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 glauco ma. 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.
This Article contains errors in the Reference list. Reference 26 is incorrectly listed as ‘Cook, J. R. D., Diego, S., Kubelick, Kelsey, P., Luci, Jeffrey, Emelianov, Stanislav, Y. in SPIE BiOS.’ The correct reference 26 appears below as ref. 1. Additionally, reference 27 is incorrectly listed as ‘Kubelick, K. P., Snider, E. J., Ethier, C. R. & Emelianov, S. Photoacoustic Properties of the Anterior Eye. Journal of Biomedical Optics (In Preparation) (2017).’ The correct reference 27 appears below as ref. 2.
Uveal melanoma is the most common primary intraocular malignancy. A vast majority of metastasizing tumors have mutations in the BAP1 gene. Here, we investigate the spatiotemporal timing of these mutations. The size of 177 uveal melanomas and 8.3 million individual tumor cells was measured. BAP1 sequencing results and BAP1 IHC were available and for 76 (43%) and 101 (57%) of these, respectively. Tumors with a BAP1 mutation had significantly larger volume (2109 vs. 1552 mm3, p = 0.025). Similarly, tumor cells with loss of BAP1 protein expression had significantly larger volume (2657 vs. 1593 μm3, p = 0.027). Using observations of the time elapsed between mitoses, the BAP1 mutation was calculated to occur when the primary tumor had a size of a few malignant cells to 6 mm3, 0.5 to 4.6 years after tumor initiation and at least 9 years before diagnosis. We conclude that BAP1 mutations occur early in the growth of uveal melanoma, well before the average tumor is diagnosed. Its timing coincides with the seeding of micrometastases.
by
Lawrence C. Tam;
Ester Reina-Torres;
Joseph M. Sherwood;
Paul S. Cassidy;
Darragh E. Crosbie;
Elke Luetjen-Drecoll;
Cassandra Fluegel-Koch;
Kristin Perkumas;
Marian M. Humphries;
Anna-Sophia Kiang;
Jeffrey O'Callaghan;
John J. Callanan;
A. Thomas Read;
Christopher Ethier;
Colm O'Brien;
Matthew Lawrence;
Matthew Campbell;
W. Daniel Stamer;
Darryl R. Overby;
Pete Humphries
The juxtacanalicular connective tissue of the trabecular meshwork together with inner wall endothelium of Schlemm's canal (SC) provide the bulk of resistance to aqueous outflow from the anterior chamber. Endothelial cells lining SC elaborate tight junctions (TJs), down-regulation of which may widen paracellular spaces between cells, allowing greater fluid outflow. We observed significant increase in paracellular permeability following siRNA-mediated suppression of TJ transcripts, claudin-11, zonula-occludens-1 (ZO-1) and tricellulin in human SC endothelial monolayers. In mice claudin-11 was not detected, but intracameral injection of siRNAs targeting ZO-1 and tricellulin increased outflow facility significantly. Structural qualitative and quantitative analysis of SC inner wall by transmission electron microscopy revealed significantly more open clefts between endothelial cells treated with targeting, as opposed to non-targeting siRNA. These data substantiate the concept that the continuity of SC endothelium is an important determinant of outflow resistance, and suggest that SC endothelial TJs represent a specific target for enhancement of aqueous movement through the conventional outflow system.
In this work, we develop a robust, extensible tool to automatically and accurately count retinal ganglion cell axons in optic nerve (ON) tissue images from various animal models of glaucoma. We adapted deep learning to regress pixelwise axon count density estimates, which were then integrated over the image area to determine axon counts. The tool, termed AxoNet, was trained and evaluated using a dataset containing images of ON regions randomly selected from whole cross sections of both control and damaged rat ONs and manually annotated for axon count and location. This rat-trained network was then applied to a separate dataset of non-human primate (NHP) ON images. AxoNet was compared to two existing automated axon counting tools, AxonMaster and AxonJ, using both datasets.
AxoNet outperformed the existing tools on both the rat and NHP ON datasets as judged by mean absolute error, R2 values when regressing automated vs. manual counts, and Bland-Altman analysis. AxoNet does not rely on hand-crafted image features for axon recognition and is robust to variations in the extent of ON tissue damage, image quality, and species of mammal. Therefore, AxoNet is not species-specific and can be extended to quantify additional ON characteristics in glaucoma and potentially other neurodegenerative diseases.
We retrospectively evaluate the actual anterior–posterior (AP) corneal radius ratio in eyes with previous laser correction for myopia (M-LVC) according to axial length (AL) using biometry data exported from swept-source optical coherence tomography between January 2018 and October 2021 in a tertiary hospital (1018 eyes with a history of M-LVC and 19,841 control eyes). The AP ratio was significantly higher in the LVC group than in the control group. Further, it was significantly positively correlated with AL in the LVC group. We also investigated the impact of the AP ratio, AL and keratometry (K) on the absolute prediction error (APE) in 39 eyes that underwent cataract surgery after M-LVC. In linear regression analyses, there were significant correlations between APE and AL/TK, while APE and AP ratio had no correlation. The APE was significantly lower in the Barrett True-K with total keratometry (Barrett True-TK) than in the Haigis-L formula on eyes with AL above 26 mm and K between 38 and 40 D. In conclusion, in eyes with previous M-LVC, AP ratio increases with AL. The Barrett True-K or Barrett True-TK formulas are recommended rather than Haigis-L formula in M-LVC eyes with AL above 26 mm and K between 38 and 40D.