GNUV201, a novel human/mouse cross-reactive and low pH-selective anti-PD-1 monoclonal antibody for cancer immunotherapy.

BACKGROUND: Several PD-1 antibodies approved as anti-cancer therapies work by blocking the interaction of PD-1 with its ligand PD-L1, thus restoring anti-cancer T cell activities. These PD-1 antibodies lack inter-species cross-reactivity, necessitating surrogate antibodies for preclinical studies, which may limit the predictability and translatability of the studies. RESULTS: To overcome this limitation, we have developed an inter-species cross-reactive PD-1 antibody, GNUV201, by utilizing an enhanced diversity mouse platform (SHINE MOUSE™). GNUV201 equally binds to human PD-1 and mouse PD-1, equally inhibits the binding of human PD-1/PD-L1 and mouse PD-1/PD-L1, and effectively suppresses tumor growth in syngeneic mouse models. The epitope of GNUV201 mapped to the "FG loop" of hPD-1, distinct from those of Keytruda® ("C'D loop") and Opdivo® (N-term). Notably, the structural feature where the protruding epitope loop fits into GNUV201's binding pocket supports the enhanced binding affinity due to slower dissociation (8.7 times slower than Keytruda®). Furthermore, GNUV201 shows a stronger binding affinity at pH 6.0 (5.6 times strong than at pH 7.4), which mimics the hypoxic and acidic tumor microenvironment (TME). This phenomenon is not observed with marketed antibodies (Keytruda®, Opdivo®), implying that GNUV201 achieves more selective binding to and better occupancy on PD-1 in the TME. CONCLUSIONS: In summary, GNUV201 exhibited enhanced affinity for PD-1 with slow dissociation and preferential binding in TME-mimicking low pH. Human/monkey/mouse inter-species cross-reactivity of GNUV201 could enable more predictable and translatable efficacy and toxicity preclinical studies. These results suggest that GNUV201 could be an ideal antibody candidate for anti-cancer drug development.

Impact of COVID-19 on ophthalmic medical access during successive waves: Demographics, disease factors, and wave locations.

BACKGROUND: The coronavirus disease (COVID-19) pandemic significantly impacted medical care, including ophthalmology. This study aimed to identify factors associated with reduced ophthalmic medical access during the pandemic. METHODS: This nationwide population-based cohort study analysed South Korean health insurance claims data from January 2019 to November 2021. Outpatient visits and surgeries for age-related macular degeneration, cataract, diabetic retinopathy, glaucoma, and retinal detachment during the two pandemic waves were compared with those in the non-pandemic period. Poisson regression was used to estimate incidence rate ratios and changes in outpatient visits and surgeries between waves concerning patient age, sex, residential location, and health insurance type. RESULTS: Outpatient visits for five eye diseases decreased in the first wave (0.733-0.985, P < 0.001). In the second wave, only outpatient visits for age-related macular degeneration, cataract, and glaucoma decreased (0.754, 0.878, and 0.874, respectively, all P < 0.001). Age-related macular degeneration, cataract, and glaucoma surgeries were significantly reduced in the first wave (0.829, P < 0.001; 0.836, P < 0.001; 0.904, P = 0.030, respectively). Age-related macular degeneration (0.852) and cataract (0.716) surgeries dropped in the second wave. Women and elderly (>65 years) patients curtailed outpatient visits and surgeries more throughout the pandemic and were less resilient during the second wave. Wave location was also related to outpatient visits and surgeries. CONCLUSIONS: The COVID-19 pandemic decreased outpatient visits and surgeries for eye diseases, with more significant impact on women, older patients, and those residing near wave locations. These findings can inform healthcare policies to minimise future pandemic impacts on healthcare delivery.

Construction of Asbestos Slate Deep-Learning Training-Data Model Based on Drone Images.

The detection of asbestos roof slate by drone is necessary to avoid the safety risks and costs associated with visual inspection. Moreover, the use of deep-learning models increases the speed as well as reduces the cost of analyzing the images provided by the drone. In this study, we developed a comprehensive learning model using supervised and unsupervised classification techniques for the accurate classification of roof slate. We ensured the accuracy of our model using a low altitude of 100 m, which led to a ground sampling distance of 3 cm/pixel. Furthermore, we ensured that the model was comprehensive by including images captured under a variety of light and meteorological conditions and from a variety of angles. After applying the two classification methods to develop the learning dataset and employing the as-developed model for classification, 12 images were misclassified out of 475. Visual inspection and an adjustment of the classification system were performed, and the model was updated to precisely classify all 475 images. These results show that supervised and unsupervised classification can be used together to improve the accuracy of a deep-learning model for the detection of asbestos roof slate.

