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To investigate nasal displacement of central retinal vessel (CRV) on the optic nerve head (ONH) in glaucoma in association with its passage through lamina cribrosa (LC). This cross-sectional study included 113 eyes with glaucoma and 60 normal eyes. Horizontal spectral-domain optical coherence tomography (SD-OCT) scans of the ONH were acquired, and point where CRV emerged on the ONH surface was defined as the position of the CRV. Next, radial scans of the ONH were acquired, and angle of the CRV passing through the LC was measured. These parameters were compared between glaucomatous and normal eyes by t-test, and their relationship with possible confounders was assessed by multiple regression analyses. In glaucoma, CRV was significantly more nasally displaced than it was in normal eyes (66.0 +/- 8.6 vs. 54.3 +/- 9.5, P<0.0001), and eyes with more vessel displacement exhibited significantly worse glaucomatous visual field defects (P=0.0004). Greater nasal displacement of the CRV was significantly associated with a more nasally angled path through the LC (rs=0.569, P<0.0001). By using SD-OCT, we confirmed that nasal displacement of the CRV on the ONH was associated with glaucoma and was induced by its nasally angled path through the LC.

Purpose The influence of myopia on glaucoma progression remains unknown, possibly because of the multifactorial nature of glaucoma and difficulty in assessing a solo contribution of myopia. The purpose of this study is to investigate the association of myopia with visual field (VF) progression in glaucoma using a paired-eye design to minimize the influence of confounding systemic factors that are diverse among individuals. Methods This retrospective study evaluated 144 eyes of 72 subjects with open-angle glaucoma, with similar intra-ocular pressure between paired eyes, spherical equivalent (SE) <= -2 diopter (D), and axial length >= 24 mm. Paired eyes with faster and slower VF progression were grouped separately, according to the global VF progression rate assessed by automated pointwise linear regression analysis. The SE, axial length, tilt ratio and torsion angle of optic discs, Bruch's membrane (BM) opening area, and gamma zone parapapillary atrophy (PPA) width were compared between the two groups. Factors associated with faster VF progression were determined by logistic regression analysis. Results The mean follow-up duration was 8.9 +/- 4.4 years. The mean value of SE and axial length were -6.31 +/- 1.88 D and 26.05 +/- 1.12 mm, respectively. The mean global visual field progression rate was -0.32 +/- 0.38 dB/y. Tilt ratio, BM opening area, and gamma zone PPA width were significantly greater in the eyes with faster VF progression than those with slower progression. In multivariate analysis, these factors were significantly associated with faster VF progression (all P < 0.05), while SE and axial length were not associated with it. Conclusion In myopic glaucoma subjects, tilt of the optic disc and temporal shifting and enlargement of the BM opening were associated with faster rate of VF progression between paired eyes. This suggests that myopia influences VF progression in glaucomatous eyes via optic disc deformations rather than via refractive error itself.

Purpose To examine the association of myopia with the visual field (VF) defects in open-angle glaucoma (OAG) using paired eyes to eliminate the effect of unknown confounding factors that are diverse among individuals. Methods One hundred eighteen eyes of 59 subjects with myopia (spherical equivalent [SE] >= -2 diopter [D] and axial length >= 24.0 mm) whose intra-ocular pressure between paired eyes was similar and the mean deviation (MD) of the Humphrey VF test differed by more than 6 dB were included. Refractive errors (SE, axial length) and parameters associated with the papillary and parapapillary myopic deformation (tilt ratio, torsion angle, and beta-zone parapapillary atrophy [PPA] area without Bruch's membrane) were measured in each eye. The paired eyes were divided into worse and better eyes according to the MD of the VF, and parameters were compared between them. Further, multiple linear regression analysis was performed to examine the correlation of the difference in various parameters with the MD difference between paired eyes. Results The SE of all eyes was -6.39 +/- 2.15 D (mean +/- standard deviation) and axial length was 26.42 +/- 1.07 mm. MD of the worse and better VF eyes were -13.56 +/- 6.65 dB and -4.87 +/- 5.32 dB, respectively. Eyes with worse VFs had significantly greater SE, axial length, tilt ratio, and PPA area without Bruch's membrane than those with better VFs (all P < 0.05). In multiple linear regression analysis, the difference of the MD between paired eyes was significantly correlated with the difference in the tilt ratio and PPA area without Bruch's membrane. Conclusion The myopic papillary and parapapillary deformations, but not refractive error itself, were related to the worse VF in paired eyes with OAG. This suggests that myopia influences the severity of the glaucomatous VF defects via structural deformation.

