Trabecular Meshwork

Meldonium (MID) is a synthetic drug designed to decrease the availability of L-carnitine-a main player in mitochondrial energy generation-thus modulating the cell pathways of energy metabolism. Its clinical effects are mostly evident in blood vessels during ischemic events, when the hyperproduction of endogenous carnitine enhances cell metabolic activities, leading to increased oxidative stress and apoptosis. MID has shown vaso-protective effects in model systems of endothelial dysfunction induced by high glucose or by hypertension. By stimulating the endothelial nitric oxide synthetase (eNOS) via PI3 and Akt kinase, it has shown beneficial effects on the microcirculation and blood perfusion. Elevated intraocular pressure (IOP) and endothelial dysfunction are major risk factors for glaucoma development and progression, and IOP remains the main target for its pharmacological treatment. IOP is maintained through the filtration efficiency of the trabecular meshwork (TM), a porous tissue derived from the neuroectoderm. Therefore, given the effects of MID on blood vessels and endothelial cells, we investigated the effects of the topical instillation of MID eye drops on the IOP of normotensive rats and on the cell metabolism and motility of human TM cells in vitro. Results show a significant dose-dependent decrease in the IOP upon topic treatment and a decrease in TM cell motility in the wound-healing assay, correlating with an enhanced expression of vinculin localized in focal adhesion plaques. Motility inhibition was also evident on scleral fibroblasts in vitro. These results may encourage a further exploration of MID eye drops in glaucoma treatment.

Background: The extracellular matrix (ECM) in the trabecular meshwork (TM) may play a role in the steroid-induced aqueous humor outflow resistance pathophysiology. Topical steroids such as fluorometholone can cause elevated intraocular pressure. Increased synthesis and accumulation of TM ECM proteins due to steroids result in TM dysfunction and elevated intraocular pressure. Purpose: This study aims to analyze the effect of duration of administration and discontinuation of fluorometholone eye drops on the thickness of the TM ECM of Wistar rats. This study was an experimental study with a posttest-only control group design. The total sample of 25 rats was divided into 5 groups: Treatment 1 was given topical fluorometholone for 4 weeks and stopped for 4 weeks. Treatment 2 was given fluorometholone for 6 weeks and stopped for 4 weeks. Control 1 was given topical fluorometholone for 4 weeks, Control 2 was given topical fluorometholone for 6 weeks, and the negative control was used as a baseline. TM ECM examination was assessed using histopathological score grading. This study used the Mann-Whitney test and the Kruskal-Wallis comparative hypothesis test. The difference in ECM thickness was not statistically significant either between treatment group 1 and treatment group 2 (p=1.000) or control group 1 (p=0,1000). There was a significant change in the thickness of the TM ECM in treatment group 1, treatment 2, control 1, control 2 compared to the negative control (p=0.003, p=0.003, p=0.003, p=0.004) and The thickness was statistically significant betweent treatment 2 and control group 2 (p = 0,014). Conclusion: TM ECM thickness did not return to normal thickness after administration of fluorometholone eye drops one drop 4 times a day for 4 weeks and 6 weeks followed by discontinuation of the drug for 4 weeks. The thickness of the TM ECM was thicker in experimental rats with a longer duration of administration of fluorometholone eye drops.

Glaucoma is a multifaceted eye disorder primarily associated with increased intraocular pressure (IOP), which can progressively lead to vision impairment. It is broadly classified into primary and secondary types, further divided into open-angle and closed-angle forms. Among adults, the most common types include primary openangle glaucoma (POAG) and angle-closure glaucoma, as well as their secondary counterparts. POAG remains the most frequently diagnosed form. Researchers continue to explore both genetic predispositions and environmental influences that contribute to the onset and progression of glaucoma. While current treatment options cannot reverse optic nerve damage or restore lost vision, they are effective in slowing disease progression. Management strategies focus on lowering IOP through medications, laser therapies, or surgical procedures. A multidisciplinary healthcare team plays a crucial role in optimizing treatment plans and preventing further visual deterioration. This discussion covers various types of glaucoma, including congenital, infantile, developmental, and juvenile forms, with particular emphasis on cases affecting individuals over 40 years old. Given its significant impact on vision, a collaborative approach among healthcare professionals is essential for effective disease management. Since glaucoma is the second leading cause of irreversible blindness among older adults in the United States, early diagnosis and routine monitoring are key to preserving vision and enhancing patient outcomes.

Glaucoma is a disease characterized by progressive damage to the optic nerve, with or without elevated intraocular pressure; and is one of the leading causes of irreversible blindness worldwide. Pseudoexfoliation has been identified as the leading cause of secondary open-angle glaucoma. It is a disease that affects over 60-70 million people. The pathophysiology of pseudoexfoliation is characterized by the deposition in the eye tissues of a fibrillar material. Intraocular deposits are found in the trabecular meshwork, cornea, lens, and iris, leading to significant ocular and visual morbidity. The prevalence of the disease varies by geographic location and ethnicity, and a number of environmental, demographic, genetic, and molecular factors have been identified as potential causes. Despite the high morbidity, there is still no definitive cure for pseudoexfoliation. Treatments are aimed at managing elevated intraocular pressure, including local, systemic, or surgical therapy.

Primary open-angle glaucoma remains a global issue, lacking a definitive treatment. Increased intraocular pressure (IOP) is considered the primary risk factor of the disease and it can be caused by fibrotic-like changes in the trabecular meshwork (TM) such as increased tissue stiffness and outflow resistance. Previously, we demonstrated that the sigma-1 receptor (S1R) agonist fluvoxamine (FLU) has anti-fibrotic properties in the kidney and lung. In this study, the localization of the S1R in TM cells was determined, and the anti-fibrotic efficacy of FLU was examined in both mouse and human TM cells. Treatment with FLU reduced the F-actin rearrangement, inhibited cell proliferation and migration induced by the platelet-derived growth factor and decreased the levels of fibrotic proteins. The protective role of the S1R in fibrosis was confirmed by a more pronounced increase in alpha smooth muscle actin and F-actin bundle and clump formation in primary mouse S1R knockout TM cells. Furthe...

