上原亜衣 ティガレ。 Jon Belcher

HODGE PODGE:本

上原亜衣 ティガレ

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ティガレックス (てぃがれっくす)とは【ピクシブ百科事典】

上原亜衣 ティガレ

背景:運転席用supplemental restraint system SRS エアバッグは、最高時速約300kmで運転手に向かって展開し、それに伴う臓器障害は多岐にわたる。 本稿では、SRSエアバッグ展開に伴い網膜再剥離と気胸を発症した症例の臨床経過を報告する。 症例:73歳、男性。 北海道大学病院眼科で左眼裂孔原性網膜剥離 RRD に対する水晶体再建術、硝子体手術および輪状締結術後の経過観察中に、展開するSRSエアバッグで受傷した。 受傷2週間後に再診し、左眼のRRDの再発があり、硝子体手術およびシリコーンオイルタンポナーデを施行した。 術後8日目に、突然の胸痛と動悸を発症した。 右気胸と診断され、治療された。 受傷後12ヵ月の現在、全身状態は安定しており、網膜再剥離はない。 結論:SRSエアバッグ作動に伴う外傷は、網膜再剥離のリスクになると同時に、全身合併症を伴うこともあるため注意が必要である。 著者抄録• BACKGROUND: We report a rare case of sudden bilateral vision loss due to third ventricular cavernous angioma with intratumoral hemorrhage. CASE PRESENTATION: A 45-year-old woman presented decreased visual acuity in both eyes. Her best corrected visual acuity was 0. 1 in the right eye and 0. 15 in the left eye. Goldmann perimetry showed bilateral central scotomas and bitemporal visual field defects. MRI demonstrated a lesion with mixed hypo- and hyperintensity at the optic chiasm, which was thought to be an intratumoral hemorrhage. The patient underwent bifrontal craniotomy. The tumor was exposed via an anterior interhemispheric approach, and histological evaluation of the mass led to a diagnosis of cavernous angioma. Six months after the surgery, her best corrected visual acuity was 0. 9 in the right eye and 0. 9 in the left, with slight bitemporal visual field defects. CONCLUSION: Third ventricular cavernous angioma is considered in the differential diagnosis of chiasmal syndrome. Contrast-enhanced MRI and FDG-PET might be useful for differential diagnosis of cavernous angioma from other chiasmal tumors including glioblastoma. Precis: A positive correlation was observed between intraocular pressure IOP and central venous pressure CVP in patients with single ventricle SV during the perioperative period. IOP needs to be carefully monitored in the postoperative period after the Glenn and Fontan procedures, particularly the Glenn procedure. Purpose: SV is a cardiac malformation characterized by the existence of only 1 functional ventricle and is treated using the Glenn and Fontan procedures. Significant changes occur in CVP after these procedures. IOP has been reported to differ in the same individual when measured in a seated or supine position, which may be related to CVP. In the present study, we examined the relationship between CVP and IOP before and after surgery for SV. Patients and Methods: This study was a prospective, nonrandomized case series. All patients had SV and this study excluded those with eye diseases associated with ocular hypertension. We measured IOP before and after the Glenn or Fontan procedure. CVP was concurrently monitored. 7 months for the Glenn procedure and 24. 7 months for the Fontan procedure. A correlation was observed between CVP and IOP in the perioperative period. Conclusions: Elevations in CVP significantly increased IOP in patients with SV who underwent the Glenn or Fontan procedure. IOP needs to be carefully monitored in the postoperative period after both procedures. Purpose: Relentless placoid chorioretinitis RPC is a new disease concept that was proposed by Jones et al. in 2000. Some cases of RPC have been reported; however, a treatment strategy has not yet been established. We report herein four cases of patients diagnosed with RPC. Observations: We experienced four cases of RPC in patients aged 24-51 years. All patients exhibited retinal lesions similar to that seen in acute posterior multifocal placoid pigment epitheliopathy or serpiginous choroiditis from the posterior pole to the surrounding region. Although patients underwent systemic prednisolone PSL therapy, recurrence was observed and the retinal scar formation was progressive; they were then diagnosed with RPC. In all cases, cyclosporine CyA was administered in addition to PSL, no recurrence was observed thereafter. Conclusions and Importance: RPC is a rare disease, and a treatment strategy has not yet been established. CyA and PSL combination therapy is considered to be effective in the treatment of RPC. PURPOSE: To evaluate corneal tactile and pain sensations in patients with short tear film break-up time dry eye sBUT DE. METHODS: This study enrolled 60 patients with sBUT DE and 46 healthy volunteers from Japan. We evaluated corneal tactile and pain sensations using a modified method with the Cochet-Bonnet corneal esthesiometer. RESULTS: Patients with sBUT DE had higher corneal pain sensitivity 26. 1 mm than healthy subjects 6. 4 mm , but similar corneal tactile sensation 52. 5 mm and 52. 9 mm, respectively. However, for the entire cohort, we found a weak positive correlation between the subjective pain score and objective corneal pain sensation. CONCLUSIONS: Patients with sBUT DE were hypersensitive to corneal pain, which suggested that corneal hyperalgesia partly accounted for subjective symptoms in patients with sBUT DE. Pro renin receptor [ P RR], a new component of the tissue renin-angiotensin system RAS , plays a crucial role in inflammation and angiogenesis in the eye, thus contributing to the development of proliferative diabetic retinopathy PDR. In this study, we investigated systemic factors related to plasma levels of soluble form of P RR [s P RR] in patients with PDR. Twenty type II diabetic patients with PDR and 20 age-matched, non-diabetic patients with idiopathic macular diseases were enrolled, and plasma levels of various molecules were measured by enzyme-linked immunosorbent assays. Human retinal microvascular endothelial cells were stimulated with several diabetes-related conditions to evaluate changes in gene expression using real-time quantitative PCR. Of various systemic parameters examined, the PDR patients had significantly higher blood sugar and serum creatinine levels than non-diabetic controls. Protein levels of s P RR, prorenin, tumor necrosis factor TNF -alpha, complement factor D CFD , and leucine-rich alpha-2-glycoprotein 1 LRG1 significantly increased in the plasma of PDR subjects as compared to non-diabetes, with positive correlations detected between s P RR and these inflammatory molecules but not prorenin. Estimated glomerular filtration rate and serum creatinine were also correlated with plasma s P RR, but not prorenin, levels. Among the inflammatory molecules correlated with s P RR in the plasma, TNF-alpha, but not CFD or LRG1, application to retinal endothelial cells upregulated the mRNA expression of P RR but not prorenin, while stimulation with high glucose enhanced both P RR and prorenin expression. These findings suggested close relationships between plasma s P RR and diabetes-induced factors including chronic inflammation, renal dysfunction, and hyperglycemia in patients with PDR. The purpose of this study was to report the clinical outcomes of patients with conjunctival melanoma treated with interferon IFN alpha-2b eye drops following local tumor resection. Five eyes of five patients were enrolled in this study. Ophthalmological findings, histopathological findings, and imaging modalities were retrospectively analyzed. The age of the patients ranged from 65 to 84 years mean: 75. 4 years. Locations of the tumor were the bulbar conjunctiva in three eyes, multiple palpebral conjunctivas in one eye, and palpebral conjunctiva and caruncle in one eye. All patients received topical IFN alpha-2b eye drop treatment for 6-10 months. Follow-up periods after resection ranged from 18 to 78 months. Histologically, all excised conjunctival tumors were diagnosed with malignant melanoma, where the surgical margins were completely negative in one patient. No patients had suffered from severe adverse effects related to IFN alpha-2b. Four out of five patients consequently achieved complete remission. Since one eye in one case showed resistance to the local chemotherapy containing IFN alpha-2b eye drops and the subconjunctival injection of IFN-beta, orbital exenteration was eventually required 12 months after local resection. Topical IFN alpha-2b eye drops may be safe and one of the useful adjunctive treatments following surgical resection for patients with conjunctival melanoma. Diabetic retinopathy DR is an inflammatory and progressive vaso-occlusive disease resulting in angiogenesis. Galectin-1 is a hypoxia-induced angiogenic factor associated with cancer and proliferative DR. Here we reveal a significant upregulation of galectin-1 in eyes of DR patients along with progression of clinical stages beginning from the pre-ischemic, inflammatory stage with diabetic macular edema, but not in eyes with non-diabetic retinal vascular occlusions. In vivo inhibition of AGE generation with aminoguanidine, macrophage depletion with clodronate liposomes, and antibody-based blockade of Il-1 beta and Tlr4 attenuated diabetes-induced retinal Lgals1 expression in mice. Fibrovascular tissues from proliferative DR eyes were immunoreactive for AGE, TRL4 and IL-1 beta in macrophages, and IL-1 beta receptor-positive glial cells expressed galectin-1. Therefore, diabetes-induced retinal AGE accumulation was suggested to activate IL-1 beta-related inflammatory cues in macrophages followed by Muller cells, linking to galectin-1 upregulation in human DR with time. Our data highlight AGE-triggered inflammation as the DR-selective inducer of galectin-1. The aim of this study was to disclose results of FCM, which were compared among IgG4-related ophthalmic disease IgG4-ROD , idiopathic orbital inflammation IOI , and extranodal marginal zone B-cell lymphoma EMZL. Materials and Methods: This is a retrospective observational study. Sixty-nine tumors comprising of 16 IgG4-ROD, 24 IOI, and 29 EMZL were enrolled in the study. All tumors, surgically excised, were diagnosed based on histopathology, immunoglobulin Ig heavy chain gene rearrangement, and FCM. 05 in every factor. There was no significant difference in any marker between IgG4-ROD and IOI. Sensitivity and specificity of Ig light chain restriction were 65. 5 and 92. Sensitivity of Ig light chain restriction was relatively low in diagnosis of EMZL using FCM. The receptor-associated prorenin system RAPS refers to the pathogenic mechanism whereby prorenin binding to the pro renin receptor [ P RR] dually activates the tissue reninangiotensin system RAS and RAS-independent intracellular signaling. Here we revealed significant upregulation of prorenin and soluble P RR levels in the vitreous fluid of patients with uveitis compared to non-inflammatory controls, together with a positive correlation between these RAPS components and monocyte chemotactic protein-1 among several upregulated cytokines. Moreover, we developed a novel single-strand RNAi agent, proline-modified short hairpin RNA directed against human and mouse P RR [ P RR-PshRNA], and we determined its safety and efficacy in vitro and in vivo. Application of P RR-PshRNA in mice caused significant amelioration of acute uveitic and chronic diabetic models of ocular inflammation with no apparent adverse effects. Our findings demonstrate the significant implication of RAPS in the pathogenesis of human uveitis and the potential usefulness of P RR-PshRNA as a therapeutic agent to reduce ocular inflammation. PURPOSE. To investigate the effect of the vascular adhesion protein-1 VAP-1 inhibitor RTU-1096 on retinal morphologic changes and ocular inflammation after retinal laser photocoagulation in mice. METHODS. Laser photocoagulation was performed on the peripheral retina of the animals. The semicarbazide sensitive amine oxidase SSAO activities in plasma and chorioretinal tissues were measured. Optical coherence tomography OCT images were acquired before and at 1, 3, and 7 days after laser photocoagulation, and thickness of the individual retinal layers was measured. Intravitreal leukocyte infiltration was assessed by histologic analysis. The expression level of intercellular adhesion molecule-1 ICAM-1 in retinal tissues were examined by quantitative real-time PCR. RESULTS. One day after laser photocoagulation, the thickness of the outer nuclear layer ONL increased in the laser group compared with in the control group, and RTU-1096 administration abrogated the ONL thickening. Histologic analysis and OCT observation revealed that laser photocoagulation caused infiltration of inflammatory cells and the appearance of hyperreflective foci at the vitreoretinal surface, both of which were suppressed by RTU-1096 administration. In addition, systemic administration of RTU-1096 reduced upregulation of the leukocyte adhesion molecules ICAM-1 in the retina. CONCLUSIONS. It has been demonstrated that topical administration of rebamipide, which is an antiulcer agent, increases the mucin level of the tear film and ameliorates ocular surface conditions such as lid wiper epitheliopathy. The aim of the present study was to analyze the changes in goblet cell number, cell proliferation, and epidermal growth factor receptor EGFR induced by topical rebamipide addition to the lid wiper of humans. A total of 30 eyelid tissue samples were obtained during involutional entropion surgeries, fixed in paraformaldehyde, embedded in paraffin and divided into two groups: Rebamipide or non-rebamipide. The tissues in the rebamipide group were obtained from patients who had a medical history of topical rebamipide use prior to surgery. The number of goblet cells was counted under light microscopy. A total of 22 eyelid tissue samples were further examined using immunohistochemistry with anti-Ki-67 and anti-EGFR antibodies to evaluate cell proliferation and EGFR expression, respectively. Histologically, the lid wiper and palpebral conjunctiva were clearly identified in the tissues. 0367. There was no significant difference in lid wiper cell proliferation between the rebamipide and non-rebamipide groups. 0237. These results suggest that topical rebamipide application increases the number of goblet cells in the lid wiper, which in turn upregulates the expression of EGFR. These findings may be clinically relevant and provide a therapeutic basis for the treatment of ocular disease such as dry eye and lid wiper epitheliopathy. Background: Choroidal circulation hemodynamics in eyes with ocular blunt trauma has not been quantitatively examined yet. We quantitatively examined changes in choroidal blood flow velocity and thickness at the lesion site using laser speckle flowgraphy LSFG and enhanced depth imaging optical coherence tomography EDI-OCT in a patient with chorioretinopathy associated with ocular blunt trauma. Case presentation: A 13-year-old boy developed a chorioretinal lesion with pigmentation extending from the optic disc to the superotemporal side in the right eye after ocular blunt trauma. The patient's best-corrected visual acuity BCVA was 0. 2 in the right eye. Indocyanine green angiography showed hypofluorescence from the initial phase, with a decrease of mean blur rate MBR on LSFG color map, which corresponded to the chorioretinal lesion. The BCVA and foveal outer retinal morphologic abnormality spontaneously improved during follow-up. In contrast, these parameters showed little or no changes at the normal retinal site in the affected eye and the fovea in the fellow eye. Conclusions: Current data revealed that both blood flow velocity and thickness in the choroid at the lesion site decreased in the acute stage and subsequently increased together with improvements in visual function and outer retinal morphology. These results suggest that LSFG and EDI-OCT may be useful indices that can noninvasively evaluate activity of choroidal involvement in ocular blunt trauma-associated chorioretinopathy. Background: The efficacy of epinastine 0. The present study investigated the efficacy of this solution against birch pollen conjunctivitis in a CAC test. Methods: Ten adult subjects eight males and two females with asymptomatic birch pollen conjunctivitis were enrolled in this study. The average age of the subjects was 41. 1 years. This study was conducted during a period without birch pollen dispersion. In each subject, the epinastine 0. Five minutes or 4 h after the drug instillation, both eyes were challenged with an optimal concentration of birch pollen, and ocular itching and conjunctival hyperemia were then graded. Tears were collected before the drug instillation and 20 min after the pollen challenge, and the histamine level was measured. Results: The ocular itching scores and palpebral conjunctival hyperemia scores of the epinastine-treated eyes were significantly lower than those of the contralateral control eyes when the eyes were pretreated with the drug 4 h before the CAC. There was a significant correlation between the tear histamine level and mean ocular itching score of three time points 3, 5 and 10 min following the CAC in the control eyes but not the epinastine-treated eyes. Conclusions: Epinastine is effective in suppressing ocular itching and conjunctival hyperemia in birch pollen conjunctivitis. Copyright C 2017, Japanese Society of Allergology. Production and hosting by Elsevier B. Receptor-associated prorenin system RAPS refers to the pathogenic mechanism whereby prorenin binding to pro renin receptor [ P RR] dually activates tissue renin-angiotensin system RAS and RASindependent signaling via P RR. The aim of this study is to determine the association of RAPS with idiopathic epiretinal membrane iERM. Reverse transcription-PCR indicated the expression of RAPS components, including P RR and Ang II type 1 receptor AT1R , in iERM tissues and human Muller glial cell line. Double-labeling analyses demonstrated that P RR and AT1R were detected in cells positive for glial fibrillary acidic protein, a marker for glial cells, and co-localized with prorenin and angiotensinogen, respectively. Administration of prorenin to Muller glial cells enhanced mRNA expression of fibroblast growth factor 2, while Ang II application stimulated the expression of glial cell line-derived neurotrophic factor, nerve growth factor, and transforming growth factor-alpha 1. These expression levels induced by prorenin or Ang II were reversed by P RR or AT1R blockade, respectively. Immunofluorescence revealed tissue co-localization of P RR and AT1R with the products of the upregulated genes in vitro. The present findings suggest the involvement of RAPS in the pathogenesis of iERM. Purpose To determine if early post-treatment central choroidal thickness CCT changes can predict sunset glow fundus SGF development in patients with Vogt-Koyanagi-Harada VKH disease treated using systemic corticosteroids. Methods This retrospective case series included 39 eyes of 21 treatment-naive patients with acute VKH disease who could be followed up for more than 12 months after systemic corticosteroid therapy. The eyes were divided into two groups according to whether SGF was present or absent at 12 months 9 eyes of 5 patients versus 30 eyes of 16 patients, respectively. Using enhanced depth imaging optical coherence tomography, CCT values were measured before treatment, then at 1 week and 1 and 3 months after treatment in both groups and compared between the two groups. Results Development of SGF was found 4-11 months after treatment. Mean post-treatment CCT decreased significantly at all examinations compared with baseline in both groups, along with resolution of serous retinal detachment. 024. 003. Conclusions The current study suggested the potential validity of early post-treatment CCT as a feasible index to alert future progression to SGF in patients with VKH disease treated using systemic corticosteroids. Purpose: Behcet disease BD is predominantly found between East Asia and the Mediterranean basin along the historic Silk Road. HLA-B51 is known to be strongly associated with BD. We investigated the association between HLA-B51 and the ocular manifestations of BD among various ethnic groups. Methods: A literature survey was conducted, and 18 articles written in English were reviewed. 000057. 35 areas. This correlation seemed to become stronger towards the east. Conclusions: A meta-analysis showed that the correlation became stronger towards the east along the Silk Road. The study results may facilitate understanding of the etiology and characteristics of BD. Purpose: To determine the presence of N-epsilon- 3-formyl-3,4-dehydropiperidino lysine adduct FDP-Lys , unsaturated aldehyde acrolein-derived lipoxidation end-product, in fibrovascular tissues obtained from patients with proliferative diabetic retinopathy PDR. Methods: Fibrovascular tissues were collected from 11 eyes of 11 patients with PDR and paraffin-embedded tissue sections were prepared. Tissue localization of FDP-Lys was studied by immunohistochemistry. Signal intensity was quantified by two masked evaluators and graded into three discrete categories. The relationship between FDP-Lys staining and vascular density was analyzed. In addition, subcellular localization of FDP-Lys was studied by immunofluorescent microscopy. The impact of acrolein on cell viability and proliferation was assessed and the expression level of heme oxygenase-1 HO-1 mRNA was quantified by real-time polymerase chain reaction PCR in cultured retinal microvascular endothelial cells. Results: In fibrovascular tissues, FDP-Lys staining was found in vascular components containing CD34-positive cells and alpha smooth muscle actin -SMA -positive cells, and clusters of rabbit anti-glial fibrillary acid protein GFAP -positive cells. Immunofluorescent staining depicted subcellular localization of FDP-Lys in the nucleus and cytoplasm of the cells. Morphological analysis revealed that fibrovascular tissues with FDP-Lys staining in vascular components showed high vascular density. Exposure of cultured endothelial cells to high concentration of acrolein resulted in the decrease of cell viability and proliferation, whereas lower concentration of acrolein increased cell viability and proliferation. Sublethal concentration of acrolein upregulated HO-1 mRNA expression in retinal microvascular endothelial cells. Conclusions: The current data demonstrated the presence of FDP-Lys in fibrovascular tissues and indicate its involvement in fibrovascular proliferation in PDR. Purpose: Environmental and lifestyle changes influence the clinical features of uveitis. This study reviewed the epidemiologic trends of uveitis in the Japanese population. Methods: A retrospective review of the past 80 years of reports from Hokkaido University Hospital. The three most common specific diagnoses were: sarcoidosis, Vogt-Koyanagi-Harada disease, and Behcet disease. Although Behcet disease was the most frequent non-infectious uveitis until the 1980s, sarcoidosis is now the most frequent cause of newly diagnosed non-infectious uveitis. Conclusions: The etiology of uveitis has changed with the times. Tubercular and syphilitic cases have greatly decreased, and sarcoidosis is the most frequent type of uveitis today. To elucidate the current clinical practice patterns of diabetic macular edema DME management by retinal specialists in Japan in the era of anti-vascular endothelial growth factor VEGF therapy. Forty-six retinal specialists were administered a survey regarding the pathology and clinical practice of DME. Nearly, half of the specialists 45. Most specialists 70. For focal macular edema, focal laser is used as first-line therapy by 70. For diffuse macular edema, anti-VEGF therapy is the first choice 72. Vitrectomy is often performed for vitreomacular traction 86. For persistent DME after vitrectomy, anti-VEGF agents 46. When applying anti-VEGF treatment regimen, most specialists continue loading injections until central retinal thickness stabilized 51. In the maintenance phase, many specialists provide injections with pro re nata 76. Our survey presents the current views about the DME management and practice patterns of anti-VEGF therapy by one part of the retinal specialists in Japan, and highlights the differences or gaps between evidence and actual clinical practice. Purpose. To evaluate sequential changes in choroidal thickness at the affected area in patients with acute zonal occult outer retinopathy AZOOR. Methods. This retrospective observational case series included 14 affected eyes and 6 unaffected fellow eyes from 10 AZOOR patients with impaired macular area. Using enhanced depth imaging optical coherence tomography, choroidal thicknesses at the subfovea and at nasal and temporal sites 1000 mu m away from the fovea were manually measured at baseline and 3 and 6 months thereafter. Changes in the choroidal thicknesses and the average threshold at the affected area on Humphrey perimetry were compared during the 6-month follow-up. Results. In AZOOR eyes, the average threshold at the affected area significantly increased over time, while outer retinal structure ameliorated. The mean choroidal thicknesses at all the sites measured significantly decreased at 3 and 6 months compared with baseline values in AZOOR eyes, but not in fellow eyes. There was an inverse correlation between the changing rates of the average threshold and the subfoveal choroidal thickness at 6 months from baseline. Conclusion. The current data suggest that choroidal thickness at AZOOR-affected area significantly decreased with regression of AZOOR and this anatomical change correlated with the functional recovery. Purpose: To evaluate the safety and tolerability of conjunctival rings CRs , a novel device for drug delivery to the posterior segment of the eye. Contact lenses CLs containing vehicle solution were used as a control. Twenty-four hours after placement of the CRs, corneal fluorescein staining was graded based on the McDonald-Shadduck scoring system, ranging from 0 to 4. In humans, CRs containing vehicle solution were placed on the right eye of healthy volunteers for 9 hours. The corneal curvature, corneal thickness, intraocular pressure, visual acuity, tear production Schirmer I test , tear film break-up time and fluorescein staining scores of the cornea scores ranging from 0 to 3 and conjunctiva scores ranging from 0 to 6 were assessed before and after wearing the CRs. The release characteristics of DSP from CRs were also evaluated. Results: In animal experiments, corneal fluorescein staining scores were 1 or less in all the groups, and there was no significant difference between the CR group and the CL group. The DSP release from CRs occurs within a few hours, which is similar to the drug-release property of medicated CL, as reported previously. Conclusions: The current data showed the safety and tolerability of CR as a drug delivery device for the treatment of posterior segment diseases. Natural killer T NKT cells recognize lipid antigens and produce large amounts of cytokines upon activation. NKT cell-deficient mice developed more severe EAU pathology than WT mice. When WT mice were treated with ligands of the invariant subset of NKT cells alpha-GalCer or RCAI-56 , EAU was ameliorated in mice treated with RCAI-56 but not alpha-GalCer. Moreover, the eyes of RCAI-56-treated mice contained fewer IRBP-specific T cells compared with control mice. These results suggest that invariant NKT iNKT cells suppress the induction of Th17 cells and infiltration of IRBP-specific T cells into the eyes, thereby reducing ocular inflammation. However, in sharp contrast to the ameliorating effects of iNKT cell activation during the initiation phase of EAU, iNKT cell activation during the effector phase exacerbated disease pathology. Thus, we conclude that iNKT cells exhibit dual roles in the development of EAU. C 2016 Elsevier Ltd. All rights reserved. PurposeTo assess choroidal inflammation-related circulatory changes associated with the anterior recurrence of Vogt-Koyanagi-Harada VKH disease, using indocyanine green angiography ICGA and laser speckle flowgraphy LSFG. MethodsThis retrospective case series included 17 eyes of 11 patients with VKH disease showing recurrent inflammatory findings in the anterior, but not posterior, segment i. anterior recurrence. Indocyanine green angiography ICGA and LSFG were performed at the time of recurrence and one month after the initiation of corticosteroid therapy. The number and total area of hypofluorescent dark dots HDDs on ICGA were independently counted by three physicians and measured with ImageJ, respectively. Mean blur rate MBR , a quantitative index of relative blood flow velocity, was calculated via the LSFG Analyzer software. The change ratio of MBR significantly increased by 17. Importantly, there was no significant association between the change ratios of HDDs and MBR. ConclusionsThese findings on LSFG and ICGA clearly demonstrated subclinical involvement as well as post-treatment improvement of choroidal circulation impairment due to granulomatous inflammation in eyes with the anterior recurrence of VKH disease. The present data suggest the validity of using these two examinations, capable of detecting different circulatory changes, in the management of recurrent VKH disease. PURPOSE: To assess the efficacy and safety of a modified 360-degree suture trabeculotomy combined with a cataract surgery technique in patients with glaucoma and coexisting cataract. SETTING: Hokkaido University Hospital, Sapporo, Japan. DESIGN: Retrospective case series. METHODS: Medical records of patients with glaucoma having a modified 360-degree trabeculotomy combined with cataract surgery Group 1 were reviewed. Another group of patients who had the modified 360-degree suture trabeculotomy alone served as controls Group 2. RESULTS: Both groups comprised 46 patients. In each group, eyes were diagnosed with primary angle-closure glaucoma in 2 eyes, primary open-angle glaucoma in 24 eyes, exfoliation glaucoma in 4 eyes, uveitic glaucoma in 15 eyes, and steroid glaucoma in 1 eye. The mean preoperative intraocular pressure IOP values were 27. 