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Purpose: To determine the prevalence of macular abnormalities detected by optical coherence tomography (OCT) in patients with retinitis pigmentosa (RP), and to report the results of pars plana vitrectomy (PPV) in five patients with RP. Methods: OCT images of the macula of 622 eyes of 323 patients with RP were evaluated. All patients had a complete clinical examination, and PPV was performed on two RP patients with a macular hole (MH), two patients with vitreomacular traction (VMT) syndrome, and one patient with cystoid macular oedema (CME). Results: A macular lesion was detected by OCT in 46 eyes (7.4%) of 37 patients (11.5%). CME was detected in 34 eyes (5.5%) of 26 patients, an epiretinal membrane in four eyes of four patients, VMT in five eyes of four patients, and full-thickness MH in three eyes of three patients. PPV was performed on five of these eyes. The MH was closed with vision improvement after a single surgery in one eye, and was closed after repeated PPVs with a decrease of vision in another eye. In both patients with VMT, the visual acuity decreased after the surgery. The macular morphology and visual acuity did not improve postoperatively on the one patient with CME who underwent PPV. Conclusion: When OCT is used, macular abnormalities are present in 7.4% of patients with RP, which is lower than the prevalence reported earlier. Although vitrectomy can improve the macular morphology in some patients with RP, improvement of visual function may be limited most likely because of the long-standing retinal dysfunction.

Background: Ocular angiogenesis is regulated by polypeptides including cytokines, which are known to affect vascular endothelial cells. We have reported that hyalocytes interact with vascular endothelial cells, and some cytokines affect these interactions. Aims: To determine the effect of various chemically active agents on the viability of endothelial cells alone and cocultured with hyalocytes. Methods: The viability of human retinal endothelial cells (HRECs) was determined after exposure to IL-1α, IL-1β, IL-6, TNFα and VEGF using the MTT assay. These results were compared to the viability when the HRECs were cocultured with porcine hyalocytes that had been exposed to different types of cytokines. The effects of bevacizumab, fenofibrate and dexamethasone on the viability of HRECs in coculture with hyalocytes were also assessed. Results: Ten micrograms/millilitre of bevacizumab decreased the percentage of living HRECs stimulated by VEGF without hyalocytes, but with the hyalocytes, 100 μg/ml of bevacizumab was required to decrease the percentage of viable HRECs stimulated by VEGF. Fenofibrate, at 5 μg/ml, decreased the viability of HRECs stimulated by IL-1β and VEGF without hyalocytes but could not decrease the viability of HRECs cocultured with hyalocytes. Dexamethasone, at 50 μg/ml, decreased the viability of HRECs stimulated by IL-1α, IL-1β, IL-6 and VEGF without hyalocytes but could not decrease the viability of HRECs cocultured. Conclusions: Coculturing HRECs with vitreous-derived hyalocytes depressed the effects of cytokines, bevacizumab, fenofibrate and dexamethasone. This suggests that the vitreal hyalocytes may play a role in pathogenic endothelial cell proliferation in vivo. Future studies to better understand this pathobiology should utilize coculture systems of HRECs and vitreal hyalocytes.

Purpose To determine the effect of high doses of AGEs on neurite regeneration in isolated rat retinas, and the regenerative effects of different neurotrophic factors. Methods Retinal explants of 4 adult SD rats were three-dimensionally cultured in collagen gel, and incubated in: 1) serum free control culture media; 2) 100 μg/ml glucose-AGE-BSA, glycolaldehyde-AGE-BSA, glyceraldehyde-AGE-BSA media; 3) glucose, glycol, glycer+100 ng/ml neurotrophin 4 (NT-4)media; 4) glucose, glycol, glycer+100 ng/ml hepatocyte growth factor (HGF) media; 5)glucose, glycol, glycer+100 ng/ml glial cell line derived neurotrophic factor (GDNF) media; or 6) glucose, glycol, glycer+100 ng/ml tauroursodeoxycholic acid (TUDCA) media. After 7 days, the number of regenerating neurites were counted under a phase-contrast microscope. The explants were immunostained for NFkB transcription factor. Statistical analyses were performed by one-way ANOVA. Results In retinas incubated with AGEs, the number of regenerating neurites were fewer than in control. Neurotrophic factors increased the number of neurites, but more significantly in the NT4 group. The number of NFkB immunopositive cells was higher in retinas exposed to AGEs than in control (53,2 ± 7,2% vs.31,6 ± 16,08%,P = 0,0146). Neurotrophic factors decreased the number of immunopositives cell, but more significantly in the NT4 group. Conclusion High dose AGEs induce activation of NFkB and NT4 significantly suppresses this activation and enhances neurite regeneration in isolated retinas compared with other neurotrophic factors such as HGF,GDNF,and TUDCA.

