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This randomized trial involved 160 patients with the acquired immunodeficiency syndrome (AIDS) and newly diagnosed cytomegalovirus retinitis. After four weeks, the response to induction therapy was satisfactory in 72 percent of patients who received oral valganciclovir, as compared with 77 percent of those who received intravenous ganciclovir. The median time to progression of retinitis was 160 days for the valganciclovir group and 125 days for the ganciclovir group. Cytomegalovirus retinitis remains the leading cause of visual loss in patients with the acquired immunodeficiency syndrome (AIDS). 1 – 3 Induction therapy with intravenous ganciclovir, 4 , 5 foscarnet, 5 , 6 or cidofovir, 7 , 8 followed by maintenance therapy, can effectively make cytomegalovirus retinitis inactive. If recovery of immune function is not possible, indefinite treatment is needed, and an indwelling catheter and daily intravenous medication may be required. The cost, the risk of sepsis, and the adverse effect on the quality of life associated with an indwelling catheter spurred the development of an oral formulation of ganciclovir. 9 When administered orally, ganciclovir requires three doses (up to . . .

Retinitis pigmentosa (RP) is characterized by progressive photoreceptor cells death accelerated by the proliferation and activation of microglia pathologically. No consensus exists on the treatment. Minocycline is recognized as a microglia inhibitor with great anti-inflammatory and neuro-protective functions. However, efficacy of minocycline in RP patients is lacking. We conducted a prospective, open-label, and single-arm trial, in which daily oral minocycline of 100 mg was administered for 12 months in RP patients with light-adapted 30 Hz flicker electroretinography (ERG) amplitude >0 µV in at least one eye (NCT04068207). The primary outcome was the proportion of participants with improvement in the ERG amplitude at month 12. The secondary outcomes included improvements of the following items: other ERGs amplitudes, visual field, best-corrected visual acuity, contrast sensitivity, color vision, and NEI-VFQ-25. 35 of 288 patients met inclusive criteria were enrolled (median [IQR] age, 36 [31–45] years; 17 female [48.6%]). 32 participants completed all examinations, while 3 participants completed the 12-month online visit via conducting NEI-VFQ-25. The primary outcome showed improvement was 34.3% (12 of 35 [95% CI 19.1–52.2]). Similarly, all secondary outcomes showed improvements. Adverse events were reported in 22 participants (62.9%) and were all resolved without extra medication during the study period. No severe adverse events were recorded. Our findings identified daily oral minocycline of 100 mg for 12 months was beneficial in improving the visual function of RP patients with good safety. This study indicates minocycline may be a promising therapy for RP, but a randomized controlled trial is still needed of further exploration.

Background Glaucoma, the leading cause of irreversible blindness, is a retinal neurodegenerative disease, which results from progressive apoptotic death of retinal ganglion cells (RGCs). Although the mechanisms underlying RGC apoptosis in glaucoma are extremely complicated, an abnormal cross-talk between retinal glial cells and RGCs is generally thought to be involved. However, how interaction of Müller cells and microglia, two types of glial cells, contributes to RGC injury is largely unknown. Methods A mouse chronic ocular hypertension (COH) experimental glaucoma model was produced. Western blotting, immunofluorescence, quantitative real-time polymerase chain reaction (q-PCR), transwell co-culture of glial cells, flow cytometry assay, ELISA, Ca 2+ image, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) techniques were employed to investigate the interaction of Müller cells and microglia, and its underlying mechanisms in COH retina. Results We first showed that Müller cell activation in mice with COH induced microglia activation through the ATP/P2X7 receptor pathway. The activation of microglia resulted in a significant increase in mRNA and protein levels of pro-inflammatory factors, such as tumor necrosis factor-α and interleukin-6. These inflammatory factors in turn caused the up-regulation of mRNA expression of pro-inflammatory factors in Müller cells through a positive feedback manner. Conclusions These findings provide robust evidence, for the first time, that retinal inflammatory response may be aggravated by an interplay between activated two types of glial cells. These results also suggest that to reduce the interplay between Müller cells and microglia could be a potential effective strategy for preventing the loss of RGCs in glaucoma.

