Identification of genes contributing to attenuation of rat model of galactose-induced cataract by pyruvate.

Cataracts are a disease that reduces vision due to opacity formation of the lens. Diabetic cataracts occur at young age and progress relatively quickly, so the development of effective treatment has been awaited. Several studies have shown that pyruvate inhibits oxidative stress and glycation of lens proteins, which contribute to onset of diabetic cataracts. However, detailed molecular mechanisms have not been revealed. In this study, we attempted to reduce galactose-induced opacity by pyruvate with rat ex vivo model. Rat lenses were extracted and cultured in galactose-containing medium to induce lens opacity. After opacity had developed, continued culturing with pyruvate in the medium resulted in a reduction of lens opacity. Subsequently, we conducted microarray analysis to investigate the genes that contribute to the therapeutic effect. We performed quantitative expression measurements using RT-qPCR for extracted genes that were upregulated in cataract-induced lenses and downregulated in pyruvate-treated lenses, resulting in the identification of 34 candidate genes. Functional analysis using the STRING database suggests that metallothionein-related factors (Mt1a, Mt1m, and Mt2A) and epithelial-mesenchymal transition-related factors (Acta2, Anxa1, Cd81, Mki67, Timp1, and Tyms) contribute to the therapeutic effect of cataracts.

Flare levels after intravitreal injection of brolucizumab for diabetic macular edema.

PURPOSE: This study aimed to evaluate anterior flare intensity (AFI) after intravitreal injection of brolucizumab (IVBr) in patients with diabetic macular edema (DME), and to identify the factors associated with the change of AFI after IVBr. METHODS: This prospective multicenter study was conducted at five sites in Japan for patients with DME who underwent a single IVBr. AFI and central retinal thickness (CRT) were measured using a laser flare meter and spectral-domain optical coherence tomography, respectively, at weeks 0 and 6. RESULTS: Sixty-five patients (phakia, 37 eyes; pseudophakia, 28 eyes) were enrolled. Six weeks after IVBr, CRT and best-corrected visual acuity significantly improved (p < 0.0001). AFI (p = 0.0003) and age (p = 0.0054) were significantly higher in patients with pseudophakic eyes than those with phakic eyes. The AFI of the phakic eyes decreased after IVBr (p = 0.043). As the AFI before injection is higher (p = 0.0363) and the age is lower (p = 0.0016), the AFI decreases after IVBr. There was a significant positive correlation between the rates of change in CRT and AFI (p = 0.024). CONCLUSION: After IVBr, AFI decreases in phakic eyes but not in pseudophakic eyes. The age, AFI and CRT before injection and changes of CRT are involved in the change in AFI after IVBr.

Intraocular Pressure-Lowering Effect of Intraocular Lens Refixation in Patients with Elevated Intraocular Pressure Due to Intraocular Lens Subluxation.

Background and Objectives: To evaluate the surgical outcomes of intraocular lens (IOL) refixation with vitrectomy in patients with elevated intraocular pressure (IOP) due to IOL subluxation. Materials and Methods: Patients with elevated IOP due to IOL subluxation who had undergone IOL refixation with vitrectomy between 1 June 2013 and 31 December 2023 were retrospectively evaluated. The primary outcome measure was surgical success or failure. Surgical success was defined as a reduction of ≥20% in the preoperative IOP or IOP ≤ 21 mmHg (criterion A), IOP ≤ 18 mmHg (criterion B), or IOP ≤ 15 mmHg (criterion C). Reoperation, loss of light perception, and hypotony were considered as surgical failure. The IOP, number of glaucoma medications used, postoperative complications, and visual acuity were evaluated as the secondary outcomes. The surgical outcomes were compared between the glaucoma and ocular hypertension (OH) groups. Results: At 12 months postoperatively, the probability of success was 72.5%, 54.1%, and 28.4% using criterion A, B, and C, respectively, and the mean IOP and mean number of glaucoma medications used had decreased significantly (p < 0.01 and p = 0.03, respectively). Furthermore, the cumulative success rate was significantly higher in the OH group than in the glaucoma (100% vs. 47.4%; p < 0.01) when using criterion A. Additional glaucoma surgery was required only in the glaucoma group. Conclusions: IOL refixation surgery significantly decreases the IOP and number of glaucoma medications required in patients with elevated IOP due to IOL subluxation. Thus, IOL refixation surgery alone without glaucoma surgery might be effective as the primary procedure in such patients.

