Potentially compromised systemic and local lactate metabolic balance in glaucoma, which could increase retinal glucose and glutamate concentrations.

To investigate the association between lactate metabolism and glaucoma, we conducted a multi-institutional cross-sectional clinical study and a retinal metabolomic analysis of mice with elevated intraocular pressure (IOP) induced by intracameral microbead injection. We compared lactate concentrations in serum and aqueous humor in age-matched 64 patients each with primary open-angle glaucoma (POAG) and cataract. Neither serum nor aqueous humor lactate concentrations differed between the two groups. Multiple regression analysis revealed that only body mass index showed a significant positive correlation with serum and aqueous humor lactate concentration in POAG patients (rs = 0.376, P = 0.002, and rs = 0.333, P = 0.007, respectively), but not in cataract patients. L-Lactic acid was one of the most abundantly detected metabolites in mouse retinas with gas chromatography and mass spectrometry, but there were no significant differences among control, 2-week, and 4-week IOP elevation groups. After 4 weeks of elevated IOP, D-glucose and L-glutamic acid ranked as the top two for a change in raised concentration, roughly sevenfold and threefold, respectively (ANOVA, P = 0.004; Tukey-Kramer, P < 0.05). Glaucoma may disrupt the systemic and intraocular lactate metabolic homeostasis, with a compensatory rise in glucose and glutamate in the retina.

Effects of Elevated Intraocular Pressure on Retinal Ganglion Cell Density and Expression and Interaction of Retinal Aquaporin 9 and Monocarboxylate Transporters.

INTRODUCTION: Astrocyte-to-neuron lactate shuttle (ANLS) plays an important role in the energy metabolism of neurons, including retinal ganglion cells (RGCs). Aquaporin 9 (AQP9), which is an aquaglyceroporin that can transport lactate, may be involved in ANLS together with monocarboxylate transporters (MCTs) to maintain RGC function and survival. This study aimed to investigate the impact of elevated intraocular pressure (IOP) on AQP9-MCT interaction and RGC survival. METHODS: IOP was elevated in Aqp9 knock-out (KO) mice and wild-type (WT) littermates by anterior chamber microbead injection. RGC density was measured by TUBB3 immunostaining on retinal flat mounts. Immunolabeling, immunoblot, and immunoprecipitation were conducted to identify and quantitate expressions of AQP9, MCT1, MCT2, and MCT4 in whole retinas and ganglion cell layer (GCL). RESULTS: Aqp9 KO and WT mice had similar RGC density at baseline. Microbead injection increased cumulative IOP by approximately 32% up to 4 weeks, resulting in RGC density loss of 42% and 34% in WT and Aqp9 KO mice, respectively, with no statistical difference. In the retina of WT mice, elevated IOP decreased the amount of AQP9, MCT1, and MCT2 protein and changed the AQP9 immunoreactivity and reduced MCT1 and MCT2 immunoreactivities in GCL. Meanwhile, it decreased MCT1 and increased MCT2 that interact with AQP9, without affecting MCT4 expression. Aqp9 gene deletion increased baseline MCT2 expression in the GCL and counteracted IOP elevation regarding MCT1 and MCT2 expressions. CONCLUSION: The compensatory upregulation of MCT1 and MCT2 with Aqp9 gene deletion and ocular hypertension may reflect the need to maintain lactate transport in the retina for RGC survival.

Randomized Multicenter Clinical Trial Comparing 0.1% Brimonidine/0.5% Timolol Versus 1% Dorzolamide/0.5% Timolol as Adjuncts to Prostaglandin Analogues: Aibeta Crossover Study.

INTRODUCTION: This multicenter, randomized, comparative, and investigator-masked crossover clinical trial sought to compare the efficacy and tolerability of fixed combinations of 0.1% brimonidine/0.5% timolol (BTFC) versus 1% dorzolamide/0.5% timolol (DTFC) as adjunctive therapies to prostaglandin analogues. METHODS: A total of 110 patients with open-angle glaucoma or ocular hypertension previously treated with prostaglandin analogue monotherapy were randomized to receive either BTFC or DTFC as adjunctive therapy for 8 weeks. These patients were then crossed over to the alternative treatment arm for another 8 weeks. The reduction in intraocular pressure (IOP) (primary outcome), occurrence of adverse events, ocular discomfort after instillation, and patient preference (secondary outcomes) were recorded through patient interviews. RESULTS: BTFC instillation for 8 weeks reduced IOP by 3.55 mmHg, demonstrating non-inferiority to DTFC instillation (3.60 mmHg; P < 0.0001, mixed-effects model). Although adverse events were rare with both combinations, patients reported greater discomfort with DTFC than with BTFC (P < 0.0001). More patients preferred BTFC (P < 0.0001) over DTFC, as BTFC caused minimal or no eye irritation. CONCLUSION: As BTFC offered better tolerability than DTFC with comparable reduction in IOP, we recommend it as an alternative for patients who experience ocular discomfort with DTFC-prostaglandin analogue combination therapy. TRIAL REGISTRATION NUMBER: jRCTs051190125.