Optic Nerve Head Morphology is Associated with the Initial Location of Structural Progression in Early Open Angle Glaucoma.

PRCIS: Glaucoma eyes with a small cup-to-disk ratio (CDR) tend to show retinal nerve fiber layer progression earlier than ganglion cell-inner plexiform layer progression. PURPOSE: To investigate the effects of clinical variables on the temporal relationship between macular ganglion cell-inner plexiform layer (mGCIPL) loss and peripapillary retinal nerve fiber layer (pRNFL) loss in glaucoma. METHODS: This retrospective observational study used medical records of patients diagnosed with open angle glaucoma. Structural change was determined using guided progression analysis software of Cirrus optical coherence tomography. Based on the time of detection of pRNFL and mGCIPL changes, eyes showing progressive layer loss were categorized into the pRNFL-first and mGCIPL-first groups. The association between sites of layer thinning and clinical variables such as major retinal arterial angles and several optic disk measurements, including disk area, average CDR, and vertical CDR, were analyzed. RESULTS: A total of 282 eyes were included in the study, of which 104 showed structural progression either in the mGCIPL or pRNFL. Out of these, 49 eyes showed the first progression in pRNFL, while 37 eyes showed the first progression in mGCIPL. The minimum mGCIPL thickness, pRNFL thickness, average CDR, vertical CDR, and location of progression were significantly different between the 2 groups ( P =0.041, P =0.034, P =0.015, P <0.001, and P <0.001, respectively). In multivariate analysis, average CDR and vertical CDR were significantly associated with the progression site ( P =0.033 and P =0.006, respectively). The structural changes in the inferoinferior area and the superior vulnerability zone were significantly associated with RNFL-first progression ( P <0.001 for both). CONCLUSION: The location of layer loss and CDR are related to the layer where loss is first detected (either pRNFL or mGCIPL) in open angle glaucoma.

Effect of Intraoperative Mitomycin C on the Surgical Outcomes of Ahmed Glaucoma Valve Implantation with Ciliary Sulcus Tube Placement.

PURPOSE: To evaluate the effect of intraoperative mitomycin C (MMC) on the surgical outcomes of ciliary sulcus (CS) Ahmed glaucoma valve (AGV) tube placement. METHODS: A retrospective review of medical records of 54 consecutive patients who underwent AGV implantation with tube placed in CS was performed. Consecutive cases operated without the use of intraoperative MMC from 2017 to 2019 were compared with consecutive cases operated with MMC from 2019 to 2021. Surgical failure was defined as intraocular pressure (IOP) exceeding 21 mmHg in two consecutive visits after postoperative 3 months or ≤30% IOP reduction, IOP ≤5 mmHg in two consecutive visits, or loss of light perception. Kaplan-Meier survival analysis and log-rank test were performed to compare the surgical failure rates. RESULTS: A total of 54 eyes of 54 patients were investigated. Mean follow-up period after AGV implantation was 1.4 ± 0.8 years. The MMC group showed significantly lower IOP during the 1st postoperative month (20.5 ± 8.6 mmHg vs. 15.8 ± 6.4 mmHg, p = 0.027), but the difference did not persist 6 months after the surgery (p = 0.805). The mean number of postoperative antiglaucoma medications was significantly lower in the MMC group in the 1st postoperative month (p = 0.047) but no difference was found at 6 months. No statistical difference was noted in the rates of postoperative complications. Kaplan-Meier survival analysis showed comparable survival rates between MMC group and no MMC group (p = 0.356). CONCLUSIONS: The intraoperative use of MMC significantly lowered IOP in the 1st postoperative month but did not increase 6 months success rates in patients receiving AGV tube placement in CS.

Ciliary Neurotrophic Factor Derived From Astrocytes Protects Retinal Ganglion Cells Through PI3K/AKT, JAK/STAT, and MAPK/ERK Pathways.

