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ABSTRACT Aims/Introduction To conduct a multicenter survey of visually impaired patients with diabetes mellitus (DM) and to identify the physical and ocular characteristics that lead to blindness in Japan. Materials and Methods Visually impaired patients with diabetes mellitus in Japan were divided into blind and low‐vision groups according to the World Health Organization classification. Data on parameters related to diabetes mellitus and ocular complications in the right and left eyes were collected from 19 highly advanced medical facilities and compared between the two groups. Results Among 408 visually impaired persons (blind group: 257, low‐vision group: 151), 72.1% were under 70 years of age. The rates of neovascular glaucoma (NVG) (right eye, P = 0.041; left eye, P = 0.0031) or proliferative diabetic retinopathy (PDR) (right eye: P = 0.014, left eye: P = 0.0047) and the rate of proliferative membrane beyond half of the retinal area (right eye: P = 0.0263, left eye: P = 0.037) were significantly higher in the blind group. The direct cause of visual impairment was retinal atrophy, common in both groups. Neovascular glaucoma and diabetic macular edema were equally prevalent in the blind and low‐vision groups, respectively. Conclusions In Japan, blind patients with diabetes mellitus are characterized by severe conditions such as neovascular glaucoma and progressive proliferative diabetic retinopathy upon their initial visit to an advanced care facility. These results highlight the importance of monitoring retinopathy through regular ophthalmological examinations, internal medicine, and appropriate therapeutic intervention.

Abstract Childhood maltreatment is reportedly associated with atypical gray matter structures in the primary visual cortex (V1). This study explores the hypothesis that retinal structures, the sensory organs of vision, are associated with brain atypicality and child maltreatment and examines their interrelation. General ophthalmologic examinations, visual cognitive tasks, retinal imaging, and structural magnetic resonance imaging (MRI) were conducted in children and adolescents aged 9–18 years with maltreatment experiences (CM) and typically developing (TD) children. The retinal nerve fiber layer (RNFL), the most superficial of the ten distinct retinal layers, was found to be significantly thinner in both eyes in CM. While whole-brain analysis using Voxel-based morphometry revealed a significantly larger gray matter volume (GMV) in the thalamus in CM, no significant correlation with RNFL thickness was observed. However, based on region-of-interest analysis, a thinner RNFL was associated with a larger GMV in the right V1. Although it cannot be ruled out that this outcome resulted from maltreatment alone, CM demonstrated subclinical structural atypicality in the retina, which may also correlate with the immaturity of V1 development. Examination of retinal thickness offers a novel clinical approach to capturing characteristics associated with childhood maltreatment.

Abstract Although cataract is the leading cause of blindness worldwide, the detailed pathogenesis of cataract remains unclear, and clinically useful drug treatments are still lacking. In this study, we examined the effects of glutamate using an ex vivo model in which rat lens is cultured in a galactose-containing medium to induce opacity formation. After inducing lens opacity formation in galactose medium, glutamate was added, and the opacity decreased when the culture was continued. Next, microarray analysis was performed using samples in which the opacity was reduced by glutamate, and genes whose expression increased with galactose culture and decreased with the addition of glutamate were extracted. Subsequently, STRING analysis was performed on a group of genes that showed variation as a result of quantitative measurement of gene expression by RT-qPCR. The results suggest that apoptosis, oxidative stress, endoplasmic reticulum (ER) stress, cell proliferation, epithelial-mesenchymal transition (EMT), cytoskeleton, and histones are involved in the formation and reduction of opacity. Therefore, glutamate may reduce opacity by inhibiting oxidative stress and its downstream functions, and by regulating the cytoskeleton and cell proliferation.

Purpose: To report a rare case of globe rupture with broken calcified senile scleral plaque (SSP). Observations: A 94-year-old male patient presented with left eye pain and severely decreased left vision immediately after the injury while farming. Examination of the left eye revealed edematous cornea, diffuse subconjunctival hemorrhage, total hyphema and iris prolapse. Preoperative computed tomography (CT) scan revealed calcified SSP in both eyes, and the calcified SSP was found to be broken during surgery. Although it was impossible to thread the broken calcified SSP, threading and suturing with long bites outside of the broken calcified SSP was effective for wound closure. Postoperatively, we were able to observe the broken calcified SSP and the wound closure using anterior segment optical coherence tomography (AS-OCT). Conclusions and importance: In a case of globe rupture with calcified SSP on preoperative CT, the possibility that the SSP has also ruptured should be considered. AS-OCT is also useful to observe the wound in a case of globe rupture with broken SSP during follow-up.