Patients with glaucoma who require further reduction in intraocular pressure while undergoing monotherapy with prostaglandin analogue ophthalmic solution have been prescribed two enhanced treatment options: 0.1% brimonidine/0.5% timolol fixed combination ophthalmic solution (BTFC) and 1% dorzolamide/0.5% timolol fixed combination ophthalmic solution (DTFC). The Aibeta Crossover Study Group in Japan compared the efficacy and tolerability of fixed combinations of BTFC versus DTFC when an additional fixed combination ophthalmic solution was prescribed in patients with open-angle glaucoma or ocular hypertension who had been treated with prostaglandin analogue monotherapy. We recruited 110 patients previously treated with prostaglandin analogue monotherapy at 20 clinical centers in Japan, then randomly assigned them to two alternative treatment groups: the BTFC to DTFC group or the DTFC to BTFC group, as an adjunctive therapy to prostaglandin analogues for total of 16 weeks. We compared the reduction in intraocular pressure, occurrence of side effects, eye discomfort after instillation, and patient preference between BTFC versus DTFC instillations. The intraocular pressure reduction of BTFC instillation was comparable to that of DTFC instillation, showing non-inferiority to DTFC (3.55 mmHg vs. 3.60 mmHg; P < 0.0001, mixed-effects model). Both eye drops caused few side effects; however, patients felt greater eye discomfort with DTFC than with BTFC (P < 0.0001). Because of less eye irritation, more patients preferred BTFC (P < 0.0001) over DTFC. We can recommend using BTFC for patients who feel eye discomfort with DTFC­prostaglandin analogue combination therapy.

Risk of surgical failure and hemorrhagic complications associated with antithrombotic medication in glaucoma surgery.

PURPOSE: The purpose of this retrospective study was to determine the extent to which the use of antithrombotic drugs during glaucoma surgery contributes to surgical failure and postsurgical hemorrhagic complications. METHODS: Glaucoma surgeries were categorized into three groups: trabeculotomy (TLO), trabeculectomy (TLE), and long-Tube shunt surgery (Tube). At 1 year after surgery, the following criteria for surgical success were met: intraocular pressure (IOP) in the 5-21-mmHg range, IOP reduction of at least 20% from the preoperative level, and no additional glaucoma surgeries. We compared the percentages of the success rates and hemorrhagic complications between antithrombotic medication experiencers and non-experiencers. Furthermore, we adjusted the preoperative factors between the two groups using a propensity score analysis in TLO and TLE surgeries. RESULTS: A total of 910 glaucoma surgeries were included, with TLO, TLE, and Tube accounting for 353, 444, and 113 surgeries, respectively. Preoperative antithrombotic medications were administered to 149 patients in all glaucoma surgeries: 37 patients used only anticoagulants, 102 used only antiplatelets, and 10 used both. There was no significant difference in the success rates of any of the procedures. The hemorrhagic complications (hyphema and vitreous hemorrhage rate) were significantly higher in the patients who underwent TLE and Tube. The surgical success rates of TLO and TLE were not significantly different after the two groups were matched by propensity score. CONCLUSION: The perioperative use of antithrombotic drugs did not affect success for any of the procedures. However, it increased early postoperative hemorrhagic complications for TLE and Tube.

Association of the prolonged use of anti-glaucoma medications with the surgical failure of ab interno microhook trabeculotomy.