Purpose: The purpose of this study was to investigate the roles of ciliary neurotrophic factor (CNTF) on the protective effects of astrocytes on retinal ganglion cells (RGCs). Methods: Primary RGCs were isolated from neonatal rats. Oxidative stress was induced, and the effects of co-culture with astrocytes and CNTF treatment on RGCs were evaluated. The pathways commonly altered by astrocytes and CNTF were investigated. Effects of each pathway were investigated using pathway inhibitors against PI3K/AKT, JAK/STAT, and MAPK/ERK. RNA sequencing was performed to identify the genes upregulated and downregulated by CNTF treatment. Results: Astrocytes improved the viability and increased ß3-tubulin expression in RGCs. The concentration of CNTF increased in the RGC-astrocyte co-culture medium. The protective effects of astrocytes were abolished by neutralization with the anti-CNTF antibody; thus, CNTF may play an important role in the effects mediated by astrocytes. Furthermore, CNTF treatment alone enhanced the viability and ß3-tubulin expression of RGCs and increased the population of viable RGCs under oxidative stress. The PI3K/AKT pathway was associated with both RGC viability and ß3-tubulin expression. However, the JAK/STAT pathway increased the viability of RGCs, whereas the MAPK/ERK pathway was associated with ß3-tubulin expression. RNA sequencing revealed the CNTF-upregulated genes associated with response to DNA damage and downregulated genes associated with photoreceptor cell differentiation. Conclusions: Our data revealed protective effects of astrocyte-derived CNTF on RGCs. In addition, we showed that multiple pathways exert these protective effects and identified the novel genes involved. These results may be helpful in developing treatments for RGC injury.

Risk factors for undergoing surgery in patients with newly diagnosed open-angle glaucoma.

Despite the clinical importance of glaucoma surgery, studies on its prevalence and risk factors are limited. We analyzed a database comprising approximately 1,000,000 Korean residents to investigate the prevalence and risk factors for undergoing glaucoma surgery within 5 years of diagnosis with open-angle glaucoma. Of the 4,303 patients evaluated, 226 (5.3%) underwent glaucoma surgery. Factors associated with the likelihood of glaucoma surgery included the use of two or more eye drops (odds ratio [OR], 30.30; 95% confidence interval [CI], 10.95-83.84), intake of oral carbonic anhydrase inhibitor (OR, 1.79; 95% CI, 1.23-2.61), age > 55 years (55-65 years: OR, 1.71; 95% CI, 1.06-2.76; > 65 years: OR 1.72; 95% CI, 1.10-2.70), female sex (OR, 1.46; 95% CI, 1.10-1.94), middle- and high-income (OR, 2.36; 95% CI, 1.30-4.28, OR, 1.86; 95% CI, 1.03-3.35, respectively), and metropolitan residence (OR, 1.61; 95% CI, 1.14-2.26). Our nomogram for predicting the likelihood of glaucoma surgery showed an acceptable result. In conclusion, older age, female sex, and the intensity of intraocular pressure lowering treatment increased the likelihood of undergoing glaucoma surgery. Our findings indicated that a lower socioeconomic status may forestall receiving this necessary surgery, which requires further attention.

Factors Associated With Differences in the Initial Location of Structural Progression in Normal-Tension Glaucoma.

PRCIS: Different clinical factors are associated with the location of the first structural progression in glaucoma. PURPOSE: The aim was to investigate the underlying clinical parameters affecting the location of the initial structural progression of glaucoma in patients with normal-tension glaucoma (NTG). METHODS: This retrospective study included 228 eyes of 228 patients with NTG. In total, 130 eyes of 130 patients demonstrated structural progression (as determined by event-based guided progression analysis using Cirrus HD-optical coherence tomography) in the peripapillary retinal nerve fiber layer (ppRNFL) or macular ganglion cell inner plexiform layer (mGCIPL). Depending on where the progression occurred first, it was defined as either ppRNFL first progression or mGCIPL first progression. Clinical parameters associated with each first progression were identified using logistic regression. RESULTS: In total, 50 eyes showed ppRNFL first progression and 64 eyes showed mGCIPL first progression. ppRNFL first progression was significantly associated with female sex [odds ratio (OR)=5.705, P=0.015], lack of systemic hypertension (OR=0.199, P=0.014), disc hemorrhage (OR=4.188, P=0.029), higher mean intraocular pressure (OR=1.300, P=0.03), and lower pattern SD (OR=0.784, P=0.028). In contrast, male sex (OR=0.450, P=0.043), lower central corneal thickness (OR=0.987, P=0.032), higher intraocular pressure fluctuation (OR=1.753, P=0.047), lower systolic blood pressure fluctuation (OR=0.839, P=0.002), and higher diastolic blood pressure fluctuation (OR=1.208, P=0.015) were significantly associated with mGCIPL first progression. CONCLUSIONS: Different clinical factors were associated with the initial site of structural glaucoma progression in patients with NTG depending on its peripapillary or macular location, and these findings suggest possible differences in underlying mechanisms of glaucoma damage.

