The association between intraocular pressure dynamics during dark-room prone testing and intraocular pressure over a relatively long-term follow-up period in primary open-glaucoma patients.

PURPOSE: To investigate the relationship between the dynamics of intraocular pressure (IOP) during dark-room prone testing (DRPT) and IOP over a relatively long-term follow-up period. METHODS: This retrospective study enrolled 84 eyes of 51 primary open-angle glaucoma patients who underwent DRPT for whom at least three IOP measurements made using Goldmann applanation tonometry were available over a maximum follow-up period of two years. We excluded eyes with a history of intraocular surgery or laser treatment and those with changes in topical anti-glaucoma medication during the follow-up period. In DRPT, IOP was measured in the sitting position, and after 60 min in the prone position in a dark room, IOP was measured again. In this study, IOP fluctuation refers to the standard deviation (SD) of IOP, and IOP max indicates the maximum value of IOP during the follow-up. The relationship between these parameters was analyzed with a linear mixed-effects model, adjusting for clinical parameters including age, gender, and axial length. RESULTS: IOP increased after DRPT with a mean of 6.13 ± 3.55 mmHg. IOP max was significantly associated with IOP after DRPT (ß = 0.38; p < 0.001). IOP fluctuation was significantly associated with IOP change in DRPT (ß = 0.29; p = 0.007). CONCLUSION: Our findings suggest that short-term and relatively long-term IOP dynamics are associated. Long-term IOP dynamics can be predicted by DRPT to some extent.

The relationship between equol production status and normal tension glaucoma.

PURPOSE: Equol is metabolized by intestinal bacteria from soy isoflavones and is chemically similar to estrogen. Dietary habits, such as consumption of soy products, influence equol production. A relationship between glaucoma and estrogen has been identified; here, we investigated the relationship between equol production status and glaucoma in Japan. METHODS: We recruited 68 normal-tension glaucoma (NTG) patients (male to female ratio 26:42, average age 63.0 ± 7.6 years) and 31 controls (male to female ratio 13:18, average age 66.0 ± 6.3 years) from our hospital. All women included were postmenopausal. Urinary equol concentration was quantified with the ELISA method. MD was calculated based on the Humphrey visual field. The association between MD and equol was analyzed with Spearman's rank correlation coefficient. The Mann-Whitney U test was used to compare the equol-producing (> 1 µM) and non-producing (< 1 µM) subjects. We also investigated the association between equol and glaucoma with a logistic regression analysis. RESULTS: There was a significant association between equol and MD (r = 0.36, P < 0.01) in the NTG patients. Glaucoma, represented by MD, was significantly milder in the equol-producing subjects than the non-equol producing subjects (P = 0.03). A multivariate analysis revealed the independent contributions of equol, cpRNFLT, and IOP to MD (P = 0.03, P = 0.04, and P < 0.01, respectively). CONCLUSION: Our results suggest that equol, acting through estrogen receptor-mediated neuroprotective effects, might be involved in suppressing the progression of NTG. This result also adds to evidence that glaucoma may be influenced by lifestyle.

Changes in glial cells and neurotrophic factors due to rotenone-induced oxidative stress in Nrf2 knockout mice.