3 SD on 3. 5 medications in Group 1 and 27. 7 mm Hg on 2. 6 medications in Group 2. Twelve months after surgery, the mean IOPs were 13. 7 mm Hg on 0. 1 medications in Group 1 and 13. 1 mm Hg on 0. 9 medications in Group 2. Major complications included transient IOP spikes 30. CONCLUSION: The data showed the equivalent effects of suture trabeculotomy combined with cataract surgery and suture trabeculotomy surgery alone on postoperative safety and efficacy. Glaucoma is characterized by axonal degeneration of retinal ganglion cells RGCs and apoptotic death of their cell bodies, and lowering intraocular pressure is associated with an attenuation of progressive optic nerve damage. Nevertheless, intraocular pressure IOP reduction alone was not enough to inhibit the progression of disease, which suggests the contribution of other factors to the glaucoma pathogenesis. At 5 weeks after birth, the number of RGCs was counted in paraffin sections of retinal tissues stained with hematoxylin and eosin. In addition, retrograde labeling technique was also used to quantify the number of RGC. Expression and localization of heat shock protein 70 HSP70 in retinas were evaluated by reverse transcription polymerase chain reaction and immunohistochemistry, respectively. Activities of caspase-9 and -3 in retinas were also assessed. Following GGA administration, HSP70 was significantly upregulated together with reduction in the activities of caspase-9 and -3. Our studies highlight HSP70 induction in the retina is available to suppress RGC degeneration, and thus GGA may be applicable for NTG as a promising therapy. Horie Y, Kitaichi N, Hijioka K, Sonoda KH, Saishin Y, Kezuka T, Goto H, Takeuchi M, Nakamura S, Kimoto T, Shimakawa M, Kita M, Sugita S, Mochizuki M, Hori J, Iwata M, Shoji J, Fukuda M, Kaburaki T, Numaga J, Kawashima H, Fukushima A, Joko T, Takai N, Ozawa Y, Meguro A, Mizuki N, Namba K, Ishida S, Ohno SClinical and experimental rheumatology 34 6 Suppl 102 111 - 114 2016年09月 [査読有り][通常論文]• Vascular endothelial growth factor C VEGF-C plays an important role in the development of a pterygium through lymphangiogenesis. We examined the association between VEGF-C and tumor necrosis factor- TNF- in the pathogenesis of pterygia. Cultured conjunctival epithelial cells were treated with TNF-, and the gene expression levels of VEGFC were evaluated by quantitative polymerase chain reaction qPCR and VEGF-C protein expression levels were measured using an enzyme-linked immunosorbent assay ELISA. In addition, using ELISA, we evaluated the VEGF-C protein expression in the supernatants of cultured conjunctival epithelial cells, in which we neutralized TNF- using anti-TNF- antibody. The gene expression of tumor necrosis factor receptor superfamily, member 1A TNFRSF1A , known as TNF receptor 1 TNFR1 , was confirmed using reverse transcription PCR in cultured conjunctival epithelial cells. Immunofluorescence microscopy was used to examine the localization of VEGF-C and TNFR1 in pterygium tissues and TNFR1 expression in cultured conjunctival epithelial cells. Immunohistochemistry was used to examine the localization of TNFR1 in pterygia and normal conjunctival tissues. VEGFC gene expression increased in cultured conjunctival epithelial cells 24 h after the addition of TNF-. The secretion of VEGF-C protein was significantly increased 48 h after the stimulation of cultured conjunctival epithelial cells with TNF-. Increased VEGF-C protein secretion stimulated by TNF- was significantly reduced by anti-TNF- neutralizing antibody treatment. In cultured conjunctival epithelial cells, TNFRSF1A and TNFR1 were expressed. TNFR1 was immunolocalized in normal conjunctival tissues and in human pterygium tissues as well as in VEGF-C-positive epithelial cells from human pterygia. Our data demonstrate that TNF- mediates VEGF-C expression, which plays a critical role in the pathogenesis of pterygia. AIM: To examine phosphorylation of alphaB-crystallin p-alpha BC , a vascular endothelial growth factor VEGF chaperone, and immunohistochemically investigate relationship between p-alpha BC, VEGF and phosphorylated p38-mitogen-activated protein kinase p-p38 MAPK in the epiretinal membrane of human proliferative diabetic retinopathy PDR. METHODS: Eleven epiretinal membranes of PDR surgically excised were included in this study. Two normal retinas were also collected from enucleation tissues due to choroidal melanoma. Paraformaldehyde-fixed, paraffin-embedded tissue sections were processed for immunohistochemistry with anti-p-alpha BC, VEGF, CD31, and p-p38 MAPK antibodies. The immunolocalization of p-alpha BC was detected in the CD31-positive endothelial cells, and co-localized with VEGF and p-p38 MAPK in PDR membranes. Immunoreactivity for p-alpha BC, however, was undetectable in endothelial cells of the normal retinas, where p-p38 MAPK immunoreactivity was less marked than PDR membranes. CONCLUSION: Phosphorylation of alpha BC, in particular, phosphorylation on Ser59 by p-p38 MAPK may play a potential role as a molecular chaperon for VEGF in the pathogenesis of epiretinal membranes in PDR. Purpose To quantitatively examine changes in choroidal circulation hemodynamics in patients with acute posterior multifocal placoid pigment epitheliopathy APMPPE. Methods Retrospective observational case series. Five eyes of 3 APMPPE patients were included. In all APMPPE eyes, laser speckle flowgraphy was conducted to evaluate the mean blur rate MBR , a quantitative index of relative blood flow velocity. The changes in MBR at the initial visit and after 3 and 6 months were statistically analyzed. In 2 eyes, enhanced depth imaging optical coherence tomography was used to measure central choroidal thickness. Results In all eyes, multiple subretinal placoid lesions spontaneously regressed with recovery of outer retinal morphology. The average MBR significantly increased at 3 and 6 months after baseline at the fovea by 49. 6 and 54. 2 and 70. 02 for each. The mean central choroidal thickness decreased with time 518. 0 A mu m at baseline to 344. 5 A mu m at 6 months. Conclusions Our data revealed the significant elevation of choroidal blood flow velocity and the substantial reduction of choroidal thickness with regression of APMPPE, suggesting that impaired choroidal circulation is involved in the pathogenesis of APMPPE. PURPOSE. To evaluate intraocular pressure IOP changes during nocturnal sleep in patients with obstructive sleep apnea syndrome OSAS using a contact lens sensor CLS. METHODS. This was a prospective cohort study. Seven OSAS patients who had no ocular diseases except mild cataract were enrolled. Each subject underwent CLS-based continuous IOP monitoring on one eye simultaneously with overnight polysomnography. We classified the nocturnal IOP records into nonapnea IOP and apnea IOP, according to the duration of apnea events on polysomnography within each IOP measurement time of 30 seconds every 5 minutes. RESULTS. Differences between IOP levels during nonapnea and apnea phases were statistically analyzed. The mean apnea-hypopnea index, the total number of these events per hour of sleep, was 44. 0, indicating the participants' severity of OSAS as moderate to severe. The mean range of IOP fluctuations during nocturnal sleep was 22. 5 mV eq. All patients showed lower mean IOP levels during apnea events than during nonapnea phases, with statistically significant differences detected in four of the seven patients. On average, in all seven eyes, IOP values significantly decreased by 23. 4 mV eq in association with apnea events. CONCLUSIONS. Obstructive apnea led to an immediate IOP decline during nocturnal sleep in patients with OSAS. Attention should be paid to IOP-independent etiology, such as episodic hypoxia, potentially linking OSAS and glaucoma. Aim To assess choroidal thickness changes associated with anterior segment recurrences in patients with Vogt-Koyanagi-Harada VKH disease using enhanced depth imaging optical coherence tomography EDI-OCT. Methods EDI-OCT images were obtained periodically from 11 patients with VKH disease 22 eyes who were followed-up due to anterior segment recurrences. Subfoveal choroidal thickness SCT values at the following stages were evaluated: 1 during the remission phase, 2 1 month before detecting the anterior recurrence, 3 during the anterior recurrence and 4 after systemic prednisolone PSL treatment leading to remission. In comparison with SCT values in remission as baseline, the changing ratios of SCT were statistically analysed at subsequent three stages. Results The average of the SCT changing ratios compared with the remission phase significantly increased to 1. 00044 lacking any funduscopic signs of posterior involvement. Interestingly, the average SCT ratio 1 month before detecting the recurrence had already increased to 1. 002. After the PSL treatment, the ratio of SCT recovered to 0. 03, which was equivalent to the remission level. However, in patients with their remission SCT values less than 240 mm, the SCT ratio did not increase significantly at any time points evaluated. Conclusions The choroid in eyes with VKH disease thickened in association with the anterior segment recurrence, and this thickening was observed prior to the recurrence. EDI-OCT may be useful for detecting latent choroidal inflammation in VKH disease, whereas it may not for patients with the relatively thin choroid. Background: Vitreoretinal lymphoma VRL is a life- and sight-threatening disorder. The aim of this study was to analyze the usefulness of the cell block method for diagnosis of VRL. Methods: Sixteen eyes in 12 patients with VRL, and 4 eyes in 4 patients with idiopathic uveitis presenting with vitreous opacity were enrolled in this study. Both undiluted vitreous and diluted fluids were isolated during micro-incision vitrectomy. Cell block specimens were prepared in 19 eyes from diluted fluid containing shredding vitreous. These specimens were then submitted for HE staining as well as immunocytological analyses with antibodies against the B-cell marker CD20, the T-cell marker CD3, and cell proliferation marker Ki67. Conventional smear cytology was applied in 14 eyes with VRL using undiluted vitreous samples. The diagnosis of VRL was made based on the results of cytology, concentrations of interleukin IL -10 and IL-6 in undiluted vitreous, and immunoglobulin heavy chain gene rearrangement analysis. Results: Atypical lymphoid cells were identified in 14 out of 15 cell block specimens of VRL positive rate: 93. Atypical lymphoid cells showed immunoreactivity for CD20 and Ki67. Seven cell block specimens were smear cytology-negative and cell block-positive. The cell block method showed no atypical lymphoid cells in any patient with idiopathic uveitis. Conclusions: Cell block specimens using diluted vitreous fluid demonstrated a high diagnostic sensitivity and a low pseudo-positive rate for the cytological diagnosis of VRL. The cell block method contributed to clear differentiation between VRL and idiopathic uveitis with vitreous opacity. Purpose: To investigate the alteration of N-glycans in the vitreous fluid of patients with neovascular glaucoma NVG secondary to proliferative diabetic retinopathy PDR. Methods: Vitreous samples were collected from 18 patients with PDR including 7 with NVG and 11 without NVG , and 17 patients without diabetes. Profiles of N-glycans were analyzed by glycoblotting-based high throughput protocol, which we recently developed. Protein levels of vascular endothelial growth factor VEGF -A were measured by ELISA. Results: The concentration of total N-glycans and the concentration of N-glycans with sialic acids were significantly higher in NVG group compared with those in non-NVG group or control group, whereas there was no significant difference in concentrations of high-mannose N-glycans among three groups. There was a moderate correlation between the concentrations of sialylated N-glycans and VEGF-A. Conclusions: Our data demonstrate the distinct changes of N-glycan profile and the increase of sialylated N-glycans in eyes with NVG secondary to PDR. Vascular endothelial growth factor VEGF -A-driven angiogenesis contributes to various disorders including cancer and proliferative diabetic retinopathy PDR. Here, we revealed a novel anti-angiogenic function for aflibercept beyond its antagonism against VEGF family members. Immunoprecipitation and mass spectrometry analyses identified galectin-1 as an aflibercept-interacting protein. Biolayer interferometry revealed aflibercept binding to galectin-1 with higher affinity than VEGFR1-Fc and VEGFR2-Fc, which was abolished by deglycosylation of aflibercept with peptide: N-glycosidase F. Galectin-1 immunoreactivity co-localized with VEGFR2 in neovascular tissues surgically excised from human eyes with PDR. Compared with non-diabetic controls, intravitreal galectin-1 protein levels were elevated in PDR eyes, showing no correlation with increased VEGF-A levels. Preoperative injection of bevacizumab, a monoclonal antibody to VEGF-A, reduced the VEGF-A, but not galectin-1, levels. Galectin-1 application to human retinal microvascular endothelial cells up-regulated VEGFR2 phosphorylation, which was eliminated by aflibercept. Our present findings demonstrated the neutralizing efficacy of aflibercept against galectin-1, an angiogenic factor associated with PDR independently of VEGF-A. Background: Which of the choroidal layers suffers the most extensive morphological changes during the course of Vogt-Koyanagi-Harada VKH disease is still unknown. The aim of this study was to investigate the relationship between total thickness and the thickness of inner or outer layers in the choroid during systemic corticosteroid therapy in patients with VKH disease. Methods: This retrospective case series included 15 eyes of 10 patients with treatment-naive VKH disease 4 men and 6 women; mean age, 41. 7 years received systemic corticosteroid therapy. Whole, inner, and outer choroidal thickness was measured manually at 1 week and at 1 and 3 months after initiation of systemic corticosteroid therapy using enhanced depth imaging optical coherence tomography. The mean thickness values of the layers were compared at each stage. 008 and 0. 008 and 0. 02, respectively , whereas the inner layer did not significantly thin. 0001 , but not between the rates of whole and inner layer thickness changes. Conclusions: The thinning of total choroidal thickness observed after treatment with corticosteroids strongly correlated with outer layer thinning, suggesting that the choroidal outer layer is the primary target in acute-stage VKH disease. PURPOSE. To quantitatively evaluate the pulse waveform changes in macular choroidal blood flow by using laser speckle flowgraphy LSFG with regression of acute central serous chorioretinopathy CSC. METHODS. This retrospective observational case series included 20 eyes of 20 patients with acute CSC. Laser speckle flowgraphy was performed at baseline and after 6 months. On the LSFG monochrome map, automatically divided 5 x 5 grid segments within the macula were classified into predominantly delayed filling PDF or minimally or no delayed filling MDF areas according to the degree of choroidal filling delay on early-phase indocyanine green angiography. The average mean blur rate MBR and the pulse waveform parameters, including the skew and blowout time BOT , were compared between the total PDF and MDF areas during follow-up. RESULTS. 001 for each , showing significant reduction in vascular resistance at 6 months. 001, respectively in the PDF area than in the MDF area. CONCLUSIONS. Changes in the skew and BOT, indices for vascular resistance, confirmed the involvement of circulatory disturbance at the acute stage of CSC. The present findings suggested that the pathogenesis of CSC stems from imbalanced distribution of choroidal blood flow due to augmented vascular resistance. On the basis of angiographic features, it is suggested that choroidal circulation disturbance may be involved in the pathogenesis of multiple evanescent white dot syndrome MEWDS. The aim of this study is to quantitatively evaluate changes in choroidal circulation hemodynamics using laser speckle flowgraphy LSFG in patients with MEWDS. Twelve eyes of 12 patients with MEWDS and 12 unaffected fellow eyes as controls were included. The macular mean blur rate MBR , a quantitative index of relative blood flow velocity in the choroid, was measured by LSFG. Sequential changes in the average MBR values at the macula with granular changes and the lesion area with white dots were analysed. Moreover, correlations between the MRR changing rate and initial visual functions were examined. Visual functions significantly improved 3 months after initial visit with accompanying improvements in outer retinal morphology. When compared with the baseline measurements, the MBR significantly increased at the macula of the affected eyes by 20. 01 for both , while no significant change was detected in fellow eyes. Similarly, the MBR increased at the lesion area by 17. 05 for both. 03, respectively , suggesting a close link between initially reduced choroidal blood flow and functional abnormalities at the onset of MEWDS. These results, in concert with angiographic findings, are likely to reinforce the concept of choroidal circulation impairment as a predisposing factor for MEWDS. Satoshi Morooka, Mitsuteru Hoshina, Isao Kii, Takayoshi Okabe, Hirotatsu Kojima, Naoko Inoue, Yukiko Okuno, Masatsugu Denawa, Suguru Yoshida, Junichi Fukuhara, Kensuke Ninomiya, Teikichi Ikura, Toshio Furuya, Tetsuo Nagano, Kousuke Noda, Susumu Ishida, Takamitsu Hosoya, Nobutoshi Ito, Nagahisa Yoshimura, Masatoshi HagiwaraMOLECULAR PHARMACOLOGY 88 2 316 - 325 2015年08月 [査読有り][通常論文] Excessive angiogenesis contributes to numerous diseases, including cancer and blinding retinopathy. Antibodies against vascular endothelial growth factor VEGF have been approved and are widely used in clinical treatment. Our previous studies using SRPIN340, a small molecule inhibitor of SRPK1 serine-arginine protein kinase 1 , demonstrated that SRPK1 is a potential target for the development of antiangiogenic drugs. In this study, we solved the structure of SRPK1 bound to SRPIN340 by X-ray crystallography. Using pharmacophore docking models followed by in vitro kinase assays, we screened a large-scale chemical library, and thus identified a new inhibitor of SRPK1. This inhibitor, SRPIN803, prevented VEGF production more effectively than SRPIN340 owing to the dual inhibition of SRPK1 and CK2 casein kinase 2. In a mouse model of age-related macular degeneration, topical administration of eye ointment containing SRPIN803 significantly inhibited choroidal neovascularization, suggesting a clinical potential of SRPIN803 as a topical ointment for ocular neovascularization. Thus SRPIN803 merits further investigation as a novel inhibitor of VEGF. PURPOSE. To investigate the alteration of vitreal N-glycans in patients with proliferative diabetic retinopathy PDR. METHODS. Plasma and vitreous samples were collected from 17 patients 10 females and 7 males with PDR PDR group and 17 nondiabetic patients 8 females and 9 males with epiretinal membrane ERM and idiopathic macular hole MH non-diabetes mellitus [DM] group. Profiles of N-glycans were analyzed by a glycoblotting-based high-throughput protocol that we recently developed. Human retinal microvascular endothelial cells HRMECs were cultivated with culture media containing either low glucose 5 mM or high glucose 25 mM , and expression levels of sialyltransferases were analyzed by real-time PCR and ELISA. RESULTS. Amount of N-glycans in the vitreous fluid of the PDR group was significantly higher than that of the non-DM group 495. 4 vs. 142. 005 , whereas there was no significant difference in the plasma samples between the PDR and the non-DM group. In addition, profile analysis showed that N-glycans with sialic acids increased in the vitreous of the PDR group 328. 0005. Expression levels of sialyltransferases ST3GAL1 and ST3GAL4 were upregulated in the HRMECs after high-glucose stimulation. Consistent with the real-time PCR data, high-glucose stimulation elevated the protein levels of ST3GAL1 117. 01 and ST3GAL4 6. 05 in the HRMECs compared with the cells cultured with low-glucose culture media ST3GAL1, 64. CONCLUSIONS. Our data demonstrate distinct changes in the N-glycan profile and an increase in sialylated N-glycans in eyes with PDR. Purpose To investigate sequential post-operative thickness changes in inner and outer retinal layers in eyes with an idiopathic macular hole MH. Methods Retrospective case series. Twenty-four eyes of 23 patients who had received pars plana vitrectomy PPV for the closure of MH were included in the study. Spectral domain optical coherence tomography C-scan was used to automatically measure the mean thickness of the inner and outer retinal layers pre-operatively and up to 6 months following surgery. The photoreceptor outer segment PROS length was measured manually and was used to assess its relationship with best-corrected visual acuity BCVA. 01 , but not perifoveal, area. 002 , whereas the nerve fiber layer was unaltered. 001. 03 , but not with any of the other thickness parameters examined. Conclusions Following PPV for MH, retinal inner layers other than the nerve fiber layer thinned, suggestive of subclinical thickening in the inner layers where no cyst was evident pre-operatively. In contrast, retinal outer layer thickness significantly increased, potentially as a result of PROS elongation linking tightly with favorable visual prognosis in MH eyes. Purpose The pathogenesis of unilateral acute idiopathic maculopathy UAIM is unknown. The aim of this study was to quantitatively examine changes in choroidal circulation hemodynamics in patients with UAIM. Methods This was a retrospective observational case-series which included five eyes of four patients with UAIM. All UAIM eyes and the fellow eyes in remaining three patients were studied using laser speckle flowgraphy LSFG to evaluate the mean blur rate MBR , a quantitative index of relative blood flow velocity. The changes in MBR between the initial visit and after 1 and 3 months were statistically analyzed. Subfoveal choroidal thickness was measured in three UAIM eyes by enhanced depth imaging optical coherence tomography. 04 with recovery of outer retinal morphology. 001 , whereas the fellow eyes did not show this tendency. The mean values of subfoveal choroidal thickness decreased with time 316. 0 mu m at baseline, 186. 6 mu m at 1 month, and 167. 3 mu m at 3 months. Conclusions These results reveal that there is a significant elevation of choroidal blood flow velocity and substantial reduction of choroidal thickness with regression of UAIM, suggesting that impaired choroidal circulation may be involved in the pathogenesis of UAIM. To investigate the relationship between circulation hemodynamics and morphology in the choroid during systemic corticosteroid therapy for patients with Vogt-Koyanagi-Harada VKH disease. This retrospective case series includes 18 eyes of nine patients with VKH disease two men and seven women; average age, 40. 8 years who received systemic corticosteroid therapy. Laser speckle flowgraphy LSFG and enhanced-depth imaging optical coherence tomography EDI-OCT were performed before treatment and at 1 week and 1 and 3 months after treatment. The average values of the mean blur rate MBR at the macula and the central choroidal thickness CCT were compared at each stage. 0002 for all. 0002 for all. 0097. 0093 but not with CCT. Our data suggest that circulatory disturbances and increased thickness of the choroid relate to the pathogenesis of VKH disease with link mutually. LSFG is useful as an index for evaluating the choroiditis activity of VKH disease as well as EDI-OCT. Aerobic glucose metabolism is indispensable for metabolically active cells; however, the regulatory mechanism of efficient energy generation in the highly evolved mammalian retina remains incompletely understood. Here, we revealed an unsuspected role for pro renin receptor, also known as ATP6AP2, in energy metabolism. Immunoprecipitation and mass spectrometry analyses identified the pyruvate dehydrogenase PDH complex as Atp6ap2-interacting proteins in the mouse retina. Yeast two-hybrid assays demonstrated direct molecular binding between ATP6A P2 and the PDH El 13 subunit PDHB. Pdhb immunoreactivity co-localized with Atp6ap2 in multiple retinal layers including the retinal pigment epithelium RPE. A TP6AP2 knockdown in RPE cells reduced PDH activity, showing a predilection to anaerobic glycolysis. ATP6AP2 protected PDHB from phosphorylation, thus controlling its protein stability. Down-regulated PDH activity due to ATP6AP2 knockdown inhibited glucose-stimulated oxidative stress in RPE cells. Purpose To evaluate the clinical features and investigate their relationship with visual function in Japanese patients with acute zonal occult outer retinopathy AZOOR. Methods Fifty-two eyes of 38 Japanese AZOOR patients 31 female and 7 male patients; mean age at first visit, 35. 0 years; median follow-up duration, 31 months were retrospectively collected: 31 untreated eyes with good visual acuity and 21 systemic corticosteroid-treated eyes with progressive visual acuity loss. Variables affecting the logMAR values of best-corrected visual acuity BCVA and the mean deviation MD on Humphrey perimetry at initial and final visits were examined using multiple stepwise linear regression analysis. 00002. 02, respectively. The final logMAR BCVA was 0. Variables affecting initial visual function were moderate anterior vitreous cells, myopia severity, and a-wave amplitudes on electroretinography; factors affecting final visual function were the initial MD values, female sex, moderate anterior vitreous cells, and retinal atrophy. Conclusions Our data indicated that visual functions in enrolled patients significantly improved spontaneously or after systemic corticosteroids therapy, suggesting that Japanese patients with AZOOR have good visual outcomes during the follow-up period of this study. Furthermore, initial visual field defects, gender, anterior vitreous cells, and retinal atrophy affected final visual functions in these patients. Background: Leber's hereditary optic neuropathy LHON refers to an optic nerve dysfunction due to mutations in the mitochondrial DNA, resulting in visual loss by apoptosis of retinal ganglion cells RGC. There are some reports regarding the circumpapillary retinal nerve fiber layer cpRNFL and the ganglion cell analysis around the macula in LHON patients and carriers by using optical coherence tomography. Case presentation: A 40-year-old female complained of acute visual loss in both eyes. Her best-corrected visual acuity was 0. 3 in the right eye and 0. 2 in the left eye at the initial visit. Goldmann perimetry revealed bilateral central scotomas. Fundus examination and fluorescein angiography findings were normal, but decreased retinal inner layer thickness was detected around the macular area on spectral domain optical coherence tomography SD-OCT. One month later, her visual acuity deteriorated to counting fingers in both eyes, and the thinning area of retinal inner layer spread rapidly. Suspected progressive RGC loss led us to check the possibility of LHON, with which the patient was diagnosed due to a positive result for the mitochondrial DNA mtDNA 11778 mutation. The ganglion cell complex GCC and cpRNFL thicknesses were observed for 24 months by using SD-OCT. The GCC thickness plunged sharply within 3 months followed by gradual decline until 6 months, thereafter showing a plateau up to 24 months. On the cpRNFL map, the temporal quadrant also showed the earliest thinning as seen in the macular area of the GCC map. The thicknesses of the superior, nasal, and inferior quadrants decreased gradually, keeping their normal ranges up to 6 months. Conclusions: SD-OCT was a useful tool in the diagnosis and follow-up of LHON. The macular GCC thickness map may detect the earliest morphological changes in LHON, as well as the temporal area of cpRNFL, before funduscopic examination reveals optic nerve atrophy. For the purpose of investigating Behcet's disease BD in Russia, 250 consecutive patients 177 men and 73 women diagnosed with BD between 1990 and 2010 at the Research Institute of Rheumatology, Russian Academy of Medical Sciences in Moscow were enrolled in this study. The ethnic backgrounds of the patients were reported as follows: 23. The remaining 19. More than half 57. The mean age at disease onset was 31. 