PURPOSE. This study aimed to investigate the differential responses of trabecular meshwork stem cells (TMSCs) and trabecular meshwork (TM) cells to endoplasmic reticulum (ER) stress inducers. Human TM cells and TMSCs were exposed to tunicamycin, brefeldin A, or thapsigargin. Cell apoptosis was evaluated by flow cytometry. ER stress markers were detected by quantitative PCR, Western blotting, and immunostaining. Morphologic changes were evaluated by transmission electron microscopy. Cells were treated with the PERK inhibitor GSK2606414 or the elF2a dephosphorylation inhibitor Salubrinal together with tunicamycin to evaluate their effects on ER stress. Both TMSCs and TM cells underwent apoptosis after 48-and 72-hour treatment with ER stress inducers. ER stress triggered the unfolded protein response (UPR) with increased expression of GRP78, sXBP1, and CHOP, which was significantly lower in TMSCs than TM cells. Swollen ER and mitochondria were detected in both TMSCs and TM cells. Neither GSK2606414 nor salubrinal alone activated UPR. GSK2606414 significantly reduced cell survival rates after tunicamycin treatment, and salubrinal increased cell survival rates. The increased expression of GRP78, sXBP1, CHOP, and GADD34 peaked at 6 or 12 hours and lasted longer in TM cells than TMSCs. Salubrinal treatment dramatically increased OCT4 and CHI3L1 expression in TMSCs. In response to ER stress inducers, TMSCs activated a lower level of UPR and lasted shorter than TM cells. Inhibition of elF2a dephosphorylation had a protective mechanism against cell death. Stem cells combined with salubrinal may be a more effective way for TM regeneration in glaucoma.

Background: More than ~70% of the aqueous humor exits the eye through the conventional aqueous outflow pathway that is comprised of the trabecular meshwork (TM), juxtacanalicular tissue (JCT), the inner wall endothelium of Schlemm’s canal (SC). The flow resistance in the JCT and SC inner wall basement membrane is thought to play an important role in the regulation of the intraocular pressure (IOP) in the eye, but current imaging techniques do not provide enough information about the mechanics of these tissues or the aqueous humor in this area. Methods: A normal human eye was perfusion-fixed and a radial wedge of the TM tissue from a high-flow region was dissected. The tissues were then sliced and imaged using serial block-face scanning electron microscopy. Slices from these images were selected and segmented to create a 3D finite element model of the JCT and SC cells with an inner wall basement membrane. The aqueous humor was used to replace the intertrabecular spaces, pores, and gi...

Elevated intraocular pressure (IOP) is a critical factor in the progression of several ocular conditions, including glaucoma, ocular hypertension, and various retinal disorders. This study introduces Presigen IV, a novel biocellular stimulation formula developed from an applied Biocellular-Sensory Matrix (BSM-IV). Through extensive clinical trials, Presigen IV has shown remarkable efficacy in reducing IOP and decreasing light sensitivity in patients with various ocular conditions. The initial trial, involving 35 participants with various ocular hypertension and glaucoma, demonstrated that 87% of subjects experienced significant reductions in IOP. This paper explores the mechanism underlying Presigen IV's effectiveness, its clinical outcomes, and its potential role in the broader context of the management of elevated IOP across various ocular conditions. It examines the role of inflammation in ocular disease progression and the emerging importance of biomarkers in early diagnosis and personalized treatment strategies. The study also highlights the incorporation of ocular supporting nutrients, such as allicin, in Presigen IV's formulation, which has been linked to reducing inner eye distress and inflammation, thereby also decreasing the risk of serious eye diseases like age-related macular degeneration and cataracts. By synthesizing recent advancements in ocular research and treatment, this study positions Presigen IV as a promising innovation in the management of elevated IOP, with the potential to revolutionize treatment strategies and improve patient outcomes across a spectrum of ocular conditions. As research continues to unravel the intricacies of ocular pathophysiology and refine treatment approaches, Presigen IV represents a significant step forward in the quest to preserve vision and improve the lives of millions affected by sight-threatening conditions related to elevated IOP.

To establish anterior chamber measurements in children and investigate the influence of demographic factors on anterior chamber development. Methods: Handheld optical coherence tomography was used to scan the anterior chamber of participants' eyes, without sedation. ImageJ was used to generate quantitative anterior chamber measurements, including central corneal thickness (CCT), anterior chamber width, trabecular meshwork length (TML), Schwalbe's line-angle opening distance (SL-AOD), and trabecular iris surface area (SL-TISA). The average anterior chamber measurements per age group, with 95% prediction intervals, were estimated using fractional polynomial modeling. Mixed regression models were used to evaluate the influence of age, gender, eye, angle, and refractive error variation on anterior chamber measurements. Results: Scans from 223 healthy children (2 days to 15 years of age) and 59 adults (16 to 47 years of age) were included. The anterior chamber width, TML, Schwalbe's lineangle opening distance, and Schwalbe's line-trabecular iris surface area significantly increased, whereas CCT decreased with aging (all P < 0.001). The anterior chamber has a rapid phase of development during the first 18 months of age and reaches maturity by the age of 5 years. Girls have significantly smaller anterior chambers compared with boys (all P < 0.001). There was no difference between right and left eye development (all P > 0.05). The temporal TML development was significantly greater than the nasal TML (P < 0.05). CCT development was negatively correlated with refractive power. This novel, non-invasive study describes the postnatal development of anterior chamber in newborn children.