Ischemic retinopathies (IRs) are leading causes of visual impairment. They are characterized by an initial phase of microvascular degeneration and a second phase of aberrant pre-retinal neovascularization (NV). microRNAs (miRNAs) regulate gene expression, and a number play a role in normal and pathological NV. But, post-transcriptional modulation of miRNAs in the eye during the development of IRs has not been systematically evaluated. Using Next Generation Sequencing (NGS) we profiled miRNA expression in the retina and choroid during vasodegenerative and NV phases of oxygen-induced retinopathy (OIR). Approximately 20% of total miRNAs exhibited altered expression (up- or down-regulation); 6% of miRNA were found highly expressed in retina and choroid of rats subjected to OIR. During OIR-induced vessel degeneration phase, miR-199a-3p, -199a-5p, -1b, -126a-3p displayed a robust decreased expression (> 85%) in the retina. While in the choroid, miR-152-3p, -142-3p, -148a-3p, -532-3p were upregulated (>200%) and miR-96-5p, -124-3p, -9a-3p, -190b-5p, -181a-1-3p, -9a-5p, -183-5p were downregulated (>70%) compared to controls. During peak pathological NV, miR-30a-5p, -30e-5p and 190b-5p were markedly reduced (>70%), and miR-30e-3p, miR-335, -30b-5p strongly augmented (by up to 300%) in the retina. Whereas in choroid, miR-let-7f-5p, miR-126a-5p and miR-101a-3p were downregulated by (>81%), and miR-125a-5p, let-7e-5p and let-7g-5p were upregulated by (>570%) during NV. Changes in miRNA observed using NGS were validated using qRT-PCR for the 24 most modulated miRNAs. In silico approach to predict miRNA target genes (using algorithms of miRSystem database) identified potential new target genes with pro-inflammatory, apoptotic and angiogenic properties. The present study is the first comprehensive description of retinal/choroidal miRNAs profiling in OIR (using NGS technology). Our results provide a valuable framework for the characterization and possible therapeutic potential of specific miRNAs involved in ocular IR-triggered inflammation, angiogenesis and degeneration.

AimsTo compare optical coherence tomography (OCT) features of active necrotising infectious retinitis (NIR) due to toxoplasmosis or herpesviruses and to determine distinctive OCT signs for these two causes of infectious retinitis.MethodsOCT scans from eyes with active NIR due to varicella zoster virus (VZV), herpes simplex virus (HSV), cytomegalovirus (CMV), and toxoplasmosis (TOXO) were reviewed. All images were evaluated for the presence of previously described OCT findings in TOXO-NIR and compared with the viral group. New OCT findings were recorded and compared. Retinal and choroidal thickness were measured at the site of NIR and compared.Results10 eyes diagnosed with TOXO-NIR and 13 eyes affected by viral-NIR (9 CMV and 4 VZV) were analysed. All eyes showed full thickness hyper-reflectivity, disruption of the retina and a variable degree of vitritis. Among previously described OCT signs, hyper-reflective oval deposits and hypo-reflectivity of the choroid had a higher prevalence in TOXO (p=0.018 and p<0.0001, respectively). Among the new signs, hyper-reflective round deposits along the posterior hyaloid, retrohyaloid hyper-reflective spots and a disruption of the choroidal architecture were more frequent in TOXO eyes (all p<0.01). Intra-retinal oedema and hyper-reflective vertical strips within the outer nuclear layer were suggestive of a viral aetiology (p=0.045). Retinal thickness at the site of NIR did not differ between the two groups. Choroidal thickness was significantly higher in TOXO eyes (p=0.01).ConclusionsThe diagnosis of NIR is largely based on clinical and laboratory findings. OCT changes may be useful in differentiating different causes of NIR.

