Visual deterioration in patients with photoreceptor loss after retinal reattachment surgery.

PURPOSE: Assess the relationship between photoreceptor degeneration and visual function after retinal reattachment surgery (RRS) in a prospective cohort. METHODS: Patients with rhegmatogenous retinal detachment (RRD) were reviewed before and 6 months after vitreoretinal surgery. Optical coherence tomographical thickness of the outer nuclear layer (ONL), outer retinal segment (ORS), retinal pigmented epithelium to ellipsoid zone (RPE-EZ) and external limiting membrane to EZ (ELM-EZ) were recorded 6 months post-operatively. These were compared to best corrected visual acuity (BCVA) and retinal sensitivity (Humphrey visual field). RESULTS: Thirteen macula-off and 8 macula-on RRD patients were included. The mean ONL thickness was higher after macula-on RRD compared to macula-off RRD (97.70 ± 3.62 µm vs. 73.10 ± 4.98 µm). In all RRD eyes, every 1 µm decrease in ONL thickness correlated with a 0.052 dB decrease and in retinal sensitivity and every 1 µm decrease in ORS thickness was associated with a 0.062 dB reduction in retinal sensitivity. ORS, ELM-EZ and RPE-EZ thickness did not correlate with BCVA post-RRS. CONCLUSION: There was greater ONL and ORS thinning following macula-off compared to macula-on RRD. Correlations between ONL and ORS thinning with decreased retinal sensitivity may be explained by RRD-induced photoreceptor death.

Visual outcomes after blunt ocular trauma.

OBJECTIVE: To describe the prognosis and retinal location in patients presenting with acute traumatic maculopathy and extramacular retinal injuries. DESIGN: Retrospective, noninterventional case series. PARTICIPANTS AND CONTROLS: All patients presenting with commotio retinae or sclopetaria retinae to the Birmingham Midland Eye Centre Eye Casualty from October 1, 2007, to February 23, 2011. METHODS: The notes of all patients presenting with ocular trauma in the specified time period were examined to identify suitable patients and demographic and injury data were extracted. MAIN OUTCOME MEASURES: Outcome was assessed by visual acuity (VA). RESULTS: For macular commotio retinae, 53 patients were identified, of whom 34 had adequate follow-up to determine final VA. The median presenting VA was 20/40; 25 patients (74%) recovered to ≥ 20/30. The median extent of visual recovery was 0.18 logarithm of the minimum angle of resolution (logMAR). For extramacular commotio retinae, 117 patients were identified, of whom 58 had adequate follow-up to determine final VA. The median presenting VA retinae was 20/30; 55 patients (95%) recovered to ≥ 20/30. The median extent of visual recovery was logMAR 0.076. There was 1 case of extramacular sclopetaria retinae. The 3 most common retinal locations of extramacular commotio retinae, in order of frequency, were inferotemporal (37%), temporal (17%), and superotemporal (17%); <5% of cases were in a nasal location. CONCLUSIONS: This is the first report on the prognosis of acute traumatic maculopathy and extramacular commotio retinae. After macular injury, 26% of patients were left with a VA of ≤ 20/30, although the proportion with visual impairment is higher than this because (1) a deterioration from 20/15 to 20/30 is significant to many patients; and (2) additional patients are visually impaired by symptomatic paracentral visual field defects despite a normal VA. Reduced VA after extramacular commotio retinae may represent occult macular injury or previously undiagnosed visual impairment in the affected eye. Extramacular commotio occurs mostly in an inferotemporal to temporal location, consistent with direct trauma to the sclera overlying the injured retina. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Reversible branch retinal artery occlusion following intravenous cisplatin chemotherapy for cervical carcinoma.

Cisplatin (CDDP) is a chemotherapeutic agent widely used to treat solid tumours. We present a case of reversible CDDP-associated branch retinal artery occlusion.

Inflammatory and Fibrogenic Factors in Proliferative Vitreoretinopathy Development.