Intermitochondrial signaling regulates the uniform distribution of stationary mitochondria in axons.

In the central nervous system (CNS), many neurons develop axonal arbors that are crucial for information processing. Previous studies have demonstrated that premature axons contain motile and stationary mitochondria, and their balance is important for axonal arborization. However, the mechanisms by which neurons determine the positions of stationary mitochondria as well as their turnover remain to be elucidated. We observed that the distribution of stationary mitochondrial spots along the unmyelinated and nonsynaptic axons is not random but rather relatively uniform both in primary cultured neurons and in tissues. Intriguingly, whereas the positions of each mitochondrial spot changed over time, the overall distribution remained uniform. In addition, local inactivation of mitochondria by KillerRed mediated chromophore-assisted light inactivation (CALI) inhibited the translocation of mitochondrial spots in adjacent axonal regions, suggesting that functional mitochondria enhance the motility of other mitochondria in the vicinity. Signals of ATP:ADP sensor, PercevalHR indicated that the ATP:ADP ratio was relatively high around mitochondria, and treating axons with phosphocreatine (PCr), which supplies ATP, reduced the immobile mitochondria induced by the local mitochondrial inactivation. In a mathematical model, we found that the ATP gradient generated by mitochondria, and ATP dependent regulation of mitochondrial motility could establish uniform mitochondrial distribution. These observations suggest that axons in the CNS possess the system that distributes mitochondria uniformly, and intermitochondrial signaling contribute to the regulation. In addition, our results suggest the possibility that ATP might be one of the molecules mediating the signaling.

Optic Nerve Injury Enhanced Mitochondrial Fission and Increased Mitochondrial Density without Altering the Uniform Mitochondrial Distribution in the Unmyelinated Axons of Retinal Ganglion Cells in a Mouse Model.

Glaucomatous optic neuropathy (GON), a major cause of blindness, is characterized by the loss of retinal ganglion cells (RGCs) and the degeneration of their axons. Mitochondria are deeply involved in maintaining the health of RGCs and their axons. Therefore, lots of attempts have been made to develop diagnostic tools and therapies targeting mitochondria. Recently, we reported that mitochondria are uniformly distributed in the unmyelinated axons of RGCs, possibly owing to the ATP gradient. Thus, using transgenic mice expressing yellow fluorescent protein targeting mitochondria exclusively in RGCs within the retina, we assessed the alteration of mitochondrial distributions induced by optic nerve crush (ONC) via in vitro flat-mount retinal sections and in vivo fundus images captured with a confocal scanning ophthalmoscope. We observed that the mitochondrial distribution in the unmyelinated axons of survived RGCs after ONC remained uniform, although their density increased. Furthermore, via in vitro analysis, we discovered that the mitochondrial size is attenuated following ONC. These results suggest that ONC induces mitochondrial fission without disrupting the uniform mitochondrial distribution, possibly preventing axonal degeneration and apoptosis. The in vivo visualization system of axonal mitochondria in RGCs may be applicable in the detection of the progression of GON in animal studies and potentially in humans.

Role of Microaneurysms in the Pathogenesis and Therapy of Diabetic Macular Edema: A Descriptive Review.

Background and Objectives: This study aims to elucidate the role of microaneurysms (MAs) in the pathogenesis and treatment of diabetic retinopathy (DR) and diabetic macular edema (DME), the major causes of acquired visual impairment. Materials and Methods: We synthesized the relevance of findings on the clinical characteristics, pathogenesis, and etiology of MAs in DR and DME and their role in anti-vascular endothelial growth factor (VEGF) therapy. Results: MAs, a characteristic feature in DR and DME, can be detected by fluorescein angiography, optical coherence tomography (OCT) and OCT angiography. These instrumental analyses demonstrated a geographic and functional association between MA and ischemic areas. MA turnover, the production and loss of MA, reflects the activity of DME and DR. Several cytokines are involved in the pathogenesis of MAs, which is characterized by pericyte loss and endothelial cell proliferation in a VEGF-dependent or -independent manner. Ischemia and MAs localized in the deep retinal layers are characteristic of refractory DME cases. Even in the current anti-VEGF era, laser photocoagulation targeting MAs in the focal residual edema is still an effective therapeutic tool, but it is necessary to be creative in accurately identifying the location of MAs and performing highly precise and minimally invasive coagulation. Conclusions: MAs play a distinctive and important role in the pathogenesis of the onset, progression of DR and DME, and response to anti-VEGF treatment. Further research on MA is significant not only for understanding the pathogenesis of DME but also for improving the effectiveness of treatment.