Enhanced Immunomodulation, Anti-Apoptosis, and Improved Tear Dynamics of (PEG)-BHD1028, a Novel Adiponectin Receptor Agonist Peptide, for Treating Dry Eye Disease.

Dry eye disease (DED) is characterized by impaired tear dynamics, leading to complex pathophysiological conditions. (PEG)-BHD1028, a peptide agonist to AdipoRs, was evaluated as a potential therapeutic agent for DED based on the reported physiological function of adiponectin, including anti-inflammation and epithelial protection. Therapeutic effects of (PEG)-BHD1028 were evaluated in experimentally induced EDE with 0.001%, 0.01%, and 0.1% (PEG)-BHD1028 in mice and 0.1%, 0.2%, and 0.4% in rabbits for 10 days. In the rabbit study, 0.05% cyclosporine was also tested as a comparator. The results from the mouse study revealed significant improvement in tear volumes, tear breakup time (TBUT), inflammation, and corneal severity score (CSS) within 10 days at all (PEG)-BHD1028 concentrations. In the rabbit study, the tear volume and TBUT significantly increased in (PEG)-BHD1028 groups compared with vehicle and 0.05% cyclosporine groups. The CSS, apoptosis rate, and corneal thickness of all (PEG)-BHD1028 and 0.05% cyclosporine groups were significantly improved relative to the vehicle group. The immune cell counts of 0.2% and 0.4% (PEG)-BHD1028 treated groups were significantly lower than those of the vehicle group. These results represent the potential of (PEG)-BHD1028 as an effective therapeutic agent for DED.

Effect of red ginseng on visual function and vision-related quality of life in patients with glaucoma.

BACKGROUND: Red ginseng has been found to improve ocular perfusion and dry eye syndrome in glaucomatous eyes; however, its effects on visual function and vision-related quality of life have not been investigated. This study sought to evaluate the effects of red ginseng on visual function and vision-related quality of life in glaucoma patients using contrast sensitivity and a questionnaire. METHODS: Participants were randomly assigned to two groups in this prospective, randomized, double-blind study: in one group, red ginseng was taken first, followed by a placebo, and in the other, placebo was taken first, followed by red ginseng. We measured and compared changes in contrast sensitivity and vision-related quality of life between the two groups. Contrast sensitivity was measured using OPTEC® 6500P, and vision-related quality of life was evaluated using the 25-item National Eye Institute Visual Function Questionnaire. One-way and two-way repeated measure analyses of variance were used for the comparison. Relationships between respective changes in dry eye syndrome and contrast sensitivity were also analyzed. RESULTS: Daytime contrast sensitivity and ocular pain improved after the administration of red ginseng. Nighttime contrast sensitivity was improved in early or moderate glaucoma. Improved contrast sensitivity was not associated with improvement in dry eye syndrome. CONCLUSION: Red ginseng could improve contrast sensitivity and ocular pain in patients with glaucoma. The mechanism underlying improvement in contrast sensitivity appears to be associated with enhanced retinal perfusion or retinal ganglion cell function, but not dry eye syndrome.

Effects of Glaucoma Medication on Dry Eye Syndrome and Quality of Life in Patients with Glaucoma.

PURPOSE: To investigate ocular surface diseases and changes in the quality of life of patients using glaucoma medications. METHODS: Participants were divided into the normal (31 individuals, 62 eyes) and glaucoma medication (30 patients, 60 eyes) groups. Changes in tear break-up time, lipid layer thickness (LLT), corneal and conjunctival staining scores, ocular surface disease index (OSDI), and Visual Function Questionnaire 25 (VFQ-25) score were assessed for 1 year. RESULTS: The change in mean LLT was lower in glaucomatous eyes than in control eyes (p = 0.019) after 1 year. The results of OSDI deteriorated (p' = 0.008), but conjunctival staining and Schirmer test results showed improvement in glaucomatous eyes compared to those in control eyes (p' =0.035 and 0.009, respectively). The average LLT decreased at 6 and 12 months, but there was no change at 24 months. In pairwise analysis, the decrease in LLT over the first 6 months was statistically significant (p < 0.001) and remained unchanged until 24 months. Among the VFQ items, scores for near activity and social function deteriorated over 1 year in the medication group (p' = 0.033 and 0.015, respectively). However, there was no difference in the total VFQ score. CONCLUSIONS: Significant reduction in LLT and deterioration of OSDI were observed in the medication group compared to the control group. However, this deterioration was observed only in the first 6 months. There was no significant difference in the VFQ total score. Nonetheless, there were significant differences in near activity and social function between the control and medication groups. Therefore, the results of this study showed that although glaucoma medication worsened eye dryness, the change was limited and did not worsen the quality of life. Glaucoma medication should be used with the consideration that they can limit near activity and social functioning.

