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Glaucoma treatment is usually initiated with topical medication that lowers the intraocular pressure (IOP) by reducing the aqueous production, enhancing the aqueous outflow, or both. However, the effect of topical IOP-lowering medications on the microstructures of the aqueous outflow pathway are relatively unknown. In this retrospective, observational study, 56 treatment-naïve patients with primary open-angle glaucoma were enrolled. Images of the nasal and temporal corneoscleral limbus were obtained using anterior segment optical coherence tomography (AS-OCT). The conjunctival vessels and iris anatomy were used as landmarks to select the same limbal area scan, and the trabecular meshwork (TM) width, TM thickness, and Schlemm's canal (SC) area were measured before and after using the IOP-lowering agents for 3 months. Among the 56 patients enrolled, 33 patients used prostaglandin (PG) analogues, and 23 patients used dorzolamide/timolol fixed combination (DTFC). After 3 months of DTFC usage, the TM width, TM thickness, and SC area did not show significant changes in either the nasal or temporal sectors. Conversely, after prostaglandin analog usage, the TM thickness significantly increased, and the SC area significantly decreased (all P < 0.01). These findings warrant a deeper investigation into their relationship to aqueous outflow through the conventional and unconventional outflow pathways after treatment with PG analogues., (© 2021. The Author(s).)

Chronically elevated intraocular pressure (IOP) is the major risk factor of primary open-angle glaucoma, a leading cause of blindness. Dysfunction of the trabecular meshwork (TM), which controls the outflow of aqueous humor (AqH) from the anterior chamber, is the major cause of elevated IOP. Here, we demonstrate that mice deficient in the Krüppel-like zinc finger transcriptional factor GLI-similar-1 (GLIS1) develop chronically elevated IOP. Magnetic resonance imaging and histopathological analysis reveal that deficiency in GLIS1 expression induces progressive degeneration of the TM, leading to inefficient AqH drainage from the anterior chamber and elevated IOP. Transcriptome and cistrome analyses identified several glaucoma- and extracellular matrix-associated genes as direct transcriptional targets of GLIS1. We also identified a significant association between GLIS1 variant rs941125 and glaucoma in humans (P = 4.73 × 10 -6 ), further supporting a role for GLIS1 into glaucoma etiology. Our study identifies GLIS1 as a critical regulator of TM function and maintenance, AqH dynamics, and IOP., (© 2021. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Abstract: To report the changes of trabecular meshwork (TM) pigmentation and clinical outcomes of patients with pigment dispersion syndrome (PDS) after resolution of reverse pupillary block.Twenty one eyes of 11 PDS patients were followed up periodically for 15 years after resolution of reverse pupillary block with either Nd: YAG laser peripheral iridotomy (LPI) or trabeculectomy. Visual acuity (VA), best-corrected visual acuity (BCVA), slit lamp examination, intraocular pressure (IOP), Humphrey visual field analysis (VFA), gonioscopy and stereoscopic funduscopy were performed on admission and every 6 months postoperatively. TM pigmentation was quantitatively evaluated and graded every 5 years after the treatment, in which the circumference of anterior chamber angle was divided into 4 quadrants: superior, inferior, nasal and temporal. Postoperative IOP, VA, BCVA, VFA, TM pigmentation and adjunctive anti-glaucoma medications were main outcome measurements and compared with baseline.Eleven patients (9 males, 2 females) were identified as PDS according to the diagnostic criteria, with average age of 38.25 ± 6.93 years (range, 31-55 years) at initial diagnosis. The mean IOP level was 33.1 ± 9.8 mmHg (range, 22-56 mmHg) at diagnosis. Ten PDS eyes received LPI, and the other eleven eyes underwent uneventful trabeculectomy. The median TM pigmentation score of the 21 PDS eyes was 16 (interquartile range [IQR], 15-16) on admission, which changed to 14 (IQR, 13-15), 13 (IQR, 12-14), 12(IQR, 10.5-12) at 5-, 10-, 15-year follow-up visits respectively. The decrease rate of TM pigmentation was 37% in inferior quadrant, while in nasal, temporal, and superior quadrant the reduction rate was 28%, 23%, and 18%, respectively, at the last follow-up visit. Majority of these enrolled eyes (19/21) had stable VA and BCVA with average endpoint IOP of 15.1 ± 3.4 mmHg.TM pigmentation in PDS patients attenuates with time after reverse pupillary block was resolved, in which the inferior quadrant seems faster than the other quadrants., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Primary congenital glaucoma (PCG) occurs in only one eye in some patients. We aimed to characterize anatomical features of the angle and Schlemm's canal (SC) in vivo among fellow eyes of patients with unilateral primary congenital glaucoma., Methods: Both eyes of 33 children with unilateral PCG and 30 healthy, age-matched children, old enough to co-operate were analysed using high-resolution anterior segment spectral domain (SD) OCT. Subgroup analysis was done for the presence/absence of angle dysgenesis as defined by the presence of abnormal tissue/hyper-reflective membrane within angle recess and/or the absence of SC. Other anatomical landmarks differentiating the fellow eyes from eyes with glaucoma were also evaluated and compared with healthy subjects., Results: The presence of abnormal tissue at the angle and/or a hyper-reflective membranous structure covering the meshwork was seen in all affected PCG eyes (100%) and in 21 (63%) unaffected fellow eyes; p = 0.001. The SC could be seen in 8 (24%) affected in comparison with 29 (88%) fellow unaffected eyes; p = 0.001. The ASOCT scans of 54 (90%) healthy eyes and 3 (9%) fellow PCG eyes revealed a direct communication of anterior portion of the SC with the anterior chamber. Among the fellow eyes, a communication of the supraciliary space with anterior chamber could be discerned in 26 eyes (79%)., Conclusions: Despite angle dysgenesis, outflow channels such as the uveoscleral or a direct communication of SC with the anterior chamber play a role in preventing the development of glaucoma in fellow eyes of unilateral PCG., (© 2020 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Reactive oxygen species (ROS) plays a key role in the pathogenesis of primary open-angle glaucoma (POAG), a chronic neurodegenerative disease that damages the trabecular meshwork (TM) cells, inducing apoptosis of the retinal ganglion cells (RGC), deteriorating the optic nerve head, and leading to blindness. Aqueous humor (AH) outflow resistance and intraocular pressure (IOP) elevation contribute to disease progression. Nevertheless, despite the existence of pharmacological and surgical treatments, there is room for the development of additional treatment approaches. The following review is aimed at investigating the role of different microRNAs (miRNAs) in the expression of genes and proteins involved in the regulation of inflammatory and degenerative processes, focusing on the delicate balance of synthesis and deposition of extracellular matrix (ECM) regulated by chronic oxidative stress in POAG related tissues. The neutralizing activity of a couple of miRNAs was described, suggesting effective downregulation of pro-inflammatory and pro-fibrotic signaling pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), transforming growth factor-beta 2 (TGF-β2), Wnt/β-Catenin, and PI3K/AKT. In addition, with regards to the elevated IOP in many POAG patients due to increased outflow resistance, Collagen type I degradation was stimulated by some miRNAs and prevented ECM deposition in TM cells. Mitochondrial dysfunction as a consequence of oxidative stress was suppressed following exposure to different miRNAs. In contrast, increased oxidative damage by inhibiting the mTOR signaling pathway was described as part of the action of selected miRNAs. Summarizing, specific miRNAs may be promising therapeutic targets for lowering or preventing oxidative stress injury in POAG patients.

