Masahiko Ayaki

Detection of cytotoxic anti-LEDGF autoantibodies in atopic dermatitis

In the last two decades, atopic dermatitis (AD) has been of increasing clinical significance in Japan. Eight-20% of patients with AD developed progressive cataracts (cataract-AD) and lens epithelial cells (LECs) were severely damaged. Lens epithelium-derived growth factor (LEDGF) is a newly isolated survival factor. In the presence of LEDGF, LECs survive well and in the absence of LEDGF, they become highly susceptible to stress. We investigated (1) whether auto-antibody (auto-Ab) to LEDGF is present in sera of AD patients and (2) whether depletion of LEDGF by the auto-Ab kills LECs. In sera from 26 patients with AD using ELISA, we found significantly higher levels of auto-Ab to LEDGF than that in a normal control group. Affinity purified auto-Ab to LEDGF from these sera killed LECs without complement activation. Levels of histamine in the AD group were significantly higher and levels of prostaglandin E2 were significantly lower than in the normal group. However, statistically there are no differences between sera from AD and cataract-AD in levels of Ab to LEDGF, histamine, prostaglandin E2 (PGE2), immunoglobulin E (IgE) and eosinophiles. We speculate that cataract-AD may be induced, in part, by a combination of high levels of serum histamine and eye rubbing which could break the blood-aqueous barrier to allow the entry of Ab to LEDGF into the privileged compartment, thus, reducing LEDGF levels, resulting in damage to LECs, and cataract formation.

Methylglyoxal induces endoplasmic reticulum stress and DNA demethylation in the Keap1 promoter of human lens epithelial cells and age-related cataracts

Age-related cataracts are a leading cause of blindness. Previously, we have demonstrated the association of the unfolded protein response with various cataractogenic stressors. However, DNA methylation alterations leading to suppression of lenticular antioxidant protection remains unclear. Here, we report the methylglyoxal-mediated sequential events responsible for Keap1 promoter DNA demethylation in human lens epithelial cells, because Keap1 is a negative regulatory protein that regulates the Nrf2 antioxidant protein. Methylglyoxal induces endoplasmic reticulum stress and activates the unfolded protein response leading to overproduction of reactive oxygen species before human lens epithelial cell death. Methylglyoxal also suppresses Nrf2 and DNA methyltransferases but activates the DNA demethylation pathway enzyme TET1. Bisulfite genomic DNA sequencing confirms the methylglyoxal-mediated Keap1 promoter DNA demethylation leading to overexpression of Keap1 mRNA and protein. Similarly, bisulfite genomic DNA sequencing shows that human clear lenses (n = 15) slowly lose 5-methylcytosine in the Keap1 promoter throughout life, at a rate of 1% per year. By contrast, diabetic cataractous lenses (n = 21) lose an average of 90% of the 5-methylcytosine regardless of age. Overexpressed Keap1 protein is responsible for decreasing Nrf2 by proteasomal degradation, thereby suppressing Nrf2-dependent stress protection. This study demonstrates for the first time the associations of unfolded protein response activation, Nrf2-dependent antioxidant system failure, and loss of Keap1 promoter methylation because of altered active and passive DNA demethylation pathway enzymes in human lens epithelial cells by methylglyoxal. As an outcome, the cellular redox balance is altered toward lens oxidation and cataract formation.

High prevalence of sleep and mood disorders in dry eye patients: survey of 1,000 eye clinic visitors