Purpose: Proliferative vitreoretinopathy (PVR) occurs in 5%-10% of rhegmatogenous retinal detachment cases and is the principle cause for failure of retinal reattachment surgery. Although there are a number of surgical adjunctive agents available for preventing the development of PVR, all have limited efficacy. Discovering predictive molecular biomarkers to determine the probability of PVR development after retinal reattachment surgery will allow better patient stratification for more targeted drug evaluations. Methods: Narrative literature review. Results: We provide a summary of the inflammatory and fibrogenic factors found in ocular fluid samples during the development of retinal detachment and PVR and discuss their possible use as molecular PVR predictive biomarkers. Conclusions: Studies monitoring the levels of the above factors have found that few if any have predictive biomarker value, suggesting that widening the phenotype of potential factors and a combinatorial approach are required to determine predictive biomarkers for PVR. Translational Relevance: The identification of relevant biomarkers relies on an understanding of disease signaling pathways derived from basic science research. We discuss the extent to which those molecules identified as biomarkers and predictors of PVR relate to disease pathogenesis and could function as useful disease predictors. (http://www.umin.ac.jp/ctr/ number, UMIN000005604).

Metabolomic analysis of human vitreous humor differentiates ocular inflammatory disease.

PURPOSE: Vitreoretinal disorders lack specific biomarkers that define either disease type or response to treatment. We have used NMR-based metabolomic analysis of human vitreous humor to assess the applicability of this approach to the study of ocular disease. METHODS: Vitreous samples from patients with a range of vitreoretinal disorders were subjected to high-resolution (1)H-nuclear magnetic resonance spectroscopy (NMR). Good quality spectra were derived from the vitreous samples, and the profiles were analyzed by three different methods. RESULTS: Principal component analysis (PCA) showed a wide dispersal of the different clinical conditions. Partial least squares discriminant analysis (PLS-DA) was used to define differences between lens-induced uveitis (LIU) and chronic uveitis (CU) and could distinguish between these conditions with a sensitivity of 78% and specificity of 85%. A genetic algorithm coupled with multivariate classification identified a small number of spectral components that showed clear discrimination between LIU and CU samples with sensitivity and specificity >90%. Assignment of specific resonances indicated that some metabolites involved in the arginase pathway were significantly more abundant in LIU than CU. CONCLUSION: The discrimination we observed based on PCA, PLS-DA, and multivariate variable selection analysis of the NMR spectra suggests that a complex mix of metabolites are present in vitreous fluid of different uveitic conditions as a result of the disease process. Collectively the data demonstrates the efficacy of metabolomic analysis to distinguish between ocular inflammatory diseases.

Effects of siRNA-Mediated Knockdown of GSK3ß on Retinal Ganglion Cell Survival and Neurite/Axon Growth.

There are contradictory reports on the role of the serine/threonine kinase isoform glycogen synthase kinase-3ß (GSK3ß) after injury to the central nervous system (CNS). Some report that GSK3 activity promotes axonal growth or myelin disinhibition, whilst others report that GSK3 activity prevents axon regeneration. In this study, we sought to clarify if suppression of GSK3ß alone and in combination with the cellular-stress-induced factor RTP801 (also known as REDD1: regulated in development and DNA damage response protein), using translationally relevant siRNAs, promotes retinal ganglion cell (RGC) survival and neurite outgrowth/axon regeneration. Adult mixed retinal cell cultures, prepared from rats at five days after optic nerve crush (ONC) to activate retinal glia, were treated with siRNA to GSK3ß (siGSK3ß) alone or in combination with siRTP801 and RGC survival and neurite outgrowth were quantified in the presence and absence of Rapamycin or inhibitory Nogo-A peptides. In in vivo experiments, either siGSK3ß alone or in combination with siRTP801 were intravitreally injected every eight days after ONC and RGC survival and axon regeneration was assessed at 24 days. Optimal doses of siGSK3ß alone promoted significant RGC survival, increasing the number of RGC with neurites without affecting neurite length, an effect that was sensitive to Rapamycin. In addition, knockdown of GSK3ß overcame Nogo-A-mediated neurite growth inhibition. Knockdown of GSK3ß after ONC in vivo enhanced RGC survival but not axon number or length, without potentiating glial activation. Knockdown of RTP801 increased both RGC survival and axon regeneration, whilst the combined knockdown of GSK3ß and RTP801 significantly increased RGC survival, neurite outgrowth, and axon regeneration over and above that observed for siGSK3ß or siRTP801 alone. These results suggest that GSK3ß suppression promotes RGC survival and axon initiation whilst, when in combination with RTP801, it also enhanced disinhibited axon elongation.