Glaucoma is a leading cause of irreversible visual impairment, and primary angle closure glaucoma (PACG) affects Asians disproportionately. Whereas advances in ocular imaging have identified several anatomical risk factors, our ability to predict PACG still requires considerable improvement. The iris plays a crucial role in the pathophysiology of angle closure disease, either through a mechanical or vascular mechanism. Irises of closed-angle eyes inhibit vastly different structural constituents as compared with those of open-angle eyes, thereby effecting variations in biomechanical properties and iris fluid conductivity. The clinical consequences include a smaller change in iris volume on pupil dilation in closed-angle eyes, thereby bringing the iris and trabecular meshwork closer in apposition. In this review, we summarise the potential role of the iris in the pathogenesis of angle closure disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The purpose of this study was to investigate the difference in pulsatile trabecular meshwork (TM) motion between normal and eyes with POAG using phase-sensitive optical coherence tomography (PhS-OCT)., Methods: In this cross-sectional study, eight healthy subjects (16 eyes) and nine patients with POAG (18 eyes) were enrolled. A laboratory-based prototype PhS-OCT system was used to measure pulsatile TM motion. PhS-OCT images were analyzed to obtain parameters of pulsatile TM motion (i.e. maximum velocity [MV] and cumulative displacement [CDisp]). Outflow facility and ocular pulse amplitude were measured using pneumotonography. Detection sensitivity was compared among various parameters by calculating the area under the receiver operating characteristic curves (AUCs)., Results: A pulsatile TM motion waveform synchronous with digital pulse was observed using PhS-OCT in both healthy and POAG eyes. The mean MV in eyes with glaucoma was significantly lower than healthy eyes (P < 0.001). The mean CDisp in POAG eyes was also significantly lower than healthy eyes (P < 0.001). CDisp showed a significant correlation (r = 0.46; P = 0.0088) with ocular pulse amplitude in the study. Compared with the outflow facility, both the MV and CDisp were found to have a better discrimination of glaucoma (P < 0.001 and P = 0.0074, respectively)., Conclusions: Pulsatile TM motion was reduced in patients with POAG compared to healthy subjects. The underlying mechanism may be due to the altered tissue stiffness or other biomechanical properties of the TM in POAG eyes. Our evidence suggests that the measurement of pulsatile TM motion with PhS-OCT may help in characterizing outflow pathway abnormalities.

The ability to ablate a gene in a given tissue by generating a conditional knockout (cKO) is crucial for determining its function in the targeted tissue. Such tissue-specific ablation is even more critical when the gene's conventional knockout (KO) is lethal, which precludes studying the consequences of its deletion in other tissues. Therefore, here we describe a successful strategy that generated a Matrix Gla floxed mouse (Mgp.floxed) by the CRISPR/Cas9 system, that subsequently allowed the generation of cKOs by local viral delivery of the Cre-recombinase enzyme. MGP is a well-established inhibitor of calcification gene, highly expressed in arteries' smooth muscle cells and chondrocytes. MGP is also one of the most abundant genes in the trabecular meshwork, the eye tissue responsible for maintenance of intraocular pressure (IOP) and development of Glaucoma. Our strategy entailed one-step injection of two gRNAs, Cas9 protein and a long-single-stranded-circular DNA donor vector (lsscDNA, 6.7 kb) containing two loxP sites in cis and 900-700 bp 5'/3' homology arms. Ocular intracameral injection of Mgp.floxed mice with a Cre-adenovirus, led to an Mgp.TMcKO mouse which developed elevated IOP. Our study discovered a new role for the Mgp gene as a keeper of physiological IOP in the eye.

The aqueous humor (AH) outflow pathways definition is still matter of intense debate. To date, the differentiation between conventional (trabecular meshwork) and unconventional (uveoscleral) pathways is widely accepted, distinguishing the different impact of the intraocular pressure on the AH outflow rate. Although the conventional route is recognized to host the main sites for intraocular pressure regulation, the unconventional pathway, with its great potential for AH resorption, seems to act as a sort of relief valve, especially when the trabecular resistance rises. Recent evidence demonstrates the presence of lymphatic channels in the eye and proposes that they may participate in the overall AH drainage and intraocular pressure regulation, in a presumably adaptive fashion. For this reason, the uveolymphatic route is increasingly thought to play an important role in the ocular hydrodynamic system physiology. As a result of the unconventional pathway characteristics, hydrodynamic disorders do not develop until the adaptive routes cannot successfully counterbalance the increased AH outflow resistance. When their adaptive mechanisms fail, glaucoma occurs. Our review deals with the standard and newly discovered AH outflow routes, with particular attention to the importance they may have in opening new therapeutic strategies in the treatment of ocular hypertension and glaucoma., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Primary open-angle glaucoma is the leading cause of irreversible blindness worldwide, and intraocular pressure reduction remains the only proven treatment strategy. Elevated intraocular pressure occurs as the result of impaired aqueous humor outflow. Both a passive model and a dynamic model have been used to explain trabecular outflow resistance. The passive model posits that the trabecular meshwork acts as a static filter that exerts stable and passive resistance to outflow. In contrast, the dynamic model involves a "biomechanical pump." In recent years, the range of surgical management options for glaucoma has dramatically expanded, particularly the class of procedures known as microinvasive glaucoma surgery. These procedures typically target and enhance specific outflow routes. Optimal patient outcomes with microinvasive glaucoma surgery require a clear understanding of aqueous outflow and a surgical approach that is targeted to overcome the site of abnormal resistance in the individual. We review the anatomy and physiology of trabecular and suprachoroidal outflow that is of relevance to microinvasive glaucoma surgery-performing surgeons., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Myocilin is highly expressed in the trabecular meshwork (TM), which plays an important role in the regulation of intraocular pressure (IOP). Myocilin abnormalities may cause dysfunction of the TM, potentially leading to increased IOP. High IOP is a well‑known primary risk factor for glaucoma. Myocilin mutations are common among glaucoma patients, and they are implicated in juvenile‑onset open‑angle glaucoma (JOAG) and adult‑onset primary open‑angle glaucoma (POAG). Aggregation of aberrant mutant myocilins is closely associated with glaucoma pathogenesis. The aim of the present review was to discuss the recent findings regarding the major physiological functions of myocilin, such as intra‑ and extracellular proteolytic processes. We also aimed to discuss the risk factors associated with myocilin and the development of glaucoma, such as misfolded/mutant myocilin, imbalance of myocilin and extracellular proteins, and instability of mutant myocilin associated with temperature. Finally, we further outlined certain issues that are yet to be resolved, which may represent the basis for future studies on the role of myocilin in glaucoma.

Purpose: To study the change in intraocular pressure (IOP) and angle status after phacoemulsification in a cohort of primary angle closure hypertension (PACHT) patients., Setting: Tertiary Eye Care, India., Design: Prospective interventional case-series., Methods: Case-series of 18 eyes of 18 patients. Preoperative biometry including axial length, anterior chamber depth (ACD), lens thickness, and central corneal thickness were studied. Preoperative and postoperative IOP, number of topical glaucoma medications, angle swept source optical coherence tomography (SS-OCT) parameters of nasal and temporal angle opening distance, trabecular iris space area, scleral spur angle, lens vault and circumferential iridotrabecular contact (ITC) were studied and their correlations derived., Results: The mean preoperative IOP, 31±6 mm Hg, decreased to 14±1 mm Hg at 6-months postoperative period, P<0.001, a fall by 58±14%. The number of glaucoma medications reduced from 4(3-5) to 2(1-3), P<0.001. All SS-OCT studied parameters denoted significant angle widening postsurgery. The ITC% reduced from 52(16-100) to 19(0-97), P<0.001. The preoperative ITC showed moderate to strong correlation with all preoperative nasal and temporal angle parameters. It also showed moderate positive correlation with percentage fall in IOP at 1-month postoperative period. The preoperative ACD showed significant negative correlation with preoperative and postoperative ITC., Conclusions: PACHT patients benefit significantly from cataract surgery with marked angle widening, IOP reduction and a decrease in the number of glaucoma medications. The SS-OCT derived circumferential iridotrabecular contact index can be used as the single best parameter to indicate the preoperative angle status and predict postoperative change in IOP, as against the numerous single section measured angle parameters.

Purpose: To compare Schlemm canal (SC) and trabecular meshwork (TM) in children with healthy eyes and those with and without glaucoma after lensectomy., Design: Cross-sectional observational study., Participants: Fifty children 4 to 16 years of age with healthy eyes and 48 children who underwent lensectomy (124 healthy and 72 postlensectomy eyes)., Methods: Anterior segment (AS) OCT (Tomey SS-1000 CASIA; Tomey, Nagoya, Japan) of the nasal iridocorneal angle at 2 levels of accommodative effort (2.5 diopters [D] and 15 D). For each parameter and state of accommodation, a random effects model was fitted to estimate differences between healthy eyes and eyes with history of lensectomy., Main Outcome Measures: Dimensions of SC and TM and conventional AS OCT iridocorneal angle measurements., Results: The horizontal diameter of SC and its cross-sectional area (CSA) are significantly smaller in eyes that have undergone lensectomy versus healthy eyes. Accommodative effort increases SC size in healthy eyes, but not in eyes that have undergone lensectomy., Conclusions: Lensectomy is associated with a reduction in SC size and a loss of physiologic SC dilatation during accommodative effort, which may reflect a reduction in outflow facility and may contribute to the development of glaucoma after lensectomy., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Ocular corticosteroids are commonly used clinically. Unfortunately, their administration frequently leads to ocular hypertension, i.e., elevated intraocular pressure (IOP), which, in turn, can progress to a form of glaucoma known as steroid-induced glaucoma. The pathophysiology of this condition is poorly understood yet shares similarities with the most common form of glaucoma. Using nanotechnology, we created a mouse model of corticosteroid-induced ocular hypertension. This model functionally and morphologically resembles human ocular hypertension, having titratable, robust, and sustained IOPs caused by increased resistance to aqueous humor outflow. Using this model, we then interrogated the biomechanical properties of the trabecular meshwork (TM), including the inner wall of Schlemm's canal (SC), tissues known to strongly influence IOP and to be altered in other forms of glaucoma. Specifically, using spectral domain optical coherence tomography, we observed that SC in corticosteroid-treated mice was more resistant to collapse at elevated IOPs, reflecting increased TM stiffness determined by inverse finite element modeling. Our noninvasive approach to monitoring TM stiffness in vivo is applicable to other forms of glaucoma and has significant potential to monitor TM function and thus positively affect the clinical care of glaucoma, the leading cause of irreversible blindness worldwide., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

