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Aya Ikeda, Asami Shimokawa, Kazuhiro Harada, Tomoko Tsukahara-Kawamura, Jane Huang, Hiroaki Ozaki, Eiichi Uchio Department of Ophthalmology, Fukuoka University School of Medicine, Fukuoka, JapanCorrespondence: Eiichi Uchio, Department of Ophthalmology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan, Tel +81 92 801 1011, Fax +81 92 865 4445, Email euchio@fukuoka-u.ac.jpBackground: We have previously studied the physiological and mechanical responses of the eye to blunt trauma in various situations using finite element analysis (FEA). In this study, we evaluated the volume kinetics of an airbag impact on the eye using FEA to sequentially determine the volume change rates of intraocular segments at various airbag deployment velocities.Methods: The human eye model we created was used in simulations with the FEA program PAM-GENERISTM (Nihon ESI, Tokyo, Japan). Different airbag deployment velocities, 30, 40, 50, 60 and 70 m/s, were applied in the forward direction. The volume of the deformed eye impacted by the airbag was calculated as the integrated value of all meshes in each segment, and the decrease rate was calculated as the ratio of the decreased volume of each segment at particular timepoints to the value before the airbag impact.Results: The minimum volume of the anterior chamber was 63%, 69% and 50% at 50, 60 and 70 m/s airbag impact velocity, respectively, showing a curve with a sharp decline followed by gradual recovery. In contrast to the anterior chamber, the volume of the lens recovered promptly, reaching 80– 90% at the end of observation, except for the case of 60 m/s. Following the decrease, the volume increased to more than that of baseline at 60 m/s. The rate of volume change of the vitreous was distributed in a narrow range, 99.2– 100.4%.Conclusion: In this study, we found a large, prolonged decrease of volume in the anterior chamber, a similar large decrease followed by prompt recovery of volume in the lens, and a time-lag in the volume decrease between these tissues. These novel findings may provide an important insight into the pathophysiological mechanism of airbag ocular injuries through this further evaluation, employing a refined FEA model representing cuboidal deformation, to develop a more safe airbag system.Keywords: airbag, ocular trauma, computer simulation, lens, anterior chamber, vitreous body, finite element analysis, volume

Asami Shimokawa, Aya Ikeda, Kazuhiro Harada, Rie Takahashi, Jane Huang, Tomoko Tsukahara-Kawamura, Hiroaki Ozaki, Eiichi Uchio Department of Ophthalmology, Fukuoka University School of Medicine, Fukuoka, JapanCorrespondence: Eiichi Uchio, Department of Ophthalmology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan, Tel +81 92 801 1011, Fax +81 92 865 4445, Email euchio@fukuoka-u.ac.jpPurpose: Vernal keratoconjunctivitis (VKC) is a refractory ocular allergic disorder that mainly affects boys. Long-term follow-up has been rarely reported for VKC. We investigated the long-term clinical outcome of VKC to identify relevant clinical features of prognostic value based on follow-up for a median of 70 months.Methods: In total, 45 consecutive patients clinically diagnosed with VKC aged 4 to 12 years at onset at the Department of Ophthalmology of Fukuoka University Hospital were included. Patients were treated with immunosuppressive eye drops without simultaneous corticosteroid eye drops, except for the occurrence of exacerbations. Collated variables were gender, age at onset, clinical score of ocular lesions (conjunctival giant papillae, limbal edema and corneal epithelial lesions) at the first visit, and clinical score of atopic dermatitis (AD) at baseline. Cumulative cure rate was estimated using Kaplan–Meier method. A binomial logistic predictive model was used to determine the most reliable clinical predictors of VKC outcome.Results: The observation period ranged from 24 to 188 months, with median of 70 months. Among the 45 cases enrolled, all non-cured cases (14 cases) observed clinically were complicated by AD. Cumulative cure rate was 74.5% and 84.9% at eight- and ten-year follow-up, respectively. Ten-year cumulative cure rates of cases with and without AD were 50.5% and 100%, respectively, and a significant difference was found between these cumulative cure curves. Binomial regression analysis revealed that AD and gender were significantly related to worse outcome, and this binomial regression model had high sensitivity and specificity.Conclusion: This study demonstrated that th eclinical outcomeof VKC might be predicted by several factors that can beobtained in the early clinical phase. Information on the long-term prognosis of VKC patients might play an important role for precision medicine for VKC in childhood.Keywords: vernal keratoconjunctivitis, cumulative cure rate, atopic dermatitis, immunosuppressive eye drops, binomial logistic analysis