Altered Decorin Biology in Proliferative Vitreoretinopathy: A Mechanistic and Cohort Study.

Purpose: To determine if vitreous levels of the pro-fibrotic cytokine transforming growth factor beta2 (TGF-ß2) and its opposing regulator decorin predict subsequent proliferative vitreoretinopathy (PVR) development in patients with rhegmatogenous retinal detachment (RRD). Methods: We examined the effect of TGF-ß2 and decorin on epithelial-mesenchymal transition (EMT) and collagen expression in vitro using ARPE-19 cells, and we analyzed extracellular matrix marker expression in PVR membrane and internal limiting membrane patient samples. We performed a prospective noninterventional cohort study, recruiting 125 patients undergoing vitrectomy for RRD and macular hole surgery, measured vitreous levels of TGF-ß2 and decorin by ELISA, and followed them up for 6 months. Patients who did not develop PVR were compared to those who did, in order to determine whether vitreous TGF-ß2 and decorin levels predicted PVR development. Results: In vitro, TGF-ß2 induced EMT and collagen production. Decorin strongly inhibited EMT and collagen production at high levels. PVR membranes expressed high levels of fibrosis-associated proteins, consistent with EMT. Vitreous TGF-ß2 levels were unchanged between patients with macular holes and RRD who did or did not subsequently develop PVR. Average decorin levels were higher in the vitreous of RRD patients who subsequently developed PVR compared to those who did not, but at the measured vitreous concentrations (1-2 µg/mL), decorin did not demonstrate an in vitro inhibitory effect on EMT. Conclusions: In vitro, high concentrations of decorin inhibited EMT and fibrosis. At the levels seen in human vitreous, decorin did not prevent fibrosis or EMT in vitro, and higher initial vitreous decorin levels were associated with the development of postoperative PVR after vitrectomy to treat RRD, but did not reliably predict the outcome.

Multiplex bead analysis of vitreous humor of patients with vitreoretinal disorders.

PURPOSE: Vitreoretinal disorders are frequently characterized by increased vitreous levels of cellular mediators, including cytokines, chemokines, and growth factors. The study was conducted to investigate whether multiplex bead analysis could identify disease-specific profiles of these mediators in a variety of vitreoretinal diseases. METHODS: Levels of 19 mediators were measured: the cytokines IL-6, IL-10, IL-12, IL-13, IL-15, IL-17, TNF, IFN-gamma, granulocyte-macrophage-colony-stimulating factor (GM-CSF), and granulocyte-stimulating factor (G-CSF); the chemokines CCL2, CCL3, CCL4, CCL5, CCL11, and CXCL8; and the growth factors epidermal growth factor (EGF), FGF, and VEGF, by using multiplex bead analysis of vitreous humor of 58 eyes undergoing vitrectomy for a variety of vitreoretinal disorders. RESULTS: The predominant mediators detected were IL-6, CXCL8, and CCL2. The most complex pattern of mediators was seen in patients with proliferative vitreoretinopathy (PVR) and included a mixture of cytokines, chemokines, and growth factors. Patients with chronic uveitis showed a limited mediator pattern that did not suggest either a Th1 or Th2 response. By comparison, patients with lens-induced uveitis (LIU) showed significantly greater levels of cytokines than did patients with chronic uveitis, including IFN-gamma and IL-12, with a trend toward an acute Th1 inflammatory response. Moreover, in samples from patients with LIU, CXCL8 inversely correlated with time after initial surgery and duration of treatment. CONCLUSIONS: Multiplex bead analysis allows the measurement of multiple mediators from a single vitreous sample. The data confirm patterns of mediators previously described in different vitreoretinal conditions. In addition, LIU mediator levels correlate with duration of treatment and time after cataract surgery.

