Metabolic reprogramming of the retinal pigment epithelium by cytokines associated with age-related macular degeneration.

The complex metabolic relationship between the retinal pigment epithelium (RPE) and photoreceptors is essential for maintaining retinal health. Recent evidence indicates the RPE acts as an adjacent lactate sink, suppressing glycolysis in the epithelium in order to maximize glycolysis in the photoreceptors. Dysregulated metabolism within the RPE has been implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of vision loss. In the present study, we investigate the effects of four cytokines associated with AMD, TNFα, TGF-ß2, IL-6, and IL-1ß, as well as a cocktail containing all four cytokines, on RPE metabolism using ARPE-19 cells, primary human RPE cells, and ex vivo rat eyecups. Strikingly, we found cytokine-specific changes in numerous metabolic markers including lactate production, glucose consumption, extracellular acidification rate, and oxygen consumption rate accompanied by increases in total mitochondrial volume and ATP production. Together, all four cytokines could potently override the constitutive suppression of glycolysis in the RPE, through a mechanism independent of PI3K/AKT, MEK/ERK, or NF-κB. Finally, we observed changes in glycolytic gene expression with cytokine treatment, including in lactate dehydrogenase subunit and glucose transporter expression. Our findings provide new insights into the metabolic changes in the RPE under inflammatory conditions and highlight potential therapeutic targets for AMD.

Effectiveness of Conventional Digital Fundus Photography-Based Teleretinal Screening for Diabetic Retinopathy and Diabetic Macular Edema: A Report by the American Academy of Ophthalmology.

PURPOSE: This American Academy of Ophthalmology Ophthalmic Technology Assessment aims to assess the effectiveness of conventional teleretinal screening (TS) in detecting diabetic retinopathy (DR) and diabetic macular edema (DME). METHODS: A literature search of the PubMed database was conducted most recently in July 2023 to identify data published between 2006 and 2023 on any of the following elements related to TS effectiveness: (1) the accuracy of TS in detecting DR or DME compared with traditional ophthalmic screening with dilated fundus examination or 7-standard field Early Treatment Diabetic Retinopathy Study photography, (2) the impact of TS on DR screening compliance rates or other patient behaviors, and (3) cost-effectiveness and patient satisfaction of TS compared with traditional DR screening. Identified studies then were rated based on the Oxford Centre for Evidence-Based Medicine grading system. RESULTS: Eight level I studies, 14 level II studies, and 2 level III studies were identified in total. Although cross-study comparison is challenging because of differences in reference standards and grading methods, TS demonstrated acceptable sensitivity and good specificity in detecting DR; moderate to good agreement between TS and reference-standard DR grading was observed. Performance of TS was not as robust in detecting DME, although the number of studies evaluating DME specifically was limited. Two level I studies, 5 level II studies, and 1 level III study supported that TS had a positive impact on overall DR screening compliance, even increasing it by more than 2-fold in one study. Studies assessing cost-effectiveness and patient satisfaction were not graded formally, but they generally showed that TS was cost-effective and preferred by patients over traditional surveillance. CONCLUSIONS: Conventional TS is an effective approach to DR screening not only for its accuracy in detecting referable-level disease, but also for improving screening compliance in a cost-effective manner that may be preferred by patients. Further research is needed to elucidate the ideal approach of TS that may involve integration of artificial intelligence or other imaging technologies in the future. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Treatment of Noninfectious Uveitic Macular Edema with Periocular and Intraocular Corticosteroid Therapies: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the evidence on the effectiveness and complications of periocular and intraocular corticosteroid therapies for noninfectious uveitic macular edema. METHODS: A literature search of the PubMed database was conducted last in December 2021 and a post-assessment search was conducted in March 2023. The searches were limited to articles published in English and no date restrictions were imposed. The combined searches yielded 739 citations; 53 articles were selected for inclusion because the studies (1) evaluated periocular corticosteroid injection, intraocular corticosteroid injection or implant, suprachoroidal corticosteroid injection, or a combination thereof for uveitic macular edema; (2) had outcomes that included visual acuity (VA) or macular edema assessed clinically or imaged by OCT or fluorescein angiography; and (3) included more than 20 patients. RESULTS: This assessment reviewed 23 articles that provided level I or level II evidence from 18 studies on the use of periocular, suprachoroidal, and intravitreal triamcinolone acetonide injections and intravitreal dexamethasone and fluocinolone acetonide implants or inserts in noninfectious uveitic macular edema. These reports consistently demonstrated that all investigated periocular and intraocular corticosteroid therapies improved VA, macular structure, or both. One comparative study showed that intravitreal triamcinolone acetonide injection and the dexamethasone intravitreal implant had effectiveness superior to that of periocular triamcinolone acetonide injection for these outcomes. As a group, the studies highlighted the potential for these therapies to elevate intraocular pressure and to accelerate cataract formation. CONCLUSIONS: The published literature provides high-quality evidence that periocular and intraocular corticosteroid therapies are effective and safe for the treatment of noninfectious uveitic macular edema. However, information on the relative effectiveness and complication rates across the different therapies is limited. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Characterisation of social media conversations on syphilis: an unobtrusive observational study.