Glaucoma is one of the most common causes of blindness worldwide. It is thought to be a multifactorial disease with underlying mechanisms that include mitochondrial dysfunction and oxidative stress. Here, we used NF-E2 related factor 2 (Nrf2) knockout (KO) mice, which are vulnerable to oxidative stress, to examine a neuroprotective effect against oxidative stress due to rotenone, a mitochondrial complex I inhibitor. Wild-type (WT) and Nrf2 KO mice received an oral solution of rotenone for 30 days. We then extracted the retinas and performed immunohistochemistry and quantitative RT-PCR. We also prepared a primary Müller cell culture of samples from each mouse, added 30 µM rotenone, and then measured cell viability, cytotoxicity and CellRox absorbance. We also examined gene expression. We found a significant increase in the number of 8-OHdG-positive retinal ganglion cells (RGCs) after rotenone administration in both the WT and Nrf2 KO mice. There was no difference in the number of RNA-binding protein with multiple splicing (RBPMS)-positive RGCs in the WT and Nrf2 KO mice, but Nrf2 KO mice that were given rotenone had significantly less retinal gene expression of RBPMS than Nrf2 KO mice given a control. Moreover, there was significantly higher mRNA gene expression of vimentin and glial fibrillary acidic protein (GFAP) in Nrf2 KO mice that received rotenone than WT mice that received rotenone. A statistical analysis of the in vitro experiment showed that cell viability was lower, cytotoxicity was higher, and oxidative stress was higher in the Müller cells of the Nrf2 KO mice than the WT mice. Finally, brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF) were significantly higher in the Müller cells of the Nrf2 KO mice than the WT mice. These findings suggest that in Nrf2 KO mice under oxidative stress caused by rotenone, temporary neurotrophic factors are secreted from the Müller cells, conferring neuroprotection in these cells.

Familial Paget's disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27).

INTRODUCTION: Paget's disease of bone (PDB) is a skeletal disorder characterized by disorganized bone remodeling due to abnormal osteoclasts. Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) gene encodes the receptor activator of nuclear factor kappa B (RANK), which has a critical role in osteoclast function. There are five types of rare PDB and related osteolytic disorders due to TNFRSF11A tandem duplication variants so far, including familial expansile osteolysis (84dup18), expansile skeletal hyperphosphatasia (84dup15), early-onset familial PDB (77dup27), juvenile PDB (87dup15), and panostotic expansile bone disease (90dup12). MATERIALS AND METHODS: We reviewed a Japanese family with PDB, and performed whole-genome sequencing to identify a causative variant. RESULTS: This family had bone symptoms, hyperphosphatasia, hearing loss, tooth loss, and ocular manifestations such as angioid streaks or early-onset glaucoma. We identified a novel duplication variant of TNFRSF11A (72dup27). Angioid streaks were recognized in Juvenile Paget's disease due to loss-of-function variants in the gene TNFRSF11B, and thought to be specific for this disease. However, the novel recognition of angioid streaks in our family raised the possibility of occurrence even in bone disorders due to TNFRSF11A duplication variants and the association of RANKL-RANK signal pathway as the pathogenesis. Glaucoma has conversely not been reported in any case of Paget's disease. It is not certain whether glaucoma is coincidental or specific for PDB with 72dup27. CONCLUSION: Our new findings might suggest a broad spectrum of phenotypes in bone disorders with TNFRSF11A duplication variants.

Clinical characteristics of glaucoma patients with various risk factors.

BACKGROUND: Glaucoma is multifactorial, but the interrelationship between risk factors and structural changes remains unclear. Here, we adjusted for confounding factors in glaucoma patients with differing risk factors, and compared differences in structure and susceptible areas in the optic disc and macula. METHODS: In 458 eyes with glaucoma, we determined confounding factors for intraocular pressure (IOP), central corneal thickness (CCT), axial length (AL), LSFG-measured ocular blood flow (OBF), which was assessed with laser speckle flowgraphy-measured mean blur rate in the tissue area (MT) of the optic nerve head, biological antioxidant potential (BAP), and systemic abnormalities in diastolic blood pressure (dBP). To compensate for measurement bias, we also analyzed corrected IOP (cIOP; corrected for CCT) and corrected MT (cMT; corrected for age, weighted retinal ganglion cell count, and AL). Then, we determined the distribution of these parameters in low-, middle-, and high-value subgroups and compared them with the Kruskal-Wallis test. Pairwise comparisons used the Steel-Dwass test. RESULTS: The high-cIOP subgroup had significantly worse mean deviation (MD), temporal, superior, and inferior loss of circumpapillary retinal nerve fiber layer thickness (cpRNFLT), and large cupping. The low-CCT subgroup had temporal cpRNFLT loss; the high-CCT subgroup had low cup volume. The high-AL subgroup had macular ganglion cell complex thickness (GCCT) loss; the low-AL subgroup had temporal cpRNFLT loss. The high-systemic-dBP subgroup had worse MD, total, superior, and inferior cpRNFLT loss and macular GCCT loss. The low-BAP subgroup had more male patients, higher dBP, and cpRNFLT loss in the 10 o'clock area. The high-OBF subgroup had higher total, superior and temporal cpRNFLT and macular GCCT. CONCLUSIONS: Structural changes and local susceptibility to glaucomatous damage show unique variations in patients with different risk factors, which might suggest that specific risk factors induce specific types of pathogenesis and corresponding glaucoma phenotypes. Our study may open new avenues for the development of precision medicine for glaucoma.

