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Purpose: To evaluate the impact of age, glaucoma-specific diagnosis, and history of prior glaucoma surgery on outcomes in pediatric patients treated with latanoprost monotherapy., Patients and Methods: Prospective, randomized, double-masked 12-week, multicenter study included individuals 18 years or younger with glaucoma. Subjects stratified by age (0 to <3, 3 to <12, 12 to 18 y), diagnosis [primary congenital glaucoma (PCG) vs. non-PCG], and baseline intraocular pressure (IOP; 22 to <27, 27 to 31, >31 mm Hg), and randomized (1:1) to latanoprost vehicle (8 AM) and latanoprost 0.005% (8 PM) or timolol 0.5% (or 0.25% for those less than 3 y old; 8 AM/8 PM). IOP and safety assessments performed and adverse events recorded at baseline, weeks 1, 4, 12. Post hoc analyses in age-specific and diagnosis-specific groups of latanoprost-treated subjects were conducted (intent-to-treat population)., Results: Sixty-eight subjects were treated with latanoprost (0 to <3, n=17; 3 to <12, n=26; 12 to 18, n=25); 82%, 42%, and 24%, respectively, had a primary diagnosis of PCG. Among Non-PCG subjects, 0% (0/3), 47% (7/15), and 63% (12/19) had a primary diagnosis of juvenile open-angle glaucoma in the 0 to <3, 3 to <12, and 12 to 18 year cohorts, respectively. Mean percent IOP reductions from baseline at week 12 were 22%, 24%, and 30% in the youngest through oldest age groups, respectively (P=0.3600). At week 12, a higher responder rate (≥15% IOP reduction) was observed in the non-PCG than in the PCG group (70% vs. 45%, respectively; P=0.0361). Latanoprost was well tolerated., Conclusion: All age and diagnosis subgroups showed clinically relevant (>20%) mean IOP reduction at week 12 with latanoprost monotherapy.

Purpose: To report on the medical treatments used for pediatric glaucomas., Patients and Methods: A retrospective case series consisting of reviewing the medical notes of pediatric glaucoma patients under the care of the Glaucoma Service at Moorfields Eye Hospital NHS Foundation Trust. The medical notes of 200 patients were selected. The following outcomes were assessed: (1) the use of individual medical therapies; (2) the intraocular pressure (IOP) reduction effect of individual medicines; (3) the reporting of side effects., Results: Medicines were prescribed 1592 times (200 patients). The median % IOP reduction for latanoprost 50 mcg/mL was -17.2% and for the topical beta blockers was -17.7% (as monotherapy), with no statistical difference in IOP-lowering effect between all the medicines (P=0.19). Side effects were reported in 19.5% of all patients-the highest occurrence with brimonidine tartrate 0.2% (in 17% patients) and the lowest occurrence with the prostaglandin analogue and prostamide medicines (in 3.8% patients). The combination of dorzolamide hydrochloride 2%, timolol maleate 0.5% had the greatest persistence of 1 year., Conclusions: The IOP-lowering effects of all the glaucoma medicines were not significantly different although the combination of dorzolamide hydrochloride 2%, timolol maleate 0.5% had the greatest persistence.

Background: Over 1.2 million people are blind from trachomatous trichiasis (TT). Lid rotation surgery is the mainstay of treatment, but recurrence rates can be high. We investigated the outcomes (recurrence rates and other complications) of posterior lamellar tarsal rotation (PLTR) surgery, one of the two most widely practised TT procedures in endemic settings., Methodology/principal Findings: We conducted a two-year follow-up study of 1300 participants who had PLTR surgery, conducted by one of five TT nurse surgeons. None had previously undergone TT surgery. All participants received a detailed trachoma eye examination at baseline and 6, 12, 18 and 24 months post-operatively. The study investigated the recurrence rates, other complications and factors associated with recurrence. Recurrence occurred in 207/635 (32.6%) and 108/641 (16.9%) of participants with pre-operative major (>5 trichiatic lashes) and minor (<5 lashes) TT respectively. Of the 315 recurrences, 42/315 (3.3% overall) had >5 lashes (major recurrence). Recurrence was greatest in the first six months after surgery: 172 cases (55%) occurring in this period. Recurrence was associated with major TT pre-operatively (OR 2.39, 95% CI 1.83-3.11), pre-operative entropic lashes compared to misdirected/metaplastic lashes (OR 1.99, 95% CI 1.23-3.20), age over 40 years (OR 1.59, 95% CI 1.14-2.20) and specific surgeons (surgeon recurrence risk range: 18%-53%). Granuloma occurred in 69 (5.7%) and notching in 156 (13.0%)., Conclusions/significance: Risk of recurrence is high despite high volume, highly trained surgeons. However, the vast majority are minor recurrences, which may not have significant corneal or visual consequences. Inter-surgeon variation in recurrence is concerning; surgical technique, training and immediate post-operative lid position require further investigation.

Objectives: A comparison of glaucoma referral refinement schemes (GRRS) in the UK during a time period of considerable change in national policy and guidance., Design: Retrospective multisite review., Setting: The outcomes of clinical examinations by optometrists with a specialist interest in glaucoma (OSIs) were compared with optometrists with no specialist interest in glaucoma (non-OSIs). Data from Huntingdon and Nottingham assessed non-OSI findings, while Manchester and Gloucestershire reviewed OSI findings., Participants: 1086 patients. 434 patients were from Huntingdon, 179 from Manchester, 204 from Gloucestershire and 269 from Nottingham., Results: The first-visit discharge rate (FVDR) for all time periods for OSIs was 14.1% compared with 36.1% from non-OSIs (difference 22%, CI 16.9% to 26.7%; p<0.001). The FVDR increased after the April 2009 National Institute for Health and Clinical Excellence (NICE) glaucoma guidelines compared with pre-NICE, which was particularly evident when pre-NICE was compared with the current practice time period (OSIs 6.2-17.2%, difference 11%, CI -24.7% to 4.3%; p=0.18, non-OSIs 29.2-43.9%, difference 14.7%, CI -27.8% to -0.30%; p=0.03). Elevated intraocular pressure (IOP) was the commonest reason for referral for OSIs and non-OSIs, 28.7% and 36.1%, respectively, of total referrals. The proportion of referrals for elevated IOP increased from 10.9% pre-NICE to 28.0% post-NICE for OSIs, and from 19% to 45.1% for non-OSIs., Conclusions: In terms of 'demand management', OSIs can reduce FVDR of patients reviewed in secondary care; however, in terms of 'patient safety' this study also shows that overemphasis on IOP as a criterion for referral is having an adverse effect on both the non-OSIs and indeed the OSIs ability to detect glaucomatous optic nerve features. It is recommended that referral letters from non-OSIs be stratified for risk, directing high-risk patients straight to secondary care, and low-risk patients to OSIs.

Background/aims: To investigate longitudinal changes in anterior chamber depth (ACD) and axial length (AXL) over 5 years after trabeculectomy surgery in Asian patients with primary glaucoma, and to identify factors associated with these changes., Methods: In this prospective cohort study, phakic subjects with primary glaucoma who underwent trabeculectomy had ACD and AXL measured over 5 years. The effect of intraocular pressure (IOP) on ACD and AXL was determined. Subjects were divided into two groups (high or low fluctuation of ACD/AXL) and factors were compared to determine if there were factors associated with greater fluctuation., Results: 122 subjects were analysed. The majority of subjects were male (75.4%) and Chinese (77%). ACD and AXL were shallower/shorter compared with baseline at all postoperative visits, with a mean decrease of 0.11 mm (95% CI 0.07 to 0.15 mm, p<0.01) and 0.16 mm (95%CI 0.11 to 0.20 mm, p<0.01), respectively. Patients with primary open angle glaucoma (POAG) had higher odds of fluctuations in longitudinal measurements of ACD (OR=8.74, p<0.01) and AXL (OR=5.60, p<0.01) compared with patients with primary angle closure glaucoma. For every 1 mm Hg decrease in IOP, ACD and AXL decreased by 0.02 mm (p<0.01) and 0.01 mm (p=0.03), respectively, for POAG patients with emmetropia or mild myopia., Conclusions: Trabeculectomy resulted in a decrease in both ACD and AXL, and these changes were persistent over a period of 5 years.