Preserving the delicate balance between the antioxidant defense mechanisms and oxidative stress caused by the accumulation of ROS/RNS is essential for maintaining redox homeostasis, a critical determinant of ocular health. Imbalances in this system result in oxidative stress, a key pathological factor implicated in numerous eye diseases. This review thoroughly looks at the information that is currently available, illuminating the intricate relationship between mitochondrial malfunction and oxidative stress in conditions that impact the anterior and posterior portions of the eye. Our analysis highlights the pivotal role of redox imbalance in the onset and progression of major eye conditions while emphasizing the therapeutic potential of strategies aimed at restoring redox equilibrium and fostering regenerative responses. These methods might successfully slow down or stop the development of crippling eye conditions. In addition to improving our knowledge of the molecular processes underlying the pathophysiology of ocular diseases, ongoing research in this area makes it easier to identify new antioxidant targets and treatment approaches. These advancements are expected to transform ocular care, introducing targeted treatments that can greatly enhance the standard of living for those who suffer from disorders that endanger their vision.

Primary open angle glaucoma (POAG) is a common late-onset neurodegenerative disease. Ocular hypertension represents a major risk factor, but POAG etiology remains poorly understood. Some cases of early-onset congenital glaucoma and adult POAG are linked to mutations in myocilin, a secreted protein of poorly defined function. Transgenic overexpression of myocilin in Drosophila and experiments in mice and human populations implicate the unfolded protein response (UPR) in the pathogenesis of glaucoma. We postulate that compromised ability of the UPR to eliminate misfolded mutant or damaged proteins, including myocilin, causes endoplasmic reticulum stress, resulting in functional impairment of trabecular meshwork cells that regulate intraocular pressure. This mechanism of POAG is reminiscent of other age-dependent neurodegenerative diseases that involve accumulation of protein aggregates.

Background: Glaucoma is the world's second leading cause of bilateral blindness with progressive loss of vision due to retinal ganglion cell death. Myocilin has been associated with congenital glaucoma and 2-4% of primary open angle glaucoma (POAG) cases, but the pathogenic mechanisms remain largely unknown. Among several hypotheses, activation of the unfolded protein response (UPR) has emerged as a possible disease mechanism. Methodology / Principal Findings: We used a transgenic Drosophila model to analyze whole-genome transcriptional profiles in flies that express human wild-type or mutant MYOC in their eyes. The transgenic flies display ocular fluid discharge, reflecting ocular hypertension, and a progressive decline in their behavioral responses to light. Transcriptional analysis shows that genes associated with the UPR, ubiquitination, and proteolysis, as well as metabolism of reactive oxygen species and photoreceptor activity undergo altered transcriptional regulation. Following up on the results from these transcriptional analyses, we used immunoblots to demonstrate the formation of MYOC aggregates and showed that the formation of such aggregates leads to induction of the UPR, as evident from activation of the fluorescent UPR marker, xbp1-EGFP. Conclusions / Significance: Our results show that aggregation of MYOC in the endoplasmic reticulum activates the UPR, an evolutionarily conserved stress pathway that culminates in apoptosis. We infer from the Drosophila model that MYOCassociated ocular hypertension in the human eye may result from aggregation of MYOC and induction of the UPR in trabecular meshwork cells. This process could occur at a late age with wild-type MYOC, but might be accelerated by MYOC mutants to account for juvenile onset glaucoma.

Glaucoma is one of the leading causes of blindness worldwide. Decreased aqueous humor drainage causes an increase in intraocular pressure (IOP), which in turn damages the ganglion cells of the retina and optic nerve. A mouse model of glaucoma was used to examine the behavior of Myo/Nog (M/N) cells, which were previously shown to respond to cataract surgery and retinopathy induced by hypoxia, light damage, and intravitreal injection of human retinal pigment epithelial cells. M/N cells express the skeletal-muscle-specific transcription factor MyoD, the bone morphogenetic protein inhibitor Noggin, and brain-specific angiogenesis inhibitor 1 (BAI1). Glaucoma was induced by injecting microbeads into the anterior chamber (AC) of the right eye to obstruct the flow of aqueous humor into the trabecular meshwork. IOP was elevated within three days of addition of microbeads. Loss of retinal ganglion cells (RGCs) and thinning of the ganglion cell layer–nerve fiber layer (GCL-NFL) was observed i...

A 42-year-old woman presented with bilateral proptosis, chemosis, leg pain, and vision loss. Orbital, chorioretinal, and multi-organ involvement of Erdheim-Chester disease, a rare non-Langerhans histiocytosis, with a negative BRAF mutation was diagnosed based on clinical, radiological, and pathological findings. Interferon-alpha-2a (IFNα-2a) was started, and her clinical condition improved. However, 4 months later, she had vision loss with a history of IFNα-2a cessation. The same therapy was administered, and her clinical condition improved. The Erdheim-Chester disease is a rare chronic histiocytic proliferative disease that requires a multidisciplinary approach and can be fatal if left untreated because of multisystemic involvements.