Purpose We present a case of orbital mucosa-associated lymphoid tissue lymphoma accompanied with refractory serous retinal detachment. Methods A 44-year-old man who developed uveitis in the right eye was referred to Chiba National Hospital. His visual acuity was 0.5, and the IOP was 34 mmHg OD. Keratic precipitates and inflammatory cells were observed in the anterior chamber. Fundus examinations showed a serous retinal detachment (SRD) and a hyperemic disc. B-mode ultrasonography showed a thickened choroidal membrane and a retrobulbar mass. The MRI findings showed that the mass had T1- and T2-low intensities. Although topical steroid treatments improved the inflammation, the SRD was not improved. Because the oral steroid administration did not reduce the size of the retrobulbar mass, he was referred to the Chiba University Hospital. Results Two month later, the retrobulbar mass had increased, and a partial resection biopsy combined with flow cytometry was performed. The final diagnosis was mucosa-associated lymphoid tissue lymphoma. The intraocular IL-10 was not measurable. After R-CHOP chemotherapy, the tumor size decreased but the SRD was not improved. Not only lymphoma cell infiltration but also choroidal circulatory disturbance may be associated with the development of the SRD. Conclusion Retrobulbar malignant lymphomas accompanied by refractory SRD are very rare and difficult to diagnose without biopsy. But, early diagnosis is more helpful in deciding the appropriate therapy.

Purpose To investigate the association of the Fourier domain optical coherence tomography (FD-OCT, Optovue) parameters with the level of HbA1c and duration of the diabetes mellitus (DM) in patients at the early stage of diabetic retinopathy (DR). Methods Thirty eyes of 30 patients with minimal DR (non-DR or mild NPDR) that were examined at the Chiba University Hospital from December 2011 to March 2012 were studied. The participants had no other ocular diseases and no history of surgeries. Three parameters embedded in the Optovue, the macular mapping 5 (MM5), RNFL, and ganglion cell complex (GCC), were performed, and the coefficients of correlation between these parameters and the HbA1c and the DM duration were analyzed with the Spearman rank correlation. A P

Purpose: Hyperglycaemia has been identified as major risk factor for diabetic retinopathy (DR). It is widely accepted that the progression of DR is mainly due to a local imbalance of pro- versus anti-angiogenic factors in the retina. In this study, we investigated whether retinal pigment epithelial (RPE) cells produced pro-angiogenic factors under high glucose (HG) conditions in vitro. Methods: Cultured human retinal endothelial (RE) cells were exposed to conditioned medium from retinal pigment epithelium cells (ARPE-19) grown in HG medium and assessed for tube formation. Based on the expression profiles of ARPE-19, we investigated whether ANGPTL4 was a major angiogenic factor released from ARPE-19 under HG conditions using cultured human RE cells as the test system for experiments with recombinant protein, conditioned medium from ARPE-19 and RNA interference (RNAi). Results: The conditioned medium from ARPE-19 cultured under HG conditions promoted tube formation of cultured human RE cells. GeneChip analysis showed that ANGPTL4 was one of the highest upregulated genes under HG conditions. In addition, recombinant ANGPTL4 promoted all of the elements of angiogenesis in human RE cells in vitro. The results of experiments using conditioned medium from ARPE-19 combined with RNAi demonstrated that ANGPTL4 was a major angiogenic factor released from ARPE-19 under HG conditions. Conclusions: ANGPTL4 was induced by high glucose in RPE cells and exhibited potent angiogenic activity on RE cells. Our results are unique and may potentially add a new candidate to the long list of molecules involved in diabetic retinopathy.