Abstract We demonstrated whether the difference of trabecular meshwork remodeling occur depending on the incisional cross-sectional area by comparing Kahook dual-blade goniotomy (KDB) and ab interno trabeculotomy with a microhook. Phakic eyes with primary open-angle or exfoliative glaucoma were randomised into a KDB or a microhook group. The primary outcome was an incisional cross-sectional area quantified by anterior segment optical coherence tomography. In subgroup analysis, the number of patients with the unidentifiable incisional area was compared between the groups. Secondary outcomes were the rate of intraocular pressure changes, the laser flare metre values, corneal endothelial cell densities, the number of glaucoma medications, the usage rate per glaucoma medication type and postoperative complications between the two groups. A total of 29 eyes in 29 patients in the KDB and microhook group were included respectively, with an overall mean age of 72.6 ± 8.1 years. The incisional cross-sectional area of the KDB group was significantly larger at 1 week and at 1, 6 and 12 months (p

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.

Purpose: We describe a rare case of tube obstruction caused by intraocular lens (IOL) capture following a PreserFlo MicroShunt (PMS) surgery and its subsequent management. Observations: Tube obstruction was noted following PMS implantation at 8 days postoperatively. The intraocular pressure (IOP) increased to 42 mmHg because of tube occlusion that was caused by iris and IOL capture at the tip of the tube. The occlusion was released surgically to free the lumen, and the IOP rapidly decreased to 14 mmHg. Conclusions and importance: IOP elevation due to tube obstruction caused by iris and IOL capture after PMS surgery was resolved by surgical intervention without tube reinsertion. Extra care is required regarding the IOL position in relation to the PMS tube when hypotony occurs in the early postoperative period.

Abstract Cataracts are opacifications of the lens that cause loss of visual acuity and ultimately of eyesight. Age-related cataract develops in most elderly people, but the mechanisms of cataract onset are incompletely understood. The Ihara Cataract Rat (ICR) is an animal model of hereditary cataracts showing cortical opacity that commonly develops prematurely. We identified putative mechanisms of cataract onset in the ICR rat model by measuring gene expression changes before and after cortical cataract development and conducting point mutation analysis. Genes differentially expressed between 4-week-old animals without cortical cataracts and 8–10-week-old animals with cortical cataracts were selected from microarray analysis. Three connections were identified by STRING analysis: (i) Epithelial-Mesenchymal Transition (EMT), including Col1a2, and Pik3r1. (ii) Lens homeostasis, including Aqp5, and Cpm. (iii) Lipid metabolism, including Scd1, Srebf1, and Pnpla3. Subsequently, mutation points were selected by comparing ICR rats with 12 different rats that do not develop cataracts. The apolipoprotein Apoc3 was mutated in ICR rats. Analyses of gene expression changes and point and mutations suggested that abnormalities in EMT or lipid metabolism could contribute to cataract development in ICR rats.

Abstract Introduction The factors related to the ocular penetration of drugs after the administration of eye drops in humans have not been examined in detail. Therefore, this study assessed the influence of patient factors on the intraocular penetration of eye drops. Methods A pooled analysis was performed on the data of 42 participants from three studies to evaluate the ocular pharmacokinetics in humans after the topical application of brimonidine-related eye drops. The patients were scheduled for vitrectomy and received brimonidine-related eye drops (0.1% brimonidine tartrate ophthalmic solution, 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution, or 0.1% brimonidine tartrate and 1% brinzolamide fixed-combination suspension) twice daily for 1 week. We analyzed the effects of patient factors (sex, the presence or absence of lens, age, corneal thickness, corneal endothelial cell density, tear secretion, eye axial length, height, weight and body mass index [BMI]) on brimonidine, timolol and brinzolamide concentrations in the aqueous and vitreous humor after topical application. Results The drug concentrations in the aqueous and vitreous humor were not significantly different, regardless of sex or the presence or absence of lens. Age correlated positively with brimonidine (r = 0.3948, p = 0.012) and brinzolamide (r = 0.6809, p = 0.030) concentrations in the aqueous humor; the correlation with timolol showed a trend towards significance (r = 0.6425, p = 0.086). Corneal thickness, corneal endothelial cell density, tear secretion, eye axial length, height and BMI did not correlate with the drug concentrations in the aqueous or vitreous humor. Timolol concentration in the vitreous humor was negatively correlated with weight (r = − 0.8333, p = 0.010). Conclusion The findings of this study emphasize the necessity of considering individual differences in ocular pharmacokinetics during drug therapy (formulation design of the eye drops and dose regimen).

