A systematically derived overview of the non-ubiquitous pathways and genes that define the molecular and genetic signature of the healthy trabecular meshwork.

PURPOSE: The trabecular meshwork (TM) is situated in the most frontal part of the eye and is thought to play an important role in the regulation of the eye pressure. However, this tissue is rather difficult to harvest for research. The purpose of this study is therefore to integrate the existing gene expression data of the healthy TM to increase sample size and identify its signature genes and pathways. This provides a robust reference for the study of molecular disease processes and supports the selection of candidate target genes for new treatments. METHODS: A systematic search identified microarray data of healthy TM tissue. After quality control, datasets of low quality and deviating samples were excluded. Remaining individuals were jointly normalized and integrated into one database. The average gene expression of each tested gene over all individuals was calculated. The 25% genes with the highest average expression were identified as the most active genes in the healthy TM and used as input for pathway and network analysis. Additionally, ubiquitous pathways and genes were identified and excluded from the results. Lastly, we identified genes which are likely to be TM-specific. RESULTS: The gene expression data of 44 individuals, obtained from 18 datasets, were jointly normalized. Ubiquitous genes (n = 688) and ubiquitous pathways (n = 73) were identified and excluded. Following, 1882 genes and 211 pathways were identified as the signature genes and pathways of the healthy TM. Pathway analysis revealed multiple molecular processes of which some were already known to be active in the TM, for example extracellular matrix and elastic fiber formation. Forty-six candidate TM-specific genes were identified. These consist mainly of pseudogenes or novel transcripts of which the function is unknown. CONCLUSIONS: In this comprehensive meta-analysis we identified non-ubiquitous genes and pathways that form the signature of the functioning of the healthy TM. Additionally, 46 candidate TM-specific genes were identified. This method can also be used for other tissues that are difficult to obtain for study.

The Molecular Processes in the Trabecular Meshwork After Exposure to Corticosteroids and in Corticosteroid-Induced Ocular Hypertension.

Purpose: To identify processes that contribute to corticosteroid-induced ocular hypertension and candidate target genes for treatment. Methods: A systematic search identified five human microarray datasets investigating the effect of dexamethasone versus a control medium on trabecular meshwork (TM) tissue. After thorough quality control, samples of low quality were removed, and the datasets were integrated. Additionally, a bovine RNA-sequencing dataset allowed to investigate differences in gene expression profiling between cows with and without corticosteroid-induced ocular hypertension (responders vs. nonresponders). The obtained datasets were used as input for parallel pathway analyses. Significantly changed pathways were clustered into functional categories and the results were further investigated. A network visualizing the differences between the responders and nonresponders was created. Results: Seven functional pathway clusters were found to be significantly changed in TM cells exposed to dexamethasone versus a control medium and in TM cells of responders versus nonresponders: collagen, extracellular matrix, adhesion, WNT-signaling, inflammation, adipogenesis, and glucose metabolism. In addition, cell cycle and senescence were only significantly changed in responders versus nonresponders. The network of the differential gene expression between responders and nonresponders shows many connections between the identified processes via shared genes. Conclusions: Nine functional pathway clusters synthesize the molecular response to dexamethasone exposure in TM cells and are likely to be involved in the pathogenesis of corticosteroid-induced ocular hypertension.

Risk Factors for the Development of Ocular Hypertension After Keratoplasty: A Systematic Review.

