Interleukin 1 beta promoter polymorphism is associated with keratoconus in a Japanese population.

PURPOSE: Polymorphisms in the interleukin 1 alpha (IL1A) and IL1B gene regions were previously associated with keratoconus in a Korean population. In the present study, we investigated whether the IL1A and IL1B polymorphisms are associated with keratoconus in a Japanese population. METHODS: A total of 169 Japanese patients with keratoconus and 390 Japanese healthy controls were recruited. We genotyped one IL1A single nucleotide polymorphism (SNP; rs2071376) and two IL1B SNPs (rs1143627 and rs16944) to compare the frequencies of alleles, genotypes, and haplotypes between cases and controls. RESULTS: Statistically significant association was observed for rs1143627 (-31 T>C) in the IL1B promoter region; the T allele of rs1143627 was associated with an increased risk of keratoconus (p=0.014, corrected p value [pc]=0.043, odds ratio=1.38). The C allele of rs16944 (-511 C>T) in the IL1B promoter region had a 1.33-fold increased risk of keratoconus, although this increase did not reach statistical significance (p=0.033, pc=0.098). The TT genotype of rs1143627 was weakly associated with an increased risk of keratoconus (p=0.033, pc=0.099, odds ratio=1.52). However, no significant differences were found in the allele and genotype frequencies between the cases and controls for rs2071376 in IL1A. Regarding haplotypic diversity, the haplotype created by the T allele of rs1143627 and C allele of rs16944 was associated with a 1.72-fold increased risk of keratoconus (p=4.0×10(-5), pc=1.6×10(-4)). CONCLUSIONS: Our results replicate associations reported recently in a Korean population. Thus, IL1B may play an important role in the development of keratoconus through genetic polymorphisms.

Peripheral optical quality and myopia progression in children.

BACKGROUND: To investigate the peripheral optical quality and its relationship with axial elongation, myopic progression in Japanese children. METHODS: Twenty-nine Japanese children, ages 10 to 12 years old, with baseline refraction from +0.75 D to -5.5 D, were included and followed for 9 months. The central and peripheral point spread functions (PSFs; 0°, 10°, 20°, 30° nasally) were obtained at 0.25 D steps around ±2.5 D of best-focus PSF (BF-PSF) using double-pass PSF system. Modulation transfer function (MTF) area of the BF-PSF was calculated from BF-PSF to represent the peripheral optical quality. Relative peripheral defocus (RPD), the refraction of anterior/posterior focal lines, MTF area, and their correlations with myopia progression were analyzed. RESULTS: The average refractive change in 9 months was -0.5 ± 0.8 D. The change in axial length was significantly positively correlated with the amount of myopic progression (P = 0.0058) and RPD (P = 0.0007, 0.0036 and 0.0040, at 10°, 20°, 30° respectively) at the initial visit, but did not correlate with the peripheral MTF area. Myopic progression of more than 0.5 D with axial elongation was observed in seven children (MP group). The RPDs at 20° and 30° in the MP group were significantly more hyperopic than in the non-MP group (P = 0.002 and 0.007), whereas there was no significant difference in axial length, and central and peripheral MTF area between the MP and non-MP groups. MP group had more hyperopic focal lines compared with non-MP group at 20° and 30°. CONCLUSION: These results suggest that the progression of axial myopia in children is associated with hyperopic RPD and refraction of focal lines, not with peripheral optical quality.

Difficulties in ensuring review quality performed by committees under the Act on the Safety of Regenerative Medicine in Japan.

We outlined five studies regarding the quality of the review by committees based on the Act on the Safety of Regenerative Medicine. The findings raise serious concerns about the independence, integrity, and quality of reviews of therapeutic plans by these committees with inappropriately close relationships to medical institutions and companies.

A web-based survey on various symptoms of computer vision syndrome and the genetic understanding based on a multi-trait genome-wide association study.