38 13-60 years old, and the most typical initial manifestations were oral aphthous ulcers. Patients aged 20-39 years old were more commonly affected and displayed a wide clinical spectrum of the disease, with varieties of severe internal organ involvement. 01 lesions were more frequent in men than in women. HLA-B51 and HLA-A26 typing was performed in 127 patients and 508 healthy controls. HLA-B51 was found in 63. 001 , and HLA-A26 was present in 11. This study shows the presence of BD in Russia, and it is suggested that its prevalence in Central Asian people is much higher than that in White Russian. For the purpose of investigating Behcet's disease BD in Russia, 250 consecutive patients 177 men and 73 women diagnosed with BD between 1990 and 2010 at the Research Institute of Rheumatology, Russian Academy of Medical Sciences in Moscow were enrolled in this study. The ethnic backgrounds of the patients were reported as follows: 23. The remaining 19. More than half 57. The mean age at disease onset was 31. 38 13-60 years old, and the most typical initial manifestations were oral aphthous ulcers. Patients aged 20-39 years old were more commonly affected and displayed a wide clinical spectrum of the disease, with varieties of severe internal organ involvement. 01 lesions were more frequent in men than in women. HLA-B51 and HLA-A26 typing was performed in 127 patients and 508 healthy controls. HLA-B51 was found in 63. 001 , and HLA-A26 was present in 11. This study shows the presence of BD in Russia, and it is suggested that its prevalence in Central Asian people is much higher than that in White Russian. PURPOSE. Extranodal marginal zone B-cell lymphoma EMZL is the most common subtype of conjunctival lymphoma, though its molecular mechanisms of pathogenesis are largely unknown. We attempted to explore the association of the renin-angiotensin system RAS and pro renin receptor [P] RR in the pathogenesis of conjunctival lymphoma. METHODS. Surgically removed conjunctiva EMZL samples were used for gene expression, and immunohistochemical and immunofluorescence analyses of P RR and RAS components. Human B-lymphoblast IM-9 cells were treated with prorenin or angiotensin II Ang II , and gene expression levels were analyzed using real-time quantitative PCR qPCR. In addition, immunofluorescence analysis of EMZL samples was used to evaluate the in vivo expression of those components. RESULTS. Gene expression and immunohistochemical analyses revealed the expression of RAS components, including P RR and angiotensin II type 1 receptor AT1R , in EMZL tissues. Double-labeling analyses demonstrated that P RR and AT1R were detected in cells positive for CD20, a marker for B-cells, where they colocalized with prorenin and angiotensinogen, respectively. Prorenin stimulation of human B-lymphoblast IM-9 cells increased mRNA expression levels of fibroblast growth factor 2 FGF2 , while angiotensin II treatment upregulated the expression levels of basigin BSG , matrix metallopeptidase MMP 2, 9, and 14, which were abolished by P RR and AT1R blockades, respectively. Immunofluorescence analyses of clinical samples showed colocalizations of P RR and AT1R with the products of these upregulated genes. CONCLUSIONS. The present study suggests that activation of P RR and AT1R is associated with the pathogenesis of conjunctival EMZL by stimulating the production of FGF2 and MMPs. Zhenyu Dong, Daiju Iwata, Nobuyoshi Kitaichi, Masayoshi Takeuchi, Masashi Sato, Noriko Endo, Kazuya Iwabuchi, Ryo Ando, Junichi Fukuhara, Satoshi Kinoshita, Anton Lennikov, Mizuki Kitamura, Kazuomi Mizuuchi, Atsuhiro Kanda, Kousuke Noda, Kenichi Namba, Sho-Ichi Yamagishi, Shigeaki Ohno, Susumu IshidaJOURNAL OF LEUKOCYTE BIOLOGY 96 6 1077 - 1085 2014年12月 [査読有り][通常論文] Formation of glyceraldehyde-derived advanced glycation endoproducts contributes to the pathogenesis of endogenous uvetitis in human and animals. AGEs are permanently modified macromolecule derivatives that form through nonenzymatic glycation of amino groups of proteins. Glycer-AGEs are highly toxic and play an important role in the pathogenesis of chronic inflammatory diseases. However, the contribution of glycer-AGEs to the pathogenesis of uveitis is unclear. In this study, we measured serum levels of glycer-AGEs in 100 patients with endogenous uveitis 22 with HLA-B27-associated uveitis, 20 with VKH disease, 14 with Behcet's disease, and 44 with sarcoidosis and 33 healthy volunteers. Regardless of the etiology, serum glycer-AGE levels were significantly higher in patients with uveitis than in healthy subjects. Serum glycer-AGE levels may therefore serve as a biomarker of human uveitis, as well as systemic inflammation, and may contribute to the progression of uveitis, including diabetic iritis, via the activation of NF-B. Genistein is a dietary-derived flavonoid abundantly present in soybeans and known to possess various biological effects including anti-inflammation and anti-angiogenic activity. To investigate the effects of genistein on intraocular neovascularization, we used an animal model of laser-induced choroidal neovascularization CNV. CNV was induced by laser photocoagulation. The animals were fed a mixture diet containing 0. Seven days after laser injury, the size of CNV lesions was quantified. Retinal pigment epithelium RPE -choroid complex was also harvested 1 or 3 days after laser injury and the level of monocyte chemoattractant protein MCP -1, intercellular adhesion molecule ICAM -1, and matrix metalloproteinase MMP -9 were measured by enzyme-linked immunosorbent assay. A significant decrease in CNV size was observed in animals treated with genistein 15441. 8 mu m 2 compared to control mice 21074. The current data indicate the anti-angiogenic property of genistein during CNV formation. C 2014 Elsevier Inc. All rights reserved. Background: The mechanism underlying focal choroidal excavation FCE remains largely unknown. We evaluated the sequential progression of FCE generation using enhanced depth imaging optical coherence tomography EDI-OCT in a patient with multiple evanescent white dot syndrome MEWDS. Case presentation: A 37-year-old woman suffered MEWDS in the right eye. After 1 month, almost all white dots spontaneously resolved together with improvements of the perifoveal OCT findings. Interestingly, perifoveal region developed a conforming-type FCE. An abnormal hyper-reflective lesion on OCT, regarded as fibrosis formation, simultaneously appeared within the choroid below the FCE and subsequently increased in size. Human adenovirus species D HAdV-D , which is composed of clinically and epidemiologically important pathogens worldwide, contains more taxonomic "types" than any other species of the genus Mastadenovirus, although the mechanisms accounting for the high level of diversity remain to be disclosed. Recent studies of known and new types of HAdV-D have indicated that intertypic recombination between distant types contributes to the increasing diversity of the species. However, such findings raise the question as to how homologous recombination events occur between diversified types since homologous recombination is suppressed as nucleotide sequences diverge. In order to address this question, we investigated the distribution of the recombination boundaries in comparison with the landscape of intergenomic sequence conservation assessed according to the synonymous substitution rate d s. The results revealed that specific genomic segments are conserved between even the most distantly related genomes; we call these segments "universally conserved segments" UCSs. These findings suggest that UCSs facilitate homologous recombination, resulting in intergenomic segmental exchanges of UCS-flanking genomic regions as recombination modules. With the aid of such a mechanism, the haploid genomes of HAdV-Ds may have been reshuffled, resulting in chimeric genomes out of diversified repertoires in the HAdV-D population analogous to the MHC region reshuffled via crossing over in vertebrates. In addition, some HAdVs with chimeric genomes may have had the opportunity to avoid host immune responses thereby causing epidemics. C 2014 Elsevier B. All rights reserved. To investigate the concentration and composition of N-glycans in plasma and vitreous samples obtained from patients with non-proliferative vitreoretinal diseases. Plasma and vitreous samples were collected from 11 patients with idiopathic macular hole MH and 9 patients with epiretinal membrane ERM. The samples were pretreated for enzymatic cleaving, and subsequently glycans released from proteins were captured on BlotGlyco H beads. Sialic acids were methyl-esterified. The concentration and composition of N-glycans in the samples were assessed. 001. Predominant N-glycan in both plasma 39. By contrast, the second-ranked N-glycan in vitreous samples 15. The current data provide useful information on N-glycan profile in the vitreous fluid, which is distinct from that in the plasma. Purpose: To analyze the histopathology and expression of 8-hydroxydeoxyguanosine OHdG , a marker of oxidative stress, in the levator aponeurosis tissues of involutional aponeurotic and congenital blepharoptosis patients, and adult subjects with no history of blepharoptosis. Methods: Fourteen and 4 levator aponeurosis tissues obtained from Asian patients with involutional and congenital blepharoptosis and 3 normal adult tissues were examined. Results: The levator aponeurosis tissues contained spindle smooth muscle fibers and striated muscles. Nuclear immunoreactivity for 8-OHdG was noted in striated and smooth muscle cells in all the tissues. In contrast, there was a rare positive -8-OHdG-immunoreactivity of smooth muscle cells in the aponeurotic tissues of the involutional blepharoptosis patients. Conclusions: Levator aponeurosis in involutional aponeurotic blepharoptosis tissues showed oxidative stress in the muscle, indicating that oxidative stress plays a potential role in the pathologic study of the disease. A case of retinoschisis associated with peripapillary intrachoroidal cavitation ICC was successfully treated with pars plana vitrectomy. A 70-year-old woman developed macular elevation and peripapillary ICC in her right eye. Optical coherence tomography revealed retinoschisis with retinal detachment in the macula. A microhole was observed within the myopic conus. A narrow passage was observed linking the ICC with the schisis cavity, complicated by a peripapillary epiretinal membrane tissue adjacent to the passage. The patient underwent vitrectomy with removal of the membrane tissue. Complete regression of the retinoschisis was observed, with closure of the connection channel between the ICC and schisis cavity. These findings suggest that the communication channel between the vitreous and schisis cavities was formed due to the traction exerted by the membrane tissue on the ICC that had generated a connecting path to the schisis cavity. PURPOSE. To examine the expression of VEGF in extranodal marginal zone B-cell lymphoma EMZL and reactive lymphoid hyperplasia RLH of human ocular adnexa, and analyze the correlation with the intratumoral microvessel density MVD. METHODS. Twenty-two EMZL and 16 RLH tissues were examined in this study. Paraformaldehyde-fixed, paraffin-embedded tissue sections were processed for immunohistochemistry with antibodies against VEGF and CD20. Vascular endothelial growth factor expression was analyzed using the ELISA and RT-PCR in the EMZL tissues. Microvessel density was determined based on the immunoreactivity for anti-CD34 antibody. RESULTS. Vascular endothelial growth factor immunoreactivity was detected in the cytoplasm of lymphoid cells in EMZL and RLH. ELISA and RT-PCR confirmed VEGF protein and mRNA expressions in the EMZL tissue, respectively. The MVD showed a significant positive correlation with the VEGF-immunopositive rate in conjunctival and orbital EMZLs. CONCLUSIONS. This study demonstrated increased VEGF expression in human conjunctival and orbital EMZL compared with that in RLH, suggesting that VEGF plays a significant role in the pathogenesis and tumor angiogenesis of ocular adnexal lymphoma. Adenosquamous carcinoma ASC is a rare form of malignancy which consists of two types of cell, including squamous cells and glandular-like cells. The current report presents the first known case of ASC in the conjunctiva and analyzes the histological findings. A 76-year-old female presented with right eyelid swelling in 2001. A right conjunctival tumor was noted and a biopsy was performed. Histologically, the tumor was diagnosed as a squamous cell carcinoma. The patient underwent radiotherapy, but the tumor rapidly relapsed. Subsequently, the patient underwent orbital exenteration. Histologically, the conjunctival tissues had been replaced with invasive tumor cells. A number of tumor cells demonstrated squamous differentiation with a keratinizing tendency, while other tumor cells exhibited mucin-producing activity with glandular formation. The conjunctival tumor was diagnosed as an ASC. At the time of writing, the patient is well without local recurrence or distant metastases. ASC typically exhibits aggressive biological behavior, and is associated with worse prognosis than conventional adenocarcinoma. Therefore, complete surgical excision is considered a key treatment for ASC of the conjunctiva. Background: Changes in choroidal circulation hemodynamics during the course of punctate inner choroidopathy PIC remain unknown. The aim of this study was to quantitatively evaluate changes in choroidal blood flow velocity by using laser speckle flowgraphy LSFG in patients with PIC. Case presentation: This PIC patient was initially treated with systemic corticosteroids for 4 months. LSFG measurements were taken 10 consecutive times before treatment and at 1, 3, 12, 20 and 23 months after the initiation of therapy. The mean blur rate MBR , a quantitative index of relative blood flow velocity, was calculated using LSFG in three regions: Circles 1, 2 and 3 were set at the fovea, a lesion site, and an area of normal-appearing retina, respectively. The PIC lesions scarred after treatment along with improvements in visual function and outer retinal morphology. At the time of PIC recurrence after 20 months, the MBR decreased temporarily but subsequently increased after retreatment with systemic corticosteroids. This trend was accompanied by a decrease in choroidal thickness at the lesion site after retreatment. Conclusions: Macular choroidal blood flow velocity increased and choroidal thickness decreased concurrently with regression of PIC. The present findings suggest that inflammation-related impairments in choroidal circulation may relate to the pathogenesis of PIC, extending over a wider area in the posterior pole than the PIC lesions per se. BackgroundTo evaluate changes of choroidal circulation quantitatively using laser speckle flowgraphy in patients with acute zonal occult outer retinopathy. DesignRetrospective observational case series. ParticipantsSixteen eyes of 11 acute zonal occult outer retinopathy patients: seven non-treated eyes with good visual acuity and nine systemic corticosteroid-treated eyes with progressive visual acuity loss. Six eyes with thyroid-associated ophthalmopathy receiving systemic corticosteroid therapy served as controls. MethodsThe mean blur rate, an index of quantitative relative blood flow velocity, in the affected area was measured by laser speckle flowgraphy. The changes of mean blur rate, best-corrected visual acuity and the average threshold at the affected area on Humphrey perimetry during 24-week follow up were analysed. Main Outcome MeasuresMean blur rate, best-corrected visual acuity, and the average threshold. ResultsIn non-treated eyes, the average mean blur rate significantly increased at 24 weeks, with a significant increase of the average threshold. In corticosteroid-treated eyes, the mean blur rates at 1, 4, 12 and 24 weeks were significantly higher than the pretreatment value, with significant improvement of best-corrected visual acuity and the average threshold. The increase in mean blur rate at 4 weeks in corticosteroid-treated acute zonal occult outer retinopathy eyes was significantly higher than that in corticosteroid-treated control eyes. ConclusionsIn eyes with acute zonal occult outer retinopathy, the mean blur rate at the affected area significantly increases along with improvement of visual functions. These results suggest that impaired choroidal circulation is involved in the pathogenesis of acute zonal occult outer retinopathy. To investigate postoperative thickness changes in the retinal layers in eyes with epiretinal membrane ERM. Correlations between these changes and visual outcomes were also examined. Retrospective review of 25 eyes 24 patients that had undergone pars plana vitrectomy for ERM and had a postoperative follow-up period a parts per thousand yen6 months. Optical coherence tomography 6 x 6 mm macular thickness map was used to measure mean thickness of the inner and outer retinal layers 1 week and 1, 3, and 6 months following surgery. Photoreceptor outer segment PROS length was evaluated manually, and used to assess the association between best-corrected visual acuity BCVA and retinal layer thickness at the fovea. At 1 week and 1, 3, and 6 months, retinal layer thickness was 388, 377, 362, and 352 mu m for the whole layer; 133, 115, 107, and 101 mu m for the inner layer; 138, 145, 147, and 148 mu m for the outer layer; and 28, 35, 36, and 40 mu m for the PROS length, respectively. In comparison to 1-week data, the inner layers were significantly thinner at 1 month and later, as was the thickness of the entire retina. Outer layer thickness and PROS length were also significantly thicker at these time points. Retinal outer layer thickness significantly increased following pars plana vitrectomy for ERM. Visual improvement was positively correlated with PROS length recovery. Purpose: Echinochrome is a pigment present in the shells and spines of sea urchins. Endotoxin-induced uveitis EIU is an animal model of acute anterior segment intraocular inflammation that is induced by the injection of lipopolysaccharide LPS. In this study, the therapeutic effect of echinochrome was examined in uveitis using the EIU model. Methods: EIU was induced in Lewis rats via 200 mu g subcutaneous injections of LPS from Escherichia coli. Echinochrome was administered intravenously in 10, 1, or 0. Twenty-four hours after LPS injection, the number of infiltrating cells and the protein concentration in aqueous humor were determined. Aqueous tumor necrosis factor alpha TNF-alpha concentration was quantified with enzyme-linked immunosorbent assay, eyes were stained with nuclear factor NF kappa B antibodies, and ROS production was determined by dihydroethidium staining in fresh frozen samples. Conclusions: Echinochrome ameliorated intraocular inflammation caused by EIU by reducing ROS production, thereby also decreasing the expression of NF kappa B and TNF-alpha. As a natural pigment, echinochrome may therefore be a promising candidate for the safe treatment of intraocular inflammation. The use of sea urchin shells and spines in health foods and medical products is thus both economically and environmentally meaningful. This study was conducted to elucidate pathophysiological roles of the lysosomal phospholipase A2 LPLA2 , a phospholipid-degrading enzyme, of the aqueous humor AH in uveitis using an animal model and clinical specimens. Endotoxin-induced uveitis EIU was induced by subcutaneous injections of lipopolysaccharide from Escherichia coli to seven-week-old male Lewis rats. Inflammation of the anterior chamber AC was evaluated by measurement of the protein concentration of rat AH. Immunohistochemical analysis was performed using antibodies against CD11b and LPLA2. Sixty-five human AH specimens, in which 11 eyes had a history of chronic uveitis, were collected during patient cataract surgeries and used to determine LPLA2 activity. The LPLA2 activity in rat AH was significantly increased by EIU induction, and was correlated to the extent of inflammation in the AC. By contrast, the LPLA2 activity in rat serum or cerebrospinal fluid was not influenced by EIU induction. According to the immunohistochemistry, LPLA2 was found in CD11b positive cells in the AC of the EIU rats. In the clinical specimens, the AH obtained from the patients with a history of uveitis possessed significantly higher LPLA2 activity than that from the senile patients with cataract but without other ocular diseases. These results demonstrate that the LPLA2 activity in the AH is augmented with the inflammation in the AC and suggest that the LPLA2 in the AH participates in the inflammation process in the AC. C 2013 Published by Elsevier Ltd. Background: Specific cross-reacting autoimmunity against recoverin or collapsin response mediator protein CRMP -5 is known to cause cancer-associated retinopathy or paraneoplastic optic neuropathy, respectively. We report a rare case with small cell lung carcinoma developing bilateral neuroretinitis and unilateral focal outer retinitis positive for these antibodies. Case presentation: A 67-year-old man developed bilateral neuroretinitis and foveal exudation in the right eye. Optical coherence tomography showed a dome-shaped hyperreflective lesion extending from inner nuclear layer to the photoreceptor layer at the fovea in the right eye. Single-flash electroretinography showed normal a-waves in both eyes and slightly reduced b-wave in the left eye. Results of serological screening tests for infection were within normal limits. The patient's optic disc swelling and macular exudation rapidly improved after oral administration of prednisolone. Systemic screening detected lung small cell carcinoma and systemic chemotherapy was initiated. Immunoblot analyses using the patient's serum detected autoantibodies against recoverin, CRMP-5, and a-enolase, but not carbonic anhydrase II. Neuroretinitis once resolved after almost remission of carcinoma on imaging but it recurred following the recurrence of carcinoma. Conclusions: The development of neuroretinitis in this cancer patient with anti-retinal and anti-optic nerve antibodies depended largely on the cancer activity, suggesting the possible involvement of paraneoplastic mechanisms. Patients with paraneoplastic optic neuropathy and retinopathy are likely to develop autoimmune responses against several antigens, thus leading to various ophthalmic involvements. Pro renin receptor [ P RR], also known as Atp6ap2, has attracted growing attention as a key molecule for tissue renin-angiotensin system RAS. PURPOSE. METHODS. We examined the cytokine concentrations in the tear fluid by CytoBead assay , tear film break-up time, amount of tear production, and expressions of mucins 1, 4, and 5AC, by RT-PCR. We also performed vital staining of the ocular surface, PAS staining for muc5AC, and immunohistochemical stainings for 4-hydroxy-2-nonenal 4-HNE , 8-hydroxy-2'-deoxyguanosine 8-OHdG , in the conjunctiva to compare the results before and after rebamipide instillations. RESULTS. The mean IL-6, IL-17, TNF-alpha, and IFN-gamma levels in the tear fluid were reduced significantly along with a significant decrease in the density of cells positive for 4-HNE and 8-OHdG in the conjunctiva. CONCLUSIONS. Two percent Rebamipide ophthalmic solution significantly improved the tear stability and corneal epithelial damage, and enhanced the expression of muc5 mRNA on the ocular surface. We also observed anti-inflammatory effects in the tear film together with antioxidative effects in the conjunctiva, suggesting the efficacy of rebamipide in age-related dry eye disease attributable to SOD1 knockout. Yun Jong Lee, Yukihiro Horie, Graham R. Wallace, Yong Seok Choi, Ji Ah Park, Ji Yong Choi, Ran Song, Young-Mo Kang, Seong Wook Kang, Han Joo Baek, Nobuyoshi Kitaichi, Akira Meguro, Nobuhisa Mizuki, Kenichi Namba, Susumu Ishida, Jinhyun Kim, Edyta Niemczyk, Eun Young Lee, Yeong Wook Song, Shigeaki Ohno, Eun Bong LeeANNALS OF THE RHEUMATIC DISEASES 72 9 1510 - 1516 2013年09月 [査読有り][通常論文] Objectives To identify non-major histocompatibility complex susceptible genes that might contribute to Behcet's disease BD. Methods We performed a genome-wide association study using DNA samples from a Korean population consisting of 379 BD patients and 800 controls. A replication study was performed in a Japanese population 363 BD patients and 272 controls. To evaluate the functional implication of the target single nucleotide polymorphisms SNP , gene expression levels in peripheral T cells, allele-specific modulation of promoter activity and biological effect of mRNA knockdown were investigated. Results We found a novel association of BD to the GIMAP locus, mapped to chromosome 7q36. 60x10 -6. 53x10 -5 in GIMAP1 areas. Replication study using DNA samples from the Japanese population validated the significant association between BD and the GIMAP locus. The GIMAP4 promoter construct plasmid with the minor allele of rs1608157 displayed significantly lower activity than one with the major allele. Moreover, CD4 T cells from BD patients showed a lower level of GIMAP4 mRNA, and GIMAP4 knockdown was protective against Fas-mediated apoptosis. Conclusions These results suggest that a GIMAP cluster is a novel susceptibility locus for BD, which is involved in T-cell survival, and T-cell aberration can contribute to the development of BD. Aim: To examine the expression of alpha B-crystallin and vascular endothelial growth factor VEGF in conjunctival squamous cell carcinoma CSCC. Materials and Methods: Seven CSCCs and three normal conjunctivas that were surgically excised were studied. Paraformaldehyde-fixed, paraffin-embedded tissue sections were processed for immunohistochemistry with antibodies against alpha B-crystallin, its phosphorylated forms, and VEGF. In vitro experiments were conducted to investigate the effects of mitomycin C MMC treatment on the expression of alpha B-crystallin and VEGF secretion. Results: alpha B-Crystallin and VEGF were strongly expressed in CSCCs compared to normal conjunctivas. alpha B-Crystallin immunoreactivity was co-localized with that for VEGF in CSCCs, whereas these signals were reduced in CSCC tissues treated with MMC before excision. MMC treatment suppressed the alpha B-crystallin expression and VEGF secretion in cultured conjunctival cells in a dose-dependent manner. Conclusion: This study demonstrated alpha B-crystallin and VEGF expressions in human CSCCs, which may play a role in the pathogenesis. alpha B-Crystallin expression, and VEGF secretion were reduced by MMC, indicating a novel therapeutic mechanism in MMC treatment for human CSCC. Human adenovirus HAdV causing epidemic keratoconjunctivitis is limited to D and E species. Recent progress in bioinformatics revealed that these viruses attach to the host with fibers, infiltrate the host cells via RGD Arg-Gly-Asp motif of penton base, and reveal their serological reaction by hexons. Loops 1 and 2 are the variable regions of each hexon. The possibility that a novel adenovirus later named HAdV-52 was transmitted over the wall of species' from monkeys to humans was reported. The recombination of the above three hot spots introduces novel types such as HAdV-53, -54, and -56. Boinformatics may provide rapid genotyping in nosocomial infection, predicting future epidemics, and an estimate of the therapeutic target molecules in the near future. To clarify the clinical features of human lymphotropic virus type 1 HTLV-1 -associated uveitis HAU in patients of Hokkaido University Hospital, Hokkaido, northern Japan. We reviewed the records of a consecutive series of 21 patients with HAU who were followed up for more than 12 months at Hokkaido University Hospital. Of the 21 patients enrolled in this study, 19 as well as their parents 90. One patient was a member of the Ainu ethnic group. Intraocular inflammation was controlled by topical treatment, while systemic corticosteroids were required in less than one-fourth of patients. Visual acuity improved in 15 patients, remained unchanged in four patients, and deteriorated in two patients. A number of clinical features were unique to Hokkaido, namely, predominant unilateral involvement, as well as two HAU patients with ATLL. The phylogenetic difference of HTLV-1 and HLA typing may correlate with different clinical manifestations in HAU. Asymmetrical secretion of vascular endothelial growth factor VEGF by retinal pigment epithelial RPE cells in situ is critical for maintaining the homeostasis of the retina and choroid. VEGF is also involved in the development and progression of age-related macular degeneration AMD. We studied the effect of tumor necrosis factor-alpha TNF-alpha on the secretion of VEGF in polarized and non-polarized RPE cells P-RPE cells and N-RPE cells, respectively in culture and in situ in rats. A subretinal injection of TNF-alpha caused a decrease in VEGF expression and choroidal atrophy. Porcine RPE cells were seeded on Transwell TM filters, and their maturation and polarization were confirmed by the asymmetrical VEGF secretion and trans electrical resistance. Exposure to TNF-alpha decreased the VEGF secretion in P-RPE cells but increased it in N-RPE cells in culture. TNF-alpha inactivated JNK in P-RPE cells but activated it in N-RPE cells, and TNF-alpha activated NF-kappa B in P-RPE cells but not in N-RPE cells. Inhibition of NF-kappa B activated JNK in both types of RPE cells indicating crosstalk between JNK and NF-kappa B. TNF-alpha induced the inhibitory effects of NF-kappa B on JNK in P-RPE cells because NF-kappa B is continuously inactivated. In N-RPE cells, however, it was not evident because NF-kappa B was already activated. The basic activation pattern of JNK and NF-kappa B and their crosstalk led to opposing responses of RPE cells to TNF-alpha. These results suggest that VEGF secretion under inflammatory conditions depends on cellular polarization, and the TNF-alpha-induced VEGF down-regulation may result in choroidal atrophy in polarized physiological RPE cells. TNF-alpha-induced VEGF up-regulation may cause neovascularization by non-polarized or non-physiological RPE cells. Aim To quantitatively evaluate the time course of macular choroidal blood flow velocity in acute central serous chorioretinopathy CSC. Methods This retrospective observational case series included 21 eyes of 20 patients 17 men, 3 women; mean age, 53. 