The present work analyses the performance of four glaucoma drainage devices, by means of a novel patient-oriented numerical procedure. The procedure is based on the three-dimensional geometry reconstruction from the stacks of tomographic images of a human eye, at different angles, on meshing and on thermo-fluid dynamics modelling activities, carried out on the reconstructed computational domain. The current three-dimensional eye model considers anterior chamber (AC), trabecular meshwork, Schlemm's canal, and collector channels, making use of generalised porous medium approach for modelling ocular porous tissue and cavities. The intraocular pressure (IOP) management inside AC of human eye is analysed, by comparing the results obtained for four drainage devices implanted in a human eye for glaucoma treatment, ie, ExPRESS shunt, iStent inject, SOLX gold micro shunt, and the novel silicon shunt device. The numerical results allow predicting the effects of the installation of these implants on human eyes, in terms of IOP decrease, aqueous humour velocity, pressure, friction coefficient, and local Nusselt number, pointing out the clear distinction between pre-operative and post-operative eye conditions for different glaucoma surgical techniques., (© 2018 John Wiley & Sons, Ltd.)

Purpose: To correlate outflow function and outflow tract vessel diameter changes induced by nitric oxide (NO)., Methods: In a porcine anterior segment perfusion model, the effects of a nitric oxide donor (100 μM DETA-NO) on outflow facility were compared with controls (n = 8 per group) with trabecular meshwork (TM) and after circumferential ab interno trabeculectomy (AIT). Outflow structures were assessed with spectral-domain optical coherence tomography (SD-OCT) before and after NO, or an NO synthase inhibitor (100 μM L-NAME) and the vasoconstrictor, endothelin-1 (100 pg/mL ET-1). Scans were processed with a custom macroscript and aligned for automated reslicing and quantification of cross-sectional outflow tract areas (CSA)., Results: The facility increased after DETA-NO (Δ of 0.189 ± 0.081 μL/min·mm Hg, P = 0.034) and AIT (Δ of 0.251 ± 0.094 μL/min·mm Hg, P = 0.009), respectively. Even after AIT, DETA-NO increased the facility by 61.5% (Δ of 0.190 ± 0.074 μL/min·mm Hg, P = 0.023) and CSA by 13.9% (P < 0.001). L-NAME + ET-1 decreased CSA by -8.6% (P < 0.001). NO increased the diameter of focal constrictions 5.0 ± 3.8-fold., Conclusions: NO can dilate vessels of the distal outflow tract and increase outflow facility in a TM-independent fashion. There are short, focally constricting vessel sections that display large diameter changes and may have a substantial impact on outflow.

Purpose: The purpose of this study was to characterize the pulsatile motion of trabecular meshwork (TM) in normal subjects and demonstrate its changes in accommodation with phase-sensitive optical coherence tomography (PhS-OCT)., Methods: A new PhS-OCT laboratory prototype was designed to measure pulsatile TM motion in 13 healthy humans. Two sets of images were captured in 10 subjects, first with best corrective refraction and the other with an additional 3.0 diopters of accommodation. In each image, both maximum velocity (MV) and cumulative displacement (CD) in two selected regions of TM, the internal (IMV and ICD) and external (EMV and ECD) region, were measured., Results: For all parameters the intraclass correlation coefficient was >0.75. Neither MV nor CD was significantly different between eyes in individual subjects (PIMV = 0.967, PEMV = 0.391, PICD = 0.603, PECD = 0.482). In 26 eyes, with best corrective refraction, the EMV was higher than the IMV (23.9 ± 9.8 vs. 18.9 ± 8.08 μm/s; P = 0.0001), as was the ECD compared with the ICD (0.340 ±0.125 vs. 0.264 ± 0.111 μm; P = 0.000004). With accommodation, MV and CD significantly increased (PIMV = 0.0003, PEMV = 0.0003, PICD = 0.019, and PECD = 0.007), whereas MV and CD in the external region were still larger than those in the internal area (PEMV vs. IMV = 0.009, PECD vs. ICD = 0.023)., Conclusions: This study demonstrates the differences in TM motion between the internal and external regions of TM and displays its change with accommodation. The findings and good reproducibility suggest PhS-OCT helps to understand TM function in regulation of IOP, and, with further refinements, it may be useful in clinical management of glaucoma.

It has been suggested that common mechanisms may underlie the pathogenesis of primary open-angle glaucoma (POAG) and steroid-induced glaucoma (SIG). The biomechanical properties (stiffness) of the trabecular meshwork (TM) have been shown to differ between POAG patients and unaffected individuals. While features such as ocular hypertension and increased outflow resistance in POAG and SIG have been replicated in mouse models, whether changes of TM stiffness contributes to altered IOP homeostasis remains unknown. We found that outer TM was stiffer than the inner TM and, there was a significant positive correlation between outflow resistance and TM stiffness in mice where conditions are well controlled. This suggests that TM stiffness is intimately involved in establishing outflow resistance, motivating further studies to investigate factors underlying TM biomechanical property regulation. Such factors may play a role in the pathophysiology of ocular hypertension. Additionally, this finding may imply that manipulating TM may be a promising approach to restore normal outflow dynamics in glaucoma. Further, novel technologies are being developed to measure ocular tissue stiffness in situ. Thus, the changes of TM stiffness might be a surrogate marker to help in diagnosing altered conventional outflow pathway function if those technologies could be adapted to TM.

Introduction: This study evaluates long-term outcomes of two trabecular micro-bypass stents, one suprachoroidal stent, and postoperative prostaglandin in eyes with refractory open angle glaucoma (OAG)., Methods: Prospective ongoing 5-year study of 80 eligible subjects (70 with 4-year follow-up) with OAG and IOP ≥ 18 mmHg after prior trabeculectomy and while taking 1-3 glaucoma medications. Subjects received two iStent ® trabecular micro-bypass stents, one iStent Supra ® suprachoroidal stent, and postoperative travoprost. Postoperative IOP was measured with medication and annually following medication washouts. Performance was measured by the proportion of eyes with ≥ 20% IOP reduction on one medication (the protocol-specified prostaglandin) versus preoperative medicated IOP (primary outcome); and the proportion of eyes with postoperative IOP ≤ 15 and ≤ 18 mmHg on one medication (secondary outcome). Additional clinical and safety data included medications, visual field, pachymetry, gonioscopy, adverse events, visual acuity, and slit-lamp and fundus examinations., Results: Preoperatively, mean medicated IOP was 22.0 ± 3.1 mmHg on 1.2 ± 0.4 medications, and mean unmedicated IOP was 26.4 ± 2.4 mmHg. Postoperatively, among eyes without later cataract surgery, mean medicated IOP at all visits through 48 months was ≤ 13.7 mmHg (≥ 37% reduction), and annual unmedicated IOP was ≤ 18.4 mmHg (reductions of ≥ 30% vs. preoperative unmedicated IOP and ≥ 16% vs. preoperative medicated IOP). At all postoperative visits among eyes without additional surgery or medication, ≥ 91% of eyes had ≥ 20% IOP reduction on one medication versus preoperative medicated IOP. At month 48, 97 and 98% of eyes achieved IOP ≤ 15 and ≤ 18 mmHg, respectively, on one medication. Six eyes required additional medication, no eyes required additional glaucoma surgery, and safety measurements were favorable throughout follow-up., Conclusion: IOP control was achieved safely with two trabecular micro-bypass stents, one suprachoroidal stent, and postoperative prostaglandin. This microinvasive, ab interno approach introduces a possible new treatment option for refractory disease., Trial Registration: NCT01456390., Funding: Glaukos Corporation.

