, with a focus on their specific mechanisms of action.

Diabetic retinopathy (DR) is the most common diabetic eye disease and the worldwide leading cause of vision loss in working-age adults. It progresses from mild to severe non-proliferative or proliferative DR based on several pathological features including the magnitude of blood-retinal barrier breakdown and neovascularization. Available pharmacological and retinal laser photocoagulation interventions are mostly applied in the advanced stages of DR and are inefficient in halting disease progression in a significantly high percentage of patients. Yet, recent evidence has shown that some therapies could potentially limit DR progression if applied at early stages, highlighting the importance of early disease diagnostics. In the past few decades, different imaging modalities have proved their utility for examining retinal and optic nerve changes in patients with retinal diseases. However, imaging based-methodologies solely rely on morphological examination of the retinal vascularization and are not suitable for recurrent and personalized patient evaluation. This raises the need for new technologies to enable accurate and early diagnosis of DR. In this review, we critically discuss the potential clinical benefit of minimally-invasive molecular biomarker identification and profiling of diabetic patients who are at risk of developing DR. We provide a comparative overview of conventional and recently developed lab-on-a-chip technologies for quantitative assessment of potential DR molecular biomarkers and discuss their advantages, current limitations and challenges for future practical implementation and continuous patient monitoring at the point-of-care.

Shear stress is recognized as a regulator of angiogenesis. However, the shear stress experienced by the endothelial cells of capillary sprouts remains unknown. The objective of this study was to estimate shear stress due to local interstitial flow along endothelial tip cells at the end of the capillary sprout lumen. Computational fluid dynamics were used to model flow within a blind-ended vessel, transendothelial flow across the vessel wall, and flow within the surrounding perivascular/interstitial space. Shear stress along the wall of the tip cells was calculated while varying sprout length, perivascular space channel width, and vessel wall hydraulic conductivity. Increasing sprout length, increasing wall hydraulic conductivity, and decreasing perivascular space width increased shear stress magnitude. Wall shear stress magnitude within the lumen ranged from 0.015 to 0.55 dyne/cm² at the sprout entrance and linearly decreased to near zero at the base of the tip cells. Tip cell wall shear stress magnitude due to interstitial flow ranged from 0.009 to 4.65 dyne/cm². In 3 out of 8 cases, shear stress magnitude was above 1 dyne/cm² and considered physiologically relevant. The results provide a framework for discussing the role of local mechanical cues in regulating endothelial cell dynamics involved in angiogenesis. Mainly, interstitial flows may generate physiologically relevant shear stresses on tip cells in certain scenarios. This source of tip cell shear stress has not been previously considered or modeled.

Diabetic retinopathy, a symptomless medical condition of diabetes, is one of the significant reasons of vision impairment all over the world. The prior detection and diagnosis can decrease the occurrence of acute vision loss and enhance efficiency of treatment. Fundus imaging, a non-invasive diagnostic technique, is the most frequently used mode for analyzing retinal abnormalities related to diabetic retinopathy. Computer-aided methods based on retinal fundus images support quick diagnosis, impart an additional perspective during decision-making, and behave as an efficient means to assess response of treatment on retinal abnormalities. However, in order to evaluate computer-aided systems, a benchmark database of clinical retinal fundus images is required. Therefore, a representative database comprising of 2942 clinical retinal fundus images is developed and presented in this work. This clinical database, having varying attributes such as position, dimensions, shapes, and color, is formed to evaluate the generalization capability of computer-aided systems for diabetic retinopathy diagnosis. A framework for the development of benchmark retinal fundus images database is also proposed. The developed database comprises of medical image annotations for each image from expert ophthalmologists corresponding to anatomical structures, retinal lesions and stage of diabetic retinopathy. In addition, the substantial performance comparison capability of the proposed database aids in analyzing candidature of different methods, and subsequently its usage in medical practice for real-time applications.

