Synthetic Strategies for Improving Solubility: Optimization of Novel Pyrazolo[1,5-a]pyrimidine CFTR Activator That Ameliorates Dry Eye Disease.

Dry eye disease (DED) is one of the most prevalent ocular diseases but has limited treatment options. Cystic fibrosis transmembrane conductance regulator (CFTR), a major chloride channel that stimulates fluid secretion in the ocular surface, may pave the way for new therapeutic strategies for DED. Herein, we report the optimization of Cact-3, a potent CFTR activator with poor solubility, to 16d, a potent CFTR activator with suitable solubility for eye drop formulation. Notably, 16d was well distributed in target tissues including cornea and conjunctiva with minimal systemic exposure in rabbit. Topical ocular instillation of 16d significantly enhanced tear secretion and improved corneal erosion in a mouse model of DED. In addition, 16d significantly reduced mRNA expression of pro-inflammatory cytokines including IL-1ß, IL-17, and TNF-α and MMP2 in cornea and conjunctiva of DED mice.

Potential Therapeutic Role of Bone Morphogenic Protein 7 (BMP7) in the Pathogenesis of Graves' Orbitopathy.

Purpose: We investigated a role of bone morphogenic protein 7 (BMP7), a member of the TGF-ß superfamily on pathogenic mechanism of Graves' orbitopathy (GO). The therapeutic effects of BMP7 on inflammation and fibrosis were evaluated in cultured Graves' orbital fibroblasts. Methods: Expression of BMP7 was compared in cultured orbital tissue explants from GO (n = 12) and normal control (n = 12) subjects using real-time PCR. Orbital fibroblasts were cultured from orbital connective tissues obtained from GO (n = 3) and normal control patients (n = 3). Cells were pretreated with recombinant human BMP7 (rhBMP7) before stimulation with TGF-ß, IL-1ß, and TNF-α. Fibrosis-related proteins and inflammatory cytokines were analyzed by Western blotting. The activation of signaling molecules in inflammation and fibrosis was also analyzed. Results: The expressions of BMP7 mRNA were lower in GO orbital tissues than control. Fibrosis-related proteins, fibronectin, collagen 1α, and α-SMA induced by TGF-ß were suppressed by treating rhBMP7, and rhBMP7 upregulated TGF-ß induced SMAD1/5/8 protein expression, whereas downregulated SMAD2/3. Increased pro-inflammatory molecules, IL-6, IL-8, and intercellular adhesion molecule-1 (ICAM-1) by IL-1ß or TNF-α were blocked by rhBMP7 treatment, and the expression of phosphorylated NFκB and Akt was suppressed by rhBMP7 treatment. Conclusions: BMP7 transcript levels were downregulated in Graves' orbital tissues. Exogenous BMP7 treatment showed inhibitory effects on the production of profibrotic proteins and proinflammatory cytokines in orbital fibroblasts. Our results provide a molecular basis of BMP7 as a new potential therapeutic agent through the opposing mechanism of profibrotic TGF-ß/SMAD signaling and proinflammatory cytokine production.

Comparison of Anterior Segment Measurements with a New Multifunctional Unit and Five Other Devices.

PURPOSE: To evaluate the clinical availability of a multifunctional ocular biometric unit, MR-6000, for simultaneous keratometry, tonometry, topography, and pachymetry evaluation, and compare anterior segment measurements with five other devices: autokeratometer (KR-1), Scheimpflug camera (Pentacam HR), swept-source optical coherence tomography (IOLMaster 700), Placido disk scanning-slit topography (Orbscan II), and noncontact tonometry (FT-1000). METHODS: Thirty eyes from thirty patients who visited Severance Hospital for cataract surgery were examined using MR6000 and the other devices. The mean keratometry, central corneal thickness (CCT), white-to-white (WTW) distance, and intraocular pressure (IOP) values were compared. Repeated measures analysis of variance, Wilcoxon signed-rank test, intraclass correlation coefficient (ICC), and Bland-Altman plot were used to assess the correlation and agreement between devices. RESULTS: Thirty eyes of thirty patients were evaluated. Statistically significant differences in mean keratometry between MR6000, KR-1, Pentacam HR, and IOLMaster 700 were not observed (p > 0.05). All five devices, including Orbscan II, had almost perfect agreement in measuring keratometry (ICC > 0.80, p < 0.05). CCT measured by MR-6000 was significantly different from that of Pentacam HR and Orbscan II measurements (p < 0.05) but correlated with that of Pentacam HR and Orbscan II measurements (ICC > 0.60, p < 0.05). The WTW distance measured by MR-6000 was not significantly different from that measured by IOLMaster 700 but was different from that measured by Orbscan II. IOP measured by MR-6000 was not correlated with FT-1000. CONCLUSIONS: Keratometric values obtained through MR-6000 can be used interchangeably with other devices based on good correlation and agreement. However, the CCT, WTW, and IOP values were not interchangeable with a single multifunctional unit for cataract surgery preoperative examination.

How Long to Continue Eyelid Hygiene to Treat Meibomian Gland Dysfunction.

