T-cell activation requires co-stimulation through receptors such as CD28 and antigen-specific signalling through the T-cell antigen receptor. Here we describe a new murine costimulatory receptor-ligand pair. The receptor, which is related to CD28 and is the homologue of the human protein ICOS, is expressed on activated T cells and resting memory T cells. The ligand, which has homology to B7 molecules and is called B7-related protein-1 (B7RP-1), is expressed on B cells and macrophages. ICOS and B7RP-I do not interact with proteins in the CD28-B7 pathway, and B7RP-1 co-stimulates T cells in vitro independently of CD28. Transgenic mice expressing a B7RP-1-Fc fusion protein show lymphoid hyperplasia in the spleen, lymph nodes and Peyer's patches. Presensitized mice treated with B7RP-1-Fc during antigen challenge show enhanced hypersensitivity. Therefore, B7RP-1 exhibits co-stimulatory activities in vitro and in vivo. ICOS and B7RP-1 define a new and distinct receptor-ligand pair that is structurally related to CD28-B7 and is involved in the adaptive immune response.

Summary The regulation of apoptosis is critical for controlling tissue homeostasis and preventing tumor formation and growth. Reactive Oxygen Species (ROS) generation plays a key role in such regulation. Here, we describe a HIF-1 target, ATIA (anti-TNFα-induced apoptosis), which protects cells against TNFα- and hypoxia-induced apoptosis. Through the generation of ATIA knockout mice, we show that ATIA protects cells from apoptosis through regulating the function of the mitochondrial antioxidant, thioredoxin-2, and ROS generation. ATIA is highly expressed in human glioblastoma and ATIA knockdown in glioblastoma cells renders them sensitive to hypoxia-induced apoptosis. Therefore, ATIA is not only a HIF-1 target that regulates mitochondrial redox pathways but a potentially diagnostic marker and therapeutic target in human glioblastoma.

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Primary open-angle glaucoma, a long-term degenerative ocular neuropathy, remains a significant cause of vision impairment worldwide. While many risk factors have been correlated with increased risk for primary open-angle glaucoma, intraocular pressure (IOP) remains the only modifiable risk factor and primary therapeutic target. Pharmacologic therapies are administered topically; these include α2-agonists, β-antagonists, prostaglandin analogs and carbonic anhydrase inhibitors. Some of these topical medications exhibit secondary neuroprotective effects independent of their effect on IOP. This review covers the possible mechanisms of neuroprotection stimulated by drugs currently marketed for the lowering of IOP, based on known literature. While the neuroprotective properties of many glaucoma pharmaceuticals are promising from an experimental standpoint, key challenges for the development of new clinical practices include unknown systemic side effects, limited methods of drug delivery to the retina and optic nerve, and development of extended-release formulations.

Purpose: We examined the efficacy of an extended-release drug delivery system, nanosponge (NS) encapsulated compounds, administered intravitreally to lower intraocular pressure (IOP) in mice.Methods: Bilateral ocular hypertension was induced in mice by injecting microbeads into the anterior chamber. Hypertensive mice received NS loaded with ocular hypotensive drugs via intravitreal injection and IOP was monitored. Retinal deposition and retinal ganglion cell (RGC) uptake of Neuro-DiO were examined following intravitreal injection of Neuro-DiO-NS using confocal microscopy.Results: Brimonidine-loaded NS lowered IOP 12% to 30% for up to 6 days (P , 0.02), whereas travoprost-NS lowered IOP 19% to 29% for up to 4 days (P , 0.02) compared to saline injection. Three bimatoprost NS were tested: a 400-nm NS and two 700-nm NS with amorphous (A-NS) or amorphous/crystalline (AC-NS) crosslinkers. A single injection of 400 nm NS lowered IOP 24% to 33% for up to 17 days compared to saline, while A-NS and AC-NS lowered IOP 22% to 32% and 18% to 26%, respectively, for up to 32 days (P , 0.046). Over time retinal deposition of Neuro-DiO increased from 19% to 71%; Neuro-DiO released from NS was internalized by RGCs.Conclusions: A single injection of NS can effectively deliver ocular hypotensive drugs in a linear and continuous manner for up to 32 days. Also, NS may be effective at targeting RGCs, the neurons that degenerate in glaucoma.Translational Relevance: Patient compliance is a major issue in glaucoma. The use of NS to deliver a controlled, sustained release of therapeutics could drastically reduce the number of patients that progress to vision loss in this disease.