PURPOSE: To identify risk factors for the development of ocular hypertension after keratoplasty. METHODS: A systematic search in PubMed and Embase identified 67 relevant articles published between January 1990 and 2019. We preferentially searched for data on an intraocular pressure increase above 21 mmHg at 6 months or a threshold or time point close to that and reported whether the preoperative or intraoperative status of risk factors was defined. The results were presented in evidence tables, visualizing the direction of the association, whether univariate and/or multivariate analysis was performed, and the significance level (P < 0.05). Four researchers, blinded for the risk factors, independently assigned a level of evidence (definitely, probably, possibly, not associated). Consensus was met during group meetings. RESULTS: From the 110 studied risk factors, pre-existing glaucoma, high preoperative IOP and combined keratoplasty with removal or exchange of an intraocular lens (IOL) were definitely associated with an increased risk. In addition, if the pre-or postoperative lens status was undefined, aphakia and pseudophakia with the IOL in the anterior or posterior chamber were also definitely associated with an increased risk when compared to phakia. Glaucoma in the contralateral eye, indication of bullous keratopathy, African American descent, preoperative treatment with cyclosporine or olopatadine 0.1%, postoperative treatment with prednisolone acetate 1%, and combined surgery in general (ie, the type of surgeries undefined in primary studies) were probably associated. Multiple other identified risk factors lack sufficient evidence and need additional investigation. CONCLUSIONS: Risk factors with a definite association can help clinicians select patients at risk and adjust their follow-up and treatment. The other factors need further investigation.

Comprehensive bioinformatics analysis of trabecular meshwork gene expression data to unravel the molecular pathogenesis of primary open-angle glaucoma.

PURPOSE: Performing bioinformatics analyses using trabecular meshwork (TM) gene expression data in order to further elucidate the molecular pathogenesis of primary open-angle glaucoma (POAG), and to identify candidate target genes. METHODS: A systematic search in Gene Expression Omnibus and ArrayExpress was conducted, and quality control and preprocessing of the data was performed with ArrayAnalysis.org. Molecular pathway overrepresentation analysis was performed with PathVisio using pathway content from three pathway databases: WikiPathways, KEGG and Reactome. In addition, Gene Ontology (GO) analysis was performed on the gene expression data. The significantly changed pathways were clustered into functional categories which were combined into a network of connected genes. RESULTS: Ninety-two significantly changed pathways were clustered into five functional categories: extracellular matrix (ECM), inflammation, complement activation, senescence and Rho GTPase signalling. ECM included pathways involved in collagen, actin and cell-matrix interactions. Inflammation included pathways entailing NF-κB and arachidonic acid. The network analysis showed that several genes overlap between the inflammation cluster on the one hand, and the ECM, complement activation and senescence clusters on the other hand. GO analysis, identified additional clusters, related to development and corticosteroids. CONCLUSION: This study provides an overview of the processes involved in the molecular pathogenesis of POAG in the TM. The results show good face validity and confirm findings from histological, biochemical, genome-wide association and transcriptomics studies. The identification of known points of action for drugs, such as Rho GTPase, arachidonic acid, NF-κB, prostaglandins and corticosteroid clusters, supports the value of this approach to identify potential drug targets.

Corneal endothelial cell loss after Baerveldt glaucoma drainage device implantation in the anterior chamber.

PURPOSE: To investigate central and peripheral corneal endothelial cell density (ECD) in relation to Baerveldt (BV) glaucoma drainage device (GDD) tube corneal (TC) distance. METHODS: Prospective study of all patients scheduled for glaucoma tube surgery with 36 months follow-up. A BV GDD was inserted into the anterior chamber (AC). Anterior segment optical coherence tomography (AS-OCT) scans were made to determine the TC distance. Central and peripheral ECD was measured, preoperatively and at 3, 6, 12, 24 and 36 months postoperatively. RESULTS: Fifty-three eyes were included [primary open-angle glaucoma, (n = 13); secondary glaucoma, (n = 30); and primary angle-closure glaucoma, (n = 10)]. Central ECD significantly decreased during follow-up, with a mean decrease of 4.54% per year (p < 0.001), and 6.57% in the peripheral quadrant closest to the BV GDD tube (PQC, p < 0.001). In the PQC, a yearly decrease of 1.57% was shown after transiridial tube placement versus 7.43% after placement 'free' into the AC (p = 0.006). Endothelial cell (EC) loss was related to TC distance (mean 1.69 mm), with a central loss of 6.20% and 7.25% in the PQC per year with shorter TC distances, versus a central loss of 4.11% and 5.77% in the PQC per year with longer TC distances (outside mean ± 2SD, p < 0.001). A difference in EC loss by glaucoma subtype was not identified. CONCLUSION: The TC distance is of significant influence on corneal ECD, a shorter TC distance causing more severe EC loss, especially in the PQC. Transiridial placement of the BV GDD tube seems safer than placement 'free' into the AC.