0 years with treatment-naive acute CSC. Laser speckle flowgraphy was performed to calculate macular mean blur rate MBR , an indicator of relative blood flow velocity at the first visit, 3 and 6 months thereafter. Changes in average MBR values were compared with visual improvement at 6 months. Results Subretinal fluid completely resolved in all eyes within 6 months, while best-corrected visual acuity BCVA significantly improved at 6 months compared to the initial BCVA. During the follow-up period, the average MBR significantly decreased to 92. Importantly, there was a negative correlation between the BCVA recovery and the MBR decrease, showing the possible association of MBR increase with poor visual prognosis. Multiple regression analysis demonstrated no significant correlation between MBR and ocular perfusion pressure. Conclusions These results indicate that macular choroidal blood flow velocity decreases concurrently with regression of CSC, suggesting a validity of choroidal blood flow elevation in the pathogenesis of acute CSC. Immuno globulin IgG 4-related disease is characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. We report a case of IgG4-related inflammation of the orbit simulating extranodal marginal zone B-cell lymphoma EMZL. A 72-year-old female complained of bilateral eyelid swelling for three years. A MRI scan demonstrated two kinds of lesions, tumor 1, presenting with a predominantly low density, and tumor 2, of relatively high density. Partial resection of each tumor was conducted in September 2011. Based on the clinicopathological findings, tumors 1 and 2 were diagnosed as IgG4-related inflammation and EMZL, respectively. The bilateral tumors consequently diminished, and she is currently well with no recurrence or systemic involvement. In conclusion, EMZL can arise from massive IgG4-related orbital inflammation. Since IgG4-related inflammation can represent multiple nodular lesions, biopsies from multiple sites within the lesion are required to make a correct diagnosis in selected cases. Oral prednisolone combined with radiotherapy is an effective treatment for patients with IgG4-related ophthalmic disease simulating EMZL. Saori Yaguchi, Yoko Ogawa, Shigeto Shimmura, Tetsuya Kawakita, Shin Hatou, Shingo Satofuka, Shigeru Nakamura, Toshihiro Imada, Hideyuki Miyashita, Satoru Yoshida, Tomonori Yaguchi, Yoko Ozawa, Takehiko Mori, Shinichiro Okamoto, Yutaka Kawakami, Susumu Ishida, Kazuo TsubotaPLOS ONE 8 6 e64724 2013年06月 [査読有り][通常論文] Chronic graft-versus-host disease cGVHD , a serious complication following allogeneic HSCT hematopoietic stem cell transplantation , is characterized by systemic fibrosis. The tissue renin-angiotensin system RAS is involved in the fibrotic pathogenesis, and an angiotensin II type 1 receptor AT1R antagonist can attenuate fibrosis. Tissue RAS is present in the lacrimal gland, lung, and liver, and is known to be involved in the fibrotic pathogenesis of the lung and liver. This study aimed to determine whether RAS is involved in fibrotic pathogenesis in the lacrimal gland and to assess the effect of an AT1R antagonist on preventing lacrimal gland, lung, and liver fibrosis in cGVHD model mice. We used the B10. First, we examined the localization and expression of RAS components in the lacrimal glands using immunohistochemistry and quantitative real-time polymerase chain reaction PCR. We demonstrated that fibroblasts expressed angiotensin II, AT1R, and AT2R, and that the mRNA expression of angiotensinogen was greater in the lacrimal glands of cGVHD model mice than in controls generated by syngeneic-HSCT. The inhibition experiment revealed that fibrosis of the lacrimal gland, lung, and liver was suppressed in mice treated with the AT1R antagonist, but not the AT2R antagonist. We conclude that RAS is involved in fibrotic pathogenesis in the lacrimal gland and that AT1R antagonist has a therapeutic effect on lacrimal gland, lung, and liver fibrosis in cGVHD model mice. Our findings point to AT1R antagonist as a possible target for therapeutic intervention in cGVHD. PURPOSE: Since some patients develop depigmentation of the trabecular meshwork in the course of Vogt-Koyanagi-Harada VKH disease, we examined the incidence of trabecular depigmentation and its correlation with other ocular findings and systemic symptoms. METHODS: We retrospectively reviewed the clinical charts of 53 Japanese patients diagnosed with VKH disease. The scores of trabecular and limbal pigmentation of all patients were recorded. We then examined the correlation between trabecular pigmentation and the presence of sunset glow fundus or skin lesions. 022 , whereas limbal pigmentation showed no significance. However, there were no significant differences in trabecular and limbal pigmentation between the patients with and those without skin lesions. Furthermore, there was no correlation between trabecular and limbal pigmentation. CONCLUSIONS: Depigmentation of the trabecular meshwork develops in some patients in the course of VKH disease. This depigmentation is significantly correlated with sunset glow fundus, but not with limbal depigmentation or skin lesions. Aims: To study serum levels of soluble vascular adhesion protein sVAP -1 in type II diabetic patients with retinopathy. Methods: Serum samples were obtained from 53 consecutive patients, including 14 cases with non-angiogenic ocular diseases, i. , epiretinal membrane ERM and idiopathic macular hole MH , 19 cases with age-related macular degeneration AMD , and 20 cases with diabetic retinopathy DR. Protein levels of sVAP-1, intercellular adhesion molecule ICAM -1, vascular cell adhesion molecule VCAM -1, and vascular endothelial growth factor VEGF were determined by enzyme-linked immunosorbent assay. Enzymatic activity of semicarbazide-sensitive amine oxidase SSAO was also measured. Results: Serum level of sVAP-1 showed a moderate correlation with SSAO activity in all cases. Patients with DR had higher levels of serum sVAP-1 than subjects with ERM and MH, or those with AMD; however, severity of DR is not related to the serum levels of sVAP-1. Serum sVAP-1 correlated positively with VEGF in patients with DR, but not in those with ERM and MH, or those with AMD. Neither soluble ICAM-1 nor VCAM-1 correlated with VEGF, even in subjects with DR. Conclusion: The current data demonstrate the elevated serum levels of sVAP-1 and correlation between sVAP-1 and VEGF in patients with type II diabetes. C 2013 Elsevier Inc. All rights reserved. Seven days after the treatment, the CNV size was evaluated using a flatmount technique. Protein levels of vascular endothelial growth factor VEGF and inflammation-associated molecules, such as monocyte chemoattractant protein MCP -1 and intercellular adhesion molecule ICAM -1, in the retinal pigment epithelium-choroid complex were measured with enzyme-linked immunosorbent assay. Results: SRPIN340 inhibited CNV formation in a dose-dependent manner. Compared with the vehicle, SRPIN340 significantly decreased the protein levels of VEGF, MCP-1, ICAM-1, and consequently inhibited macrophage infiltration. Furthermore, SRPIN340 suppressed the gene expression levels of total Vegf and exon 8a-containing Vegf isoforms. Conclusions: SRPIN340, a specific inhibitor of SRPK, suppressed Vegf expression and attenuated CNV formation. Our data suggest the possibility that SRPIN340 is applicable for neovascular age-related macular degeneration as a novel chemical therapeutics. Acute ultraviolet UV B exposure causes photokeratitis and induces apoptosis in corneal cells. Geranylgeranylacetone GGA is an acyclic polyisoprenoid that induces expression of heat shock protein HSP 70, a soluble intracellular chaperone protein expressed in various tissues, protecting cells against stress conditions. We examined whether induction of HSP70 has therapeutic effects on UV-photokeratitis in mice. ROS signal was not affected by GGA. PURPOSE. To examine the expression of vascular endothelial growth factor VEGF and VEGF receptor VEGFR -2 in enucleated eyes with Coats' disease. METHODS. Formalin-fixed, paraffin-embedded tissue sections from nine globes with Coats' disease were submitted for hematoxylin and eosin staining and immunohistochemistry with anti-VEGF and VEGFR antibodies. RESULTS. Histologically, the enucleated eyes demonstrated the presence of macrophage infiltration and cholesterol clefts in the subretinal space. There were marked retinal vascular abnormalities, including dilated vessels with hyalinized vessel walls in six globes. Exudative retinal detachment was noted in all globes. VEGF immunoreactivity was observed in macrophages infiltrating the subretinal space, and in the detached retina including several blood vessels. VEGFR-2 immunoreactivity was detected in endothelial cells lining the abnormal retinal vessels, where VEGFR-1 or VEGFR-3 was not expressed. CONCLUSIONS. Immunoreactivity for VEGF and VEGFR-2 was detected in macrophages and endothelia of abnormal vessels in eyes with Coats' disease. These results suggest that anti-VEGF approach is a promising therapy for patients with Coats' disease. Invest Ophthalmol Vis Sci. 2013; 54: 57-62 DOI: 10. 12-10613• PURPOSE. To investigate the antiangiogenic properties of tissue kallikrein in a murine model of laser-induced choroidal neovascularization CNV. METHODS. Seven days after laser injury, the CNV size was quantified. The levels of monocyte chemoattractant protein MCP -1, intercellular adhesion molecule ICAM -1, and interleukin IL -6 were assessed by enzyme-linked immunosorbent assay 3 days after laser injury. Cleavage of mouse VEGF with tissue kallikrein was assessed in vivo and in vitro. The protein levels of bradykinin were assessed in the RPE-choroid complexes and hearts. RESULTS. A significant decrease in CNV size was observed in animals treated with tissue kallikrein 27,168. 2 mu m 2 compared with vehicle-treated controls 36,374. Tissue kallikrein treatment significantly reduced MCP-1, ICAM-1, and IL-6 levels in RPE-choroid complexes. Furthermore, immunoblotting showed the bands, presumably corresponding to the fragmented VEGF 164 protein, in the samples of both mouse VEGF preincubated with tissue kallikrein and RPE-choroid complexes obtained from animals treated with tissue kallikrein. In addition, bradykinin was unchanged in the RPE-choroid complexes of animals treated with tissue kallikrein, whereas the level of bradykinin was increased in the heart obtained from these experimental animals. CONCLUSIONS. The current data indicate that kallikrein exhibits antiangiogenic properties by cleaving VEGF164 in a laser-induced CNV model. Invest Ophthalmol Vis Sci. 2013; 54: 274279 DOI: 10. 12-10512• Angiopoietin-like protein Angptl 2 is a key mediator linking obesity to chronic adipose-tissue inflammation and systemic insulin resistance, and increasing evidence has shown that Angptl2 is associated with various chronic inflammatory diseases such as cancer and dermatomyositis; however, it remains unclear that Angptl2 functions in acute inflammation. In this study, we investigate whether Angptl2 has a role in acute inflammation in the eye with endotoxin-induced uveitis EIU. Treatment with lipopolysaccharide LPS stimulated retinal Angptl2 mRNA expression in vivo and in vitro. In vitro, antibody-based inhibition of alpha 5 beta 1 integrin, a receptor for Angptl2, significantly repressed LPS-induced expression of IL-6 and TNF-alpha, both of which are the major inflammatory cytokines derived from macrophages. The present findings indicate that Angptl2 mediates endotoxin-induced retinal inflammation through the activation of NF-kappa B signaling pathway and suggest a potential validity of Angptl2 as a new molecular target for the treatment of acute inflammation. Laboratory Investigation 2012 92, 1553-1563; doi:10. 2012. 111; published online 6 August 2012• The renin-angiotensin system RAS potentially has a role in the development of end-organ damage, and tissue RAS activation has been suggested as a risk factor for diabetic retinopathy. We have recently shown significant involvement of pro renin receptor [P]RR in retinal inflammation in a rodent model of early diabetes. In this study we aim to elucidate the P RR-associated pathogenesis of fibrovascular proliferation, a late-stage angiogenic complication in human diabetic retinopathy. Vitreous fluids from 23 eyes of patients with proliferative diabetic retinopathy PDR and 16 eyes of controls with non-diabetic, idiopathic macular diseases macular hole and epiretinal membrane were collected. Protein levels of soluble P RR were measured by ELISA, and immunofluorescence was performed to assess the localisation of P RR and related molecules in fibrovascular tissues from PDR eyes. P RR immunoreactivity was detected in neovascular endothelial cells, colocalised with prorenin, phosphorylated extracellular signal-regulated kinase ERK and vascular endothelial growth factor VEGF. Prorenin application to human retinal microvascular endothelial cells significantly upregulated mRNA expression of VEGF, especially the VEGF165 isoform, which was abolished by P RR or ERK signalling blockade. Proteases known to cleave P RR, including furin, were positive in endothelial cells in fibrovascular tissues. Protein levels of soluble P RR in vitreous fluids were higher in PDR eyes than in non-diabetic control eyes, and correlated significantly with vitreous prorenin and VEGF levels and the vascular density of fibrovascular tissues. Our data using human samples provide the first evidence that P RR is associated with angiogenic activity in PDR. Purpose: Endotoxin-induced uveitis EIU is an animal model for acute ocular inflammation. Several substances play major roles in the development of inflammatory changes in EIU, including tumor necrosis factor-alpha TNF-alpha , interleukin IL -1 beta, and IL-6. These inflammatory cytokines trigger the degradation of I kappa B by activating I kappa B kinases IKKs. Released nuclear factor kappaB NF kappa B subsequently translocates to the nucleus, where NF kappa B expresses its proinflammatory function. IMD-0354, N- 3,5-Bis-trifluoromethylphenyl -5-chloro-2-hydroxybenzamide, selectively inhibits IKK beta, particularly when induced by proinflammatory cytokines, such as TNF-alpha and IL-1 beta. In the present study, we examined whether IKK beta inhibition has therapeutic effects on EIU by using IMD-0354 and its prodrug IMD-1041. Methods: Six-week-old male Lewis rats were used. EIU was induced with subcutaneous injections of 200 mu g of lipopolysaccharide LPS from Escherichia coli that had been diluted in 0. 1 ml of phosphate-buffered saline. 0 ml of 0. The rats were euthanized 24 h after LPS injection, and EIU severity was evaluated histologically. The number of infiltrating cells and the protein, TNF-alpha, and monocyte chemoattractant protein-1 MCP-1 concentrations in the aqueous humor were determined. TNF-alpha and MCP-1 concentrations were quantified with enzyme-linked immunosorbent assay. Eye sections were also stained with anti-NF kappa B and phosphorylated I-kappa B alpha antibodies. Results: The number of infiltrating cells in aqueous humor was 53. 8x10 5 , 72. 0x10 5 , 127. 0x10 5 , and 132. The total protein concentrations of aqueous humor were 92. 01 in aqueous humor. The number of NF kappa B positive nuclei was reduced when treated with IMD-0354. Furthermore, IMD-0354-treated EIU rats showed only background levels of phosphorylated I-kappa B alpha; however, it was strongly expressed in the iris-ciliary body cell cytoplasm of the IMD-0354 untreated EIU rats. 05 of aqueous humor in EIU. Conclusions: Acute uveitis was ameliorated by inhibition of IKK beta in rats. Extra nodal marginal zone B-cell lymphoma EMZL of the conjunctiva typically arises in the marginal zone of mucosa-associated lymphoid tissue. The pathogenesis of conjunctival EMZL remains unknown. We describe an unusual case of EMZL arising from reactive lymphoid hyperplasia RLH of the conjunctiva. A 35-year-old woman had fleshy salmon-pink conjunctival tumors in both eyes, oculus uterque OU. Specimens from conjunctival tumors in the right eye, oculus dexter OD , revealed a collection of small lymphoid cells in the stroma. Immunohistochemically, immunoglobulin Ig light chain restriction was not detected. In contrast, diffuse atypical lymphoid cell infiltration was noted in the left eye, oculus sinister OS , and positive for CD20, a marker for B cells OS. The tumors were histologically diagnosed as RLH OD, and EMZL OS. PCR analysis detected IgH gene rearrangement in the joining region JH region OU. After 11 months, a re-biopsy specimen demonstrated EMZL based on compatible pathological and genetic findings OD, arising from RLH. This case suggests that even if the diagnosis of the conjunctival lymphoproliferative lesions is histologically benign, confirmation of the B-cell clonality by checking IgH gene rearrangement should be useful to predict the incidence of malignancy. Purpose: To investigate the effects of a modified 360-degree suture trabeculotomy technique for primary and secondary open-angle glaucoma POAG and SOAG. Methods: We modified the procedure for 360-degree trabeculotomy by using a 5-0 nylon suture, making a scleral flap to allow clear identification of Schlemm canal, and creating a corneal side port incision opposite to the scleral flap to retrieve the suture used to cannulate and cleave the canal. The modified 360-degree suture trabeculotomy not combined with cataract surgery was performed on 25 eyes with POAG and 18 eyes with SOAG, and the results were compared retrospectively with those of standard trabeculotomy with metal trabeculotomes 16 eyes with POAG and 19 eyes with SOAG. " Results: Using this modified technique, Schlemm canal was appropriately incised without resistance. At 12 months after the modified 360-degree suture trabeculotomy and trabeculotomy with metal trabeculotomes, the mean postoperative IOP values were 13. 1 and 15. 2 mm Hg, respectively, and the mean numbers of antiglaucoma medications were 0. 5 and 1. 4, respectively. There was no significant difference between preoperative visual acuity and postoperative visual acuity in either procedure. Conclusions: This modified 360-degree suture trabeculotomy is a feasible surgical option for POAG and SOAG. PURPOSE. To investigate the expression, localization, and physiologic function of renin-angiotensin system RAS components in the mouse lacrimal gland. METHODS. To examine the change in tear secretion, mice received ARB AT1R blocker or AT2R antagonist. Tear secretion was assessed by cotton thread test before and after drug administration. RESULTS. The mRNAs coding for angiotensinogen, prorenin, ACE, and both AT1R and AT2R were found in normal lacrimal gland tissue and cultured lacrimal gland fibroblasts. Angiotensin II, AT1R, and AT2R were observed in the ducts and interstitial fibroblasts. AT1R and AT2R were also localized in blood vessels. All the cultured lacrimal gland fibroblasts expressed angiotensin II, AT1R, and AT2R. Tear secretion increased in mice that received ARB. CONCLUSIONS. The results are consistent with the hypothesis that a tissue-specific RAS is present in the lacrimal gland, and suggest that fibroblasts are one of the cell types playing a role in the tissue RAS. Tissue RAS might be involved in tissue function of regulating tear secretion in the lacrimal gland. Invest Ophthalmol Vis Sci. 2012;53:5416-5425 DOI: 10. 12-9891• Infliximab, an anti-TNF-alpha monoclonal antibody, administered to Beh double dagger et's disease BD patients in Japan with refractory intraocular inflammation, has shown excellent clinical results. However, some patients demonstrate a decreased response to infliximab during the course of the treatment. In the present study, we investigated the correlation between this reduced therapeutic effect and elevation of the serum antinuclear antibody ANA titers in patients with BD who were undergoing infliximab therapy. Seventeen patients 14 males and three females with uveitis in BD who were undergoing treatment with infliximab for 2 years or longer were enrolled. Their blood test results and clinical histories were obtained from medical records. One patient 5. The appearance of ANA was observed 6 months after the initiation of the infliximab therapy, and its titers gradually increased. None of the patients showed lupus symptoms. Five patients 29. In contrast, four patients 23. Here we report the positive conversion and subsequent elevation of serum ANA titers in some patients with BD after the initiation of infliximab therapy. Since all recurrences of uveitis were shown only in the ANA-positive patients, serum ANA titer may be a helpful biomarker for predicting the recurrence of ocular attacks in BD patients treated with anti-TNF-alpha antibody therapies. Objective. Behcet's disease is one of the major aetiologies of uveitis causing blindness in Asian countries. A genome-wide association study identified six microsatellite markers as disease susceptibility loci for Japanese patients with Behcet's disease. To confirm our recent results, these microsatellite markers were examined in a Korean population as a replication study. Methods. Study participants included 119 Behcet's disease patients and 141 controls. All were enrolled in Korea. Association between the six reported microsatellite markers D3S0186i, D6S0014i, D6S0032i, 536G12A, D12S0645i and D22S0104i and Behcet's disease was analysed. HLA-B was genotyped by sequence-based typing methods. Results. 028. 1 and 39. 2 and 20. 001. Conclusion. Purpose: To examine the expression of alphaB-crystallin and its colocalization with vascular endothelial growth factor in the epiretinal membrane of human proliferative diabetic retinopathy. Methods: Ten epiretinal membranes of proliferative diabetic retinopathy and three normal retinas surgically excised were included in this study. Paraformaldehyde-fixed, paraffin-embedded tissue sections were processed for immunohistochemistry with alphaB-crystallin, vascular endothelial growth factor, and CD31 antibodies. Results: AlphaB-crystallin was expressed in all epiretinal membranes examined. The immunolocalization of alphaB-crystallin was detected in the cytoplasm of CD31-positive endothelial cells, but not in normal retinal blood vessels. Furthermore, alphaB-crystallin immunoreactivity was colocalized in vascular endothelial growth factor-positive endothelial cells in proliferative diabetic retinopathy membranes. Conclusion: AlphaB-crystallin was expressed in proliferative diabetic retinopathy membranes, and colocalized with vascular endothelial growth factor-positive neovessels. AlphaB-crystallin may play a potential role in the pathogenesis of epiretinal membranes in proliferative diabetic retinopathy, together with vascular endothelial growth factor. RETINA 32:1190-1196, 2012• PURPOSE. Vascular adhesion protein VAP -1, a multifunctional molecule with adhesive and enzymatic properties, is expressed at the surface of vascular endothelial cells of mammals. It also exists as a soluble form sVAP-1 , which is implicated in oxidative stress via its enzymatic activity. This study explores a link between increased level of sVAP-1 and oxidative stress in proliferative diabetic retinopathy PDR with a focus on mechanistic components to form sVAP-1 by shedding from retinal endothelial cells. METHODS. Protein levels of sVAP-1 and N epsilon- hexanoyl lysine HEL , an oxidative stress marker, in the vitreous samples from patients with PDR or non-PDR were measured by ELISA. RESULTS. Protein level of sVAP-1 was increased and correlated with HEL in the vitreous fluid of patients with PDR. Retinal capillary endothelial cells released sVAP-1 when stimulated with high glucose or inflammatory cytokines, such as TNF-alpha and IL-1 beta in vitro. Furthermore, matrix metalloproteinase-2 and -9, type IV collagenases, were the key molecules to mediate the protein cleavage of VAP-1 from retinal capillary endothelial cells. CONCLUSIONS. Our data for the first time provide evidence on the link between sVAP-1 and type IV collagenases in the pathogenesis of PDR. Invest Ophthalmol Vis Sci. 2012;53:4055-4062 DOI:10. 12-9857• Lutein, a xanthophyll of a carotenoid, is anticipated as a therapeutic product to prevent human eye diseases. However, its biological mechanism is still unclear. Here, we show the molecular mechanism of lutein's effect to reduce photodamage of the retina. Visual function was measured by electroretinogram, and histological changes were observed. Immunohistochemical and immunoblot analyses were performed to analyze molecular mechanism. The reactive oxygen species induced in the retina was evaluated by fluorescent probes. In the mice after light exposure, reduction of a-wave and b-wave amplitudes in electroretinogram, indicating visual impairment, and thinning of the photoreceptor cell layer owing to apoptosis were both attenuated by lutein diet. Interestingly, gamma-H2AX, a marker for double-strand breaks DSBs in DNA, was up-regulated in the photoreceptor cells after light exposure, but this increase was attenuated by lutein diet, suggesting that DSBs caused by photodamage contributed to the photoreceptor cell death and that this change was suppressed by lutein. Moreover, the expression of eyes absent EYA , which promotes DNA repair and cell survival, was significantly up-regulated with lutein diet in the light-exposed retina. Therefore, lutein induced EYA for DNA repair, which could suppress DNA damage and photoreceptor cell apoptosis. Lutein reduced light-induced oxidative stress in the retina, which might contribute to promote DNA repair. The lutein-supplemented diet attenuated light-induced visual impairment by protecting the photoreceptor cells' DNA. C 2012 Elsevier Inc. All rights reserved. BACKGROUND: Chickenpox is rarely associated with posterior segment inflammation. We report on a case of unilateral chickenpox chorioretinitis with retinal exudates and periphlebitis. CASE PRESENTATION: A 21-year-old healthy man, who suffered from chickenpox 2 weeks prior to symptom development, exhibited mild anterior chamber cells, vitreous opacity, sheathing of retinal veins, and yellow-white exudates in his right eye. Varicella zoster virus DNA was detected by polymerase chain reaction in the aqueous humor. He was treated with intravenous acyclovir followed by oral prednisolone and valaciclovir. Aqueous cells quickly disappeared and retinal exudates diminished within 1 month, leaving faint retinal scarring. Retinal arteritis had never been observed in this patient.