Topical Delivery of Anti-VEGF Drugs to the Ocular Posterior Segment Using Cell-Penetrating Peptides.

Purpose: To evaluate the efficacy of anti-VEGF agents for treating choroidal neovascularization (CNV) when delivered topically using novel cell-penetrating peptides (CPPs) compared with delivery by intravitreal (ivit) injection. Methods: CPP toxicity was investigated in cell cultures. Ivit concentrations of ranibizumab and bevacizumab after topical administration were measured using ELISA. The biological efficacy of topical anti-VEGF + CPP complexes was compared with ivit anti-VEGF injections using an established model of CNV. Results: CPPs were nontoxic in vitro. In vivo, after topical eye drop delivery, CPPs were present in the rat anterior chamber within 6 minutes. A single application of CPP + bevacizumab eye drop delivered clinically relevant concentrations of bevacizumab to the posterior chamber of the rat eye in vivo. Similarly, clinically relevant levels of CPP + ranibizumab and CPP + bevacizumab were detected in the porcine vitreous and retina ex vivo. In an established model of CNV, mice treated with either a single ivit injection of anti-VEGF, twice daily CPP + anti-VEGF eye drops or daily dexamethasone gavage for 10 days all had significantly reduced areas of CNV when compared with lasered eyes without treatment. Conclusions: CPPs are nontoxic to ocular cells and can be used to deliver therapeutically relevant doses of ranibizumab and bevacizumab by eye drop to the posterior segment of mouse, rat, and pig eyes. The CPP + anti-VEGF drug complexes were cleared from the retina within 24 hours, suggesting a daily eye drop dosing regimen. Daily, topically delivered anti-VEGF with CPP was as efficacious as a single ivit injection of anti-VEGF in reducing areas of CNV in vivo.

Antimicrobial peptide coatings for hydroxyapatite: electrostatic and covalent attachment of antimicrobial peptides to surfaces.

The interface between implanted devices and their host tissue is complex and is often optimized for maximal integration and cell adhesion. However, this also gives a surface suitable for bacterial colonization. We have developed a novel method of modifying the surface at the material-tissue interface with an antimicrobial peptide (AMP) coating to allow cell attachment while inhibiting bacterial colonization. The technology reported here is a dual AMP coating. The dual coating consists of AMPs covalently bonded to the hydroxyapatite surface, followed by deposition of electrostatically bound AMPs. The dual approach gives an efficacious coating which is stable for over 12 months and can prevent colonization of the surface by both Gram-positive and Gram-negative bacteria.

Mass and shape as factors in intraocular foreign body injuries.

