The use of the Ex-PRESS implant under a scleral flap was effective for lowering IOP both alone and combined with cataract surgery. The most common device-related complication was tube blockage, which was treated with the Nd:YAG laser.
Glaucoma is a multifactorial optic neuropathy in which there is a characteristic acquired loss of retinal ganglion cells, at levels beyond normal age-related baseline loss, and corresponding atrophy of the optic nerve. Although asymptomatic in its earlier stages, the disease is nevertheless one of the leading global causes of irreversible blindness. Although elevated intraocular pressure (IOP) is one of the most important risk factors and lowering of IOP is the only proven treatment so far, the definition of glaucoma has evolved from a disease caused by increased IOP to one characterised by an IOP-sensitive, progressive optic neuropathy. In recent years, safer and better tolerated topical medications have been developed to control IOP more effectively, thereby limiting the need for surgery. New research has also noted the importance of diurnal IOP variation as a critical risk factor for progression of glaucomatous optic neuropathy (GON) and subsequent visual field loss. Moreover, new discoveries have further elucidated the basic pathophysiological and genetic mechanisms underlying the elevated levels of IOP, as well as the cellular mechanisms of GON. As our understanding of these complex pathways continues to improve, development opportunities for new therapeutic modalities will be enhanced.
Opsin, a member of the G-protein-coupled receptor family, is a polytopic membrane protein that does not encode a cleaved amino-terminal signal sequence. The amino terminus of opsin precedes the first known targeting information, suggesting that it translocates across the endoplasmic reticulum (ER) membrane after synthesis, uncoupled from translation. However, translocation across the mammalian ER is believed to be coupled to protein synthesis. In this study we show that opsin, within a range of nascent peptide lengths, targets and translocates equally efficiently co- and posttranslationally. Longer nascent opsin peptides have a lower efficiency of cotranslational translocation but an even lower efficiency of posttranslational translocation. We also show that SRP is required for both co- and posttranslational targeting.
As with many diseases, glaucoma increases in frequency in older populations, and is very often encountered in patients taking multiple medications. While the exact mechanism of glaucomatous optic neuropathy (GON) is not known, intraocular pressure (IOP) is thought to be central to the process, and reducing IOP is the only known effective treatment. The newer definition of glaucoma is an IOP-sensitive optic neuropathy. While large, controlled studies have indicated that reducing IOP will slow the progression of disease, the contributions of other conditions and medications have not been adequately studied. As the adverse effect profiles of medical therapies for glaucoma have improved, use of these agents has increased greatly. This has resulted in a large number of older patients taking glaucoma medications. Since topical medications can easily be overlooked in a medical history, and are for the most part well tolerated, systemic complications from these agents can be missed. In addition to being a common disease requiring treatment, glaucoma is also a model system for other degenerative diseases, and many of the concepts originally developed in relation to neurodegenerative diseases such as Alzheimer's disease are under investigation for glaucoma. These include approaches targeted towards neuroprotection and excitotoxicity.
The tight coupling between ongoing translation and translocation across the mammalian endoplasmic reticulum has made it difficult to determine the requirements that are specific for translocation. We have developed an in vitro assay that faithfully mimics the cotranslational targeting and translocation of the amino terminus of opsin without ongoing translation. Using this system we demonstrate that this post-translational targeting and translocation requires nucleotide triphosphates but not cytosolic proteins. The addition of GTP alone was sufficient to fully restore targeting. The addition of ATP was not specifically required, and nonhydrolyzable analogs of ATP that blocked 90% of the ATPase activity also had no inhibitory effect on translocation.
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