Glaucoma is a progressive and chronic neurodegenerative disorder characterized by damage to the inner layers of the retina and deformation of the optic nerve head. The degeneration of retinal ganglion cells and their axons results in an irreversible loss of vision and is correlated with increasing age. Extracellular matrix changes related to natural aging generate a stiffer extracellular environment throughout the body. Altered age-associated ocular tissue stiffening plays a major role in a significant number of ophthalmic pathologies. In glaucoma, both the trabecular meshwork and the optic nerve head undergo extensive extracellular matrix remodeling, characterized by fibrotic changes associated with cellular and molecular events (including myofibroblast activation) that drive further tissue fibrosis and stiffening. Here, we review the literature concerning the role of age-related ocular stiffening in the trabecular meshwork, lamina cribrosa, sclera, cornea, retina, and Bruch membrane/choroid and discuss their potential role in glaucoma progression. Because both trabecular meshwork and lamina cribrosa cells are mechanosensitive, we then describe molecular mechanisms underlying tissue stiffening and cell mechanotransduction and how these cellular activities can drive further fibrotic changes within ocular tissues. An improved understanding of the interplay between age-related tissue stiffening and biological responses in the trabecular meshwork and optic nerve head could potentially lead to novel therapeutic strategies for glaucoma treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To compare the effectiveness and safety of 120 applications versus 160 applications of selective laser trabeculoplasty (SLT) at reducing intraocular pressure (IOP) from baseline in glaucoma patients over a 1-year period., Methods: A retrospective chart review was conducted, comprising 376 eyes from 199 patients who underwent SLT treatment performed by the same glaucoma subspecialist from 2014 to 2015. Data were obtained on patients' clinical features, management, and outcomes. Patients were treated with either 120 applications or 160 applications of SLT per 360 degrees of trabecular meshwork over 2 sessions. Statistical analyses were performed comparing baseline IOP with IOP at 6 weeks and 1-year follow-up after completion of treatment. The incidence and severity of transient IOP rises immediately post-SLT was also recorded., Results: Both SLT regimes were effective at reducing IOP. Univariate t tests showed that the 160 applications group had significantly greater mean reduction of IOP from baseline at both 6 weeks (4.6 vs. 3.6 mm Hg, P=0.015) and 1-year time points (4.1 vs. 2.8 mm Hg, P=0.019). However, when multivariate analyses were used to account for the effects of clustering and include other covariates such as age, baseline IOP, history of previous SLT there was no significant difference between success rates of the 2 treatment groups at either time points. Higher baseline IOP was associated with greater IOP reduction at 6 weeks (P<0.001) and 1 year (P<0.001) for both treatment groups. There was no statistical difference in incidence and severity of IOP spikes at 1-hour post-SLT between the 2 treatment groups., Conclusions: SLT produces a significant IOP-lowering effect and treatment with 160 applications per 360 degrees may be more effective than 120 applications per 360 degrees. Furthermore, 160 applications of SLT does not increase the risk of transient IOP spikes.

The pathological mechanisms underlying increased outflow resistance at the trabecular meshwork (TM) that is responsible for elevating intraocular pressure (IOP) have not been fully delineated. Recent studies have shown that progressive accumulation of misfolded proteins and induction of endoplasmic reticulum (ER) stress is associated with the pathophysiology of glaucomatous TM damage and IOP elevation. We have shown that known causes of human glaucoma, including expression of mutant myocilin or dexamethasone treatment induce abnormal protein accumulation and ER stress in the TM in vitro and in vivo models. To cope up with abnormal protein accumulation, TM cells activate a cytoprotective pathway of unfolded protein response (UPR). However, chronic ER stress can lead to TM dysfunction and IOP elevation. Using cell culture, mouse models, and human postmortem tissues as well as genetic and pharmacological manipulations, we have analyzed ER stress and UPR mediators in the glaucomatous TM damage and IOP elevation. In this chapter, we have described a detailed protocol for the analysis of protein misfolding and ER stress in TM cells and tissues and its association with glaucomatous TM damage and IOP elevation.

Background: Trabecular meshwork (TM) plays an important role in maintaining normal intraocular pressure (IOP). Studies have shown that glaucomatous TM tissues are stiffer than those of normal tissue. The high expression of fibronectin protein (FN) and adaptor protein (LNK) may be related to high resistance to aqueous humor outflow as well as high IOP. Our concern is what factors lead to the variation of the stiffness of trabecular tissue/cells., Methods: Atomic force microscope (AFM) and Western blot (WB) analysis were applied to test TM cells of rats cultured with different concentrations of dexamethasone (DEX) and mifepristone (MIF). Rat TM cells were randomly divided into 7 groups, marked as D1, D2, D3 and M1, M2 M3 for different concentrations of DEX and MIF, respectively, and C for blank control., Results: The elastic modulus of the treated cells were 2.67 ± 0.914 KPa, 2.92 ± 0.986 KPa, 4.52 ± 1.22 KPa for D1, D2, D3, 2.06 ± 0.745 KPa, 1.23 ± 0.462 KPa, 0.467 ± 0.275 KPa for M1, M2, M3, and 2.43 ± 0.713 KPa for C group, respectively. Expressions of FN and LNK increase (decrease) with the increase of the concentrations of DEX (MIF)., Discussion: We focus on the relationship between the stiffness and the expressions of FN and LNK of rat TM cells. We analyzed the correlation between cell stiffness and FN, LNK expression, discussed the relationship between cell stiffness and aqueous humor outflow resistance., Conclusions: The changes of TM cell stiffness and the expressions of FN and LNK are positively correlated.

Glaucoma is the second leading cause of blindness in the world next to cataract. Aging is a strong risk factor leading to elevated intraocular pressure (IOP). IOP is associated with aqueous humor circulation. Trabecular meshwork cells and Schlemm canal endothelial cells, which form the conventional outflow pathway, play an important role in maintaining the IOP. Cell senescence induces abnormalities of the aqueous humor dynamics, leading to elevated IOP. Trabecular meshwork cells cause increased intrinsic stiffness, autophagy dysfunction, abnormal expression of microRNA and mitochondrial dysfunction with senescence. The senescence of Schlemm canal endothelial cells decreases cell permeability and mechanotransduction and disrupts the endothelial nitric oxide synthase signaling pathway. The changes will increase aqueous humor outflow resistance and elevate IOP. This review discusses how cell senescence induces aqueous humor dynamics abnormalities and the relation with glaucoma. (Chin J Ophthalmol, 2017, 53: 868-873) .

Elevation of intraocular pressure has been correlated to changes in stiffness of trabecular meshwork (TM) in glaucomatous eyes although mechanical properties of the TM remain to be quantitatively determined. Data in the literature suggest that the TM cannot be considered mechanically as a uniform layer of isotropic elastic material, because the value of its Young's modulus depends on the methods of measurements and can vary up to five orders of magnitude. To this end, we proposed a new theoretical framework for mechanical analysis of the TM, in which the inner wall of Schlemm's canal and the juxtacanalicular tissue in the TM were treated as a uniform layer of isotropic elastic material, and the rest of the TM, i.e., the uveal and corneoscleral meshworks, were modeled as a uniform layer of transversely isotropic material. Using the model, we demonstrated that the large discrepancy in the apparent Young's modulus reported in the literature could be caused by the anisotropy of the meshwork that was significantly stiffer in the longitudinal direction than in the transverse direction. The theoretical framework could be used to integrate existing data of the stiffness, investigate anisotropic behaviors of the tissues, and develop new methods to measure mechanical properties of the TM., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Goniosynechialysis (GSL) to remove peripheral anterior synechiae (PAS) alongside standard cataract surgery has potential theoretical advantages, Published randomised trials, however, have not shown conclusive functional benefits and aqueous outflow changes following GSL are unknown. This study aimed to compare electronic Shiøtz tonographic aqueous outflow facility (TOF) following phacoemulsification with or without GSL in patients with primary angle closure (PAC) and PAC glaucoma. Secondary outcomes were changes in intraocular pressure (IOP) and use of glaucoma medications., Methods: Prospective randomised pilot study of 26 patients on glaucoma medication, with ≥90° PAS and significant lens opacity. Patients were randomised 1:1 to receive phacoemulsification with intraocular lens (IOL) implantation only (phaco) or phacoemulsification with IOL plus GSL (phaco-GSL)., Results: Fourteen patients were randomised to phaco-GSL and 12 to phaco alone. TOF increased with phaco-GSL from 0.099±0.07 μL/min/mm Hg to 0.194±0.07, μL/min/mm Hg, p=0.0006, while the phaco group showed no significant change. IOP reduced in both groups, but reduced significantly more following phaco-GSL (46.0%) compared with phaco alone (27.6%, p=0.04). Medication use and extent of PAS only reduced with phaco-GSL, from 0.923±0.86 to 0.384±0.18 medications, p=0.0279, and from 249.2±83.4 to 110.8±53.9° PAS, 6 months postoperatively. No serious adverse events occurred in either group., Conclusions: Eyes randomised to both surgical groups had similar and good outcomes at 6 months in this pilot study. However, only eyes undergoing GSL combined with standard phacoemulsification had significantly increased TOF, reduced glaucoma medication dependence and PAS postoperatively. GSL should therefore be considered in such patients., Trial Registration Number: NCT00719290, Results., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