Abstract This study evaluated the long-term surgical outcomes of Baerveldt glaucoma implant (BGI) surgery in patients with refractory glaucoma (204 eyes/204 patients). Surgical failure was defined by: 21 mmHg), criterion B (IOP > 17 mmHg), or criterion C (IOP > 14 mmHg). Reoperation, loss of light perception vision, or hypotony also denoted failure. The probability of success at 5 years postoperatively using criteria A, B, and C was 72.4%, 49.7%, and 24.4%, respectively. The mean IOP decreased significantly from 32.7 ± 9.7 mmHg preoperatively to 13.1 ± 3.9 mmHg at 5 years; the mean number of glaucoma medications also decreased from 3.7 ± 1.2 to 1.8 ± 1.9 (both P

Abstract The coronavirus disease (COVID-19) pandemic has led to a dramatic increase in facemask use. Consequently, it has been reported that exhaled airflow toward the eyes can cause the dispersal of bacteria into the eyes, potentially increasing the incidence of postoperative endophthalmitis. In addition to wearing a facemask, gaps between the surgical drape and skin can also direct exhaled airflow toward the eyes. Here, we aimed to examine how the risk of contamination varies depending on the state of the drapes. We used a carbon dioxide imaging camera to visualize changes in exhaled airflow under different drape conditions and a particle counter to evaluate changes in the number of particles around the eye. The results revealed airflow present around the eye and a significant increase in the number of particles when the nasal side of the drape was detached from the skin. However, when a metal rod called “rihika” was used to create space above the body, the airflow and number of particles were significantly reduced. Thus, if drape coverage becomes incomplete during surgery, exhaled airflow toward the eye may contaminate the surgical field. On hanging up the drape, airflow can escape in the direction of the body, potentially preventing contamination.

Abstract This study aimed to quantify the changes in corneal higher-order aberrations (HOAs) before and after treatment for infectious keratitis and verify the correlation between corneal HOAs and visual acuity. Corneal HOAs were analysed using swept-source anterior segment optical coherence tomography (AS-OCT). Ninety-eight eyes of 96 consecutive patients with infectious keratitis treated with topical eye drops were retrospectively evaluated. Corneal HOAs increased with the infection but decreased with infection resolution following antimicrobial treatment. Corneal HOAs became larger as the degree of corneal findings became more severe. The increase in HOAs of the total cornea was correlated with the decrease in visual acuity both before and after treatment (4 mm, ρ = 0.530 and 0.590; 6 mm, ρ = 0.479 and 0.567, respectively; all P

Abstract To investigate whether the topical administration of ripasudil ophthalmic solution enhances aqueous outflow in the episcleral vein of the human eye. Two-sequence, prospective, randomized, double-blind, crossover trial. Sixteen eyes of 16 healthy participants were recruited in this study. Participants were randomized into one of the two crossover sequences to the instillation of ripasudil or the control drug, latanoprost, followed by a washout period of more than 2 days, and crossed over to the alternative instillation. The aqueous columns in the episcleral veins were recorded using a video capture system connected to a slit-light microscope (hemoglobin video imaging) before and 2 and 8 h after the instillation. Comparisons between ripasudil and latanoprost for the changes of the aqueous column width after the instillation. Two hours after the instillation, the ripasudil group had significantly greater dilation of the aqueous column width than the latanoprost group. Eight hours after the instillation, the ripasudil group had significantly greater dilation of the aqueous column width than the latanoprost group. Hemoglobin video imaging revealed that the topical administration of ripasudil ophthalmic solution enhanced aqueous outflow in the episcleral vein of the human eye.

Abstract Silicone oil (SO) is a safe and widely used intraocular tamponade agent for treating complicated vitreoretinal diseases, such as retinal detachments (RRDs) with inferior proliferative vitreoretinopathy (PVR). However, as the human vitreous cavity is irregularly shaped, it is difficult to predict the area of the inferior retina covered with SO and the retro-oil fluid currents in each patient. Here, we performed fluid simulation analysis using the moving particle semi-implicit method on the oil cover rates and absolute velocity gradient of retro-oil fluid to the retina using vitreous cavity models derived from magnetic resonance imaging of patients to determine the appropriate amount of SO and postoperative position to achieve a sufficient tamponade effect on the inferior retina. In all seven vitreous cavity models tested, the inferior quadrant of the retina was completely covered by SO in more positions and the absolute velocity gradient of the retro-oil fluid in contact with the retinal wall caused by eye and head movements was lower when the vitreous cavity was filled with 95% SO and 5% retro-oil fluid versus 80% SO and 20% retro-oil fluid. Taken together, these findings have clinical implications for the treatment of complicated RRDs with inferior PVR requiring SO tamponade.