BACKGROUND: Conversations around disease conducted through social media provide a means for capturing public perspectives that may be useful in considering public health approaches. Syphilis is a sexually transmitted disease that is re-emerging. We sought to characterise online discourse on syphilis using data collected from the social media platform, Twitter. METHODS: We extracted English-language tweets containing the word 'syphilis' posted on Twitter in 2019. Tweet identification number and URL, date and time of posting, number of retweets and likes, and the author's screen name, username and biographical statement were included in the dataset. A systematically sampled 10% subset of the data was subjected to qualitative analysis, involving categorisation on content. All tweets assigned to the category of medical resource were assessed for clinical accuracy. The engagement ratio for each category was calculated as (retweets+likes):tweets. RESULTS: In 2019, 111,388 tweets mentioning syphilis were posted by 69,921 authors. The most frequent content category - totalling 5370 tweets (48%) - was a joke. Of 1762 tweets (16%) categorised as a medical resource, 1484 (84%) were medically correct and 240 (14%) were medically incorrect; for 38 (2%), medical accuracy could not be judged from the information posted. Tweets categorised as personal experiences had the highest engagement ratio at approximately 19:1. Medical resource tweets had an engagement ratio of approximately 7:1. CONCLUSIONS: We found medical information about syphilis was limited on Twitter. As tweets about personal experiences generate high engagement, coupling an experience with information may provide opportunity for public health education.

Systemic and Ocular Manifestations of Arboviral Infections: A Review.

PURPOSE: To provide an overview of pre-selected emerging arboviruses (arthropod-borne viruses) that cause ocular inflammation in humans. METHODS: A comprehensive review of the literature published between 1997 and 2023 was conducted in PubMed database. We describe current insights into epidemiology, systemic and ocular manifestations, diagnosis, treatment, and prognosis of arboviral diseases including West Nile fever, Dengue fever, Chikungunya, Rift Valley fever, Zika, and Yellow fever. RESULTS: Arboviruses refer to a group of ribonucleic acid viruses transmitted to humans by the bite of hematophagous arthropods, mainly mosquitoes. They mostly circulate in tropical and subtropical zones and pose important public health challenges worldwide because of rising incidence, expanding geographic range, and occurrence of prominent outbreaks as a result of climate change, travel, and globalization. The clinical signs associated with infection from these arboviruses are often inapparent, mild, or non-specific, but they may include serious, potentially disabling or life-threatening complications. A wide spectrum of ophthalmic manifestations has been described including conjunctival involvement, anterior uveitis, intermediate uveitis, various forms of posterior uveitis, maculopathy, optic neuropathy, and other neuro-ophthalmic manifestations. Diagnosis of arboviral diseases is confirmed with either real time polymerase chain reaction or serology. Management involves supportive care as there are currently no specific antiviral drug options. Corticosteroids are often used for the treatment of associated ocular inflammation. Most patients have a good visual prognosis, but there may be permanent visual impairment due to ocular structural complications in some. Community-based integrated mosquito management programs and personal protection measures against mosquito bites are the best ways to prevent human infection and disease. CONCLUSION: Emerging arboviral diseases should be considered in the differential diagnosis of ocular inflammatory conditions in patients living in or returning from endemic regions. Early clinical consideration followed by confirmatory testing can limit or prevent unnecessary treatments for non-arboviral causes of ocular inflammation. Prevention of these infections is crucial.

