Publications by authors named "Kazuo Tsubota"

901 Publications

A Novel Lid Hygiene Detergent Successfully Eliminated Demodex Mites, a Common PRefractory Obstructive Meibomian Gland Dysfunction.

J Oleo Sci 2021 May 7. Epub 2021 May 7.

Department of Ophthalmology, Keio University School of Medicine.

Introduction: Demodex mites are microscopic arthropods that have been shown to be responsible for chronic blepharitis. Although many reports have demonstrated positive effects of lid hygiene on demodicosis, some have produced conflicting results. We retrospectively evaluated the effect of lid margin cleansing with a novel lid hygiene detergent, Eye Shampoo, in patients with ocular demodicosis.

Methods: Outpatient clinic notes recorded over a 24-month period between June 30, 2016, and June 29, 2018, at Keio University Hospital in Japan were reviewed to identify patients diagnosed with ocular demodicosis who started cleansing their lid margins with Eye Shampoo at least once daily as a lid hygiene therapy.

Results: Five patients diagnosed with ocular demodicosis who started cleansing their lid margins using Eye Shampoo for lid hygiene were identified. In four cases, Demodex mites were successfully eliminated, and ocular conditions were ultimately improved with no recurrence. Active Demodex mites were still noted after 3 months of lid hygiene therapy in one case; further observation of this case was not available. There were no adverse effects of Eye Shampoo in any of these cases.

Conclusion: Lid hygiene therapy using Eye Shampoo successfully eliminated Demodex mites, a common pathogen of refractory obstructive meibomian gland dysfunction.
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http://dx.doi.org/10.5650/jos.ess20365DOI Listing
May 2021

ADIPOR1 deficiency-induced suppression of retinal ELOVL2 and docosahexaenoic acid levels during photoreceptor degeneration and visual loss.

Cell Death Dis 2021 May 7;12(5):458. Epub 2021 May 7.

Laboratory of Retinal Cell Biology, Tokyo, Japan.

Lipid metabolism-related gene mutations can cause retinitis pigmentosa, a currently untreatable blinding disease resulting from progressive neurodegeneration of the retina. Here, we demonstrated the influence of adiponectin receptor 1 (ADIPOR1) deficiency in retinal neurodegeneration using Adipor1 knockout (KO) mice. Adipor1 mRNA was observed to be expressed in photoreceptors, predominately within the photoreceptor inner segment (PIS), and increased after birth during the development of the photoreceptor outer segments (POSs) where photons are received by the visual pigment, rhodopsin. At 3 weeks of age, visual function impairment, specifically photoreceptor dysfunction, as recorded by electroretinography (ERG), was evident in homozygous, but not heterozygous, Adipor1 KO mice. However, although photoreceptor loss was evident at 3 weeks of age and progressed until 10 weeks, the level of visual dysfunction was already substantial by 3 weeks, after which it was retained until 10 weeks of age. The rhodopsin mRNA levels had already decreased at 3 weeks, suggesting that reduced rhodopsin may have contributed to early visual loss. Moreover, inflammation and oxidative stress were induced in homozygous KO retinas. Prior to observation of photoreceptor loss via optical microscopy, electron microscopy revealed that POSs were present; however, they were misaligned and their lipid composition, including docosahexaenoic acid (DHA), which is critical in forming POSs, was impaired in the retina. Importantly, the expression of Elovl2, an elongase of very long chain fatty acids expressed in the PIS, was significantly reduced, and lipogenic genes, which are induced under conditions of reduced endogenous DHA synthesis, were increased in homozygous KO mice. The causal relationship between ADIPOR1 deficiency and Elovl2 repression, together with upregulation of lipogenic genes, was confirmed in vitro. Therefore, ADIPOR1 in the retina appears to be indispensable for ELOVL2 induction, which is likely required to supply sufficient DHA for appropriate photoreceptor function and survival.
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http://dx.doi.org/10.1038/s41419-021-03741-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105316PMC
May 2021

Positive Effects of Oral Antibiotic Administration in Murine Chronic Graft-Versus-Host Disease.

Int J Mol Sci 2021 Apr 3;22(7). Epub 2021 Apr 3.

Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan.

Chronic graft-versus-host disease (cGVHD) is one of the most frequent complications experienced after allogeneic hematopoietic stem cell transplantation. Reportedly, dysbiosis and severe damage to the microbiome are also closely associated with GVHD. Herein, we aimed to elucidate the positive and negative effects of the administration of various antibiotics in a murine model of cGVHD. For allogeneic bone marrow transplantation (allo-BMT), bone marrow from B10.D2 mice were transplanted in BALB/c mice to induce cGVHD. The cGVHD mice were orally administered ampicillin, gentamicin (GM), fradiomycin, vancomycin, or the solvent vehicle (control group). Among the antibiotic-treated mice, the systemic cGVHD phenotypes and ocular cGVHD manifestations were suppressed significantly in GM-treated mice compared to that in control mice. Inflammatory cell infiltration and fibrosis in cGVHD-targeted organs were significantly attenuated in GM-treated mice. Although regulatory T cells were retained at greater levels in GM-treated mice, there were significantly fewer Th17 cells and interleukin (IL)-6-producing macrophages in cGVHD-targeted organs in these mice. Collectively, our results revealed that orally administered GM may exert positive effects in a cGVHD mouse model.
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http://dx.doi.org/10.3390/ijms22073745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038334PMC
April 2021

Sleep and subjective happiness between the ages 40 and 59 in relation to presbyopia and dry eye.

PLoS One 2021 23;16(4):e0250087. Epub 2021 Apr 23.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

Purpose: The aim of this study was to explore the status of quality of life between the ages 40-59 in relation to presbyopia and dry eye.

Methods: Near add power and preferred contact lens power were examined in 219 participants at three clinics. 2000 participants completed a web-based survey on presbyopic symptoms, symptomatic dry eye, sleep quality, and subjective happiness.