Radiocapitellar joint pressures following transradial amputation increase during elbow motion.

This study aimed to compare the contact area, mean pressure, and peak pressure of the radiocapitellar joint (RCJ) in the upper limb after transradial amputation with those of the normal upper limb during elbow flexion and forearm rotation. Testing was performed using ten fresh-frozen upper limbs, and the transradial amputation was performed 5 cm proximal to the radial styloid process. The specimens were connected to a custom-designed apparatus for testing. A pressure sensor was inserted into the RCJ. The biomechanical indices of the RCJ were measured during elbow flexion and forearm rotation in all specimens. There was no significant difference in the contact area between the normal and transradial amputated upper limbs. However, in the upper limbs after transradial amputation, the mean pressure was higher than that in the normal upper limbs at all positions of elbow flexion and forearm rotation. The peak pressure was significantly higher in the upper limbs after transradial amputation than in the normal upper limbs, and was especially increased during pronation at 45° of elbow flexion. In conclusion, these results could cause cartilage erosion in the RCJ of transradial amputees. Thus, methods to reduce the pressure of the RCJ should be considered when a myoelectric prosthesis is developed.

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.

Efficacy and Safety of Preservative-free Latanoprost Eyedrops Compared with Preserved Prostaglandin Analogues in Patients with Open-angle Glaucoma.

PURPOSE: To evaluate the safety and efficacy of preservative-free (PF) latanoprost in glaucoma patients. METHODS: In this prospective, open-label, observational study, a total of 27 primary open-angle glaucoma patients who used benzalkonium chloride-preserved prostaglandin analogues for at least 6 months were enrolled. After changing the eye drops to PF lataprost, the intraocular pressure (IOP) and ocular surface symptoms and signs were evaluated in all patients on days 0 (first visit, D0), 45 (D45), and 90 (D90). RESULTS: Mean IOP remained stable during the study period (14.0 ± 2.4 mmHg at D0, 13.9 ± 2.0 mmHg at D45, 13.7 ± 2.2 mmHg at D90; p = 0.603). Mean deviation, pattern standard deviation, and best-corrected visual acuity were similar before and after eye drops replacement. Bulbar conjunctival hyperemia, corneal staining, and conjunctival staining were significantly decreased over 90 days (p = 0.025, p < 0.001, p = 0.020, respectively). The ocular surface disease index score showed a statistically significant improvement from 26.4 ± 18.5 at D0 to 19.8 ± 17.0 at D45 and 15.7 ± 15.6 at D90 (p < 0.001). In the evaluation of ocular tolerability, burning symptoms and dryness were significantly decreased (p = 0.001, p = 0.040). CONCLUSIONS: The effects of PF latanoprost on reducing IOP were comparable with those of benzalkonium chloride-preserved prostaglandin analogues, but side effects on the ocular surface were much less pronounced when PF latanoprost was used. With this efficacy, PF latanoprost could slow the progression of glaucoma by increasing patient compliance.

Correlation between Severity of Synovitis and Clinical Features in Rotator Cuff Tears.