The ciliary muscle plays a major role in controlling both accommodation and outflow facility in primates. The ciliary muscle and the choroid functionally form an elastic network that extends from the trabecular meshwork all the way to the back of the eye and ultimately attaches to the elastic fiber ring that surrounds the optic nerve and to the lamina cribrosa through which the nerve passes. The ciliary muscle governs the accommodative movement of the elastic network. With age ciliary muscle mobility is restricted by progressively inelastic posterior attachments and the posterior restriction makes the contraction progressively isometric; placing increased tension on the optic nerve region. In addition, outflow facility also declines with age and limbal corneoscleral contour bows inward. Age-related loss in muscle movement and altered limbal corneoscleral contour could both compromise the basal function of the trabecular meshwork. Further, recent studies in non-human primates show that the central vitreous moves posteriorly all the way back to the optic nerve region, suggesting a fluid current and a pressure gradient toward the optic nerve. Thus, there may be pressure and tension spikes on the optic nerve region during accommodation and these pressure and tension spikes may increase with age. This constellation of events could be relevant to glaucomatous optic neuropathy. In summary, our hypothesis is that glaucoma and presbyopia may be literally linked to each other, via the choroid, and that damage to the optic nerve may be inflicted by accommodative intraocular pressure and choroidal tension "spikes", which may increase with age., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Alterations in stiffness of the trabecular meshwork (TM) may play an important role in primary open-angle glaucoma (POAG), the second leading cause of blindness. Specifically, certain data suggest an association between elevated intraocular pressure (IOP) and increased TM stiffness; however, the underlying link between TM stiffness and IOP remains unclear and requires further study. We here first review the literature on TM stiffness measurements, encompassing various species and based on a number of measurement techniques, including direct approaches such as atomic force microscopy (AFM) and uniaxial tension tests, and indirect methods based on a beam deflection model. We also briefly review the effects of several factors that affect TM stiffness, including lysophospholipids, rho-kinase inhibitors, cytoskeletal disrupting agents, dexamethasone (DEX), transforming growth factor-β 2 (TGF-β 2 ), nitric oxide (NO) and cellular senescence. We then describe a method we have developed for determining TM stiffness measurement in mice using a cryosection/AFM-based approach, and present preliminary data on TM stiffness in C57BL/6J and CBA/J mouse strains. Finally, we investigate the relationship between TM stiffness and outflow facility between these two strains. The method we have developed shows promise for further direct measurements of mouse TM stiffness, which may be of value in understanding mechanistic relations between outflow facility and TM biomechanical properties., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In glaucoma, lowered intraocular pressure (IOP) confers neuroprotection. Elevated IOP characterizes glaucoma and arises from impaired aqueous humor (AH) outflow. Increased resistance in the trabecular meshwork (TM), a filter-like structure essential to regulate AH outflow, may result in the impaired outflow. Flow through the 360° circumference of TM structures may be non-uniform, divided into high and low flow regions, termed as segmental. After flowing through the TM, AH enters Schlemm's canal (SC), which expresses both blood and lymphatic markers; AH then passes into collector channel entrances (CCE) along the SC external well. From the CCE, AH enters a deep scleral plexus (DSP) of vessels that typically run parallel to SC. From the DSP, intrascleral collector vessels run radially to the scleral surface to connect with AH containing vessels called aqueous veins to discharge AH to blood-containing episcleral veins. However, the molecular mechanisms that maintain homeostatic properties of endothelial cells along the pathways are not well understood. How these molecular events change during aging and in glaucoma pathology remain unresolved. In this review, we propose mechanistic possibilities to explain the continuum of AH outflow control, which originates at the TM and extends through collector channels to the episcleral veins., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Steroid medications may cause elevation of intraocular pressure, sometimes with permanent damage to the optic nerve. These therapies, via various routes of administration, are commonly prescribed for children, but the potential sequelae of elevated intraocular pressure and glaucomatous optic nerve damage can be even more severe and devastating in children than in adults. This review discusses the pathophysiology and potential risk factors, including the impact of intraocular pressure elevation via the different common routes of administration of steroids, clinical evaluation, and management of steroid response and steroid-induced glaucoma in children., (Copyright © 2017 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Polymorphisms in the CAV1/2 genes that encode signature proteins of caveolae are associated with glaucoma, the second leading cause of blindness worldwide, and with its major risk factor, intraocular pressure (IOP). We hypothesized that caveolin-1 (Cav-1) participates in IOP maintenance via modulation of aqueous humor drainage from the eye. We localize caveolae proteins to human and murine conventional drainage tissues and show that caveolae respond to mechanical stimulation. We show that Cav-1-deficient (Cav-1 -/- ) mice display ocular hypertension explained by reduced pressure-dependent drainage of aqueous humor. Cav-1 deficiency results in loss of caveolae in the Schlemm's canal (SC) and trabecular meshwork. However, their absence did not appear to impact development nor adult form of the conventional outflow tissues according to rigorous quantitative ultrastructural analyses, but did affect cell and tissue behavior. Thus, when IOP is experimentally elevated, cells of the Cav-1 -/- outflow tissues are more susceptible to plasma membrane rupture indicating that caveolae play a role in mechanoprotection. Additionally, aqueous drainage from Cav-1 -/- eyes was more sensitive to nitric oxide (NO) synthase inhibition than controls, suggesting that excess NO partially compensates for outflow pathway dysfunction. These results provide a functional link between a glaucoma risk gene and glaucoma-relevant pathophysiology.

Purpose: To evaluate the effect of selective laser trabeculoplasty (SLT) on ocular biomechanics as measured with the ocular response analyzer (ORA, AMETEK Inc. and Reichert Inc.)., Methods: In a prospective case series, 52 eyes of 52 patients (aged 66.6 ± 9.6 years) with insufficient intraocular pressure (IOP) control despite maximum tolerated medical therapy underwent SLT (Solo(™) SLT, Ellex Inc.) for further IOP reduction. Goldmann-correlated IOP (IOPg), corneal-compensated IOP (IOPcc), corneal hysteresis (CH) and the corneal resistance factor (CRF) were measured with the ORA prior to and at least 4 weeks following SLT., Results: IOPg decreased statistically significantly from 18.0 ± 6.4 to 14.8 ± 3.8 mmHg and IOPcc from 20.2 ± 6.5 to 16.7 ± 3.4 mmHg (p < 0.001). CH increased from 8.53 ± 2.03 to 9.12 ± 1.83 mmHg (p = 0.028) and CRF decreased from 9.58 ± 2.18 to 9.1 ± 2.1 mmHg (p = 0.037), which was statistically significant. Correcting the CH and CRF data for the influence of IOP reduction with a covariance analysis, however, resulted in an unchanged CH (IOPg adjusted: p = 0.318; IOPcc adjusted: p = 0.468) and CRF (IOPg adjusted: p = 0.320; IOPcc adjusted: p = 0.464) after SLT., Conclusion: Selective laser trabeculoplasty does not change corneal biomechanical properties as measured with the ORA in already pretreated patients with glaucoma. The measured increase in CH and decrease in CRF can be solely explained by IOP reduction., (© 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