Shuji Suzuki,1 Aya Ikeda,1 Takashi Uemura,1 Kazuhiro Harada,1 Rie Takahashi,1 Jane Huang,1 Tomoko Tsukahara-Kawamura,1 Hiroaki Ozaki,1 Kazuaki Kadonosono,2 Eiichi Uchio1 1Department of Ophthalmology, Fukuoka University School of Medicine, Fukuoka, Japan; 2Department of Ophthalmology, Yokohama City University Medical Center, Yokohama, JapanCorrespondence: Eiichi Uchio, Department of Ophthalmology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan, Fukuoka, 814-0180, Japan, Email euchio@fukuoka-u.ac.jpPurpose: We studied the kinetic phenomenon of an airbag impact on eyes after trabeculectomy using finite element analysis (FEA), a computerized method for predicting how an object reacts to real-world physical effects and showing whether an object will break, to sequentially determine the responses at various airbag deployment velocities.Methods: A human eye model was used in the simulations using the FEA program PAM-GENERISTM (Nihon ESI, Tokyo, Japan). A half-thickness incised scleral flap was created on the limbus and the strength of its adhesion to the outer sclera was set at 30%, 50%, and 100%. The airbag was set to hit the surface of the post-trabeculectomy eye at various velocities in two directions: perpendicular to the corneal center or perpendicular to the scleral flap (30° gaze-down position), at initial velocities of 20, 30, 40, 50, and 60 m/s.Results: When the airbag impacted at 20 m/s or 30 m/s, the strain on the cornea and sclera did not reach the mechanical threshold and globe rupture was not observed. Scleral flap lacerations were observed at 40 m/s or more in any eye position, and scleral rupture extending posteriorly from the scleral flap edge and rupture of the scleral flap resulting from extension of the corneal laceration through limbal damage were observed. Even in the case of 100% scleral flap adhesion strength, scleral flap rupture occurred at 50 m/s impact velocity in the 30° gaze-down position, whereas in eyes with 30% or 50% scleral flap adhesion strength, scleral rupture was observed at an impact velocity of 40 m/s or more in both eye positions.Conclusion: An airbag impact of ≥ 40 m/s might induce scleral flap rupture, indicating that current airbags may induce globe rupture in the eyes after trabeculectomy. The considerable damage caused by an airbag on the eyes of short-stature patients with glaucoma who have undergone trabeculectomy might indicate the necessity of ocular protection to avoid permanent eye damage.Keywords: airbag, trabeculectomy, sclera, flap, rupture, finite element analysis