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第90春季年会会場別プログラム

上原亜衣 ティガレ

背景:運転席用supplemental restraint system SRS エアバッグは、最高時速約300kmで運転手に向かって展開し、それに伴う臓器障害は多岐にわたる。 本稿では、SRSエアバッグ展開に伴い網膜再剥離と気胸を発症した症例の臨床経過を報告する。 症例:73歳、男性。 北海道大学病院眼科で左眼裂孔原性網膜剥離 RRD に対する水晶体再建術、硝子体手術および輪状締結術後の経過観察中に、展開するSRSエアバッグで受傷した。 受傷2週間後に再診し、左眼のRRDの再発があり、硝子体手術およびシリコーンオイルタンポナーデを施行した。 術後8日目に、突然の胸痛と動悸を発症した。 右気胸と診断され、治療された。 受傷後12ヵ月の現在、全身状態は安定しており、網膜再剥離はない。 結論:SRSエアバッグ作動に伴う外傷は、網膜再剥離のリスクになると同時に、全身合併症を伴うこともあるため注意が必要である。 著者抄録• BACKGROUND: We report a rare case of sudden bilateral vision loss due to third ventricular cavernous angioma with intratumoral hemorrhage. CASE PRESENTATION: A 45-year-old woman presented decreased visual acuity in both eyes. Her best corrected visual acuity was 0. 1 in the right eye and 0. 15 in the left eye. Goldmann perimetry showed bilateral central scotomas and bitemporal visual field defects. MRI demonstrated a lesion with mixed hypo- and hyperintensity at the optic chiasm, which was thought to be an intratumoral hemorrhage. The patient underwent bifrontal craniotomy. The tumor was exposed via an anterior interhemispheric approach, and histological evaluation of the mass led to a diagnosis of cavernous angioma. Six months after the surgery, her best corrected visual acuity was 0. 9 in the right eye and 0. 9 in the left, with slight bitemporal visual field defects. CONCLUSION: Third ventricular cavernous angioma is considered in the differential diagnosis of chiasmal syndrome. Contrast-enhanced MRI and FDG-PET might be useful for differential diagnosis of cavernous angioma from other chiasmal tumors including glioblastoma. Precis: A positive correlation was observed between intraocular pressure IOP and central venous pressure CVP in patients with single ventricle SV during the perioperative period. IOP needs to be carefully monitored in the postoperative period after the Glenn and Fontan procedures, particularly the Glenn procedure. Purpose: SV is a cardiac malformation characterized by the existence of only 1 functional ventricle and is treated using the Glenn and Fontan procedures. Significant changes occur in CVP after these procedures. IOP has been reported to differ in the same individual when measured in a seated or supine position, which may be related to CVP. In the present study, we examined the relationship between CVP and IOP before and after surgery for SV. Patients and Methods: This study was a prospective, nonrandomized case series. All patients had SV and this study excluded those with eye diseases associated with ocular hypertension. We measured IOP before and after the Glenn or Fontan procedure. CVP was concurrently monitored. 7 months for the Glenn procedure and 24. 7 months for the Fontan procedure. A correlation was observed between CVP and IOP in the perioperative period. Conclusions: Elevations in CVP significantly increased IOP in patients with SV who underwent the Glenn or Fontan procedure. IOP needs to be carefully monitored in the postoperative period after both procedures. Purpose: Relentless placoid chorioretinitis RPC is a new disease concept that was proposed by Jones et al. in 2000. Some cases of RPC have been reported; however, a treatment strategy has not yet been established. We report herein four cases of patients diagnosed with RPC. Observations: We experienced four cases of RPC in patients aged 24-51 years. All patients exhibited retinal lesions similar to that seen in acute posterior multifocal placoid pigment epitheliopathy or serpiginous choroiditis from the posterior pole to the surrounding region. Although patients underwent systemic prednisolone PSL therapy, recurrence was observed and the retinal scar formation was progressive; they were then diagnosed with RPC. In all cases, cyclosporine CyA was administered in addition to PSL, no recurrence was observed thereafter. Conclusions and Importance: RPC is a rare disease, and a treatment strategy has not yet been established. CyA and PSL combination therapy is considered to be effective in the treatment of RPC. PURPOSE: To evaluate corneal tactile and pain sensations in patients with short tear film break-up time dry eye sBUT DE. METHODS: This study enrolled 60 patients with sBUT DE and 46 healthy volunteers from Japan. We evaluated corneal tactile and pain sensations using a modified method with the Cochet-Bonnet corneal esthesiometer. RESULTS: Patients with sBUT DE had higher corneal pain sensitivity 26. 1 mm than healthy subjects 6. 4 mm , but similar corneal tactile sensation 52. 5 mm and 52. 9 mm, respectively. However, for the entire cohort, we found a weak positive correlation between the subjective pain score and objective corneal pain sensation. CONCLUSIONS: Patients with sBUT DE were hypersensitive to corneal pain, which suggested that corneal hyperalgesia partly accounted for subjective symptoms in patients with sBUT DE. Pro renin receptor [ P RR], a new component of the tissue renin-angiotensin system RAS , plays a crucial role in inflammation and angiogenesis in the eye, thus contributing to the development of proliferative diabetic retinopathy PDR. In this study, we investigated systemic factors related to plasma levels of soluble form of P RR [s P RR] in patients with PDR. Twenty type II diabetic patients with PDR and 20 age-matched, non-diabetic patients with idiopathic macular diseases were enrolled, and plasma levels of various molecules were measured by enzyme-linked immunosorbent assays. Human retinal microvascular endothelial cells were stimulated with several diabetes-related conditions to evaluate changes in gene expression using real-time quantitative PCR. Of various systemic parameters examined, the PDR patients had significantly higher blood sugar and serum creatinine levels than non-diabetic controls. Protein levels of s P RR, prorenin, tumor necrosis factor TNF -alpha, complement factor D CFD , and leucine-rich alpha-2-glycoprotein 1 LRG1 significantly increased in the plasma of PDR subjects as compared to non-diabetes, with positive correlations detected between s P RR and these inflammatory molecules but not prorenin. Estimated glomerular filtration rate and serum creatinine were also correlated with plasma s P RR, but not prorenin, levels. Among the inflammatory molecules correlated with s P RR in the plasma, TNF-alpha, but not CFD or LRG1, application to retinal endothelial cells upregulated the mRNA expression of P RR but not prorenin, while stimulation with high glucose enhanced both P RR and prorenin expression. These findings suggested close relationships between plasma s P RR and diabetes-induced factors including chronic inflammation, renal dysfunction, and hyperglycemia in patients with PDR. The purpose of this study was to report the clinical outcomes of patients with conjunctival melanoma treated with interferon IFN alpha-2b eye drops following local tumor resection. Five eyes of five patients were enrolled in this study. Ophthalmological findings, histopathological findings, and imaging modalities were retrospectively analyzed. The age of the patients ranged from 65 to 84 years mean: 75. 4 years. Locations of the tumor were the bulbar conjunctiva in three eyes, multiple palpebral conjunctivas in one eye, and palpebral conjunctiva and caruncle in one eye. All patients received topical IFN alpha-2b eye drop treatment for 6-10 months. Follow-up periods after resection ranged from 18 to 78 months. Histologically, all excised conjunctival tumors were diagnosed with malignant melanoma, where the surgical margins were completely negative in one patient. No patients had suffered from severe adverse effects related to IFN alpha-2b. Four out of five patients consequently achieved complete remission. Since one eye in one case showed resistance to the local chemotherapy containing IFN alpha-2b eye drops and the subconjunctival injection of IFN-beta, orbital exenteration was eventually required 12 months after local resection. Topical IFN alpha-2b eye drops may be safe and one of the useful adjunctive treatments following surgical resection for patients with conjunctival melanoma. Diabetic retinopathy DR is an inflammatory and progressive vaso-occlusive disease resulting in angiogenesis. Galectin-1 is a hypoxia-induced angiogenic factor associated with cancer and proliferative DR. Here we reveal a significant upregulation of galectin-1 in eyes of DR patients along with progression of clinical stages beginning from the pre-ischemic, inflammatory stage with diabetic macular edema, but not in eyes with non-diabetic retinal vascular occlusions. In vivo inhibition of AGE generation with aminoguanidine, macrophage depletion with clodronate liposomes, and antibody-based blockade of Il-1 beta and Tlr4 attenuated diabetes-induced retinal Lgals1 expression in mice. Fibrovascular tissues from proliferative DR eyes were immunoreactive for AGE, TRL4 and IL-1 beta in macrophages, and IL-1 beta receptor-positive glial cells expressed galectin-1. Therefore, diabetes-induced retinal AGE accumulation was suggested to activate IL-1 beta-related inflammatory cues in macrophages followed by Muller cells, linking to galectin-1 upregulation in human DR with time. Our data highlight AGE-triggered inflammation as the DR-selective inducer of galectin-1. The aim of this study was to disclose results of FCM, which were compared among IgG4-related ophthalmic disease IgG4-ROD , idiopathic orbital inflammation IOI , and extranodal marginal zone B-cell lymphoma EMZL. Materials and Methods: This is a retrospective observational study. Sixty-nine tumors comprising of 16 IgG4-ROD, 24 IOI, and 29 EMZL were enrolled in the study. All tumors, surgically excised, were diagnosed based on histopathology, immunoglobulin Ig heavy chain gene rearrangement, and FCM. 05 in every factor. There was no significant difference in any marker between IgG4-ROD and IOI. Sensitivity and specificity of Ig light chain restriction were 65. 5 and 92. Sensitivity of Ig light chain restriction was relatively low in diagnosis of EMZL using FCM. The receptor-associated prorenin system RAPS refers to the pathogenic mechanism whereby prorenin binding to the pro renin receptor [ P RR] dually activates the tissue reninangiotensin system RAS and RAS-independent intracellular signaling. Here we revealed significant upregulation of prorenin and soluble P RR levels in the vitreous fluid of patients with uveitis compared to non-inflammatory controls, together with a positive correlation between these RAPS components and monocyte chemotactic protein-1 among several upregulated cytokines. Moreover, we developed a novel single-strand RNAi agent, proline-modified short hairpin RNA directed against human and mouse P RR [ P RR-PshRNA], and we determined its safety and efficacy in vitro and in vivo. Application of P RR-PshRNA in mice caused significant amelioration of acute uveitic and chronic diabetic models of ocular inflammation with no apparent adverse effects. Our findings demonstrate the significant implication of RAPS in the pathogenesis of human uveitis and the potential usefulness of P RR-PshRNA as a therapeutic agent to reduce ocular inflammation. PURPOSE. To investigate the effect of the vascular adhesion protein-1 VAP-1 inhibitor RTU-1096 on retinal morphologic changes and ocular inflammation after retinal laser photocoagulation in mice. METHODS. Laser photocoagulation was performed on the peripheral retina of the animals. The semicarbazide sensitive amine oxidase SSAO activities in plasma and chorioretinal tissues were measured. Optical coherence tomography OCT images were acquired before and at 1, 3, and 7 days after laser photocoagulation, and thickness of the individual retinal layers was measured. Intravitreal leukocyte infiltration was assessed by histologic analysis. The expression level of intercellular adhesion molecule-1 ICAM-1 in retinal tissues were examined by quantitative real-time PCR. RESULTS. One day after laser photocoagulation, the thickness of the outer nuclear layer ONL increased in the laser group compared with in the control group, and RTU-1096 administration abrogated the ONL thickening. Histologic analysis and OCT observation revealed that laser photocoagulation caused infiltration of inflammatory cells and the appearance of hyperreflective foci at the vitreoretinal surface, both of which were suppressed by RTU-1096 administration. In addition, systemic administration of RTU-1096 reduced upregulation of the leukocyte adhesion molecules ICAM-1 in the retina. CONCLUSIONS. It has been demonstrated that topical administration of rebamipide, which is an antiulcer agent, increases the mucin level of the tear film and ameliorates ocular surface conditions such as lid wiper epitheliopathy. The aim of the present study was to analyze the changes in goblet cell number, cell proliferation, and epidermal growth factor receptor EGFR induced by topical rebamipide addition to the lid wiper of humans. A total of 30 eyelid tissue samples were obtained during involutional entropion surgeries, fixed in paraformaldehyde, embedded in paraffin and divided into two groups: Rebamipide or non-rebamipide. The tissues in the rebamipide group were obtained from patients who had a medical history of topical rebamipide use prior to surgery. The number of goblet cells was counted under light microscopy. A total of 22 eyelid tissue samples were further examined using immunohistochemistry with anti-Ki-67 and anti-EGFR antibodies to evaluate cell proliferation and EGFR expression, respectively. Histologically, the lid wiper and palpebral conjunctiva were clearly identified in the tissues. 0367. There was no significant difference in lid wiper cell proliferation between the rebamipide and non-rebamipide groups. 0237. These results suggest that topical rebamipide application increases the number of goblet cells in the lid wiper, which in turn upregulates the expression of EGFR. These findings may be clinically relevant and provide a therapeutic basis for the treatment of ocular disease such as dry eye and lid wiper epitheliopathy. Background: Choroidal circulation hemodynamics in eyes with ocular blunt trauma has not been quantitatively examined yet. We quantitatively examined changes in choroidal blood flow velocity and thickness at the lesion site using laser speckle flowgraphy LSFG and enhanced depth imaging optical coherence tomography EDI-OCT in a patient with chorioretinopathy associated with ocular blunt trauma. Case presentation: A 13-year-old boy developed a chorioretinal lesion with pigmentation extending from the optic disc to the superotemporal side in the right eye after ocular blunt trauma. The patient's best-corrected visual acuity BCVA was 0. 2 in the right eye. Indocyanine green angiography showed hypofluorescence from the initial phase, with a decrease of mean blur rate MBR on LSFG color map, which corresponded to the chorioretinal lesion. The BCVA and foveal outer retinal morphologic abnormality spontaneously improved during follow-up. In contrast, these parameters showed little or no changes at the normal retinal site in the affected eye and the fovea in the fellow eye. Conclusions: Current data revealed that both blood flow velocity and thickness in the choroid at the lesion site decreased in the acute stage and subsequently increased together with improvements in visual function and outer retinal morphology. These results suggest that LSFG and EDI-OCT may be useful indices that can noninvasively evaluate activity of choroidal involvement in ocular blunt trauma-associated chorioretinopathy. Background: The efficacy of epinastine 0. The present study investigated the efficacy of this solution against birch pollen conjunctivitis in a CAC test. Methods: Ten adult subjects eight males and two females with asymptomatic birch pollen conjunctivitis were enrolled in this study. The average age of the subjects was 41. 1 years. This study was conducted during a period without birch pollen dispersion. In each subject, the epinastine 0. Five minutes or 4 h after the drug instillation, both eyes were challenged with an optimal concentration of birch pollen, and ocular itching and conjunctival hyperemia were then graded. Tears were collected before the drug instillation and 20 min after the pollen challenge, and the histamine level was measured. Results: The ocular itching scores and palpebral conjunctival hyperemia scores of the epinastine-treated eyes were significantly lower than those of the contralateral control eyes when the eyes were pretreated with the drug 4 h before the CAC. There was a significant correlation between the tear histamine level and mean ocular itching score of three time points 3, 5 and 10 min following the CAC in the control eyes but not the epinastine-treated eyes. Conclusions: Epinastine is effective in suppressing ocular itching and conjunctival hyperemia in birch pollen conjunctivitis. Copyright C 2017, Japanese Society of Allergology. Production and hosting by Elsevier B. Receptor-associated prorenin system RAPS refers to the pathogenic mechanism whereby prorenin binding to pro renin receptor [ P RR] dually activates tissue renin-angiotensin system RAS and RASindependent signaling via P RR. The aim of this study is to determine the association of RAPS with idiopathic epiretinal membrane iERM. Reverse transcription-PCR indicated the expression of RAPS components, including P RR and Ang II type 1 receptor AT1R , in iERM tissues and human Muller glial cell line. Double-labeling analyses demonstrated that P RR and AT1R were detected in cells positive for glial fibrillary acidic protein, a marker for glial cells, and co-localized with prorenin and angiotensinogen, respectively. Administration of prorenin to Muller glial cells enhanced mRNA expression of fibroblast growth factor 2, while Ang II application stimulated the expression of glial cell line-derived neurotrophic factor, nerve growth factor, and transforming growth factor-alpha 1. These expression levels induced by prorenin or Ang II were reversed by P RR or AT1R blockade, respectively. Immunofluorescence revealed tissue co-localization of P RR and AT1R with the products of the upregulated genes in vitro. The present findings suggest the involvement of RAPS in the pathogenesis of iERM. Purpose To determine if early post-treatment central choroidal thickness CCT changes can predict sunset glow fundus SGF development in patients with Vogt-Koyanagi-Harada VKH disease treated using systemic corticosteroids. Methods This retrospective case series included 39 eyes of 21 treatment-naive patients with acute VKH disease who could be followed up for more than 12 months after systemic corticosteroid therapy. The eyes were divided into two groups according to whether SGF was present or absent at 12 months 9 eyes of 5 patients versus 30 eyes of 16 patients, respectively. Using enhanced depth imaging optical coherence tomography, CCT values were measured before treatment, then at 1 week and 1 and 3 months after treatment in both groups and compared between the two groups. Results Development of SGF was found 4-11 months after treatment. Mean post-treatment CCT decreased significantly at all examinations compared with baseline in both groups, along with resolution of serous retinal detachment. 024. 003. Conclusions The current study suggested the potential validity of early post-treatment CCT as a feasible index to alert future progression to SGF in patients with VKH disease treated using systemic corticosteroids. Purpose: Behcet disease BD is predominantly found between East Asia and the Mediterranean basin along the historic Silk Road. HLA-B51 is known to be strongly associated with BD. We investigated the association between HLA-B51 and the ocular manifestations of BD among various ethnic groups. Methods: A literature survey was conducted, and 18 articles written in English were reviewed. 000057. 35 areas. This correlation seemed to become stronger towards the east. Conclusions: A meta-analysis showed that the correlation became stronger towards the east along the Silk Road. The study results may facilitate understanding of the etiology and characteristics of BD. Purpose: To determine the presence of N-epsilon- 3-formyl-3,4-dehydropiperidino lysine adduct FDP-Lys , unsaturated aldehyde acrolein-derived lipoxidation end-product, in fibrovascular tissues obtained from patients with proliferative diabetic retinopathy PDR. Methods: Fibrovascular tissues were collected from 11 eyes of 11 patients with PDR and paraffin-embedded tissue sections were prepared. Tissue localization of FDP-Lys was studied by immunohistochemistry. Signal intensity was quantified by two masked evaluators and graded into three discrete categories. The relationship between FDP-Lys staining and vascular density was analyzed. In addition, subcellular localization of FDP-Lys was studied by immunofluorescent microscopy. The impact of acrolein on cell viability and proliferation was assessed and the expression level of heme oxygenase-1 HO-1 mRNA was quantified by real-time polymerase chain reaction PCR in cultured retinal microvascular endothelial cells. Results: In fibrovascular tissues, FDP-Lys staining was found in vascular components containing CD34-positive cells and alpha smooth muscle actin -SMA -positive cells, and clusters of rabbit anti-glial fibrillary acid protein GFAP -positive cells. Immunofluorescent staining depicted subcellular localization of FDP-Lys in the nucleus and cytoplasm of the cells. Morphological analysis revealed that fibrovascular tissues with FDP-Lys staining in vascular components showed high vascular density. Exposure of cultured endothelial cells to high concentration of acrolein resulted in the decrease of cell viability and proliferation, whereas lower concentration of acrolein increased cell viability and proliferation. Sublethal concentration of acrolein upregulated HO-1 mRNA expression in retinal microvascular endothelial cells. Conclusions: The current data demonstrated the presence of FDP-Lys in fibrovascular tissues and indicate its involvement in fibrovascular proliferation in PDR. Purpose: Environmental and lifestyle changes influence the clinical features of uveitis. This study reviewed the epidemiologic trends of uveitis in the Japanese population. Methods: A retrospective review of the past 80 years of reports from Hokkaido University Hospital. The three most common specific diagnoses were: sarcoidosis, Vogt-Koyanagi-Harada disease, and Behcet disease. Although Behcet disease was the most frequent non-infectious uveitis until the 1980s, sarcoidosis is now the most frequent cause of newly diagnosed non-infectious uveitis. Conclusions: The etiology of uveitis has changed with the times. Tubercular and syphilitic cases have greatly decreased, and sarcoidosis is the most frequent type of uveitis today. To elucidate the current clinical practice patterns of diabetic macular edema DME management by retinal specialists in Japan in the era of anti-vascular endothelial growth factor VEGF therapy. Forty-six retinal specialists were administered a survey regarding the pathology and clinical practice of DME. Nearly, half of the specialists 45. Most specialists 70. For focal macular edema, focal laser is used as first-line therapy by 70. For diffuse macular edema, anti-VEGF therapy is the first choice 72. Vitrectomy is often performed for vitreomacular traction 86. For persistent DME after vitrectomy, anti-VEGF agents 46. When applying anti-VEGF treatment regimen, most specialists continue loading injections until central retinal thickness stabilized 51. In the maintenance phase, many specialists provide injections with pro re nata 76. Our survey presents the current views about the DME management and practice patterns of anti-VEGF therapy by one part of the retinal specialists in Japan, and highlights the differences or gaps between evidence and actual clinical practice. Purpose. To evaluate sequential changes in choroidal thickness at the affected area in patients with acute zonal occult outer retinopathy AZOOR. Methods. This retrospective observational case series included 14 affected eyes and 6 unaffected fellow eyes from 10 AZOOR patients with impaired macular area. Using enhanced depth imaging optical coherence tomography, choroidal thicknesses at the subfovea and at nasal and temporal sites 1000 mu m away from the fovea were manually measured at baseline and 3 and 6 months thereafter. Changes in the choroidal thicknesses and the average threshold at the affected area on Humphrey perimetry were compared during the 6-month follow-up. Results. In AZOOR eyes, the average threshold at the affected area significantly increased over time, while outer retinal structure ameliorated. The mean choroidal thicknesses at all the sites measured significantly decreased at 3 and 6 months compared with baseline values in AZOOR eyes, but not in fellow eyes. There was an inverse correlation between the changing rates of the average threshold and the subfoveal choroidal thickness at 6 months from baseline. Conclusion. The current data suggest that choroidal thickness at AZOOR-affected area significantly decreased with regression of AZOOR and this anatomical change correlated with the functional recovery. Purpose: To evaluate the safety and tolerability of conjunctival rings CRs , a novel device for drug delivery to the posterior segment of the eye. Contact lenses CLs containing vehicle solution were used as a control. Twenty-four hours after placement of the CRs, corneal fluorescein staining was graded based on the McDonald-Shadduck scoring system, ranging from 0 to 4. In humans, CRs containing vehicle solution were placed on the right eye of healthy volunteers for 9 hours. The corneal curvature, corneal thickness, intraocular pressure, visual acuity, tear production Schirmer I test , tear film break-up time and fluorescein staining scores of the cornea scores ranging from 0 to 3 and conjunctiva scores ranging from 0 to 6 were assessed before and after wearing the CRs. The release characteristics of DSP from CRs were also evaluated. Results: In animal experiments, corneal fluorescein staining scores were 1 or less in all the groups, and there was no significant difference between the CR group and the CL group. The DSP release from CRs occurs within a few hours, which is similar to the drug-release property of medicated CL, as reported previously. Conclusions: The current data showed the safety and tolerability of CR as a drug delivery device for the treatment of posterior segment diseases. Natural killer T NKT cells recognize lipid antigens and produce large amounts of cytokines upon activation. NKT cell-deficient mice developed more severe EAU pathology than WT mice. When WT mice were treated with ligands of the invariant subset of NKT cells alpha-GalCer or RCAI-56 , EAU was ameliorated in mice treated with RCAI-56 but not alpha-GalCer. Moreover, the eyes of RCAI-56-treated mice contained fewer IRBP-specific T cells compared with control mice. These results suggest that invariant NKT iNKT cells suppress the induction of Th17 cells and infiltration of IRBP-specific T cells into the eyes, thereby reducing ocular inflammation. However, in sharp contrast to the ameliorating effects of iNKT cell activation during the initiation phase of EAU, iNKT cell activation during the effector phase exacerbated disease pathology. Thus, we conclude that iNKT cells exhibit dual roles in the development of EAU. C 2016 Elsevier Ltd. All rights reserved. PurposeTo assess choroidal inflammation-related circulatory changes associated with the anterior recurrence of Vogt-Koyanagi-Harada VKH disease, using indocyanine green angiography ICGA and laser speckle flowgraphy LSFG. MethodsThis retrospective case series included 17 eyes of 11 patients with VKH disease showing recurrent inflammatory findings in the anterior, but not posterior, segment i. anterior recurrence. Indocyanine green angiography ICGA and LSFG were performed at the time of recurrence and one month after the initiation of corticosteroid therapy. The number and total area of hypofluorescent dark dots HDDs on ICGA were independently counted by three physicians and measured with ImageJ, respectively. Mean blur rate MBR , a quantitative index of relative blood flow velocity, was calculated via the LSFG Analyzer software. The change ratio of MBR significantly increased by 17. Importantly, there was no significant association between the change ratios of HDDs and MBR. ConclusionsThese findings on LSFG and ICGA clearly demonstrated subclinical involvement as well as post-treatment improvement of choroidal circulation impairment due to granulomatous inflammation in eyes with the anterior recurrence of VKH disease. The present data suggest the validity of using these two examinations, capable of detecting different circulatory changes, in the management of recurrent VKH disease. PURPOSE: To assess the efficacy and safety of a modified 360-degree suture trabeculotomy combined with a cataract surgery technique in patients with glaucoma and coexisting cataract. SETTING: Hokkaido University Hospital, Sapporo, Japan. DESIGN: Retrospective case series. METHODS: Medical records of patients with glaucoma having a modified 360-degree trabeculotomy combined with cataract surgery Group 1 were reviewed. Another group of patients who had the modified 360-degree suture trabeculotomy alone served as controls Group 2. RESULTS: Both groups comprised 46 patients. In each group, eyes were diagnosed with primary angle-closure glaucoma in 2 eyes, primary open-angle glaucoma in 24 eyes, exfoliation glaucoma in 4 eyes, uveitic glaucoma in 15 eyes, and steroid glaucoma in 1 eye. The mean preoperative intraocular pressure IOP values were 27. 