A novel suprachoroidal microinvasive glaucoma implant: in vivo biocompatibility and biointegration.

Background: A major challenge for any glaucoma implant is their ability to provide long-term intraocular pressure lowering efficacy. The formation of a low-permeability fibrous capsule around the device often leads to obstructed drainage channels, which may impair the drainage function of devices. These foreign body-related limitations point to the need to develop biologically inert biomaterials to improve performance in reaching long-term intraocular pressure reduction.

Secretory proteostasis of the retinal pigmented epithelium: Impairment links to age-related macular degeneration.

Secretory proteostasis integrates protein synthesis, processing, folding and trafficking pathways that are essential for efficient cellular secretion. For the retinal pigment epithelium (RPE), secretory proteostasis is of vital importance for the maintenance of the structural and functional integrity of apical (photoreceptors) and basal (Bruch's membrane/choroidal blood supply) sides of the environment it resides in. This integrity is achieved through functions governed by RPE secreted proteins, which include extracellular matrix modelling/remodelling, angiogenesis and immune response modulation.

Thrombospondin-2 is up-regulated by TGFβ2 and increases fibronectin expression in human trabecular meshwork cells.

Elevated intraocular pressure (IOP) is a major risk factor for the development of primary open-angle glaucoma (POAG). This is from an increased aqueous humour (AH) outflow resistance through the trabecular meshwork (TM). The pathogenic mechanisms leading to the increase in TM outflow resistance are poorly understood but are thought to be from a dysregulation of the TM extracellular matrix (ECM) environment.

Advanced glycation end products-related modulation of cathepsin L and NF-κB signalling effectors in retinal pigment epithelium lead to augmented response to TNFα.

The retinal pigment epithelium (RPE) plays a central role in neuroretinal homoeostasis throughout life. Altered proteolysis and inflammatory processes involving RPE contribute to the pathophysiology of age-related macular degeneration (AMD), but the link between these remains elusive. We report for the first time the effect of advanced glycation end products (AGE)-known to accumulate on the ageing RPE's underlying Bruch's membrane in situ-on both key lysosomal cathepsins and NF-κB signalling in RPE.

Safety and acceptability of an organic light-emitting diode sleep mask as a potential therapy for retinal disease.

PurposeThe purpose of the study was to study the effect of an organic light-emitting diode sleep mask on daytime alertness, wellbeing, and retinal structure/function in healthy volunteers and in diabetic macular oedema (DMO).Patients and methodsHealthy volunteers in two groups, 18-30 yrs (A), 50-70 yrs (B) and people with DMO (C) wore masks (504 nm wavelength; 80 cd/m luminance; ≤8 h) nightly for 3 months followed by a 1-month recovery period. Changes from baseline were measured for (means): psychomotor vigilance task (PVT) (number of lapses (NL), response time (RT)), sleep, depression, psychological wellbeing (PW), visual acuity, contrast sensitivity, colour, electrophysiology, microperimetry, and retinal thickness on OCT.

Bovine posterior limbus: an evaluation of an alternative source for corneal endothelial and trabecular meshwork stem/progenitor cells.

A growing body of evidence has revealed that stem-like cells in the posterior limbus of the eye between the corneal endothelium (CE) and trabecular meshwork (TM) may be able to rejuvenate these tissues in disease. However, these cells have not been clearly defined and we have named them PET cells (progenitor cells of the endothelium and trabeculum). A good and inexpensive animal model for PET cells is lacking, so we investigated bovine eyes as an effective large tissue source.

Measurement and computer modeling of temporary arrangements of polygonal actin structures in trabecular meshwork cells which consist of cross-linked actin networks and polygonal actin arrangements.

Purpose: In trabecular meshwork (TM) cells, actin geodesic arrangements were measured and then subjected to computational modeling to appreciate the response of different dome shapes to mechanical force.

Methods: Polygonal actin arrangements (PAAs) and cross-linked actin networks (CLANs) were induced and imaged by Alexa Flour(®) 488 Phalloidin in bovine TM and human TM cells. Masked images were examined for size, circularity, and spoke and hub dimensions using ImageJ.

A Novel Schlemm's Canal Scaffold: Histologic Observations.

Purpose: To assess the biocompatibility of a novel implant made of Nitinol (nickel-titanium alloy), designed to improve aqueous humor outflow.

Materials And Methods: In the first arm of biocompatibility testing, microstents were surgically inserted into Schlemm's canal (SC) of 2 non-human primates (NHPs), and a third NHP served as a surgical sham control. After 13 weeks the animals were killed, and the eyes were examined by light and scanning electron microscopy.

Progenitors for the corneal endothelium and trabecular meshwork: a potential source for personalized stem cell therapy in corneal endothelial diseases and glaucoma.