CHOP deletion and anti-neuroinflammation treatment with hesperidin synergistically attenuate NMDA retinal injury in mice.

Glaucoma is a leading cause of blindness worldwide and is characterized by degeneration associated with the death of retinal ganglion cells (RGCs). It is believed that glaucoma is a group of heterogeneous diseases with multifactorial pathomechanisms. Here, we investigate whether anti-inflammation treatment with an ER stress blockade can selectively promote neuroprotection against NMDA injury in the RGCs. Retinal excitotoxicity was induced with an intravitreal NMDA injection. Microglial activation and neuroinflammation were evaluated with Iba1 immunostaining and cytokine gene expression. A stable HT22 cell line transfected with an NF-kB reporter was used to assess NF-kB activity after hesperidin treatment. CHOP-deficient mice were used as a model of ER stress blockade. Retinal cell death was evaluated with a TUNEL assay. As results, in the NMDA injury group, Iba1-positive microglia increased 6 h after NMDA injection. Also at 6 h, pro-inflammatory cytokines and chemokine increased, including TNFα, IL-1b, IL-6 and MCP-1. In addition, the MCP-1 promoter-driven EGFP signal, which we previously identified as a stress signal in injured RGCs, also increased; hesperidin treatment suppressed this inflammatory response and reduced stressed RGCs. In CHOP-deficient mice that received an NMDA injection, the gene expression of pro-inflammatory cytokines, chemokines, markers of active microglia, and inflammatory regulators was greater than in WT mice. In WT mice, hesperidin treatment partially prevented retinal cell death after NMDA injury; this neuroprotective effect was enhanced in CHOP-deficient mice. These findings demonstrate that ER stress blockade is not enough by itself to prevent RGC loss due to neuroinflammation in the retina, but it has a synergistic neuroprotective effect after NMDA injury when combined with an anti-inflammatory treatment based on hesperidin.

The association between systemic oxidative stress and ocular blood flow in patients with normal-tension glaucoma.

PURPOSE: To evaluate the association between ocular blood flow and biomarkers of systemic oxidative stress, as well as the potential of these biomarkers to assess normal-tension glaucoma (NTG). METHODS: This study included 73 eyes of 73 patients with NTG. We assessed ocular blood flow by measuring mean blur rate (MBR) in the optic nerve head using laser speckle flowgraphy, both overall and separately in the vessel and tissue areas. We also measured urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and skin autofluorescence (SAF), and lastly, determined correlations between these measurements and with other clinical parameters. RESULTS: SAF was correlated with age, circumpapillary retinal nerve fiber layer thickness (cpRNFLT), mean deviation (MD), and overall MBR (P = 0.003, P = 0.013, P = 0.015 and P = 0.006, respectively). SAF and 8-OHdG were both correlated with tissue-area MBR (P = 0.006 and P = 0.010, respectively). Visual acuity, cpRNFLT, mean deviation and tissue-area MBR had a significant tendency to change with NTG severity (P = 0.014, P < 0.001, P < 0.001 and P = 0.006, respectively). Multiple regression analysis revealed that cpRNFLT and 8-OHdG were independent contributing factors to MD (P < 0.001 and P = 0.040, respectively), and that cpRNFLT and 8-OHdG were independent contributing factors to tissue-area MBR (P = 0.005 and P = 0.028, respectively). CONCLUSIONS: We found a close relationship between cpRNFLT, MD, tissue MBR, SAF and 8-OHdG, suggesting that systemic oxidative stress is associated with decreased ocular blood flow and may be involved in the pathogenesis of NTG.

