Mizuki Tagami

Expression of ATP-binding cassette transporters at the inner blood-retinal barrier in a neonatal mouse model of oxygen-induced retinopathy.

ATP-binding cassette (ABC) transporters at the blood-brain barrier (BBB) are responsible for the majority of the transcellular movement of various substrates, including various drugs, and contribute to the maintenance of brain homeostasis. Clinically, the abnormal expression of efflux transporters at the BBB is known to be associated with brain diseases such as epilepsy. In the retina, vascular endothelial cells outline the inner blood-retinal barrier (BRB) like the BBB, and some ABC efflux transporters are expressed in the adult retina. However, little is known about ABC transporter expression during retinal development or under pathological conditions. Here, we examined ABC transporter expression in the mouse retina, and demonstrated that P-glycoprotein (P-gp)/ABCB1, Mrp4/ABCC4, and Bcrp/ABCG2 were almost uniformly expressed in these blood vessels, including the capillaries and large vessels. This expression persisted throughout the developmental period, and the hyaloid vessels that normally feed the developing eye were immunoreactive for P-gp and Mrp4. Furthermore, we investigated ABC transporter expression in pathological angiogenesis using an oxygen-induced retinopathy model where hypoxia-induced preretinal neovascularization occurred around the central avascular retina. P-gp was prominently immunoexpressed but Mrp4 and Bcrp were weakly immunoexpressed, in the preretinal neovascular tufts. These findings will be helpful for understanding the roles of ABC transporters during both physiological and pathological retinal angiogenesis, and might provide new insights for safe and effective drug administration to infants or patients with angiogenic ocular disease.

MRP4 knockdown enhances migration, suppresses apoptosis, and produces aggregated morphology in human retinal vascular endothelial cells

The multidrug resistance protein (MRP) MRP4/ABCC4 is an ATP-binding cassette transporter that actively effluxes endogenous and xenobiotic substrates out of cells. In the rodent retina, Mrp4 mRNA and protein are exclusively expressed in vascular endothelial cells, but the angiogenic properties of Mrp4 are poorly understood so far. This study aims to explore the angiogenic properties of MRP4 in human retinal microvascular endothelial cells (HRECs) utilizing the RNA interference (RNAi) technique. MRP4 expression was decreased at the mRNA and protein levels after stimulation with exogenous vascular endothelial growth factor in a dose-dependent manner. RNAi-mediated MRP4 knockdown in HRECs do not affect cell proliferation but enhances cell migration. Moreover, cell apoptosis induced by serum starvation was less prominent in MRP4 siRNA-treated HRECs as compared to control siRNA-treated HRECs. In a Matrigel-based tube-formation assay, although MRP4 knockdown did not lead to a significant change in the total tube length, MRP4 siRNA-treated HRECs assembled and aggregated into a massive tube-like structure, which was not observed in control siRNA-treated HRECs. These results suggest that MRP4 is uniquely involved in retinal angiogenesis.

Uveal extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type with concomitant extraocular lesions in a Japanese man

Extranodal marginal zone B-cell lymphoma of the mucosaassociated lymphoid tissue type (MALT lymphoma) of the uvea is a rare clinical condition, and the diagnosis is challenging [1, 2]. Recently, the clinical diagnosis has been reached by precise histopathological analysis of the biopsy specimen of the concomitant extraocular lesion [3, 4] sometimes detected using imaging modalities [3]. Here, we report the first case of uveal MALT lymphoma with concomitant extraocular lesions in a Japanese man. Case report

Impact of Intravitreal Injection of Tissue Plasminogen Activator on Full-Field Electroretinogram in Patients with Macular Oedema Secondary to Retinal Vein Occlusion

Purpose: To evaluate the retinal toxicity of intravitreal tissue plasminogen activator (tPA) injection for branch and central retinal vein occlusion (BRVO and CRVO) using the electroretinogram (ERG). Procedures: Ten BRVO patients and 5 CRVO patients were enrolled. A complete examination including full-field ERG, visual acuity, central retinal thickness (CRT), and evaluation of systemic and ocular complications was performed before and after intravitreal tPA injection. Results: No significant differences were found in the amplitude or implicit time of any ERG component after tPA injection, and no systemic or ocular complication was observed. The improvement of visual acuity was significant at month 3 in the BRVO group (p < 0.05) but not in the CRVO group. CRT significantly decreased over the course of 3 months in both groups (p < 0.01). Conclusion: Intravitreal tPA injection seems to be a safe and effective treatment option for macular oedema caused by retinal vein occlusions.