OBJECTIVES: To relate the nature, mass, and shape of intraocular foreign bodies (IOFBs) in a consecutive series of 69 patients to the mechanism, location, and visual outcome of the injuries and to compare these outcomes with data collected in our department over the last 70 years. DESIGN: Interventional case series of consecutive patients with IOFBs. PARTICIPANTS: Sixty-nine patients with unilateral IOFBs. INTERVENTION: All patients underwent surgical removal of the IOFB. MAIN OUTCOME MEASURES: Patient data included best-corrected visual acuity (BCVA), imaging and complication rates. For the IOFBs, material, mass, shape, and entry site were determined. RESULTS: The IOFB was metallic in 91% of cases. All but 2 patients were male (mean age, 37). Increasing IOFB mass was associated with posterior segment injury, retinal impact, presenting and final BCVAs< or =20/200, the need for a primary globe repair before secondary IOFB removal, increasing complications, and the development of retinal detachment. Blade-shaped IOFBs penetrated to the posterior segment (97%) more frequently (P<0.05) than disc (74%), cylinder (7.5%), or sphere (7.5%) shapes despite having the second lowest mass. Two patients were shown to have a second previously unrecognized IOFB on computed tomography (CT). Overall, 49% of patients experienced some sort of complication as a result of their injury. The development of endophthalmitis was associated with the failure to use prophylactic systemic antibiotics. There was no association between increased time to IOFB removal and the development of endophthalmitis. The frequency of posterior vitreous detachment was not increased in eyes with more severe injury or those in which surgery was deferred. Final BCVA> or =20/40 was achieved in 56% of the patients. CONCLUSIONS: Intraocular foreign bodies of greater mass were associated with worse outcomes. We have observed an 82% reduction in number of IOFB injuries presenting over the last 70 years and outcomes have improved with advances in surgical technique. We advise that all patients with a visible or suspected IOFB be investigated with x-ray or CT and that they should all receive systemic antibiotics. We detected no advantage or disadvantage in delaying surgery until optimal surgical expertise and/or environment is available.

Triamcinolone during pars plana vitrectomy for open globe trauma: a pilot randomised controlled clinical trial.

PURPOSE: To investigate the feasibility of conducting a randomised controlled trial in patients undergoing pars plana vitrectomy surgery following open globe trauma (OGT). Additionally, to investigate the treatment effect and toxicity of intensive anti-inflammatory agents. METHODS: A 2-year, pilot, single-centre prospective, participant and surgeon-masked randomised controlled trial (RCT). Forty patients requiring vitrectomy surgery following OGT were randomised to either standard (control) or study treatment (adjuncts) in a 1:1 allocation ratio. Perioperatively, the adjunct group received intravitreal and subtenons triamcinolone acetonide, oral flurbiprofen and guttae prednisolone acetate 1%. The control group received standard care. Primary outcome was anatomical success at 6 months. Secondary outcomes included final visual acuity, occurrence of proliferative vitreoretinopathy, intraocular pressure rise, number of operations and recruitment rate. RESULTS: 40 patients were recruited within 21 months. Primary outcome assessment showed similar results in anatomical success with 50% (10/20) in the adjunct group compared with 47% (9/19) in the standard group (OR 1.11, 95% CI 0.316 to 3.904). Visual outcomes were better in the adjunct group with a final median visual acuity of 31 Early Treatment Diabetic Retinopathy Study (ETDRS) letters compared with 25 ETDRS letters in the standard group. A higher proportion of patients gained 10, 20 and 30 ETDRS letters in the adjunct group (80%, 65% and 50%, respectively) compared with the standard group (52.6%, 52.6% and 42.1%). Fewer adjunct patients (15%, n=3) had poor visual outcomes (Zero ETDRS letters) compared with 42.1%, (n=8). CONCLUSIONS: An RCT in this population is deliverable and estimated recruitment rates are realistic. Results and patient discussions determined that the definitive study should have vision as a primary outcome. This pilot study is supportive of there being a positive treatment effect of intensive anti-inflammatory agents in OGT. TRIAL REGISTRATION NUMBER: European Clinical Trials Database 2007-005138-35; Results.

siRNA-Mediated Knockdown of the mTOR Inhibitor RTP801 Promotes Retinal Ganglion Cell Survival and Axon Elongation by Direct and Indirect Mechanisms.