Results: Mean preferred corrected visual acuity was less than 20/20 in women (vs men, P<0.01) who were more often prescribed under-corrected contact lenses, whereas men preferred full correction. According to the annual progression rate of near add power in men (0.1468D/year), the estimated difference in presbyopia progression between men and women was 0.75 years in the right eye, and 1.69 years in the left eye, implying men might suffer presbyopia earlier than women due to higher myopic power of daily use contact lenses. The web-based survey revealed that men reported lower subjective happiness than women (P<0.001) and earlier onset of presbyopic symptoms by 1.1-1.7 years (P<0.05). Men received their first reading glasses 0.8 years earlier than women (P = 0.066). Multiple regression analysis demonstrated that awareness of presbyopic symptoms, visual burden, and dry eyes were significantly correlated with poor sleep quality and subjective happiness.

Conclusion: Presbyopia and dry eye were significantly associated with sleep quality and subjective happiness in middle-adulthood.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250087PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064542PMC
April 2021

Relationship between unhealthy sleep status and dry eye symptoms in a Japanese population: The JPHC-NEXT study.

Ocul Surf 2021 Apr 17. Epub 2021 Apr 17.

Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.

Purpose: To investigate whether and how unhealthy sleep habits (i.e., the frequency of difficulty falling or staying asleep, and the frequency of waking up tired) and the duration of sleep are related to the prevalence of dry eye disease (DED) in a general population.

Methods: This study included a total of 106,282 subjects aged 40-74 years who participated in a baseline survey of the Japan Public Health Center-based Prospective Study for the Next Generation. DED was defined as the presence of clinically diagnosed DED or severe symptoms. Multivariable-adjusted logistic regression models were used to assess the relationships of various components of sleep status with DED.

Results: Higher frequencies of having difficulty falling or staying asleep, and waking up tired were significantly related to increased DED in both sexes (P<0.001). Compared with those with 8 h/day of sleep, shorter sleepers had an increased prevalence of DED in both sexes, although DED was increased among men who slept ≥10 h/day. By comparing participants with the greatest vs. the least difficulty of falling asleep, the multivariable-adjusted odds ratios (95% confidence interval [CI]) were 2.23 (95% CI, 1.99-2.49) for men and 1.91 (95% CI, 1.76-2.07) for women. When analyzed separately, the magnitude of each relationship was stronger with severe DED symptoms than with clinically diagnosed DED.

Conclusions: Sleep deprivation and poor sleep quality were significantly related to DED in a Japanese population.
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http://dx.doi.org/10.1016/j.jtos.2021.04.001DOI Listing
April 2021

Two case reports of continued progression of chronic ocular graft-versus-host disease without concurrent systemic comorbidities treated by amniotic membrane transplantation.

BMC Ophthalmol 2021 Apr 7;21(1):164. Epub 2021 Apr 7.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

Background: Chronic ocular graft-versus-host disease (oGVHD) is an ocular comorbidity of graft-versus-host disease (GVHD) that usually occurs concurrently with systemic manifestations. Failure to detect and treat oGVHD in its early stages may lead to progression of ocular signs and symptoms leading to oGVHD that is refractory to conventional treatment.

Case Presentation: We report the clinical course of a 19-year-old male and a 59-year-old female with severe and progressive chronic oGVHD without concurrent systemic signs of chronic graft-versus-host disease (cGVHD). Although their systemic conditions had been stable, both suffered from severe oGVHD and were referred to our clinic. Both cases exhibited marked improvement in conjunctival inflammation and fibrotic changes after amniotic membrane transplantation (AMT). Both cases underwent keratoplasty eventually to stabilize ocular surface conditions and to improve visual function.

Conclusions: We reported the clinical outcomes of 2 cases of chronic oGVHD without concurrent systemic comorbidities that were treated with AMT. The clinician should be aware that cGVHD may persist in target organs even in the absence of concurrent systemic comorbidities following seemingly successful systemic treatment. A multidisciplinary team approach is essential in the early detection and therapeutic intervention for chronic oGVHD.
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http://dx.doi.org/10.1186/s12886-021-01925-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028795PMC
April 2021

Clinical Observation of Allergic Conjunctival Diseases with Portable and Recordable Slit-Lamp Device.

Diagnostics (Basel) 2021 Mar 17;11(3). Epub 2021 Mar 17.

Department of Ophthalmology, Tsurumi University School of Dental Medicine, Kanagawa 230-0063, Japan.

Background: The incidence of allergic conjunctival diseases (ACDs) is gradually increasing worldwide. Both ophthalmologists and non-ophthalmologists prescribe eye drops to treat ACDs; however, there are many cases which are treated without sufficient examination and diagnosis of the eyes. We have invented a portable, recordable, and smartphone-attachable slit-lamp device-Smart Eye Camera (SEC). The purpose of this study was to compare the diagnostic abilities of ACDs between the SEC and the conventional, non-portable slit-lamp microscope.

Methods: This prospective observational study included 32 eyes of 17 Japanese patients (mean age: 21.5 ± 14.8 years; range: 11-51 years; female: 5). The severity of 10 objective signs in the palpebral conjunctiva, bulbar conjunctiva, limbus, and cornea were scored on a grading scale of 0 to 4 (0 = normal; 1+ = mild; 2+ = moderate; 3+ = severe), respectively. First, the conventional slit-lamp microscope was used to examine the grade of the ACDs. Second, another ophthalmologist filmed the eyes using the SEC and two other ophthalmologists evaluated the grades on another day. The correlation and inter-rater reproducibility in total scores among the two devices were determined.

Results: Total scores of clinical signs, evaluated by the two approaches, correlated significantly (both eyes: r = 0.918 (95% CI: 0.839 to 0.959; < 0.001)), with substantial inter-rater agreement (weighted value = 0.631 (95% CI: 0.601 to 0.661; < 0.001)).