Quantification of the filtering bleb's structure with anterior segment optical coherence tomography.

BACKGROUND: The aim of the study is to determine the relationship between post-trabeculectomy bleb structure evaluated using anterior segment optical coherence tomography (AS-OCT) and postoperative intraocular pressure (IOP). DESIGN: Rretrospective is showed for the design of this study. PARTICIPANTS: There are twenty-seven eyes of 27 trabeculectomy patients. METHODS: We drew contour lines for the bleb and cleft on 8-radius-scanned AS-OCT images, and determined correlations of AS-OCT measurements to postoperative IOP at 6 months. MAIN OUTCOME MEASURES: The parameter used in this study is an anterior segment optical coherence tomography measurements of bleb structure, including cleft volume, wall volume, and the brightness of the bleb wall. RESULTS: We found significant correlations between postoperative IOP at 6 months and cleft volume at 3 and 6 months (r = -0.56, P = 0.007 and r = -0.82, P <0.001), bleb wall volume at 6 months (r = -0.48, P = 0.042), bleb vertical brightness at 3 and 6 months (r = 0.73, P < 0.001 and r = 0.49, P = 0.040), and bleb horizontal brightness at 1 week, 2 weeks, 3 months and 6 months (r = 0.49, P = 0.016, r = 0.65, P < 0.001, r = 0.52, P = 0.013 and r = 0.71, P = 0.001). A stepwise multiple regression analysis of bleb structural measurements made ≤2 weeks postoperatively showed that the strongest independent factor indicating postoperative IOP at 6 months was bleb horizontal brightness at 2 weeks (ß = 0.50, P = 0.006). CONCLUSIONS: Early postoperative AS-OCT measurements of blebs, especially horizontal brightness of the bleb wall, were associated with postoperative IOP at 6 months. AS-OCT measurements of blebs may be useful predictors of trabeculectomy outcomes.

The role of calpain in an in vivo model of oxidative stress-induced retinal ganglion cell damage.

PURPOSE: In this study, we set out to establish an in vivo animal model of oxidative stress in the retinal ganglion cells (RGCs) and determine whether there is a link between oxidative stress in the RGCs and the activation of calpain, a major part of the apoptotic pathway. MATERIALS AND METHODS: Oxidative stress was induced in the RGCs of C57BL/6 mice by the intravitreal administration of 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH, 30mM, 2µl). Control eyes were injected with 2µl of vehicle. Surviving Fluorogold (FG)-labeled RGCs were then counted in retinal flat mounts. Double staining with CellROX and Annexin V was performed to investigate the co-localization of free radical generation and apoptosis. An immunoblot assay was used both to indirectly evaluate calpain activation in the AAPH-treated eyes by confirming α-fodrin cleavage, and also to evaluate the effect of SNJ-1945 (a specific calpain inhibitor: 4% w/v, 100mg/kg, intraperitoneal administration) in these eyes. RESULTS: Intravitreal administration of AAPH led to a significant decrease in FG-labeled RGCs 7days after treatment (control: 3806.7±575.2RGCs/mm(2), AAPH: 3156.1±371.2RGCs/mm(2), P<0.01). CellROX and Annexin V signals were co-localized in the FG-labeled RGCs 24h after AAPH injection. An immunoblot assay revealed a cleaved α-fodrin band that increased significantly 24h after AAPH administration. Intraperitoneally administered SNJ-1945 prevented the cleavage of α-fodrin and had a neuroprotective effect against AAPH-induced RGC death (AAPH: 3354.0±226.9RGCs/mm(2), AAPH+SNJ-1945: 3717.1±614.6RGCs/mm(2), P<0.01). CONCLUSION: AAPH administration was an effective model of oxidative stress in the RGCs, showing that oxidative stress directly activated the calpain pathway and induced RGC death. Furthermore, inhibition of the calpain pathway protected the RGCs after AAPH administration.

Artemin augments survival and axon regeneration in axotomized retinal ganglion cells.