The advent of optogenetics provides a new direction for the field of neuroscience and biotechnology, serving both as a refined investigative tool and as potential cure for many medical conditions via genetic manipulation. Although still in its infancy, recent advances in optogenetics has made it possible to remotely manipulate in vivo cellular functions using light. Coined Nature Methods' 'Method of the Year' in 2010, the optogenetic toolbox has the potential to control cell, tissue and even animal behaviour. This optogenetic toolbox consists of light-sensitive proteins that are able to modulate membrane potential in response to light. Channelrhodopsins (ChR) are light-gated microbial ion channels, which were first described in green algae. ChR2 (a subset of ChR) is a seven transmembrane α helix protein, which evokes membrane depolarization and mediates an action potential upon photostimulation with blue (470 nm) light. By contrast to other seven-transmembrane proteins that require second messengers to open ion channels, ChR2 form ion channels themselves, allowing ultrafast depolarization (within 50 milliseconds of illumination). It has been shown that integration of ChR2 into various tissues of mice can activate neural circuits, control heart muscle contractions, and even restore breathing after spinal cord injury. More compellingly, a plethora of evidence has indicated that artificial expression of ChR2 in retinal ganglion cells can reinstate visual perception in mice with retinal degeneration., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To report the 8-year outcomes of Asian subjects who underwent trabeculectomy augmented by intraoperative 5-fluorouracil (5-FU) or placebo., Design: Retrospective review of a randomized controlled trial., Participants: Subjects with primary open-angle or angle-closure glaucoma., Methods: Study subjects were prospectively followed up for 3 years. After the last subject recruited had completed 8 years of follow-up, the charts of all subjects were reviewed to capture data from the year 3 visit onward. Kaplan-Meier survival function with Cox regression was performed to identify risk factors associated with trabeculectomy failure at 8 years., Main Outcome Measures: The primary outcome was trabeculectomy failure defined as intraocular pressure (IOP) >21 or <6 mmHg on 2 consecutive occasions after the first 6 weeks after surgery, repeat glaucoma surgery, or loss of light perception. Further end points were defined at IOP levels >17 and >14 mmHg. Secondary outcomes included IOP at 8 years and number of glaucoma medications. Complete success was defined using IOP end points ≤ 21, ≤ 17, or ≤ 14 mmHg at 8 years without medications., Results: Of the 243 enrolled subjects, 170 (70.0%) completed 8 years follow-up, 86 in the 5-FU and 84 in the placebo group. There was no significant difference in failure rates at 8 years for the failure definitions of IOP >21 mmHg (11.6% of the 5-FU group vs. 16.7% of the placebo group; P = 1.00), IOP >17 mmHg (23.3% of the 5-FU group vs. 31% of the placebo group; P = 0.78), and IOP >14 mmHg (46.5% of the 5-FU group vs. 58.3% of the placebo group; P = 0.37). Mean IOP at 8 years was 13.7 mmHg in the 5-FU versus 14.4 mmHg in the placebo group (P = 0.24). Mean number of medications was 0.65 drops in the 5-FU versus 0.93 drops in the placebo group (P = 0.06). Complete success with IOP ≤ 21 mmHg at 8 years was achieved in 48 subjects (55.8%) in the 5-FU and 33 subjects (39.3%) in the placebo group (P = 0.09). Absence of bleb microcysts at 1 year, preoperative IOP, and number of bleb needlings performed within the first year were significantly associated with failure., Conclusions: There was no significant difference in IOP between the 5-FU and the placebo group at 8 years., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To test agreement of two methods to measure intraocular pressure (IOP): rebound tonometry (RBT) and gold standard Goldmann applanation tonometry (GAT) in children with glaucoma., Design: Observational prospective cohort study., Setting: Tertiary paediatric glaucoma clinic at a single centre., Participants: 102 individuals attending a paediatric glaucoma clinic, mean (SD) age 11.85 (3.17), of whom 53 were male., Primary and Secondary Outcome Measures: Intraocular pressure, central corneal thickness, child preference for measurement method., Results: Limits of agreement for intraobserver and interobserver were, respectively, (-2.71, 2.98) mm Hg and (-5.75, 5.97) mm Hg. RBT frequently gave higher readings than GAT and the magnitude of disagreement depend on the level of IOP being assessed. Differences of 10 mm Hg were not uncommon. RBT was the preferred method for 70% of children., Conclusions: There is poor agreement between RBT and GAT in children with glaucoma. RBT frequently and significantly overestimates IOP. However, 'normal' RBT readings are likely to be accurate and may spare children an examination under anaesthesia (EUA). High RBT readings should prompt the practitioner to use another standard method of IOP measurement if possible, or consider the RBT measurement in the context of clinical findings before referring the child to a specialist clinic or considering EUA.

Vascular endothelial growth factor A (VEGF-A) is a validated therapeutic target in several angiogenic- and vascular permeability-related pathological conditions, including certain cancers and potentially blinding diseases, such as age-related macular degeneration and diabetic retinopathy. We and others have shown that VEGF-A also plays an important role in neuronal development and neuroprotection, including in the neural retina. Antagonism of VEGF-A function might therefore present a risk to neuronal survival as a significant adverse effect. Herein, we demonstrate that VEGF-A acts directly on retinal ganglion cells (RGCs) to promote survival. VEGF receptor-2 signaling via the phosphoinositide-3-kinase/Akt pathway was required for the survival response in isolated RGCs. These results were confirmed in animal models of staurosporine-induced RGC death and experimental hypertensive glaucoma. Importantly, we observed that VEGF-A blockade significantly exacerbated neuronal cell death in the hypertensive glaucoma model. Our findings highlight the need to better define the risks associated with use of VEGF-A antagonists in the ocular setting., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: Primary congenital glaucoma (isolated trabeculodysgensis, PCG) generally presents between birth and 3 years of age. Recently, mutations in Latent Transforming Growth Factor (TGF)-beta Binding Protein 2 (LTBP2) have been reported in several families that were diagnosed with PCG, who actually had a more complex ocular phenotype with ectopia lentis and Marfanoid features. We screened this gene for mutations in the original Turkish GLC3C-linked PCG family and in a group of CYP1B1-negative British PCG cases and their matched normal control subjects., Methods: The 36-coding exons of the LTBP2 gene were sequenced in 94 familial or sporadic CYP1B1-negative PCG cases and 96 matched normal control subjects., Results: No disease-causing mutations were identified in the original GLC3C-linked family. Screening of LTBP2 in 94 PCG and 96 control subjects identified three novel synonymous variations (L429L, P680P, S1031S) in 12 PCG and seven control subjects. A novel heterozygous missense mutation (R538W) was also identified in 1 of 90 PCG cases that is unlikely to be disease-causative., Conclusions: LTBP2 mutations were not found in the Turkish GLC3C-linked PCG family or in 94 British CYP1B1-negative PCG cases. Our data suggest that LTBP2 mutations are not a significant cause for isolated trabeculodysgenesis.

Despite the advent of many new devices for glaucoma surgery, scarring is the main cause of suboptimal pressure control and surgical failure in all forms of surgery. The cytotoxic antimetabolites, 5-flurouracil and mitomycin C both prolong success but with the increased risk of blinding complications. A greater understanding of the cellular mechanisms of the wound healing response has led to the identification and modulation of potential therapeutic targets. These include transforming factor β, inflammatory mediators, the acute phase protein serum amyloid P, vascular endothelial growth factor and the matrix metallaproteinases. While optimal drug delivery is still a major challenge, modulating these effects either directly or through downstream signalling promises to yield anti-scarring efficacy, while minimising side effects., (Copyright © 2012. Published by Elsevier Ltd.)

Purpose: To compare the results of intraocular pressure (IOP) reduction by 3 treatment modalities, (a) glaucoma tube implants, (b) noncontact YAG laser cyclophotocoagulation (cycloYAG), and (c) contact transscleral diode laser cyclophotocoagulation (cyclodiode), in cases of advanced glaucoma refractory to alternative treatments., Methods: A consecutive group of 45 eyes that received cycloYAG were matched against two control groups of patients who had received tube surgery or cyclodiode, each control group having been derived from a database of patients., Results: Mean pretreatment IOP improved from 41.3, 38.6, and 32.0 mmHg for the tube, cycloYAG, and cyclodiode groups, respectively, to 16.4, 22.1, and 19.3 mmHg, respectively. Treatment success was achieved in 78%, 69%, and 71% of the tube, cycloYAG, and cyclodiode groups, respectively. Visual acuity deteriorated 2 or more Snellen lines in 16%, 7%, and 9% of the patients in the tube, cycloYAG, and cyclodiode groups, respectively. Complications included retinal detachment, hypotony, and phthisis., Conclusions: All 3 methods provided acceptable IOP lowering in the short and medium term. Control of IOP was best in patients receiving tube surgery. Cyclodiode and cycloYAG treatments were similarly effective in lowering IOP. Tube surgery was associated with a greater incidence of sight threatening complications.