Conclusions: The SEC is as reliable as the conventional non-portable slit-lamp microscope for assessing ACDs.
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http://dx.doi.org/10.3390/diagnostics11030535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002473PMC
March 2021

Fenofibrate Protects against Retinal Dysfunction in a Murine Model of Common Carotid Artery Occlusion-Induced Ocular Ischemia.

Pharmaceuticals (Basel) 2021 Mar 7;14(3). Epub 2021 Mar 7.

Laboratory of Photobiology, Keio University School of Medicine, Tokyo 160-8582, Japan.

Ocular ischemia is a common cause of blindness and plays a detrimental role in various diseases such as diabetic retinopathy, occlusion of central retinal arteries, and ocular ischemic syndrome. Abnormalities of neuronal activities in the eye occur under ocular ischemic conditions. Therefore, protecting their activities may prevent vision loss. Previously, peroxisome proliferator-activated receptor alpha (PPARα) agonists were suggested as promising drugs in ocular ischemia. However, the potential therapeutic roles of PPARα agonists in ocular ischemia are still unknown. Thus, we attempted to unravel systemic and ocular changes by treatment of fenofibrate, a well-known PPARα agonist, in a new murine model of ocular ischemia. Adult mice were orally administered fenofibrate (60 mg/kg) for 4 days once a day, followed by induction of ocular ischemia by unilateral common carotid artery occlusion (UCCAO). After UCCAO, fenofibrate was continuously supplied to mice once every 2 days during the experiment period. Electroretinography was performed to measure retinal functional changes. Furthermore, samples from the retina, liver, and blood were subjected to qPCR, Western blot, or ELISA analysis. We found that fenofibrate boosted liver function, increased serum levels of fibroblast growth factor 21 (FGF21), one of the neuroprotective molecules in the central nervous system, and protected against UCCAO-induced retinal dysfunction. Our current data suggest a promising fenofibrate therapy in ischemic retinopathies.
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http://dx.doi.org/10.3390/ph14030223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999063PMC
March 2021

Possible favorable lifestyle changes owing to the coronavirus disease 2019 (COVID-19) pandemic among middle-aged Japanese women: An ancillary survey of the TRF-Japan study using the original "Taberhythm" smartphone app.

PLoS One 2021 25;16(3):e0248935. Epub 2021 Mar 25.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

Coronavirus disease 2019 (COVID-19) has had a global effect on people's lifestyles. Many people have become physically inactive and developed irregular eating patterns, which leads to unhealthier lifestyles and aggravation of lifestyle-related diseases; these in turn increase the severity of COVID-19. Prior to the COVID-19 pandemic, we developed a smartphone application called "Taberhythm" to investigate eating patterns, physical activity, and subjective feelings of happiness. We aimed to compare lifestyle data before and during the first phase of the COVID-19 pandemic to objectively assess lifestyle changes during quarantine. A total of 464 smartphone users (346 women, 35 ± 12 years old, body mass index [BMI] 23.4 ± 4.5) participated in Period A (January 7 to April 28, 2019) and 622 smartphone users (533 women, 32 ± 11 years old, BMI 23.3 ± 4.0) participated in Period B (January 6 to April 26, 2020). Compared with Period A, there was a sharp decline in physical activity during Period B (4642 ± 3513 vs. 3814 ± 3529 steps/day, p<0.001), especially during the final 9 weeks in both periods (4907 ± 3908 vs. 3528 ± 3397 steps/day, p<0.001); however, there were large variations in physical activity among participants. We found a surprising trend during Period B toward increased happiness among women aged 30-50 years, the group most affected by stay-at-home policies that led to working from home and school closure. Moreover, daily eating duration declined in this population. Additionally, there was a positive association of happiness with steps per day in Period B (ρ = 0.38, p = 0.02). Despite the many negative effects of the COVID-19 pandemic, subjective feelings of happiness among middle-aged Japanese women tended to increase, which indicates that some favorable lifestyle changes that could be adopted during quarantine in the ongoing COVID-19 pandemic.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248935PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993768PMC
April 2021

Randomized, crossover clinical efficacy trial in humans and mice on tear secretion promotion and lacrimal gland protection by molecular hydrogen.

Sci Rep 2021 Mar 19;11(1):6434. Epub 2021 Mar 19.

Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan.

The incidence of dry eye disease is increasing worldwide because of the aging population and increasing use of information technology. Dry eye disease manifests as tear-layer instability and inflammation caused by osmotic hypersensitization in tear fluids; however, to our knowledge, no agent that treats both pathologies simultaneously is available. Molecular hydrogen (H) is known to be effective against various diseases; therefore, we aimed to elucidate the effects of H on tear dynamics and the treatment of dry eye disease. We revealed that administering a persistent H-generating supplement increased the human exhaled H concentration (p < 0.01) and improved tear stability (p < 0.01) and dry eye symptoms (p < 0.05) significantly. Furthermore, H significantly increased tear secretion in healthy mice (p < 0.05) and significantly suppressed tear reduction in a murine dry eye model (p = 0.007). H significantly and safely improved tear stability and dry eye symptoms in a small exploratory group of 10 human subjects, a subset of whom reported dry eye symptoms prior to treatment. Furthermore, it increased tear secretion rapidly in normal mice. Therefore, H may be a safe and effective new treatment for dry eye disease and thus larger trials are warranted.
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http://dx.doi.org/10.1038/s41598-021-85895-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979688PMC
March 2021

Myopia, corneal endothelial cell density and morphology in a Japanese population-based cross-sectional study: the JPHC-NEXT Eye Study.

Sci Rep 2021 Mar 18;11(1):6366. Epub 2021 Mar 18.

Department of Public Health, Graduate School of Medicine, Osaka University, Suita, Japan.