Abstract 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

Abstract We investigated the change in the retinal gas cover rates due to intraocular gas volume and positions using computational eye models and demonstrated the appropriate position after pars plana vitrectomy (PPV) with gas tamponade for rhegmatogenous retinal detachments (RRDs). Computational fluid dynamic (CFD) software was used to calculate the retinal wall wettability of a computational pseudophakic eye models using fluid analysis. The model utilized different gas volumes from 10 to 90%, in increments of 10% to the vitreous cavity in the supine, sitting, lateral, prone with closed eyes, and prone positions. Then, the gas cover rates of the retina were measured in each quadrant. When breaks are limited to the inferior retina anterior to the equator or multiple breaks are observed in two or more quadrants anterior to the equator, supine position maintained 100% gas cover rates in all breaks for the longest duration compared with other positions. When breaks are limited to either superior, nasal, or temporal retina, sitting, lower temporal, and lower nasal position were maintained at 100% gas cover rates for the longest duration, respectively. Our results may contribute to better surgical outcomes of RRDs and a reduction in the duration of the postoperative prone position.

Abstract Intraocular surgery is associated with increased ocular inflammation. If maintained for a prolonged period after surgery, this inflammation can cause various complications, including subconjunctival fibrosis and bleb scarring. This clinical trial was a prospective, randomised, single-blind, interventional study comparing the efficacy and safety of 0.1% bromfenac sodium ophthalmic solution and 0.02% fluorometholone ophthalmic suspension in the inhibition of multiple inflammatory cytokines in the aqueous humour of 26 patients with pseudophakic eyes who had undergone phacoemulsification and intraocular lens implantation. The patients were randomly assigned to one of the trial drugs, and aqueous humour samples were collected before and after drug administration. Platelet-derived growth factor-AA levels significantly decreased in both drug groups, but they were significantly higher in the fluorometholone group than in the bromfenac group (P = 0.034). Bromfenac also significantly decreased vascular endothelial growth factor level (P = 0.0077), as well as monocyte chemoattractant protein-1 level (P = 0.013), which was elevated for a prolonged period after phacoemulsification. These data suggest that bromfenac is useful to alleviate prolonged microenvironmental alterations in the aqueous humour of pseudophakic eyes.

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.

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.

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.

Abstract Intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF) is the standard treatment modality in various types of retinal diseases. However, endophthalmitis remains the most serious complication. Despite the lack of evidence that antibiotics prevent endophthalmitis, topical antibiotics are still used routinely in Japan. We conducted a retrospective multicenter study by analyzing records from patients who underwent IVI of anti-VEGF agents with or without antibiotic treatment. In the analysis of a total of 147,440 eyes, the incidence of endophthalmitis was 0.007%: 0.005% with no use of antibiotics, 0.009% with antibiotic pretreatment, 0.012% with posttreatment, and 0.005% with pre- and posttreatment. There was no statistically significant difference among the four groups (chi-square test, p = 0.57). Most facilities used masks, sterilized gloves, and drapes. Nine of the 10 eyes that developed endophthalmitis received topical antibiotics, and all infected eyes underwent IVI with aflibercept, not the prefilled syringe delivery system. In four patients who received multiple IVI, the detection of causative bacteria revealed resistance to used antibiotics. Data from this large population, treated with or without antibiotics, suggests that antibiotic prophylaxis does not reduce the rate of endophthalmitis after IVI.

Abstract Background To determine the effect of various factors to the preservation rate of the conjunctival layer borderlines of glaucomatous eyes treated with anti-glaucoma eye drops. Methods Anterior segment optical coherence tomography (AS-OCT) images of the bulbar conjunctiva of 328 eyes were analyzed with and without anti-glaucoma eye drops to quantify the preservation rates of the conjunctival layer borderlines. Results More anti-glaucoma eye drops and a longer duration of administration were associated with lower preservation rates of the borderlines between both the conjunctival stroma/Tenon’s capsule (P

AIM: To compare surgical outcomes of phacoemulsification combined with glaucoma surgical techniques performed with either Kahook Dual Blade (KDB) or iStent for Japanese patients with either primary open angle glaucoma or exfoliation glaucoma. METHODS: We retrospectively evaluated the surgical outcomes of 129 eyes of 84 Japanese patients with glaucoma who underwent KDB or 44 eyes of 34 patients who underwent phacoemulsification with iStent procedures combined with cataract surgery. The primary outcome was surgical success or failure [with surgical failure being indicated by 18 mm Hg as criterion A; IOP>14 mm Hg as criterion B on two consecutive study visits; or reoperation requirement]. In addition, we assessed the number of postoperative glaucoma medications and the resulting complications. RESULTS: The probability of success was significantly higher in the KDB group than in the iStent group for criterion A (60.2% vs 46.4%, P=0.019). In the KDB group, the mean preoperative IOP of 19.8±7.3 mm Hg decreased significantly to 13.0±3.1 mm Hg (P