Background: To identify the baseline factors influencing success following trabeculectomy with mitomycin C in a case series of African-Caribbean patients., Design: A prospective, observational and non-comparative cohort study., Participants: Forty-seven consecutive African-Caribbean patients (47 eyes) with glaucoma., Methods: Association between trabeculectomy survival and study factors was examined using Fisher's exact test and the Wilcoxon rank sum test at 12, 24 and 36 months following trabeculectomy. Logistic regression was used to establish the combination of factors best predicting survival., Main Outcome Measures: Surgical success was based upon intraocular pressure reduction to ≤21 mmHg, ≤18 mmHg and ≤15 mmHg without glaucoma medication (criterion 1), or intraocular pressure reduction to ≤21 mmHg, ≤18 mmHg and ≤15 mmHg with or without glaucoma medication (criterion 2)., Results: Trabeculectomy survival at 36 months was significantly decreased with the use of preoperative acetazolamide, pseudophakic status and higher preoperative intraocular pressure (P < 0.05). In pseudophakic eyes, there was a lower rate of success for criterion 2 when aiming for an intraocular pressure ≤15 mmHg at 2 years post-trabeculectomy, the odds ratio being 12., Conclusions: Three major independent risk factors were identified that influenced trabeculectomy failure at 3 years in African-Caribbean ethnicity: the preoperative use of acetazolamide, pseudophakic status and higher preoperative intraocular pressure. The presence of these risk factors may guide the clinician to use a more aggressive antiproliferative and postoperative management regime to enhance survival rates in this high-risk population., (© 2012 The Authors. Clinical and Experimental Ophthalmology © 2012 Royal Australian and New Zealand College of Ophthalmologists.)

We are developing tablet dosage forms for implantation directly into the subconjunctival space of the eye. The matrix metalloproteinase inhibitor, ilomastat, has previously been shown to be efficacious at suppressing scarring following glaucoma filtration surgery (GFS). We report on the physical characterisation of ilomastat which is being developed for ocular implantation. Since ilomastat is being considered for implantation it is necessary to examine its polymorphs and their influence on aspects of the in vitro drug release profile. X-ray powder diffraction identified two polymorphs of ilomastat from different commercial batches of the compound. Tablets were prepared from the two different polymorphs. Isothermal perfusion calorimetry was used to show that amorphous content is not increased during tablet formulation. The melting points of the two polymorphs are 188 and 208°C as determined by differential scanning calorimetry. Utilising single crystal X-ray diffraction, the structural conformations and packing arrangements of the different polymorphs were determined. The orthorhombic crystal crystallised as a monohydrate while the second monoclinic crystal form is non-solvated. Ilomastat tablets prepared from the two different solid forms exhibited similar drug release profiles in vitro under conditions mimicking the aqueous composition, volume and flow of the subconjunctival space after GFS. This suggests that a reproducible dose at each time point during release after implantation should be achievable in vivo with ilomastat tablets prepared from the two polymorphs identified.

Purpose: To determine if transplantation of olfactory ensheathing cells (OECs) can reduce loss of optic nerve axons after raised intraocular pressure (IOP) in the rat., Methods: OECs cultured from the adult olfactory mucosa were transplanted into the region of the optic disc. The IOP was raised by injection of magnetic microspheres into the anterior chamber., Results: At 4 weeks after raising the IOP, the transplanted OECs had migrated into the dorsal area of the optic nerve head (ONH) where they surrounded the optic nerve fibers with a non-myelinated ensheathment. The mean amount of damage to the ONH astrocytic area in rats was 51.0% compared with 85.8% in those without OEC transplants ( P < 0.02) and the mean loss of axons in the optic nerve was 51.0% compared with 80.3% in the absence of OECs ( P < 0.01)., Conclusions: OECs transplanted into the region of the ONH of the rat can reduce the loss of axons and the damage to ONH astrocytes caused by raised IOP., Translational Relevance: Confirmation of these preliminary experimental data, further understanding of possible mechanisms of axonal protection by OECs, and the longer-term time course of protection could provide a basis for future human clinical trials of autografted OECs, which would be available from autologous nasal epithelial biopsies.

Purpose: To evaluate the efficiency of Rac1 inhibition in preventing matrix contraction by Tenon's capsule fibroblasts., Methods: The involvement of Rac1 in serum-stimulated matrix contraction by human Tenon's fibroblasts (HTFs) was investigated in a classic collagen contraction model and our ex vivo model of tissue contraction using immunocytochemistry, chemical inhibitors, and small interfering RNA (siRNA) technology. Matrix integrity was assessed using confocal reflection microscopy and Coomassie blue staining. Quantitative real-time polymerase chain reaction (QRT-PCR) and Western blot analysis were used to assess matrix metalloproteinase (MMP) expression., Results: Serum induced Rac1 activation in HTF-populated collagen gels and stimulated HTFs to contract collagen matrices down to ~90% of their original size. Rac1 inhibition using NSC23766 or depletion using siRNA both significantly reduced HTF-mediated contraction. Early brief exposure to NSC23766 reduced HTF-mediated gel contraction by 70%, while transient treatment with the Rac1 inhibitor once a week decreased ex vivo tissue contraction down to serum-free levels. Transient exposure to NSC23766 prevented early cell protrusions, fiber alignment, and matrix degradation, as seen upon continuous exposure to broad-spectrum MMP inhibitor. However, unlike MMP inhibition, transient treatment with NSC23766 led to a significant reduction in MMP1 mRNA and protein expression during contraction, without increasing MMP2 and MMP14 expression., Conclusions: Rac1 inhibition efficiently prevents conjunctival tissue and collagen matrix contraction and prevents matrix degradation.

Background: To evaluate long-term outcomes and complication rates following trabeculectomy with mitomycin C in a case series of African Caribbean patients., Design: A prospective, observational and non-comparative case series., Participants: Forty-seven consecutive African Caribbean patients (47 eyes) with glaucoma., Methods: All patients underwent augmented trabeculectomy with mitomycin C for uncontrolled intraocular pressure (IOP). Survival analysis was performed with a minimum of 12 months' follow up., Main Outcome Measures: Surgical success was based upon IOP reduction to ≤ 21 mmHg, ≤ 18 mmHg and ≤ 15 mmHg without glaucoma medication (complete); or IOP reduction to ≤ 21 mmHg, ≤ 18 mmHg and ≤ 15 mmHg with or without glaucoma medication (qualified)., Results: The mean follow-up period was 48.6 months. At 3 years post-trabeculectomy 92.6% achieved a qualified success and 59.3% a complete success for an IOP ≤ 21 mmHg. At final follow up the mean IOP reduced from 33.7 mmHg to 13.1 mmHg (P < 0.0001). Survival rates were 96%, 90% and 86% at 12, 24 and 36 months, respectively, with a mean survival time of 97.4 months (95% confidence interval, 86.0-108.8) for an IOP ≤ 21 mmHg. Early postoperative hypotony requiring surgical intervention occurred in four (8.5%) patients. There were no cases of blebitis, endophthalmitis, suprachoroidal haemorrhage, malignant glaucoma or hypotony maculopathy., Conclusions: Good long-term stable IOP can be achieved with low complication rates and high success rates amongst African Caribbean patients following trabeculectomy with mitomycin C. A proactive postoperative management regime is needed to ensure trabeculectomy survival in high-risk populations., (© 2011 The Authors. Clinical and Experimental Ophthalmology © 2011 Royal Australian and New Zealand College of Ophthalmologists.)

Müller glia with stem cell characteristics have been identified in the adult human eye, and although there is no evidence that they regenerate retina in vivo, they can be induced to grow and differentiate into retinal neurons in vitro. We differentiated human Müller stem cells into retinal ganglion cell (RGC) precursors by stimulation with fibroblast growth factor 2 together with NOTCH inhibition using the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT). Differentiation into RGC precursors was confirmed by gene and protein expression analysis, changes in cytosolic [Ca(2+)] in response to neurotransmitters, and green fluorescent protein (GFP) expression by cells transduced with a transcriptional BRN3b-GFP reporter vector. RGC precursors transplanted onto the inner retinal surface of Lister hooded rats depleted of RGCs by N-methyl-d-aspartate aligned onto the host RGC layer at the site of transplantation but did not extend long processes toward the optic nerve. Cells were observed extending processes into the RGC layer and expressing RGC markers in vivo. This migration was observed only when adjuvant anti-inflammatory and matrix degradation therapy was used for transplantation. RGC precursors induced a significant recovery of RGC function in the transplanted eyes as determined by improvement of the negative scotopic threshold response of the electroretinogram (indicative of RGC function). The results suggest that transplanted RGC precursors may be capable of establishing local interneuron synapses and possibly release neurotrophic factors that facilitate recovery of RGC function. These cells constitute a promising source of cells for cell-based therapies to treat retinal degenerative disease caused by RGC dysfunction.