PURPOSE: This study examined the perioperative factors affecting surgical success in ab interno microhook trabeculotomy (µTLO). METHODS: A total of 146 consecutive patients who underwent µTLO were included in this retrospective study. We performed Cox proportional hazard modelling by setting surgical success at 1 year as an objective variable. The explanatory variables included age, sex, glaucoma type, preoperative intraocular pressure (IOP), glaucoma drug score, mean deviation (MD) of the Humphrey visual field test, duration of glaucoma drug use, antithrombotic drug use, combined cataract surgery, incision range and diabetes mellitus. Additionally, we performed 1:1 matching using propensity score analysis and compared the perioperative parameters between durations of glaucoma drug use of <4.5 years and ≥ 4.5 years (50 patients each). We defined surgical success as satisfaction of all three criteria: IOP 5-21 mmHg, IOP reduction of ≥20% from the preoperative IOP and no additional glaucoma surgery. RESULTS: The Cox proportional hazard model revealed that a longer duration of anti-glaucoma medication was significantly associated with surgical failure. Propensity score matching analysis showed that the <4.5-year users of anti-glaucoma drugs had significantly higher success rates than the ≥4.5-year users (72% versus 52%; p = 0.04). CONCLUSIONS: The prolonged use of multiple glaucoma drugs adversely affected the outcome of µTLO at least at 1 year postoperatively.

The beneficial impact of filtration surgery on antiviral therapy cessation in patients with cytomegalovirus-related secondary glaucoma.

PURPOSE: Cytomegalovirus (CMV)-related keratouveitis elevates intraocular pressure (IOP). Antiviral therapy does not always control IOP and some patients do not tolerate systemic antiviral therapy because of the side effects. The purpose of this study is to evaluate the clinical characteristics of patients with CMV-related keratouveitis and determine the impact of glaucoma surgeries on the postoperative antiviral therapy regimen. METHODS: We enrolled twenty-two patients with CMV-DNA-positive keratouveitis between June 2012 and July 2019 in Kobe University Hospital. The following clinical parameters were collected: gender, age, history of previous intraocular surgery, antiviral medications, visual acuity, IOP, glaucoma drug score, corneal endothelial cells density, and the mean deviation of a Humphrey visual field test at the first visit and before and 1 year after glaucoma surgery. RESULTS: All twenty-two patients started on oral and/or topical antiviral therapy. Eighteen patients needed glaucoma surgery despite their antiviral medications. Nine patients underwent trabeculotomy (TLO) and nine underwent trabeculectomy (TLE) as the first surgical intervention. Six of patients who initially underwent TLO and two of the patients who initially underwent TLE required additional TLE within 1 year. Each of the 15 patients who underwent at least 1 TLE showed a reduction in the magnitude and variation of IOP and glaucoma drug scores and 13 patients were able to discontinue antiviral therapy. For the remaining 4 patients, IOP and inflammation were controlled but with antiviral medications. CONCLUSIONS: In patients with CMV-related keratouveitis, TLE decreases and stabilizes IOP and contributes to withdrawal from antiviral medications.

Protocol to test the efficacy and safety of frequent applications of skin electrical stimulation for Leber hereditary optic neuropathy: a single-arm, open-label, non-randomised prospective study.

INTRODUCTION: Leber hereditary optic neuropathy (LHON) is an acute or subacute inherited optic neuropathy caused by mitochondrial mutations. More than 90% of patients with LHON have one of three point mutations (ie, G3460A, G11778A and T14484C). We previously reported that a 12-week session of skin electrical stimulation (SES) with a 2-week interval significantly improved visual acuity and field tests 1 week after the last stimulation and without adverse effects in 10 cases of LHON carrying the mt DNA G11778A mutation. In the present study, we will examine the magnitude and persistence of the efficacy and presence or absence of adverse events using SES with a more frequent stimulation protocol. METHODS AND ANALYSIS: This study will be a single-arm, open-labelled, non-randomised clinical study that analyses 15 cases of LHON with G11778A mutation. All participants will take a portable SES device home and perform SES by themselves every other day for 12 weeks. The logarithm for the minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA) at 1 week after the last SES will be measured as the primary outcome. LogMAR BCVA will be measured at four and 8 weeks after the last SES treatment. The Humphrey visual field sensitivity test using size V stimulation and critical fusion frequency at 1, 4 and 8 weeks after the last SES session will be secondary outcome measurements. Slit-lamp examination, optical coherence tomography and specular microscopy will also be performed to verify the safety of SES. ETHICS AND DISSEMINATION: The protocol was approved by the Institutional Review Board at Kobe University, Japan (Approval No.C190030). This study is in progress and deserves Pre-result. All documents communicating with the ethics committee will be reposited by the researcher. Modifications to the protocol will be reviewed by the ethics committee and implemented after approval. Data monitoring will be performed by a researcher who is not involved in the study every 6 months after approval. The research summary results will be registered in the Japan Registry of Clinical Trials (jRCTs) and made available to participants in accordance with the terms described in the documents. In addition, the results of this study will be presented at domestic and international meetings and published in peer-reviewed journals within a year after data is fixed. TRIAL REGISTRATION NUMBER: jRCTs052200033.