BACKGROUND: Rotator cuff tears can be asymptomatic in some cases; however, even when the tear size is small, clinical symptoms can be very severe. This suggests that symptoms of rotator cuff tears are related to factors other than the size. Although synovitis has been cited as one of the factors, there is no grading system for synovitis in rotator cuff tears. Moreover, there are few studies that evaluated the relationship between synovitis and clinical features in patients with rotator cuff tears. METHODS: Patients with medium-sized rotator cuff tears, who were scheduled for arthroscopic repair, were recruited for this study. The glenohumeral joint was divided into 4 quarters. Then, vascularity and hypertrophy of the joint were graded in each quarter using a modified scoring system. Clinical assessment was performed preoperatively and at 3 months and 6 months after surgery. Finally, correlation between the severity of synovitis and clinical features was analyzed. RESULTS: The intraobserver correlation coefficient was 0.815 to 0.918 and the interobserver correlation coefficient was 0.779 to 0.992 for the single measurement. Vascularity was significantly correlated with the range of motion, strength, and constant score within 6 months after surgery. Hypertrophy was correlated with the range of motion within 6 months after surgery. CONCLUSIONS: Synovitis in the shoulder with rotator cuff tears can be graded by using our modified scoring system. The severity of synovitis was closely related to the clinical features after surgery. Therefore, when treating patients with rotator cuff tears, treatment of synovitis should also be considered.

Shoulder outcome scoring systems have substantial ceiling effects 2 years after arthroscopic rotator cuff repair.

PURPOSE: Previous studies show no difference in clinical outcomes between patients with healed and structurally failed rotator cuff repairs. The objective of this study was to assess ceiling effects when reporting surgical outcomes of arthroscopic rotator cuff repair using four of the currently most popular clinical shoulder outcome scoring systems. METHODS: Ninety-two patients who underwent arthroscopic rotator cuff repair were examined. The simple shoulder test (SST), American Shoulder and Elbow Surgeons (ASES) score, University of California at Los Angeles (UCLA) shoulder rating scale, and Constant-Murley shoulder score were completed 2 years postoperatively. Demographic data of the subjects were analysed using descriptive statistics. The ceiling effects in the outcome data assessed for each scale were estimated based on two previously reported definitions. RESULTS: The number of patients with the maximum possible score was 31 (33.7%) with the SST, 26 (28.3%) with the ASES score, 28 (30.4%) with the UCLA scale, and 18 (19.6%) with the Constant-Murley score. The standardised distance of the outcome data assessed by the SST, ASES score, UCLA scale, and Constant-Murley scores were 0.92, 0.97, 0.96, and 1.18, respectively. CONCLUSION: The SST, ASES score, and UCLA scale evaluated at 2 years postoperatively have substantial ceiling effects showing that the proportion of patients with the maximum possible score is > 20%, and the standardised distance is < 1.0. Researchers should be aware of possible biases due to ceiling effects when interpreting the results of studies investigating the surgical outcomes of arthroscopic rotator cuff repair. It could increase the likelihood of a type II error. LEVEL OF EVIDENCE: IV.

Effect of systemic blood pressure on optical coherence tomography angiography in glaucoma patients.

BACKGROUND: The association between retinal microvascular structure and glaucoma has been revealed in multiple studies using optical tomography angiography (OCTA), but limited information on the macular vessel density (mVD) in patients with glaucoma is available. In this study, we tried to identity the factors that affected macular VD (mVD) in glaucomatous eyes. METHODS: This retrospective cross-sectional study evaluated OCT and OCTA images from 92 eyes from 58 healthy subjects and 179 eyes from 103 glaucoma patients using the SD-OCT database from July 2017 to July 2018. Glaucomatous eyes were further divided into two groups according to history of disc haemorrhage (DH). Association between mVD and demographic characteristics, ganglion cell-inner plexiform layer (GCIPL) thickness, visual field mean deviation (MD) and systemic blood pressure was analysed in each group. RESULTS: In both healthy and glaucomatous eyes, mVD was inversely associated with age (ß = -0.035, P = 0.025; ß = -0.039, P = 0.018). In the glaucomatous eyes, mVD was significantly decreased, as the MD value was worse (ß = 0.109, P = 0.002). In glaucomatous eyes with DH, mVD decreased as blood pressure increased (ß = -0.111, P = 0.003) CONCLUSIONS: Reduced mVD is more common in older individuals in both healthy and glaucomatous eyes, and correlates with functional deterioration than structural damage in glaucomatous eyes. In glaucomatous eyes with DH, high systemic BP is associated with a reduction in mVD. This may indicate that glaucoma patients with DH are more susceptible to vascular damage secondary to hypertension.

Progression patterns of normal-tension glaucoma groups classified by hierarchical cluster analysis.