Increased intraocular pressure (IOP) damages the retinal ganglion cell axons as they pass through the optic nerve head (ONH). The massive connective tissue structure of the human lamina cribrosa is generally assumed to be the pressure transducer responsible for the damage. The rat, however, with no lamina cribrosa, suffers the same glaucomatous response to raised IOP. Here, we show that the astrocytes of the rat ONH are "fortified" by extraordinarily dense cytoskeletal filaments that would make them ideal transducers of distorting mechanical forces. The ONH astrocytes are arranged as a fan-like radial array, firmly attached ventrally to the sheath of the ONH by thick basal processes, but dividing dorsally into progressively more slender processes with only delicate attachments to the sheath. At 1 week after raising the IOP by an injection of magnetic microspheres into the anterior eye chamber, the fine dorsal processes of the ONH astrocytes are torn away from the surrounding sheath. There is no indication of distortion or compression of the axons. Subsequently, despite return of the IOP toward normal levels, the damage to the ONH progresses ventrally through the astrocytic cell bodies, resulting in complete loss of the fortified astrocytes and of the majority of the axons by around 4 weeks. We propose that the dorsal attachments of the astrocytes are the site of initial damage in glaucoma, and that the damage to the axons is not mechanical, but is a consequence oflocalized loss of metabolic support from the astrocytes (Tsacopoulos and Magistretti (1996) J Neurosci 16:877-885)., (Copyright © 2011 Wiley Periodicals, Inc.)

Purpose: Eight million people have trachomatous trichiasis (TT). The World Health Organization (WHO) recommends entropion surgery for TT regardless of severity. However, epilation is widely practiced for treating minor TT (1-5 lashes touching the globe). We report the frequency and effectiveness of patient-initiated epilation and its relationship to corneal opacity., Design: Cross-sectional baseline data of individuals recruited to 2 randomized, clinical trials., Participants: We included 2556 individuals (4310 eyes) with previously unoperated TT in ≥ 1 eye., Methods: A single ophthalmologist examined all participants for signs of trachoma using WHO grading systems with additional assessment of entropion grading, location and number of trichiatic lashes, and evidence of epilation. A questionnaire enquired about epilation practices., Main Outcome Measures: The association between epilation and degree of corneal opacity. Epilation practices of TT patients., Results: Central corneal scarring was present in 1436 (33%) eyes. Entropion was absent/mild in 2328 (54%) eyes, moderate in 1259 (29.2%), and severe in 723 (16.8%). The median number of lashes touching the eye was 2 (interquartile range, 1-5; range, 0-133). There was clinical evidence of epilation in 3018 (70%) eyes, of which 738 (24%) were successfully epilated (no lashes touching globe). Epilation was performed frequently (at least monthly in 3311 [76.8%] eyes), by someone other than the patient (92.8%), and using locally made forceps (88.9%). Controlling for age and degree of entropion, successful epilation was associated with less corneal opacity (odds ratio [OR], 0.61; 95% confidence interval [CI]. 0.43-0.88; P = 0.007). The association was only significant in patients with severe entropion (OR, 0.07; 95% CI, 0.02-0.25; P<0.005)., Conclusions: We found an association between successful epilation and less central corneal opacity. This indicates the importance of preventing eyelashes from touching the cornea, particularly in individuals with severe entropion. This is a cross-sectional study; therefore, a causative relationship cannot be concluded. However, the results suggest that among patients who decline or are unable to access surgery, and perhaps in minor TT where the management remains controversial, the provision of high-quality forceps and epilation training may be beneficial., Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Trabeculectomy with anti-fibrotic treatment is still the most popular incisional procedure for glaucoma filtration surgery (GFS) worldwide. The advent of anti-fibrotic agents reduced failure due to scarring but resulted in increased complications. Advances in trabeculectomy surgery have been driven by the need to minimise the risk of: (1) complications and (2) surgical failure. This chapter covers preoperative, intraoperative and postoperative strategies, which improve the outcome of GFS. Strategies to reduce the risk of complications centre on the prevention of postoperative hypotony by minimising the risk of overdrainage, postoperative wound leaks and poor bleb morphology. Surgical techniques to reduce the risk of postoperative fibrosis by the use of anti-fibrotic agents (including mitomycin C) are discussed in detail. These techniques are based on a combination of considerable clinical experience, observation and laboratory research. The need to address pre-, intra- and postoperative issues in each individual patient is emphasised. These changes are embodied in the system we call the 'Moorfields Safer Surgery System'. The use of these strategies has considerably reduced the incidence of major complications including hypotony, cystic blebs and endophthalmitis in practices around the world. Most of these techniques are simple, require minimal equipment and can be easily mastered. They are associated with an improvement in overall outcome and it is hoped that this chapter will help the reader benefit from these advances., (Copyright © 2012 S. Karger AG, Basel.)

Background: Surgery for trachomatous trichiasis (TT) is a key component of the SAFE Strategy for trachoma control. Unfortunately, recurrent TT following surgery is common, probably due to various surgical and disease factors. To develop strategies to reduce recurrence rates it is necessary to understand its pathological basis. In this study we investigated the relationship between recurrent trichiasis and the expression of various cytokines and fibrogenic genes during a two-year follow-up period., Methodology/principal Findings: Individuals undergoing surgery for TT were examined at baseline (pre-operative), 6, 12, 18 and 24 months. Conjunctival swab samples were collected from the tarsal conjunctiva for RNA isolation on each occasion. Individuals who developed recurrent TT with at least 3 lashes touching the eye on one or more occasion were designated "cases" and an equal number of "controls" were randomly selected from those without recurrent TT, frequency matched for age and baseline TT severity. The expression of the following genes was measured by quantitative RT-PCR: S100A7, IL1B, CXCL5, TNFA, NOS2A, CTGF, MMP7, MMP9 and MMP12. Thirteen hundred individuals were enrolled and underwent surgery. By two years 122 had developed recurrent TT with at least 3 lashes touching the eye. Recurrent TT was consistently associated across multiple time points with about a 2-fold increase in S100A7 expression (p = 0.008). Clinically visible conjunctival inflammation was associated with increased S100A7, IL1B, CXCL5, MMP9 and MMP12 expression., Conclusions/significance: Increased S100A7 expression was associated with trachomatous conjunctival scarring and may be linked to the pathophysiology of recurrent TT. S100A7 expression could be a potential biomarker for this disease process. As part of the epithelial innate immune response S100A7 has multiple actions, potentially contributing to a chronic pro-inflammatory response, which may lead to ongoing tissue damage and increased scarring.

Purpose: Previous work has suggested a major role of scleral biomechanics in the pathogenesis of glaucoma. Since fiber orientation in connective tissues is a key determinant of tissue biomechanics, experimental characterization of scleral fiber orientation is needed to fully understand scleral biomechanics. This is a report of baseline experimental measurements of fiber orientation in whole normal rat scleras., Methods: Twenty ostensibly normal Norway brown rat eyes were fixed in 4% paraformaldehyde. The scleras were cleaned of intra- and extraorbital tissues and dissected into five patches, and each patch was glycerol treated to maximize its transparency. Fiber orientation was measured using small-angle light scattering (SALS). Scattering patterns were analyzed to extract two microstructural parameters at each measurement location-the preferred fiber orientation and the degree of alignment-yielding a fiber orientation map for each sclera., Results: Rat sclera is structurally anisotropic with several consistent features. At the limbus, fibers were highly aligned and organized primarily into a distinct ring surrounding the cornea. In the equatorial region, the fibers were primarily meridionally aligned. In the posterior and peripapillary region, the scleral fibers were mostly circumferential but less aligned than those in the anterior and equatorial regions., Conclusions: Circumferential scleral fibers may act as reinforcing rings to limit corneal and optic nerve head deformations, whereas equatorial meridional fibers may either provide resistance against extraocular muscle forces or limit globe axial elongation.