We analysed all of the PubMed publications on ab-interno trabeculectomy (AIT) with the Trabectome (Neomedix, Irvine, California, USA) to determine the reduction in intraocular pressure (IOP) and medications following the procedure. For IOP outcomes, PubMed was searched for 'trabectome', 'ab interno trabeculotomy' and 'ab interno trabeculectomy' and all available papers retrieved. The meta-analysis used a random-effects model to achieve conservative estimates and assess statistical heterogeneity. To investigate complications, we included all abstracts from the American Glaucoma Society, American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery and the Association for Research in Vision and Ophthalmology. The overall arithmetic mean baseline IOP for standalone Trabectome was 26.71±1.34 mm Hg and decreased by 10.5±1.9 mm Hg (39% decrease) on 0.99±0.54 fewer medications. Defining success as IOP ≤21 with a 20% decrease while avoiding reoperation, the overall average success rate after 2 years was 46±34%. For combined phacoemulsification-Trabectome, the baseline IOP of 21±1.31 mm Hg decreased by 6.24±1.98 mm Hg (27% decrease) on 0.76±0.35 fewer medications. The success rate using the same definition at 2 years was 85±7%. The weighted mean IOP difference from baseline to study endpoint was 9.77 mm Hg (95% CI 8.90 to 10.64) standalone and 6.04 mm Hg (95% CI 4.95 to 7.13) for combined cases. Despite heterogeneity, meta-analysis showed significant and consistent decrease in IOP and medications from baseline to end point in AIT and phaco-AIT. The rate of visually threatening complications was <1%. On average, trabectome lowers the IOP by approximately 31% to a final IOP near 15 mm Hg while decreasing the number of medications by less than one, with a low rate of serious complications. After 2 years, the overall average success rate is 66%., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Purpose: To compare intraocular pressure (IOP) reduction and to develop a predictive surgery calculator based on the results between trabectome-mediated ab interno trabeculectomy in pseudophakic patients versus phacoemulsification combined with trabectome-mediated ab interno trabeculectomy in phakic patients., Methods: This observational surgical cohort study analyzed pseudophakic patients who received trabectome-mediated ab interno trabeculectomy (AIT) or phacoemulsification combined with AIT (phaco-AIT). Follow up for less than 12 months or neovascular glaucoma led to exclusion. Missing data was imputed by generating 5 similar but non-identical datasets. Groups were matched using Coarsened Exact Matching based on age, gender, type of glaucoma, race, preoperative number of glaucoma medications and baseline intraocular pressure (IOP). Linear regression was used to examine the outcome measures consisting of IOP and medications., Results: Of 949 cases, 587 were included consisting of 235 AIT and 352 phaco-AIT. Baseline IOP between groups was statistically significant (p≤0.01) in linear regression models and was minimized after Coarsened Exact Matching. An increment of 1 mmHg in baseline IOP was associated with a 0.73±0.03 mmHg IOP reduction. Phaco-AIT had an IOP reduction that was only 0.73±0.32 mmHg greater than that of AIT. The resulting calculator to determine IOP reduction consisted of the formula -13.54+0.73 × (phacoemulsification yes:1, no:0) + 0.73 × (baseline IOP) + 0.59 × (secondary open angle glaucoma yes:1, no:0) + 0.03 × (age) + 0.09 × (medications)., Conclusions: This predictive calculator for minimally invasive glaucoma surgery can assist clinical decision making. Only a small additional IOP reduction was observed when phacoemulsification was added to AIT. Patients with a higher baseline IOP had a greater IOP reduction.

Purpose: Increased intraocular pressure (IOP) is a frequent complication after penetrating keratoplasty and can be due to reduced trabecular meshwork outflow facility. Descemet stripping endothelial keratoplasty (DSEK) is a lamellar technique for replacing pathologic corneal endothelium and may be associated with a lower risk of postoperative IOP rise. In a prospective clinical study we studied IOP and outflow facility before and after DSEK., Methods: In 23 eyes of 23 patients before, 1 day, 6 weeks, and 3, 6, and 12 months after DSEK, IOP was measured using Goldmann applanation tonometry (GAT) and dynamic contour tonometry (DCT). Trabecular meshwork outflow facility (C-value) was assessed by impression tonography with the Schioetz tonometer. Central corneal thickness was measured by Haag-Streit pachymetry. Best spectacle corrected visual acuity, ocular surface fluorescein staining, and corneal sensation were also recorded., Results: Mean IOP showed a trend toward increase from preoperatively to 1 year postoperatively, which was not statistically significant (GAT: 13.5±3.3 to 15.3±4.7 mm Hg; DCT: 13.7±2.9 to 16.7±4.8 mm Hg; Schioetz: 12.4±2.8 to 15.3±2.9 mm Hg). Outflow facility increased significantly from 0.19±0.03 before to 0.29±0.05 mm/Δmm Hg/min at 1 year after DSEK (P=0.002). Best spectacle corrected visual acuity increased significantly from 0.98±0.48 to 0.36±0.17 logMAR (P=0.0004). Corneal sensitivity was unchanged and corneal staining significantly decreased from the preoperative to 1 year postoperative period (P=0.01). Mean central corneal thickness changed significantly from 650±59 to 621±73 μm (P=0.002)., Conclusions: IOP as measured by GAT, DCT, and Schioetz tends to increase during the first year after DSEK in eyes without previous glaucoma, whereas trabecular meshwork outflow facility as measured by Schioetz tonography improves. These findings are likely to be due to a progressive increase of corneal rigidity affecting transcorneal pressure measurements of both IOP and trabecular meshwork outflow facility.

Purpose: To evaluate outcomes of trabeculectomy bleb needle revision with 5-fluorouracil augmentation performed in the operating theater., Methods: Retrospective study of all patients undergoing trabeculectomy bleb needle revisions in the operating theater performed by a single surgeon in a metropolitan hospital in Australia. A total of 51 needle revisions were performed on 33 eyes over a mean follow-up time of 1.81±1.56 years., Results: A total of 29% achieved intraocular pressure (IOP) ≤20 mm Hg off all glaucoma medications, and an additional 39% achieved qualified success with the addition of glaucoma medications, giving overall success of 68%. Analyzing success rate for target IOP≤16 mm Hg, 24% achieved target off all glaucoma medications, 35% achieved qualified success with the addition of glaucoma medications, giving an overall success rate of 59%. There was a statistically significant improvement in IOP, as compared with preoperative levels, at all timepoints postoperatively (P<0.05). However, number of glaucoma medications remained unchanged (P>0.05) contributing to the high percentage of qualified successes. Visual acuity remained unchanged and there were no major postoperative complications. The Kaplan-Meier survival shows a survival rate of 60% with IOP≤20 mm Hg and 40% for IOP≤16 mm Hg at 5 years., Conclusions: Trabeculectomy needle revision is a useful option for the management of elevated IOP in the presence of a failed or failing trabeculectomy bleb. However, as with trabeculectomy, there tends to be a failure rate over time. This often leads to reinstitution of glaucoma medications and/or further needle revisions to maintain IOPs at target level. The procedure itself is minimally invasive with an acceptable safety profile.

Purpose: To investigate the intraocular pressure (IOP) characteristics of patients with exfoliation glaucoma (XFG) and exfoliation syndrome (XFS) during the water drinking test (WDT)., Methods: This was a prospective observational study undertaken at an academic setting. Consecutive patients with XFG whose office IOP levels were <21 mm Hg, normotensive XFS patients, and control subjects underwent WDT, which involved ingestion of 1 L of water within 5 minutes. The IOP was measured before and 4 times after water ingestion at 15-minute intervals. Maximum IOP (IOPmax), mean IOP (IOPmean), IOP increase (IOPΔ) from baseline IOP to IOPmax, and percentage of IOP fluctuation (IOPfluct) during the WDT were compared across groups. One-way analysis of variance (ANOVA) test or the Kruskal-Wallis test was used for comparisons., Results: The age, gender ratios, visual acuity level, central corneal thickness, and office IOP levels were similar between the 3 groups. As compared with patients with XFS and controls, XFG patients revealed significantly higher values for all IOP measurements at 15 minutes intervals as well as IOPmax (25.1±4.0 mm Hg, 18.7±2.8 mm Hg, 18.6±2.5mm Hg; P<0.001), IOPmean (22.6±3.3mm Hg, 17.2±2.6 mm Hg, 17.2±2.4 mm Hg; P<0.001), IOPΔ (9.2±3.4 mm Hg, 4.4±2.1 mm Hg, 3.7±1.5 mm Hg; P<0.001), and IOPfluct (60.1±24.0%, 33.4±20.0%, 25.7±11.3%; P<0.001)., Conclusions: Medically treated XFG patients, but not XFS subjects, reveal significant IOP elevations during WDT indicative of impaired trabecular outflow facility.