A variety of eye-related symptoms due to the overuse of digital devices is collectively referred to as computer vision syndrome (CVS). In this study, a web-based survey about mind and body functions, including eye strain, was conducted on 1998 Japanese volunteers. To investigate the biological mechanisms behind CVS, a multi-trait genome-wide association study (GWAS), a multivariate analysis on individual-level multivariate data, was performed based on the structural equation modeling methodology assuming a causal pathway for a genetic variant to influence each symptom via a single common latent variable. Twelve loci containing lead variants with a suggestive level of significance were identified. Two loci showed relatively strong signals and were associated with TRABD2B relative to the Wnt signaling pathway and SDK1 having neuronal adhesion and immune functions, respectively. By utilizing publicly available eQTL data, colocalization between GWAS and eQTL signals for four loci was detected, and a locus on 2p25.3 showed a strong colocalization (PPH4 > 0.9) on retinal MYT1L, known to play an important role in neuronal differentiation. This study suggested that the use of multivariate questionnaire data and multi-trait GWAS can lead to biologically reasonable findings and enhance our genetic understanding of complex relationships among symptoms related to CVS.

A prospective, randomized clinical study comparing accelerated corneal collagen crosslinking with 5% NaCl hypertonic saline for bullous keratopathy in Asian eyes.

BACKGROUND: We compared the clinical outcomes of accelerated corneal collagen crosslinking (CXL) and 5% NaCl hypertonic saline (HS) for the treatment of symptomatic bullous keratopathy (BK). METHODS: A randomized controlled trial was held at Department of Ophthalmology, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan. Twenty-three eyes of 23 consecutive patients with symptomatic BK were enrolled. The etiology of BK included pseudophakic BK, previous keratoplasty, previous endotheliitis, previous glaucoma surgery, trauma, herpes infection, as well as unknown causes. Eleven eyes received epi-off accelerated CXL (with epithelial abrasion and 18 mW/cm ultraviolet A irradiation for 5 minutes) and 12 eyes received HS instillation. In addition to the usual ophthalmic examination, the best-corrected visual acuity (BCVA) and central corneal thickness (CCT) were determined. The CCT was measured using anterior segment optical coherence tomography before and up to 6 months after treatments. Subjective symptoms of pain, blurred vision, photophobia, and irritation were also recorded. RESULTS: The follow-up was completed for all patients in the CXL group. However, 6 patients in the HS group requested CXL treatments after 3 months. The BCVA was not significantly changed during the study periods in both groups. The CCT was significantly thinner in the CXL group compared to the HS group at 1 and 6 months (P = .015 and 0.144, respectively). Among the subjective symptoms recorded, irritation was significantly lower in the CXL group at 1 month (P = .013). CONCLUSIONS: Accelerated CXL may produce transient improvement in pain and corneal edema in patients with BK.

Corneal cross-linking for keratoconus caused by compulsive eye rubbing in patients with Tourette syndrome: Three case reports.

RATIONALE: Eye rubbing is an important risk factor for keratoconus progression. Tourette syndrome (TS) is a neurological disorder, and approximately 50% of individuals with TS exhibit obsessive-compulsive behaviors including eye rubbing. We report the effects of corneal cross-linking (CXL) on the progression of keratoconus combined with psychiatric treatment for 3 patients with TS. PATIENTS' CONCERNS: Three cases, 24-year-old male, 14-year-old male, and 17-year-old male, were all referred to our institute, due to decreased visual acuity. DIAGNOSIS: All 3 patients were diagnosed with progressive keratoconus. They were found to rub their eyes, and were also diagnosed with TS by psychiatrists. INTERVENTION: Upon diagnosis of keratoconus, we performed CXL on 1 eye of each patient. OUTCOMES: After CXL, there was no further progression. Psychiatric medication was also required. LESSONS: For patients with keratoconus caused by eye rubbing due to TS, CXL seems to be effective when done in association with psychiatric treatment.

Corneal crosslinking for keratoconus in Japanese populations: one year outcomes and a comparison between conventional and accelerated procedures.