PurposeTo evaluate the concentrations of brimonidine and timolol in the vitreous and aqueous humors after instillation of a 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution.MethodsThis single-arm open-label interventional study included patients with macular holes or idiopathic epiretinal membranes who were scheduled for vitrectomy. Written informed consent was obtained from all participants. A 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution was administered topically twice daily for 1 week preoperatively. The vitreous and aqueous humors were sampled before vitrectomy, and brimonidine and timolol concentrations were quantified using liquid chromatography-tandem spectrometry. This study was registered with the Japan Registry of Clinical Trials (jRCT, ID jRCTs051200008; date of access and registration: April 28, 2020). The study protocol was approved by the University of Fukui Certified Review Board (CRB) and complied with the tenets of the Declaration of Helsinki.ResultsEight eyes of eight patients (7 phakic eyes and 1 pseudophakic eye) were included in this study. The mean brimonidine concentrations in the vitreous and aqueous humors were 5.04 ± 4.08 nM and 324 ± 172 nM, respectively. Five of the eight patients had brimonidine concentrations >2 nM in the vitreous humor, which is necessary to activate α2 receptors. The mean timolol concentrations in the vitreous and aqueous humors were 65.6 ± 56.0 nM and 3,160 ± 1,570 nM, respectively. Brimonidine concentrations showed significant positive correlations with timolol concentrations in the vitreous humor (P < 0.0001, R2 = 0.97) and aqueous humor (P < 0.0001, R2 = 0.96).ConclusionsThe majority of patients who received a 0.1% brimonidine tartrate and 0.5% timolol topical fixed-combination ophthalmic solution showed a brimonidine concentration >2 nM in the vitreous humor. Brimonidine and timolol may be distributed in the ocular tissues through an identical pathway after topical instillation.

Although cataracts affect almost all people at advanced age and carry a risk of blindness, the mechanisms of cataract development remain incompletely understood. Oxidative stress, which is a causative factor in cataract, results in DNA breakage, which suggests that DNA damage could contribute to the formation of cataracts. We developed an ex vivo experimental system to study changes in gene expression during the formation of opacities in the lens by culturing explanted rat lenses with Methylmethanesulfonate (MMS) or Bleomycin, which induce DNA damage. Lenses cultured using this experimental system developed cortical opacity, which increased in a concentration- and time-dependent manner. In addition, we compared expression profiles at the whole gene level using microarray analysis of lenses subjected to MMS or Bleomycin stress. Microarray findings in MMS-induced opacity were validated and gene expression was measured from Days 1-4 using RT-qPCR. Altered genes were classified into four groups based on the days of peak gene expression: Group 1, in which expression peaked on Day 1; Group 2, in which expression peaked on Day 2; Group 3, in which expression progressively increased from Days 1-4 or were upregulated on Day 1 and sustained through Day 4; and Group 4, in which expression level oscillated from Days 1-4. Genes involved in lipid metabolism were restricted to Group 1. DNA repair- and cell cycle-related genes were restricted to Groups 1 and 2. Genes associated with oxidative stress and drug efflux were restricted to Group 2. These findings suggest that in temporal changes of MMS-induced opacity formation, the activated pathways could occur in the following order: lipid metabolism, DNA repair and cell cycle, and oxidative stress and drug efflux.

Cataract, a disease that causes opacity of the lens, is the leading cause of blindness worldwide. Cataracts secondary to diabetes are common, even in young patients, so they are of significant clinical importance. Here, we used an ex vivo model of galactose-induced cataracts in the rat lens to investigate the therapeutic effects of histone acetyltransferase (HAT) inhibitors. Among the tested HAT inhibitors, TH1834 was the only one that could reverse most of the opacity once it had formed in the lens. Combination treatment with C646/CPTH2 and CBP30/CPTH2 also had therapeutic effects. In lens cross-sections, vacuoles were present in the tissue of the cortical equatorial region of untreated cataract samples. In treated cataract samples, lens tissue regenerated to fill the vacuoles. To identify the genes regulated by HAT inhibitors, qRT-PCR was performed on treated and untreated cataract samples to determine candidate genes. Expression of Acta1 and Stmn4, both of which are involved in the cytoskeleton, were altered significantly in C646+CPTH2 samples. Expression of Emd, a nuclear membrane protein, and Prtfdc1, which is involved in cancer cell proliferation, were altered significantly in CBP30+CPTH2 samples. Acta1, Acta2, Arrdc3, Hebp2, Hist2h2ab, Pmf1, Ppdpf, Rbm3, RGD1561694, Slc16a6, Slfn13, Tagln, Tgfb1i1, and Tuba1c in TH1834 samples were significantly altered. These genes were primarily related to regulation of cell proliferation, the cytoskeleton, and cell differentiation. Expression levels increased with the onset of cataracts and was suppressed in samples treated with HAT inhibitors.