Tomohiro Ueno, Hideaki Fujita, Aya Ikeda, Kazuhiro Harada, Tomoko Tsukahara-Kawamura, Hiroaki Ozaki, Eiichi Uchio Department of Ophthalmology, Fukuoka University School of Medicine, Fukuoka, JapanCorrespondence: Eiichi Uchio, Department of Ophthalmology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan, Tel +81 92 801 1011, Fax +81 92 865 4445, Email euchio@fukuoka-u.ac.jpBackground: We studied the kinetic phenomenon of an airbag impact on eyes with different axial lengths using finite element analysis (FEA) to sequentially determine the physical and mechanical responses of intraocular segments at various airbag deployment velocities.Methods: The human eye model we created was used in simulations with the FEA program PAM-GENERISTM. The airbag was set to impact eyes with axial lengths of 21.85 mm (hyperopia), 23.85 mm (emmetropia) and 25.85 mm (myopia), at initial velocities of 20, 30, 40, 50 and 60 m/s. The deformation rate was calculated as the ratio of the length of three segments, anterior chamber, lens and vitreous, to that at the baseline from 0.2 ms to 2.0 ms after the airbag impact.Results: Deformation rate of the anterior chamber was greater than that of other segments, especially in the early phase, 0.2– 0.4 ms after the impact (P < 0.001), and it reached its peak, 80%, at 0.8 ms. A higher deformation rate in the anterior chamber was found in hyperopia compared with other axial length eyes in the first half period, 0.2– 0.8 ms, followed by the rate in emmetropia (P < 0.001). The lens deformation rate was low, its peak ranging from 40% to 75%, and exceeded that of the anterior chamber at 1.4 ms and 1.6 ms after the impact (P < 0.01). The vitreous deformation rate was lower throughout the simulation period than that of the other segments and ranged from a negative value (elongation) in the later phase.Conclusion: Airbag impact on the eyeball causes evident deformation, especially in the anterior chamber. The results obtained in this study, such as the time lag of the peak deformation between the anterior chamber and lens, suggest a clue to the pathophysiological mechanism of airbag ocular injury.Keywords: airbag, ocular trauma, computer simulation, lens, anterior chamber, vitreous body, finite element analysis, deformation

Hideaki Fujita, Tomohiro Ueno, Shuji Suzuki, Kazuhiro Harada, Tomoko Tsukahara-Kawamura, Hiroaki Ozaki, Eiichi Uchio Department of Ophthalmology, Fukuoka University School of Medicine, Fukuoka, JapanCorrespondence: Eiichi Uchio, Department of Ophthalmology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan, Tel +81 92 801 1011, Fax +81 92 865 4445, Email euchio@fukuoka-u.ac.jpBackground: Vernal keratoconjunctivitis (VKC) is a refractory ocular allergic disorder that mainly affects boys. A few studies have attempted to develop a classification of subtypes of VKC. In this study, we investigated a computational approach called cluster analysis to separate VKC cases into groups based on clinically relevant characteristics.Methods: In total, 41 consecutive patients clinically diagnosed with VKC at the Department of Ophthalmology of Fukuoka University Hospital were included. Patients were treated with immunosuppressive eye drops without simultaneous corticosteroid eye drops, except for the occurrence of exacerbations. Collated variables were age at onset, clinical score of ocular lesions at baseline, clinical score of ocular lesions at final visit, clinical score of atopic dermatitis (AD) at baseline, frequency of exacerbations of VKC, serum total IgE level and peripheral blood eosinophil count.Results: VKC patients were grouped into three clusters by cluster analysis, and cluster 1, 2, and 3 comprised 25, 9 and 7 cases, respectively. There were differences in the incidence of complications of AD and age at onset among the clusters; therefore, we named the three clusters for better understanding as traditional VKC (cluster 1), early-onset atopic keratoconjunctivitis (AKC)/VKC (cluster 2) and puberty-onset AKC (cluster 3).Conclusion: We found in this study that VKC in childhood has three phenotypes which were previously unknown. Our findings may help to establish precision medicine by focusing on the phenotype of each case to develop individualized medicine to prevent exacerbations.Keywords: vernal keratoconjunctivitis, subtype, atopic dermatitis, atopic keratoconjunctivitis, cluster analysis