This population-based cross-sectional study was performed to determine the mean corneal endothelial cell density (ECD), coefficient of variation (CV), and hexagonality (HEX), and their associations with myopia in Japanese adults living in Chikusei city. Of 7109 participants with available data, 5713 (2331 male and 3382 female) participants were eligible for analysis. After assessing the relationship between participant characteristics and spherical equivalent refraction (SER), the association of SER with the abnormal value of ECD (< 2000 cells/mm), CV (≥ 0.40), and HEX (≤ 50%) were determined using the logistic regression models adjusting for potential confounders (age, intraocular pressure, keratometric power, height, and antihypertensive drug use). In male participants, there was no statistically significant relationships between SER and endothelial parameters. In female participants, compared to emmetropia, SER ≤ - 6 D had significantly higher odds ratio (OR) of having the abnormal value of CV (OR = 2.07, 95% confidence interval [CI] 1.39-3.10) and HEX (OR = 2.04, 95% CI 1.29-3.23), adjusted for potential confounders, indicating that the high myopia was associated with the abnormal values of CV and HEX. Further adjustment for contact lenses wear partly attenuated these associations. Association between the SER and ECD was not detected.
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http://dx.doi.org/10.1038/s41598-021-85617-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973534PMC
March 2021

Taurine rescues mitochondria-related metabolic impairments in the patient-derived induced pluripotent stem cells and epithelial-mesenchymal transition in the retinal pigment epithelium.

Redox Biol 2021 May 28;41:101921. Epub 2021 Feb 28.

Laboratory of Retinal Cell Biology, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan; Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan; Department of Ophthalmology, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan; St. Luke's International University, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan. Electronic address:

Mitochondria participate in various metabolic pathways, and their dysregulation results in multiple disorders, including aging-related diseases. However, the metabolic changes and mechanisms of mitochondrial disorders are not fully understood. Here, we found that induced pluripotent stem cells (iPSCs) from a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) showed attenuated proliferation and survival when glycolysis was inhibited. These deficits were rescued by taurine administration. Metabolomic analyses showed that the ratio of the reduced (GSH) to oxidized glutathione (GSSG) was decreased; whereas the levels of cysteine, a substrate of GSH, and oxidative stress markers were upregulated in MELAS iPSCs. Taurine normalized these changes, suggesting that MELAS iPSCs were affected by the oxidative stress and taurine reduced its influence. We also analyzed the retinal pigment epithelium (RPE) differentiated from MELAS iPSCs by using a three-dimensional culture system and found that it showed epithelial mesenchymal transition (EMT), which was suppressed by taurine. Therefore, mitochondrial dysfunction caused metabolic changes, accumulation of oxidative stress that depleted GSH, and EMT in the RPE that could be involved in retinal pathogenesis. Because all these phenomena were sensitive to taurine treatment, we conclude that administration of taurine may be a potential new therapeutic approach for mitochondria-related retinal diseases.
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http://dx.doi.org/10.1016/j.redox.2021.101921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944050PMC
May 2021

Predicting Keratoconus Progression and Need for Corneal Crosslinking Using Deep Learning.

J Clin Med 2021 Feb 18;10(4). Epub 2021 Feb 18.

Department of Ophthalmology, School of Medicine, Keio University, Tokyo 160-8582, Japan.

We aimed to predict keratoconus progression and the need for corneal crosslinking (CXL) using deep learning (DL). Two hundred and seventy-four corneal tomography images taken by Pentacam HR (Oculus, Wetzlar, Germany) of 158 keratoconus patients were examined. All patients were examined two times or more, and divided into two groups; the progression group and the non-progression group. An axial map of the frontal corneal plane, a pachymetry map, and a combination of these two maps at the initial examination were assessed according to the patients' age. Training with a convolutional neural network on these learning data objects was conducted. Ninety eyes showed progression and 184 eyes showed no progression. The axial map, the pachymetry map, and their combination combined with patients' age showed mean AUC values of 0.783, 0.784, and 0.814 (95% confidence interval (0.721-0.845) (0.722-0.846), and (0.755-0.872), respectively), with sensitivities of 87.8%, 77.8%, and 77.8% ((79.2-93.7), (67.8-85.9), and (67.8-85.9)) and specificities of 59.8%, 65.8%, and 69.6% ((52.3-66.9), (58.4-72.6), and (62.4-76.1)), respectively. Using the proposed DL neural network model, keratoconus progression can be predicted on corneal tomography maps combined with patients' age.
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http://dx.doi.org/10.3390/jcm10040844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923054PMC
February 2021

A Study Validating the Estimation of Anterior Chamber Depth and Iridocorneal Angle with Portable and Non-Portable Slit-Lamp Microscopy.

Sensors (Basel) 2021 Feb 19;21(4). Epub 2021 Feb 19.

Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan.

This study assessed the anterior chamber depth (ACD) and iridocorneal angle using a portable smart eye camera (SEC) compared to the conventional slit-lamp microscope and anterior-segment optical coherence tomography (AS-OCT). This retrospective case-control study included 170 eyes from 85 Japanese patients. The correlation between the ACD evaluations conducted with the SEC and conventional slit-lamp was high (r = 0.814). The correlation between the Van-Herick Plus grade obtained using two devices was also high (r = 0.919). A high kappa value was observed for the Van-Herick Plus grading (Kappa = 0.757). A moderate correlation was observed between the ACD measured using AS-OCT and the slit-lamp image acquired with the conventional slit-lamp microscope and SEC (r = 0.609 and 0.641). A strong correlation was observed between the trabecular-iris angle (TIA) measured using AS-OCT and Van-Herick Plus grade obtained with the conventional slit-lamp microscope and SEC (r = 0.702 and 0.764). Strong correlations of ACD evaluation and high kappa value of the Van-Herick Plus grading indicated the adequate subjective assessment function of the SEC. Moderate correlations between the ACD objective measurement and evaluation and strong correlation between the TIA and Van-Herick Plus grade suggested the good objective assessment function of the SEC. The SEC demonstrated adequate performance for ACD evaluation and angle estimation.
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http://dx.doi.org/10.3390/s21041436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921911PMC
February 2021

Circadian clock regulates tear secretion in the lacrimal gland.

Exp Eye Res 2021 May 2;206:108524. Epub 2021 Mar 2.