Cataract causes vision loss and blindness due to formation of opacities of the lens. The regulatory mechanisms of cataract formation and progression remain unclear, and no effective drug treatments are clinically available. In the present study, we tested the effect of ataxia telangiectasia mutated (Atm) inhibitors using an ex vivo model in which rat lenses were cultured in galactose-containing medium to induce opacity formation. After lens opacities were induced by galactose, the lenses were further incubated with the Atm inhibitors AZD0156 or KU55933, which decreased lens opacity. Subsequently, we used microarray analysis to investigate the underlying molecular mechanisms of action, and extracted genes that were upregulated by galactose-induced opacity, but not by inhibitor treatment. Quantitative measurement of mRNA levels and subsequent STRING analysis revealed that a functional network consisting primarily of actin family and actin-binding proteins was upregulated by galactose treatment and downregulated by both Atm inhibitors. In particular, Acta2 is a known marker of epithelial-mesenchymal transition (EMT) in epithelial cells, and other genes connected in this functional network (Actn1, Tagln, Thbs1, and Angptl4) also suggested involvement of EMT. Abnormal differentiation of lens epithelial cells via EMT could contribute to formation of opacities; therefore, suppression of these genes by Atm inhibition is a potential therapeutic target for reducing opacities and alleviating cataract-related visual impairment.

Purpose To compare the intraocular pressure (IOP) after an intravitreal triamcinolone acetonide (IVTA) between vitrectomised and non-vitrectomised eyes in patients with diabetes and diabetic macular oedema (DME).Design Retrospective comparative studyMethods Medical records of 157 patients (157 eyes) with type 2 diabetes who received IVTA for DME were reviewed, and the best-corrected visual acuity, IOP and optical central retinal thickness (CRT) were compared preoperatively, at 1, 4, 12 and 24 weeks after IVTA between the vitrectomised and non-vitrectomised groups.Results IOP significantly increased at 1 (p

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.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The rabbit retinal vein occlusion (RVO) model is an experimental system that mimics retinal ischemic diseases in humans. The rabbit RVO model is widely used to assess the therapeutic efficacy of various experimental surgical procedures. In the present study, we measured temporal retinal expression of Vegfa, which is known as an ischemic response gene, in rabbit RVO. This analysis revealed that the retinal Vegfa transcriptional response began 7 days after generation of RVO, rather than immediately after induction of ischemia. Next, in order to analyze ischemia-induced changes in gene expression profiles, we performed microarray analysis of day 7 RVO retina versus control retina. The angiogenic regulators Dcn and Mmp1 and pro-inflammatory factors Mmp12 and Cxcl13 were significantly upregulated in RVO retinas. Further, we suggest that epigenetic regulation via the REST/cofactor-complex could contribute to RVO pathology. Among human homologous genes in rabbits, genes associated with hypoxia, angiogenesis, and inflammation were significantly upregulated in RVO retinas. Components of the Tumor necrosis factor-alpha (TNFα) and Nuclear factor-kappa B (NF-κB) pathways, which play regulatory roles in angiogenesis and inflammation, were significantly upregulated in RVO, and the expression levels of downstream factors, such as the transcription factor AP-1 and chemokines, were increased. Further, connectivity map analyses suggested that inhibitors of the NF-κB pathway are potential therapeutic agents for retinal ischemic disease. The present study revealed new insights into the pathology of retinal ischemia using the rabbit RVO model, which accurately recapitulates human disease.

Abstract Background To compare the lamina cribrosa between eyes with and without neovascular glaucoma (NVG) using enhanced depth imaging spectral-domain optical coherence tomography. Methods Forty-six patients with proliferative diabetic retinopathy were enrolled in this cross-sectional study. The patients were divided into two groups based on the absence or presence of NVG (the non-NVG group and the NVG group, respectively). The intraocular pressure (IOP), circumpapillary retinal nerve fiber layer (cpRNFL) thickness, anterior lamina cribrosa depth (ALD), and laminar thickness (LT) were compared between the groups. Results In the non-NVG group, the mean age was 66.2 ± 2.4 (mean ± standard error) years, mean maximum IOP was 18.8 ± 1.8 mmHg, mean cpRNFL thickness was 91.2 ± 3.9 μm, mean ALD was 407.0 ± 22.9 μm, and mean LT was 155.0 ± 4.7 μm. In the NVG group, the mean age was 61.4 ± 2.1 years, mean maximum IOP was 33.1 ± 1.6 mmHg, mean cpRNFL thickness was 73.6 ± 3.4 μm, mean ALD was 403.9 ± 20.1 μm, and mean LT was 156.9 ± 4.2 μm. The IOP was significantly higher and the cpRNFL was significantly thinner in the NVG group (P