The Infectious Uveitis Treatment Algorithm Network (TITAN) Report 1-global current practice patterns for the management of Herpes Simplex Virus and Varicella Zoster Virus anterior uveitis.

AIMS: To present current expert practice patterns and to formulate a consensus for the management of HSV and VZV AU by uveitis specialists worldwide. METHODS: A two-round online modified Delphi survey with masking of the study team was conducted. Responses were collected from 76 international uveitis experts from 21 countries. Current practices in the diagnosis and treatment of HSV and VZV AU were identified. A working group (The Infectious Uveitis Treatment Algorithm Network [TITAN]) developed data into consensus guidelines. Consensus is defined as a particular response towards a specific question meeting ≥75% of agreement or IQR ≤ 1 when a Likert scale is used. RESULTS: Unilaterality, increased intraocular pressure (IOP), decreased corneal sensation and diffuse or sectoral iris atrophy are quite specific for HSV or VZV AU from consensus opinion. Sectoral iris atrophy is characteristic of HSV AU. Treatment initiation is highly variable, but most experts preferred valacyclovir owing to simpler dosing. Topical corticosteroids and beta-blockers should be used if necessary. Resolution of inflammation and normalisation of IOP are clinical endpoints. CONCLUSIONS: Consensus was reached on several aspects of diagnosis, choice of initial treatment, and treatment endpoints for HSV and VZV AU. Treatment duration and management of recurrences varied between experts.

The Infectious Uveitis Treatment Algorithm Network (TITAN) Report 2-global current practice patterns for the management of Cytomegalovirus anterior uveitis.

AIMS: To present current practice patterns in the diagnosis and management of Cytomegalovirus anterior uveitis (CMV AU) by uveitis experts worldwide. METHODS: A two-round modified Delphi survey with masking of the study team was performed. Based on experience and expertise, 100 international uveitis specialists from 21 countries were invited to participate in the survey. Variation in the diagnostic approaches and preferred management of CMV AU was captured using an online survey platform. RESULTS: Seventy-five experts completed both surveys. Fifty-five of the 75 experts (73.3%) would always perform diagnostic aqueous tap in suspected CMV AU cases. Consensus was achieved for starting topical antiviral treatment (85% of experts). About half of the experts (48%) would only commence systemic antiviral treatment for severe, prolonged, or atypical presentation. The preferred specific route was ganciclovir gel 0.15% for topical treatment (selected by 70% of experts) and oral valganciclovir for systemic treatment (78% of experts). The majority of experts (77%) would commence treatment with topical corticosteroid four times daily for one to two weeks along with antiviral coverage, with subsequent adjustment depending on the clinical response. Prednisolone acetate 1% was the drug of choice (opted by 70% of experts). Long-term maintenance treatment (up to 12 months) can be considered for chronic course of inflammation (88% of experts) and those with at least 2 episodes of CMV AU within a year (75-88% of experts). CONCLUSIONS: Preferred management practices for CMV AU vary widely. Further research is necessary to refine diagnosis and management and provide higher-level evidence.

Effects of tumor necrosis factor-α and interleukin-1ß on human retinal endothelial cells.