To compare the e cacy and safety between trabeculectomy (TE) and canaloplasty (CP) either as standalone or combined with phacoemulsi cation (PTE and PCP). Nine databases were searched for studies reporting e cacy and safety of TE/PTE and CP/PCP. E cacy endpoints included postoperative intraocular pressure (IOP), complete, and quali ed success, while safety endpoints included failure, revision surgery, and complications. STATA was used to pool the crude mean difference (MD) or log odds ratio (logOR) for continuous and categorical outcomes, respectively. Fourteen studies were included. TE/PTE was associated with lower IOP when compared to CP/PCP [MD=-2.55; 95%CI=-3.30: -1.80, I 2 = 61.43%]. Similarly, TE/PTE was associated with signi cantly higher odds of complete [logOR = 1.20; 95%CI = 0.79:1.61, I 2 = 7.41] and quali ed success [logOR = 0.64; 95%CI = 0.16:1.13, I 2 = 0%] when compared to CP/PCP, respectively. Although no signi cant differences in failure and revision surgery were noted between TE/PTE and CP/PCP, in the TE subgroup, a signi cant reduction in failure was observed as compared to CP [logOR=-0.82; 95%CI=-1.61: -0.04, I 2 = 28.18%]. TE/PTE was associated with higher odds for hypotony and choroidal detachment and lower odds for Descemet's membrane detachment and hyphema. TE/PTE has superiority over CP/PCP regarding IOP control and revision surgery rates. However, the certainty of these ndings is low to very low.

Glaucoma is a leading cause of blindness in virtually every country. Development of an accurate diagnostic test for presymptomatic detection of individuals at risk is an urgent requisition for this condition. Herein, we report mapping of a new adult-onset primary open-angle glaucoma (POAG) locus on 5q22.1 (GLC1G ) and identification of its defective gene. Mutation screening of seven candidate genes from the GLC1G critical region (2 Mb between D5S1466 and D5S2051) identified only one significant alteration in the WDR36 (WD40-repeat 36) gene. This mutation (i.e. D658G) was segregated in all affected members of our first GLC1G-linked family but it was absent in 476 normal control chromosomes. Further screening of WDR36 in a total of 130 POAG families revealed 24 DNA variations. Overall, four mutations (N355S, A449T, R529Q and D658G) were identified in 17 (5.02 -6.92%) unrelated POAG subjects, 11 with high-pressure and six with low-pressure glaucoma. These mutations were absent in a minimum of 200 normal control chromosomes and, further they were conserved between WDR36 orthologues in mouse, rat, dog, chimp and human. WDR36 is a novel gene with 23 exons, which encodes for 951 amino acids and a protein with multiple G-beta WD40 repeats. By northern blotting, two distinct mRNA transcripts of 5.9 and 2.5 kb were observed in human heart, placenta, liver, skeletal muscle, kidney and pancreas. WDR36 gene expression in lens, iris, sclera, ciliary muscles, ciliary body, trabecular meshwork, retina and optic nerve were established by RT -PCR. In mouse, two transcripts of 3.5 and 2.9 kb showed analogous expression patterns to human. mRNA expressions were detected in 7-, 11-, 15-and 17-day-old developing mouse embryos. In summary, WDR36 is a novel causative gene for adult-onset POAG at the GLC1G locus. Specific ocular expressions and observed mutations are consistent with WDR36 role in etiology of both high-and low-pressure glaucoma.

Primary angle closure glaucoma (PACG) is a major form of glaucoma. Early detection and proper management of PACG to reduce visual loss are intricately related to correctly assessing the anterior chamber angle (ACA). This review describes clinical assessment of the ACA by gonioscopy, as well as novel ACA imaging devices and discusses their advantages and limitations. Specifically, we review ultrasound biomicroscopy, anterior segment optical coherence tomography, and a method similar to goniophotography using the EyeCam TM , all of which are used to assess the ACA directly. In addition, we discuss surrogate approaches to measuring angle configuration by Scheimpflug photography and the SPAC scanning peripheral anterior chamber depth analyzer.

Objective: To evaluate the change of biomechanical properties of the trabecular meshwork (TM) and configuration of collector channels (CC) by high-resolution optical coherence tomography (HR-OCT) induced by Schlemm’s canal (SC) dilation. Methods: The anterior segments of two human eyes were divided into four quadrants. One end of a specially designed cannula was placed in SC and the other end connected to a perfusion reservoir. HR-OCT provided three-dimensional (3D) volumetric and two-dimensional (2D) cross-sectional imaging permitting assessment of the biomechanical properties of the TM. A large fluid bolus was introduced into SC. Same-sample, pre and post deformation and disruption of SC and CC lumen areas were analyzed. Results: Morphologic 3D reconstructions documented pressure-dependent changes in lumen dimension of SC, CC, and circumferential intrascleral channels. 2D imaging established volumetric stress-strain curves (elastance curves) of the TM in quadrants. The curves of T...

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). 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). 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). 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.

Glaucoma is a leading cause of blindness worldwide and results from damage to the optic nerve. Currently, intraocular pressure is the only treatable risk factor. Changes in aqueous outflow regulate pressure; regulation becomes abnormal in glaucoma. From inside the eye aqueous flows out through the trabecular meshwork into a venous sinus called Schlemm&#39;s canal, next into collector channels and finally returns to the episcleral vessels of the venous system. The location of aqueous outflow regulation is unknown. Ex vivo and in vivo studies implicate both pressure-dependent trabecular tissue motion and tissues distal to Schlemm&#39;s canal in regulation of aqueous outflow. Technologies have not previously been available to study these issues. New ex vivo imaging in human eyes identifies hinged flaps or leaflets at collector channel entrances using a high-resolution spectral domain optical coherence tomography (SD-OCT) platform. The hinged flaps open and close in synchrony with press...

Background and Objective: A novel computer-guided laser treatment for open-angle glaucoma, called patterned laser trabeculoplasty, and its preliminary clinical evaluation is described. Patients and Methods: Forty-seven eyes of 25 patients with open-angle glaucoma received 532-nm laser treatment with 100-μm spots. Power was titrated for trabecular meshwork blanching at 10 ms and sub-visible treatment was applied with 5-ms pulses. The arc patterns of 66 spots rotated automatically after each laser application so that the new pattern was applied at an untreated position. Results: Approximately 1,100 laser spots were placed per eye in 16 steps, covering 360° of trabecular meshwork. The intraocular pressure decreased from the pretreatment level of 21.9 ± 4.1 to 16.0 ± 2.3 mm Hg at 1 month (n = 41) and remained stable around 15.5 ± 2.7 mm Hg during 6 months of follow-up (n = 30). Conclusion: Patterned laser trabeculoplasty provides rapid, precise, and minimally traumatic (sub-visible) com...