Purpose To compare the effect of posterior sub-Tenon's capsule triamcinolone acetonide injection (STTA) with the surgical outcomes of pars plana vitrectomy (PPV) for diffuse diabetic macular edema (DME). Methods The medical records of 52 patients (52 eyes) with diffuse DME were reviewed. 26 eyes underwent STTA (20mg) and other 26 eyes – vitrectomy combined with cataract surgery. The central macular thickness (CMT) measured by OCT and best-corrected visual acuity (BCVA) were examined before and 1, 3, and 6 months after treatment. Statistical analysis was performed with student t-test, Mann-Whitney U-test and repeated measured ANOVA. Results Preop BCVA was 0.65±0.4 logMAR units in the STTA group and 0.77±0.3 logMAR units in the PPV group. One, 3 and 6 months postop BCVA were 0.59±0.4, 0.53±0.5 and 0.47±0.4 in the STTA group and 0.77±0.3, 0.59±0.4, and 0.59±0.4 in the PPV group. Preop CMT were 608.1±220μm in the STTA group and 534.4±157μm in the PPV group. One, 3 and 6 months postop CMT were 392.1±193μm, 284.4±101.7μm and 331.4±121μm in the STTA group and 386.8±175μm, 354.2±101.7μm and 354.2±156.4μm in the PPV group. The differences in the BCVA and the CMT between two groups were not significant at any periods before and after treatment. Conclusion Although STTA and PPV can significantly improve the BCVA and reduce the CMT in patients with diffuse DME, the differences in the BCVA and the CMT were not significant. Considering the minor invasion, STTA can be the first choice for the treatment of diffuse DME.

Purpose To determine the effect of AGEs with or without NT-4 on neuronal cell death and regeneration in isolated rat retinas. Methods Retinal explants of 4 adult SD rats were three-dimensionally cultured in collagen gel and were incubated either in; 1) serum free control culture media, 2) 10 μg/ml glucose-AGE-BSA media, 3) 10 μg/ml glycolaldehyde-AGE-BSA media, 4) 10 μg/ml glyceraldehyde-AGE-BSA media, 5) glucose-AGE+100ng/ml NT-4 media, 6) glycol-AGE+100ng/ml NT-4 media, or 7) glycer-AGE+100 ng/ml NT-4 supplemented culture media. After 7 days, the number of regenerating neurites from the explants was counted under a phase-contrast microscope. After counting, retinal explants were fixed, cryosectioned, and stained by TUNEL and DAPI. The ratio of TUNEL-positive cells to the number of DAPI-staining nuclei in the ganglion cell layer was calculated. Statistical analysis was performed by one-way ANOVA. Results In retinas incubated with AGEs (glucose-AGE, glycol-AGE, and glycer-AGE), the numbers of regenerating neurites were fewer than in retinas without AGE (P=0.0033, P=0.0044, and P=0.0238, respectively) and the numbers of TUNEL-positive cells were higher than in control media (P