Ryosuke Izaki,1 Ayaka Kobayashi,1 Hideaki Fujita,1 Kazuhiro Harada,1 Hiroaki Ozaki,1 Kazuaki Kadonosono,2 Eiichi Uchio1 1Department of Ophthalmology, Fukuoka University School of Medicine, Fukuoka, Japan; 2Department of Ophthalmology, Yokohama City University Medical Center, Yokohama, JapanCorrespondence: Eiichi Uchio, Department of Ophthalmology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan, Tel +81 92 801 1011, Fax +81 92 865 4445, Email euchio@fukuoka-u.ac.jpPurpose: We have previously studied clinical and allergological aspects of sick building syndrome (SBS) cases with ocular disorders and found that SBS is suggested to be partially induced by an allergic response. We analyzed the cytokine production profiles of conjunctival and peripheral blood lymphocytes in patients with SBS with ocular manifestations to further evaluate the pathophysiology of SBS from an immunological standpoint.Methods: We obtained conjunctival samples and peripheral blood mononuclear cells (PBMC) from 15 cases of SBS with ocular findings, 49 cases of allergic conjunctival diseases (ACD) (allergic conjunctivitis (AC), atopic keratoconjunctivitis (AKC), and vernal keratoconjunctivitis (VKC)), and normal controls. Frequencies of cytokine-producing T cells were analyzed by flow cytometry based on an intracellular cytokine staining method.Results: Although no significant difference was observed in the percentage of interferon (IFN)-γ-producing CD4+ T cells in PBMC between patients with SBS and controls, the percentage of interleukin (IL)-4-producing PBMC CD4+ T cells in patients with SBS was significantly higher than that in controls. The percentage of IL-4-producing CD4+ T cells in the conjunctiva in patients with SBS was significantly higher than that in controls, whereas it was significantly lower than that in AKC and VKC. A significant correlation was observed between the percentage of IL-4-producing CD4+ T cells in the conjunctiva and clinical score.Conclusion: These results suggest that SBS may be a kind of allergic disorder and that IL-4 plays a role in the development of allergic disorders in SBS ocular lesions.Keywords: sick building syndrome, allergic conjunctival disease, interferon-γ, interleukin-4, lymphocyte

Hidehiro Sugisawa,1 Ken Harada,2 Yoko Sugihara,3 Shizuko Yanagisawa,4 Masaya Shinmei5 1International Graduate School for Advanced Studies, J. F. Oberlin University, Machida-shi, Tokyo, Japan; 2Department of Humanities and Social Sciences, Jissen Women’s University, Shibuya-ku, Japan; 3Department of Urban Science and Policy, Tokyo Metropolitan University, Hachioji-shi, Japan; 4Department of Oral Health Science and Social Welfare, Institute of Biomedical Sciences, Tokushima University, Tokushima-shi, Japan; 5Faculty of Human Welfare, Den-En Chofu University, Kawasaki Shi, JapanCorrespondence: Hidehiro Sugisawa, International Graduate School for Advanced Studies, J. F. Oberlin University, 3758, Machida-shi, Tokyo, 194-0294, Japan, Tel/Fax +81(0)02-797-9847, Email sugisawa@obirin.ac.jpPurpose: Few studies have examined together the psychosocial mediators of how life-course and late-life socioeconomic status (SES) influence late-life health. This study explored psychosocial mediators of influences of not only life-course but also late-life financial strain on late-life health in Japan, using a cross-sectional survey. It was hypothesized that: 1) both life-course and late-life financial strain will influence late-life health through common mediators, and 2) such mediating influences will be large on health indicators strongly related to psychosocial resources, such as depressive tendencies and self-rated health.Methods: The participants (N = 739) were aged 65 years and older and lived in metropolitan Tokyo, Japan. Life-course financial strain was measured retrospectively by the number of financially strenuous experiences over the participants’ life-courses. Possible mediators included stressors (life-course and late-life major traumatic life events) and psychosocial resources (self-esteem, sense of control, health literacy, social networks, and social support). Health indicators included multimorbidity, disabled activities of daily living (ADL), depressive tendency, and poorer self-rated health.Results: Having a sense of control mediated the significant influences of both life-course and late-life financial strain on disabled ADL. Furthermore, self-esteem significantly mediated the influences of both life-course and late-life financial strain on depressive tendencies and poorer self-rated health. All such mediating influences were significant at p < 0.05. Psychosocial resources did not mediate significant influences of life-course and financial strain on multimorbidity.Conclusion: The results support our hypotheses and make three main contributions on the mechanism through which SES influences late-life health: 1) psychosocial resources mediate the effect of life-course SES on late-life health; 2) the influence differs depending on health type; and 3) these results can generalize to older adults in not only Japan but also Western countries.Keywords: accumulative effects model, multiple health indicators, multiple mediation, social class, self-concept