Department of Ophthalmology, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan; Tsubota Laboratory, Inc., 304 Toshin-ekimae Bldg., 34 Shinanomachi, Shinjuku-ku, Tokyo, 160-0016, Japan. Electronic address:

Although diurnal variations have been observed in tear film parameters in various species, the molecular mechanisms that control circadian tear secretion remain unclear. The aim of our study was to evaluate the role of clock genes in the lacrimal gland (LG) in regulation of tear secretion. Tear volume was measured by cotton thread test in core clock genes deficient (Cry1Cry2) mice which are behaviorally arrhythmic. Real-time quantitative RT-PCR was used to examine expression profiles of core clock genes in the LG including Per1, Per2, Per3, Clock, Bmal1. All experiments were performed under a 12 h of light and 12 h of darkness (LD) and constant dark (DD) conditions. Under both LD and DD conditions, diurnal and circadian rhythms were observed in tear secretion of wild-type mice with tear volume increased in the objective and subjective night while disruption in diurnal and circadian variations of tear secretion were found in Cry1Cry2mice. In wild-type mice, the expression level of major clock genes in the LG showed oscillatory patterns under both LD and DD conditions. In contrast, expression clock genes in the lacrimal gland of Cry1Cry2 mice showed complete loss of oscillation regardless of environmental light conditions. These findings confirmed the presence of diurnal and circadian rhythms of tear secretion and provided evidences supporting a critical role for the clock in the control of tear secretion.
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http://dx.doi.org/10.1016/j.exer.2021.108524DOI Listing
May 2021

Efficacy and safety of 0.01% atropine for prevention of childhood myopia in a 2-year randomized placebo-controlled study.

Jpn J Ophthalmol 2021 May 14;65(3):315-325. Epub 2021 Feb 14.

Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, Kyoto, 602-0841, Japan.

Purpose: Atropine eye drops prevent the progression of myopia, but their use has not been tested in the Japanese schoolchildren population. Here, we evaluate the efficacy and safety of 0.01% atropine eye drops for myopia control in Japanese children.

Study Design: Multicenter (7 university hospitals), randomized, double-masked, placebo-controlled trial.

Methods: Participants were 171 Japanese schoolchildren aged 6 to 12 years, with progressive myopia, spherical equivalence (SE) of -1.00 to -6.00 diopters (D), and astigmatism of ≤1.5 D. They were randomized to receive either 0.01% atropine (n=85) or placebo (n=86) eye drops once nightly OU for 24 months. Primary and secondary efficacy endpoints were changes in SE and axial length (AL), respectively, from baseline to month 24.

Results: Data from 168 subjects were analyzed. At month 24, compliance was similar in both groups (atropine: 83.3%; placebo: 85.7%). The least squares mean change in SE and AL from baseline were, respectively, -1.26 D (95% confidence interval [CI]: -1.35, -1.17) and 0.63 mm (0.59, 0.67) for atropine and -1.48 D (- 1.57, -1.39) and 0.77 mm (0.73, 0.81) for placebo. Inter-group differences were 0.22 D (95% CI: 0.09, 0.35; P < 0.001) for SE and - 0.14 mm (-0.20, -0.08; P < 0.001) for AL. Three patients experienced mild allergic conjunctivitis side effects, with no inter-group difference in incidence (atropine: 2.4%; 2/84 patients; placebo: 1.4%; 1/84 patients).

Conclusion: With good compliance, 0.01% atropine is effective and safe for preventing the progression of childhood myopia.
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http://dx.doi.org/10.1007/s10384-021-00822-yDOI Listing
May 2021

Oral administration of resveratrol or lactic acid bacterium improves lens elasticity.

Sci Rep 2021 Jan 26;11(1):2174. Epub 2021 Jan 26.

Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

A decrease in the elasticity of the ocular lens during aging is associated with loss of the accommodative ability of the eye, leading to presbyopia. Although near vision impairment is a social issue affecting the length of healthy life expectancy and productivity of elderly people, an effective treatment to improve near vision has not yet become available. Here we examined the effect of Enterococcus faecium WB2000, Lactobacillus pentosus TJ515, and resveratrol on lens elasticity in rats, where the stiffness of the ocular lens increases exponentially during the aging process. A combination of WB2000 and resveratrol improved lens elasticity not only in the long term but also with just short-term treatment. In addition, TJ515 decreased stiffness in the eye lens with long-term treatment. Therefore, the oral administration of WB2000 and resveratrol or TJ515 may be a potential approach for managing the progression of near vision impairment.
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http://dx.doi.org/10.1038/s41598-021-81748-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838312PMC
January 2021

A Novel Technique to Treat a Recurrent Giant Conjunctival Cyst: A Case Report.

Cornea 2021 Apr;40(4):e8-e9

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.1097/ICO.0000000000002673DOI Listing
April 2021

Cataract type and pupillary response to blue and white light stimuli.

Sci Rep 2021 Jan 19;11(1):1828. Epub 2021 Jan 19.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

We evaluated the pupil reaction to blue and white light stimulation in 70 eyes with cataract and in 38 eyes with a selective blue-light filtering intra-ocular lens. The diameter of the pupil before stimulation was set as baseline (BPD) and, after a stimulus duration of 1 s, the post-illumination pupillary response (PIPR) was measured using an electronic pupillometer. The BPD showed no significant difference among three grades of nuclear sclerosis (NS). In contrast, the PIPRs differed significantly among the NS grades eyes including with and without subcapsular cataract (SC) and IOL eyes for white light (p < 0.05, Kruskal-Wallis test), but not for blue light. Subcapsular opacity did not affect the BPD or PIPR in all cataract grades for either light stimulus. The tendency of larger PIPR in the pseudophakic eyes than the cataract eyes for both lights, however significant difference was found only for white light (p < 0.05 for white light, p > 0.05 for blue light). Our study demonstrates retention of the PIPR for blue light, but not for white light in cataract eyes. We also confirmed that the pupillary response in pseudohakic eyes with a selective blue light-filtering intra ocular lens was greater than that in cataractous eyes for white light.
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http://dx.doi.org/10.1038/s41598-020-79751-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815835PMC
January 2021

Axial Length and Prevalence of Myopia among Schoolchildren in the Equatorial Region of Brazil.