Purpose We aimed to explore the prevalence of probable sleep and mood disorders in eye clinic visitors. Methods This was a cross-sectional study. The participants were outpatients at six eye clinics from January through March, 2014. Outpatients were invited to complete a questionnaire containing the Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS). A final diagnosis was made, and patients were classified into six diagnostic groups. The main outcome measures were the scores of the PSQI and HADS among the diagnostic groups. Results A total 1,000 outpatients participated, and 730 patients (mean age 59.5±19.0 years; 487 females) were analyzed after exclusion of children and patients diagnosed with healthy eyes, acute injury, or unilateral pseudophakia. The mean PSQI and HADS scores across all patients were 5.3±3.1 and 9.2±6.2, respectively. For the diagnostic groups, the mean PSQI and HADS scores, respectively, were 5.7±3.3 and 10.2±6.0 for dry eye (n=247), 5.4±3.2 and 9.2±5.7 for bilateral cataracts (n=159), 5.3±3.3 and 8.0±5.3 for bilateral pseudophakia (n=99), and, 5.0±3.1 and 9.8±6.6 for glaucoma (n=109). Overall, 37.3% of patients were poor sleepers (PSQI ≥6), and 45.5% had possible mood disorders (HADS ≥10). Stepwise regression analysis revealed that the PSQI and HADS scores were significantly correlated with both age (P<0.05) and the presence of dry eye (P<0.05). Conclusion The prevalence of sleep and mood disorders was significantly higher in patients with dry eye. The present results suggest consultation-liaison psychiatry services may be beneficial among eye disease patients.

Protective effect of blue-light shield eyewear for adults against light pollution from self-luminous devices used at night

ABSTRACT We investigated sleep quality and melatonin in 12 adults who wore blue-light shield or control eyewear 2 hours before sleep while using a self-luminous portable device, and assessed visual quality for the two eyewear types. Overnight melatonin secretion was significantly higher after using the blue-light shield (P < 0.05) than with the control eyewear. Sleep efficacy and sleep latency were significantly superior for wearers of the blue-light shield (P < 0.05 for both), and this group reported greater sleepiness during portable device use compared to those using the control eyewear. Participants rated the blue-light shield as providing acceptable visual quality.

Cytotoxicity of five fluoroquinolone and two nonsteroidal anti-inflammatory benzalkonium chloride-free ophthalmic solutions in four corneoconjunctival cell lines

Purpose: Epithelial disorders after eye surgery can result in visual deterioration and patient discomfort. Such disorders may be caused by drug toxicity. In the present study, we evaluated the toxicity of ophthalmic solutions, with or without benzalkonium chloride (BAK) as the preservative, used for postoperative care. Methods: A range of commercially available antibiotic and anti-inflammatory ophthalmic solutions used postoperatively (ie, levofloxacin, moxifloxacin, gatifloxacin, norfloxacin, tosufloxacin, dibekacin, cefmenoxime, diclofenac, bromfenac, pranoprofen, betamethasone, and fluoromethorone) were assessed in three corneal cell lines and one conjunctival cell line. All antibiotic solutions were BAK free. Cell viability was determined with the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay after cells had been exposed to the drugs for 48 h. The effects of preservatives on cell viability were also determined. Toxicity was compared using the cell viability score (CVS). Results: Based on results of the MTT assay and CVS, the order of cell viability after exposure to the antibiotic solutions was cefmenoxime ≥ tosufloxicin ≥ dibekacin ≥ levofloxacin ≥ norfloxacin = gatifloxacin = moxifloxacin. For the anti-inflammatory solutions, the order of cell viability was betamethasone ≥ betamethasone + fradiomycin > preservative-free diclofenac ≥ preservative-free bromfenac >> 0.02% fluoromethorone ≥ 0.1% fluoromethorone = diclofenac + preservative = bromfenac + preservative = pranoprofen. The anti-inflammatory drugs were more toxic than the antibiotics. The toxicity of antibiotic drugs against ocular surface cells was dependent on the pharmaceutical components of the solution, whereas that of the anti-inflammatory drugs was dependent on both the pharmaceutical components and the preservatives. Conclusion: Postoperative drug-induced epitheliopathy may be caused primarily by anti-inflammatory drugs. CVS is useful in comparing the cytotoxicity of different drugs.

Postpartum central retinal artery occlusion simulating Purtscher's retinopathy.

A 30-year-old woman noticed sudden visual loss in her right eye 3 days after a normal childbirth and without eclampsia during pregnancy. An ophthalmic examination revealed that she had impending central retinal artery occlusion and her right visual acuity was 20/2000, which recovered to 20/30. A systemic examination showed hypercoagulability and hyperlipidemia but no abnormal findings on brain CT scan and echocardiography. Clinical features of this case were very similar to Purtschers retinopathy.