In this study the retinal transcriptome was investigated during the development of experimental autoimmune uveoretinitis (EAU) in mice. EAU was induced by immunizing B10.RIII mice with human interphotoreceptor retinoid binding protein (hIRBP) 161–180 peptide. Genome-wide transcriptional profiles of EAU (day 7, 14 or 21 after immunization) and of control retinas were generated using DNA-microarrays and bioinformatic data mining. Microglia-associated transcripts were identified. Quantitative real-time polymerase chain reaction was performed to validate the expression of differentially expressed genes. Retinal transcript validation revealed that complement and interferon-related pathways, as well as gene clusters specific for antigen-processing and -presentation, and immunosuppression are involved during the course of the disease. Immunofluorescence analysis confirm that upregulated transcripts in EAU are also expressed by retinal microglia. Furthermore, the heterogenous expression patterns observed in retinal microglia, suggests the presence of different subpopulations of retinal microglia in EAU. This study expands our knowledge of the local immune processes involved in EAU pathology.

The retinal pigment epithelium (RPE) forms the outer blood–retina barrier and facilitates the transepithelial transport of glucose into the outer retina via GLUT1. Glucose is metabolized in photoreceptors via the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS) but also by aerobic glycolysis to generate glycerol for the synthesis of phospholipids for the renewal of their outer segments. Aerobic glycolysis in the photoreceptors also leads to a high rate of production of lactate which is transported out of the subretinal space to the choroidal circulation by the RPE. Lactate taken up by the RPE is converted to pyruvate and metabolized via OXPHOS. Excess lactate in the RPE is transported across the basolateral membrane to the choroid. The uptake of glucose by cone photoreceptor cells is enhanced by rod-derived cone viability factor (RdCVF) secreted by rods and by insulin signaling. Together, the three cells act as symbiotes: the RPE supplies the glucose from the choroidal circulation to the photoreceptors, the rods help the cones, and both produce lactate to feed the RPE. In age-related macular degeneration this delicate ménage à trois is disturbed by the chronic infiltration of inflammatory macrophages. These immune cells also rely on aerobic glycolysis and compete for glucose and produce lactate. We here review the glucose metabolism in the homeostasis of the outer retina and in macrophages and hypothesize what happens when the metabolism of photoreceptors and the RPE is disturbed by chronic inflammation.

Perinatal hypoxic–ischemic encephalopathy (HIE) is a condition resulting from oxygen deprivation around the time of birth and may be associated with death, brain damage, and disability. Alongside this, studies have shown that HIE may result in visual impairment. Previously, this was thought to be due to damage to the visual pathways in the brain, in a condition known as cerebral visual impairment. However, recent studies suggest that direct injury to the retina may occur after HIE. Of note, the nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) inflammasome is thought to play a role in perpetuating inflammatory damage in the brain after hypoxia–ischemia (HI). As such, this study aimed to characterize retinal inflammation and the role of the NLRP3 inflammasome after HI using a modified Rice-Vannucci model in postnatal day 10 (P10) rat. Eighteen Sprague-Dawley rats were allocated evenly to three groups. Two groups received surgery to ligate the right common-carotid artery and induce HI, while another group received only sham surgery. Rats exposed to HI received subcutaneous injections of tonabersat (HI + Ton) or saline (HI + vehicle) at 1, 24 and 48 h after HI, and were culled at P17 for analysis. The results showed that the protein expression of GFAP, Iba-1, NLRP3, caspase-1 and connexin43 increased in the retina at 7 d after HI-vehicle compared with sham surgery, much more so in the ipsilateral = than the contralateral retina. Furthermore, = inflammasome components NLRP3, cleaved caspase-1 and connexin43 were significantly upregulated in the ipsilateral retina following HI-vehicle compared to the sham surgery group. Treatment with a connexin43 hemichannel blocker, tonabersat, significantly decreased the expression of the inflammasome markers, cleaved caspase-1 and connexin43, and diminished Iba-1+ cell infiltration in the ipsilateral retina. These findings suggest that direct retinal damage and inflammation may occur after HI. Furthermore, these inflammatory changes are likely mediated and propagated by activation of the NLRP3 inflammasome. Importantly, inhibition of the inflammasome by tonabersat may be able to inhibit retinal inflammation and damage, potentially preventing visual impairment after HI. Further investigation in humans is required to determine the efficacy of tonabersat in treating hypoxic–ischemic injuries to the brain and eye.