J Clin Med 2020 Dec 31;10(1). Epub 2020 Dec 31.

Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

The prevalence of myopia is increasing globally, and the outdoor light environment is considered as a possible factor that can retard myopia. The aim of this study was to evaluate the prevalence of myopia and the light environment in Aracati, equatorial Brazil. We surveyed 421 children (421 right eyes; mean age, 10.6 years) and performed ocular examinations that included non-cycloplegic refraction and axial length (AL). Multiple regression analyses were performed to identify factors affecting myopia such as time spent outdoors and in near work. We measured illuminance and violet light irradiance in Aracati. The mean spherical equivalent (SE) and AL were -0.44 ± 1.38 diopters (D) and 22.98 ± 0.87 mm, respectively. The prevalence of myopia (SE ≤ -0.75 D) and high myopia (SE ≤ -6.0 D/AL ≥ 26.0 mm) was 20.4 and 1.4/0.48%, respectively. Multiple regression analyses showed that myopia was not associated with lifestyle factors. The average illuminance in Aracati was about 100,000 lux from morning to evening. The current results reflect the ALs and the prevalence of myopia among Brazilian schoolchildren. There is a possibility that the light environment in addition to other confounding factors including racial differences affects the ALs and refractive errors.
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http://dx.doi.org/10.3390/jcm10010115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794886PMC
December 2020

A New Modified Experimental Meibomian Gland Injury Model: Partial Loss of Gland Due to Orifice Cauterization and the Alleviating Potential of 22-Oxacalcitriol.

J Clin Med 2020 Dec 22;10(1). Epub 2020 Dec 22.

Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan.

1α,-25-dihydroxy-22-oxacalcitriol (maxacalcitol) is a non-calcemic vitamin D3 analog clinically approved to treat psoriasis, and its role has been increasingly recognized in suppressing keratinocyte proliferation, mediating inflammation, and regulating the immune response. A large number of studies have suggested that vitamin D plays an important role in maintaining ocular surface health. However, its topical effects on the Meibomian gland (MG) has been insufficiently investigated. Here, we introduce an experimental MG orifice injury model, where the partial glandular loss occurred after electrical cauterization on a limited number of MG orifices, and investigate the efficacy and safety of maxacalcitol ointment in treating this MG orifice injury model. We confirm the alleviation of MG atrophy and ductal dilation by maxacalcitol ointment application. The recovery of injured MG visualizing as the residual MG area is significantly better in the maxacalcitol group ( = 0.020) compared with the Vaseline group, especially during the first two weeks. The cornea and other ocular tissues were not affected by maxacalcitol ointment application during our two-month observation period. Altogether, this work indicates that maxacalcitol has therapeutic potential in the amelioration of initial injury of MG orifices caused by electrocautery.
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http://dx.doi.org/10.3390/jcm10010006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792963PMC
December 2020

Long-term follow-up of a Chinese patient with -retinopathy.

Ophthalmic Genet 2021 04 29;42(2):144-149. Epub 2020 Dec 29.

Ophthalmology Department, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China.

: To characterize and monitor the clinical and electrophysiological features of a Chinese patient with retinopathy.: A 17-year-old Chinese male with the diagnosis of cone dystrophy with supernormal rod response (CDSRR) was followed-up for 5 years, with full ophthalmological examinations, including decimal best corrected visual acuity (BCVA), fundus photography, fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinogram (ERG). Genetic screening was performed to detect the sequence variations in the retinal dystrophy associated genes in the patient and his parents.: The patient demonstrated the characteristic full-field electroretinography (ERG) features of CDSRR, namely a profound enlargement of the dark-adapted ERG b-wave amplitude with increasing flash strength and a broadened a-wave trough; this case also had undetectable light-adapted ERGs. A BCVA of 0.15 was maintained over 5 years in both eyes; while progressive macular atrophy was identified. Molecular genetic analyses revealed two novel disease-causing variants in compound heterozygous state: c.1408 G > C (p.Gly470Arg) and c.1500 C > G (p.Tyr500Ter).: This is the first long-term case study of an East Asian patient with molecularly confirmed CDSRR. The progressive atrophy with maintained VA demonstrated in this case will be valuable for increasing the understanding of the natural course of retinopathy and it will help in counselling patients with this disease.
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http://dx.doi.org/10.1080/13816810.2020.1861307DOI Listing
April 2021

Axial length shortening in a myopic child with anisometropic amblyopia after wearing violet light-transmitting eyeglasses for 2 years.

Am J Ophthalmol Case Rep 2020 Dec 11;20:101002. Epub 2020 Dec 11.

Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Purpose: To report a case in which the axial length (AL) shortened and the choroid thickened due to the use of violet light-transmitting eyeglasses.

Observations: A 4-year-old boy with high myopia was referred to Keio University Hospital. He was prescribed standard eyeglasses. Six months after the first visit, his best-corrected visual acuities were 1.2 and 0.4 in the right and left eyes, respectively, with the standard eyeglasses, and he was diagnosed with anisometropic amblyopia. The right eye then was patched for 6 hours daily during the daytime. Because of the availability of violet light-transmitting eyeglasses, we changed the eyeglasses and instructed his parents to have him engage in outdoor activities for over 2 hours daily to be exposed to sufficient violet light. As a result, the violet light entered his left eye and minimal violet light entered his right eye. The changes in the ALs, choroidal thicknesses, and cycloplegic objective refractions in the right and left eyes during 2 years of wearing violet light-transmitting eyeglasses were +0.85 and -0.20 mm, +4.9 and + 115.7 μm, and -1.02 and + 1.88 D, respectively.