Sleep and mood disorders in dry eye disease and allied irritating ocular diseases.

The aim of the present study was to evaluate sleep and mood disorders in patients with irritating ocular diseases. The study design was a cross-sectional/case-control study conducted in six eye clinics. Out of 715 outpatients diagnosed with irritating ocular surface diseases and initially enrolled, 301 patients with dry eye disease (DED) and 202 age-matched control participants with other ocular surface diseases were analyzed. The mean Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS) scores were 6.4 ± 3.2 and 11.1 ± 5.7 for severe DED (n = 146), 5.5 ± 3.3 and 9.8 ± 4.0 for mild DED (n = 155), 5.5 ± 3.1 and 9.5 ± 6.6 for chronic conjunctivitis (n = 124), and 5.0 ± 3.3 and 8.9 ± 5.3 for allergic conjunctivitis (n = 78). There were significant differences among these diagnostic groups for PSQI (P < 0.05). Regression analysis of patients with DED revealed the PSQI and HADS scores were significantly correlated with the severity of DED (P < 0.05). Our results demonstrate that sleep quality in patients with DED is significantly worse than in patients with other irritating ocular surface diseases and it is correlated with the severity of DED.

Rejuvenation Effects of Cataract Surgery with Ultraviolet Blocking Intra-Ocular Lens on Circadian Rhythm and Gait Speed

BACKGROUND Previously, we reported improvements in sleep quality and gait speed after implantation of a yellow-colored, blue light-blocking intra-ocular lens (IOL). This study evaluated systemic health parameters for 7 months after cataract surgery with implantation of a clear, ultraviolet (UV)-blocking IOL. METHODS A total of consecutive 71 patients (average age 74.1 years) underwent cataract surgery with the implantation of a clear, UV-blocking IOL. Participants were evaluated using the Pittsburgh Sleep Quality Index (PSQI) and the National Eye Institute Visual Function Questionnaire (VFQ-25) before and at 2 and 7 months after surgery. Four-meter gait speed was also determined. The metabolic parameters of serum glycated hemoglobin (HbA1c), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were tested. RESULTS The pre-operative and post-operative (2 and 7 months after surgery) results were 66.4±16.5, 79.5±12.6, and 81.0±13.0 for VFQ-25 score, 5.7±3.5, 5.1±3.1, and 4.8±2.9 for PSQI, and 0.90±0.22, 0.91±0.22, and 0.92±0.22 meters/sec for gait speed. Significant improvements following surgery were noted in the VFQ-25 score for all cases and in the PSQI for poor sleepers (preoperative PSQI >5.5) (P<0.05, paired t-test). The gait speed and metabolic parameters showed no significant changes. CONCLUSIONS Cataract surgery with implantation of an UV-blocking clear IOL has the potential for improving circadian rhythm and systemic health parameters.

Rhinogenous optic neuritis with drastic diurnal variation of visual function

We report a case of rhinogenous optic neuritis in a 50-year-old man demonstrating drastic diurnal variation in visual function. His left vision was 20/15 in the morning, which gradually decreased to counting fingers at night. Pupillary reaction and visual field showed the same fluctuation as vision. Complete remission of visual symptoms was achieved after endonasal ethmoid sinusotomy.

Decreased sleep quality in high myopia children

The aim of the present study was to evaluate sleep quality in myopic children and adults. This cross sectional study surveyed 486 participants aged from 10 to 59 years with refractive errors using a questionnaire containing the Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS). Children (< 20 years) in the high myopia group exhibited the poorest PSQI scores (P < 0.01), while the adults showed no such correlations. Subscales of PSQI and HADS in children disclosed that the high myopia groups had the shortest sleep duration (P < 0.01), worst subjective sleep scores (P < 0.001), and latest bedtime (P < 0.05). Regression analyses in children significantly correlated myopic errors with PSQI (P < 0.05), sleep duration (P < 0.01), and bedtime (P < 0.01). Sleep efficacy (P < 0.05) and daytime dysfunction (P < 0.05) were significantly better in contact-lens users compared to the respective non-user groups across all participants. In conclusion, sleep quality in children was significantly correlated with myopic error, with the high myopia group worst affected.