Uveitis, or intraocular inflammation, is a potentially blinding condition that mostly affects the working-age population. The cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, play a role in the pathogenesis of non-infectious uveitis and have been linked to the breakdown of the inner blood-retinal barrier, composed mainly of retinal endothelial cells, leading to macular oedema and vascular leakage. However, the effects of TNF-α and IL-1ß on human retinal endothelial function are not fully understood. In this work, we investigated the impact of TNF-α and IL-1ß on several aspects of human retinal endothelial cell biology. Through a real-time biosensor, the impact of TNF-α and IL-1ß on formation of a retinal endothelial cell barrier was analyzed. Changes in junctional components were assessed via RT-qPCR and immunolabelling. Cell survival, necrosis and apoptosis were appraised via cell proliferation and flow cytometric studies. Tumor necrosis factor-α and IL-1ß impaired the electrical resistance of the retinal endothelial cell barrier, while the addition of a potentially barrier-impairing cytokine, IL-6, did not enhance the effect of TNF-α and IL-1ß. Level of the gene transcript encoding zonula occludens (ZO)-1 was diminished, while ZO-1 protein configuration was changed by TNF-α and IL-1ß. Both cytokines affected human retinal endothelial cell proliferation and viability, while only TNF-α increased rates of necrosis. These results indicate that TNF-α and IL-1ß are important drivers of retinal endothelial dysfunction in non-infectious uveitis, suggesting that targeting these cytokines is critical when treating complications of uveitis, such as macular oedema and vascular leakage.

Inflammatory cytokines as mediators of retinal endothelial barrier dysfunction in non-infectious uveitis.

Characterised by intraocular inflammation, non-infectious uveitis includes a large group of autoimmune and autoinflammatory diseases that either involve the eye alone or have both ocular and systemic manifestations. When non-infectious uveitis involves the posterior segment of the eye, specifically the retina, there is substantial risk of vision loss, often linked to breakdown of the inner blood-retinal barrier. This barrier is formed by non-fenestrated retinal vascular endothelial cells, reinforced by supporting cells that include pericytes, Müller cells and astrocytes. Across the published literature, a group of inflammatory cytokines stand out as prominent mediators of intraocular inflammation, with effects on the retinal endothelium that may contribute to breakdown of the inner blood-retinal barrier, namely tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-8, IL-17 and chemokine C-C motif ligand (CCL)2. This article reviews the function of each cytokine and discusses the evidence for their involvement in retinal endothelial barrier dysfunction in non-infectious uveitis, including basic laboratory investigations, studies of ocular fluids collected from patients with non-infectious uveitis, and results of clinical treatment trials. The review also outlines gaps in knowledge in this area. Understanding the disease processes at a molecular level can suggest treatment alternatives that are directed against appropriate biological targets to protect the posterior segment of eye and preserve vision in non-infectious uveitis.

Sarcoid Uveitis in Children.

Sarcoidosis is a multi-system granulomatous disease that often presents with uveitis. Although sarcoidosis and sarcoid uveitis typically occur in adulthood, children also may be affected. There are two distinct clinical presentations of the pediatric disease, associated with younger and older age groups, and having different causations. "Early-onset sarcoidosis", beginning at age 5 years or less, is an autosomal dominant genetic disease, caused by a mutation in the NOD2 gene. It is also known as sporadic Blau syndrome or Jabs syndrome. "Adult-type sarcoidosis", usually beginning between the ages of 8 and 15 years, is believed to represent an excessive response to an environmental antigen. There is limited literature on the management of pediatric sarcoidosis, and treatment follows an approach applied to other forms of pediatric non-infectious uveitis. When systemic immunomodulatory therapy is indicated, methotrexate and/or adalimumab are often employed. The condition may persist into adulthood, and thus long-term follow-up is indicated.

Vision-related quality of life in patients treated for ocular syphilis.

Multiple studies have showed negative impact of non-infectious uveitis on quality of life (QoL). Less is understood regarding life experiences in patients with infectious uveitis. We investigated vision-related QoL in individuals who had recovered from ocular syphilis. 32 adults treated for ocular syphilis at a uveitis service in Brazil completed the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25), and a comprehensive ophthalmic examination was performed. Medical records were reviewed to confirm resolution of ocular inflammation for 3 months pre-enrolment, and collect clinical data. The NEI VFQ-25 composite score was low overall (75.5 ± 19.8, mean ± standard deviation), and subscale scores varied from relative lows of 59.1 ± 39.6 (driving) and 60.9 ± 24.5 (mental health), to relative highs of 84.8 ± 21.8 (ocular) and 89.1 ± 21.0 (color vision). Adults aged over 40 years and those with a final visual acuity of 20/50 or worse had significantly lower mean composite and subscale scores. Other clinical characteristics-including gender, HIV co-infection, and type of uveitis-did not significantly influence scores. Our findings, taken in context with previous observations that prompt recognition achieves better vision outcomes, suggest early treatment may improve QoL after recovery from ocular syphilis.