Conclusions And Importance: We successfully described a case in which the myopia improved, the AL shortened, and the choroid thickened after using violet light-transmitting eyeglasses.
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http://dx.doi.org/10.1016/j.ajoc.2020.101002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750137PMC
December 2020

Renin-angiotensin system impairs macrophage lipid metabolism to promote age-related macular degeneration in mouse models.

Commun Biol 2020 Dec 9;3(1):767. Epub 2020 Dec 9.

Laboratory of Retinal Cell Biology, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo, 160-8582, Japan.

Metabolic syndrome, a condition involving obesity and hypertension, increases the risk of aging-associated diseases such as age-related macular degeneration (AMD). Here, we demonstrated that high-fat diet (HFD)-fed mice accumulated oxidized low-density lipoprotein (ox-LDL) in macrophages through the renin-angiotensin system (RAS). The ox-LDL-loaded macrophages were responsible for visual impairment in HFD mice along with a disorder of the retinal pigment epithelium (RPE), which is required for photoreceptor outer segment renewal. RAS repressed ELAVL1, which reduced PPARγ, impeding ABCA1 induction to levels that are sufficient to excrete overloaded cholesterol within the macrophages. The ox-LDL-loaded macrophages expressed inflammatory cytokines and attacked the RPE. An antihypertensive drug, angiotensin II type 1 receptor (AT1R) blocker, resolved the decompensation of lipid metabolism in the macrophages and reversed the RPE condition and visual function in HFD mice. AT1R signaling could be a future therapeutic target for macrophage-associated aging diseases, such as AMD.
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http://dx.doi.org/10.1038/s42003-020-01483-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725839PMC
December 2020

Defining Dry Eye from a Clinical Perspective.

Int J Mol Sci 2020 Dec 4;21(23). Epub 2020 Dec 4.

Cornea & Refractive Surgery, Massachusetts Eye & Ear, Boston, MA 02114, USA.

Over the past decades, the number of patients with dry eye disease (DED) has increased dramatically. The incidence of DED is higher in Asia than in Europe and North America, suggesting the involvement of cultural or racial factors in DED etiology. Although many definitions of DED have been used, discrepancies exist between the various definitions of dry eye disease (DED) used across the globe. This article presents a clinical consensus on the definition of DED, as formulated in four meetings with global DED experts. The proposed new definition is as follows: "Dry eye is a multifactorial disease characterized by a persistently unstable and/or deficient tear film (TF) causing discomfort and/or visual impairment, accompanied by variable degrees of ocular surface epitheliopathy, inflammation and neurosensory abnormalities." The key criteria for the diagnosis of DED are unstable TF, inflammation, ocular discomfort and visual impairment. This definition also recommends the assessment of ocular surface epitheliopathy and neurosensory abnormalities in each patient with suspected DED. It is easily applicable in clinical practice and should help practitioners diagnose DED consistently. This consensus definition of DED should also help to guide research and clinical trials that, to date, have been hampered by the lack of an established surrogate endpoint.
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http://dx.doi.org/10.3390/ijms21239271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730816PMC
December 2020

Oral Bovine Milk Lactoferrin Administration Suppressed Myopia Development through Matrix Metalloproteinase 2 in a Mouse Model.

Nutrients 2020 Dec 5;12(12). Epub 2020 Dec 5.

Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

Recent studies have reported an association between myopia development and local ocular inflammation. Lactoferrin (LF) is an iron-binding protein present in saliva, tears, and mother's milk. Furthermore, sequestering iron by LF can cause its antibacterial property. Moreover, LF has an anti-inflammatory effect. We aimed to determine the suppressive effect of LF against the development and progress of myopia using a murine lens-induced myopia (LIM) model. We divided male C57BL/6J mice (3 weeks old) into two groups. While the experimental group was orally administered LF (1600 mg/kg/day, from 3-weeks-old to 7-weeks-old), a similar volume of Ringer's solution was administered to the control group. We subjected the 4-week-old mice to -30 diopter lenses and no lenses on the right and left eyes, respectively. We measured the refraction and the axial length at baseline and 3 weeks after using a refractometer and a spectral domain optical coherence tomography (SD-OCT) system in both eyes. Furthermore, we determined the matrix metalloproteinase-2 (MMP-2) activity, and the amount of interleukin-6 (IL-6), MMP-2, and collagen 1A1 in the choroid or sclera. The eyes with a minus lens showed a refractive error shift and an axial length elongation in the control group, thus indicating the successful induction of myopia. However, there were no significant differences in the aforementioned parameters in the LF group. While LIM increased IL-6 expression and MMP-2 activity, it decreased collagen 1A1 content. However, orally administered LF reversed these effects. Thus, oral administration of LF suppressed lens-induced myopia development by modifying the extracellular matrix remodeling through the IL-6-MMP-2 axis in mice.
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http://dx.doi.org/10.3390/nu12123744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762016PMC
December 2020

The Overlap Syndrome: A Case Report of Chronic Graft-Versus-Host Disease After the Development of a Pseudomembrane.

Cornea 2020 Dec 7. Epub 2020 Dec 7.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

Background: Ocular graft-versus-host disease (GVHD) is one of the most severe complications of hematopoietic stem cell transplantation. It manifests as an impairment of the ocular surface, such as severe dry eye disease, and deteriorates the recipient's visual function and quality of life. We encountered an "overlap syndrome" of ocular GVHD, which is characterized by the presence of both acute and chronic GVHD symptoms. In this report, we present the treatment progress of the overlap syndrome in a case with ocular GVHD.

Case Presentation: A 57-year-old man with acute myeloblastic leukemia underwent hematopoietic stem cell transplantation. Six weeks after the treatment, the recipient complained of eye pain and discharge. He was diagnosed with the overlap syndrome due to low tear volume, severe corneal epithelitis, hyperemia, and a pseudomembrane on the conjunctiva. Immune cells infiltration, fibrinoid degeneration, fibroblastic and spindle-shaped cells, and fibrosis were observed in the pathology of the pseudomembrane. The recipient was treated with topical immunosuppression and pseudomembrane removal. One week after the initial treatment, ocular GVHD improved. Twelve weeks after the treatment, the topical steroid was discontinued due to the elevation of intraocular pressure.