To determine the efficacy duration of eyelid hygiene for meibomian gland dysfunction (MGD) treatment, a total of 1015 participants with primary MGD, followed for at least 6 months, were enrolled. The participants were classified into the eyelid hygiene group and the control group. The participants who had stopped eyelid hygiene at any point in the observation period after the initial 2 months were classified into the withdrawal group. Analysis was conducted with a generalized linear mixed model. Treatment group, age, sex, ocular surface inflammation, anti-inflammatory treatments, and baseline MGD subtype were considered as fixed effects, and the individual factor was considered as a random effect. The MGD stage decreased significantly for the observational period in the eyelid hygiene group (p < 0.001). Approximately 40.1% of the participants continuously maintained eyelid hygiene throughout the observational period. The MGD stage in the eyelid hygiene group continued to decrease for 6 months and was maintained thereafter. After 4 months of stopping eyelid hygiene, the MGD stage in the withdrawal group was worse than in the eyelid hygiene group (p < 0.001) and similar to that in the control group (p = 0.762). Maintaining eyelid hygiene was significantly effective in MGD treatment. Efficacy increased with treatment for 6 months, and the efficacy duration was maintained for 4 months even after stopping eyelid hygiene. Therefore, we recommend that patients with MGD maintain eyelid hygiene, and compliance should be checked continuously.

Simple Code Implementation for Deep Learning-Based Segmentation to Evaluate Central Serous Chorioretinopathy in Fundus Photography.

PURPOSE: Central serous chorioretinopathy (CSC) is a retinal disease that frequently shows resolution and recurrence with serous detachment of the neurosensory retina. Here, we present a deep learning analysis of subretinal fluid (SRF) lesion segmentation in fundus photographs to evaluate CSC. METHODS: We collected 194 fundus photographs of SRF lesions from the patients with CSC. Three graders manually annotated of the entire SRF area in the retinal images. The dataset was randomly separated into training (90%) and validation (10%) datasets. We used the U-Net segmentation model based on conditional generative adversarial networks (pix2pix) to detect the SRF lesions. The algorithms were trained and validated using Google Colaboratory. Researchers did not need prior knowledge of coding skills or computing resources to implement this code. RESULTS: The validation results showed that the Jaccard index and Dice coefficient scores were 0.619 and 0.763, respectively. In most cases, the segmentation results overlapped with most of the reference areas in the annotated images. However, cases with exceptional SRFs were not accurate in terms of prediction. Using Colaboratory, the proposed segmentation task ran easily in a web-based environment without setup or personal computing resources. CONCLUSIONS: The results suggest that the deep learning model based on U-Net from the pix2pix algorithm is suitable for the automatic segmentation of SRF lesions to evaluate CSC. TRANSLATIONAL RELEVANCE: Our code implementation has the potential to facilitate ophthalmology research; in particular, deep learning-based segmentation can assist in the development of pathological lesion detection solutions.

Risk Factors for the Structural Progression of Myopic Glaucomatous Eyes with a History of Laser Refractive Surgery.

As laser refractive surgeries (LRS) have been widely performed to correct myopia, ophthalmologists easily encounter patients with glaucoma who have a history of LRS. It is well known that intraocular pressure (IOP) in eyes with glaucoma is not accurate when measured using Goldmann applanation tonometry. However, risk factors for glaucoma progression, particularly those associated with measured IOP, have rarely been studied. We analysed data for 40 patients with a history of LRS and 50 age-matched patients without a history of LRS. Structural progression was defined as significant changes in thickness in the peripapillary retinal nerve fibre layer as identified using optical coherence tomography event-based guided progression analysis. Risk factors were determined via Cox regression analysis. Disc haemorrhage (DH) was associated with glaucoma progression in both the non-LRS group and LRS group (hazard ratio (HR): 4.650, p = 0.012 and HR: 8.666, p = 0.019, respectively). However, IOP fluctuation was associated with glaucoma progression only in the LRS group (HR: 1.452, p = 0.023). Our results show that DH was a significant sign of progression in myopic glaucoma eyes. When treating patients with myopia and glaucoma, IOP fluctuation should be monitored more carefully, even if IOP seems to be well controlled.

Peripheral Brain-Derived Neurotrophic Factor Levels in Alzheimer's Disease and Mild Cognitive Impairment: a Comprehensive Systematic Review and Meta-analysis.

Alzheimer's disease (AD) is becoming a growing global problem, and there is an urgent need to identify reliable blood biomarkers of the risk and progression of this condition. A potential candidate is the brain-derived neurotrophic factor (BDNF), which modulates major trophic effects in the brain. However, findings are apparently inconsistent regarding peripheral blood BDNF levels in AD patients vs. healthy people. We thus performed a systematic review and meta-analysis of the studies that have examined peripheral BDNF levels in patients with AD or mild cognitive impairment (MCI) and healthy controls. We searched articles through PubMed, EMBASE, and hand searching. Over a total pool of 2061 potential articles, 26 met all inclusion criteria (including a total of 1584 AD patients, 556 MCI patients, and 1294 controls). A meta-analysis of BDNF levels between early AD and controls showed statistically significantly higher levels (SMD [95 % CI]: 0.72 [0.31, 1.13]) with no heterogeneity. AD patients with a low (<20) mini-mental state examination (MMSE) score had lower peripheral BDNF levels compared with controls (SMD [95 % CI]: -0.33 [-0.60, -0.05]). However, we found no statistically significant difference in blood (serum/plasma) BDNF levels between all AD patients and controls (standard mean difference, SMD [95 % CI]: -0.16 [-0.4, 0.07]), and there was heterogeneity among studies (P < 0.0001, I 2 = 85.8 %). There were no differences in blood BDNF levels among AD or MCI patients vs. controls by subgroup analyses according to age, sex, and drug use. In conclusion, this meta-analysis shows that peripheral blood BDNF levels seem to be increased in early AD and decreased in AD patients with low MMSE scores respectively compared with their age- and sex-matched healthy referents. At present, however, this could not be concluded from individual studies.