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Yoshihito Sakanishi, Ayumi Usui-Ouchi, Kazunori Tamaki, Keitaro Mashimo, Rei Ito, Nobuyuki Ebihara Department of Ophthalmology, Juntendo University Urayasu Hospital, Urayasu City, Chiba, Japan Purpose: The purpose of this study was to determine the short-term outcomes for patients who received intravitreal aflibercept (IVA) with or without intravitreal ranibizumab (IVR) for macular edema (ME) due to branch retinal vein occlusion (BRVO). Patients and methods: Patients received IVA for ME due to BRVO. Patients who initially received IVA were defined as the treatment-naïve group and those who were switched from IVR to IVA after ME recurrence were defined as the switching group. Patient outcomes were examined at 1 week and 1 month postinjection. Results: Both groups comprised 27 eyes from 27 patients. There was a significant decrease in central macular thickness (CMT) at 1 week and 1 month postinjection in both groups. There was also a significant improvement in best-corrected visual acuity (BCVA) at 1 week and 1 month postinjection in the treatment-naïve group and 1 month in the switching group. Younger age was associated with a good BCVA at 1 month postinjection in the switching group, and the absence of epiretinal membrane was associated with a reduction in CMT at 1 month postinjection in the switching group. Conclusion: IVA is temporarily effective for treating ME due to BRVO regardless of a history of IVR use. Keywords: BRVO, IVR, IVA, switch

Sonoko Tatsui,1 Hitoshi Ishikawa,2 Kimiya Shimizu,1 Kimiyo Mashimo1 1Department of Ophthalmology, School of Medicine, Kitasato University, 2Department of Orthoptics and Visual Sciences, School of Allied Health Sciences, Kitasato University, Sagamihara, Japan Purpose: Brimonidine is an imidazoline compound used for the treatment of glaucoma, but having very little effect on pupil diameter. Like para-aminoclonidine, most imidazoline compounds interact with postsynaptic α-adrenoceptors and cause pupil dilatation. Therefore, as part of an investigation of the mechanism of action of brimonidine on pupil diameter, the present study was initiated to measure, in vitro, the relative potency of brimonidine on the pre- and postsynaptic α-adrenoceptors of rabbit iris dilator muscle. Methods: The contractile activity of brimonidine and its effect on twitch contraction evoked by electrical field stimulation were studied in isolated rabbit iris dilator muscles by isometric tension recording. Results: Brimonidine significantly inhibited the twitch contraction of the dilator muscle caused by field stimulation, without affecting the response to exogenously applied phenylephrine. Compared to phenylephrine, brimonidine caused only a small contractile response with % maximum contraction values of

Etching of magnetic materials, NiFe, CoFe, and Fe, has been studied with a high-density helicon plasma source using non-corrosive CO/NH3 gas. High etch rates, ranging from 45 to 130 nm/min, were achieved. The etch rate strongly depended on both plasma density and ion energy. The main etching mechanism is interpreted as physical sputtering rather than as chemical reaction. A high selectivity of 6–16 was achieved by using hard masks of Ti or Ta. This is attributed to the hardening surface layer of the masks by nitradation, carbonization, or oxidation in CO/NH3 gas plasma. This etching process is named as hardening mask etching. This etching process was also applied for tunneling magneto-resistive (TMR) multi-layers that uses magnetic random access memory with a Ta mask. A high anisotropy of about 80° was obtained without residues, sidewall deposition, and corrosion. This process is potentially applicable to the etching of thin magnetic materials in TMR stacks, patterned media, and read/write head. [Copyright &y& Elsevier]