Diabetes is one of the fastest growing diseases worldwide, projected to affect 693 million adults by 2045. Devastating macrovascular complications (cardiovascular disease) and microvascular complications (such as diabetic kidney disease, diabetic retinopathy and neuropathy) lead to increased mortality, blindness, kidney failure and an overall decreased quality of life in individuals with diabetes. Clinical risk factors and glycaemic control alone cannot predict the development of vascular complications; numerous genetic studies have demonstrated a clear genetic component to both diabetes and its complications. Early research aimed at identifying genetic determinants of diabetes complications relied on familial linkage analysis suited to strong-effect loci, candidate gene studies prone to false positives, and underpowered genome-wide association studies limited by sample size. The explosion of new genomic datasets, both in terms of biobanks and aggregation of worldwide cohorts, has more than doubled the number of genetic discoveries for both diabetes and diabetes complications. We focus herein on genetic discoveries for diabetes and diabetes complications, empowered primarily through genome-wide association studies, and emphasize the gaps in research for taking genomic discovery to the next level.

Hypertension is closely associated with eye diseases, including hypertensive retinopathy. However, the molecular mechanism controlling the progression of hypertensive retinopathy remains poorly understood. G-Protein Coupled Receptor 174 (GPR174) is expressed in various tissues, and plays a critical role in regulating immune and inflammatory responses. However, if GPR174 is involved in angiotensin II (Ang II)-induced retinopathy is still unclear. In this study, hypertensive retinopathy was induced by Ang II infusion in the wild type (GPR174^+/+) and GPR174 knockout (GPR174^-/-) mice. Clinical data indicated that GPR174 levels were markedly up-regulated in serum of patients with hypertension (HP) or hypertensive retinopathy (HR), along with increased trypsin-like activity. Similar changes of GRP174 and trypsin-like activity were observed in Ang II-infused mice. Furthermore, Ang IIsignificantly increased the central retinal thickness, vascular permeability and inflammatory response in GPR174^+/+ micewhen compared with the saline GPR174^+/+ mice. Of note, these effects were markedly alleviated by the knockout ofGPR174 in Ang II-treated mice. Consistently, vascular endothelial growth factor (VEGF) expression levels in retinal tissue were also stimulated by Ang II, which were clearly attenuated by GPR174^-/-. In addition, phosphatidylinositol 3-kinase (PI3 K)/AKT and nuclear factor-κB (NF-κB) signaling pathways were markedly activated in retinas of Ang II-infused GPR174^+/+ mice, whereas being greatly ameliorated by GPR174^-/-. The in vitro data showed that pre-treatment of PI3 K/AKT specific inhibitor LY294002 remarkably abrogated GPR174 over-expression-accelerated expression levels of Iba-1, tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in lipopolysaccharide (LPS)-incubated retinal microglial cells.Furthermore, in LPS-exposed retinal microglial cells, PI3 K/AKT and NF-κB pathways were further promoted by GPR174 over-expression, which were significantlyabolished by LY294002. Thus, GPR174 might be a positive meditator of inflammation, contributing to Ang II-induced retinopathy by activating PI3 K/AKT signaling, and could be considered as a novel therapeutic target for the treatment of hypertensive retinopathy.

Diabetes mellitus (DM) is a important health problem that induces ernestful complications and it causes significant morbidity owing to specific microvascular complications such as, retinopathy, nephropathy and neuropathy, and macrovascular complications such as, ischaemic heart disease, and peripheral vasculopathy. It can affect children, young people and adults and is becoming more common. Ocular complications associated with DM are progressive and rapidly becoming the world's most significant cause of morbidity and are preventable with early detection and timely treatment. This review provides an overview of five main ocular complications associated with DM, diabetic retinopathy and papillopathy, cataract, glaucoma, and ocular surface diseases.

This study investigated the referral pathways offered to patients with age-related macular degeneration (AMD), diabetic retinopathy (DR) or glaucoma (GL) by ophthalmologists and optometrists.

Australian ophthalmologists and optometrists were surveyed regarding referral decisions to other eye-care specialists (inter- or intra-professional), general medical practitioners (GPs), low vision rehabilitation (LVR) and support services. Thematic analysis and concept mapping were applied to highlight current and ideal referral pathways.

The survey was completed by 155 optometrists and 50 ophthalmologists and deemed representative of their respective professions in Australia. Not surprisingly, the vast majority of the participating optometrists (97 to 99 per cent) referred to ophthalmologists regardless of the underlying condition. Clear differences (Chi-square: p < 0.05) were observed in the referral patterns of optometrists and ophthalmologists to GPs and support services. General medical practitioner services were almost exclusively used for patients with DR, while AMD triggered a significantly higher referral rate to low vision rehabilitation and support services than the other two disorders.