Artemin, a recently discovered member of the glial cell line-derived neurotrophic factor (GDNF) family, has neurotrophic effects on damaged neurons, including sympathetic neurons, dopamine neurons, and spiral ganglion neurons both in vivo and in vitro. However, its effects on retinal cells and its intracellular signaling remain relatively unexplored. During development, expression of GFRα3, a specific receptor for artemin, is strong in the immature retina and gradually decreases during maturation, suggesting a possible role in the formation of retinal connections. Optic nerve damage in mature rats causes levels of GFRα3 mRNA to increase tenfold in the retina within 3 days. GFRα3 mRNA levels continue to rise within the first week and then decline. Artemin, a specific ligand for GFRα3, has a neuroprotective effect on axotomized retinal ganglion cells (RGCs) in vivo and in vitro via activation of the extracellular signal-related kinase- and phosphoinositide 3-kinase-Akt signaling pathways. Artemin also has a substantial effect on axon regeneration in RGCs both in vivo and in vitro, whereas other GDNF family members do not. Therefore, artemin/GFRα3, but not other GDNF family members, may be of value for optic nerve regeneration in mature mammals.

Critical neuroprotective roles of heme oxygenase-1 induction against axonal injury-induced retinal ganglion cell death.

Although axonal damage induces significant retinal ganglion cell (RGC) death, small numbers of RGCs are able to survive up to 7 days after optic nerve crush (NC) injury. To develop new treatments, we set out to identify patterns of change in the gene expression of axonal damage-resistant RGCs. To compensate for the low density of RGCs in the retina, we performed retrograde labeling of these cells with 4Di-10ASP in adult mice and 7 days after NC purified the RGCs with fluorescence-activated cell sorting. Gene expression in the cells was determined with a microarray, and the expression of Ho-1 was determined with quantitative PCR (qPCR). Changes in protein expression were assessed with immunohistochemistry and immunoblotting. Additionally, the density of Fluoro-gold-labeled RGCs was counted in retinas from mice pretreated with CoPP, a potent HO-1 inducer. The microarray and qPCR analyses showed increased expression of Ho-1 in the post-NC RGCs. Immunohistochemistry also showed that HO-1-positive cells were present in the ganglion cell layer (GCL), and cell counting showed that the proportion of HO-1-positive cells in the GCL rose significantly after NC. Seven days after NC, the number of RGCs in the CoPP-treated mice was significantly higher than in the control mice. Combined pretreatment with SnPP, an HO-1 inhibitor, suppressed the neuroprotective effect of CoPP. These results reflect changes in HO-1 activity to RGCs that are a key part of RGC survival. Upregulation of HO-1 signaling may therefore be a novel therapeutic strategy for glaucoma.

Mobile infrared slit-light scanner for rapid eye disease screening.

Purpose: Timely detection and treatment of visual impairments and age-related eye diseases are essential for maintaining a longer, healthier life. However, the shortage of appropriate medical equipment often impedes early detection. We have developed a portable self-imaging slit-light device utilizing NIR light and a scanning mirror. The objective of our study is to assess the accuracy and compare the performance of our device with conventional nonportable slit-lamp microscopes and anterior segment optical coherence tomography (AS-OCT) for screening and remotely diagnosing eye diseases, such as cataracts and glaucoma, outside of an eye clinic. Approach: The NIR light provides an advantage as measurements are nonmydriatic and less traumatic for patients. A cross-sectional study involving Japanese adults was conducted. Cataract evaluation was performed using photographs captured by the device. Van-Herick grading was assessed by the ratio of peripheral anterior chamber depth to peripheral corneal thickness, in addition to the iridocorneal angle using Image J software. Results: The correlation coefficient between values obtained by AS-OCT, and our fabricated portable scanning slit-light device was notably high. The results indicate that our portable device is equally reliable as the conventional nonportable slit-lamp microscope and AS-OCT for screening and evaluating eye diseases. Conclusions: Our fabricated device matches the functionality of the traditional slit lamp, offering a cost-effective and portable solution. Ideal for remote locations, healthcare facilities, or areas affected by disasters, our scanning slit-light device can provide easy access to initial eye examinations and supports digital eye healthcare initiatives.

