Regeneration of blood vessels in ischemic neuronal tissue is critical to reduce tissue damage in diseases. In proliferative retinopathy, initial vessel loss leads to retinal ischemia, which can induce either regrowth of vessels to restore normal metabolism and minimize damage, or progress to hypoxia-induced sight-threatening pathologic vaso-proliferation. It is not well understood how retinal neurons mediate regeneration of vascular growth in response to ischemic insults. In this study we aim to investigate the potential role of Sirtuin 1 (Sirt1), a metabolically-regulated protein deacetylase, in mediating the response of ischemic neurons to regulate vascular regrowth in a mouse model of oxygen-induced ischemic retinopathy (OIR). We found that Sirt1 is highly induced in the avascular ischemic retina in OIR. Conditional depletion of neuronal Sirt1 leads to significantly decreased retinal vascular regeneration into the avascular zone and increased hypoxia-induced pathologic vascular growth. This effect is likely independent of PGC-1α, a known Sirt1 target, as absence of PGC-1α in knockout mice does not impact vascular growth in retinopathy. We found that neuronal Sirt1 controls vascular regrowth in part through modulating deacetylation and stability of hypoxia-induced factor 1α and 2α, and thereby modulating expression of angiogenic factors. These results indicate that ischemic neurons induce Sirt1 to promote revascularization into ischemic neuronal areas, suggesting a novel role of neuronal Sirt1 in mediating vascular regeneration in ischemic conditions, with potential implications beyond retinopathy.

Abnormal lipid metabolism has been linked to age-related macular degeneration (AMD); choroidal neovascularization in late AMD commonly causes blindness. Sene et al. (2013) now demonstrate that in aged macrophages decreased ABCA1 expression, regulated by liver X receptor and miR-33, impairs export of intracellular cholesterol, which promotes neovascular AMD.

PURPOSE: A majority of experimental data on dry eye disease (DED) immunopathogenesis have been derived from a murine model of DED that combines desiccating environmental stress with systemic muscarinic acetylcholine receptor (mAChR) inhibition. However, to our knowledge the effects of pharmacologic mAChR blockade on the pathogenesis of experimental DED have not been evaluated systemically. The purpose of our study was to investigate the differential effects of desiccating environmental stress and mAChR inhibition on the pathogenesis of DED. METHODS: DED was induced in female C57BL/6 mice by exposure to a desiccating environment in the controlled-environment chamber or to systemic scopolamine, or by performing extraorbital lacrimal gland excision. Clinical disease was assessed using corneal fluorescein staining (CFS) and the cotton thread test (CTT). Corneal CD11b(+) and conjunctival CD3(+) T-cell infiltration were evaluated by flow cytometry. T-cells from draining cervical lymph nodes (CLN) and distant inguinal lymph nodes (ILN) were analyzed for Th1, Th2, Th17, and Treg responses by flow cytometry and ELISA. RESULTS: Desiccating environmental stress and systemic mAChR blockade induced similar clinical signs of DED. However, desiccating environmental stress imparted higher conjunctival CD3(+) T-cell infiltration, and greater Th17-cell activity and Treg dysfunction than mAChR blockade, while mAChR blockade decreased tear secretion to a greater extent than desiccating environmental stress. Systemic mAChR blockade attenuated Th17 activity and enhanced Th2 and Treg responses without affecting Th1 activity. CONCLUSIONS: In vivo inhibition of mAChRs variably affects CD4(+) T-cell subsets, and desiccating environmental stress and systemic mAChR blockade induce DED through different primary pathogenic mechanisms.

OBJECTIVE: To report the retention rate of the Boston keratoprosthesis type 1 and to identify risk factors for keratoprosthesis loss. DESIGN: Cohort study. PARTICIPANTS: A total of 300 eyes of 300 patients who underwent implantation of the Boston keratoprosthesis type I device between January 2003 and July 2008 by 19 surgeons at 18 medical centers. METHODS: Forms reporting preoperative, intraoperative, and postoperative parameters were prospectively collected and subsequently analyzed at a central data collection site. MAIN OUTCOME MEASURES: Keratoprosthesis retention. RESULTS: A total cumulative number of 422 life-years of device implantation are included in this analysis. The average duration of follow-up was 17.1 ± 14.8 months, with a range of 1 week to >6.1 years. Ninety-three percent of the 300 Boston keratoprosthesis implants were retained at their last follow-up, corresponding to a retention time of 396 patient-years or 1.42 years/keratoprosthesis. The probability of retention after 1 year and 2 years was 94% and 89%, respectively. During the study period, 21 (7%) eyes failed to retain the device; the reasons for keratoprosthesis loss include sterile keratolysis (9), fungal infections (8), dense retroprosthetic membranes (3), and bacterial endophthalmitis (1). Multivariate analysis demonstrated 3 independent risk factors for keratoprosthesis loss: autoimmune cause (hazard ratio [HR], 11.94; 95% confidence interval [CI], 3.31-43.11), ocular surface exposure requiring a concomitant tarsorrhaphy (HR, 3.43; 95% CI, 1.05-11.22), and number of prior failed penetrating keratoplasties (HR, 1.64; 95% CI, 1.18-2.28). CONCLUSIONS: The Boston keratoprosthesis type 1 seems to be a viable option for eyes that are not candidates for penetrating keratoplasty (PK). Ocular surface disease due to an autoimmune cause demonstrated the lowest retention rate. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Audio-based Environment Simulator (AbES) is virtual environment software designed to improve real world navigation skills in the blind. Using only audio based cues and set within the context of a video game metaphor, users gather relevant spatial information regarding a building's layout. This allows the user to develop an accurate spatial cognitive map of a large-scale three-dimensional space that can be manipulated for the purposes of a real indoor navigation task. After game play, participants are then assessed on their ability to navigate within the target physical building represented in the game. Preliminary results suggest that early blind users were able to acquire relevant information regarding the spatial layout of a previously unfamiliar building as indexed by their performance on a series of navigation tasks. These tasks included path finding through the virtual and physical building, as well as a series of drop off tasks. We find that the immersive and highly interactive nature of the AbES software appears to greatly engage the blind user to actively explore the virtual environment. Applications of this approach may extend to larger populations of visually impaired individuals.