Rie Takahashi, Kanno Okamura, Tomoko Tsukahara-Kawamura, Kazuhiro Harada, Yusuke Saeki, Hiroaki Ozaki, Eiichi Uchio Department of Ophthalmology, Fukuoka University School of Medicine, Fukuoka, JapanCorrespondence: Eiichi UchioDepartment of Ophthalmology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Fukuoka, Jonan-Ku 814-0180, JapanTel +81 92 801 1011Fax +81 92 865 4445Email euchio@fukuoka-u.ac.jpPurpose: We have carried out three-dimensional finite element analysis (FEA) to determine the physical and mechanical response in several ocular injuries. We applied this FEA model to evaluate an airsoft gun impact on an eye and the deformation rate of eyes of various axial lengths at various velocities.Methods: This study was carried out on a human eye model using an FEA program created by Nihon, ESI Group. The airsoft gun pellet was set to impact the eye at initial velocities of 45, 60 and 75 m/s with the addition of variation in axial length of 20 mm (hyperopia), 22 mm (emmetropia), 24 mm (myopia) and 26 mm (high myopia). Deformation of the eye was calculated as the decrease rate of the volume of the eyeball and the decrease rate of the axial length.Results: In all emmetropic cases, the cornea reached its strain threshold during the impact, and scleral strain showed a patchy strength distribution in the simulation. The deformation was most evident in the anterior segment, while deformation of the posterior segment was less. The decrease rate of the volume of the eyeball and decrease rate of the axial length were highest in the hyperopic eye, followed by the emmetropic eye and myopic eye, and the high myopic eye showed the lowest decrease rates among the four axial lengths in all impact velocity simulations.Conclusion: These results suggest that hyperopic eyes are most susceptible to deformation by an airsoft gun impact compared with other axial length eye models in this simulation. The considerable deformation by an airsoft gun impact shown in this study might indicate the necessity of ocular protection to avoid permanent eye injury. FEA using a human eyeball model might be a useful method to analyze and predict the mechanical features of ocular injury by an airsoft gun.Keywords: airsoft gun, finite element analysis, globe, cornea, rupture, deformation

Wendi Yan,1,* Xue Wang,1,* Tesi Liu,1 Liyan Chen,2 Longzhe Han,3 Jing Xu,4 Guihua Jin,5 Kenichi Harada,6 Zhenhua Lin,1 Xiangshan Ren1,21Department of Pathology and Cancer Research Center, Yanbian University Medical College, Yanji 133002, People’s Republic of China; 2Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules (Yanbian University), Ministry of Education, Yanji 133002, People’s Republic of China; 3Department of Yanbian University Affiliated Hospital, Yanji 133002, People’s Republic of China; 4Department of Shanxi Medical University Medical College, Taiyuan 030001, People’s Republic of China; 5Department of Immunology and Pathogenic Biology, Yanbian University College of Medicine, Yanji 133002, People’s Republic of China; 6Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan*These authors contributed equally to this workAbstract: Endoplasmic reticulum oxidoreductase 1-α (ERO1A) is a kind of hypoxia-induced endoplasmic reticulum oxidase that regulates translation and folding of oxidized proteins. This study aimed to explore the clinicopathological significance of ERO1A and the effect on the biological behavior of cholangiocarcinoma (CCA) cells.Methods: Immunohistochemical staining was used to detect the expression of ERO1A, carcinoembryonic antigen (CEA), and carbohydrate antigen 19–9 (CA19-9) in cholangiocarcinoma. Immunofluorescence staining was performed to detect the subcellular localization of ERO1A in CCA cells. The expression of ERO1A in CAA cells after depletion or overexpression was verified by Western blot assay. Then, the effect of ERO1A on proliferation in CCA cells was verified by MTT assay and colony formation assay. Wound healing assays and migration assays were performed to detect the effect of ERO1A on cell migration ability. Finally, we explored the role of ERO1A in EMT and Akt/mTOR signaling pathway.Results: In this study, our data demonstrated that ERO1A, CEA, and CA19-9 were expressed in cholangiocarcinoma tissues, and the positive rates were 95%, 95%, and 55%, respectively. The high expression of ERO1A is associated with clinical stage and pathological stage of CCA. In vitro data indicate that deletion of ERO1A can inhibit the proliferation and migration of CCA cells and vice versa. In addition, ERO1A has been shown to be closely related to EMT and Akt/mTOR pathways.Conclusion: In summary, we found that high expression of ERO1A is associated with poor prognosis in patients, and ERO1A can promote the proliferation and migration of CCA cells. In conclusion, ERO1A can be used as an independent biomarker for predicting the prognosis of CCA.Keywords: ERO1A, cholangiocarcinoma, survival, prognosis, EMT