This review is intended to illuminate the emerging understanding of epigenetic modifications that regulate both adaptive and innate immunity in the skin. Host defense of the epidermis and dermis involves the interplay of many cell types to enable homeostasis; tolerance to the external environment; and appropriate response to transient microbial, chemical, and physical insults. To understand this process, the study of cutaneous immunology has focused on immune responses that reflect both adaptive learned and genetically programmed innate defense systems. However, recent advances have begun to reveal that epigenetic modifications of chromatin structure also have a major influence on the skin immune system. This deeper understanding of how enzymatic changes in chromatin structure can modify the skin immune system and may explain how environmental exposures during life, and the microbiome, lead to both short-term and long-term changes in cutaneous allergic and other inflammatory processes. Understanding the mechanisms responsible for alterations in gene and chromatin structure within skin immunocytes could provide key insights into the pathogenesis of inflammatory skin diseases that have thus far evaded understanding by dermatologists.

The skin typically tolerates exposure to various microbes and chemicals in the environment. Here, we investigated how the epidermis maintains this innate immune tolerance to stimuli that are recognized by Toll-like receptors (TLRs). Loss of tolerance to TLR ligands occurred after silencing of the histone deacetylases (HDACs) HDAC8 and HDAC9 in keratinocytes. Transcriptional analysis identified MAP2K3 as suppressed by HDAC8/9 activity and a potential key intermediary for establishing this tolerance. HDAC8/9 influenced acetylation at H3K9 and H3K27 marks in the MAP2K3 promoter. Proteomic analysis further identified SSRP1 and SUPT16H as associated with HDAC8/9 and responsible for transcriptional elongation of MAP2K3. Silencing of MAP2K3 blocked the capacity of HDAC8/9 to influence cytokine responses. Relevance in vivo was supported by observations of increased MAP2K3 in human inflammatory skin conditions and the capacity of keratinocyte HDAC8/9 to influence dendritic cell maturation and T cell proliferation. Keratinocyte-specific deletion of HDAC8/9 also increased inflammation in mice after exposure to ultraviolet radiation, imiquimod, or Staphylococcus aureus These findings define a mechanism for the epidermis to regulate inflammation in the presence of ubiquitous TLR ligands.

To investigate nasal displacement of central retinal vessel (CRV) on the optic nerve head (ONH) in glaucoma in association with its passage through lamina cribrosa (LC). This cross-sectional study included 113 eyes with glaucoma and 60 normal eyes. Horizontal spectral-domain optical coherence tomography (SD-OCT) scans of the ONH were acquired, and point where CRV emerged on the ONH surface was defined as the position of the CRV. Next, radial scans of the ONH were acquired, and angle of the CRV passing through the LC was measured. These parameters were compared between glaucomatous and normal eyes by t-test, and their relationship with possible confounders was assessed by multiple regression analyses. In glaucoma, CRV was significantly more nasally displaced than it was in normal eyes (66.0 +/- 8.6 vs. 54.3 +/- 9.5, P<0.0001), and eyes with more vessel displacement exhibited significantly worse glaucomatous visual field defects (P=0.0004). Greater nasal displacement of the CRV was significantly associated with a more nasally angled path through the LC (rs=0.569, P<0.0001). By using SD-OCT, we confirmed that nasal displacement of the CRV on the ONH was associated with glaucoma and was induced by its nasally angled path through the LC.