Purpose Although multicentric Castleman disease is a rare but life-threatening disease, eye complications are extremely uncommon. We present a case of refractory uveitis accompanied with Castleman disease successfully treated with tocilizmab. Methods A 58-year-old man with Castleman disease was introduced for refractory uveitis to Chiba University Hospital. Large cells were detected in the anterior chamber and increased vascular permeability of retinal vessels has been found in both eyes. Although the patient was treated with oral and eye drop steroid treatment, the uveitis symptoms had not decreased. The serum levels of CRP and IL-6 were increased. The level of IL-6 concentration in the anterior chamber was the same as the serum level of IL-6. The humanized anti-IL-6 receptor-antibody (tocilizumab: 8 mg/kg per two weeks) was administrated for the patient because of poor general condition. The effect of tocilizumab was evaluated with routine ophthalmological examinations, fluorescein angiography (FA), Glodmann perimetry, and OCT. Results After tocilizmab treatment, large cells in the anterior chamber were undetectable and vascular permeability was improved in FA. The serum levels of CRP and IL-6 decreased and the general condition improved. The side effect of tocilizumab was not observed during the treatment. Conclusion Tocilizumab treatment was significantly effective for uveitis accompanied with Castleman disease. Although it is extremely rare, uveitis accompanied with Castleman disease may reflect poor general condition in patients with Castleman disease, and it may be one of the hallmarks to consider tocilizumab treatment.

Purpose To present a case of Werner syndrome accompanied with refractory cystoid macular edema (CME), and analyze the expression and the distribution of WRN proteins in human retinas. Methods A 35-year-old individual with Werner syndrome exhibited CME after YAG laser treatment. Optical coherence tomography (OCT) scans were indicative of CME in the right eye. The patient received topical eye drops (0.1% bromfenac sodium hydrate twice daily and 1% dorzolamide hydrochloride thrice daily), sub-Tenon triamcinolone injection thrice, intravitreal bevacizumab injection twice, and pars plana vitrectomy in the right eye. Genetic analyses were performed to conduct diagnosis of the individual. To examine the expression and distribution of WRN proteins in the retinas, immunohistochemistry for WRN proteins in human retinas was performed. Results CME in the right eye could not be improved by any of the treatment. During the follow-up period, CME developed in the left eye. Genetic analyses detected compound heterozygosity of Mut4 and Mut11 in WRN gene and the individual was diagnosed with Werner syndrome. Immunohistochemical analysis of WRN proteins expression in human retinas indicated that WRN proteins were expressed in Muller cells of the inner nuclear layer and the outer nuclear layer. Conclusion Patients with Werner syndrome may develop severe CME. A pathological link may exist between the potential mutation in WRN gene and the development of CME in patients with Werner syndrome.

PURPOSE This study aimed to investigate the roles played by vitreous-derived cells in the pathogenesis of vitreoretinal vascular diseases. METHODS The vitreous was removed from porcine eyes and small pieces were cultured from which vitreous-derived cells were isolated. Polymerase chain reaction and ELISA were performed to determine the expression of vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6) at the mRNA and protein levels, respectively. The viability of human retinal endothelial cells (HRECs) exposed to vitreous-derived cells was assessed by MTT assay. RESULTS Expression of the mRNA and protein of VEGF and IL-6 was increased by exposing the porcine vitreous-derived cells (PVDCs) to interleukin-1alpha (IL-1alpha), interleukin-1beta (IL-1beta) and tumour necrosis factor alpha (TNFalpha), but not to VEGF or IL-6. The percentage of living human vascular endothelial cells was increased by including VEGF and IL-6 in the culture media. The viability of HRECs was affected by co-culturing them with PVDCs that had been exposed to IL-1alpha, IL-1beta, IL-6, TNFalpha and VEGF. CONCLUSIONS Porcine vitreous-derived cells are stimulated by IL-1alpha, IL-1beta and TNFalpha, and produce VEGF and IL-6, which then enhance the proliferation of vascular endothelial cells. This network, including the cytokines and different types of cells, may contribute to the pathogenesis of proliferative vitreoretinal diseases.

We recorded visually evoked cortical potentials to pattern stimuli (PVECPs) in 22 patients who received a posterior chamber intraocular lens implant. The mean latency of the P100 obtained from patients was not significantly different from that of age-matched normal phakic subjects. Furthermore, we found that both groups showed a similar increased delay of the P100 latency with age. The results of this study indicated that the senile opacity of the crystalline lens does not contribute to changes of PVECPs with age. These alterations may be due to senile changes of the neural pathway.