Conclusions: The assessment of conjunctival pseudomembrane in ocular GVHD is important to determine the stage of the case and to assess systemic GVHD. Furthermore, prompt removal of the pseudomembrane after diagnosis is an appropriate management to reduce the symptoms of ocular GVHD. The combination of topical steroids and immunosuppressive agents is suggested to be an effective treatment in management of overlap syndrome.
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http://dx.doi.org/10.1097/ICO.0000000000002593DOI Listing
December 2020

Efficacy of the Newly Invented Eyelid Clamper in Ultra-Widefield Fundus Imaging.

Life (Basel) 2020 Dec 2;10(12). Epub 2020 Dec 2.

Laboratory of Photobiology, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

Background: Ultra-widefield fundus imaging is widely used for obtaining wide angle images of the retina in one single image. Although it has a potential to obtain a wide area of retinal photographs, images are often obstructed by eyelashes or eye lids. In this study, we used a newly invented eyelid clamper, which can keep an eye open without touching conjunctiva or lid margin, to assess the efficacy in clinical use by comparing with conventional tape fixation.

Methods: Ultra-widefield fundus images were captured with an ultra-widefield imaging system in 19 patients who visited to the outpatient clinic of Department of Ophthalmology, Keio University Hospital with the eyelid clamper or a conventional tape fixation. The area of imaged retinas was outlined and quantified with pixels. After obtaining images, patients answered a questionnaire.

Results: The average number of pixels in total areas with the eyelid clamper or with tape fixation were 4.31 ± 0.35 and 4.32 ± 0.34 mega pixels, respectively, showing no significant difference between the groups ( = 0.889). The average face pain scale of the eyelid clamper was 1.13 on a scale of 0 to 5. The number of patients who did not feel any pain was nine (47.4%).

Conclusions: The eyelid clamper can be applied in clinical setting and can better support obtaining sufficiently wide fundus images compared to a conventional tape fixation.
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http://dx.doi.org/10.3390/life10120323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761601PMC
December 2020

Strip Meniscometry Correlates With Ocular Surface Tests and Symptoms.

Transl Vis Sci Technol 2020 11 25;9(12):31. Epub 2020 Nov 25.

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

Purpose: The aim of this study was to investigate the association of dry eye disease (DED)-related signs and symptoms with two tear function tests.

Methods: This was a clinic-based, cross-sectional study with recruitment of consecutive participants. Schirmer test (ST), tear strip meniscometry (SM), and fluorescein tear breakup time were measured and corneal staining score was examined in outpatients at three clinics. Seven subjective symptoms were assessed by interview, including dryness, irritation, pain, lacrimation, fatigue, blurring, and photophobia. Statistical analyses included regression analysis and comparison tests.

Results: The mean age of the 210 participants was 61.2 ± 15.2 years (range, 12-91 years), with 135 women (64.3%) in the cohort. The mean ST value was 12.9 ± 9.3 (0-35) mm, and SM was 2.5 ± 1.6 (0-10) mm, with no difference between women and men. SM values were lower in the presence of irritation ( = 0.046) and photophobia ( = 0.011). Regression analysis revealed ST and SM values were strongly correlated (β = 0.255, < 0.001). SM was significantly correlated with breakup time (β = 0.149, = 0.032), whereas there was no correlation between ST and DED-related signs and symptoms.

Conclusions: SM was correlated with DED-related symptoms and breakup time, whereas ST was not. A low SM value could be an alternative clinical parameter to determine tear film-oriented therapy.

Translational Relevance: Tear strip meniscometry could be a useful tear function examination on a routine clinical basis since it is a 5-second noninvasive procedure and associated with subjective symptoms and the value of the conventional Schirmer test.
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http://dx.doi.org/10.1167/tvst.9.12.31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691796PMC
November 2020

Rice Bran and Vitamin B6 Suppress Pathological Neovascularization in a Murine Model of Age-Related Macular Degeneration as Novel HIF Inhibitors.

Int J Mol Sci 2020 Nov 25;21(23). Epub 2020 Nov 25.

Laboratory of Photobiology, Keio University School of Medicine, Tokyo 160-8582, Japan.

Pathological neovascularization in the eye is a leading cause of blindness in all age groups from retinopathy of prematurity (ROP) in children to age-related macular degeneration (AMD) in the elderly. Inhibiting neovascularization via antivascular endothelial growth factor (VEGF) drugs has been used for the effective treatment. However, anti-VEGF therapies may cause development of chorioretinal atrophy as they affect a physiological amount of VEGF essential for retinal homeostasis. Furthermore, anti-VEGF therapies are still ineffective in some cases, especially in patients with AMD. Hypoxia-inducible factor (HIF) is a strong regulator of VEGF induction under hypoxic and other stress conditions. Our previous reports have indicated that HIF is associated with pathological retinal neovascularization in murine models of ROP and AMD, and HIF inhibition suppresses neovascularization by reducing an abnormal increase in VEGF expression. Along with this, we attempted to find novel effective HIF inhibitors from natural foods of our daily lives. Food ingredients were screened for prospective HIF inhibitors in ocular cell lines of 661W and ARPE-19, and a murine AMD model was utilized for examining suppressive effects of the ingredients on retinal neovascularization. As a result, rice bran and its component, vitamin B6 showed inhibitory effects on HIF activation and suppressed mRNA induction under a CoCl-induced pseudo-hypoxic condition. Dietary supplement of these significantly suppressed retinal neovascularization in the AMD model. These data suggest that rice bran could have promising therapeutic values in the management of pathological ocular neovascularization.
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http://dx.doi.org/10.3390/ijms21238940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728083PMC
November 2020