Purpose The influence of myopia on glaucoma progression remains unknown, possibly because of the multifactorial nature of glaucoma and difficulty in assessing a solo contribution of myopia. The purpose of this study is to investigate the association of myopia with visual field (VF) progression in glaucoma using a paired-eye design to minimize the influence of confounding systemic factors that are diverse among individuals. Methods This retrospective study evaluated 144 eyes of 72 subjects with open-angle glaucoma, with similar intra-ocular pressure between paired eyes, spherical equivalent (SE) <= -2 diopter (D), and axial length >= 24 mm. Paired eyes with faster and slower VF progression were grouped separately, according to the global VF progression rate assessed by automated pointwise linear regression analysis. The SE, axial length, tilt ratio and torsion angle of optic discs, Bruch's membrane (BM) opening area, and gamma zone parapapillary atrophy (PPA) width were compared between the two groups. Factors associated with faster VF progression were determined by logistic regression analysis. Results The mean follow-up duration was 8.9 +/- 4.4 years. The mean value of SE and axial length were -6.31 +/- 1.88 D and 26.05 +/- 1.12 mm, respectively. The mean global visual field progression rate was -0.32 +/- 0.38 dB/y. Tilt ratio, BM opening area, and gamma zone PPA width were significantly greater in the eyes with faster VF progression than those with slower progression. In multivariate analysis, these factors were significantly associated with faster VF progression (all P < 0.05), while SE and axial length were not associated with it. Conclusion In myopic glaucoma subjects, tilt of the optic disc and temporal shifting and enlargement of the BM opening were associated with faster rate of VF progression between paired eyes. This suggests that myopia influences VF progression in glaucomatous eyes via optic disc deformations rather than via refractive error itself.

Purpose To examine the association of myopia with the visual field (VF) defects in open-angle glaucoma (OAG) using paired eyes to eliminate the effect of unknown confounding factors that are diverse among individuals. Methods One hundred eighteen eyes of 59 subjects with myopia (spherical equivalent [SE] >= -2 diopter [D] and axial length >= 24.0 mm) whose intra-ocular pressure between paired eyes was similar and the mean deviation (MD) of the Humphrey VF test differed by more than 6 dB were included. Refractive errors (SE, axial length) and parameters associated with the papillary and parapapillary myopic deformation (tilt ratio, torsion angle, and beta-zone parapapillary atrophy [PPA] area without Bruch's membrane) were measured in each eye. The paired eyes were divided into worse and better eyes according to the MD of the VF, and parameters were compared between them. Further, multiple linear regression analysis was performed to examine the correlation of the difference in various parameters with the MD difference between paired eyes. Results The SE of all eyes was -6.39 +/- 2.15 D (mean +/- standard deviation) and axial length was 26.42 +/- 1.07 mm. MD of the worse and better VF eyes were -13.56 +/- 6.65 dB and -4.87 +/- 5.32 dB, respectively. Eyes with worse VFs had significantly greater SE, axial length, tilt ratio, and PPA area without Bruch's membrane than those with better VFs (all P < 0.05). In multiple linear regression analysis, the difference of the MD between paired eyes was significantly correlated with the difference in the tilt ratio and PPA area without Bruch's membrane. Conclusion The myopic papillary and parapapillary deformations, but not refractive error itself, were related to the worse VF in paired eyes with OAG. This suggests that myopia influences the severity of the glaucomatous VF defects via structural deformation.

Emi Mashima, Akiha Inoue, Yumiko Sakuragi, Takashi Yamaguchi, Natsuko Sasaki, Yoko Hara, Daisuke Omoto, Shun Ohmori, Sanehito Haruyama, Yu Sawada, Manabu Yoshioka, Daisuke Nishio, Motonobu Nakamura Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan Abstract: Nivolumab was developed as a monoclonal antibody against programmed death receptor-1, an immune checkpoint inhibitor which negatively regulates T-cell proliferation and activation. Intravenous administration of nivolumab was approved for the treatment of unresectable malignant melanoma in 2014 in Japan. When advanced melanoma patients were treated with nivolumab, median overall survival became longer. Overall survival rate was significantly better in nivolumab-treated melanoma patients than dacarbazine-treated melanoma patients. Nivolumab had an acceptable long-term tolerability profile, with 22% of patients experiencing grade 3 or 4 adverse events related to the drug. Therefore, nivolumab can become an alternative therapy for advanced malignant melanoma. Keywords: monoclonal antibody, PD-1, PD-L1

