Ab-Externo MicroShunt versus Trabeculectomy in Primary Open-Angle Glaucoma: Two-Year Results from a Randomized, Multicenter Study.

PURPOSE: To compare the effectiveness and safety of the MicroShunt (Santen Inc) versus trabeculectomy in patients with primary open-angle glaucoma (POAG). DESIGN: Prospective, randomized, multicenter trial conducted in the United States and Europe. PARTICIPANTS: Adult patients (aged 40-85 years) with mild to severe POAG inadequately controlled on maximum tolerated medical therapy and intraocular pressure (IOP) ≥ 15 mmHg and ≤ 40 mmHg. METHODS: Patients were randomized 3:1 to stand-alone MicroShunt implantation (n = 395) or trabeculectomy (n = 132), both augmented with mitomycin C (MMC) 0.2 mg/ml for 2 minutes. MAIN OUTCOME MEASURES: The primary effectiveness end point was surgical success, defined as ≥ 20% reduction in mean diurnal IOP from baseline with no increase in glaucoma medications. Secondary end points included changes in mean IOP and medication use from baseline and the need for postoperative interventions. RESULTS: At 2 years, the rate of surgical success was lower in the MicroShunt group than in the trabeculectomy group (50.6% vs. 64.4%, P = 0.005). Mean diurnal IOP was reduced from 21.1 ± 4.9 mmHg at baseline to 13.9 ± 3.9 mmHg at 24 months in the MicroShunt group and from 21.1 ± 5.0 mmHg at baseline to 10.7 ± 3.7 mmHg at 24 months in the trabeculectomy group (P < 0.001 compared with baseline in both groups). Mean medication use decreased from 3.1 to 0.9 in the MicroShunt group and from 2.9 to 0.4 in the trabeculectomy group (P < 0.001 compared with baseline in both groups). Adverse events at 2 years were generally similar in the 2 groups, except that hypotony was more common in eyes undergoing trabeculectomy (51.1% vs. 30.9%, P < 0.001). Repositioning or explantation of the implant occurred in 6.8% of MicroShunt patients. The majority of these patients had device removal at the time of subsequent glaucoma surgery. Vision-threatening complications were uncommon in both groups. CONCLUSION: At 2 years, both the MicroShunt and trabeculectomy provided significant reductions in IOP and medication use, with trabeculectomy continuing to have greater surgical success. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Are Disposable and Standard Gonioscopy Lenses Comparable?

PURPOSE: Gonioscopy is important in the evaluation and treatment of glaucoma. With increased scrutiny of acceptable sterilization processes for health care instruments, disposable gonioscopy lenses have recently been introduced. Single-time use lenses are theorized to decrease infection risk and eliminate the issue of wear and tear seen on standard, reusable lenses. However, patient care would be compromised if the quality of images produced by the disposable lens were inferior to those produced by the reusable lens. The purpose of this study was to compare the quality of images produced by disposable versus standard gonioscopy lenses. MATERIALS AND METHODS: A disposable single mirror lens (Sensor Medical Technology) and a standard Volk G-1 gonioscopy lens were used to image 21 volunteers who were prospectively recruited for the study. Images of the inferior and temporal angles of each subject's left eye were acquired using a slit-lamp camera through the disposable and standard gonioscopy lens. In total, 74 images were graded using the Spaeth gonioscopic system and for clarity and quality. Clarity was scored as 1 or 2 and defined as either (1) all structures perceived or (2) all structures not perceived. Quality was scored as 1, 2, or 3, and defined as (1) all angle landmarks clear and well focused, (2) some angle landmarks clear, others blurred, or (3) angle landmarks could not be ascertained. The 74 images were divided into images taken with the disposable single mirror lens and images taken with the standard Volk G-1 gonioscopy lens. The clarity and quality scores for each of these 2 image groups were averaged and P-values were calculated. RESULTS: Average quality of images produced with the standard lens was 1.46±0.56 compared with 1.54±0.61 for those produced with the disposable lens (P=0.55). Average clarity of images produced with the standard lens was 1.47±0.51 compared with 1.49±0.51 (P=0.90) with the disposable lens. CONCLUSIONS: We conclude that there is no significant difference in quality of images produced with standard versus disposable gonioscopy lenses. Disposable gonioscopy lenses may be an acceptable alternative to standard reusable lenses, especially in conditions where sterilization is difficult.

The low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate.

BACE is a transmembrane protease with beta-secretase activity that cleaves the amyloid precursor protein (APP). After BACE cleavage, APP becomes a substrate for gamma-secretase, leading to release of amyloid-beta peptide (Abeta), which accumulates in senile plaques in Alzheimer disease. APP and BACE are co-internalized from the cell surface to early endosomes. APP is also known to interact at the cell surface and be internalized by the low density lipoprotein receptor-related protein (LRP), a multifunctional endocytic and signaling receptor. Using a new fluorescence resonance energy transfer (FRET)-based assay of protein proximity, fluorescence lifetime imaging (FLIM), and co-immunoprecipitation we demonstrate that the light chain of LRP interacts with BACE on the cell surface in association with lipid rafts. Surprisingly, the BACE-LRP interaction leads to an increase in LRP C-terminal fragment, release of secreted LRP in the media and subsequent release of the LRP intracellular domain from the membrane. Taken together, these data suggest that there is a close interaction between BACE and LRP on the cell surface, and that LRP is a novel BACE substrate.

Demonstration of BACE (beta-secretase) phosphorylation and its interaction with GGA1 in cells by fluorescence-lifetime imaging microscopy.

beta-Secretase (BACE) carries out the first of two proteolysis steps to generate the amyloid-beta peptides that accumulate in the senile plaques in Alzheimer's disease (AD). Because most BACE activity occurs in endosomes, signals regulating its trafficking to these compartments are important to an understanding of AD pathogenesis. A DISLL sequence near the BACE C-terminus mediates binding of BACE to the VHS domains of Golgi-localized gamma-ear-containing ARF-binding (GGA) proteins, which are involved in the sorting of proteins to endosomes. Phosphorylation of the motif's serine residue regulates BACE recycling back to the cell surface from early endosomes and enhances the interaction of BACE with GGA proteins in isolated protein assays. We found that BACE phosphorylation influences BACE-GGA interactions in cells using a new fluorescence-resonance-energy-transfer-based assay of protein proximity, fluorescence lifetime imaging. Although serine-phosphorylated BACE was distributed throughout the cell, interaction of GGA1 with the wild-type protein occurred in juxtanuclear compartments. Pseudo-phosphorylated and non-phosphorylated BACE mutants remained localized with GGA1 in the Golgi body, but the latter mutation diminished the two proteins' FRET signal. Because BACE phosphorylated at serine residues can be identified in human brain, these data suggest that serine phosphorylation of BACE is a physiologically relevant post-translational modification that regulates trafficking in the juxtanuclear compartment by interaction with GGA1.