Ocular surface inflammation associated with Sjögren's syndrome is characterized by a loss of secretory function and alteration in numbers of mucin secreting goblet cells. Such changes are a prominent feature of ocular surface inflammatory diseases and are attributed to inflammation; however, the exact effect of the inflammatory cytokines on conjunctival goblet cell function remains largely unknown. In this study, we developed a primary culture of mouse goblet cells from conjunctival tissue and evaluated the effects on their function by inflammatory cytokines detected in the conjunctiva of mouse model of Sjögren's syndrome (Thrombospondin-1 deficient mice). We found that apoptosis of goblet cells was primarily induced by TNF-α and IFN-γ. These two cytokines also inhibited mucin secretion by goblet cells in response to cholinergic stimulation, whereas IL-6 enhanced such secretion. No changes in secretory response were detected in the presence of IL-13 or IL-17. Goblet cells proliferated to varying degrees in response to all the tested cytokines with the greatest response to IL-13 followed by IL-6. Our results therefore reveal that inflammatory cytokines expressed in the conjunctiva during an ocular surface disease directly disrupt conjunctival goblet cell functions, compromising the protective function of tears, thereby contributing to ocular surface damage.

Lacrimal gland inflammation during autoimmune Sjögren's syndrome (SS) leads to ocular surface inflammation - Keratoconjunctivitis sicca (KCS). This condition afflicts both the cornea and conjunctiva that form the ocular surface. Thrombospondin-1 (TSP-1) deficiency in mice results in lacrimal gland and corneal inflammation that resembles the human disease. In this study we report conjunctival pathology in this mouse model of SS. We found that TSP-1 null mice develop inflammation in the conjunctiva and associated loss of goblet cell function similar to that seen in patients with SS. Increased expression of Th1 (IFN-γ, TNF-α) and Th17 (IL-6, IL-17A) inflammatory cytokines and related transcription factors (Tbet and RORγt) were detected in TSP-1 null conjunctiva as well as their draining lymph nodes (LNs). The conjunctival inflammation was also accompanied by an increase in local lymphatic vessels. Interestingly, migration of antigen-bearing dendritic cells (DCs) from the ocular surface to the LNs was dependent on the TSP-1 available in the tissue. These results not only reveal potential immunopathogenic mechanisms underlying KCS in SS but also highlight the therapeutic potential of TSP-1.

PURPOSE: To compare the anatomy of the graft-host junction and anterior chamber angle after Boston Keratoprosthesis (KPro) placement using oversized (9.5-mm) and standard (8.5-mm) back plates. METHODS: Six patients with 9.5-mm titanium back plates and 10 patients with 8.5-mm titanium back plates were imaged by anterior segment optical coherence tomography 6 to 12 months after KPro placement. The location of the graft-host junction in relation to the back plate, the corneal thickness at the graft-host junction, and the anterior chamber angle were assessed. The clinical outcomes and incidence of retroprosthetic membrane (RPM) formation in this cohort were retrospectively evaluated. RESULTS: The oversized back plates completely covered the graft-host junction in all quadrants, allowing the complete apposition of the posterior surface of the carrier graft with the host cornea, with decreased graft-host junction wound thickness. The standard back plates covered the posterior aspect of the carrier graft but not the graft-host junction or the host cornea, resulting in a significantly thicker graft-host junction. None of the patients with larger back plates developed a significant RPM during a 12-month follow-up period. One patient with a larger back plate developed a corneal melt at the KPro stem as a result of chronic exposure. CONCLUSIONS: Oversized KPro back plates effectively cover the graft-host junction without any adverse effects on angle anatomy or wound healing. This may be a strategy to provide better wound apposition, reduce RPM formation, and reduce angle closure from iris synechiae to the wound.