3 SD on 3. 5 medications in Group 1 and 27. 7 mm Hg on 2. 6 medications in Group 2. Twelve months after surgery, the mean IOPs were 13. 7 mm Hg on 0. 1 medications in Group 1 and 13. 1 mm Hg on 0. 9 medications in Group 2. Major complications included transient IOP spikes 30. CONCLUSION: The data showed the equivalent effects of suture trabeculotomy combined with cataract surgery and suture trabeculotomy surgery alone on postoperative safety and efficacy. Glaucoma is characterized by axonal degeneration of retinal ganglion cells RGCs and apoptotic death of their cell bodies, and lowering intraocular pressure is associated with an attenuation of progressive optic nerve damage. Nevertheless, intraocular pressure IOP reduction alone was not enough to inhibit the progression of disease, which suggests the contribution of other factors to the glaucoma pathogenesis. At 5 weeks after birth, the number of RGCs was counted in paraffin sections of retinal tissues stained with hematoxylin and eosin. In addition, retrograde labeling technique was also used to quantify the number of RGC. Expression and localization of heat shock protein 70 HSP70 in retinas were evaluated by reverse transcription polymerase chain reaction and immunohistochemistry, respectively. Activities of caspase-9 and -3 in retinas were also assessed. Following GGA administration, HSP70 was significantly upregulated together with reduction in the activities of caspase-9 and -3. Our studies highlight HSP70 induction in the retina is available to suppress RGC degeneration, and thus GGA may be applicable for NTG as a promising therapy. Horie Y, Kitaichi N, Hijioka K, Sonoda KH, Saishin Y, Kezuka T, Goto H, Takeuchi M, Nakamura S, Kimoto T, Shimakawa M, Kita M, Sugita S, Mochizuki M, Hori J, Iwata M, Shoji J, Fukuda M, Kaburaki T, Numaga J, Kawashima H, Fukushima A, Joko T, Takai N, Ozawa Y, Meguro A, Mizuki N, Namba K, Ishida S, Ohno SClinical and experimental rheumatology 34 6 Suppl 102 111 - 114 2016年09月 [査読有り][通常論文]• Vascular endothelial growth factor C VEGF-C plays an important role in the development of a pterygium through lymphangiogenesis. We examined the association between VEGF-C and tumor necrosis factor- TNF- in the pathogenesis of pterygia. Cultured conjunctival epithelial cells were treated with TNF-, and the gene expression levels of VEGFC were evaluated by quantitative polymerase chain reaction qPCR and VEGF-C protein expression levels were measured using an enzyme-linked immunosorbent assay ELISA. In addition, using ELISA, we evaluated the VEGF-C protein expression in the supernatants of cultured conjunctival epithelial cells, in which we neutralized TNF- using anti-TNF- antibody. The gene expression of tumor necrosis factor receptor superfamily, member 1A TNFRSF1A , known as TNF receptor 1 TNFR1 , was confirmed using reverse transcription PCR in cultured conjunctival epithelial cells. Immunofluorescence microscopy was used to examine the localization of VEGF-C and TNFR1 in pterygium tissues and TNFR1 expression in cultured conjunctival epithelial cells. Immunohistochemistry was used to examine the localization of TNFR1 in pterygia and normal conjunctival tissues. VEGFC gene expression increased in cultured conjunctival epithelial cells 24 h after the addition of TNF-. The secretion of VEGF-C protein was significantly increased 48 h after the stimulation of cultured conjunctival epithelial cells with TNF-. Increased VEGF-C protein secretion stimulated by TNF- was significantly reduced by anti-TNF- neutralizing antibody treatment. In cultured conjunctival epithelial cells, TNFRSF1A and TNFR1 were expressed. TNFR1 was immunolocalized in normal conjunctival tissues and in human pterygium tissues as well as in VEGF-C-positive epithelial cells from human pterygia. Our data demonstrate that TNF- mediates VEGF-C expression, which plays a critical role in the pathogenesis of pterygia. AIM: To examine phosphorylation of alphaB-crystallin p-alpha BC , a vascular endothelial growth factor VEGF chaperone, and immunohistochemically investigate relationship between p-alpha BC, VEGF and phosphorylated p38-mitogen-activated protein kinase p-p38 MAPK in the epiretinal membrane of human proliferative diabetic retinopathy PDR. METHODS: Eleven epiretinal membranes of PDR surgically excised were included in this study. Two normal retinas were also collected from enucleation tissues due to choroidal melanoma. Paraformaldehyde-fixed, paraffin-embedded tissue sections were processed for immunohistochemistry with anti-p-alpha BC, VEGF, CD31, and p-p38 MAPK antibodies. The immunolocalization of p-alpha BC was detected in the CD31-positive endothelial cells, and co-localized with VEGF and p-p38 MAPK in PDR membranes. Immunoreactivity for p-alpha BC, however, was undetectable in endothelial cells of the normal retinas, where p-p38 MAPK immunoreactivity was less marked than PDR membranes. CONCLUSION: Phosphorylation of alpha BC, in particular, phosphorylation on Ser59 by p-p38 MAPK may play a potential role as a molecular chaperon for VEGF in the pathogenesis of epiretinal membranes in PDR. Purpose To quantitatively examine changes in choroidal circulation hemodynamics in patients with acute posterior multifocal placoid pigment epitheliopathy APMPPE. Methods Retrospective observational case series. Five eyes of 3 APMPPE patients were included. In all APMPPE eyes, laser speckle flowgraphy was conducted to evaluate the mean blur rate MBR , a quantitative index of relative blood flow velocity. The changes in MBR at the initial visit and after 3 and 6 months were statistically analyzed. In 2 eyes, enhanced depth imaging optical coherence tomography was used to measure central choroidal thickness. Results In all eyes, multiple subretinal placoid lesions spontaneously regressed with recovery of outer retinal morphology. The average MBR significantly increased at 3 and 6 months after baseline at the fovea by 49. 6 and 54. 2 and 70. 02 for each. The mean central choroidal thickness decreased with time 518. 0 A mu m at baseline to 344. 5 A mu m at 6 months. Conclusions Our data revealed the significant elevation of choroidal blood flow velocity and the substantial reduction of choroidal thickness with regression of APMPPE, suggesting that impaired choroidal circulation is involved in the pathogenesis of APMPPE. PURPOSE. To evaluate intraocular pressure IOP changes during nocturnal sleep in patients with obstructive sleep apnea syndrome OSAS using a contact lens sensor CLS. METHODS. This was a prospective cohort study. Seven OSAS patients who had no ocular diseases except mild cataract were enrolled. Each subject underwent CLS-based continuous IOP monitoring on one eye simultaneously with overnight polysomnography. We classified the nocturnal IOP records into nonapnea IOP and apnea IOP, according to the duration of apnea events on polysomnography within each IOP measurement time of 30 seconds every 5 minutes. RESULTS. Differences between IOP levels during nonapnea and apnea phases were statistically analyzed. The mean apnea-hypopnea index, the total number of these events per hour of sleep, was 44. 0, indicating the participants' severity of OSAS as moderate to severe. The mean range of IOP fluctuations during nocturnal sleep was 22. 5 mV eq. All patients showed lower mean IOP levels during apnea events than during nonapnea phases, with statistically significant differences detected in four of the seven patients. On average, in all seven eyes, IOP values significantly decreased by 23. 4 mV eq in association with apnea events. CONCLUSIONS. Obstructive apnea led to an immediate IOP decline during nocturnal sleep in patients with OSAS. Attention should be paid to IOP-independent etiology, such as episodic hypoxia, potentially linking OSAS and glaucoma. Aim To assess choroidal thickness changes associated with anterior segment recurrences in patients with Vogt-Koyanagi-Harada VKH disease using enhanced depth imaging optical coherence tomography EDI-OCT. Methods EDI-OCT images were obtained periodically from 11 patients with VKH disease 22 eyes who were followed-up due to anterior segment recurrences. Subfoveal choroidal thickness SCT values at the following stages were evaluated: 1 during the remission phase, 2 1 month before detecting the anterior recurrence, 3 during the anterior recurrence and 4 after systemic prednisolone PSL treatment leading to remission. In comparison with SCT values in remission as baseline, the changing ratios of SCT were statistically analysed at subsequent three stages. Results The average of the SCT changing ratios compared with the remission phase significantly increased to 1. 00044 lacking any funduscopic signs of posterior involvement. Interestingly, the average SCT ratio 1 month before detecting the recurrence had already increased to 1. 002. After the PSL treatment, the ratio of SCT recovered to 0. 03, which was equivalent to the remission level. However, in patients with their remission SCT values less than 240 mm, the SCT ratio did not increase significantly at any time points evaluated. Conclusions The choroid in eyes with VKH disease thickened in association with the anterior segment recurrence, and this thickening was observed prior to the recurrence. EDI-OCT may be useful for detecting latent choroidal inflammation in VKH disease, whereas it may not for patients with the relatively thin choroid. Background: Vitreoretinal lymphoma VRL is a life- and sight-threatening disorder. The aim of this study was to analyze the usefulness of the cell block method for diagnosis of VRL. Methods: Sixteen eyes in 12 patients with VRL, and 4 eyes in 4 patients with idiopathic uveitis presenting with vitreous opacity were enrolled in this study. Both undiluted vitreous and diluted fluids were isolated during micro-incision vitrectomy. Cell block specimens were prepared in 19 eyes from diluted fluid containing shredding vitreous. These specimens were then submitted for HE staining as well as immunocytological analyses with antibodies against the B-cell marker CD20, the T-cell marker CD3, and cell proliferation marker Ki67. Conventional smear cytology was applied in 14 eyes with VRL using undiluted vitreous samples. The diagnosis of VRL was made based on the results of cytology, concentrations of interleukin IL -10 and IL-6 in undiluted vitreous, and immunoglobulin heavy chain gene rearrangement analysis. Results: Atypical lymphoid cells were identified in 14 out of 15 cell block specimens of VRL positive rate: 93. Atypical lymphoid cells showed immunoreactivity for CD20 and Ki67. Seven cell block specimens were smear cytology-negative and cell block-positive. The cell block method showed no atypical lymphoid cells in any patient with idiopathic uveitis. Conclusions: Cell block specimens using diluted vitreous fluid demonstrated a high diagnostic sensitivity and a low pseudo-positive rate for the cytological diagnosis of VRL. The cell block method contributed to clear differentiation between VRL and idiopathic uveitis with vitreous opacity. Purpose: To investigate the alteration of N-glycans in the vitreous fluid of patients with neovascular glaucoma NVG secondary to proliferative diabetic retinopathy PDR. Methods: Vitreous samples were collected from 18 patients with PDR including 7 with NVG and 11 without NVG , and 17 patients without diabetes. Profiles of N-glycans were analyzed by glycoblotting-based high throughput protocol, which we recently developed. Protein levels of vascular endothelial growth factor VEGF -A were measured by ELISA. Results: The concentration of total N-glycans and the concentration of N-glycans with sialic acids were significantly higher in NVG group compared with those in non-NVG group or control group, whereas there was no significant difference in concentrations of high-mannose N-glycans among three groups. There was a moderate correlation between the concentrations of sialylated N-glycans and VEGF-A. Conclusions: Our data demonstrate the distinct changes of N-glycan profile and the increase of sialylated N-glycans in eyes with NVG secondary to PDR. Vascular endothelial growth factor VEGF -A-driven angiogenesis contributes to various disorders including cancer and proliferative diabetic retinopathy PDR. Here, we revealed a novel anti-angiogenic function for aflibercept beyond its antagonism against VEGF family members. Immunoprecipitation and mass spectrometry analyses identified galectin-1 as an aflibercept-interacting protein. Biolayer interferometry revealed aflibercept binding to galectin-1 with higher affinity than VEGFR1-Fc and VEGFR2-Fc, which was abolished by deglycosylation of aflibercept with peptide: N-glycosidase F. Galectin-1 immunoreactivity co-localized with VEGFR2 in neovascular tissues surgically excised from human eyes with PDR. Compared with non-diabetic controls, intravitreal galectin-1 protein levels were elevated in PDR eyes, showing no correlation with increased VEGF-A levels. Preoperative injection of bevacizumab, a monoclonal antibody to VEGF-A, reduced the VEGF-A, but not galectin-1, levels. Galectin-1 application to human retinal microvascular endothelial cells up-regulated VEGFR2 phosphorylation, which was eliminated by aflibercept. Our present findings demonstrated the neutralizing efficacy of aflibercept against galectin-1, an angiogenic factor associated with PDR independently of VEGF-A. Background: Which of the choroidal layers suffers the most extensive morphological changes during the course of Vogt-Koyanagi-Harada VKH disease is still unknown. The aim of this study was to investigate the relationship between total thickness and the thickness of inner or outer layers in the choroid during systemic corticosteroid therapy in patients with VKH disease. Methods: This retrospective case series included 15 eyes of 10 patients with treatment-naive VKH disease 4 men and 6 women; mean age, 41. 7 years received systemic corticosteroid therapy. Whole, inner, and outer choroidal thickness was measured manually at 1 week and at 1 and 3 months after initiation of systemic corticosteroid therapy using enhanced depth imaging optical coherence tomography. The mean thickness values of the layers were compared at each stage. 008 and 0. 008 and 0. 02, respectively , whereas the inner layer did not significantly thin. 0001 , but not between the rates of whole and inner layer thickness changes. Conclusions: The thinning of total choroidal thickness observed after treatment with corticosteroids strongly correlated with outer layer thinning, suggesting that the choroidal outer layer is the primary target in acute-stage VKH disease. PURPOSE. To quantitatively evaluate the pulse waveform changes in macular choroidal blood flow by using laser speckle flowgraphy LSFG with regression of acute central serous chorioretinopathy CSC. METHODS. This retrospective observational case series included 20 eyes of 20 patients with acute CSC. Laser speckle flowgraphy was performed at baseline and after 6 months. On the LSFG monochrome map, automatically divided 5 x 5 grid segments within the macula were classified into predominantly delayed filling PDF or minimally or no delayed filling MDF areas according to the degree of choroidal filling delay on early-phase indocyanine green angiography. The average mean blur rate MBR and the pulse waveform parameters, including the skew and blowout time BOT , were compared between the total PDF and MDF areas during follow-up. RESULTS. 001 for each , showing significant reduction in vascular resistance at 6 months. 001, respectively in the PDF area than in the MDF area. CONCLUSIONS. Changes in the skew and BOT, indices for vascular resistance, confirmed the involvement of circulatory disturbance at the acute stage of CSC. The present findings suggested that the pathogenesis of CSC stems from imbalanced distribution of choroidal blood flow due to augmented vascular resistance. On the basis of angiographic features, it is suggested that choroidal circulation disturbance may be involved in the pathogenesis of multiple evanescent white dot syndrome MEWDS. The aim of this study is to quantitatively evaluate changes in choroidal circulation hemodynamics using laser speckle flowgraphy LSFG in patients with MEWDS. Twelve eyes of 12 patients with MEWDS and 12 unaffected fellow eyes as controls were included. The macular mean blur rate MBR , a quantitative index of relative blood flow velocity in the choroid, was measured by LSFG. Sequential changes in the average MBR values at the macula with granular changes and the lesion area with white dots were analysed. Moreover, correlations between the MRR changing rate and initial visual functions were examined. Visual functions significantly improved 3 months after initial visit with accompanying improvements in outer retinal morphology. When compared with the baseline measurements, the MBR significantly increased at the macula of the affected eyes by 20. 01 for both , while no significant change was detected in fellow eyes. Similarly, the MBR increased at the lesion area by 17. 05 for both. 03, respectively , suggesting a close link between initially reduced choroidal blood flow and functional abnormalities at the onset of MEWDS. These results, in concert with angiographic findings, are likely to reinforce the concept of choroidal circulation impairment as a predisposing factor for MEWDS. Satoshi Morooka, Mitsuteru Hoshina, Isao Kii, Takayoshi Okabe, Hirotatsu Kojima, Naoko Inoue, Yukiko Okuno, Masatsugu Denawa, Suguru Yoshida, Junichi Fukuhara, Kensuke Ninomiya, Teikichi Ikura, Toshio Furuya, Tetsuo Nagano, Kousuke Noda, Susumu Ishida, Takamitsu Hosoya, Nobutoshi Ito, Nagahisa Yoshimura, Masatoshi HagiwaraMOLECULAR PHARMACOLOGY 88 2 316 - 325 2015年08月 [査読有り][通常論文] Excessive angiogenesis contributes to numerous diseases, including cancer and blinding retinopathy. Antibodies against vascular endothelial growth factor VEGF have been approved and are widely used in clinical treatment. Our previous studies using SRPIN340, a small molecule inhibitor of SRPK1 serine-arginine protein kinase 1 , demonstrated that SRPK1 is a potential target for the development of antiangiogenic drugs. In this study, we solved the structure of SRPK1 bound to SRPIN340 by X-ray crystallography. Using pharmacophore docking models followed by in vitro kinase assays, we screened a large-scale chemical library, and thus identified a new inhibitor of SRPK1. This inhibitor, SRPIN803, prevented VEGF production more effectively than SRPIN340 owing to the dual inhibition of SRPK1 and CK2 casein kinase 2. In a mouse model of age-related macular degeneration, topical administration of eye ointment containing SRPIN803 significantly inhibited choroidal neovascularization, suggesting a clinical potential of SRPIN803 as a topical ointment for ocular neovascularization. Thus SRPIN803 merits further investigation as a novel inhibitor of VEGF. PURPOSE. To investigate the alteration of vitreal N-glycans in patients with proliferative diabetic retinopathy PDR. METHODS. Plasma and vitreous samples were collected from 17 patients 10 females and 7 males with PDR PDR group and 17 nondiabetic patients 8 females and 9 males with epiretinal membrane ERM and idiopathic macular hole MH non-diabetes mellitus [DM] group. Profiles of N-glycans were analyzed by a glycoblotting-based high-throughput protocol that we recently developed. Human retinal microvascular endothelial cells HRMECs were cultivated with culture media containing either low glucose 5 mM or high glucose 25 mM , and expression levels of sialyltransferases were analyzed by real-time PCR and ELISA. RESULTS. Amount of N-glycans in the vitreous fluid of the PDR group was significantly higher than that of the non-DM group 495. 4 vs. 142. 005 , whereas there was no significant difference in the plasma samples between the PDR and the non-DM group. In addition, profile analysis showed that N-glycans with sialic acids increased in the vitreous of the PDR group 328. 0005. Expression levels of sialyltransferases ST3GAL1 and ST3GAL4 were upregulated in the HRMECs after high-glucose stimulation. Consistent with the real-time PCR data, high-glucose stimulation elevated the protein levels of ST3GAL1 117. 01 and ST3GAL4 6. 05 in the HRMECs compared with the cells cultured with low-glucose culture media ST3GAL1, 64. CONCLUSIONS. Our data demonstrate distinct changes in the N-glycan profile and an increase in sialylated N-glycans in eyes with PDR. Purpose To investigate sequential post-operative thickness changes in inner and outer retinal layers in eyes with an idiopathic macular hole MH. Methods Retrospective case series. Twenty-four eyes of 23 patients who had received pars plana vitrectomy PPV for the closure of MH were included in the study. Spectral domain optical coherence tomography C-scan was used to automatically measure the mean thickness of the inner and outer retinal layers pre-operatively and up to 6 months following surgery. The photoreceptor outer segment PROS length was measured manually and was used to assess its relationship with best-corrected visual acuity BCVA. 01 , but not perifoveal, area. 002 , whereas the nerve fiber layer was unaltered. 001. 03 , but not with any of the other thickness parameters examined. Conclusions Following PPV for MH, retinal inner layers other than the nerve fiber layer thinned, suggestive of subclinical thickening in the inner layers where no cyst was evident pre-operatively. In contrast, retinal outer layer thickness significantly increased, potentially as a result of PROS elongation linking tightly with favorable visual prognosis in MH eyes. Purpose The pathogenesis of unilateral acute idiopathic maculopathy UAIM is unknown. The aim of this study was to quantitatively examine changes in choroidal circulation hemodynamics in patients with UAIM. Methods This was a retrospective observational case-series which included five eyes of four patients with UAIM. All UAIM eyes and the fellow eyes in remaining three patients were studied using laser speckle flowgraphy LSFG to evaluate the mean blur rate MBR , a quantitative index of relative blood flow velocity. The changes in MBR between the initial visit and after 1 and 3 months were statistically analyzed. Subfoveal choroidal thickness was measured in three UAIM eyes by enhanced depth imaging optical coherence tomography. 04 with recovery of outer retinal morphology. 001 , whereas the fellow eyes did not show this tendency. The mean values of subfoveal choroidal thickness decreased with time 316. 0 mu m at baseline, 186. 6 mu m at 1 month, and 167. 3 mu m at 3 months. Conclusions These results reveal that there is a significant elevation of choroidal blood flow velocity and substantial reduction of choroidal thickness with regression of UAIM, suggesting that impaired choroidal circulation may be involved in the pathogenesis of UAIM. To investigate the relationship between circulation hemodynamics and morphology in the choroid during systemic corticosteroid therapy for patients with Vogt-Koyanagi-Harada VKH disease. This retrospective case series includes 18 eyes of nine patients with VKH disease two men and seven women; average age, 40. 8 years who received systemic corticosteroid therapy. Laser speckle flowgraphy LSFG and enhanced-depth imaging optical coherence tomography EDI-OCT were performed before treatment and at 1 week and 1 and 3 months after treatment. The average values of the mean blur rate MBR at the macula and the central choroidal thickness CCT were compared at each stage. 0002 for all. 0002 for all. 0097. 0093 but not with CCT. Our data suggest that circulatory disturbances and increased thickness of the choroid relate to the pathogenesis of VKH disease with link mutually. LSFG is useful as an index for evaluating the choroiditis activity of VKH disease as well as EDI-OCT. Aerobic glucose metabolism is indispensable for metabolically active cells; however, the regulatory mechanism of efficient energy generation in the highly evolved mammalian retina remains incompletely understood. Here, we revealed an unsuspected role for pro renin receptor, also known as ATP6AP2, in energy metabolism. Immunoprecipitation and mass spectrometry analyses identified the pyruvate dehydrogenase PDH complex as Atp6ap2-interacting proteins in the mouse retina. Yeast two-hybrid assays demonstrated direct molecular binding between ATP6A P2 and the PDH El 13 subunit PDHB. Pdhb immunoreactivity co-localized with Atp6ap2 in multiple retinal layers including the retinal pigment epithelium RPE. A TP6AP2 knockdown in RPE cells reduced PDH activity, showing a predilection to anaerobic glycolysis. ATP6AP2 protected PDHB from phosphorylation, thus controlling its protein stability. Down-regulated PDH activity due to ATP6AP2 knockdown inhibited glucose-stimulated oxidative stress in RPE cells. Purpose To evaluate the clinical features and investigate their relationship with visual function in Japanese patients with acute zonal occult outer retinopathy AZOOR. Methods Fifty-two eyes of 38 Japanese AZOOR patients 31 female and 7 male patients; mean age at first visit, 35. 0 years; median follow-up duration, 31 months were retrospectively collected: 31 untreated eyes with good visual acuity and 21 systemic corticosteroid-treated eyes with progressive visual acuity loss. Variables affecting the logMAR values of best-corrected visual acuity BCVA and the mean deviation MD on Humphrey perimetry at initial and final visits were examined using multiple stepwise linear regression analysis. 00002. 02, respectively. The final logMAR BCVA was 0. Variables affecting initial visual function were moderate anterior vitreous cells, myopia severity, and a-wave amplitudes on electroretinography; factors affecting final visual function were the initial MD values, female sex, moderate anterior vitreous cells, and retinal atrophy. Conclusions Our data indicated that visual functions in enrolled patients significantly improved spontaneously or after systemic corticosteroids therapy, suggesting that Japanese patients with AZOOR have good visual outcomes during the follow-up period of this study. Furthermore, initial visual field defects, gender, anterior vitreous cells, and retinal atrophy affected final visual functions in these patients. Background: Leber's hereditary optic neuropathy LHON refers to an optic nerve dysfunction due to mutations in the mitochondrial DNA, resulting in visual loss by apoptosis of retinal ganglion cells RGC. There are some reports regarding the circumpapillary retinal nerve fiber layer cpRNFL and the ganglion cell analysis around the macula in LHON patients and carriers by using optical coherence tomography. Case presentation: A 40-year-old female complained of acute visual loss in both eyes. Her best-corrected visual acuity was 0. 3 in the right eye and 0. 2 in the left eye at the initial visit. Goldmann perimetry revealed bilateral central scotomas. Fundus examination and fluorescein angiography findings were normal, but decreased retinal inner layer thickness was detected around the macular area on spectral domain optical coherence tomography SD-OCT. One month later, her visual acuity deteriorated to counting fingers in both eyes, and the thinning area of retinal inner layer spread rapidly. Suspected progressive RGC loss led us to check the possibility of LHON, with which the patient was diagnosed due to a positive result for the mitochondrial DNA mtDNA 11778 mutation. The ganglion cell complex GCC and cpRNFL thicknesses were observed for 24 months by using SD-OCT. The GCC thickness plunged sharply within 3 months followed by gradual decline until 6 months, thereafter showing a plateau up to 24 months. On the cpRNFL map, the temporal quadrant also showed the earliest thinning as seen in the macular area of the GCC map. The thicknesses of the superior, nasal, and inferior quadrants decreased gradually, keeping their normal ranges up to 6 months. Conclusions: SD-OCT was a useful tool in the diagnosis and follow-up of LHON. The macular GCC thickness map may detect the earliest morphological changes in LHON, as well as the temporal area of cpRNFL, before funduscopic examination reveals optic nerve atrophy. For the purpose of investigating Behcet's disease BD in Russia, 250 consecutive patients 177 men and 73 women diagnosed with BD between 1990 and 2010 at the Research Institute of Rheumatology, Russian Academy of Medical Sciences in Moscow were enrolled in this study. The ethnic backgrounds of the patients were reported as follows: 23. The remaining 19. More than half 57. The mean age at disease onset was 31. 