Posture-Induced Intraocular Pressure Changes after iStent Inject W Combined with Phacoemulsification in Open Angle Glaucoma Patients.

Background and Objectives: The purpose of this study was to evaluate the posture-induced intraocular pressure (IOP) changes after iStent inject W combined with phacoemulsification procedure in Japanese patients with open-angle glaucoma. Materials and Methods: We prospectively evaluated the posture-induced IOP changes after surgery. The primary outcome was the posture-induced IOP changes postoperatively. Secondary outcome measures included postoperative complications, visual acuity, visual field, and corneal endothelial cell density. Results: This study completed the prospective observation for 15 eyes (15 patients). The mean preoperative IOP with the Goldmann applanation tonometer was 16.0 ± 2.6 mm Hg with a mean glaucoma medication usage of 2.5 ± 1.2, which decreased to 14.4 ± 2.4 mm Hg (p = 0.14) and 0.5 ± 0.9 medications (p < 0.01), respectively, 12 months postoperatively. The mean baseline IOP with the ICare was 12.0 ± 2.7 mmHg in the sitting position, which significantly increased to 15.2 ± 3.8 mmHg in the lateral decubitus position (p < 0.01). This postural IOP difference was 3.2 ± 2.2 mmHg and 3.2 ± 2.4 mmHg at baseline and 12 months postoperatively, respectively, with no significant changes (p > 0.99). Conclusions: iStent inject W combined with cataract surgery reduced the IOP and the number of glaucoma medications during short-term follow-ups with high safety. However, iStent inject W did not affect the degree of posture-induced IOP changes.

Association of the CYP39A1 G204E Genetic Variant with Increased Risk of Glaucoma and Blindness in Patients with Exfoliation Syndrome.

PURPOSE: Carriers of functionally deficient mutations in the CYP39A1 gene have been recently reported to have a 2-fold increased risk of exfoliation syndrome (XFS). The aim of this study was to evaluate the risk of blindness and related clinical phenotypes of XFS patients carrying the loss-of-function CYP39A1 G204E mutation in comparison with XFS patients without any CYP39A1 mutation. DESIGN: Retrospective case study. PARTICIPANTS: A total of 35 patients diagnosed with XFS carrying the CYP39A1 G204E mutation and 150 XFS patients without any CYP39A1 mutation who were randomly selected from the Japanese XFS cohort. METHODS: Two-sided Fisher exact test with an alpha level < 0.05 was used to estimate the significance of the calculated odds ratio (OR) for all categorical measures. Comparisons between groups of subjects were performed using linear mixed effect models with group as random effect and taking possible dependence between eyes within a subject into account. MAIN OUTCOME MEASURES: Primary analysis compared the incidence of blindness (defined as visual acuity [VA] < 0.05 decimal), prevalence of exfoliation glaucoma (XFG), history of glaucoma surgery, and indices of glaucoma severity such as visual field (VF) mean deviation (MD), intraocular pressure (IOP), and vertical cup-disc ratio (CDR) between CYP39A1 G204E carriers and those without any CYP39A1 mutation. RESULTS: The overall risk for blindness was significantly higher in XFS patients carrying the CYP39A1 G204E variant (10/35 [28.6%]) compared with XFS patients without any CYP39A1 mutations (8/150 [5.4%]; odds ratio [OR], 7.1; 95% confidence interval [CI], 2.7-20.2]; P < 0.001). A higher proportion of XFS patients with the CYP39A1 G204E mutation (23/35 [65.7%]) had evidence of XFG in at least 1 eye compared with the comparison group (41/150 [27.3%]; OR, 5.1; 95% CI, 2.4-11.4]; P < 0.0001). Significantly higher peak IOP, larger vertical CDR, and worse VF MD were also found in CYP39A1 G204E variant carriers (P < 0.001). Additionally, patients with the CYP39A1 G204E mutation (18/35 [51.4%]) required more laser or glaucoma surgical interventions compared with those without any CYP39A1 mutation (32/150 [21.3%], P < 0.001). CONCLUSIONS: Patients with XFS carrying the CYP39A1 G204E mutation had significantly increased risk of blindness, higher occurrence of XFG, and more severe glaucoma compared with patients with XFS without any CYP39A1 mutation.