Several adult stem cell types have been found in different parts of the eye, including the corneal epithelium, conjunctiva, and retina. In addition to these, there have been accumulating evidence that some stem-like cells reside in the transition area between the peripheral corneal endothelium (CE) and the anterior nonfiltering portion of the trabecular meshwork (TM), which is known as the Schwalbe's Ring region. These stem/progenitor cells may supply new cells for the CE and TM.

Inducers of cross-linked actin networks in trabecular meshwork cells.

Purpose: It is well established that the unusual actin arrangements known as cross-linked actin networks (CLANs) can be induced by dexamethasone (DEX) in trabecular meshwork (TM) cells. Recent work reporting their presence in elderly glaucomatous and nonglaucomatous tissue, however, has highlighted the presence of other inducers. In this study, the authors sought to identify CLAN induction agents that may be present within and around the outflow system.

PERP expression stabilizes active p53 via modulation of p53-MDM2 interaction in uveal melanoma cells.

The activation and regulation of target genes by the tumour-suppressor p53 dictates the fate of a cell, with cell cycle arrest or apoptosis being two distinct outcomes. PERP (p53 apoptosis effector related to PMP-22), a p53 transcriptional target, is induced specifically during apoptosis but not cell cycle arrest. Downregulation of PERP is associated with the aggressive, monosomy 3-type of uveal melanoma (UM), the most common primary intraocular tumour in adults, and increased PERP expression has a pro-apoptotic effect in UM cells.

Expanded polytetrafluoroethylene as a substrate for retinal pigment epithelial cell growth and transplantation in age-related macular degeneration.

Background: Retinal pigment epithelial (RPE) transplantation presents a potential treatment for age-related macular degeneration (AMD). A suitable transplant membrane that can support an intact functioning RPE monolayer is required. Expanded polytetrafluoroethylene (ePTFE) possesses the physical properties required for a transplanting device; however, cells do not attach and spread on ePTFE.

Cross-linked actin networks (CLANs) are present in lamina cribrosa cells.

Aims: A study was undertaken to determine and compare the F-actin staining patterns in the cells of the lamina cribrosa (LC) of normal, dexamethasone (DEX)-treated and glaucomatous dissected tissue and cell cultures.

Methods: About 30 dissected donor eyes and nine cell lines provided the human specimens; 25 eyes and 20 primary cell cultures provided the bovine material. Appropriate samples were exposed to 1×10⁻⁷ M DEX for up to 14 days.

Cystatin C in macular and neuronal degenerations: implications for mechanism(s) of age-related macular degeneration.

Cystatin C is a strong inhibitor of cysteine proteinases expressed by diverse cells. Variant B cystatin C, which was associated with increased risk of developing age-related macular degeneration, differs from the wild type protein by a single amino acid (A25T) in the signal sequence responsible for its targeting to the secretory pathway. The same variant conveys susceptibility to Alzheimer disease.

Cross-linked actin networks (CLANs) in bovine trabecular meshwork cells.

A cytoskeletal feature of human trabecular meshwork (HTM) cells in vitro and ex vivo is the presence of cross-linked actin networks (CLANs) that are abundant in a proportion of TM cells exposed to dexamethasone (DEX) and also in cells from glaucoma patients. We wished to determine whether CLANs were present in the bovine trabecular meshwork (BTM), whether they were similarly induced by dexamethasone and whether the structures were comparable to CLANs in HTM cells. Cultures of HTM and BTM cells and ex vivo dissections of BTM tissue were stained with phalloidin (F-actin) and propidium iodide (nuclei) and imaged by confocal microscopy, thereafter being subjected to image analysis.

Spontaneous regression of human cancer cells in vitro: potential role of disruption of Cdk1/Cdk4 co-expression.

Background: Although well-acknowledged in vivo, spontaneous death of cancer cells in vitro is less widely appreciated.

Materials And Methods: Colony formation was studied in untreated control plates of standard clonogenic assays and measurements of actual and potential doubling times performed in asynchronous cultures of human cancer cells lines. Western blotting of lung large cell carcinoma, COR-L23 cells actively undergoing spontaneous cell death was also carried out.

Clinicopathological case series of four patients with inherited macular disease.

Purpose: To correlate the phenotype of four patients with inherited macular disease with the immunohistopathology of retinal tissue collected at the time of retinal pigment epithelium (RPE)-choroidal transplantation.

Methods: A clinicopathologic case series describing the phenotype of four patients, including confocal immunohistochemistry and electron microscopy (EM), and the results of genetic testing.

Results: In Case 1, electrophysiology showed only macular dysfunction.

Cathepsin S and its inhibitor cystatin C: imbalance in uveal melanoma.