Background: The association between prior bevacizumab (BEV) therapy and ramucirumab (RAM)-induced proteinuria is not known. We aimed to investigate this association in patients with metastatic colorectal cancer (mCRC)., Methods: mCRC patients who received folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus RAM were divided into with and without prior BEV treatment groups. The cumulative incidence of grade 2-3 proteinuria and rate of RAM discontinuation within 6 months (6M) after RAM initiation were compared between the two groups., Results: We evaluated 245 patients. In the Fine-Gray subdistribution hazard model including prior BEV, age, sex, comorbidities, eGFR, proteinuria ≥ 2 + at baseline, and later line of RAM, prior BEV treatment contributed to proteinuria onset (P < 0.01). A shorter interval between final BEV and initial RAM increased the proteinuria risk; the adjusted odds ratios (95% confidence intervals) for the intervals of < 28 days, 28-55 days, and > 55 days (referring to prior BEV absence) were 2.60 (1.23-5.51), 1.51 (1.01-2.27), and 1.04 (0.76-1.44), respectively. The rate of RAM discontinuation for ≤ 6M due to anti-VEGF toxicities was significantly higher in the prior BEV treatment group compared with that in the no prior BEV treatment group (18% vs. 6%, P = 0.02). Second-line RAM discontinuation for ≤ 6M without progression resulted in shorter overall survival of 132 patients with prior BEV treatment (P < 0.01)., Conclusion: Sequential FOLFIRI plus RAM after BEV failure, especially within 55 days, may exacerbate proteinuria. Its escalated anti-VEGF toxicity may negatively impact the overall survival., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Zizania latifolia cultivars infected by the endophytic fungus Ustilago esculenta develop an edible stem gall. Stem gall development varies among cultivars and individuals and may be affected by the strain of U. esculenta. To isolate haploids from two Z. latifolia cultivars in our paddy fields, Shirakawa and Ittenkou, we herein performed the sporadic isolation of U. esculenta strains from stem gall tissue, a PCR-based assessment of the mating type, and in vitro mating experiments. As a result, we obtained heterogametic strains of MAT-2 and MAT-3 as well as MAT-2, but not MAT-3, haploid strains. Another isolation method, in which we examined poorly growing small clusters of sporidia derived from teliospores, succeeded in isolating a MAT-3 haploid strain. We also identified the mating types of 10 U. esculenta strains collected as genetic resources from different areas in Japan. All strains, except for one MAT-1 haploid strain, were classified as MAT-2 haploid strains or heterogametic strains of MAT-2 and MAT-3. The isolated strains of MAT-1, MAT-2, and MAT-3 mated with each other to produce hyphae. Collectively, these results indicate that the mating types of U. esculenta infecting Z. latifolia cultivars in Japan are biased towards MAT-2 and MAT-3 and that U. esculenta populations in these Japanese cultivars may be characterized by the low isolation efficiency of the MAT-3 haploid.

Purpose: Vernal keratoconjunctivitis (VKC) is a severe, recurrent allergic conjunctivitis. Previously, we found high concentrations of oncostatin M (OSM) in the tears of patients with VKC. Here, we investigated the role of OSM in VKC by focusing on epithelial barrier function and IL-33 production., Methods: To assess the effect of OSM on the barrier function of human conjunctival epithelial cells (HConEpiCs), we measured transepithelial electrical resistance and dextran permeability. We also assessed expression of tight junction-related proteins such as E-cadherin and ZO-1 in HConEpiCs by Western blotting and immunofluorescence. Then we used immunohistochemistry to evaluate expression of Ki-67, E-cadherin, epithelial-mesenchymal transition-related proteins, and IL-33 in giant papillae (GPs) from patients with VKC. In addition, we used Western blotting, microarray, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay to examine whether OSM activates signal transducer and activator of transcription 1 (STAT1) or STAT3 and induces the expression of various genes in human conjunctival fibroblasts (HConFs)., Results: OSM reduced expression of E-cadherin and ZO-1 in HConEpiCs, indicating barrier dysfunction. In immunohistochemistry, Ki-67 expression was present in the lower epithelial layer of the GPs, and E-cadherin expression was reduced in the superficial and lower layers; double staining revealed that GPs had a high number of fibroblasts expressing IL-33. In addition, in HConFs, OSM phosphorylated both STAT1 and STAT3 and induced IL-33., Conclusions: OSM has important roles in severe, prolonged allergic inflammation by inducing epithelial barrier dysfunction and IL-33 production by conjunctival fibroblasts.