Glaucoma is a vision-threatening disorder characterized by progressive death of retinal ganglion cells (RGCs), although little is known about therapeutic milestones. Due to its complex and multifactorial pathogenesis, multipronged therapeutic approach is needed. Angiogenin (ANG), now called ribonuclease (RNase) 5, has been previously known as angiogenic factor and more recently its biologic activity is extended to promoting cell survival via its ribonucleolytic activity. Here, we revealed the defect of ANG in human glaucomatous trabecular meshwork (TM) cells and identified novel multiple functions of ANG as an anti-glaucomatous strategy. ANG was highly expressed in normal eyes and normal TM cells compared to glaucomatous TM cells. ANG induced intraocular pressure (IOP) lowering in rat models of both normal and elevated IOP, and as a possible mechanism, activated Akt-mediated signals for nitric oxide (NO) production, an important regulator of IOP in glaucomatous TM cell. Moreover, we demonstrated ANG-induced production of matrix metalloproteinase (MMP)-1 and -3 and rho-kinase inhibition for TM remodeling. For anti-glaucomatous defense optimization, ANG not only elicited immune-modulative pathways via indolamine 2,3-dioxygenase (IDO) activation in TM cells and suppression of Jurkat T cells, but also rescued neural stem cells (NSCs) from apoptosis induced by glaucomatous stress. These results demonstrate that novel multi-functional effects of ANG may have benefits against glaucoma in ocular tissues., (Copyright © 2015. Published by Elsevier B.V.)

Cross-bridge cycling rate is an important determinant of cardiac output, and its alteration can potentially contribute to reduced output in heart failure patients. Additionally, animal studies suggest that this rate can be regulated by muscle length. The purpose of this study was to investigate cross-bridge cycling rate and its regulation by muscle length under near-physiological conditions in intact right ventricular muscles of nonfailing and failing human hearts. We acquired freshly explanted nonfailing (n = 9) and failing (n = 10) human hearts. All experiments were performed on intact right ventricular cardiac trabeculae (n = 40) at physiological temperature and near the normal heart rate range. The failing myocardium showed the typical heart failure phenotype: a negative force-frequency relationship and β-adrenergic desensitization (P < 0.05), indicating the expected pathological myocardium in the right ventricles. We found that there exists a length-dependent regulation of cross-bridge cycling kinetics in human myocardium. Decreasing muscle length accelerated the rate of cross-bridge reattachment (ktr) in both nonfailing and failing myocardium (P < 0.05) equally; there were no major differences between nonfailing and failing myocardium at each respective length (P > 0.05), indicating that this regulatory mechanism is preserved in heart failure. Length-dependent assessment of twitch kinetics mirrored these findings; normalized dF/dt slowed down with increasing length of the muscle and was virtually identical in diseased tissue. This study shows for the first time that muscle length regulates cross-bridge kinetics in human myocardium under near-physiological conditions and that those kinetics are preserved in the right ventricular tissues of heart failure patients., (Copyright © 2015 the American Physiological Society.)

Purpose: To determine whether the characteristics of an intraoperative episcleral venous fluid wave (EVFW), a potential indicator of trabecular outflow patency, correlates with Trabectome (NeoMedix Corp, Tustin, CA) outcomes., Design: Retrospective, observational study., Participants: A total of 68 eyes of 49 patients with glaucoma who underwent phaco-Trabectome (63 eyes) or Trabectome alone (5 eyes)., Methods: The EVFW was evaluated in a masked fashion for wave degree (0-4) and clock hours (0-6). A diffuse EVFW (4, 5, 6 clock hours) was a near complete blanching of the episcleral vasculature, and a poorly defined wave was minimal change in the vasculature. Patients were grouped into wave categories to determine whether there was a correlation with postoperative intraocular pressure (IOP). Patients requiring further glaucoma surgery were considered failures., Main Outcome Measures: Degree and extent of EVFW, IOP, and glaucoma medications., Results: For all eyes, there was a statistically significant correlation between wave clock hours and postoperative IOP at month 1 (P = 0.043) and month 3 (P = 0.002), but not a statistically significant correlation at month 6 (P = 0.12) or 1 year (P = 0.86). A strong correlation was found among IOP, medications, and EVFW in eyes with an extensive EVFW when compared with eyes with a poorly defined EVFW. At 12 months, the mean IOP in the extensive EVFW group was 13.3±2.7 mmHg on 1.4±1.2 medications compared with an IOP of 18.4±3.1 mmHg on 2.9±0.9 medications in the poorly defined group (both P = 0.001). Overall, 5 of 68 eyes (7%), required further glaucoma surgery. Eyes with a poorly defined EVFW had a higher likelihood of further glaucoma surgery (36%)., Conclusions: The EVFW is an intraoperative gauge of patency through the trabecular outflow pathway. Absence of the EVFW implies obstruction in the collector channel-intrascleral aqueous outflow pathway, preventing flow to the visible episcleral veins. In contrast, eyes with a diffuse EVFW had sufficient flow through their collector channels, had a lower IOP, required fewer glaucoma medications, and had a lower requirement for further glaucoma surgery. The characteristics of an EFVW may be able to predict surgical outcomes after Trabectome surgery., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the long-term effectiveness and safety of mitomycin C (MMC)-augmented trabeculectomy undertaken within the first 2 years of life for the surgical management of glaucoma., Design: Retrospective, consecutive, noncomparative case series., Participants: All children who underwent MMC-augmented trabeculectomy within 2 years of birth between May 2002 and November 2012., Methods: The medical records of 40 consecutive eyes of 26 children who underwent surgery by a single surgeon were reviewed. Data collected during routine clinical care were analyzed., Main Outcome Measures: Assessment of clinical outcomes included intraocular pressure (IOP), final visual acuity, bleb morphology, surgical complications (early and late), postoperative interventions, and further glaucoma surgery performed. Surgical success was defined as final IOP of 5 mmHg or more and of 21 mmHg or less, with anti-glaucoma medications (qualified success) and without (complete success), stable ocular dimensions and optic disc cupping, and no further glaucoma surgery (including needling) or loss of light perception. Surgical outcomes were evaluated using Kaplan-Meier life table analysis., Results: Forty eyes of 26 children were studied over a mean follow-up period of 62.8 months. Most cases (80%) were of primary congenital glaucoma after failed goniotomy surgery. Cumulative probabilities of survival at 1, 5, and 7 years were 78%, 67%, and 60%, respectively. Of eyes regarded as successful, 96% (25/26 eyes) had controlled IOP without topical medication and 44% achieved visual acuity of 20/40 or better. In only 1 of the 40 eyes did a cystic avascular bleb develop, with all the other eyes being non-cystic in nature (diffuse and elevated or flat) at final follow-up. Sixty-four percent (9/14 eyes) of cases regarded as failures ultimately underwent glaucoma drainage device implantation., Conclusions: A contemporary pediatric trabeculectomy technique augmented with MMC is an effective procedure in the management of glaucoma within the first 2 years of life, as shown by the successful long-term outcomes and low incidence of sight-threatening complications. Trabeculectomy after failed goniotomy surgery or as a primary surgical intervention may offer a phakic infant with glaucoma an excellent opportunity to achieve long-term control of IOP without medications and may be associated with optimal visual outcomes., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the long-term effect of phacoemulsification on intraocular pressure (IOP) in trabeculectomized eyes and to identify the factors affecting the IOP changes., Methods: In consecutive patients with previous trabeculectomy (TE) who underwent uncomplicated clear cornea phacoemulsification we evaluated intraocular pressure, need of antiglaucomatous medical therapy or glaucoma surgery, and length of glaucoma control without therapy. Glaucoma therapy was prescribed in the presence of IOP >18 mm Hg or worsening of the visual field. A group of trabeculectomized eyes that did not receive cataract surgery was retrospectively selected as a control. Multivariate analysis was used to test factors related to final outcome of the treatment., Results: One hundred and eight eyes with previous TE that received phacoemulsification and 108 controls were included in the study. Phacoemulsification was performed 60±21 months after TE. After a mean follow-up of 66±28 months, mean IOP was significantly increased in the cataract surgery group (by 1.7±4.3 mm Hg) and in the control group (by 2.3±4.3 mm Hg)(both P<0.001); in two groups, respectively, 31 eyes (28.7%) and 17 eyes (15.7%) had received glaucoma therapy (chi-square P=0.030). Factors related to success (no need of therapy) were use of mitomycin-C (MMC) in previous TE (P<0.001), longer time from TE to cataract surgery (P=0.007), higher preoperative bleb score (P=0.021), and lower baseline IOP (P=0.042)., Conclusions: Cataract surgery reduces the function of filtering bleb in some eyes. Factors related to low rate of failure are the previous use of MMC during TE, longer time from TE to cataract surgery, and good preoperative aspect of the bleb.