38 13-60 years old, and the most typical initial manifestations were oral aphthous ulcers. Patients aged 20-39 years old were more commonly affected and displayed a wide clinical spectrum of the disease, with varieties of severe internal organ involvement. 01 lesions were more frequent in men than in women. HLA-B51 and HLA-A26 typing was performed in 127 patients and 508 healthy controls. HLA-B51 was found in 63. 001 , and HLA-A26 was present in 11. This study shows the presence of BD in Russia, and it is suggested that its prevalence in Central Asian people is much higher than that in White Russian. For the purpose of investigating Behcet's disease BD in Russia, 250 consecutive patients 177 men and 73 women diagnosed with BD between 1990 and 2010 at the Research Institute of Rheumatology, Russian Academy of Medical Sciences in Moscow were enrolled in this study. The ethnic backgrounds of the patients were reported as follows: 23. The remaining 19. More than half 57. The mean age at disease onset was 31. 38 13-60 years old, and the most typical initial manifestations were oral aphthous ulcers. Patients aged 20-39 years old were more commonly affected and displayed a wide clinical spectrum of the disease, with varieties of severe internal organ involvement. 01 lesions were more frequent in men than in women. HLA-B51 and HLA-A26 typing was performed in 127 patients and 508 healthy controls. HLA-B51 was found in 63. 001 , and HLA-A26 was present in 11. This study shows the presence of BD in Russia, and it is suggested that its prevalence in Central Asian people is much higher than that in White Russian. PURPOSE. Extranodal marginal zone B-cell lymphoma EMZL is the most common subtype of conjunctival lymphoma, though its molecular mechanisms of pathogenesis are largely unknown. We attempted to explore the association of the renin-angiotensin system RAS and pro renin receptor [P] RR in the pathogenesis of conjunctival lymphoma. METHODS. Surgically removed conjunctiva EMZL samples were used for gene expression, and immunohistochemical and immunofluorescence analyses of P RR and RAS components. Human B-lymphoblast IM-9 cells were treated with prorenin or angiotensin II Ang II , and gene expression levels were analyzed using real-time quantitative PCR qPCR. In addition, immunofluorescence analysis of EMZL samples was used to evaluate the in vivo expression of those components. RESULTS. Gene expression and immunohistochemical analyses revealed the expression of RAS components, including P RR and angiotensin II type 1 receptor AT1R , in EMZL tissues. Double-labeling analyses demonstrated that P RR and AT1R were detected in cells positive for CD20, a marker for B-cells, where they colocalized with prorenin and angiotensinogen, respectively. Prorenin stimulation of human B-lymphoblast IM-9 cells increased mRNA expression levels of fibroblast growth factor 2 FGF2 , while angiotensin II treatment upregulated the expression levels of basigin BSG , matrix metallopeptidase MMP 2, 9, and 14, which were abolished by P RR and AT1R blockades, respectively. Immunofluorescence analyses of clinical samples showed colocalizations of P RR and AT1R with the products of these upregulated genes. CONCLUSIONS. The present study suggests that activation of P RR and AT1R is associated with the pathogenesis of conjunctival EMZL by stimulating the production of FGF2 and MMPs. Zhenyu Dong, Daiju Iwata, Nobuyoshi Kitaichi, Masayoshi Takeuchi, Masashi Sato, Noriko Endo, Kazuya Iwabuchi, Ryo Ando, Junichi Fukuhara, Satoshi Kinoshita, Anton Lennikov, Mizuki Kitamura, Kazuomi Mizuuchi, Atsuhiro Kanda, Kousuke Noda, Kenichi Namba, Sho-Ichi Yamagishi, Shigeaki Ohno, Susumu IshidaJOURNAL OF LEUKOCYTE BIOLOGY 96 6 1077 - 1085 2014年12月 [査読有り][通常論文] Formation of glyceraldehyde-derived advanced glycation endoproducts contributes to the pathogenesis of endogenous uvetitis in human and animals. AGEs are permanently modified macromolecule derivatives that form through nonenzymatic glycation of amino groups of proteins. Glycer-AGEs are highly toxic and play an important role in the pathogenesis of chronic inflammatory diseases. However, the contribution of glycer-AGEs to the pathogenesis of uveitis is unclear. In this study, we measured serum levels of glycer-AGEs in 100 patients with endogenous uveitis 22 with HLA-B27-associated uveitis, 20 with VKH disease, 14 with Behcet's disease, and 44 with sarcoidosis and 33 healthy volunteers. Regardless of the etiology, serum glycer-AGE levels were significantly higher in patients with uveitis than in healthy subjects. Serum glycer-AGE levels may therefore serve as a biomarker of human uveitis, as well as systemic inflammation, and may contribute to the progression of uveitis, including diabetic iritis, via the activation of NF-B. Genistein is a dietary-derived flavonoid abundantly present in soybeans and known to possess various biological effects including anti-inflammation and anti-angiogenic activity. To investigate the effects of genistein on intraocular neovascularization, we used an animal model of laser-induced choroidal neovascularization CNV. CNV was induced by laser photocoagulation. The animals were fed a mixture diet containing 0. Seven days after laser injury, the size of CNV lesions was quantified. Retinal pigment epithelium RPE -choroid complex was also harvested 1 or 3 days after laser injury and the level of monocyte chemoattractant protein MCP -1, intercellular adhesion molecule ICAM -1, and matrix metalloproteinase MMP -9 were measured by enzyme-linked immunosorbent assay. A significant decrease in CNV size was observed in animals treated with genistein 15441. 8 mu m 2 compared to control mice 21074. The current data indicate the anti-angiogenic property of genistein during CNV formation. C 2014 Elsevier Inc. All rights reserved. Background: The mechanism underlying focal choroidal excavation FCE remains largely unknown. We evaluated the sequential progression of FCE generation using enhanced depth imaging optical coherence tomography EDI-OCT in a patient with multiple evanescent white dot syndrome MEWDS. Case presentation: A 37-year-old woman suffered MEWDS in the right eye. After 1 month, almost all white dots spontaneously resolved together with improvements of the perifoveal OCT findings. Interestingly, perifoveal region developed a conforming-type FCE. An abnormal hyper-reflective lesion on OCT, regarded as fibrosis formation, simultaneously appeared within the choroid below the FCE and subsequently increased in size. Human adenovirus species D HAdV-D , which is composed of clinically and epidemiologically important pathogens worldwide, contains more taxonomic "types" than any other species of the genus Mastadenovirus, although the mechanisms accounting for the high level of diversity remain to be disclosed. Recent studies of known and new types of HAdV-D have indicated that intertypic recombination between distant types contributes to the increasing diversity of the species. However, such findings raise the question as to how homologous recombination events occur between diversified types since homologous recombination is suppressed as nucleotide sequences diverge. In order to address this question, we investigated the distribution of the recombination boundaries in comparison with the landscape of intergenomic sequence conservation assessed according to the synonymous substitution rate d s. The results revealed that specific genomic segments are conserved between even the most distantly related genomes; we call these segments "universally conserved segments" UCSs. These findings suggest that UCSs facilitate homologous recombination, resulting in intergenomic segmental exchanges of UCS-flanking genomic regions as recombination modules. With the aid of such a mechanism, the haploid genomes of HAdV-Ds may have been reshuffled, resulting in chimeric genomes out of diversified repertoires in the HAdV-D population analogous to the MHC region reshuffled via crossing over in vertebrates. In addition, some HAdVs with chimeric genomes may have had the opportunity to avoid host immune responses thereby causing epidemics. C 2014 Elsevier B. All rights reserved. To investigate the concentration and composition of N-glycans in plasma and vitreous samples obtained from patients with non-proliferative vitreoretinal diseases. Plasma and vitreous samples were collected from 11 patients with idiopathic macular hole MH and 9 patients with epiretinal membrane ERM. The samples were pretreated for enzymatic cleaving, and subsequently glycans released from proteins were captured on BlotGlyco H beads. Sialic acids were methyl-esterified. The concentration and composition of N-glycans in the samples were assessed. 001. Predominant N-glycan in both plasma 39. By contrast, the second-ranked N-glycan in vitreous samples 15. The current data provide useful information on N-glycan profile in the vitreous fluid, which is distinct from that in the plasma. Purpose: To analyze the histopathology and expression of 8-hydroxydeoxyguanosine OHdG , a marker of oxidative stress, in the levator aponeurosis tissues of involutional aponeurotic and congenital blepharoptosis patients, and adult subjects with no history of blepharoptosis. Methods: Fourteen and 4 levator aponeurosis tissues obtained from Asian patients with involutional and congenital blepharoptosis and 3 normal adult tissues were examined. Results: The levator aponeurosis tissues contained spindle smooth muscle fibers and striated muscles. Nuclear immunoreactivity for 8-OHdG was noted in striated and smooth muscle cells in all the tissues. In contrast, there was a rare positive -8-OHdG-immunoreactivity of smooth muscle cells in the aponeurotic tissues of the involutional blepharoptosis patients. Conclusions: Levator aponeurosis in involutional aponeurotic blepharoptosis tissues showed oxidative stress in the muscle, indicating that oxidative stress plays a potential role in the pathologic study of the disease. A case of retinoschisis associated with peripapillary intrachoroidal cavitation ICC was successfully treated with pars plana vitrectomy. A 70-year-old woman developed macular elevation and peripapillary ICC in her right eye. Optical coherence tomography revealed retinoschisis with retinal detachment in the macula. A microhole was observed within the myopic conus. A narrow passage was observed linking the ICC with the schisis cavity, complicated by a peripapillary epiretinal membrane tissue adjacent to the passage. The patient underwent vitrectomy with removal of the membrane tissue. Complete regression of the retinoschisis was observed, with closure of the connection channel between the ICC and schisis cavity. These findings suggest that the communication channel between the vitreous and schisis cavities was formed due to the traction exerted by the membrane tissue on the ICC that had generated a connecting path to the schisis cavity. PURPOSE. To examine the expression of VEGF in extranodal marginal zone B-cell lymphoma EMZL and reactive lymphoid hyperplasia RLH of human ocular adnexa, and analyze the correlation with the intratumoral microvessel density MVD. METHODS. Twenty-two EMZL and 16 RLH tissues were examined in this study. Paraformaldehyde-fixed, paraffin-embedded tissue sections were processed for immunohistochemistry with antibodies against VEGF and CD20. Vascular endothelial growth factor expression was analyzed using the ELISA and RT-PCR in the EMZL tissues. Microvessel density was determined based on the immunoreactivity for anti-CD34 antibody. RESULTS. Vascular endothelial growth factor immunoreactivity was detected in the cytoplasm of lymphoid cells in EMZL and RLH. ELISA and RT-PCR confirmed VEGF protein and mRNA expressions in the EMZL tissue, respectively. The MVD showed a significant positive correlation with the VEGF-immunopositive rate in conjunctival and orbital EMZLs. CONCLUSIONS. This study demonstrated increased VEGF expression in human conjunctival and orbital EMZL compared with that in RLH, suggesting that VEGF plays a significant role in the pathogenesis and tumor angiogenesis of ocular adnexal lymphoma. Adenosquamous carcinoma ASC is a rare form of malignancy which consists of two types of cell, including squamous cells and glandular-like cells. The current report presents the first known case of ASC in the conjunctiva and analyzes the histological findings. A 76-year-old female presented with right eyelid swelling in 2001. A right conjunctival tumor was noted and a biopsy was performed. Histologically, the tumor was diagnosed as a squamous cell carcinoma. The patient underwent radiotherapy, but the tumor rapidly relapsed. Subsequently, the patient underwent orbital exenteration. Histologically, the conjunctival tissues had been replaced with invasive tumor cells. A number of tumor cells demonstrated squamous differentiation with a keratinizing tendency, while other tumor cells exhibited mucin-producing activity with glandular formation. The conjunctival tumor was diagnosed as an ASC. At the time of writing, the patient is well without local recurrence or distant metastases. ASC typically exhibits aggressive biological behavior, and is associated with worse prognosis than conventional adenocarcinoma. Therefore, complete surgical excision is considered a key treatment for ASC of the conjunctiva. Background: Changes in choroidal circulation hemodynamics during the course of punctate inner choroidopathy PIC remain unknown. The aim of this study was to quantitatively evaluate changes in choroidal blood flow velocity by using laser speckle flowgraphy LSFG in patients with PIC. Case presentation: This PIC patient was initially treated with systemic corticosteroids for 4 months. LSFG measurements were taken 10 consecutive times before treatment and at 1, 3, 12, 20 and 23 months after the initiation of therapy. The mean blur rate MBR , a quantitative index of relative blood flow velocity, was calculated using LSFG in three regions: Circles 1, 2 and 3 were set at the fovea, a lesion site, and an area of normal-appearing retina, respectively. The PIC lesions scarred after treatment along with improvements in visual function and outer retinal morphology. At the time of PIC recurrence after 20 months, the MBR decreased temporarily but subsequently increased after retreatment with systemic corticosteroids. This trend was accompanied by a decrease in choroidal thickness at the lesion site after retreatment. Conclusions: Macular choroidal blood flow velocity increased and choroidal thickness decreased concurrently with regression of PIC. The present findings suggest that inflammation-related impairments in choroidal circulation may relate to the pathogenesis of PIC, extending over a wider area in the posterior pole than the PIC lesions per se. BackgroundTo evaluate changes of choroidal circulation quantitatively using laser speckle flowgraphy in patients with acute zonal occult outer retinopathy. DesignRetrospective observational case series. ParticipantsSixteen eyes of 11 acute zonal occult outer retinopathy patients: seven non-treated eyes with good visual acuity and nine systemic corticosteroid-treated eyes with progressive visual acuity loss. Six eyes with thyroid-associated ophthalmopathy receiving systemic corticosteroid therapy served as controls. MethodsThe mean blur rate, an index of quantitative relative blood flow velocity, in the affected area was measured by laser speckle flowgraphy. The changes of mean blur rate, best-corrected visual acuity and the average threshold at the affected area on Humphrey perimetry during 24-week follow up were analysed. Main Outcome MeasuresMean blur rate, best-corrected visual acuity, and the average threshold. ResultsIn non-treated eyes, the average mean blur rate significantly increased at 24 weeks, with a significant increase of the average threshold. In corticosteroid-treated eyes, the mean blur rates at 1, 4, 12 and 24 weeks were significantly higher than the pretreatment value, with significant improvement of best-corrected visual acuity and the average threshold. The increase in mean blur rate at 4 weeks in corticosteroid-treated acute zonal occult outer retinopathy eyes was significantly higher than that in corticosteroid-treated control eyes. ConclusionsIn eyes with acute zonal occult outer retinopathy, the mean blur rate at the affected area significantly increases along with improvement of visual functions. These results suggest that impaired choroidal circulation is involved in the pathogenesis of acute zonal occult outer retinopathy. To investigate postoperative thickness changes in the retinal layers in eyes with epiretinal membrane ERM. Correlations between these changes and visual outcomes were also examined. Retrospective review of 25 eyes 24 patients that had undergone pars plana vitrectomy for ERM and had a postoperative follow-up period a parts per thousand yen6 months. Optical coherence tomography 6 x 6 mm macular thickness map was used to measure mean thickness of the inner and outer retinal layers 1 week and 1, 3, and 6 months following surgery. Photoreceptor outer segment PROS length was evaluated manually, and used to assess the association between best-corrected visual acuity BCVA and retinal layer thickness at the fovea. At 1 week and 1, 3, and 6 months, retinal layer thickness was 388, 377, 362, and 352 mu m for the whole layer; 133, 115, 107, and 101 mu m for the inner layer; 138, 145, 147, and 148 mu m for the outer layer; and 28, 35, 36, and 40 mu m for the PROS length, respectively. In comparison to 1-week data, the inner layers were significantly thinner at 1 month and later, as was the thickness of the entire retina. Outer layer thickness and PROS length were also significantly thicker at these time points. Retinal outer layer thickness significantly increased following pars plana vitrectomy for ERM. Visual improvement was positively correlated with PROS length recovery. Purpose: Echinochrome is a pigment present in the shells and spines of sea urchins. Endotoxin-induced uveitis EIU is an animal model of acute anterior segment intraocular inflammation that is induced by the injection of lipopolysaccharide LPS. In this study, the therapeutic effect of echinochrome was examined in uveitis using the EIU model. Methods: EIU was induced in Lewis rats via 200 mu g subcutaneous injections of LPS from Escherichia coli. Echinochrome was administered intravenously in 10, 1, or 0. Twenty-four hours after LPS injection, the number of infiltrating cells and the protein concentration in aqueous humor were determined. Aqueous tumor necrosis factor alpha TNF-alpha concentration was quantified with enzyme-linked immunosorbent assay, eyes were stained with nuclear factor NF kappa B antibodies, and ROS production was determined by dihydroethidium staining in fresh frozen samples. Conclusions: Echinochrome ameliorated intraocular inflammation caused by EIU by reducing ROS production, thereby also decreasing the expression of NF kappa B and TNF-alpha. As a natural pigment, echinochrome may therefore be a promising candidate for the safe treatment of intraocular inflammation. The use of sea urchin shells and spines in health foods and medical products is thus both economically and environmentally meaningful. This study was conducted to elucidate pathophysiological roles of the lysosomal phospholipase A2 LPLA2 , a phospholipid-degrading enzyme, of the aqueous humor AH in uveitis using an animal model and clinical specimens. Endotoxin-induced uveitis EIU was induced by subcutaneous injections of lipopolysaccharide from Escherichia coli to seven-week-old male Lewis rats. Inflammation of the anterior chamber AC was evaluated by measurement of the protein concentration of rat AH. Immunohistochemical analysis was performed using antibodies against CD11b and LPLA2. Sixty-five human AH specimens, in which 11 eyes had a history of chronic uveitis, were collected during patient cataract surgeries and used to determine LPLA2 activity. The LPLA2 activity in rat AH was significantly increased by EIU induction, and was correlated to the extent of inflammation in the AC. By contrast, the LPLA2 activity in rat serum or cerebrospinal fluid was not influenced by EIU induction. According to the immunohistochemistry, LPLA2 was found in CD11b positive cells in the AC of the EIU rats. In the clinical specimens, the AH obtained from the patients with a history of uveitis possessed significantly higher LPLA2 activity than that from the senile patients with cataract but without other ocular diseases. These results demonstrate that the LPLA2 activity in the AH is augmented with the inflammation in the AC and suggest that the LPLA2 in the AH participates in the inflammation process in the AC. C 2013 Published by Elsevier Ltd. Background: Specific cross-reacting autoimmunity against recoverin or collapsin response mediator protein CRMP -5 is known to cause cancer-associated retinopathy or paraneoplastic optic neuropathy, respectively. We report a rare case with small cell lung carcinoma developing bilateral neuroretinitis and unilateral focal outer retinitis positive for these antibodies. Case presentation: A 67-year-old man developed bilateral neuroretinitis and foveal exudation in the right eye. Optical coherence tomography showed a dome-shaped hyperreflective lesion extending from inner nuclear layer to the photoreceptor layer at the fovea in the right eye. Single-flash electroretinography showed normal a-waves in both eyes and slightly reduced b-wave in the left eye. Results of serological screening tests for infection were within normal limits. The patient's optic disc swelling and macular exudation rapidly improved after oral administration of prednisolone. Systemic screening detected lung small cell carcinoma and systemic chemotherapy was initiated. Immunoblot analyses using the patient's serum detected autoantibodies against recoverin, CRMP-5, and a-enolase, but not carbonic anhydrase II. Neuroretinitis once resolved after almost remission of carcinoma on imaging but it recurred following the recurrence of carcinoma. Conclusions: The development of neuroretinitis in this cancer patient with anti-retinal and anti-optic nerve antibodies depended largely on the cancer activity, suggesting the possible involvement of paraneoplastic mechanisms. Patients with paraneoplastic optic neuropathy and retinopathy are likely to develop autoimmune responses against several antigens, thus leading to various ophthalmic involvements. Pro renin receptor [ P RR], also known as Atp6ap2, has attracted growing attention as a key molecule for tissue renin-angiotensin system RAS. PURPOSE. METHODS. We examined the cytokine concentrations in the tear fluid by CytoBead assay , tear film break-up time, amount of tear production, and expressions of mucins 1, 4, and 5AC, by RT-PCR. We also performed vital staining of the ocular surface, PAS staining for muc5AC, and immunohistochemical stainings for 4-hydroxy-2-nonenal 4-HNE , 8-hydroxy-2'-deoxyguanosine 8-OHdG , in the conjunctiva to compare the results before and after rebamipide instillations. RESULTS. The mean IL-6, IL-17, TNF-alpha, and IFN-gamma levels in the tear fluid were reduced significantly along with a significant decrease in the density of cells positive for 4-HNE and 8-OHdG in the conjunctiva. CONCLUSIONS. Two percent Rebamipide ophthalmic solution significantly improved the tear stability and corneal epithelial damage, and enhanced the expression of muc5 mRNA on the ocular surface. We also observed anti-inflammatory effects in the tear film together with antioxidative effects in the conjunctiva, suggesting the efficacy of rebamipide in age-related dry eye disease attributable to SOD1 knockout. Yun Jong Lee, Yukihiro Horie, Graham R. Wallace, Yong Seok Choi, Ji Ah Park, Ji Yong Choi, Ran Song, Young-Mo Kang, Seong Wook Kang, Han Joo Baek, Nobuyoshi Kitaichi, Akira Meguro, Nobuhisa Mizuki, Kenichi Namba, Susumu Ishida, Jinhyun Kim, Edyta Niemczyk, Eun Young Lee, Yeong Wook Song, Shigeaki Ohno, Eun Bong LeeANNALS OF THE RHEUMATIC DISEASES 72 9 1510 - 1516 2013年09月 [査読有り][通常論文] Objectives To identify non-major histocompatibility complex susceptible genes that might contribute to Behcet's disease BD. Methods We performed a genome-wide association study using DNA samples from a Korean population consisting of 379 BD patients and 800 controls. A replication study was performed in a Japanese population 363 BD patients and 272 controls. To evaluate the functional implication of the target single nucleotide polymorphisms SNP , gene expression levels in peripheral T cells, allele-specific modulation of promoter activity and biological effect of mRNA knockdown were investigated. Results We found a novel association of BD to the GIMAP locus, mapped to chromosome 7q36. 60x10 -6. 53x10 -5 in GIMAP1 areas. Replication study using DNA samples from the Japanese population validated the significant association between BD and the GIMAP locus. The GIMAP4 promoter construct plasmid with the minor allele of rs1608157 displayed significantly lower activity than one with the major allele. Moreover, CD4 T cells from BD patients showed a lower level of GIMAP4 mRNA, and GIMAP4 knockdown was protective against Fas-mediated apoptosis. Conclusions These results suggest that a GIMAP cluster is a novel susceptibility locus for BD, which is involved in T-cell survival, and T-cell aberration can contribute to the development of BD. Aim: To examine the expression of alpha B-crystallin and vascular endothelial growth factor VEGF in conjunctival squamous cell carcinoma CSCC. Materials and Methods: Seven CSCCs and three normal conjunctivas that were surgically excised were studied. Paraformaldehyde-fixed, paraffin-embedded tissue sections were processed for immunohistochemistry with antibodies against alpha B-crystallin, its phosphorylated forms, and VEGF. In vitro experiments were conducted to investigate the effects of mitomycin C MMC treatment on the expression of alpha B-crystallin and VEGF secretion. Results: alpha B-Crystallin and VEGF were strongly expressed in CSCCs compared to normal conjunctivas. alpha B-Crystallin immunoreactivity was co-localized with that for VEGF in CSCCs, whereas these signals were reduced in CSCC tissues treated with MMC before excision. MMC treatment suppressed the alpha B-crystallin expression and VEGF secretion in cultured conjunctival cells in a dose-dependent manner. Conclusion: This study demonstrated alpha B-crystallin and VEGF expressions in human CSCCs, which may play a role in the pathogenesis. alpha B-Crystallin expression, and VEGF secretion were reduced by MMC, indicating a novel therapeutic mechanism in MMC treatment for human CSCC. Human adenovirus HAdV causing epidemic keratoconjunctivitis is limited to D and E species. Recent progress in bioinformatics revealed that these viruses attach to the host with fibers, infiltrate the host cells via RGD Arg-Gly-Asp motif of penton base, and reveal their serological reaction by hexons. Loops 1 and 2 are the variable regions of each hexon. The possibility that a novel adenovirus later named HAdV-52 was transmitted over the wall of species' from monkeys to humans was reported. The recombination of the above three hot spots introduces novel types such as HAdV-53, -54, and -56. Boinformatics may provide rapid genotyping in nosocomial infection, predicting future epidemics, and an estimate of the therapeutic target molecules in the near future. To clarify the clinical features of human lymphotropic virus type 1 HTLV-1 -associated uveitis HAU in patients of Hokkaido University Hospital, Hokkaido, northern Japan. We reviewed the records of a consecutive series of 21 patients with HAU who were followed up for more than 12 months at Hokkaido University Hospital. Of the 21 patients enrolled in this study, 19 as well as their parents 90. One patient was a member of the Ainu ethnic group. Intraocular inflammation was controlled by topical treatment, while systemic corticosteroids were required in less than one-fourth of patients. Visual acuity improved in 15 patients, remained unchanged in four patients, and deteriorated in two patients. A number of clinical features were unique to Hokkaido, namely, predominant unilateral involvement, as well as two HAU patients with ATLL. The phylogenetic difference of HTLV-1 and HLA typing may correlate with different clinical manifestations in HAU. Asymmetrical secretion of vascular endothelial growth factor VEGF by retinal pigment epithelial RPE cells in situ is critical for maintaining the homeostasis of the retina and choroid. VEGF is also involved in the development and progression of age-related macular degeneration AMD. We studied the effect of tumor necrosis factor-alpha TNF-alpha on the secretion of VEGF in polarized and non-polarized RPE cells P-RPE cells and N-RPE cells, respectively in culture and in situ in rats. A subretinal injection of TNF-alpha caused a decrease in VEGF expression and choroidal atrophy. Porcine RPE cells were seeded on Transwell TM filters, and their maturation and polarization were confirmed by the asymmetrical VEGF secretion and trans electrical resistance. Exposure to TNF-alpha decreased the VEGF secretion in P-RPE cells but increased it in N-RPE cells in culture. TNF-alpha inactivated JNK in P-RPE cells but activated it in N-RPE cells, and TNF-alpha activated NF-kappa B in P-RPE cells but not in N-RPE cells. Inhibition of NF-kappa B activated JNK in both types of RPE cells indicating crosstalk between JNK and NF-kappa B. TNF-alpha induced the inhibitory effects of NF-kappa B on JNK in P-RPE cells because NF-kappa B is continuously inactivated. In N-RPE cells, however, it was not evident because NF-kappa B was already activated. The basic activation pattern of JNK and NF-kappa B and their crosstalk led to opposing responses of RPE cells to TNF-alpha. These results suggest that VEGF secretion under inflammatory conditions depends on cellular polarization, and the TNF-alpha-induced VEGF down-regulation may result in choroidal atrophy in polarized physiological RPE cells. TNF-alpha-induced VEGF up-regulation may cause neovascularization by non-polarized or non-physiological RPE cells. Aim To quantitatively evaluate the time course of macular choroidal blood flow velocity in acute central serous chorioretinopathy CSC. Methods This retrospective observational case series included 21 eyes of 20 patients 17 men, 3 women; mean age, 53. 