The purpose of this study was to evaluate the relationship between elevations of intraocular pressure (IOP) and the multifocal electroretinogram (mfERG) in non-human primates. Experimental glaucoma was induced in 4 rhesus and 4 cynomolgus monkeys by laser trabecular meshwork destruction (LTD) in one eye. To evaluate the contribution of ganglion cells to mfERG changes, one monkey of each species had previously underwent unilateral optic nerve transection (ONT). After ≥ 44 weeks of elevation, the IOP was reduced by trabeculectomy in 2 non-transected animals. In the intact (non-transected) animals there was an increase in the amplitude of the early mfERG waveforms (N1 and P1) of the first order kernel (K1) throughout the period of IOP elevation in all of the rhesus, but not all of the cynomolgus monkeys. A species difference was also present as a decrease of the second order kernel, first slice (K2.1) in all of the cynomolgus monkeys but only in 1 of the rhesus monkeys (the 1 with the ONT). Similar IOP effects on the mfERG were seen in the ONT animals. Surgical lowering of IOP resulted in a return of the elevated K1 amplitudes to baseline levels. However, the depressed K2.1 RMS in the cynomolgus monkeys did not recover. These results demonstrate species-specific changes in cone-driven retinal function during periods of elevated IOP. These IOP-related effects can occur in the absence of retinal ganglion cells and may be reversible.

Background: Left ventricular non-compaction (LVNC) is a rare cardiomyopathy, with hypertrabeculation often observed in athletes. In confirmed LVNC, LV systolic strain and rotational mechanics have been shown to be abnormal. Whether healthy athletes meeting echocardiographic LVNC criteria exhibit abnormal myocardial mechanics is not known. The aim of this study is to evaluate the prevalence of healthy paediatric athletes meeting the Jenni criteria for LVNC and how this relates to LV systolic function and rotational mechanics. Methods: Professional athletes under 18 years undergoing comprehensive pre-participation screening (2014-2017) at two sports academies were included. Jenni criteria for LVNC were assessed from short axis LV views. Global and segmental peak systolic longitudinal (Sl) and circumferential strain (Sc), basal rotation (basal Rot) and apical rotation (apical Rot) were calculated using speckle tracking imaging. Results: A total of 201 boys (11.9-18 years, median 15.1 years) were included, with diverse ethnicity (47.7% Arab, 28.5% Black, 21.8% White, and 2% other) and sports background (60% football, 21.2% athletics, 18.8% other).

ABSTRACTWhile interactions between neural crest and placode cells are critical for the proper formation of the trigeminal ganglion, the mechanisms underlying this process remain largely uncharacterized. Here, we show that the microRNA-(miR)203, whose epigenetic repression is required for neural crest migration, is reactivated in coalescing and condensing trigeminal ganglion cells. Overexpression of miR-203 induces ectopic coalescence of neural crest cells and increases ganglion size. Reciprocally, loss of miR-203 function in placode, but not neural crest, cells perturbs trigeminal ganglion condensation. Demonstrating intercellular communication, overexpression of miR-203 in the neural crestin vitroorin vivorepresses a miR-responsive sensor in placode cells. Moreover, neural crest-secreted extracellular vesicles (EVs), visualized using pHluorin-CD63 vector, become incorporated into the cytoplasm of placode cells. Finally, RT-PCR analysis shows that small EVs isolated from condensing ...

We present a series of three American Bulldogs with clinical signs of glaucoma and intraocular inflammation accompanied by bilateral uveal cysts and abnormal gonioscopic findings. All dogs proved refractory to medical management and were enucleated. Histopathologic findings were similar in all three and included significant preiridal fibrovascular membranes and mononuclear inflammatory infiltrates in the anterior uvea. On microscopic evaluation, cysts appeared to arise primarily from the ciliary body and iridociliary sulcus, with smaller cysts also budding from the posterior iris. Pigment dispersion was variable but consistent, involving deposition of a small number of pigment‐laden cells in the dependent trabecular meshwork. Cataract formation was not noted. Glaucoma associated with uveal cysts has been described previously in Golden Retrievers and Great Danes, although clinical and histopathologic findings in those breeds are not identical to those described here. American Bulldog...

Introduction: To describe the 12-month efficacy and safety of goniotomy performed using the Kahook Dual Blade (KDB) in combination with cataract surgery in eyes with medically treated open-angle glaucoma (OAG). Methods: This was a prospective, interventional case series conducted at seven centers in North America. Consecutive patients with medically treated OAG and visually significant cataract underwent phacoemulsification combined with goniotomy (PE ? goniotomy) using KDB. Indications for glaucoma surgery included reduction of intraocular pressure (IOP) and reduction of IOP-lowering medications. Deidentified data were collected and included pre-, intra-, and postoperative data on IOP, the use of IOP-lowering medications, and adverse events through 12 months of follow-up. Results: Among 52 eyes undergoing surgery, mean IOP was reduced from 16.8 ± 0.6 mmHg at baseline to 12.4 ± 0.3 mmHg at month 12 (P \ 0.001), a 26.2% reduction. Mean IOP across time points ranged from 12.4-13.3 mmHg during follow-up. The mean number of topical IOPlowering medications was reduced from 1.6 ± 0.2 at baseline to 0.8 ± 0.1 at month 12 (P \ 0.05), a 50.0% reduction. At month 12, 57.7% of eyes had IOP reduction C 20% from baseline, and 63.5% were on C 1 fewer IOP-lowering medications. In subgroup analysis, 84.6% of eyes with lower mean baseline IOP were using C 1 fewer medications at month 12, and 100% of eyes with higher mean baseline IOP had IOP reductions C 20%. The most common postoperative adverse events were pain/irritation (n = 4, 7.7%), opacification of the posterior lens capsule (n = 2, 3.8%), and IOP spike [ 10 mmHg (n = 2, 3.8%).