The present study aimed to investigate, as a follow-up of microarray profiling, the expression of the lysosomal cysteine protease cathepsin S and that of its endogenous inhibitor cystatin C in the most common primary intraocular tumor in adults, uveal melanoma. The expression pattern unveiled was characterized by a relative increase in the active form of the elastolytic and collagenolytic cathepsin S that was not counterbalanced by the expression of its strongest endogenous inhibitor cystatin C in the aggressive, highly metastatic uveal melanomas. The study provides evidence for a novel correlation between a specific cysteine protease activity and the strongest predictive factor for metastatic behavior in primary uveal melanoma and documents the first investigation of both a specific protease activity and its endogenous inhibitor in uveal melanoma.

Replacement of the RPE monolayer.

There are numerous scenarios in which replacing the diseased RPE monolayer is an attractive but as yet unrealised goal. The proof of concept that vision can be improved by placing a healthy neuroretina onto a different, healthy, underlying RPE layer is demonstrated in patch graft transplantations. The surgical procedure to relocate the neuroretina is both complex and is hampered by postoperative complications and as such newer replacement procedures are also being investigated including stem cell replacement therapies.

Side effects associated with prostaglandin analog therapy.

Topical prostaglandin analogs, which have become first-line therapy in the medical management of glaucoma, have an excellent safety profile with regard to systemic side effects, but are associated with several ocular side effects. Some of these are common, with no apparent serious consequences other than cosmetic, whereas others are much less common but represent potentially sight-threatening side effects. The former group includes conjunctival hyperemia, elongation and darkening of eyelashes, induced iris darkening, and periocular skin pigmentation.

P53 apoptosis mediator PERP: localization, function and caspase activation in uveal melanoma.

p53 apoptosis effector related to PMP-22 (PERP) is a transcriptional target gene of p53 tumour suppressor that is specifically induced during apoptosis and not during cell cycle arrest. In primary uveal melanoma (UM), the most common intraocular malignancy in adults that has a reportedly unaffected signalling pathway upstream of and including p53, PERP expression is down-regulated in the metastatic monosomy 3-type tumours, compared with the less aggressive disomy 3-type tumours. Here, we demonstrate experimentally, by the use of full-length PERP-green fluorescent protein (GFP) fusions and real-time confocal microscopy, the intracellular targeting and plasma membrane localization of PERP in living UM cells and show that expression of PERP induces caspase-mediated apoptosis in UM cells.

Cross-linked actin networks (CLANs) in the trabecular meshwork of the normal and glaucomatous human eye in situ.

Purpose: A percentage of trabecular meshwork (TM) cells in tissue and organ culture have been shown to contain cross-linked actin networks (CLANs) when exposed to dexamethasone, as have TM cultures derived from glaucomatous individuals. The purpose of this study was to determine whether CLANs exist within TM cells in situ in tissue unmanipulated by culturing, thereby eliminating the possibility that CLANs are artifacts of culture conditions, and to determine their numbers and dimensions in normal and glaucoma TM cells.

Methods: Twelve human donor eyes (five normal and seven with glaucoma) provided the TM tissue.

Prostaglandin analogues in the anterior eye: their pressure lowering action and side effects.

Topical application of prostaglandin (PG) analogues are currently the most commonly used intraocular pressure lowering drugs in glaucoma. They have been available since the mid 1990's, and are efficacious and generally well tolerated, the compliance rates are good due to the once a day application regime. The mode of action of PGs is by increasing the aqueous humour outflow primarily via the uveoscleral route, and also (but to a lesser degree) the conventional trabecular meshwork pathway.

Long-term results of viscocanalostomy in pseudoexfoliative and primary open angle glaucoma.

Purpose: To document the outcome of viscocanalostomy (VC) alone or combined with phacoemulsification (phaco-VC) in eyes with pseudoexfoliation glaucoma (PEXG) and primary open angle glaucoma (POAG).

Methods: A prospective, comparative study of 314 eyes undergoing VC in two centres over 6 years was conducted. Main outcome measures were: (i) intraocular pressure (IOP) control (complete success was IOP < or = 18 mmHg without medication and failure IOP > 18 mmHg); and (ii) requirement for Nd:YAG laser goniopuncture (YAG-GP) if IOP > 21 mmHg.

Expression of COX-2 and prognostic outcome in uveal melanoma.

Purpose: The expression of cyclooxygenase-2 (COX-2) and its prognostic value in uveal melanoma was examined.

Methods: Paraffin-embedded sections from 32 clinicopathologically well-characterized cases of primary uveal melanoma were immunohistochemically stained for COX-2. COX-2 expression was evaluated in terms of both the intensity and the extent of staining for each tumor.