Diabetic retinopathy (DR) is a leading cause of visual impairment. To better understand the pathology, clinically relevant experimental models are needed. Widely used DR models (especially streptozotocin (STZ)-induced) require extended timeframes to reach DR phenotype endpoints and lack ischemic phenotypes, which are in contrast to the human condition. Unilateral common carotid artery occlusion (UCCAO) could provide a retinal ischemic insult. We explored the pathologic synergistic effects of UCCAO in STZ mice. STZ (90 mg/kg) was injected intraperitoneally into adult C57BL/6 mice for three days. Four weeks later, right UCCAO was performed. One week after UCCAO, retinal samples were stained with isolectin B4 to analyze cellular and vascular changes. Retinal samples were obtained one day and one week after UCCAO and quantitative PCR (qPCR) were performed to observe inflammatory and ischemic responses. Only the STZ UCCAO group showed increased inflammatory cells. STZ UCCAO retina demonstrated a significant difference in capillary and large vessel size compared to other groups. At one day and one week, there was a change in mRNA expressions in inflammatory genes Ccl2, Ccl12, Bnip3, Pdk1, Hsp25, and Vegfa in the STZ UCCAO group compared to other groups. Our model can serve as an accelerated DR model for studying inflammatory vascular changes.

OPTN (E50K) mutation is one of the significant pathogenic mutations in normal tension glaucoma (NTG). The molecular mechanism of NTG optic nerve injury is complex and diverse; its key mechanism is still unclear. The NLR family pyrin domain containing (NLRP3) inflammasome plays an essential role in the occurrence and development of inflammation. There is no report on whether NLRP3 inflammasome activation plays a crucial role in NTG optic nerve injury. Here, we explored the role of retinal inflammatory cascade reaction triggered by NLRP3 inflammasome activation in OPTN (E50K) mutated NTG optic nerve injury. This research may provide innovative strategies for effectively treating NTG optic nerve injury caused by OPTN (E50K) mutation. The R28 cell was constructed by AAV2 transfection, named GFP-R28, WT-R28, and E50K-R28 groups. Western blot, qPCR, and immunofluorescence were performed to measure the expression levels of the neurotrophic factors, the senescence indicators, the NLRP3-related indicators, the expression of the glial cell markers, and the inflammatory cytokines. Further, observe the changes in the above indicators in the WT-R28 and E50K-R28 groups after treatment with MCC950. Next, we compared the expression of neurotrophic factors and senescence indicators, NLRP3-related indicators, glial cell markers, and inflammatory factors between young and old WT and OPTN (E50K) mice. We examined the visual function of mice on days 1, 4 and 7. Furthermore, we observed the retinal morphology and the expression of neurotrophic factors and senescence indicators, NLRP3-related indicators, glial cell markers, and inflammatory factors between all groups were measured. We found that OPTN (E50K) mutations lead to NLRP3 inflammasome activation. The OPTN (E50K) mutant groups showed an inflammatory cascade, including glial cell activation and release of proinflammatory factors, leading to retinal structural and functional impairment in mice.MCC950 effectively inhibited the activation of the NLRP3 inflammasome and alleviated the retinal inflammatory cascade caused by the OPTN (E50K) mutation, ultimately improving visual function and retinal damage in mice. OPTN (E50K) mutation induces the activation of the NLRP3 inflammasome, which leads to a retinal inflammatory cascade. MCC950 can inhibit the activation of the NLRP3 inflammasome and retinal inflammatory cascade, improving visual function in OPTN (E50K) mutation mice.