Regional Variety of Reduction in Retinal Thickness of Diabetic Macular Edema after Anti-VEGF Treatment.

Background and Objectives: The presence of refractory cases resistant to anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME) is a problem in clinical practice. This study aimed to explore the less responsive area of optical coherence tomography (OCT) 3D map the characteristics of naïve DME cases after their first anti-VEGF. Materials and Methods: In 46 patients with DME who received an intravitreal injection of anti-VEGF agents, retinal thickness in 100 sections of the macular area was measured by 3D-mapping mode using OCT before and 1 month after injection. The density of the microaneurysm (MA) was calculated using merged images of the OCT map and fluorescein angiography. Results: One month after injection, the central retinal thickness significantly decreased (p < 0.0001). In severe edema (retinal thickness more than 500 µm), the area percentages with a reduction rate of the retinal thickness greater than 30% and less than 5% were 6.4 ± 6.6% and 10.1 ± 4.6%, respectively. The reduction rate of the retinal thickness varied from section to section. The mutual distance between the areas of maximum thickness before and after the injection averaged 1.22 ± 0.62 mm apart. The reduction rate of retinal thickness in the thickest region before injection was significantly higher (p = 0.02), and that in the thickest region after injection was lower (p = 0.001) than in the other regions. MA density in the residual edema was significantly higher than in the edema-absorbed area (p = 0.03). Conclusion: DME has areas that show low response to the reduction in retinal thickness with anti-VEGF therapy. A high density of MA may be associated with this pathogenesis.

Comparison of 5-year outcomes between trabeculectomy combined with phacoemulsification and trabeculectomy followed by phacoemulsification: a retrospective cohort study.

BACKGROUND: We aimed to compare the outcomes of trabeculectomy combined with phacoemulsification and those of trabeculectomy followed by phacoemulsification. METHODS: A total of 141 patients with primary open-angle glaucoma, exfoliation glaucoma, and glaucoma secondary to uveitis glaucoma who underwent trabeculectomy followed by (n = 48) or combined with (n = 93) phacoemulsification were included. We analyzed data collected from the Collaborative Bleb-Related Infection Incidence and Treatment Study, a prospective cohort study conducted in 34 clinical centers that included 1249 eyes. The main outcome was the cumulative probability of success based on intraocular pressure (IOP) within 5 years. Surgical failure was defined as a case in which additional glaucoma surgery is required or one of the following criteria are met: preoperative IOP > 21 (A), > 18 (B), or > 15 mmHg (C). The secondary outcomes were cumulative probability of success, risk factors of surgical failure, and Δ visual acuity. However, the data on phacoemulsification during the 5-year follow-up were censored. RESULTS: No significant difference was found in the cumulative probability of success as the main outcome. When the data on phacoemulsification during the 5-year follow-up were censored, the probabilities of success of trabeculectomy followed by phacoemulsification were significantly higher for criteria A (p = 0.02), B (p <  0.01), and C (p <  0.01). Lower preoperative IOP, younger age, and trabeculectomy combined with phacoemulsification were associated with poorer outcome. Trabeculectomy followed by phacoemulsification had significantly worse Δ logMAR visual acuity at 6 and 12 months (p <  0.01). CONCLUSION: The cumulative probability of success after trabeculectomy combined with or followed by phacoemulsification remained unchanged. Combining phacoemulsification with trabeculectomy adversely affected the cumulative probability of success after trabeculectomy. The visual acuity improvements observed in the early postoperative period after combining phacoemulsification with trabeculectomy disappeared within 5 years.