Background: Trachoma causes blindness through an anatomical abnormality called trichiasis (lashes touching the eye). Trichiasis can recur after corrective surgery. We tested the hypothesis that using absorbable sutures instead of silk sutures might reduce the risk of recurrent disease among patients with major trichiasis in a randomised trial., Methods and Findings: 1,300 individuals with major trichiasis from rural villages in the Amhara Region of Ethiopia were recruited and assigned (1:1) by computer-generated randomisation sequence to receive trichiasis surgery using either an absorbable suture (polyglactin-910) or silk sutures (removed at 7-10 days) in an otherwise identical surgical technique. Participants were examined every 6 months for 2 years by clinicians masked to allocation. The primary outcome measure was recurrent trichiasis (≥one lash touching the eye) at 1 year. There was no difference in prevalence of recurrent trichiasis at 1 year (114 [18.2%] in the absorbable suture group versus 120 [19.7%] in the silk suture group; odds ratio = 0.90, 95% CI 0.68-1.20). The two groups also did not differ in terms of corneal opacification, visual acuity, conjunctival inflammation, and surgical complications., Conclusions: There was no evidence that use of absorbable polyglactin-910 sutures was associated with a lower prevalence of trichiasis recurrence at 1 year postsurgery than silk sutures. However, from a programmatic perspective, polyglactin-910 offers the major advantage that patients do not have to be seen soon after surgery for suture removal. The postoperative review after surgery using absorbable polyglactin-910 sutures can be delayed for 3-6 months, which might allow us to better determine whether a patient needs additional surgery., Trial Registration: ClinicalTrials.gov NCT00522860.

Background: Trachomatous trichiasis can cause corneal damage and visual impairment. WHO recommends surgery for all cases. However, in many regions surgical provision is inadequate and patients frequently decline. Self-epilation is common and was associated with comparable outcomes to surgery in nonrandomised studies for minor trichiasis (

Purpose: To examine the association between central corneal thickness (CCT) and glaucoma., Methods: This was a nested case-control study using 1090 subjects from an eye disease population survey in Singapore and 243 participants from a hospital glaucoma surgery clinical trial in Singapore., Results: Mean CCT in 938 community subjects was 539 μm ± 32 μm, and in 12 community subjects with primary open angle glaucoma (POAG) the mean CCT was 545 μm ± 38 μm. In the hospital cohort, mean CCT was 552 μm ± 38 μm in 138 patients with POAG and 551 μm ± 33 μm in 105 patients with primary angle closure glaucoma (PACG). No individuals had undergone previous intraocular surgery or had other significant ocular pathology. Regression models showed POAG diagnosis was not associated with CCT (P = 0.42) or age (P = 0.062) in community subjects but was associated with IOP (P = 0.005). Similar analyses for hospital cases showed CCT to be significantly higher in both POAG and PACG (both P = 0.001), but this became nonsignificant after controlling for IOP and age (P = 0.26, POAG; P = 0.08, PACG). Both age (P = 0.043) and IOP (P = 0.001) were highly associated with hospital POAG; only IOP (P = 0.001) was associated with hospital PACG. Further regression analyses for community subjects showed diabetic status and pseudophakia had no significant effect on CCT (P = 0.33 and P = 0.11, respectively)., Conclusions: The authors found no evidence to support the previous observation that thinner corneas may be independently associated with POAG or PACG. Age and IOP are significantly associated with CCT, and this should be taken into account by future studies investigating CCT as an independent risk factor for glaucoma diagnosis.

Purpose: Trachomatous trichiasis (TT) is usually described as a cicatricial entropion of the upper lid; however, other forms of trichiasis have been reported. This variation in clinical phenotype is potentially important for treatment guidelines. Therefore, this study was conducted to investigate the range of disease type and severity encompassed by TT., Methods: Individuals presenting with TT to surgical treatment campaigns were examined by a single ophthalmologist using the Detailed WHO Trachoma Grading System. Additional features were graded, including type of trichiatic lashes (metaplastic, misdirected, and entropic), lower lid trichiasis, entropion severity, and lid margin mucocutaneous junction (MCJ) position., Results: Recruited were 2556 individuals with previously unoperated TT in at least one eye (4310 eyes). The median number of lashes touching the eye was 2 (range, 0 [epilating]-133). Entropion was absent or mild in 2328 (54.0%) eyes, moderate in 1259 (29.2%) eyes, and severe in 723 (16.8%) eyes. Trichiatic lashes were predominantly metaplastic or misdirected (80.2%), rather than secondary to entropion; 4204 (97.7%) had anteroplacement of the MCJ; and lower lid trichiasis was present in 494 (11.5%). Entropion was more severe among those with a low BMI, those who were female, those aged less than 50 years, and those with moderate to severe conjunctival inflammation, central corneal opacity, and severe conjunctival scarring., Conclusions: Many patients with TT have minimal or no entropion. The trichiasis is frequently attributable to metaplastic or misdirected eyelashes. The results of tarsal rotation surgery in TT patients without manifest entropion should be investigated and potentially alternative treatment strategies evaluated.

Purpose: To examine the relationship between education, other risk factors and incident primary angle closure glaucoma (PACG)., Method: Glaucoma was excluded in a group of 4597 Mongolian volunteers in 1999. After 6 years, 1892 traced participants had full ophthalmic examination, dilated disc photographs and agreed to complete a questionnaire on socio-economic status. PACG was diagnosed using both structural and functional evidence from objective grading of paired disc photographs, follow up visual fields and clinical examination. Ophthalmic examination included van Herick grading, Goldmann intraocular pressure (IOP), gonioscopy, lens opacity grading and dilated disc examination. Central anterior chamber depth, lens thickness and axial length were recorded using ultrasound A scan mounted on a slitlamp. Education level was assessed using national census categories., Results: PACG was diagnosed in 29 participants (6 year incidence = 1.53%, 95% confidence interval (CI) = 1.03-2.19%). In univariate analysis, risk factors for incident PACG included presence of refractive error, narrow van Herick grading of ≤15%, narrower average Shaffer grading, higher IOP, larger cup disc ratio and lower levels of education. In multivariate analysis, adjusted for age, sex, Shaffer grading, refractive error and IOP, those with no formal education were approximately 7 times more likely to develop PACG compared to those with >8 years of formal schooling (OR = 7.27, 95% CI = 2.73-19.38)., Conclusions: People with lower levels of education have a higher risk of incident PACG, independent of age, sex, IOP and axial length.

Objective: To compare the efficacy and safety of latanoprost versus timolol in pediatric patients with glaucoma., Design: Prospective, randomized, double-masked, 12-week, multicenter study., Participants: Individuals aged ≤18 years with glaucoma., Methods: Stratified by age, diagnosis, and intraocular pressure (IOP) level, subjects were randomized (1:1) to latanoprost vehicle at 8 am and latanoprost 0.005% at 8 pm or timolol 0.5% (0.25% for those aged <3 years) twice daily (8 am, 8 pm). At baseline and weeks 1, 4, and 12, IOP and ocular safety were assessed and adverse events were recorded. Therapy was switched to open-label latanoprost pm and timolol am and pm for uncontrolled IOP., Main Outcome Measures: Mean IOP reduction from baseline to week 12. Latanoprost was considered noninferior to timolol if the lower limit of the 95% confidence interval (CI) of the difference was >-3 mmHg. A proportion of responders (subjects with ≥15% IOP reduction at weeks 4 and 12) were evaluated. Analyses were performed in diagnosis subgroups: primary congenital glaucoma (PCG) and non-PCG., Results: In total, 137 subjects were treated (safety population; 12-18 years, n=48; 3-<12 years, n=55; 0-<3 years, n=34). Mean age was 8.8±5.5 years, and mean baseline IOP was 27.7±6.17 mmHg; 125 subjects completed the study, and 107 subjects were in the per protocol population. Mean IOP reductions for latanoprost and timolol at week 12 were 7.2 and 5.7 mmHg, respectively, with a difference of 1.5 mmHg (95% CI, -0.8 to 3.7; P=0.21). Responder rates were 60% for latanoprost and 52% for timolol (P=0.33). Between-treatment differences in mean IOP reduction for PCG and non-PCG subgroups were 0.6 mmHg (95% CI, -2.3 to 3.4) and 2.6 mmHg (95% CI, -0.8 to 6.1), respectively. Responder rates for latanoprost versus timolol were 50% versus 46% for the PCG group and 72% versus 57% for the non-PCG group. Both therapies were well tolerated., Conclusions: Latanoprost 0.005% is not inferior (i.e., is either more or similarly effective) to timolol and produces clinically relevant IOP reductions across pediatric patients with and without PCG. Both latanoprost and timolol had favorable safety profiles over the duration of this 3-month trial., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The serum response factor (SRF) coactivator myocardin-related transcription factor A (MAL/MKL1/MRTF-A), the nuclear transport and activity of which is regulated by monomeric actin, has been implicated in tension-based regulation of SRF-mediated transcriptional activity. However, the mechanisms involved remain unclear. We used fibroblasts grown within collagen matrices to explore whether MRTF-A transport is regulated by tissue tension. We show that MRTF-A nuclear accumulation following stimulation with serum, actin drugs or acute mechanical stress is prevented within mechanically loaded, anchored matrices at tensional homeostasis. This is accompanied by a higher G/F actin ratio, defective nuclear import and increased cofilin expression. We propose that tension regulates MRTF-A/SRF activity through cofilin-mediated modulation of actin dynamics.