Introduction: Micropulse transscleral cyclophotocoagulation (MP-TSCPC) is a method for intraocular pressure (IOP) reduction in patients with glaucoma; however, the specific mechanisms underlying its ability to reduce IOP remain unclear. We therefore investigated the morphological changes and mechanisms of IOP reduction after MP-TSCPC., Methods: The right eyes of 4 pigmented rabbits were treated with MP-TSCPC with power setting corresponding to those used in glaucoma patients (1 power: 2,000 mW; time: 160 s; duty cycle: 31.3%). Power settings of 1, 1/8, 1/16, and 1/32 power were applied to the right eyes. The left eyes were used as controls. A light microscope and electron microscope were used to observe morphological findings after 1 week of MP-TSCPC. IOP and IOP reduction rate were compared before and after MP-TSCPC application on days 1, 3, and 5, and at 1 week., Results: In the pre-MP-TSCPC, IOP was 16.7 ± 0.6 mm Hg. The IOP of rabbit treated with the 1 power was 3 mm Hg, with an IOP reduction rate of 80%; however, the eyes developed phthisis bulbi. The IOP was 7.0 ± 0.0 mm Hg 1 week after MP-TSCPC (IOP reduction rate: 59%) in rabbit treated with the 1/8 power. Reduction in IOP was observed, but there was significant tissue invasion to the ciliary body. The IOP was 10.3 ± 0.6 mm Hg (IOP reduction rate: 40%) 1 week after MP-TSCPC in rabbit treated with the 1/16 power, which was more effective to reduce IOP than that with the 1/8 power. Tissue invasion to the ciliary body was negligible, nonpigmented epithelial cells of the pars plicata were damaged, basal infoldings were destroyed, and repair was accompanied by proliferating tissue. No IOP reduction or tissue change was observed in rabbit treated with the 1/32 power., Conclusion: A potential mechanism for IOP reduction in pigmented rabbits is aqueous humor transport dysfunction due to damage to the nonpigmented epithelial cells of the pars plicata and destruction of basal infoldings. The power of MP-TSCPC was consistent with both morphological changes and IOP reduction., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: There have been no comprehensive studies of changes in heart gene expression due to ethanol exposure. Therefore, we attempted to determine gene expression in cultured neonatal rat cardiomyocytes exposed to ethanol (0, 10, 50, 100 mM) for 24 h., Methods: The total RNA extract of beating cardiomyocytes was evaluated by DNA microarray analysis, and fold changes (FCs) in differential gene expression of ethanol-exposed cardiomyocytes were analyzed against the control using Ingenuity Pathway Analysis (IPA) software., Results: The 1,394 genes with an |FC| of ≥1.8 were uploaded to IPA. IPA predicted 23 canonical pathways working in the ethanol groups. Three canonical pathways related to ethanol degradation- "Ethanol Degradation IV", "Oxidative Ethanol Degradation III", and "Ethanol Degradation II" -were inhibited in the ethanol groups. IPA predicted "ethanol" as an upregulated upstream regulator of the network with 22 downstream members for the 100 mM ethanol group only. Three members (NTRK2, TGFB3, and TLR8) were activated in all groups. Certain cellular functions were predicted to be changed dose-dependently. "Myocarditis" was dose-dependently inhibited, whereas "Cell death of heart cells" was dose-dependently activated. Several functions were inhibited in 50 mM ethanol only, eg, "Failure of heart" was enhanced in 50 mM ethanol only. Certain functions were activated in 100 mM ethanol only. "Cardiac fibrosis" was not predicted in any ethanol group., Conclusions: IPA predicted that ethanol-induced activation or inhibition of canonical pathways and functions of cardiomyocyte depended on ethanol concentration, and 3 networks related to heart functions for cardiomyocytes exposed to 3 concentrations of ethanol.