PURPOSE: To investigate, using in vivo and in vitro models, retinal ganglion cell (RGC) neuroprotective and axon regenerative effects and underlying mechanisms of siRTP801, a translatable small-interfering RNA (siRNA) targeting the mTOR negative regulator RTP801. METHODS: Adult rats underwent optic nerve (ON) crush (ONC) followed by intravitreal siRTP801 or control siRNA (siEGFP) every 8 days, with Brn3a+ RGC survival, GFAP+ reactive gliosis, and GAP43+ regenerating axons analyzed immunohistochemically 24 days after injury. Retinal cultures, prepared from uninjured animals or 5 days after ONC to activate retinal glia, were treated with siRTP801/controls in the presence/absence of rapamycin and subsequently assessed for RGC survival and neurite outgrowth, RTP801 expression, glial responses, and mTOR activity. Conditioned medium was analyzed for neurotrophin titers by ELISA. RESULTS: Intravitreal siRTP801 enabled 82% RGC survival compared to 45% with siEGFP 24 days after ONC, correlated with greater GAP43+ axon regeneration at 400 to 1200 µm beyond the ONC site, and potentiated the reactive GFAP+ Müller glial response. In culture, siRTP801 had a direct RGC neuroprotective effect, but required GFAP+ activated glia to stimulate neurite elongation. The siRTP801-induced neuroprotection was significantly reduced, but not abolished, by rapamycin. The siRTP801 potentiated the production and release of neurotrophins NGF, NT-3, and BDNF, and prevented downregulation of RGC mTOR activity. CONCLUSIONS: The RTP801 knockdown promoted RGC survival and axon elongation after ONC, without increasing de novo regenerative sprouting. The neuroprotection was predominantly direct, with mTORC1-dependent and -independent components. Enhanced neurite/axon elongation by siRTP801 required the presence of activated retinal glia and was mediated by potentiated secretion of neurotrophic factors.

Contact lenses and corrective flying spectacles in military aircrew--implications for flight safety.

BACKGROUND: Refractive devices used by aviators need to suit the aerospace environment or their failure can have serious implications. A relatively minor visual disability can result in loss of life and aircraft. We surveyed commonly occurring problems with the different types of refractive correction worn by Royal Air Force (RAF) aircrew over the previous 12 mo. We also asked if they had experienced any flight safety incidents (FSI) relating to their refractive correction. METHODS: A retrospective anonymous questionnaire survey was given to 700 active aircrew occupationally graded as requiring corrective flying spectacles (CFS) or contact lenses (CL) for flying. RESULTS: 63% (443) of the questionnaires were completed. CL were worn by 53% of aircrew; 71% of them used daily disposable CL. CFS were worn by the remaining 47% of aircrew, 14% of whom used multifocal lenses. Of CFS wearers, 83% reported problems including misting, moving, discomfort, and conflict with helmet-mounted devices (HMD). CL-related ocular symptoms were reported in 67% of wearers including cloudy vision, dry eye, photophobia, red eyes, excessive mucus formation, CL movement, itching, and grittiness. No CL-related FSI were reported over the previous 12 mo compared with 5% CFS-related FSI (p < 0.001). The graded performance of CL for vision, comfort, handling, convenience, and overall satisfaction was significantly higher than for CFS. CONCLUSION: CFS are associated with problems in terms of comfort and safety. CL are well tolerated by aircrew, and deliver improved visual performance.

Stem cell treatment of degenerative eye disease.

Stem cell therapies are being explored extensively as treatments for degenerative eye disease, either for replacing lost neurons, restoring neural circuits or, based on more recent evidence, as paracrine-mediated therapies in which stem cell-derived trophic factors protect compromised endogenous retinal neurons from death and induce the growth of new connections. Retinal progenitor phenotypes induced from embryonic stem cells/induced pluripotent stem cells (ESCs/iPSCs) and endogenous retinal stem cells may replace lost photoreceptors and retinal pigment epithelial (RPE) cells and restore vision in the diseased eye, whereas treatment of injured retinal ganglion cells (RGCs) has so far been reliant on mesenchymal stem cells (MSC). Here, we review the properties of non-retinal-derived adult stem cells, in particular neural stem cells (NSCs), MSC derived from bone marrow (BMSC), adipose tissues (ADSC) and dental pulp (DPSC), together with ESC/iPSC and discuss and compare their potential advantages as therapies designed to provide trophic support, repair and replacement of retinal neurons, RPE and glia in degenerative retinal diseases. We conclude that ESCs/iPSCs have the potential to replace lost retinal cells, whereas MSC may be a useful source of paracrine factors that protect RGC and stimulate regeneration of their axons in the optic nerve in degenerate eye disease. NSC may have potential as both a source of replacement cells and also as mediators of paracrine treatment.