Purpose: To determine the prevalence of CYP1B1 mutations in a cohort of patients with congenital corneal opacification (CCO), infantile glaucoma, or both and to describe a developmental CCO associated with CYP1B1 mutation that may explain von Hippel's original description of an internal ulcer., Design: Retrospective genotyping of a cohort of patients with infantile glaucoma and CCO., Participants: Thirty-three patients with CCO, infantile glaucoma, or both., Methods: All patients underwent a full clinical evaluation with or without examination under anesthetic including anterior segment photography, ultrasound biomicroscopy (for CCO patients; n = 22), and histopathologic analysis in patients in whom penetrating keratoplasty (PK) was performed (n = 10). Patient DNA and DNA from 50 normal control individuals who had undergone a full ophthalmologic examination were screened for CYP1B1 mutations., Main Outcome Measures: Classification of the developmental corneal opacity phenotype in infantile glaucoma patients with CYP1B1 mutations., Results: Nine distinct pathogenic recessive CYP1B1 mutations were found in 11 patients from 6 unrelated families, including 1 patient with an entire deletion of the CYP1B1 gene. Two of these patients, including the patient with the deletion, had isolated infantile congenital glaucoma with no other abnormalities. No CYP1B1 mutations were found in another 13 patients (7 of whom underwent PK in at least 1 eye) who had CCO with iridocorneal or keratolenticular adhesions (Peters' anomaly types I and II, respectively). Eight further children with CYP1B1 mutations who had CCO from birth and glaucoma underwent successful glaucoma treatment but had persistent diffuse CCO without iridocorneal or keratolenticular adhesions. Three of these underwent bilateral PK, and the histologic results were not consistent with any hitherto recognized congenital corneal dystrophy and showed abnormalities of the central corneal endothelium., Conclusions: Both severe CCO and isolated infantile glaucoma are associated with CYP1B1 mutations. The severe CCO phenotype reported herein often requires PK and has typical histopathologic changes. The mutations associated with this phenotype have not been reported previously. This phenotype may explain the patient described by Von Hippel in 1897., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Aim: To determine the feasibility of using a computer game to measure visual fields in children., Methods: The authors describe the development and assessment of a novel computer-game apparatus to measure visual fields in children. It is based upon a computer game visible on a monitor, housed in an interactive model-castle structure., Results: The authors conducted a total of 25 field tests with the final apparatus, in 25 eyes of 19 children, aged 4-14 years. On two occasions children failed to complete the exam, owing to hardware and software defects that were subsequently rectified. For the 23 completed fields, the median time for completion of the full test was 4.5 min. 16 out of 18 clinically normal patients showed normal fields; the only failures were in two 4-year-old children who still managed to complete fields, but with generalised reduced responses that were deemed abnormal by our predetermined criteria. For the five eyes with expected glaucomatous loss, all five visual fields measured were completed and showed abnormal fields consistent with their medical condition. Positive feedback was given from all children about their testing experience., Conclusions: It is feasible to develop a computer-game-based system to measure fields in children in a non-invasive, affordable and entertaining way.

Objectives: To develop and validate a novel ex vivo model of conjunctival contraction., Methods: Ex vivo segments of conjunctiva were maintained in culture for 4 weeks in permeable support plates. Digital images were obtained twice a week to monitor contraction using tissue area changes and weekly weight measurements. Investigated were the effects of known contraction stimulators (fetal bovine serum and transforming growth factor β(2)) and of the matrix metalloproteinase inhibitor GM6001. Microscopic contraction, tissue organization, and cell viability (using the cell vital dye carboxyfluorescein diacetate) were monitored by confocal reflection and 2-photon microscopy, revealing detailed real-time kinetics of tissue remodeling., Results: Fetal bovine serum and transforming growth factor β(2) induced significant tissue contraction in conjunctiva segments, with no changes in cell viability. This correlated with dramatic and specific degradation of the collagen component in the tissue. Contraction and collagen degradation were reduced in the presence of GM6001., Conclusions: Ex vivo segments of conjunctiva can be used as an integral model system to provide a higher level of understanding about the efficacy of antiscarring therapies and can help bridge the current gap between in vitro and in vivo models., Clinical Relevance: Scarring leads to the failure of several ocular surgical procedures. This novel ex vivo model recapitulates tissue contraction (with kinetics close to that of in vivo scarring) and allows for a more physiological analysis of conjunctival scarring, which could better evaluate potential therapeutic targets.

Purpose: To evaluate the long-term outcome of primary congenital glaucoma in patients followed for more than 20 years., Methods: All patients with a diagnosis of congenital glaucoma who were examined in the pediatric glaucoma clinic at Moorfields Eye Hospital from 2005 to 2006 were included. The follow-up period was a minimum of 20 years; patients with pediatric glaucoma secondary to other etiologies were excluded. Data collected included visual acuity, optic disk cupping, intraocular pressure (IOP), corneal diameter, pachymetry, visual fields, refraction, strabismus, glaucoma management, and ocular comorbidity. Progressive congenital glaucoma, defined as an increase of the cup/disk ratio of >0.2 secondary to elevated IOP, was evaluated with the use of Kaplan-Meier survival curves. Patients were divided into 1 of 3 groups: (1) stable glaucoma with no visual impairment; (2) glaucoma progression with sight-threatening consequences; and (3) poor visual acuity as a result of ocular comorbidity., Results: A total of 30 eyes of 16 patients were identified. Mean follow-up was 34 ± 10 years (range, 22-59 years). At the final clinical assessment, mean IOP was 13.6 ± 4.3 mm Hg and mean cup/disk ratio was 0.7 ± 0.3 (p < 0.05). Survival analysis demonstrated lack of progression in 90.3% at 1 year, 83.1% at 5 years, 70.8% at 10 years, 58.3% at 34 years, and 48.6% at 40 years., Conclusions: Apparently stable congenital glaucoma may progress with sight-threatening complications after many years of IOP stability. Monitoring of these patients is indicated throughout life., (Copyright © 2011 American Association for Pediatric Ophthalmology and Strabismus. Published by Mosby, Inc. All rights reserved.)

Objective: To evaluate the effectiveness of goniotomy to treat primary congenital glaucoma in an east African population., Design: A retrospective series using case records. For patients who underwent goniotomies in both eyes, only the first was analyzed., Participants: Forty-seven children undergoing goniotomy (47/80 operated eyes analyzed). Thirty-six children (77%) were male. Mean age was 19 months (range 1-204 months, standard deviation [SD] = 35)., Intervention: First goniotomy was performed from the temporal side. Repeat surgery, if necessary, was performed via nasal side approach and 100% ethanol-soaked cotton-tipped swabs were used to clear the corneal epithelium when necessary for angle visualization., Main Outcome Measures: Postoperative intraocular pressure (IOP) <21 mmHg was considered success. Potential risk factors for failure were analyzed. Quantitative visual acuities were measured with Cardiff acuity cards and Lea tests in older children., Results: A total of 36 of 47 children (77%) returned for follow-up. Mean follow-up interval was 12 months (range, 1-62 months; SD = 15). A total of 28 of 47 children (60%) had >3 months of follow-up, and 11 children had >1 year of follow-up. A total of 12 of 47 eyes (26%) required repeat goniotomy. Three of these required further trabeculectomy with mitomycin C, 1 of which required eventual enucleation after failure to control IOP, enlargement, and pain. A total of 11 of 28 children (39%) with >3 months follow-up required repeat surgery. A total of 24 of 28 children (86%) with follow-up intervals of at least 3 months achieved postoperative IOPs of <21 mmHg. Mean IOPs decreased (t = 6.1, P < 0.0005) from 23.4 mmHg (SD = 5.3 mmHg) to 14.4 mmHg (SD = 7.6 mmHg). Only 1 predictor of failure to achieve successful control of IOP was identified: female gender (relative risk = 5.3, 95% confidence interval, 1.1-26.3). Corneas were clear in 4 of 47 eyes (8.5%) preoperatively and 32 of 41 eyes (78%) postoperatively. Of 25 children with preoperative and postoperative acuities measured, 22 (88%) recorded improvement., Conclusions: Preliminary results of goniotomy in an African population with advanced disease and late presentation are reasonably encouraging. Overall results are comparable with historical drainage procedures, with the advantage of preserving conjunctiva. Further studies are justified., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: SOX2, a high-mobility group transcription factor, is expressed by retinal progenitors during development. It has been associated with the ability of progenitor cells to differentiate into retinal neurons and is highly expressed by human Müller stem cells (hMSCs) in culture. The authors investigated the role of this factor in the maintenance of progenicity and neural differentiation of hMSCs in vitro., Methods: SOX2 silencing was induced by transfection of hMSCs in culture with two pGSU6-GFP SOX2 silencing constructs and a scrambled control vector. Silencing was confirmed by examination of gene and protein expression coding for SOX2. Effects of SOX2 downregulation were investigated by expression of proliferation (Ki67) and apoptotic (TUNEL, caspase) cell markers and by the expression of markers of retinal neurons (HuD, βIII tubulin, rhodopsin, BRN3B, ISL1), glia (vimentin), and the progenitor marker PAX6., Results: SOX2 silencing caused hMSCs to rapidly adopt a neural-like morphology and was accompanied by the upregulation of specific markers of retinal neurons, including βIII tubulin, rhodopsin, BRN3B, and ISL1, and by the downregulation of the neural progenitor marker PAX6 and the glial cell marker vimentin. Interestingly, SOX2 silencing induced apoptosis, suggesting a crucial role of this factor on hMSC survival in vitro., Conclusions: These in vitro results parallel that seen when Sox2 is silenced in neural stem cells of lower species during development, and they suggest that Sox2 may have an important role in adult hMSC differentiation into retinal neurons in vitro.