Emi Mashima, Akiha Inoue, Yumiko Sakuragi, Takashi Yamaguchi, Natsuko Sasaki, Yoko Hara, Daisuke Omoto, Shun Ohmori, Sanehito Haruyama, Yu Sawada, Manabu Yoshioka, Daisuke Nishio, Motonobu Nakamura Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan Abstract: Nivolumab was developed as a monoclonal antibody against programmed death receptor-1, an immune checkpoint inhibitor which negatively regulates T-cell proliferation and activation. Intravenous administration of nivolumab was approved for the treatment of unresectable malignant melanoma in 2014 in Japan. When advanced melanoma patients were treated with nivolumab, median overall survival became longer. Overall survival rate was significantly better in nivolumab-treated melanoma patients than dacarbazine-treated melanoma patients. Nivolumab had an acceptable long-term tolerability profile, with 22% of patients experiencing grade 3 or 4 adverse events related to the drug. Therefore, nivolumab can become an alternative therapy for advanced malignant melanoma. Keywords: monoclonal antibody, PD-1, PD-L1

Makoto Ishikawa, Yu Sawada, Noriko Sato, Takeshi YoshitomiDepartment of Ophthalmology, Akita Graduate University School of Medicine, Akita, JapanBackground/aims: To describe risk factors associated with primary open-angle glaucoma (POAG) in Japanese subjects who participated in community health screenings.Methods: Residents of Akita, Japan, participating in a community health checkup were selected to undergo a comprehensive ophthalmic examination. Glaucoma was diagnosed based on optic disk appearance, perimetric results, and other ocular findings. Systemic blood pressure and intraocular pressure were measured and ocular perfusion pressure was calculated. Logistic regression analysis was performed to determine risk factors for POAG patients.Results and conclusion: Of the 710 subjects examined, 26 had POAG. The estimated prevalence of POAG was 3.7%. After adjusting for age, the prevalence of POAG was similar to that found in the Tajimi Study of Japanese subjects. Multivariate logistic regression analysis demonstrated that older age (≥60 years, odds ratio [OR]: 3.49), lower diastolic blood pressure (≤58 mmHg, OR: 2.11), higher intraocular pressure (≥19 mmHg, OR: 4.12), and lower ocular perfusion pressure (≤34 mmHg, OR: 5.78) were associated with increased risk of having POAG. These findings may be relevant for identifying high risk groups.Keywords: glaucoma, community health screening, risk factors

Makoto Ishikawa1, Masabumi Kubo2, Seiji Maeda3, Yu Sawada1, Eiichi Uchio4, Takeshi Yoshitomi11Department of Ophthalmology, Akita University School of Medicine, Akita, Japan; 2Fukiage Eye Clinic, Hachinohe, Japan; 3Maeda Eye Clinic, Honjo, Japan; 4Department of Ophthalmology, Fukuoka University School of Medicine, Fukuoka, JapanPurpose: To examine structural changes in the lacrimal sac epithelium and associated lymphoid tissue of rabbits with experimentally induced dacryocystitis.Methods: Experimental dacryocystitis was induced by an inoculation of Staphylococcus aureus into the lacrimal sac. The histological changes of the inflamed lacrimal sac epithelium and associated lymphoid tissue were studied by light and electron microscopy.Results: After 1 month, numerous inflammatory cells (CD20-positive B lymphocytes, CD3-positive T lymphocytes, IgA-positive plasma cells, and polymorphonuclear leukocytes) infiltrated the lamina propria and the epithelium overlying the diffuse lymphoid tissue. Three months later, the density of the infiltrated leukocytes was markedly decreased. The epithelial lining overlying the diffuse lymphoid tissue became thicker with numerous secretory granules in the supranuclear regions.Conclusion: The lacrimal sac epithelium and associated lymphoid tissue play a major role in the defense mechanism during inflammation. Overproduction of secretory granules after bacterial inoculation could enhance the antimicrobial defense.Keywords: experimental dacryocystitis, lacrimal sac epithelium, lymphoid tissue, structure, rabbit