Peptide aptamers: Novel coatings for orthopaedic implants.

Current processes for coating titanium implants with ceramics involve very high energy techniques with associated high cost and disadvantages such as heterogeneity of the coatings, phase transformations and inability to coat complex structures. In order to address the above problems, we propose a biomimetic hydroxyapatite coating process with the use of peptides that can bind both on titanium surfaces and hydroxyapatite. The peptides enabled homogeneous coating of a titanium surface with hydroxyapatite. The hydroxyapatite-peptide sandwich coating showed no adverse effects on cell number or collagen deposition. This makes the sandwich coated titanium a good candidate for titanium implants used in orthopaedics and dentistry.

Decorin Reduces Intraocular Pressure and Retinal Ganglion Cell Loss in Rodents Through Fibrolysis of the Scarred Trabecular Meshwork.

PURPOSE: To investigate whether Decorin, a matrikine that regulates extracellular matrix (ECM) deposition, can reverse established trabecular meshwork (TM) fibrosis, lower IOP, and reduce progressive retinal ganglion cell (RGC) death in a novel rodent model of TM fibrosis. METHODS: Adult rats had intracameral (IC) injections of human recombinant (hr) TGF-ß over 30 days (30 d; to induce TM fibrosis, raise IOP, and initiate RGC death by 17 d) or PBS (controls) and visually evoked potentials (VEP) were measured at 30 d to evaluate resultant visual pathway dysfunction. In some animals TGF-ß injections were stopped at 17 d when TM fibrosis and IOP were consistently raised and either hrDecorin or PBS IC injections were administered between 21 d and 30 d. Intraocular pressure was measured biweekly and eyes were processed for immunohistochemical analysis of ECM deposition to assess TM fibrosis and levels of matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) to assess fibrolysis. The effect of hrDecorin treatment on RGC survival was also assessed. RESULTS: Transforming growth factor-ß injections caused sustained increases in ECM deposition in the TM and raised IOP by 17 d, responses that were associated with 42% RGC loss and a significant decrease in VEP amplitude measured at 30 d. Decorin treatment from 17 d reduced TGF-ß-induced TM fibrosis, increased levels of MMP2 and MMP9 and lowered TIMP2 levels, and lowered IOP, preventing progressive RGC loss. CONCLUSIONS: Human recombinant Decorin reversed established TM fibrosis and lowered IOP, thereby rescuing RGC from progressive death. These data provide evidence for the candidacy of hrDecorin as a treatment for open-angle glaucoma.

Caspase-9 mediates photoreceptor death after blunt ocular trauma.

PURPOSE: Ocular trauma is common in civilian and military populations. Commotio retinae involves acute disruption of photoreceptor outer segments after blunt ocular trauma, with subsequent photoreceptor apoptosis causing permanent visual impairment. The mechanisms of photoreceptor death in commotio retinae have not previously been described, although caspase-dependent death is important in other nontraumatic retinal degenerations. We assessed the role of caspase-9 as a mediator of photoreceptor death in a rat model of ballistic ocular trauma causing commotio retinae. METHODS: Bilateral commotio retinae was induced in rats by ballistic ocular trauma. Caspase-9 activity was assessed by immunohistochemistry, Western blotting, and bVAD-fmk active caspase capture. Caspase-9 was inhibited by unilateral intravitreal injection of highly specific X-linked inhibitor of apoptosis (IAP) baculoviral IAP repeat 3 (XBIR3) domain linked to the cell transduction peptide penetratin 1 (Pen-1) after ballistic injury, and the affected eyes were compared with control eyes treated with Pen-1 injection alone, and retinal function was assessed by electroretinogram a-wave amplitude and photoreceptor survival by outer nuclear layer thickness. RESULTS: Increased levels of cleaved caspase-9 were shown in photoreceptors 5 hours after injury, and catalytically active full-length caspase-9 was isolated from retinas. Photoreceptor death after commotio retinae was reduced by caspase-9 inhibition by using Pen-1-XBIR3, and electroretinographic measurements of photoreceptor function was preserved, providing structural and functional neuroprotection. CONCLUSIONS: The time course of caspase-9 activation and the neuroprotective effects of inhibition suggest that caspase-9 initiates cell death in a proportion of photoreceptors after blunt ocular trauma and that an intravitreally delivered biologic inhibitor may be an effective translational treatment strategy.