Although fibroblasts play an essential part during the wound healing response, the mechanisms by which they mediate tissue remodelling and contraction are still unclear. Using live cell and matrix imaging within 3D free-floating fibroblast-populated collagen lattices as a model for tissue contraction, we compared the behaviour of a range of fibroblasts with low and high contraction abilities and analysed the effect of the broad spectrum MMP-inhibitor GM6001 on cell behaviour and matrix contraction. We identified two mechanisms underlying matrix contraction, one via direct cell-mediated contractile activity, the second through matrix degradation. These appear to be linked to cell morphology and regulated by the collagen concentration within the matrix. Cells with a rounded morphology proliferated in the matrix but did not remodel it efficiently, resulting in a poor ability to contract matrices. Cells with an elongated morphology showed higher levels of protrusive activity, leading to efficient matrix remodelling and contraction. GM6001 inhibited week-long matrix contraction to various extents with the different cell lines. However, quantitative analysis of the cell protrusive activity showed that GM6001 consistently decreased cell dynamics in 3D by about 20%, and this was correlated with a significant reduction in early matrix contraction. Overall our results suggest that although fibroblast-mediated matrix contraction depends on both cell dynamics and MMP-mediated matrix degradation, the efficiency of GM6001 treatment in preventing contraction might be linked to a direct effect on cell dynamics., (Copyright © 2010 Elsevier GmbH. All rights reserved.)

Purpose: To determine the tear cytokine profile from medicated glaucoma patients scheduled for trabeculectomy and to establish whether a specifically elevated cytokine level is related to early postoperative scarring., Design: Prospective case-control study., Participants: Sixty-one patients treated with topical antiglaucoma medications and 29 normal subjects with no prior topical treatment were recruited for the study., Methods: Schirmer strips were used to collect tear samples. A multiplex bead assay was used to quantify the presence of proinflammatory cytokines in the tears. The patients were followed up for 6 months after surgery to determine whether any postoperative intervention to maintain filtering bleb function was required., Main Outcome Measures: The level of cytokines in tear specimens from medicated glaucoma patients was the main outcome measure for the study. The need for postoperative bleb needling within 6 months was a secondary outcome measure., Results: Of the 17 cytokines assayed, only monocyte chemoattractant protein 1 (MCP-1) was elevated significantly in the medicated eyes compared with the unmedicated eyes (P < 0.0004). At 6 months after surgery, 18 (30%) of the 61 eyes required postoperative intervention. A much higher MCP-1 level was detected in these eyes compared with the remaining 43 that did not require intervention (P < 0.0001). The duration of use of topical medication correlated with increasing levels of MCP-1, although the types of glaucoma medication and the number of bottles of medications did not have any significant relationship with the level of MCP-1., Conclusions: In tears from topically medicated glaucoma eyes in an Asian population, MCP-1 was found to be the predominant cytokine elevated. Eyes with a propensity to scar in the early postoperative period have a significantly raised level of MCP-1., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Hereditary mucoepithelial dysplasia is a rare desmosomal gap junction abnormality known to produce keratitis and cataracts in addition to multiple systemic problems. It generally carries a poor visual prognosis due to corneal scarring, amblyopia, and side effects of the treatment. The authors present a sporadic case of hereditary mucoepithelial dysplasia with an unusually good visual outcome and suggest that timely and appropriate intervention can improve the visual prognosis of this rare disorder., (Copyright 2010, SLACK Incorporated.)

Aims: To determine if screening with an ultrasound A-scan and prophylactic treatment of primary angle closure (PAC) with laser peripheral iridotomy (LPI) can reduce the incidence of primary angle closure glaucoma (PACG) in Mongolia., Methods: A single-masked randomised controlled trial was initiated in 1999. 4725 volunteer Mongolian participants ≥ 50 years old from the capital Ulaanbaatar or the rural province of Bayankhongor were recruited, of which 128 were excluded with glaucoma. 4597 were randomly allocated to the control, no-screening arm or screening with ultrasound central anterior chamber depth (cACD), with the cut-off set at < 2.53 mm. 685 screen-positive participants were examined and angle closure was identified by gonioscopy in 160, of which 156 were treated with prophylactic LPI. Primary outcome of incident PACG was determined using both structural and functional evidence from objective grading of paired disc photographs from baseline and follow-up, objective grading of follow-up visual fields and clinical examination., Results: Six years later, 801 (17.42%) participants were known to have died, and a further 2047 (53.92%) were traced and underwent full ophthalmic examination. In an intention to treat analysis using available data, PACG was diagnosed in 33 participants (1.61%, 95% CI 1.11% to 2.25%), of which 19 were in the screened group and 14 in the non-screened group (OR 1.29, 95% CI 0.65 to 2.60, p = 0.47), indicating no difference between groups., Conclusions: We were not able to identify a reduction in the 6 year incidence of PACG after screening with cACD < 2.53 mm and prophylactic treatment of PAC.

The 3 most common causes of visual impairment and legal blindness in developed countries (age-related macular degeneration, glaucoma, and diabetic retinopathy) share 1 end point: the loss of neural cells of the eye. Although recent treatment advances can slow down the progression of these conditions, many individuals still suffer irreversible loss of vision. Research is aimed at developing new treatment strategies to rescue damaged photoreceptors and retinal ganglion cells (RGC) and to replace lost cells by transplant. The neuroprotective and regenerative potential of stem and progenitor cells from a variety of sources has been explored in models of retinal disease and ganglion cell loss. Continuous intraocular delivery of neurotrophic factors via stem cells (SC) slows down photoreceptor cells and RGC loss in experimental models. Following intraocular transplantation, SC are capable of expressing proteins and of developing a morphology characteristic of photoreceptors or RGC. Recently, recovery of vision has been achieved for the first time in a rodent model of retinal dystrophy, using embryonic SC differentiated into photoreceptors prior to transplant. This indicates that clinically significant synapse formation and acquisition of the functional properties of retinal neurons, and restoration of vision, are distinct future possibilities.

Recent advances in retinal stem cell research have raised the possibility that these cells have the potential to be used to repair or regenerate diseased retina. Various cell sources for replacement of retinal neurons have been identified, including embryonic stem cells, the adult ciliary epithelium, adult Müller stem cells and induced pluripotent stem cells (iPS). However, the true stem cell nature of the ciliary epithelium and its possible application in cell therapies has now been questioned, leaving other cell sources to be carefully examined as potential candidates for such therapies. The need for identification of the ontogenetic state of grafted stem cells in order to achieve their successful integration into the murine retina has been recognized. However, it is not known whether the same requirements may apply to achieve transplant cell integration into the adult human eye. In addition, the existence of natural barriers for stem cell transplantation, including microglial accumulation and abnormal extracellular matrix deposition have been demonstrated, suggesting that several obstacles need to be overcome before such therapies may be implemented. This review addresses recent scientific developments in the field and discusses various strategies that may be potentially used to design cell based therapies to treat human retinal disease.