OBJECTIVES: To investigate differences in progression patterns of normal-tension glaucoma (NTG) patients in three clusters classified by hierarchical cluster analysis (HCA). MATERIALS AND METHODS: In a retrospective study, 200 eyes of NTG patients classified by HCA in 2015 who were followed up to the current date were evaluated. Peripapillary retinal nerve fibre layer (RNFL) thicknesses were measured by Cirrus HD-OCT and progression rate was calculated by trend analysis (Guided Progression Analysis [GPA]). VF progression rate was evaluated by linear regression analysis of mean deviation (MD). Progression patterns of three clusters were compared by histograms. RESULTS: In total, 153 eyes of 153 patients were followed up. Mean observation period was 5 years. RNFL reduction rate was -0.83 µm/year in cluster 1, which showed early glaucomatous damage in previous reports; -0.45 µm/year in cluster 2, which showed moderate glaucomatous damage; and -0.36 µm/year in cluster 3, which showed young and myopic glaucomatous damage. The progression pattern of cluster 3 showed a double-peak distribution; RNFL reduction rate was 0.11 µm/year in the non-progressive group and -1.07 µm/year in the progressive group. CONCLUSION: The progression patterns were different among three NTG groups that were divided by HCA. In particular, the group of young and myopic eyes showed a mixture of two different patterns.

Caffeoyl-Prolyl-Histidine Amide Inhibits Fyn and Alleviates Atopic Dermatitis-Like Phenotypes via Suppression of NF-κB Activation.

Caffeic acid (CA) is produced from a variety of plants and has diverse biological functions, including anti-inflammation activity. It has been recently demonstrated that caffeoyl-prolyl-histidine amide (CA-PH), which is CA conjugated with proline-histidine dipeptide, relieves atopic dermatitis (AD)-like phenotypes in mouse. In this study, we investigated the molecular mechanism underlying CA-PH-mediated alleviation of AD-like phenotypes using cell line and AD mouse models. We confirmed that CA-PH suppresses AD-like phenotypes, such as increased epidermal thickening, infiltration of mast cells, and dysregulated gene expression of cytokines. CA-PH suppressed up-regulation of cytokine expression through inhibition of nuclear translocation of NF-κB. Using a CA-PH affinity pull-down assay, we found that CA-PH binds to Fyn. In silico molecular docking and enzyme kinetic studies revealed that CA-PH binds to the ATP binding site and inhibits Fyn competitively with ATP. CA-PH further suppressed spleen tyrosine kinase (SYK)/inhibitor of nuclear factor kappa B kinase (IKK)/inhibitor of nuclear factor kappa B (IκB) signaling, which is required for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. In addition, chronic application of CA-PH, in contrast with that of glucocorticoids, did not induce up-regulation of regulated in development and DNA damage response 1 (REDD1), reduction of mammalian target of rapamycin (mTOR) signaling, or skin atrophy. Thus, our study suggests that CA-PH treatment may help to reduce skin inflammation via down-regulation of NF-κB activation, and Fyn may be a new therapeutic target of inflammatory skin diseases, such as AD.

Gallic acid attenuates blood-spinal cord barrier disruption by inhibiting Jmjd3 expression and activation after spinal cord injury.

After spinal cord injury (SCI), blood-spinal cord barrier (BSCB) disruption results in secondary injury including apoptotic cell death of neurons and oligodendrocytes, thereby leads to permanent neurological deficits. Recently, we reported that the histone H3K27me3 demethylase Jmjd3 plays a role in regulating BSCB integrity after SCI. Here, we investigated whether gallic acid (GA), a natural phenolic compound that is known to be anti-inflammatory, regulates Jmjd3 expression and activation, thereby attenuates BSCB disruption following the inflammatory response and improves functional recovery after SCI. Rats were contused at T9 and treated with GA (50 mg/kg) via intraperitoneal injection immediately, 6 h and 12 h after SCI, and further treated for 7 d with the same dose once a day. To elucidate the underlying mechanism, we evaluated Jmjd3 activity and expression, and assessed BSCB permeability by Evans blue assay after SCI. GA significantly inhibited Jmjd3 expression and activation after injury both in vitro and in vivo. GA also attenuated the expression and activation of matrix metalloprotease-9, which is well known to disrupt the BSCB after SCI. Consistent with these findings, GA attenuated BSCB disruption and reduced the infiltration of neutrophils and macrophages compared with the vehicle control. Finally, GA significantly alleviated apoptotic cell death of neurons and oligodendrocytes and improved behavior functions. Based on these data, we propose that GA can exert a neuroprotective effect by inhibiting Jmjd3 activity and expression followed the downregulation of matrix metalloprotease-9, eventually attenuating BSCB disruption after SCI.