Reported toxicity in 1486 liquid detergent capsule exposures to the UK National Poisons Information Service 2009-2012, including their ophthalmic and CNS effects.

CONTEXT. Data on the ophthalmic and central nervous system (CNS) adverse effects of liquid detergent capsules (liquid laundry pods) are limited. OBJECTIVE. To ascertain the reported toxicity of liquid detergent capsules, particularly their ophthalmic and CNS adverse effects, in a large case series. METHODS. Between 1 May 2009 and 30 July 2012 the UK National Poisons Information Service collected prospectively 1509 telephone enquiries (involving 1486 exposures) relating to liquid detergent capsules. RESULTS. The majority of patients (95.6%) were children aged less than 5. Exposure to these products occurred mainly as a result of ingestion alone (n = 1215; 81.8%), with eye contact alone (n = 110; 7.4%), and skin contact alone (n = 20; 1.3%) being less common; multiple routes of exposure were involved in 141 (9.5%) cases. Following ocular exposure (n = 212), features suggesting conjunctivitis (n = 145; 68.4%) and corneal ulceration (n = 6; 2.8%) developed. The most common features reported following ingestion alone were nausea and vomiting (n = 721; 59.3%), followed by coughing (n = 53; 4.4%), drowsiness/CNS depression (n = 49; 42 of these were children were aged 2 years or less) and foaming at the mouth (n = 47; 3.9%). A rash occurred in 22 patients where ingestion was considered to be the route of exposure. Twenty patients were exposed via the dermal route alone and developed erythema (n = 9), rash (n = 6) and burn (n = 3). CONCLUSIONS. Ocular exposure to liquid detergent capsules may lead to conjunctivitis and corneal ulceration; detergent ingestion may result in central nervous system (CNS)depression. Greater consumer awareness is required to reduce injury from liquid detergent capsules, particularly that involving the eye.

Exploiting mTOR signaling: a novel translatable treatment strategy for traumatic optic neuropathy?

Retinal ganglion cell (RGC) death and a failure of axon regeneration contribute to the profound visual loss experienced by patients after traumatic optic neuropathy (TON), for which there are no effective treatments. Experimental manipulations of cellular signaling pathways in animal models have demonstrated that neuronal survival and axon regeneration in the mature central nervous system (CNS) are possible, and increased understanding of the molecular basis of prosurvival and regenerative signals has led to the identification of candidate targets for novel therapeutic strategies. The axogenic pathway is activated sequentially, after growth factor/receptor binding, through phosphoinositide-3-kinase (PI3K) and the downstream serine/threonine kinase Akt. Akt is a nodal point for the regulation of growth cone dynamics by glycogen synthase kinase (GSK3ß) and axon protein synthesis/RGC survival by the mammalian target of rapamycin (mTOR). The mTOR signaling pathway has a pivotal role in numerous cellular processes. It is active during development, but downregulated in the mature CNS and further suppressed by axonal injury, and experimental upregulation of mTOR signaling promotes RGC survival and axon regeneration after optic nerve crush injury. However, several translational challenges remain, including understanding the regulatory mechanisms of axotomy-induced mTOR and GSK3ß signaling, and the disparity between the RGC survival and axon regenerative effects. In this review, we explore the molecular basis of RGC regenerative failure and assess the potential for manipulations of mTOR signaling as a novel translatable treatment for TON.