Purpose: To determine whether prophylactic laser peripheral iridotomy (LPI) for primary angle closure (PAC) is associated with cataract progression., Methods: In 1999, Mongolian volunteers aged>or=50 years were invited to participate in a longitudinal study. Glaucoma was excluded in all participants and 712 of them were selected to undergo a full ophthalmic examination as part of the study protocol. Lenses were graded and PAC diagnosed using international classification systems. In 2005, all traced participants underwent a similar dilated examination. Diagnosis of cataract progression was based on the inter-observer variation +2 standard deviations. The association between LPI at baseline and cataract progression was assessed using chi2-test and logistic regression., Results: Of 712 participants, 158 were diagnosed with occludable angles and treated with LPI. In 2005, 137 participants (19.2%) had died, 315 (315/575=54.8%) were traced, and dilated examination was performed on 276 (48%) of them. Progression of nuclear opacity (NO), cortical, and posterior subcapsular (PSC) opacities were evident in 40 (14.5%, 95% confidence interval (CI)=10.6-19.2%), 89 (32.2%, 95% CI=26.8-38.1%), and 11 participants (4.0%, 95% CI=2.0-7.0%), respectively. Although NO was more likely to progress in those with LPI in a crude analysis (odds ratio (OR)=2.02, 95% CI=1.00-4.11, P=0.05), no evidence of an independent association was detected in multivariate analysis adjusting for age, sex, and baseline Schaffer grading (adjusted OR=1.24, 0.41-3.75, P=0.7). There was no evidence of an association between LPI and progression of PSC or cortical opacities., Conclusions: There is no evidence that prophylactic LPI is independently associated with cataract progression in this study.

Glaucoma is the most common age-related optic nerve disease and also the most common neuropathy, affecting approximately 60 million people worldwide in its most common forms. This figure is expected to rise to 80 million by 2020. Glaucoma is a neurodegenerative disease in which various triggers induce cascades of secondary events, which ultimately lead to apoptotic retinal ganglion cell (RGC) death. The main risk factor for glaucomatous nerve damage is raised pressure in the eye. Understanding the cascades mediating optic nerve damage enables the development of new, neuroprotective treatment strategies that might not only target the initial insult but also prevent or delay secondary neurodegeneration. Furthermore, neuroregeneration and repopulation of the visual pathway by stem or neural precursor cells is becoming possible. Increasing understanding of the pathways involved in directed axon growth and manipulation of stem and progenitor cells towards an RGC fate have facilitated first successes in animal models of glaucoma., (2010 Elsevier Ltd. All rights reserved.)

Retinal ganglion cell (RGC) death in glaucoma models is associated with accumulation of activated microglia, a sign of neural degeneration which has been shown to constitute a barrier for transplant cell survival and migration. This study investigated the use of triamcinolone (TA) to control macrophage/microglia accumulation in a model of RGC depletion to create a permissive environment for stem cell grafting. Intravitreal NMDA alone or in combination with TA was used to induce rapid onset of RGC death in 3-4 week old Lister hooded (LH) rat eyes prior to Müller stem cell transplantation into the vitreoretinal space. The effect of NMDA on RGC death and microglial accumulation was assessed immuno-histochemically, whilst electroretinography (ERG) was used to assess RGC function. Post transplantation, survival of grafted cells and their association with microglia were also examined by immunohistochemical methods. Intravitreal injection of NMDA alone resulted in severe macrophage/microglia accumulation associated with extensive RGC death 4-7 days post-treatment. Combination of NMDA with TA significantly reduced microglial numbers in the RGC when compared to NMDA only treated eyes while still depleting the retina of RGC. At the same time, NMDA/TA treatment also caused functional RGC loss as demonstrated by reduction of the scotopic threshold response. Upon transplantation with Müller stem cells, NMDA/TA treatment caused significant reduction in the number of transplant associated macrophage/microglia compared to eyes treated with NMDA alone. On this basis it is proposed that intravitreal injection of TA may be useful as an effective anti-inflammatory agent to control macrophage/microglia accumulation induced by RGC death, thereby creating a retinal environment permissive to cell transplantation studies., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Mechanical tension and contracture are two related facets of tissue biology. This study assessed the effect of ilomastat, a broad-spectrum matrix metalloprotease (MMP) inhibitor, on generation of tension by Dupuytren's disease fibroblasts. Nodule and cord-derived fibroblasts were isolated from five patients with Dupuytren's disease; flexor retinaculum acted as the control. A culture force monitor (CFM) provided an in vitro model of tissue organization to assess development of mechanical tension, lattice contraction and spatial remodelling by fibroblasts. Responses to ilomastat were compared to treatment with a control peptide. Nodule and cord-derived fibroblasts exhibited a two-fold increase in tension compared with flexor retinaculum. Ilomastat significantly inhibited development of tension by nodule and cord but not flexor retinaculum derived fibroblasts at 100 microM. These results imply that MMP activity mediates regulation of tensile strength by Dupuytren's disease fibroblasts and may be an important therapeutic target in patients with Dupuytren's disease.

Purpose: To assess the changes in optic nerve head (ONH) structure and visual field (VF) sensitivity over time in a cohort of patients with glaucoma after trabeculectomy., Methods: The MoreFlow Medical Research Council 5-Fluorouracil (5-FU) study was an 80-month prospective randomized controlled trial of per-operative 5-FU versus placebo on the outcomes of primary trabeculectomy. Before surgery, patients had ONH imaging with a retinal tomograph and full-threshold visual field testing. After surgery, ONH imaging was performed annually and VF testing at 4-month intervals. This analysis included only patients with a minimum of 3 years' postoperative ONH and VF data. ONH images were analyzed by linear regression of sector rim area (RA) over time with change defined as a significant slope >1% of baseline RA per year in any sector. VFs were analyzed with point-wise linear regression analysis (PLRA) techniques with the stringent three-omitting criteria used. Eyes were classed as progressing or not based on analysis with either technique. Patients' median IOP level, intervisit IOP fluctuation, and percentage reduction in IOP over the follow-up period were also determined., Results: Two hundred fifty eyes of 250 patients were suitable for analysis. Of these, 70 (28%) eyes were deemed to show glaucoma progression approximately 5 years after surgery: 20 eyes by ONH alone, 35 by VF alone, and 15 by both methods. Of the 15 shown to be progressing by both ONH and VF analysis, only 7 (3% total cohort) showed congruity in the location of change. Eyes showing changes in both ONH and VF sensitivity had slightly higher median follow-up IOP (median IOP [interquartile range; IQR] nonprogressors 14.0 mm Hg [11.8-16.0 mm Hg], progressors 15.1 mm Hg [12.7-17.0 mm Hg]; Mann-Whitney U test [MWU]; P = 0.03) and lower degrees of IOP reduction from baseline (percentage IOP reduction [IQR]: nonprogressors -38.4% [-51.8% to -26.4%]; progressors -31.4% [-43.1% to -21.5%]; MWU P = 0.01) compared with eyes showing no progression., Conclusions: The study demonstrates that approximately one third of eyes continued to show progression of glaucoma at five years after trabeculectomy, as determined by trend-based analysis of ONH structural changes and VF sensitivity over time. The study suggests that the degree of IOP reduction after trabeculectomy may play an important role in the progression of glaucoma as detected by both functional and structural methods.

Purpose: Inflammation is a risk factor for scarring after trabeculectomy surgery. Mast cells are important mediators of inflammation and scarring in allergic eye disease. This exploratory project investigated the presence of mast cells in the conjunctiva of glaucoma patients having trabeculectomy surgery., Methods: Conjunctival biopsies from glaucoma patients belonging to specific groups: medically treated glaucoma (M, n=6), repeat glaucoma surgery (S, n=8), and uveitic glaucoma (U, n=7). The control group (C, n=8) was retinal detachment patients undergoing repair surgery for the first time. Immunohistochemistry techniques stained for the presence of the intracellular mast cell enzyme tryptase., Results: The median mast cell tryptase-positive counts for all glaucoma groups (M, S, and U) ranged from 0.102-0.113 cells/mm2 compared to 0.064 cells/mm2 for group C. This was statistically significant comparing group S to group C (P=0.0063), but not when comparing groups U or M to group C. The mast cell tryptase-positive counts did not significantly differ among the groups., Conclusions: Mast cell numbers were significantly increased in glaucoma patients who have previously undergone surgery (group S). Mast cell activity may contribute to the scarring process and the increased risk of excessive conjunctival scarring after trabeculectomy surgery. Further investigation needs to be performed to evaluate this potential role.