Differences in biopsychosocial profiles of diabetes patients by level of glycaemic control and health-related quality of life: The Maastricht Study.

AIMS: Tailored, patient-centred innovations are needed in the care for persons with type 2 diabetes mellitus (T2DM), in particular those with insufficient glycaemic control. Therefore, this study sought to assess their biopsychosocial characteristics and explore whether distinct biopsychosocial profiles exist within this subpopulation, which differ in health-related quality of life (HRQoL). METHODS: Cross-sectional study based on data from The Maastricht Study, a population-based cohort study focused on the aetiology, pathophysiology, complications, and comorbidities of T2DM. We analysed associations and clustering of glycaemic control and HRQoL with 38 independent variables (i.e. biopsychosocial characteristics) in different subgroups and using descriptive analyses, latent class analysis (LCA), and logistic regressions. RESULTS: Included were 840 persons with T2DM, mostly men (68.6%) and with a mean age of 62.6 (±7.7) years. Mean HbA1c was 7.1% (±3.2%); 308 patients (36.7%) had insufficient glycaemic control (HbA1c>7.0% [53 mmol/mol]). Compared to those with sufficient control, these patients had a significantly worse-off status on multiple biopsychosocial factors, including self-efficacy, income, education and several health-related characteristics. Two 'latent classes' were identified in the insufficient glycaemic control subgroup: with low respectively high HRQoL. Of the two, the low HRQoL class comprised about one-fourth of patients and had a significantly worse biopsychosocial profile. CONCLUSIONS: Insufficient glycaemic control, particularly in combination with low HRQoL, is associated with a generally worse biopsychosocial profile. Further research is needed into the complex and multidimensional causal pathways explored in this study, so as to increase our understanding of the heterogeneous care needs and preferences of persons with T2DM, and translate this knowledge into tailored care and support arrangements.

Baerveldt drainage tube motility in the anterior chamber.

PURPOSE: To investigate the stability in position of the Baerveldt glaucoma drainage tube over time and to study movement of the drainage tube in the anterior chamber (AC) under varying light conditions. METHODS: This prospective study included 70 eyes with implantation of a Baerveldt glaucoma drainage tube in the anterior chamber. Anterior segment optical coherence tomography (AS-OCT) images were made preoperatively to quantify AC depth. AS-OCT images were made twice under photopic and twice under scotopic conditions, in the angle parallel to the Baerveldt tube to quantify drainage tube position, at 3, 6, 12, and 24 months postoperatively. Tube-corneal (T-C) and tube-iris (T-I) distances were measured. Additionally, the central AC depth and the peripheral angle opening (AOD 500) were determined. Two subgroups were distinguished according to tube position: free in the AC (group 1, n = 48) and transiridal (group 2, n = 22). RESULTS: After 24 months of follow-up, the drainage tube was found to move statistically significantly closer (0.12 mm) to the corneal endothelium in group 1 (p<0.01). There was no statistically significant difference in T-C distance over time in group 2. The T-C distance did not differ under photopic versus scotopic circumstances (p = 0.32). In both groups, the T-I distance was larger under scotopic conditions, a result of pupil dilation. CONCLUSIONS: The Baerveldt glaucoma drainage tube remained in a stable position when a transiridal implantation was performed, whereas the tube moved closer to the endothelium when placed free into the AC. Transiridal implantation of the Baerveldt tube seems a safe alternative for tube implantation with respect to tube motility.