Purpose: To investigate the role of endothelial nitric oxide synthase (eNOS) on conventional outflow function using NOS3 knockout (KO) mice., Methods: Intraocular pressure was measured in both NOS3 KO and wild type (WT) by rebound tonometry. Outflow facility was measured by perfusing enucleated mouse eyes at multiple pressure steps. A subset of eyes was sectioned and stained for histology. Mock aqueous humor ± the nitric oxide (NO) donors nitroprusside dihydrate (SNP) or S-Nitroso-N-Acetyl-D,L-Penicillamine (SNAP) was perfused into enucleated eyes. SNP and SNAP was administered topically at 0, 1, 2, and 3 hours while the contralateral eyes served as vehicle controls. Intraocular pressure was measured in both eyes before and after the last drug treatment., Results: Intraocular pressure was higher in KO mice (18.2 ± 0.7 mm Hg vs. 13.9 ± 0.5 mm Hg, mean ± SEM, n = 30, P < 0.05), and pressure-dependent conventional drainage was significantly lower (0.0058 ± 0.0005 μL/min/mm Hg, mean ± SEM, n = 21) compared with WT mice (0.0082 ± 0.0013 μL/min/mm Hg, n = 23, P < 0.05). No obvious morphological differences in iridiocorneal angle tissues were observed in hematoxylin and eosin (H&E)-stained sections. SNP and SNAP significantly increased pressure-dependent drainage in KO animals (n = 12, P < 0.05). In WT mice, SNP and SNAP caused a significant increase in pressure dependent drainage (n = 12, P < 0.05) to a similar degree as in KO mice. Topical application of SNP significantly reduced IOP in WT and KO mice (n = 12, P < 0.05), but SNAP did not change IOP significantly (n = 19)., Conclusions: NOS3 KO mice have elevated IOP, which is likely the result of reduced pressure-dependent drainage. These findings are consistent with human data showing polymorphisms in the NOS3 gene associate with ocular hypertension and the development of glaucoma.

Background: Structural changes in the course of glaucoma disease affect the trabecular meshwork and ciliary body in addition to the optic disc as the primary site of glaucoma damage., Objectives: Latest results from experimental studies, animal models and measurements in human eyes are presented and discussed., Results: The presenting scenario is complex with age, biochemical and mechanical stress factors leading to subsequent, irreversible tissue change in the trabecular meshwork and cribriform plate of the optic nerve, resulting in neuronal tissue loss., Conclusion: Knowledge of these changes will be the key for future glaucoma therapies.

Background: Normal tension glaucoma (NTG) is commonly treated with anti-glaucoma medications. Recently, selective laser trabeculoplasty (SLT) has been demonstrated to lower the intraocular pressure (IOP) and medication use in NTG. The purpose of this study was to investigate the efficacy of a single session of SLT for NTG at 1 year., Methods: This prospective cohort study recruited NTG patients taking anti-glaucoma medication. Potential subjects were excluded if they had had previous glaucoma surgery or laser and also if intraocular surgery or additional SLT procedures were performed after the first treatment. All subjects underwent a 1-month washout. A 30% IOP reduction was set as the target IOP. A single session of SLT was performed to 360 degrees of the trabecular meshwork. At 1-month after SLT, medication was resumed to achieve the target IOP. The IOP was measured every 3 months, and the number of medications was recorded at 3, 6, and 12 months. Only the right eye was used for statistical analysis., Results: In 41 right eyes, the mean pre-study IOP was 14.3 ± 3.4 mmHg while on 1.5 ± 0.8 eye drops. The post-washout IOP was 16.2 ± 2.2 mmHg. A mean of 191.1 ± 26.3 SLT shots at 1.0 ± 0.07 mJ were applied. There was significant IOP reduction at all time intervals following SLT when compared to the post-washout IOP (P < 0.0001). The number of medications was significantly reduced at all time intervals following SLT when compared to the pre-study level (P < 0.0001). At 12 months, the mean IOP was 12.2 ± 2.2 mmHg while on 1.1 ± 0.9 eye drops., Conclusions: A single session of SLT for NTG achieved an additional 15% IOP reduction while using 27% less medication at 1 year compared to pre-study levels., Trial Registration: The Clinical Trials Register of the University of Hong Kong HKCTR1847 The European Clinical Trials Database 2014-003305-15 (August 11, 2014) ( https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-003305-15 ).

Intraocular pressure (IOP), the critical risk factor for glaucoma, is generated and maintained by the aqueous humor circulation system. Aqueous humor is secreted from the epithelial layers of the ciliary body and exits the eye through the trabecular meshwork or the uveoscleral outflow pathways. IOP builds up in response to a resistance to aqueous humor flow in the trabecular outflow pathways. The trabecular outflow resistance is localized in the inner wall region, which comprises the juxtacanalicular connective tissue (JCT) and the inner wall endothelium of Schlemm's canal (SC). Outflow resistance in this region is lowered through the relaxation of contractile myofibroblast-like cells in trabecular meshwork and the adjacent scleral spur, or the contraction of the ciliary muscle. In primary open-angle glaucoma, the most frequent form of glaucoma, outflow resistance of the inner wall region is typically higher than normal. There is evidence that the increase in resistance is related to characteristic biological changes in the resident cells of the JCT, which more and more acquire the structural and functional characteristics of contractile myofibroblasts. The changes involve an augmentation of their actin cytoskeleton and of their surrounding fibrillary extracellular matrix, which connects to JCT cells via integrins. This scenario leads to an overall stiffening of the inner wall region, and is modulated by transforming growth factor-β/connective tissue growth factor signaling. Essentially comparable changes appear to occur in SC endothelial cells. Stiffening of JCT and SC cells is very likely a critical causative factor for the increase in trabecular outflow resistance in POAG., (© 2015 Elsevier Inc. All rights reserved.)

Selective laser trabeculoplasty (SLT) is a relatively new type of laser used in treating open-angle glaucoma (OAG) and is reported to be equally efficacious to a first-line medication and argon laser trabeculoplasty (ALT). We summarize available evidence for considering SLT as an alternative treatment in OAG through systematic review and meta-analysis. Among OAG patients who range from newly diagnosed to those on maximally tolerated medical therapy, SLT results in a 6.9-35.9% intraocular pressure (IOP) reduction. Complications are rare and include an IOP spike requiring surgery, persistent macular edema, and corneal haze and thinning. Meta-analysis of randomized, controlled trials shows that SLT is non-inferior to ALT and medication in IOP reduction and also in achieving treatment success. Number of medications reduction is similar between SLT and ALT. More robust evidence is needed to determine its efficacy as a repeated procedure., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Trabecular meshwork (TM) and ciliary muscle contraction and relaxation function together to provide control of outflow. The active role the TM plays in the regulation of intraocular pressure (IOP) is mediated by cytoskeletal and contractility mechanisms as well as signal/transduction factors that mediate its response to stressors. This complex system is altered with age and the glaucomas, and it can be difficult to differentiate between the various etiological effects/agents. Factors such as a compromised antioxidant defense system and altered extracellular matrix metabolism are known to contribute to impaired outflow and may be common to primary open-angle glaucoma, exfoliation syndrome, and exfoliation glaucoma (XFG). Genes differentially expressed in diseased ocular tissue or in cultured HTM cell models, and thus implicated in the disease process, include SOD2, ALDH1A1, MGST1, LOX, and LOXL1, elements of the transforming growth factor-β/bone morphogenetic protein/SMAD signaling pathways, connective tissue growth factor, matrix metalloproteinase-2, a tissue inhibitor of metalloproteinases also known as TIMP-2, and endothelin-1 (ET-1). In exfoliation syndrome and XFG fibrillar, proteinaceous extracellular material is produced in excess and accumulates in both outflow pathways but does not always lead to elevated IOP. Locally produced material may accumulate in the intertrabecular spaces, juxtacanalicular (JCT) meshwork, and the inner wall of Schlemm's canal as a result of a combination of both excessive synthesis and insufficient degradation. An increase in JCT plaque and decreased cellularity in the TM are thought to contribute to decreased outflow facility in glaucoma patients, but XFG patient specimens show reduced extracellular plaque material in the JCT, and the structural integrity of trabecular endothelial cells is mostly retained and cellularity remains unchanged. The distinctions between causes/effects of structural changes leading to reduced outflow/elevated IOP are important for developing effective, individualized treatment strategies.