PURPOSE:This study aims to compare the rate of surgical failure after trabeculectomy followed by phacoemulsification vs trabeculectomy alone for 5 years. METHOD:A total of 1,098 eyes of patients with glaucoma who underwent trabeculectomy with mitomycin C at 34 clinical centers included in CBIITS were analyzed. During follow-up, some eyes were treated with phacoemulsification because of cataract progression. The patients were divided into the "trabeculectomy followed by phacoemulsification" and "trabeculectomy alone" groups, and surgical probabilities were compared. Surgical failure was defined on the basis of mean IOP as follows; < 20% reduction in preoperative IOP or IOP ≥ 21 mmHg (criterion A), IOP ≥ 18 mmHg (criterion B), or IOP ≥ 15 mmHg (criterion C). RESULT:In total, 40 eyes were treated with trabeculectomy followed by phacoemulsification and 208 with trabeculectomy alone. Preoperative intraocular pressure was 22.1 ± 8.7 mmHg in the trabeculectomy followed by phacoemulsification group and 20.5 ± 6.3 mmHg in trabeculectomy alone group (P = 0.47). The 5-year cumulative probabilities of success in the trabeculectomy followed by phacoemulsification and trabeculectomy alone groups were respectively 40.0% and 59.1% for criterion A (P = 0.01), 35.0% and 52.9% for criterion B (P = 0.01), and 25.0% and 37.5% for criterion C (P = 0.08). Cox proportional hazards regression model indicated that shorter time gap between trabeculectomy and phacoemulsification was associated with surgical failure. CONCLUSION:Phacoemulsification following trabeculectomy adversely affects surgical outcomes. In particular, a shorter time gap between trabeculectomy and phacoemulsification reduces the probability of success.

We prospectively evaluated refractive changes in the eyes of 97 patients who underwent trabeculectomy at Fukui University Hospital, Fukui, Japan. The primary outcome measure was the refractive change after trabeculectomy. Secondary outcome measures included postoperative complications and prognostic factors for refractive change. We observed a progressive and significant mean refractive myopic shift of −0.80 D at 12 months after surgery. In phakic eyes, the mean myopic refractive shifts progressed significantly by −0.46 D at 3 months after surgery (P=0.003), by −0.52 D at 6 months (P=0.012), and by −1.31 D at 12 months (P

PURPOSE:To evaluate corneal endothelial cell loss after Baerveldt glaucoma implantation. METHODS:We prospectively evaluated changes in endothelial cell density (ECD) in the cornea of 59 patients (59 eyes) who underwent Baerveldt glaucoma implantation. Tubes were inserted into the anterior chamber in 45 eyes and pars plana in 14 eyes. The primary outcome measure was the change in corneal ECD after Baerveldt glaucoma implantation. Secondary outcome measures included relationships between corneal ECD and optical coherence tomography images of tube parameters (tube-cornea distance and tube-cornea angle) and prognostic factors for corneal ECD loss. RESULTS:Corneal ECD decreased significantly by 9.2% at 12 months after surgery (P = 0.001). In the anterior chamber Baerveldt glaucoma implantation group, corneal ECD at the tube insertion quadrant decreased significantly by 9.6% at 3 months (P =

Purpose. To introduce a novel laser photocoagulation (PC) protocol named merged image-guided PC (MIG-PC), which included merging the images of the fundus, optical coherence tomography (OCT) map, and fluorescein angiography (FA). We compared the anatomical and functional results between MIG-PC and FA-guided PC (FG-PC) for the treatment of focal diabetic macular edema (DME). Method. We examined the treatment outcomes in 27 consecutive eyes treated with MIG-PC compared with 28 matched eyes treated with FG-PC. We identified the microaneurysms (MAs) located in the focal edema areas and ablated them using focal PC. Best-corrected visual acuity (BCVA) and retinal thickness (RT) measured using OCT were compared between the groups at baseline and 2, 4, 8, 12, and 24 weeks after treatment. Results. The foveal and perifoveal RT were reduced after treatment in both the groups, and the perifoveal RT in the MIG-PC group was significantly lower than that in the FG-PC group at 4 weeks and thereafter. BCVA in the MIG-PC group was significantly higher than that in the FG-PC group at 12 and 24 weeks. The numbers of laser spots (p=0.0001), additional laser treatments (p=0.0121), and intravitreal injection of ranibizumab (p=0.0012) in the MIG-PC group were significantly lower than those in the FG-PC group (Mann–Whitney test). Conclusion. MIG-PC contributed to the improvement in BCVA and reduction in RT, number of laser shots required, and retreatment rates. Based on our data, MIG-PC can be recommended for the treatment of focal DME. This trial is registered with ID UMIN000030390.