PURPOSE: We retrospectively investigated the efficacy of corneal crosslinking (CXL) on progressive keratoconus in a Japanese population and compared the outcomes of conventional and accelerated CXL. STUDY DESIGN: A retrospective cohort study METHODS: A total of 108 consecutive eyes in 95 patients (75 men; 21.9 ± 6.2 years) with progressive keratoconus were enrolled. The epithelium was ablated in all eyes. After presoaking the corneal stroma in riboflavin, UV-A was irradiated at 3.0 mW/cm2 (conventional CXL) for 30 min on 23 eyes and 18.0 mW/cm2 for 5 min (accelerated CXL) on 85 eyes. Best spectacle-corrected visual acuity (BSCVA), manifest refraction, keratometric value, corneal thickness, corneal endothelial cell density (ECD), intraocular pressure, and complications were evaluated at 1, 3, 6, and 12 months after the procedure. RESULTS: BSCVA, manifest refraction, ECD, and corneal thickness did not change significantly after both procedures. The keratometric value was significantly decreased from the preoperative value at 12 months (p < 0.001). Progression to more than 1.0 D after CXL was observed in 10 eyes (9.3%). The ΔKmax was negatively associated with preoperative Kmax (p < 0.001) and positively associated with preoperative thinnest corneal thickness (p < 0.001). Both treatment modules showed no significant difference in all parameters. CONCLUSION: CXL was as effective in treating keratoconus in Japanese patients as in individuals of other ethnicities. Overall, CXL could be performed using either the conventional or accelerated approach to halt the progression of keratoconus in Japanese populations.

Age and topographical comparison of telomere lengths in human corneal endothelial cells.

PURPOSE: Human corneal endothelium exhibits both age-related and topographical differences in relative proliferative capacity and in senescence characteristics. The purpose of these studies was to compare telomere lengths in human corneal endothelial cells (HCEC) from the central and peripheral areas of corneas from young and older donors to determine whether these changes may be due to replicative senescence or to stress-induced premature senescence. METHODS: Pairs of corneas from five young (<30 years old) and six older donors (>65 years old) were separated into central and peripheral areas using a 9.5 mm diameter trephine to remove scleral tissue and a 6.0 mm diameter trephine to mark the central-peripheral boundary. One of the pair of corneas was cut into quarters and stained with a peptide nucleic acid (PNA)/fluorescein isothiocyanate (PNA/FITC) probe that specifically binds to telomere repeats. HCEC from the central (0-6.0 mm) and peripheral areas (6.0-9.5 mm) were isolated from the second cornea, mounted on slides by Cytospin, and stained with the PNA/FITC probe. Fluorescence confocal microscopy was used to obtain digital images. The average FITC intensity of nuclei was compared between the central and peripheral areas within and between the two age groups. Ccl185 and 1301 cells were analyzed as controls. Student's unpaired t-test was used to determine the statistical significance of the data. RESULTS: Average FITC intensity from the central endothelium was 205.8+/-4.2 (younger) and 194.2+/-10.5 (older) and from the peripheral endothelium was 208.1+/-9.3 (younger) and 195.9+/-10.8 (older). Average intensity of single cells isolated from central endothelium was 113.9+/-31.1 (younger) and 107.9+/-26.1 (older) and from the periphery was 109.9+/-12.0 (younger) and 106.9+/-32.4 (older). Average FITC intensity of Ccl185 cells and 1301 cells was 50.5+/-5.0 and 206.9+/-19.4, respectively. Comparison of the results indicates no statistically significant difference between the central and peripheral areas within each group or between the young and older age group. CONCLUSIONS: Results indicate that the age-related and topographical reduction in relative proliferative capacity and senescence characteristics observed in HCEC are not due to replicative senescence caused by critically short telomeres but implicate stress-induced premature senescence as a cause of these clinically important changes.

Flattening effect of corneal cross-linking depends on the preoperative severity of keratoconus.