We aimed to investigate the relationship between subfoveal choroidal thickness (SCT) and treatment outcomes of intravitreal aflibercept (IVA) for macular edema (ME) due to branch retinal vein occlusion (BRVO). We retrospectively evaluated 46 patients with treatment-naive BRVO-ME who underwent IVA treatment between March 2016 and February 2017. There was no significant difference in visual acuity within 6 months (0.29 ± 0.20 vs. 0.27 ± 0.19, p = 0.338), the mean central foveal thickness improvement (332.0 ± 162.2 μm vs. 303.9 ± 166.6 μm, p = 0.492), and the mean number of IVA injections (1.7 ± 0.7 vs. 1.6 ± 0.7 times, p = 0.658) between the SCT thickened ( n = 26 patients, 26 eyes) and SCT non-thickened groups ( n = 20 patients, 20 eyes). The rate of ME recurrence was significantly lower in the SCT decreased group (6/17 eyes (35.2%) vs. 19/30 eyes (63.3%); p = 0.038). In conclusion, pretreatment choroidal thickening does not affect the therapeutic effect of IVA for BRVO, but ME recurrence was lower in cases of treatment-related choroidal thinning. Thus, changes in SCT may be a therapeutic indicator of IVA for acute BRVO.

Diabetic macular edema (DME) is a common cause of visual impairment in patients with diabetes. Although intravitreal anti-vascular endothelial growth factor (VEGF) injections were efficacious in clinical trials, several patients exhibited a poor response. This study aimed to compare clinical features between patients who were susceptible to intravitreal anti-VEGF injections for DME and those who were not. A single-center, retrospective study of 102 such patients was conducted (123 eyes; mean ± standard deviation age, 63.4 ± 10.8 years; 57.8% males). Systemic and ocular data, assessed at baseline and after a month, were compared between good (>20% decrease in central macular thickness (CMT)) and poor (≤20% decrease in CMT) responders using the Mann-Whitney U test/Fisher's exact test. Eighty-one eyes (65.9%) were good responders. The glycosylated hemoglobin level was higher ( p = 0.011) in poor (7.5% ± 0.94%) than in good (7.04% ± 1.19%) responders. The foveal avascular zone was larger ( p = 0.0003) in poor (0.67 ± 0.33 μm 2 ) than in good (0.47 ± 0.23 μm 2 ) responders. The number of microaneurysms in the pericapillary network was higher ( p = 0.0007) in poor (2.7 ± 2.2) than in good (1.4 ± 2.0) responders. Baseline glycemic control and macular ischemia may be associated with the short-term response to intravitreal anti-VEGF injections.

Purpose: To investigate 24-month results of intravitreal aflibercept (IVA) for macular edema due to branch retinal vein occlusion (BRVO-ME)., Study Design: Retrospective study., Methods: Subjects were treatment-naïve BRVO-ME patients at the Ophthalmology Department of Juntendo University Urayasu Hospital from November 2015 to March 2017 who received IVA treatment for 24 months. After the first injection, reinjection was performed as needed when ME had recurred or was prolonged beyond 300 μm. Data included changes in best corrected visual acuity and central foveal thickness, total number of injections, and the case background factors that required reinjection after 12 months. ME remission was defined as patients without additional injections for 6 months., Results: Forty eyes of 40 patients (64.5 ± 11.5 years), 21 men and 19 women, were included. Average best corrected visual acuity and central foveal thickness at baseline were logMAR 0.42 ± 0.21, 601.4 ± 181.3 μm, logMAR 0.08 ± 0.25, 214.6 ± 62.7 μm at 12 months, logMAR 0.02 ± 0.16, 216.6 ± 97.8 μm at 24 months, all significantly improved from baseline. The average number of injections was 2.2 ± 1.0 times in the first year and 0.4 ± 0.8 times in the second year. The rate of ME remission was 60.0% at 12 months and 87.5% at 24 months. Period between onset and injections was significantly associated with reinjection after 12 months (p =.030)., Conclusions: IVA was effective over 24 months for ME due to BRVO in many cases. Early injection treatment may reduce the need for later injections.