Kazuhiro Harada,1 Tsuguto Fujimoto,2 Yoshimori Asato,3 Eiichi Uchio1 1Department of Ophthalmology, Fukuoka University School of Medicine, Fukuoka, 2Infectious Disease Surveillance Center, National Institute of Infectious Disease, Tokyo, 3Asato Eye Clinic, Itoman, Japan Background: Acute hemorrhagic conjunctivitis (AHC) is a highly contagious enterovirus infection of the conjunctiva and cornea. Coxsackievirus A24 variant (CA24v) is one of its etiological agents. We report a clinical, epidemiological, and virological analysis of a large epidemic of AHC that occurred from May to September, 2011, in Okinawa, Japan.Methods: Clinical and epidemic aspects were evaluated for 435 AHC patients (348 bilateral and 87 unilateral, 783 eyes). Virological studies were carried out on nine isolates from ten patients. Virus isolation and direct detection of the enterovirus genome by the reverse transcription polymerase chain reaction method and complete nucleotide sequencing of the VP1 gene and phylogeny-based classification using the VP4 sequences were carried out.Results: The 11–15-year age group comprised the highest (62.0%) proportion of cases among all age groups. Conjunctival hyperemia was present in all patients, and subconjunctival hemorrhage, superficial punctate keratitis, and preauricular lymphadenopathy were present in 25.4%, 10.3%, and 7.8% of eyes, respectively. CA24v was isolated from the epidemic strain, and phylogenetic analysis based on a fragment of the VP1 gene showed 96%–97% identity between the current strain and the recent China/GD01/2010 strain.Conclusion: These findings demonstrate that the clinical and epidemiological features of AHC observed in this study were similar to those of the past epidemic in the same region. It should be noted that sequential outbreaks of AHC due to CA24v might occur in the same location after a considerable period of time, and public health precautions are necessary to control this explosive epidemic. Keywords: enterovirus, coxsackievirus, acute hemorrhagic conjunctivitis, polymerase chain reaction, epidemiology

The search for the electric-dipole moment (EDM) of laser-cooled francium (Fr) atoms could lead to a measurement for the electron EDM. It is predicted that the electron EDM would be enhanced by approximately three orders of magnitude in heavy atoms such as Fr. Laser-cooling and trapping techniques are expected to suppress statistical and systematic errors in precision measurements. The magneto-optical trap was achieved using stable rubidium in a developing factory of laser-cooled radioactive atoms. In light of the results from the rubidium experiments, we found that an upgrade of each apparatus is preferred for Fr trapping.

For the measurement of the electron electric dipole moment using Fr atoms, a Fr ion-atom conversion is one of the most critical process. An ion-atom converter based on the “orthotropic” type of Fr source has been developed. This converter is able to convert a few keV Fr ion beam to a thermal atomic beam using a cycle of the surface ionization and neutralization. In this article, the development of the converter is reported.

We plan to measure the permanent electric dipole moment (EDM) of the electron, which has the sensitivity to the CP violation in theories beyond the standard model by using the laser-cooled francium (Fr) atom. This paper reports the present status of the EDM measurement system. A high voltage application system was constructed in order to produce the strong electric field (100 kV/cm) needed for the experiment. After conditioning, the leakage current was 10 pA when a high voltage of 43 kV was applied. Also, a drift of an environmental field was measured at the planned location of the Fr-EDM experiment. The drift is suppressed at present down to the level of 10 pT by installing a 4-layermagnetic shield. Improvements are still needed to reach the required field stability of 1 fT.