The regulation of transendothelial fluid flow by glucocorticoids was studied in vitro with use of human endothelial cells cultured from Schlemm&#39;s canal (SCE) and the trabecular meshwork (TM) in conjunction with computer-linked flowmeters. After 2-7 wk of 500 nM dexamethasone (Dex) treatment, the following physiological, morphometric, and biochemical alterations were observed: a 3- to 5-fold increase in fluid flow resistance, a 2-fold increase in the representation of tight junctions, a 10- to 30-fold reduction in the mean area occupied by interendothelial &quot;gaps&quot; or preferential flow channels, and a 3- to 5-fold increase in the expression of the junction-associated protein ZO-1. The more resistive SCE cells expressed two isoforms of ZO-1; TM cells expressed only one. To investigate the role of ZO-1 in the aforementioned Dex effects, its expression was inhibited using antisense phosphorothioate oligonucleotides, and the response was compared with that observed with the u...

Human trabecular meshwork (TM) cells play pivotal roles in maintaining homeostasis of intraocular pressure via regulation of aqueous humor outflow. These cells are capable of phagocytosis, which is considered to be essential for their regulatory function. In addition, there is a strong expression of the gap junction protein connexin43 (Cx43) in the TM. Here, we investigated functional relationships between phagocytosis activity of TM cells and their expression of Cx43. Phagocytosis was measured by showing the ability of TM cells to engulf inert fluorescent particles consisting of pHrodo. We found that internalized pHrodo was partially co-localized with Cx43 and that the phagocytic activity was dramatically reduced after knockdown of Cx43 using lentiviral Cx43 shRNA. These results suggest that Cx43 is involved in the regulation of phagocytosis by TM cells.

Cellular structures that perform essential homeostatic functions include tight junctions, gap junctions, desmosomes and adherens junctions. The aqueous humor, produced by the ciliary body, passes into the anterior chamber of the eye and is filtered by the trabecular meshwork (TM), a tiny tissue found in the angle of the eye. This tissue, along with Schlemm's canal (SC) inner wall cells, is thought to control intraocular pressure (IOP) homeostasis for normal, optimal vision. The actin cytoskeleton of the tissue plays a regulatory role in maintaining IOP. One of the key risk factors for primary open angle glaucoma is persistent elevation of IOP, which compromises the optic nerve. The ZO-1 (Zonula Occludens-1), extracellular matrix protein integrins, and gap junction protein connexin43 (Cx43) are widely expressed in many different cell populations. Here, we investigated the localization and interactions of ZO-1, α3 integrin, β1 integrin, and Cx43 in cultured porcine TM and SC cells using RT-PCR, western immunoblotting and immunofluorescence labeling with confocal microscopy, along with co-immunoprecipitation. ZO-1 partially co-localized with α3 integrin, but not with β1 integrin, and co-immunoprecipitated with Cx43, as well as with α3 integrin. The association of ZO-1 with α3 integrin and Cx43 suggests that these proteins may form a multiple protein complex in porcine TM and SC cells. Since integrins interact with the actin cytoskeleton via scaffolding proteins, these results implicate junctional and scaffolding protein ZO-1 as a potential control point in regulation of IOP to normal levels for glaucoma therapy.

Human resources development is an important component for the success of any organization. Human resource management plays a crucial role in the implementation of strategic management in cooperatives. It has, however, not been accorded the importance it deserves in the cooperative institutions. The existing organizational design of most of the cooperatives does not conform to the basic principles of human resources management of a sound institution. The cooperatives are generally headed by a committee of elected members, who are not necessarily professionals. The cooperatives will have to evolve sound personnel policies encompassing proper manpower planning and assessment. It is necessary to evolve scientific staffing norms. There should also be a conscious policy for developing the second line of management in all key functional areas. Conscious and well specified HRD principles in crucial areas like recruitment, placement, training, career progression, managerial grooming, etc., are lacking in most of the cooperatives. There was no evidence of an objective system involving professional guidance for recruitment in cooperatives in several states. Therefore, it is necessary to study on human resource development in cooperative. This paper attempts to analyze the human resource development in cooperatives. A diagnostic research design (theoretical analysis) is followed in the present study. Empirical results show human resource management and development in cooperatives are is not effective.

Brain meninges and associated vasculature participate in brain clearance and are implicated in many neurological conditions such as Alzheimer’s disease, meningitis, multiple sclerosis, stroke, and traumatic brain injury. However, most of our knowledge concerning brain clearance via meninges is based on rodent data, and relevance to human disease remains unclear. One of the technical barriers in studies of meningeal physiology in health and disease is that existing imaging modalities are suboptimal for large and optically non-transparent meningeal tissue of humans and non-human primate (NHP) animal models. To address this barrier, we performed first characterization of NHP dura by high resolution confocal microscopy of clarified tissue. We investigated vascular structures and resident cells in normal monkeys and primate models of tauopathy and synucleinopathy. We demonstrated the presence of an extensive meningeal vascular network covering the entire tissue surface with resolution to...