Purpose To evaluate whether dietary intake of lutein/zeaxanthin and B vitamins is associated with cataract prevalence and incidence. Design Clinic-based, baseline cross-sectional and prospective cohort study designs. Participants 3115 (6129 eyes) persons enrolled in the Age-Related Eye Disease Study, aged 55 to 80 years, followed for mean of 9.6 years. Methods Participants completed baseline food frequency questionnaires. Baseline and annual lens photographs were graded centrally. Multivariable models controlling for previously identified risk factors for cataracts were used to measure the association of cataracts with reported dietary intake, using the lowest quintile as reference. Main Outcome Measures Cataract surgery, cataract status (type and severity) at baseline, development of cataracts. Results At baseline, increased dietary riboflavin and B12 were inversely associated with nuclear and cortical lens opacities. In comparisons of persons with and without cataract, persons with the highest riboflavin intake vs. those with the lowest intake had the following associations: odds ratio (OR): 0.78, 95% confidence interval (CI): 0.63–0.97 for mild nuclear, OR: 0.62, 95% CI: 0.43–0.90 for moderate nuclear, and OR: 0.80, 95% CI: 0.65–0.99 for mild cortical cataracts. For B12, the results were: OR: 0.78, 95% CI: 0.63–0.96 for mild nuclear, OR: 0.62, 95% CI: 0.43–0.88 for moderate nuclear, and OR: 0.77, 95% CI: 0.63–0.95 for mild cortical cataracts. Highest dietary B6 intake was associated with a decreased risk of developing moderate nuclear lens opacity compared with the lowest quintile, OR: 0.67, 95% CI: 0.45–0.99. Highest dietary intake levels of niacin and B12 were associated with a decreased risk of development of mild nuclear or mild cortical cataracts in participants not taking Centrum® multivitamin. For participants taking Centrum® during the study, highest intake of dietary folate was associated with an increased risk of development of mild posterior subcapsular lens opacity. No statistically significant associations were found between lutein/zeaxanthin intake and presence at baseline or development of nuclear or cortical lens opacity outcomes. Conclusions Findings from our study are consistent with earlier studies suggesting that dietary intake of B vitamins may affect the occurrence of age-related lens opacities. Further investigations are warranted.

The purpose of this study was to evaluate patterns of subretinal fluid (SRF) resolution in Group D retinoblastoma eyes. Fifty-three Group D eyes were evaluated for the presence of SRF at diagnosis. They were subsequently treated with systemic chemoreduction (CRD) and the duration of SRF was evaluated. Logistic regression analysis was used to assess the association between duration of SRF and enucleation. Among the 53 Group D eyes, 42 eyes exhibited SRF at diagnosis (79%). After the first cycle of CRD, 27/42 eyes showed SRF (64%); 8/42 eyes demonstrated SRF after three cycles of CRD (19%), and only 3/42 eyes had SRF after six cycles (7%). Ten eyes were enucleated (10/53 or 19%). Only 1 of 10 eyes demonstrated persistent SRF at the time of enucleation. This retrospective analysis of patterns of subretinal fluid in retinoblastoma eyes demonstrates that 80% of Group D eyes present with SRF. Of these eyes, approximately 60% have persistent fluid after one cycle of CRD and less than 10% have persistent fluid after six cycles. However, presence or persistence of SRF during chemoreduction was not found to be a risk factor for enucleation in Group D retinoblastoma eyes.

Abstract Periorbital burns generate contraction and distortion of periorbital soft tissue, causing eyelid malfunction, further contributing to loss of vision from corneal scarring or perforation. We present our multidisciplinary algorithm to restore vision in patients with burn-related bilateral corneal blindness with light perception. Chart review was performed for four consecutive burn patients requiring periocular reconstruction and keratoprosthesis. Initial treatment included globe coverage with eyelid releases and grafts. Strategy of corneal replacement was determined by eyelid position and function and sufficiency of tear production. All patients were corneal blind with light perception only and cicatricial ectropion. The eye with better visual prognosis was reconstructed. Eyelid reconstruction procedures consisted of lid releases with full-thickness skin graft (FTSG) or split-thickness skin graft (STSG). Two patients regained adequate lid function and underwent standard keratoprosthesis placement. Two underwent mucous membrane grafts followed by keratoprosthesis. All patients experienced improved postoperative vision in their reconstructed eye. Corneal injury due to periocular burns can lead to blindness. Early involvement of ophthalmology, protective measures, and early ectropion release are critical. For severe burns, a multidisciplinary approach, where adequate globe protection is followed by keratoprosthesis placement, can effectively restore vision in patients with burn-related corneal blindness.