Oxidative Stress and Its Regulation in Diabetic Retinopathy.

Diabetic retinopathy is the retinal disease associated with hyperglycemia in patients who suffer from type 1 or type 2 diabetes. It includes maculopathy, involving the central retina and characterized by ischemia and/or edema, and peripheral retinopathy that progresses to a proliferative stage with neovascularization. Approximately 10% of the global population is estimated to suffer from diabetes, and around one in 5 of these individuals have diabetic retinopathy. One of the major effects of hyperglycemia is oxidative stress, the pathological state in which elevated production of reactive oxygen species damages tissues, cells, and macromolecules. The retina is relatively prone to oxidative stress due to its high metabolic activity. This review provides a summary of the role of oxidative stress in diabetic retinopathy, including a description of the retinal cell players and the molecular mechanisms. It discusses pathological processes, including the formation and effects of advanced glycation end-products, the impact of metabolic memory, and involvements of non-coding RNA. The opportunities for the therapeutic blockade of oxidative stress in diabetic retinopathy are also considered.

Dengue Virus Infection of Human Retinal Müller Glial Cells.

Retinopathy is a recently recognized complication of dengue, affecting up to 10% of hospitalized patients. Research on the pathogenesis has focused largely on effects of dengue virus (DENV) at the blood-retinal barrier. Involvement of retinal Müller glial cells has received little attention, although this cell population contributes to the pathology of other intraocular infections. The goal of our work was to establish the susceptibility of Müller cells to infection with DENV and to identify characteristics of the cellular antiviral, inflammatory, and immunomodulatory responses to DENV infection in vitro. Primary human Müller cell isolates and the MIO-M1 human Müller cell line were infected with the laboratory-adapted Mon601 strain and DENV serotype 1 and 2 field isolates, and cell-DENV interactions were investigated by immunolabelling and quantitative real-time polymerase chain reaction. Müller cells were susceptible to DENV infection, but experiments involving primary cell isolates indicated inter-individual variation. Viral infection induced an inflammatory response (including tumour necrosis factor-α, interleukin [IL]-1ß, and IL-6) and an immunomodulatory response (including programmed death-ligand [PD-L]1 and PD-L2). The type I interferon response was muted in the Müller cell line compared to primary cell isolates. The highest infectivity and cell responses were observed in the laboratory-adapted strain, and overall, infectivity and cell responses were stronger in DENV2 strains. This work demonstrates that Müller cells mount an antiviral and immune response to DENV infection, and that this response varies across cell isolates and DENV strain. The research provides a direction for future efforts to understand the role of human retinal Müller glial cells in dengue retinopathy.

Demystifying Ocular Syphilis - A Major Review.

Syphilis, caused by the spirochaete, Treponema pallidum, continues to be a public health challenge globally with its rates steadily increasing in the past few years. The disease is transmitted through small breaks in the skin during sexual contact, or via congenital transmission in utero, either across the placenta or by contact with an active genital lesion during delivery. Estimated 5.7-6 million new cases are detected every year worldwide in the 15-49 years age group. An increased incidence has been reported in most populations with particular clusters in special groups like men who have sex with men, female sex workers, and their male clients. Ocular syphilis has a varied presentation and is considered a great mimicker in all cases of uveitis. The laboratory diagnosis of syphilis is predominantly based on serological tests including TPHA and VDRL. Parenteral penicillin is the cornerstone of treatment for all stages of ocular syphilis.

Intercellular Adhesion Molecule 1: More than a Leukocyte Adhesion Molecule.