A retrospective observational study was conducted to validate the effect of corneal cross-linking (CXL) on eyes with progressing keratoconus, depending on severity.In total, 45 eyes of 33 patients (age: 23.9 ±â€Š6.8 years, range: 14-42 years) with progressive keratoconus who underwent CXL were enrolled. Examinations were performed at pre-, 1, 3, 6, and 12 months after surgery. In addition to a slit lamp microscopy, measurement of visual acuity, the steepest keratometric value (Kmax), the thinnest corneal thickness (TCT), and the corneal endothelial cell density (ECD) were assessed. Change in Kmax (ΔKmax) was calculated by subtracting the preoperative Kmax from the 12-month postoperative Kmax.CDVA, TCT, and ECD did not change significantly throughout the follow-up period. Kmax was 56.4 ±â€Š7.2 D preoperatively and 54.3 ±â€Š5.6 D at 12 months after CXL (P = .174). The average value of ΔKmax was -2.23 ±â€Š4.31 D at 12 months after CXL. ΔKmax was negatively correlated with preoperative Kmax (ρ = -0.5517, P = .0001), and positively correlated with preoperative TCT (ρ = 0.4791, P = .0012). However, no correlation was observed between Kmax and patient age or the decrease ratio of ECD.The more flattening was obtained after CXL in cases with the more advanced keratoconus. No complication, including corneal endothelial damage, was observed even in advanced cases.

Ocular surface reconstruction for thermal burns caused by fireworks.

PURPOSE: To describe 6 eyes with severe firework-related ocular surface injuries that were treated by limbal stem cell transplantation combined with amniotic membrane transplantation (AMT). METHODS: Six eyes of 6 patients with firework-related ocular injuries were retrospectively studied. All subjects were men, with age ranging from 9 to 26 years. All patients were in chronic stage of thermal injury, and all had total limbal stem cell dysfunction and subsequent conjunctival fibrosis. They had limbal stem cell transplantation (1 had an allograft and 5 had autograft transplantation) combined with AMT to restore vision. Mitomycin C was used in 1 eye intraoperatively. RESULTS: After ocular surface reconstruction using limbal stem cell transplantation combined with AMT, corneal epithelialization was achieved in 4 eyes after a mean duration of 20.8 +/- 12.2 days (range, 4-33 days). After a mean follow-up period of 36 months (range, 5-87 months), marked reduction of fibrosis was noted in all eyes. At last examination, the corneal surface was covered by corneal-phenotype epithelium in 4 eyes, and the remaining 2 eyes had conjunctivalization. The cornea was optically clear in 3 eyes, with corrected visual acuity of 20/100 in these 3 eyes. Both eyes that developed conjunctivalization had massive fibrosis preoperatively and severe eyelid deformities. CONCLUSION: Although severe firework-related ocular surface injuries were difficult to treat, limbal stem cell transplantation combined with AMT enable some success in cosmetic and visual outcome. Management of eyelid abnormalities and ocular surface fibrosis seemed to be a key to success in visual rehabilitation.

Japan's challenges of translational regenerative medicine: Act on the safety of regenerative medicine.

The first issue of Nature Medicine published 20 years ago featured an article that reported Japan's critical situation regarding clinical trials, calling for major reform. Twenty years later, Japan has enacted three laws to promote the use of regenerative medicine as a national policy. The first law to be enacted was the Regenerative Medicine Promotion Act, which represents the country's determination to work toward the promotion of regenerative medicine. Subsequently, the Pharmaceuticals, Medical Devices, and Other Therapeutic Products Act (PMD Act) and the Act on the Safety of Regenerative Medicine (RM Act) came into effect. The PMD Act created a new category for regenerative medicine products, and established the process for obtaining approval for cell therapy and other regenerative therapies through the implementation of clinical trials. The RM Act specified the regulations that doctors, review committees, and cell culture/processing facilities must adhere to when providing regenerative medicine in medical care, not only in clinical research but also in private practice. Previously, researchers in regenerative medicine only had a set of guidelines to follow for conducting clinical research. Now, with the enactment of the RM Act, all areas for improvement that had been enumerated 20 years ago-such as the lack of appropriate review committees and governmental control-have been addressed by law, creating a system that gives the highest priority to patient safety. In this paper, we present the particularly noteworthy points of the RM Act, along with the actual current conditions of regenerative medicine in Japanese medical care.

Comparison of the proliferative capacity of human corneal endothelial cells from the central and peripheral areas.