The Relationship Between Artificial Intelligence-Assisted OCT Angiography-Derived Foveal Avascular Zone Parameters and Visual-Field Defect Progression in Eyes with Open-Angle Glaucoma.

Purpose: To investigate clinical factors associated with foveal avascular zone (FAZ) parameters obtained using OCT angiography (OCTA) with assistance from a previously developed artificial intelligence (AI) platform in eyes with open-angle glaucoma (OAG). Design: Retrospective longitudinal. Participants: This study followed up 885 eyes of 558 patients with OAG for ≥ 2 years; all eyes underwent ≥ 5 Humphrey visual-field (VF) tests and had 3.0 × 3.0 mm macular OCTA scans available. Methods: Average total deviation (TD) in the superior, superocentral, inferocentral, and inferior sectors of the Humphrey 24-2 program was calculated. We collected 3.0 × 3.0 mm macular OCTA images from each patient and used a previously developed AI platform with these images to obtain FAZ parameters, including FAZ area, FAZ circularity index (CI), and FAZ perimeter. Multivariable linear mixed-effects models were used to analyze the relationship between FAZ parameters, TD or TD slope in each quadrant, and systemic factors, adjusting for potential confounding factors, including axial length. Main Outcome Measures: Ophthalmic and systemic variables, FAZ parameters, and TD or TD slope in each quadrant. Results: The multivariable model showed that FAZ parameters were correlated with both TD and TD slope in the inferocentral quadrant (ß = -0.244 - 0.168, P < 0.001). Both upper-half and lower-half FAZ parameters were better associated with TD-inferocentral and TD-inferocentral slope than TD-superocentral or TD-superocentral slope in terms of ß size and statistical significance, indicating that there was no evident vertical anatomical correspondence between TD in the central quadrant and FAZ parameters. Foveal avascular zone area enlargement was associated with female gender (ß = 0.242, P = 0.003). Loss of FAZ circularity was associated with both aging and comorbid sleep apnea syndrome (SAS) (yes: 1, no: 0) (ß = -0.188, P < 0.001; ß = -0.261, P = 0.031, respectively). Foveal avascular zone perimeter elongation was associated with aging and female gender (ß = 0.084, P = 0.040; ß = 0.168, P = 0.042, respectively). Conclusions: Artificial intelligence-assisted OCTA-measured FAZ enlargement and irregular shape might be good markers of ocular hypoperfusion and associated inferocentral VF defect progression in eyes with OAG. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

The Effect of ß-Blocker Eye Drops on Pulse Rate, Ocular Blood Flow, and Glaucoma Progression: A Retrospective Longitudinal Study.

INTRODUCTION: Our study was conducted to determine factors associated with the effectiveness of a ß-blocker eye drop add-on in altering pulse rate (PR) in glaucoma patients. METHODS: This retrospective study examined 236 eyes of 138 patients who received a ß-blocker eye drop add-on during follow-up. Patients were included if at least one PR measurement was available both before and after the add-on was started. We collected data on ophthalmic parameters: longitudinal PR; longitudinal choroidal blood flow, represented by laser speckle flowgraphy-measured mean blur rate (MBR); and diacron-reactive oxygen metabolites (d-ROMs). We used a multivariable linear mixed-effects model to investigate the effectiveness of the ß-blocker eye drop add-on in altering PR and examined factors contributing to a larger PR alteration after the add-on was started by analyzing the effect on PR of the interaction term between the add-on and clinical factors. We used the k-means method to classify the patients. RESULTS: The ß-blocker eye drop add-on reduced PR (- 7.61 bpm, P < 0.001). Female gender, higher PR when the add-on was started, lower central corneal thickness, and a higher d-ROM level were associated with greater reduction in PR (P < 0.05). In a cluster of patients with these clinical features, choroidal MBR increased by + 3.42% when we adjusted for change over time; MD slope, which represents the speed of glaucoma progression, improved by + 0.64 dB/year (P < 0.05). CONCLUSIONS: We identified a glaucoma subgroup in which PR decreased, choroidal blood flow increased, and glaucoma progression slowed after a ß-blocker eye drop add-on was started.