0 years with treatment-naive acute CSC. Laser speckle flowgraphy was performed to calculate macular mean blur rate MBR , an indicator of relative blood flow velocity at the first visit, 3 and 6 months thereafter. Changes in average MBR values were compared with visual improvement at 6 months. Results Subretinal fluid completely resolved in all eyes within 6 months, while best-corrected visual acuity BCVA significantly improved at 6 months compared to the initial BCVA. During the follow-up period, the average MBR significantly decreased to 92. Importantly, there was a negative correlation between the BCVA recovery and the MBR decrease, showing the possible association of MBR increase with poor visual prognosis. Multiple regression analysis demonstrated no significant correlation between MBR and ocular perfusion pressure. Conclusions These results indicate that macular choroidal blood flow velocity decreases concurrently with regression of CSC, suggesting a validity of choroidal blood flow elevation in the pathogenesis of acute CSC. Immuno globulin IgG 4-related disease is characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. We report a case of IgG4-related inflammation of the orbit simulating extranodal marginal zone B-cell lymphoma EMZL. A 72-year-old female complained of bilateral eyelid swelling for three years. A MRI scan demonstrated two kinds of lesions, tumor 1, presenting with a predominantly low density, and tumor 2, of relatively high density. Partial resection of each tumor was conducted in September 2011. Based on the clinicopathological findings, tumors 1 and 2 were diagnosed as IgG4-related inflammation and EMZL, respectively. The bilateral tumors consequently diminished, and she is currently well with no recurrence or systemic involvement. In conclusion, EMZL can arise from massive IgG4-related orbital inflammation. Since IgG4-related inflammation can represent multiple nodular lesions, biopsies from multiple sites within the lesion are required to make a correct diagnosis in selected cases. Oral prednisolone combined with radiotherapy is an effective treatment for patients with IgG4-related ophthalmic disease simulating EMZL. Saori Yaguchi, Yoko Ogawa, Shigeto Shimmura, Tetsuya Kawakita, Shin Hatou, Shingo Satofuka, Shigeru Nakamura, Toshihiro Imada, Hideyuki Miyashita, Satoru Yoshida, Tomonori Yaguchi, Yoko Ozawa, Takehiko Mori, Shinichiro Okamoto, Yutaka Kawakami, Susumu Ishida, Kazuo TsubotaPLOS ONE 8 6 e64724 2013年06月 [査読有り][通常論文] Chronic graft-versus-host disease cGVHD , a serious complication following allogeneic HSCT hematopoietic stem cell transplantation , is characterized by systemic fibrosis. The tissue renin-angiotensin system RAS is involved in the fibrotic pathogenesis, and an angiotensin II type 1 receptor AT1R antagonist can attenuate fibrosis. Tissue RAS is present in the lacrimal gland, lung, and liver, and is known to be involved in the fibrotic pathogenesis of the lung and liver. This study aimed to determine whether RAS is involved in fibrotic pathogenesis in the lacrimal gland and to assess the effect of an AT1R antagonist on preventing lacrimal gland, lung, and liver fibrosis in cGVHD model mice. We used the B10. First, we examined the localization and expression of RAS components in the lacrimal glands using immunohistochemistry and quantitative real-time polymerase chain reaction PCR. We demonstrated that fibroblasts expressed angiotensin II, AT1R, and AT2R, and that the mRNA expression of angiotensinogen was greater in the lacrimal glands of cGVHD model mice than in controls generated by syngeneic-HSCT. The inhibition experiment revealed that fibrosis of the lacrimal gland, lung, and liver was suppressed in mice treated with the AT1R antagonist, but not the AT2R antagonist. We conclude that RAS is involved in fibrotic pathogenesis in the lacrimal gland and that AT1R antagonist has a therapeutic effect on lacrimal gland, lung, and liver fibrosis in cGVHD model mice. Our findings point to AT1R antagonist as a possible target for therapeutic intervention in cGVHD. PURPOSE: Since some patients develop depigmentation of the trabecular meshwork in the course of Vogt-Koyanagi-Harada VKH disease, we examined the incidence of trabecular depigmentation and its correlation with other ocular findings and systemic symptoms. METHODS: We retrospectively reviewed the clinical charts of 53 Japanese patients diagnosed with VKH disease. The scores of trabecular and limbal pigmentation of all patients were recorded. We then examined the correlation between trabecular pigmentation and the presence of sunset glow fundus or skin lesions. 022 , whereas limbal pigmentation showed no significance. However, there were no significant differences in trabecular and limbal pigmentation between the patients with and those without skin lesions. Furthermore, there was no correlation between trabecular and limbal pigmentation. CONCLUSIONS: Depigmentation of the trabecular meshwork develops in some patients in the course of VKH disease. This depigmentation is significantly correlated with sunset glow fundus, but not with limbal depigmentation or skin lesions. Aims: To study serum levels of soluble vascular adhesion protein sVAP -1 in type II diabetic patients with retinopathy. Methods: Serum samples were obtained from 53 consecutive patients, including 14 cases with non-angiogenic ocular diseases, i. , epiretinal membrane ERM and idiopathic macular hole MH , 19 cases with age-related macular degeneration AMD , and 20 cases with diabetic retinopathy DR. Protein levels of sVAP-1, intercellular adhesion molecule ICAM -1, vascular cell adhesion molecule VCAM -1, and vascular endothelial growth factor VEGF were determined by enzyme-linked immunosorbent assay. Enzymatic activity of semicarbazide-sensitive amine oxidase SSAO was also measured. Results: Serum level of sVAP-1 showed a moderate correlation with SSAO activity in all cases. Patients with DR had higher levels of serum sVAP-1 than subjects with ERM and MH, or those with AMD; however, severity of DR is not related to the serum levels of sVAP-1. Serum sVAP-1 correlated positively with VEGF in patients with DR, but not in those with ERM and MH, or those with AMD. Neither soluble ICAM-1 nor VCAM-1 correlated with VEGF, even in subjects with DR. Conclusion: The current data demonstrate the elevated serum levels of sVAP-1 and correlation between sVAP-1 and VEGF in patients with type II diabetes. C 2013 Elsevier Inc. All rights reserved. Seven days after the treatment, the CNV size was evaluated using a flatmount technique. Protein levels of vascular endothelial growth factor VEGF and inflammation-associated molecules, such as monocyte chemoattractant protein MCP -1 and intercellular adhesion molecule ICAM -1, in the retinal pigment epithelium-choroid complex were measured with enzyme-linked immunosorbent assay. Results: SRPIN340 inhibited CNV formation in a dose-dependent manner. Compared with the vehicle, SRPIN340 significantly decreased the protein levels of VEGF, MCP-1, ICAM-1, and consequently inhibited macrophage infiltration. Furthermore, SRPIN340 suppressed the gene expression levels of total Vegf and exon 8a-containing Vegf isoforms. Conclusions: SRPIN340, a specific inhibitor of SRPK, suppressed Vegf expression and attenuated CNV formation. Our data suggest the possibility that SRPIN340 is applicable for neovascular age-related macular degeneration as a novel chemical therapeutics. Acute ultraviolet UV B exposure causes photokeratitis and induces apoptosis in corneal cells. Geranylgeranylacetone GGA is an acyclic polyisoprenoid that induces expression of heat shock protein HSP 70, a soluble intracellular chaperone protein expressed in various tissues, protecting cells against stress conditions. We examined whether induction of HSP70 has therapeutic effects on UV-photokeratitis in mice. ROS signal was not affected by GGA. PURPOSE. To examine the expression of vascular endothelial growth factor VEGF and VEGF receptor VEGFR -2 in enucleated eyes with Coats' disease. METHODS. Formalin-fixed, paraffin-embedded tissue sections from nine globes with Coats' disease were submitted for hematoxylin and eosin staining and immunohistochemistry with anti-VEGF and VEGFR antibodies. RESULTS. Histologically, the enucleated eyes demonstrated the presence of macrophage infiltration and cholesterol clefts in the subretinal space. There were marked retinal vascular abnormalities, including dilated vessels with hyalinized vessel walls in six globes. Exudative retinal detachment was noted in all globes. VEGF immunoreactivity was observed in macrophages infiltrating the subretinal space, and in the detached retina including several blood vessels. VEGFR-2 immunoreactivity was detected in endothelial cells lining the abnormal retinal vessels, where VEGFR-1 or VEGFR-3 was not expressed. CONCLUSIONS. Immunoreactivity for VEGF and VEGFR-2 was detected in macrophages and endothelia of abnormal vessels in eyes with Coats' disease. These results suggest that anti-VEGF approach is a promising therapy for patients with Coats' disease. Invest Ophthalmol Vis Sci. 2013; 54: 57-62 DOI: 10. 12-10613• PURPOSE. To investigate the antiangiogenic properties of tissue kallikrein in a murine model of laser-induced choroidal neovascularization CNV. METHODS. Seven days after laser injury, the CNV size was quantified. The levels of monocyte chemoattractant protein MCP -1, intercellular adhesion molecule ICAM -1, and interleukin IL -6 were assessed by enzyme-linked immunosorbent assay 3 days after laser injury. Cleavage of mouse VEGF with tissue kallikrein was assessed in vivo and in vitro. The protein levels of bradykinin were assessed in the RPE-choroid complexes and hearts. RESULTS. A significant decrease in CNV size was observed in animals treated with tissue kallikrein 27,168. 2 mu m 2 compared with vehicle-treated controls 36,374. Tissue kallikrein treatment significantly reduced MCP-1, ICAM-1, and IL-6 levels in RPE-choroid complexes. Furthermore, immunoblotting showed the bands, presumably corresponding to the fragmented VEGF 164 protein, in the samples of both mouse VEGF preincubated with tissue kallikrein and RPE-choroid complexes obtained from animals treated with tissue kallikrein. In addition, bradykinin was unchanged in the RPE-choroid complexes of animals treated with tissue kallikrein, whereas the level of bradykinin was increased in the heart obtained from these experimental animals. CONCLUSIONS. The current data indicate that kallikrein exhibits antiangiogenic properties by cleaving VEGF164 in a laser-induced CNV model. Invest Ophthalmol Vis Sci. 2013; 54: 274279 DOI: 10. 12-10512• Angiopoietin-like protein Angptl 2 is a key mediator linking obesity to chronic adipose-tissue inflammation and systemic insulin resistance, and increasing evidence has shown that Angptl2 is associated with various chronic inflammatory diseases such as cancer and dermatomyositis; however, it remains unclear that Angptl2 functions in acute inflammation. In this study, we investigate whether Angptl2 has a role in acute inflammation in the eye with endotoxin-induced uveitis EIU. Treatment with lipopolysaccharide LPS stimulated retinal Angptl2 mRNA expression in vivo and in vitro. In vitro, antibody-based inhibition of alpha 5 beta 1 integrin, a receptor for Angptl2, significantly repressed LPS-induced expression of IL-6 and TNF-alpha, both of which are the major inflammatory cytokines derived from macrophages. The present findings indicate that Angptl2 mediates endotoxin-induced retinal inflammation through the activation of NF-kappa B signaling pathway and suggest a potential validity of Angptl2 as a new molecular target for the treatment of acute inflammation. Laboratory Investigation 2012 92, 1553-1563; doi:10. 2012. 111; published online 6 August 2012• The renin-angiotensin system RAS potentially has a role in the development of end-organ damage, and tissue RAS activation has been suggested as a risk factor for diabetic retinopathy. We have recently shown significant involvement of pro renin receptor [P]RR in retinal inflammation in a rodent model of early diabetes. In this study we aim to elucidate the P RR-associated pathogenesis of fibrovascular proliferation, a late-stage angiogenic complication in human diabetic retinopathy. Vitreous fluids from 23 eyes of patients with proliferative diabetic retinopathy PDR and 16 eyes of controls with non-diabetic, idiopathic macular diseases macular hole and epiretinal membrane were collected. Protein levels of soluble P RR were measured by ELISA, and immunofluorescence was performed to assess the localisation of P RR and related molecules in fibrovascular tissues from PDR eyes. P RR immunoreactivity was detected in neovascular endothelial cells, colocalised with prorenin, phosphorylated extracellular signal-regulated kinase ERK and vascular endothelial growth factor VEGF. Prorenin application to human retinal microvascular endothelial cells significantly upregulated mRNA expression of VEGF, especially the VEGF165 isoform, which was abolished by P RR or ERK signalling blockade. Proteases known to cleave P RR, including furin, were positive in endothelial cells in fibrovascular tissues. Protein levels of soluble P RR in vitreous fluids were higher in PDR eyes than in non-diabetic control eyes, and correlated significantly with vitreous prorenin and VEGF levels and the vascular density of fibrovascular tissues. Our data using human samples provide the first evidence that P RR is associated with angiogenic activity in PDR. Purpose: Endotoxin-induced uveitis EIU is an animal model for acute ocular inflammation. Several substances play major roles in the development of inflammatory changes in EIU, including tumor necrosis factor-alpha TNF-alpha , interleukin IL -1 beta, and IL-6. These inflammatory cytokines trigger the degradation of I kappa B by activating I kappa B kinases IKKs. Released nuclear factor kappaB NF kappa B subsequently translocates to the nucleus, where NF kappa B expresses its proinflammatory function. IMD-0354, N- 3,5-Bis-trifluoromethylphenyl -5-chloro-2-hydroxybenzamide, selectively inhibits IKK beta, particularly when induced by proinflammatory cytokines, such as TNF-alpha and IL-1 beta. In the present study, we examined whether IKK beta inhibition has therapeutic effects on EIU by using IMD-0354 and its prodrug IMD-1041. Methods: Six-week-old male Lewis rats were used. EIU was induced with subcutaneous injections of 200 mu g of lipopolysaccharide LPS from Escherichia coli that had been diluted in 0. 1 ml of phosphate-buffered saline. 0 ml of 0. The rats were euthanized 24 h after LPS injection, and EIU severity was evaluated histologically. The number of infiltrating cells and the protein, TNF-alpha, and monocyte chemoattractant protein-1 MCP-1 concentrations in the aqueous humor were determined. TNF-alpha and MCP-1 concentrations were quantified with enzyme-linked immunosorbent assay. Eye sections were also stained with anti-NF kappa B and phosphorylated I-kappa B alpha antibodies. Results: The number of infiltrating cells in aqueous humor was 53. 8x10 5 , 72. 0x10 5 , 127. 0x10 5 , and 132. The total protein concentrations of aqueous humor were 92. 01 in aqueous humor. The number of NF kappa B positive nuclei was reduced when treated with IMD-0354. Furthermore, IMD-0354-treated EIU rats showed only background levels of phosphorylated I-kappa B alpha; however, it was strongly expressed in the iris-ciliary body cell cytoplasm of the IMD-0354 untreated EIU rats. 05 of aqueous humor in EIU. Conclusions: Acute uveitis was ameliorated by inhibition of IKK beta in rats. Extra nodal marginal zone B-cell lymphoma EMZL of the conjunctiva typically arises in the marginal zone of mucosa-associated lymphoid tissue. The pathogenesis of conjunctival EMZL remains unknown. We describe an unusual case of EMZL arising from reactive lymphoid hyperplasia RLH of the conjunctiva. A 35-year-old woman had fleshy salmon-pink conjunctival tumors in both eyes, oculus uterque OU. Specimens from conjunctival tumors in the right eye, oculus dexter OD , revealed a collection of small lymphoid cells in the stroma. Immunohistochemically, immunoglobulin Ig light chain restriction was not detected. In contrast, diffuse atypical lymphoid cell infiltration was noted in the left eye, oculus sinister OS , and positive for CD20, a marker for B cells OS. The tumors were histologically diagnosed as RLH OD, and EMZL OS. PCR analysis detected IgH gene rearrangement in the joining region JH region OU. After 11 months, a re-biopsy specimen demonstrated EMZL based on compatible pathological and genetic findings OD, arising from RLH. This case suggests that even if the diagnosis of the conjunctival lymphoproliferative lesions is histologically benign, confirmation of the B-cell clonality by checking IgH gene rearrangement should be useful to predict the incidence of malignancy. Purpose: To investigate the effects of a modified 360-degree suture trabeculotomy technique for primary and secondary open-angle glaucoma POAG and SOAG. Methods: We modified the procedure for 360-degree trabeculotomy by using a 5-0 nylon suture, making a scleral flap to allow clear identification of Schlemm canal, and creating a corneal side port incision opposite to the scleral flap to retrieve the suture used to cannulate and cleave the canal. The modified 360-degree suture trabeculotomy not combined with cataract surgery was performed on 25 eyes with POAG and 18 eyes with SOAG, and the results were compared retrospectively with those of standard trabeculotomy with metal trabeculotomes 16 eyes with POAG and 19 eyes with SOAG. " Results: Using this modified technique, Schlemm canal was appropriately incised without resistance. At 12 months after the modified 360-degree suture trabeculotomy and trabeculotomy with metal trabeculotomes, the mean postoperative IOP values were 13. 1 and 15. 2 mm Hg, respectively, and the mean numbers of antiglaucoma medications were 0. 5 and 1. 4, respectively. There was no significant difference between preoperative visual acuity and postoperative visual acuity in either procedure. Conclusions: This modified 360-degree suture trabeculotomy is a feasible surgical option for POAG and SOAG. PURPOSE. To investigate the expression, localization, and physiologic function of renin-angiotensin system RAS components in the mouse lacrimal gland. METHODS. To examine the change in tear secretion, mice received ARB AT1R blocker or AT2R antagonist. Tear secretion was assessed by cotton thread test before and after drug administration. RESULTS. The mRNAs coding for angiotensinogen, prorenin, ACE, and both AT1R and AT2R were found in normal lacrimal gland tissue and cultured lacrimal gland fibroblasts. Angiotensin II, AT1R, and AT2R were observed in the ducts and interstitial fibroblasts. AT1R and AT2R were also localized in blood vessels. All the cultured lacrimal gland fibroblasts expressed angiotensin II, AT1R, and AT2R. Tear secretion increased in mice that received ARB. CONCLUSIONS. The results are consistent with the hypothesis that a tissue-specific RAS is present in the lacrimal gland, and suggest that fibroblasts are one of the cell types playing a role in the tissue RAS. Tissue RAS might be involved in tissue function of regulating tear secretion in the lacrimal gland. Invest Ophthalmol Vis Sci. 2012;53:5416-5425 DOI: 10. 12-9891• Infliximab, an anti-TNF-alpha monoclonal antibody, administered to Beh double dagger et's disease BD patients in Japan with refractory intraocular inflammation, has shown excellent clinical results. However, some patients demonstrate a decreased response to infliximab during the course of the treatment. In the present study, we investigated the correlation between this reduced therapeutic effect and elevation of the serum antinuclear antibody ANA titers in patients with BD who were undergoing infliximab therapy. Seventeen patients 14 males and three females with uveitis in BD who were undergoing treatment with infliximab for 2 years or longer were enrolled. Their blood test results and clinical histories were obtained from medical records. One patient 5. The appearance of ANA was observed 6 months after the initiation of the infliximab therapy, and its titers gradually increased. None of the patients showed lupus symptoms. Five patients 29. In contrast, four patients 23. Here we report the positive conversion and subsequent elevation of serum ANA titers in some patients with BD after the initiation of infliximab therapy. Since all recurrences of uveitis were shown only in the ANA-positive patients, serum ANA titer may be a helpful biomarker for predicting the recurrence of ocular attacks in BD patients treated with anti-TNF-alpha antibody therapies. Objective. Behcet's disease is one of the major aetiologies of uveitis causing blindness in Asian countries. A genome-wide association study identified six microsatellite markers as disease susceptibility loci for Japanese patients with Behcet's disease. To confirm our recent results, these microsatellite markers were examined in a Korean population as a replication study. Methods. Study participants included 119 Behcet's disease patients and 141 controls. All were enrolled in Korea. Association between the six reported microsatellite markers D3S0186i, D6S0014i, D6S0032i, 536G12A, D12S0645i and D22S0104i and Behcet's disease was analysed. HLA-B was genotyped by sequence-based typing methods. Results. 028. 1 and 39. 2 and 20. 001. Conclusion. Purpose: To examine the expression of alphaB-crystallin and its colocalization with vascular endothelial growth factor in the epiretinal membrane of human proliferative diabetic retinopathy. Methods: Ten epiretinal membranes of proliferative diabetic retinopathy and three normal retinas surgically excised were included in this study. Paraformaldehyde-fixed, paraffin-embedded tissue sections were processed for immunohistochemistry with alphaB-crystallin, vascular endothelial growth factor, and CD31 antibodies. Results: AlphaB-crystallin was expressed in all epiretinal membranes examined. The immunolocalization of alphaB-crystallin was detected in the cytoplasm of CD31-positive endothelial cells, but not in normal retinal blood vessels. Furthermore, alphaB-crystallin immunoreactivity was colocalized in vascular endothelial growth factor-positive endothelial cells in proliferative diabetic retinopathy membranes. Conclusion: AlphaB-crystallin was expressed in proliferative diabetic retinopathy membranes, and colocalized with vascular endothelial growth factor-positive neovessels. AlphaB-crystallin may play a potential role in the pathogenesis of epiretinal membranes in proliferative diabetic retinopathy, together with vascular endothelial growth factor. RETINA 32:1190-1196, 2012• PURPOSE. Vascular adhesion protein VAP -1, a multifunctional molecule with adhesive and enzymatic properties, is expressed at the surface of vascular endothelial cells of mammals. It also exists as a soluble form sVAP-1 , which is implicated in oxidative stress via its enzymatic activity. This study explores a link between increased level of sVAP-1 and oxidative stress in proliferative diabetic retinopathy PDR with a focus on mechanistic components to form sVAP-1 by shedding from retinal endothelial cells. METHODS. Protein levels of sVAP-1 and N epsilon- hexanoyl lysine HEL , an oxidative stress marker, in the vitreous samples from patients with PDR or non-PDR were measured by ELISA. RESULTS. Protein level of sVAP-1 was increased and correlated with HEL in the vitreous fluid of patients with PDR. Retinal capillary endothelial cells released sVAP-1 when stimulated with high glucose or inflammatory cytokines, such as TNF-alpha and IL-1 beta in vitro. Furthermore, matrix metalloproteinase-2 and -9, type IV collagenases, were the key molecules to mediate the protein cleavage of VAP-1 from retinal capillary endothelial cells. CONCLUSIONS. Our data for the first time provide evidence on the link between sVAP-1 and type IV collagenases in the pathogenesis of PDR. Invest Ophthalmol Vis Sci. 2012;53:4055-4062 DOI:10. 12-9857• Lutein, a xanthophyll of a carotenoid, is anticipated as a therapeutic product to prevent human eye diseases. However, its biological mechanism is still unclear. Here, we show the molecular mechanism of lutein's effect to reduce photodamage of the retina. Visual function was measured by electroretinogram, and histological changes were observed. Immunohistochemical and immunoblot analyses were performed to analyze molecular mechanism. The reactive oxygen species induced in the retina was evaluated by fluorescent probes. In the mice after light exposure, reduction of a-wave and b-wave amplitudes in electroretinogram, indicating visual impairment, and thinning of the photoreceptor cell layer owing to apoptosis were both attenuated by lutein diet. Interestingly, gamma-H2AX, a marker for double-strand breaks DSBs in DNA, was up-regulated in the photoreceptor cells after light exposure, but this increase was attenuated by lutein diet, suggesting that DSBs caused by photodamage contributed to the photoreceptor cell death and that this change was suppressed by lutein. Moreover, the expression of eyes absent EYA , which promotes DNA repair and cell survival, was significantly up-regulated with lutein diet in the light-exposed retina. Therefore, lutein induced EYA for DNA repair, which could suppress DNA damage and photoreceptor cell apoptosis. Lutein reduced light-induced oxidative stress in the retina, which might contribute to promote DNA repair. The lutein-supplemented diet attenuated light-induced visual impairment by protecting the photoreceptor cells' DNA. C 2012 Elsevier Inc. All rights reserved. BACKGROUND: Chickenpox is rarely associated with posterior segment inflammation. We report on a case of unilateral chickenpox chorioretinitis with retinal exudates and periphlebitis. CASE PRESENTATION: A 21-year-old healthy man, who suffered from chickenpox 2 weeks prior to symptom development, exhibited mild anterior chamber cells, vitreous opacity, sheathing of retinal veins, and yellow-white exudates in his right eye. Varicella zoster virus DNA was detected by polymerase chain reaction in the aqueous humor. He was treated with intravenous acyclovir followed by oral prednisolone and valaciclovir. Aqueous cells quickly disappeared and retinal exudates diminished within 1 month, leaving faint retinal scarring. Retinal arteritis had never been observed in this patient.

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