We compared the effect of panretinal photocoagulation (PRP) using short-pulse laser (SPL) and conventional laser, regardless of the number of spots, in terms of their effect on the progression of diabetic macular edema (DME) and anterior flare intensity (AFI) in patients with high-risk nonproliferative diabetic retinopathy (non-PDR). Forty-two eyes of 42 patients were subjected to PRP using the conventional argon laser (Conv group) or SPL (SPL group). CRT and AFI levels in the SPL group were significantly lower than those in the Conv group (CRT at 4, 6, and 10 weeks; AFI at 6, 10, and 18 weeks). Eyes of rabbits were photocoagulated using conventional laser with 500 spots (Conv 500s), SPL with 500 spots (SPL 500s), or 1000 spots (SPL 1000s). Vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemotactic protein-1 (MCP-1) levels in vitreous humor were measured using an immunoassay. Compared to conventional laser, VEGF, IL-6, and MCP-1 levels were significantly lower in the SPL 1000s and SPL 500s groups. In patients with high-risk non-PDR, SPL has a greater preventive effect on the progression of DME and AFI and produces less inflammatory cytokines than conventional lasers.

To evaluate the efficacy of the inverted internal limiting membrane (ILM) flap technique in vitrectomy for macular hole (MH) with retinal detachment (RD) compared with vitrectomy using ILM peeling.A retrospective case series study was performed. Twenty-two eyes of 22 patients who underwent vitrectomy for MH with RD and followed-up more than 12 months after the surgery were included in this study. We retrospectively reviewed the medical records of patients who underwent vitrectomy with inverted ILM flap technique or vitrectomy with ILM peeling. Ten patients who had been treated vitrectomy with inverted ILM flap technique, and 12 patients who had been treated vitrectomy with ILM peeling were analyzed. We evaluated changes in best-corrected visual acuity (BCVA) before and after surgery, closing rates of MH, and retinal reattachment rates and compared between both groups.MH was closed and RD was reattached postoperatively in 9 eyes (90%) in the inverted ILM flap group. In the ILM peeling group, the MH was closed in 4 eyes (33.3%) and the retinas were reattached in 6 eyes (50%) after surgery. Significant improvement in BCVA after surgery (P = 0.0017) was only found in the inverted ILM flap group.Higher rates of closed MH and retinal reattachment, and small but significant improvement in BCVA were found in the inverted ILM flap group. Based on our data, the inverted ILM flap technique may be useful in vitrectomy for MH with RD.

OBJECTIVE:To compare surgical outcomes between the first and second operated eyes in patients who underwent trabeculectomy in both eyes. METHODS:This retrospective clinical cohort study at five clinical centers in Japan included 84 patients with open-angle glaucoma who underwent primary trabeculectomy in both eyes. The primary outcome was surgical success or failure, with failure being defined according to three criteria: 21 mmHg; Criterion B, IOP >18 mmHg; or Criterion C, IOP >15 mmHg. Cases of reoperation, a loss of light perception vision, or hypotony were also considered as "failures". RESULTS:There were no significant differences in success rate for any of the three criteria between the first and second operated eyes. For patients whose first trabeculectomy was successful, when the second trabeculectomy was performed ≥2 months after the first, the survival curves for all three criteria for the second trabeculectomy were significantly worse than those for patients waiting a shorter interval between trabeculectomies (Criterion A, 52.0% vs 83.6%, P = 0.0031; Criterion B, 51.5% vs 80.4%, P = 0.026; Criterion C, 51.1% vs 80.4%, P = 0.048). In multivariable analyses, a longer interval between trabeculectomies was a significant prognostic factor for surgical failure (Criterion A, P = 0.0055; Criterion B, P = 0.0023; Criterion C, P = 0.027). However, no dependency on the interval between trabeculectomies was found among patients whose first trabeculectomy failed. CONCLUSIONS:If the first trabeculectomy is successful, a long interval before the second trabeculectomy increases the risk of surgical failure in the second eye. This result has clinical implications for developing surgical strategies for patients with bilateral glaucoma.