Intercellular adhesion molecule 1 (ICAM-1) is a transmembrane protein in the immunoglobulin superfamily expressed on the surface of multiple cell populations and upregulated by inflammatory stimuli. It mediates cellular adhesive interactions by binding to the ß2 integrins macrophage antigen 1 and leukocyte function-associated antigen 1, as well as other ligands. It has important roles in the immune system, including in leukocyte adhesion to the endothelium and transendothelial migration, and at the immunological synapse formed between lymphocytes and antigen-presenting cells. ICAM-1 has also been implicated in the pathophysiology of diverse diseases from cardiovascular diseases to autoimmune disorders, certain infections, and cancer. In this review, we summarize the current understanding of the structure and regulation of the ICAM1 gene and the ICAM-1 protein. We discuss the roles of ICAM-1 in the normal immune system and a selection of diseases to highlight the breadth and often double-edged nature of its functions. Finally, we discuss current therapeutics and opportunities for advancements.

Impact of gender on clinical features and outcomes of ocular toxoplasmosis.

AIM: To investigate the effect of gender on the clinical features and outcomes of ocular toxoplasmosis. METHODS: 262 patients (139 women and 123 men) presenting to a tertiary referral uveitis service in Ribeirão Preto, Brazil, with serological and clinical evidence of ocular toxoplasmosis were prospectively enrolled in an observational study. Predefined data items including demographics, descriptors of uveitis and ocular toxoplasmosis, best-corrected visual acuity and ocular complications were disaggregated by gender and compared statistically. RESULTS: Approximately equal numbers of women and men had active versus inactive ocular toxoplasmosis. In both women and men, most infections were remotely acquired. Men were significantly more likely to present with primary active disease than women (24.4% vs 12.9%); conversely, women were significantly more likely to present with recurrent active disease than men (36.0% vs 28.5%). One toxoplasmic retinal lesion was observed in more eyes of men than eyes of women (50.4% vs 35.3%), while women's eyes were more likely to have multiple lesions than men's eyes (54.7% vs 39.8%). Lesions in women's eyes were significantly more likely to occur at the posterior pole compared with those in men's eyes (56.1% vs 39.8%). Measures of vision were similar for women and men. There were no significant differences in measures of visual acuity, ocular complications, and occurrence and timing of reactivations between the genders. CONCLUSION: Ocular toxoplasmosis has equivalent outcomes in women and men, with clinical differences in the form and type of disease, as well as characteristics of the retinal lesion.

Human retinal endothelial cells express functional interleukin-6 receptor.

BACKGROUND: Interleukin (IL)-6 is an inflammatory cytokine present in the eye during non-infectious uveitis, where it contributes to the progression of inflammation. There are two major IL-6 signaling pathways: classic signaling and trans-signaling. Classic signaling requires cellular expression of the IL-6 receptor (IL-6R), which exists in membrane-bound (mIL-6R) and soluble (sIL-6R) forms. Prevailing dogma is that vascular endothelial cells do not produce IL-6R, relying on trans-signaling during inflammation. However, the literature is inconsistent, including with respect to human retinal endothelial cells. FINDINGS: We examined IL-6R transcript and protein expression in multiple primary human retinal endothelial cell isolates, and assessed the effect of IL-6 on the transcellular electrical resistance of monolayers. Using reverse transcription-polymerase chain reaction, IL-6R, mIL-6R and sIL-6R transcripts were amplified in 6  primary human retinal endothelial isolates. Flow cytometry on 5 primary human retinal endothelial cell isolates under non-permeabilizing conditions and following permeabilization demonstrated intracellular stores of IL-6R and the presence of mIL-6R. When measured in real-time, transcellular electrical resistance of an expanded human retinal endothelial cell isolate, also shown to express IL-6R, decreased significantly on treatment with recombinant IL-6 in comparison to non-treated cells across 5 independent experiments. CONCLUSIONS: Our findings indicate that human retinal endothelial cells produce IL-6R transcript and functional IL-6R protein. The potential for classic signaling in human retinal endothelial cells has implications for the development of therapeutics targeted against IL-6-mediated pathology in non-infectious uveitis.