Comparison of efficacy and early surgery-related complications between one-quadrant and two-quadrant microhook ab interno trabeculotomy: a propensity score matched study.

PURPOSE: We compared the 1-year outcomes and early surgery-related complications between 1-quadrant and 2-quadrant microhook ab interno trabeculotomy (TLO). METHODS: Medical chart extraction was performed on 47 consecutive patients with 1-quadrant incision and 37 consecutive patients with 2-quadrant incision of trabecular meshwork. Logistic regression analysis was conducted to calculate the propensity score to create a 1:1 match for a comparative analysis of 1-year postoperative success. Success was defined as postoperative intraocular pressure (IOP) between 5-21 mmHg, >20% IOP reduction from baseline, and no additional glaucoma surgery. Outcome-related covariates were age, glaucoma type, mean deviation of visual field tests, preoperative IOP, the number of preoperative glaucoma eye drops and the presence of combined cataract surgery. Thirty eyes from each group were compared. RESULTS: The median preoperative IOP was not different between the 1-quadrant and 2-quadrant groups (28.5 mmHg, quartile range 23-33.5 versus 27 mmHg, 23.3-30.0, p = 0.47). There was no difference in median postoperative IOP at 1 year (15 mmHg versus 16 mmHg, p = 0.80). The success rate was 73% in the 1-quadrant group versus 70% in the 2-quadrant group (p = 1.00). The 2-quadrant group had a significantly higher proportion of patients with transiently elevated IOP (47%) than the 1-quadrant (17%; Fisher's exact test, p = 0.02). There was no difference of hyphema formation (Fisher's exact test, p = 0.18). CONCLUSION: The 1-year success rate was not significantly different between 1- and 2-quadrant incisions of microhook TLO. However, the 2-quadrant TLO showed significantly higher proportion of post-surgical transient IOP elevation.

Granulomatosis with Polyangiitis Presenting with Bilateral Orbital Apex Syndrome.

We report a rare case of granulomatosis with polyangiitis (GPA) presenting with bilateral orbital apex syndrome (OAS). A 73-year-old woman with a history of endoscopic sinus surgery for ethmoidal sinusitis experienced a sudden decrease in visual acuity (VA) of both eyes. At the initial examination, her VA had decreased to 0.01 in the right eye and 0.03 in the left eye, and eye movement in both eyes was mildly limited in all directions. Visual field tests of both eyes showed a large central scotoma. Laboratory tests revealed an elevation of myeloperoxidase-anti-neutrophil cytoplasmic antibody. Facial computed tomography demonstrated a thickened mucosal membrane in the entire ethmoidal sinus, and the posterosuperior walls of Onodi cells filled with infiltrative lesions had thinned. Orbital magnetic resonance imaging showed severe inflammation in the orbital apex. From these clinical findings, the patient was diagnosed with GPA presenting with OAS associated with ethmoid sinusitis. Emergent endoscopic sinus surgery was performed for biopsy and debridement of the ethmoidal and sphenoid sinusitis to decompress the optic nerve. One day after endoscopic sinus surgery, the patient's VA and visual field were improved, and steroid pulse therapy was commenced postoperatively. Four days later, VA had recovered to 1.0 in both eyes, and eye movement and visual field had were improved. Although OAS is a rare manifestation, early surgical treatment should be considered when the orbital lesion presents as risk of rapid deterioration of visual function in patients with GPA.

A comparison of the 1-year surgical outcomes of ab externo trabeculotomy and microhook ab interno trabeculotomy using propensity score analysis.