PURPOSE: To compare the relative proliferative capacity between human corneal endothelial cells (HCECs) cultured from the central and peripheral areas of the cornea. METHODS: Human corneas were divided into two groups based on donor age (younger group, < or =30 years of age; older group, > or =50 years of age). Corneas were trephined, and Descemet's membrane with HCECs was stripped from the central (0-6.75 mm) and peripheral (6.75-9.5 mm) areas. HCECs were then isolated from Descemet's membrane and cultivated. An equal number of passage-1 endothelial cells from each area were seeded, and the number of cells was determined at various times after seeding. Doubling times of cells from each area were compared. The antibody against minichromosome maintenance-2 (MCM2) protein was tested for replication competence. RESULTS: Morphologically, HCECs from the central area were similar to cells from the peripheral area. The doubling time (in hours) of HCECs from the central area was 35.20 in the younger group (n = 4) and 54.54 in the older group (n = 4) and from the peripheral area, 29.37 in the younger group and 46.23 in the older group. There was no significant difference (younger: P = 0.515; older: P = 0.222) between the central and peripheral area in each age group. MCM2-positive cells were consistently observed in cultures from the central, as well as peripheral, area. There was no significant difference (younger: P = 0.929; older: P = 0.613) in the percentage of MCM2-positive cells between these two areas in either age group. Even though there was no significant difference, there was a tendency toward increased doubling time and decreased percentage of MCM2 in the central area of the older group. CONCLUSIONS: These results indicate that corneal endothelial cells from both the central and peripheral areas retain potential proliferative capacity.

New Japanese initiatives on stem cell therapies.

Two laws aiming to provide a new legal framework to promote regenerative medicine, while ensuring the efficacy and safety of the treatments, came into effect in Japan on November 25, 2014. The scope of these laws is briefly described here.

Improved functional visual acuity after punctal occlusion in dry eye patients.

PURPOSE: To report an increased functional visual acuity, which was recently reported as a simulation of visual function of daily acts of gazing, in dry eye patients after punctal occlusion. DESIGN: Prospective comparative interventional study. METHODS: We measured ordinary best-corrected visual acuity and functional visual acuity in eight eyes of eight dry eye patients after punctal occlusion, and compared the results with those of 22 eyes of 22 dry eye patients without punctal occlusion. RESULTS: Functional visual acuity in dry eye patients after punctal occlusion was 0.962 in decimal notation, which was significantly higher than that of patients without punctal occlusion, 0.283 (P <.0001). CONCLUSIONS: This study shows that punctal occlusion can improve the impaired functional visual acuity of dry eye patients.

Long-term results of amniotic membrane transplantation for partial limbal deficiency.

PURPOSE: To evaluate the long-term efficacy of amniotic membrane transplantation as a treatment option in cases with partial limbal deficiency. METHODS: Sixteen eyes of 14 patients with partial limbal deficiency underwent amniotic membrane patch (AMP) or amniotic membrane graft with patch (AMGP) following keratectomy for conjunctivalization of the cornea. The average follow-up period was 52 months. We evaluated the mean corneal epithelialization time, visual acuity improvement, complications, and recurrence rate after the surgery. RESULTS: Eleven eyes underwent AMP, and the remaining 5 eyes received AMGP. All eyes eventually attained corneal reepithelialization. The mean time to reepithelialization was not significantly different between the AMP group (9 days) and the AMGP group (27 days). At the final follow-up visit, improved Landolt visual acuity was observed in 6 of the 11 eyes in the AMP group and in 2 of the 5 eyes in the AMGP group. No intraoperative complications were observed. However, 6 eyes in the AMP group and 3 eyes in the AMGP group had a recurrence or developed a persistent epithelial defect after mean durations of 21.2 and 17.7 months, respectively. CONCLUSION: Both AMP and AMGP appear to be effective in attaining corneal reepithelialization, but neither could provide stable, clear corneal epithelialization in the long term.

Deep stromal opacity after corneal cross-linking.