Sector-specific Association of Intraocular Pressure Dynamics in Dark-room Prone Testing and Visual Field Defect Progression in Glaucoma.

PURPOSE: To investigate sectoral differences in the relationship between intraocular pressure (IOP) dynamics during dark-room prone testing (DRPT) and visual field (VF) defect progression in primary open-angle glaucoma (POAG) patients. DESIGN: Retrospective, longitudinal study. PARTICIPANTS: This retrospective study included 116 eyes of 84 POAG patients who underwent DRPT and had at least 5 reliable VF tests conducted over a more than 2-year follow-up period. We excluded eyes with mean deviation worse than -20 dB or a history of intraocular surgery or laser treatment. METHODS: Average total deviation (TD) was calculated in the superior, central, and inferior sectors of the Humphrey 24-2 or 30-2 program. During DRPT, IOP was measured in the sitting position, and after 60 minutes in the prone position in a dark room, IOP was measured again. The relationship between IOP change during DRPT, IOP after DRPT, and TD slope in each quadrant was analyzed with a linear mixed-effects model, adjusting for other potential confounding factors. MAIN OUTCOME MEASURES: Total deviation slope in each quadrant, IOP change during DRPT, and IOP after DRPT. RESULTS: Intraocular pressure after DRPT and IOP change during DRPT were 18.16 ± 3.42 mmHg and 4.92 ± 3.12 mmHg, respectively. Superior TD slope was significantly associated with both IOP after DRPT (ß = -0.28, P = 0.003) and IOP change during DRPT (ß = -0.21, P = 0.029), while central (ß = -0.05, P = 0.595; ß = -0.05; P = 0.622) and inferior (ß = 0.05, P = 0.611; ß = 0.01, P = 0.938) TD slopes were not. CONCLUSION: Dark-room prone testing might be a useful test to predict the risk of superior VF defect progression in eyes with POAG. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Critical role of Nrf2 in oxidative stress-induced retinal ganglion cell death.

NF-E2 related factor 2 (Nrf2) is a key transcription factor that plays a pivotal role in endogenous protection against oxidative stress. However, the role of Nrf2 in visual disorders remains unclear. It has been reported that oxidative stress is thought of as one of the causes of glaucoma. Here, we investigate whether the function of Nrf2 in oxidative stress-induced retinal ganglion cell (RGC) death. This study used adult male Nrf2 deficient mice (Nrf2 KO) and age- and sex-matched wild-type (WT) mice. We dissociated and purified N-4-[4-didecylaminostryryl]-N-methyl-pyridinium iodide-labeled RGCs with fluorescence-activated cell sorting, and tried to detect the Nrf2 and Keap1 genes. In the absence of nerve crush (NC), the number of RGCs in Nrf2 KO mice was almost same as that in WT mice. 1-(2-cyano-3-, 12-dioxooleana-1, 9 (11)-dien-28-oyl) imidazole (CDDO-Im), an Nrf2 activator, prevented NC-induced loss of RGCs in WT mice. Seven days after NC, without treatment, the number of RGCs in Nrf2 KO mice was significantly lower than in WT mice. In addition, after CDDO-Im treatment, quantitative RT-PCR showed increased expression of antioxidant and phase II detoxifying enzymes. These results suggest that up-regulation of Nrf2 signaling after CDDO-Im treatment may be a novel therapeutic strategy for the protection of RGCs, especially in glaucoma. This study suggests that NF-E2 related factor 2 (Nrf2), a transcription factor, plays a pivotal role in counteracting oxidative stress. Most importantly, a neuroprotective effect against oxidative stress-induced retinal ganglion cell (RGC) death was achieved with the pharmacological Nrf2 activator CDDO-Im. This suggests that pharmacological treatment to up-regulate Nrf2 signaling may be a new therapeutic technique to protect RGCs.