While ophthalmologists predominantly referred patients with AMD, DR or GL to low vision rehabilitation services, optometrists' referrals were highly skewed toward ophthalmology. Referrals to other supporting services by the two groups were not greatly used. The perceived referral pathways by the two eye-care professionals suggested a unidirectional route, potentially highlighting the need for a more collaborative approach that facilitates optimal use of eye health care and allied services.

Proliferative diabetic retinopathy (PDR) is a serious microangiopathic complication of diabetes mellitus and a major cause of blindness in working-age adults. Diabetes-induced alterations in the vitreous protein composition in diabetic patients with PDR may be responsible for the presence of PDR. Therefore, we performed a comprehensive proteomic analysis and compared the protein profiles of vitreous humor from type 2 diabetic patients with PDR (n = 8) and that from normal human eyes donated for corneal transplant (n = 8). Using reversed phase high-performance liquid chromatography (RP-HPLC) coupled to electrospray Ionization tandem mass spectrometry (ESI-MS/MS), we identified 96 significant differentially expressed proteins (abundance ratio > 1.5, p < 0.05), including 37 and 59 proteins up- and downregulated in PDR vitreous compared with the control, respectively. Biological pathway analysis revealed 44 proteins involved in 56 biological pathways; among them, the most remarkable pathways differentially represented between PDR and normal vitreous were the glycolysis/gluconeogenesis, complement and coagulation cascades, gap junction, and phagosome pathways. The differential expressions of angiopoietin-related protein 6, apolipoprotein A-I, estrogen receptor alpha, and tubulin were confirmed by western blot analysis. These data provide insight into the molecular events possibly involved in the pathogenesis of PDR and widen the scope of potential avenues for new therapies for PDR.

Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes and remains a major cause of preventable blindness among adults at working age. DR involves an abnormal pathology of major retinal cells, including retinal pigment epithelium, microaneurysms, inter-retinal oedema, haemorrhage, exudates (hard exudates) and intraocular neovascularization. The biochemical mechanisms associated with hyperglycaemic-induced DR are through multifactorial processes. Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays an important role in the pathogenesis of DR by inhibiting diabetes-induced retinal leukostasis and leakage. Despite DR causing eventual blindness, only a few visual or ophthalmic symptoms are observed until visual loss develops. Therefore, early medical interventions and prevention are the current management strategies. Laser photocoagulation therapy is the most common treatment. However, this therapy may cause retinal damage and scarring. Herbal and traditional natural medicines may provide an alternative to prevent or delay the progression of DR. This review provides an analysis of the therapeutic potential of herbal and traditional natural medicines or their active components for the slowdown of progression of DR and their possible mechanism through the PPAR-γ pathway.

The pathophysiology of the early events leading to diabetic retinopathy is not fully understood. It has been suggested that Inflammatory processes are involved in the development of the disease; however, the concentrations of tissue retinal inflammatory mediators and their possible alteration in diabetic retinopathy have not been described. The aim of this work was to study T-helper cell cytokine and chemokine profiles, and tyrosine nitration in retinal tissue of diabetic rats.

Cytokines (interleukin IL-1a, IL-1b, IL-2, IL-4, IL-6, IL-10, TNFa, GM-CSF, IFN-g), chemokines (MIP-1a, MIP-2, MIP-3a, MCP-1, GRO/KC, RANTES, Fractalkine), and tyrosine nitration were measured in retinal homogenate obtained from Long-Evans rats after 5 months of experimental diabetes.

The T-helper type 1 cytokines IL-2 and INF-gamma, in addition to NO production (measured as nitrotyrosine), were found to be significantly elevated in diabetic rat retina homogenates. None of the other cytokines and chemokines studied were affected by the diabetic condition.

Immunoregulatory cytokines belonging to the Th-1 group (IL-2 and IFN-gamma) were increased in the retina of experimental diabetic rats. Moreover, the nitrotyrosine formation (as an expression of increased NO production) was significantly elevated in the diabetic retina, supporting the concept of an inflammatory element in the development of diabetic retinopathy.