Introduction: The role of vascular endothelial growth factor in macular edema (ME) due to branch retinal vein occlusion (BRVO) by enhancing vascular permeability has been well studied. ME due to BRVO often recurs; however, there has been no report on the relationship between this recurrence and choroidal thickness (CT), considering the high vascularity of the choroid. This study was designed to investigate this relationship., Methods: In this retrospective consecutive case series, patients with recurrence of ME within 6 months of receiving intravitreal aflibercept injection treatment for naive ME due to BRVO at Juntendo University Urayasu Hospital were included. Retinal thickness (RT) and CT were measured in the fovea and on the occlusion, non-occlusion, nasal, and temporal sides at baseline, after the first intravitreal aflibercept administration, and before and after recurrence. We also examined the change for each side before and after reinjection., Results: This study included 11 patients and 11 eyes. The subfoveal CT and RT at baseline were 261.9 ± 93.4 μm and 691.5 ± 254.4 μm, respectively, which significantly decreased to 208.5 ± 70.3 μm and 188.6 ± 33.8 μm, respectively, at 1 month after the first injection (p = 0.001 and p < 0.01, respectively). These values also significantly decreased at all the other sites after treatment. There were 14 recurrences within the 6 months following intravitreal aflibercept injection; RT significantly changed at all sites before and after recurrence and reinjection. CT significantly changed at the subfovea and on the occlusion and non-occlusion sides; however, there was no significant change on the nasal and temporal sides., Conclusion: In patients with BRVO, the CT around the macula after initial treatment was significantly reduced; however, at the time of ME recurrence and reinjection, there were site-dependent differences in the changes observed in the CT. These findings suggest that the pathologies of ME at initial occurrence and at the time of recurrence are different., (© 2020 The Author(s). Published by S. Karger AG, Basel.)

Purpose: Vernal keratoconjunctivitis (VKC) is a severe and recurrent allergic conjunctivitis, the mechanism of which is not well understood. In this study, we investigated the role of oncostatin M (OSM) in the pathogenesis of VKC, with a focus on tissue remodeling., Study Design: Clinical and experimental., Patients and Methods: The OSM concentrations in tear fluid samples obtained from VKC patients and healthy controls were measured using ELISA, and the expression of OSM mRNA and protein in giant papillae resected from VKC patients was investigated using RT-PCR and immunohistochemistry, respectively. In cultured human conjunctival epithelial cells (HconEpiCs), expression of OSM receptor β (OSMRβ) was detected using immunocytochemical and FACS analyses. Finally, we investigated whether recombinant OSM activated STAT1 and STAT3 to induce the expression of various genes related to tissue remodeling in HconEpiCs, by using Western blot analysis, microarray analysis, and RT-PCR., Results: The OSM concentration was higher in the tear fluid of VKC patients than in that of the healthy controls, and strong expression of OSM mRNA was found in the giant papillae. We also detected T cells expressing OSM in the giant papillae. In addition, HconEpiCs showed surface expression of OSMRβ. Recombinant human OSM strongly activated both STAT1 and STAT3 in HconEpiCs and induced various tissue remodeling-related genes, including MMP-1, MMP-3, IL-24, IL-20, serpinB3, S100A7, tenascin C, and SOCS3., Conclusion: Our results suggest that OSM is one of the key molecules involved in remodeling of giant papillae in VKC.

We had cases in which peripheral neuropathy was augmented after changing from mFOLFOX6, a chemotherapy for colorectal cancer, to FOLFIRI and comparatively examined disease status and trends. There were no shared points with respect to patient characteristics, timing of peripheral neuropathy augmentation, drug dosage, etc. It appeared that the change in chemotherapy itself had an effect on neuropathic symptoms. Regarding the change in chemotherapy, the therapeutic agent was switched from oxaliplatin to irinotecan; the cause was unknown, but some effects of these two drugs were suggested. Future investigation, including the examination of genetic mutations, is necessary.