Glaucoma is the second cause of blindness worldwide. This disease is a neurodegenerative disorder characterized by high intraocular pressure, loss of retinal ganglion cells (apoptosis). Even though there is much research done in this field, the results have not yet managed to stop the progression of glaucoma or to heal this pathology. Free oxygen radicals play a major role; they are formed in the aqueous humor and in the vitreous and they produce apoptosis of the neurons in the optic nerve head, degradation of the trabecular meshwork cells. The purpose of the article is to help in trying to understand the physiopathology of glaucoma and the efficacy of its treatments. Abbreviations: IOP = intraocular pressure, NO = nitric oxide, NOS = nitric oxide synthase, ROCK = coiled coil-forming protein kinase, RCG = retinal ganglion cells, NGF = nerve growth factor.

Studies of folded-to-misfolded transitions using model protein systems reveal a range of unfolding needed for exposure of amyloid-prone regions for subsequent fibrillization. Here, we probe the relationship between unfolding and aggregation for glaucoma-associated myocilin. Mutations within the olfactomedin domain of myocilin (OLF) cause a gain-of-function, namely cytotoxic intracellular aggregation, which hastens disease progression. Aggregation by wild-type OLF (OLF WT ) competes with its chemical unfolding, but only below the threshold where OLF loses tertiary structure. Representative moderate (OLF D380A ) and severe (OLF I499F ) disease variants aggregate differently, with rates comparable to OLF WT in initial stages of unfolding, and variants adopt distinct partially folded structures seen along the OLF WT urea-unfolding pathway. Whether initiated with mutation or chemical perturbation, unfolding propagates outward to the propeller surface. In sum, for this large protein prone to amyloid formation, the requirement for a conformational change to promote amyloid fibrillization leads to direct competition between unfolding and aggregation. Approximately 20 folded and disease-associated proteins are known to form amyloid, often as a result of a non-synonymous coding mutation 1 . Studies of tractable model systems demonstrate that the resultant amino acid substitution in such proteins introduces some degree of unfolding, exposing amyloid-templating peptide (or amyloid-prone region, APR) sequences that are not readily accessible in the wild-type (WT) protein 2 . A recent addition to the list of pathogenic proteins that form amyloid is the myocilin olfactomedin (OLF) domain 3 . Many different single-point mutations in myocilin (MYOC, Uniprot accession Q99972), dispersed throughout the sequence and structure, comprise the strongest genetic link to early onset open angle glaucoma 4 . Mutant myocilin hastens the causal risk factor of elevated intraocular pressure 5 , which originates from dysregulation of the trabecular meshwork extracellular matrix 6 where myocilin is robustly expressed 7 . Early cellular studies revealed a pathogenic mechanism involving a toxic gain of function where cellular secretion was impaired and, instead, detergent-insoluble aggregates accumulated . Loss of function was ruled out by the finding that individuals with heterozygous 14 and hemizygous 15 N-terminal truncation mutations do not develop glaucoma.

Purpose: Orcolon, a synthetic viscoelastic, may have contributed to refractory intraocular pressure (lOP) elevation after intracameral injection in some patients. Crosslinked polyacrylamide (microgels), an altered form of the polymer, was investigated as an etiologic candidate. Methods: Four adult rhesus monkeys underwent anterior chamber exchange with mock aqueous humor containing microgels in one eye and a vehicle in the other. Outflow facility (perfusion) and lOP (applanation) were determined before and at various times thereafter. Facility also was determined before and after microgel or vehicle infusion into organcultured individual human (n = 9) and paired calf (n = 6) anterior segments. Representative monkey and human eyes were examined by light and electron microscopy. Results: In the microgel-infused monkey eyes, lOP was consistently higher, by approximately 5 mmHg for approximately 1 month. In all three species, microgel infusion acutely decreased facility by approximately 50% to 80%. In the living monkeys where longer-term observation and retesting were possible, a facility reduction of approximately 40% to 50% persisted for at least 1 to 2 months, and rechallenge again produced an acute 80% facility decrease and subsequent 10-mmHg lOP rise. Results of electron microscopic examination in human and monkey eyes showed accumulation of microgels in the cribriform meshwork and beneath the inner wall of Schlemm's canal, with no cellular alterations or inflammatory infiltrate. Conclusions: Cross-linked polyacrylamide microgels can produce an acute and longstanding obstruction of trabecular drainage experimentally, and might therefore do so clinically.

This review summarizes the Ernst H. Ba ´ra ´ny Prize Lecture given at the XVI. meeting 2004 of the International Society of Eye Research in Sydney, Australia. The article describes the author's early studies starting with the determination of the site of aqueous humour outflow resistance and its regulation through ciliary muscle contraction, which were performed in collaborations with Ba ´ra ´ny. It continues with the qualitative and quantitative evaluation of the trabecular meshwork (TM) changes seen in different kinds of glaucoma diseases. A comparison of correlations between meshwork pathology, IOP, and axon loss in the optic nerve between eyes with pseudoexfoliation glaucoma (PEXG) and primary open angle glaucoma (POAG) indicates that in the secondary glaucoma (PEXG) optic neuropathy is mainly induced by an increase in IOP. In eyes with POAG, the correlations point towards a more complex pathogenesis of the disease. Common factors might be involved in both the TM and the optic nerve changes. In vitro studies performed in cell cultures of human TM cells and optic nerve astrocytes as well as organ culture studies of the anterior eye segment indicate that TGFb 2 might be one of the factors involved in the development of POAG. The paper is primarily focused on studies performed by the author and complete reference to other previous or contemporary studies is therefore not given as the purpose is not to present a comprehensive review article.