OBJECTIVE: To compare the 1-year outcomes of trabeculotomy ab externo (ab externo TLO) and trabeculotomy ab interno using a microhook (ab interno TLO) for glaucoma patients using propensity score analysis. METHODS AND ANALYSIS: The medical charts of 65 consecutive patients who underwent ab externo TLO and those of 69 patients who underwent ab interno TLO were reviewed. Logistic regression analysis was conducted to calculate the propensity score using 1:1 matched analysis, which indicates the likelihood of surgical success at 12 months. We set the outcome-related covariates as age, glaucoma type, mean deviation, preoperative intraocular pressure (IOP), the number of preoperative glaucoma eye drops and the presence or absence of combined cataract surgery. Fifty eyes per each surgery group were subsequently compared. RESULTS: The mean preoperative IOP was 32.5±11.2 mm Hg in the ab externo TLO group and 28.4±7.8 mm Hg in the ab interno TLO group (p=0.08). The mean postoperative IOP at 12 months was 18.3±7.4 mm Hg in the former group and 17.8±6.3 mm Hg in the latter (p=0.91). When surgical success was defined as a postoperative IOP of between 5 and 21 mm Hg with a more than 20% IOP reduction from baseline and no additional glaucoma surgery, the rate at 12 months was 78% in the ab externo TLO group and 74% in the ab interno TLO group (p=1.00). CONCLUSION: The 1-year success rate was not significantly different between ab externo and ab interno TLO.

Efficacy for the Annual Relapse Rate after the Immunosuppressive Therapy in Patients Associated with Anti-AQP4 or Anti-MOG Antibody-Positive Optic Neuritis.

PURPOSE: Although oral prednisolone is the first-line treatment for preventing recurrent optic neuritis (ON) after the completion of acute-phase treatment, especially anti-aquaporin 4 (AQP4) antibody-positive ON, and anti-myelin oligodendrocyte glycoprotein (MOG) antibody-positive ON, some patients experience relapses. Immunosuppressants could be effective in reducing the recurrence rate for neuromyelitis optica spectrum disorder and MOG antibody-related diseases, but there have been few studies addressing this issue focusing on the changes in ophthalmic parameters. The objective of the study was to analyze the impact of off-label uses of immunosuppressants to reduce recurrent ON. DESIGN: Retrospective observational study, clinical case series. METHODS: We reviewed the medical charts of 11 cases (22 eyes) who underwent immunosuppressive therapy in Kobe University Hospital and compared the annualized relapse rate (ARR) before and after immunosuppressive therapy. We also evaluated the dosage of prednisolone, complications of immunosuppressants, and other visual functional ophthalmologic parameters. RESULTS: Eleven cases in total had AQP4 antibody (9 cases) and/or MOG antibody (3 cases). One case was double positive for these antibodies. Nine patients received azathioprine and two received mycophenolate mofetil as an initial immunosuppressive therapy. The median duration of immunosuppressant treatment was 2.8 years. The median ON ARR before immunosuppressive therapy was 0.33, and this decreased significantly to 0 after the therapy (p = 0.02). The dose of prednisolone was reduced from 17.8 ± 7.1 mg/day before to 5.8 ± 2.2 mg/day after immunosuppressive therapy (p < 0.01). Although two patients presented with mild elevation of liver enzymes and nausea, all patients were able to continue taking the immunosuppressants. CONCLUSIONS: Immunosuppressants can potentially decrease relapses and steroid dosage in patients with anti-AQP4 or MOG antibody-positive ON without severe adverse events and the exacerbation of visual acuities.

Specific interactions between Dicer-like proteins and HYL1/DRB-family dsRNA-binding proteins in Arabidopsis thaliana.

Proteins that specifically bind double-stranded RNA (dsRNA) are involved in the regulation of cellular signaling events and gene expression, and are characterized by a conserved dsRNA-binding motif (dsRBM). Here we report the biochemical properties of nine such gene products, each containing one or two dsRBMs: four Arabidopsis Dicer-like proteins (DCL1-4), Arabidopsis HYL1 and four of its homologs (DRB2, DRB4, DRB5 and OsDRB1). DCL1, DCL3, HYL1 and the four HYL1 homologs exhibit significant dsRNA-binding activity, indicating that these proteins are involved in RNA metabolism. The dsRBMs from dsRBM-containing proteins (dsRBPs) also function as a protein-protein interaction domain and homo- and heterodimerization are essential for biological functioning of these proteins. We show that DRB4 interacts specifically with DCL4, and HYL1 most strongly interacts with DCL1. These results indicate that each HYL1/DRB family protein interacts with one specific partner among the four Dicer-like proteins. Localization studies using GFP fusion proteins demonstrate that DCL1, DCL4, HYL1 and DRB4 localize in the nucleus, while DRB2 is present in the cytoplasm. Subcellular localizations of HYL1, DRB4, DCL1 and DCL4 further strengthen the notion that HYL1 and DCL1, and DRB4 and DCL4, exist as complexes. The presented data suggest that each member of the HYL1/DRB protein family may individually modulate Dicer function through heterodimerization with a Dicer-like protein in vivo.