PURPOSE: To describe 3 cases with deep corneal stromal opacity that occurred several months after corneal cross-linking. METHODS: A 36-year-old man, a 19-year-old man, and a 14-year-old girl underwent corneal cross-linking for their progressive keratoconus. Corneal cross-linking was performed according to the Dresden protocol. The corneal epithelium was ablated using an excimer laser in 2 cases and manually in 1 case. After 30 minutes of riboflavin presoaking, hypotonic riboflavin solution was applied until the corneal stroma swelled, after which the eyes were exposed to ultraviolet irradiation. Slit-lamp microscopy findings, uncorrected visual acuity, best-corrected visual acuity, manifest refraction, intraocular pressure, and corneal endothelial cell counts were evaluated, and corneal topography with Scheimpflug imaging was performed. RESULTS: In all cases, the epithelium healed without delay. All eyes showed mild stromal infiltration a few days after the procedure; however, the inflammation was resolved within 1 week. The corneal stroma revealed no opacity up to 1 month after the procedure. A deep stromal opacity that extended to the inferior paracentral area developed after a few months and remained for 6 months to 1 year. Because the opacity was not on the visual axis, the visual acuity was not involved. CONCLUSIONS: Deep stromal opacity developed several months after uneventful corneal cross-linking. Postoperative inflammation may play a crucial role in its pathogenesis.

Changes in corneal sensation, epithelial damage, and tear function after descemet stripping automated endothelial keratoplasty.

PURPOSE: To study the ocular surface changes in eyes after Descemet stripping automated endothelial keratoplasty (DSAEK) compared with those after penetrating keratoplasty (PKP). METHODS: This prospective study compared the changes in 31 eyes of 28 patients who underwent DSAEK (DSAEK group) with those in 15 disease-matched eyes of 15 patients who underwent PKP (PKP group). Corneal epithelial integrity was evaluated using a fluorescein staining score. Corneal sensation was measured with a Cochet-Bonnet esthesiometer. Tear function was evaluated using the Schirmer test, tear clearance test, tear function index, and tear break-up time. RESULTS: The postoperative fluorescein staining score was significantly higher in the PKP group than in the DSAEK group (P = 0.02). Postoperative corneal sensation was significantly better in the DSAEK group than in the PKP group (P < 0.01). Corneal sensation after DSAEK was significantly better than the preoperative value (P = 0.02). There were no statistically significant changes in the Schirmer test, tear clearance test, tear function index, or break-up time before and after the surgery in both the DSAEK and PKP groups. No significant differences were observed between the DSAEK and PKP groups after the surgery. CONCLUSIONS: Corneal sensation was preserved, and epithelial damage was less severe after DSAEK compared with PKP. Preservation of corneal sensation may contribute to the early recovery of visual function and long-term maintenance of ocular surface health after DSAEK.

Outcomes of cataract surgery in eyes with a low corneal endothelial cell density.

PURPOSE: To evaluate the surgical outcomes of cataract surgery in eyes with a low preoperative corneal endothelial cell density (ECD) and analyze factors affecting the prognosis. SETTING: Tokyo Dental College, Ichikawa General Hospital, Chiba, Japan. DESIGN: Noncomparative case series. METHODS: Eyes with a preoperative ECD of less than 1000 cells/mm(2) that had cataract surgery between 2006 and 2010 were identified. Standard phacoemulsification with intraocular lenses was performed using the soft-shell technique. The rate of endothelial cell loss, incidence of bullous keratopathy, and risk factors were retrospectively assessed. RESULTS: Sixty-one eyes (53 patients) with a low preoperative ECD were identified. Preoperative diagnoses or factors regarded as causing endothelial cell loss included Fuchs dystrophy (20 eyes), laser iridotomy (16 eyes), keratoplasty (10 eyes), traumatic injury (3 eyes), trabeculectomy (3 eyes), corneal endotheliitis (2 eyes), and other (7 eyes). The corrected distance visual acuity improved from 0.59 ± 0.49 logMAR preoperatively to 0.32 ± 0.48 logMAR postoperatively (P<.001). The mean ECD was 693 ± 172 cells/mm(2) and 611 ± 203 cells/mm(2), respectively (P=.001). The mean rate of endothelial cell loss was 11.5% ± 23.4%. Greater ECD loss was associated with a shorter axial length (AL) (<23.0 mm) and diabetes mellitus. Bullous keratopathy developed in 9 eyes (14.8%) and was associated with posterior capsule rupture. CONCLUSIONS: The results suggest that modern techniques for cataract surgery provide excellent visual rehabilitation in many patients with a low preoperative ECD. Shorter AL, diabetes mellitus, and posterior capsule rupture were risk factors for greater ECD loss and bullous keratopathy.