New surgical techniques have been advocated for lowering intraocular pressure (IOP) in patients with open angle glaucoma, and the decision on how to manage concurrent glaucoma and cataract has evolved. This continuing search stems from dissatisfaction with the spectrum of undesirable early postoperative complications of trabeculectomy. Recently, a new technique of nonpenetrating glaucoma surgery viscocanalostomy has been described, designed to increase trabecular outflow. This procedure evolved from earlier techniques described by Krasnov called sinusotomy, and Stegman developed similar technique, the socalled viscocanalostomy. In this study we evaluated a nonfiltering glaucoma technique viscocanalostomy alone or in combination with

Rhokinase inhibitors is a new class of drug under trial that improve the outflow facility through conventional path way by inhibiting the contractile tone of actin cytoskeleton. They additionally protect trabecular meshwork from oxidative stress, improve Optic Nerve head blood flow, facilitate corneal endothelium wound healing, increase ganglion cell survival and reduce scarring in glaucoma surgery.

Introduction: Filtration surgery is the most effective method of lowering intraocular pressure (IOP) in patients with insufficient medical control. It consists in facilitating the drainage of the intraocular fluid (IOF) from the anterior chamber to the subconjunctival space and subsequent lowering of IOP. The formation of filtration blebs (FB) and the processes of scarring occurring in the conjunctiva are of particular importance in glaucoma surgery. In many cases, the appearance of FB does not match the IOP values, and what causes the failure after trabeculectomy often remains unclear. Often, over time, there is a change in the structure of the FB, as fibrous tissue grows, which prevents the IOF drainage. Laser scanning in vivo confocal microscopy is a non-invasive study allowing the production of layered images at the microstructural level with high resolution of both the cornea and other structures of the anterior ocular surface. To evaluate the morphological structure and function of filtering blebs after trabeculectomy using in vivo confocal microscopy taking into account the type of implant and when the surgery was performed. The study included 33 patients, 46 eyes with glaucoma. Twenty-six of the eyes had primary open-angle glaucoma (POAG), 18 eyes had pseudoexfoliative glaucoma and 2 eyes had juvenile glaucoma. All patients underwent trabeculectomy with fornix-based flap, and three of the eyes underwent retrabeculectomy. Mitomicyn C (MMC) was administered intraoperatively to all patients. The study of the filtering bleb was performed by in vivo confocal microscopy (CFM) (Heidelberg Retina Tomograph II (HRT II) /Rostock Cornea Module/ (Heidelberg Engineering GmbH, Heidelberg, Germany), the period from trabeculectomy and examination being from 1 year to 22 years. An Express implant was placed in 14 eyes, Ologen implant in 7 eyes, and 25 eyes had no implant placed. In the analysis of the morphological structure of the filtering blebs, three indicators were evaluated: the type of epithelium, the type of stroma, and blood vessels. Results: Statistical significance was established with regard to the function and morphological structure of the filtering bleb (p=0.009). Blebs with fine collagen mesh and dense collagen mesh demonstrate good function. In the case of blebs with insufficient function, those with a dense collagen network and hyper-reflective tissue predominated and there were no blebs with a fine collagen network, and in non-functioning blebs most common were those with a pronounced collagen network and hyper-reflective tissue. With regard to vascularization, we found that the functioning blebs in the shortest postoperative period were dominated by those with one blood vessel (stage 1) and there was no stage 3, with weak tortuosity, while in non-functioning blebs in the late postoperative period, there was moderate to severe vascularization and tortuosity (p=0.037), (p=0.043), (p=0.047), (p=0.021). The type of implant affects the tortuosity of the blood vessels of the filtering bleb (p=0.026). The blebs with Express implants show a slight tortuosity, followed by the blebs with Ologen implants. The highest percentage of highly kinked blood vessels occurred in blebs without an implant. In vivo confocal microscopy is an innovative method which allows visualization of the internal structure of the filtering blebs at a cellular level, giving us a new insight into the ongoing healing processes, premising the function of the filtering blebs after glaucoma surgery.

Introduction: Filtration surgery is the most effective method of lowering intraocular pressure (IOP) in patients with insufficient medical control. It consists in facilitating the drainage of the intraocular fluid (IOF) from the anterior chamber to the subconjunctival space and subsequent lowering of IOP. The formation of filtration blebs (FB) and the processes of scarring occurring in the conjunctiva are of particular importance in glaucoma surgery. In many cases, the appearance of FB does not match the IOP values, and what causes the failure after trabeculectomy often remains unclear. Often, over time, there is a change in the structure of the FB, as fibrous tissue grows, which prevents the IOF drainage. Laser scanning in vivo confocal microscopy is a non-invasive study allowing the production of layered images at the microstructural level with high resolution of both the cornea and other structures of the anterior ocular surface. Aim: To evaluate the morphological structure and f...

Background: Glucosamine is an amino monosaccharide that can directly stimulate the synthesis of glycosaminoglycans in the cartilage. It has been widely used as an osteoarthritis treatment. However, several literatures show the possible side effects of glucosamine, such as increased intraocular pressure (IOP). Objective: The objective of this study was to determine if there was any correlation between the use of glucosamine and the increase in IOP. Material and Method: This was a descriptive qualitative study that implied a systematic review design. The study sample consisted of patients with osteoarthritis (OA) and glaucoma in Iran, Indonesia, Thailand, the USA, and India between 2013 and 2018. The literature search was conducted on a database (PubMed and Google Scholar) and selected using inclusion and exclusion criteria. Discussion: The research identified 5 studies on the use of glucosamine and the increase of IOP. Two articles provide significant results on the correlation between the use of glucosamine and the increase of IOP (P < 0.05). In addition, two studies showed significant IOP reduction outcomes after discontinuation of glucosamine (P < 0.05). A case series indicated an increase in IOP during the 6 th month of glucosamine use but still at normal value. Conclusion: Many other factors contribute to IOP growth, other than the use of glucosamine. Therefore, a large-scale randomized clinical trial or a multicentre cohort study using the same parameters is still needed to improve the quality of the subsequent systematic review.