Scleral buckling for primary rhegmatogenous retinal detachment using noncontact wide-angle viewing system with a cannula-based 25 G chandelier endoilluminator

Purpose The aim of this study is to report the result of scleral buckling (SB) using a combination of a noncontact wide-angle viewing system and a cannula-based 25 G chandelier endoilluminator. Methods Retrospective analyses of the medical records of 79 eyes of 79 patients with primary uncomplicated rhegmatogenous retinal detachments who had underwent SB using a combination of a noncontact wide-angle viewing system and a chandelier endoilluminator were performed. Results There were 50 men and 29 women. The mean ± standard deviation age was 43.7±16.0 years. Their preoperative best-corrected visual acuity (BCVA) was 0.31±0.65 logMAR units. The final BCVA was 0.10±0.31 logMAR units, which was significantly better than the preoperative BCVA (P<0.01). The initial and final anatomical success rates were 92.4% and 100%, respectively. Backward logistic multiple regression analysis revealed no relationship between explanatory variables and the primary anatomic success (P=0.104). Conclusion SB using a combination of a noncontact wide-angle viewing system and a chandelier endoilluminator is a modified new technique and may be a valid option for the management of rhegmatogenous retinal detachments.

Autologous antibodies to outer retina in acute zonal occult outer retinopathy

PurposeOur aim was to use molecular biological methods to study evidence of autoimmune disease in five patients with acute zonal occult outer retinopathy (AZOOR).MethodsOphthalmologic data and sera were collected from all patients, who underwent visual field (VF) examination, optical coherence tomography (OCT), and multifocal electroretinogram (mfERG) recording. Serum was prepared from each patient’s blood and analyzed for antiretinal antibody activity using immunohistochemistry and Western blot analysis on mouse and human retinas. We also searched for antigen proteins using mass spectrometry.ResultsSymptoms were blurred vision in three patients and VF defects in two; all had enlargement of the Mariotte blind spot by VF testing. OCT findings in areas corresponding to the scotoma revealed disruptions of junction borders between inner and outer segment lines. mfERGs amplitudes were reduced in each corresponding scotoma area. Immunohistochemical serum staining revealed the target antigen was present in all photoreceptors of the mouse sensory retina. Western blot analysis using patient serum samples revealed some possible candidate antigens. Mass spectrometry could not determine the causative antigen; however, a list of candidates was discovered.ConclusionWe determined that AZOOR could be an autoimmune disease. All AZOOR patients tested using molecular biological methods had antiretinal antigens.

Topical Treatment for Orbital Capillary Hemangioma in an Adult Using a β-Blocker Solution

Purpose: To report a case of orbital capillary hemangioma in an adult who was successfully treated with topical timolol maleate 0.5% solution. Methods: Case report. Results: A 43-year-old female presented both superficial and deep orbital capillary hemangioma. Topical timolol maleate was applied twice daily. The superficial lesions have nearly disappeared after 1 year of treatment. The deeper lesions have also been reduced in size according to MRI. Conclusion: We report an adult patient with a relatively large orbital capillary hemangioma who was successfully treated with a topical β-blocker solution. This treatment might be applicable for orbital capillary hemangiomas, regardless of the patients age, because of its effectiveness and safety.

Bilateral Optic Disc Anomalies Associated with PAX2 Mutation in a Case of Potter Sequence.

Purpose: To describe the ophthalmic findings in the fundus of a Japanese infant with Potter sequence having a mutation in the PAX2 gene. Methods: A 1-month-old infant diagnosed with Potter sequence who had bilateral renal hypoplasia and a mutation in the PAX2 gene was subjected to detailed ophthalmic examination. Results: Funduscopy revealed a megalopapilla with marked excavation in the right eye. The left optic disc showed a similar abnormality, but to a lesser extent. B-mode ultrasonography and magnetic resonance imaging detected giant cystic lesions occupying the optic nerve head in both eyes. According to these results, we diagnosed this patient as having papillorenal syndrome (PRS) associated with a PAX2 mutation. Conclusions: This report shows ophthalmic findings in the youngest patient with PRS and PAX2-associated Potter sequence. Optic disc anomalies may be involved in some infants with Potter sequence. We anticipate an increase in opportunities for ophthalmic examinations in infants with diseases such as Potter sequence with previously high mortality rates.

Prolongation of injection interval after switching therapy from ranibizumab to aflibercept in Japanese patients with macular edema secondary to branch retinal vein occlusion

Purpose This study was conducted to investigate the outcome of switching therapy from ranibizumab to aflibercept in Japanese patients with macular edema (ME) secondary to branch retinal vein occlusion (BRVO) in daily practice. Materials and methods This retrospective study enrolled 15 eyes in 15 Japanese patients with ME secondary to BRVO who had been receiving a pro re nata regimen of ranibizumab and had provided written informed consent to switch to aflibercept therapy. The intravitreal injection interval, central retinal thickness, and visual acuity were evaluated before and after switching. Results The mean period of ranibizumab treatment was 11.8±4.2 months. The mean observation period after switching to aflibercept was 10.6±3.4 months, and seven patients were observed for more than 12 months after switching. The mean intravitreal injection interval was prolonged by 23.6 days with aflibercept (68.2±26.4 days with ranibizumab vs 91.8±33.2 days with aflibercept; P=0.0011). The mean intravitreal injection interval just before the switch was 81.3±35.6 days and was significantly prolonged to 100.8±34.2 days just after the switch to aflibercept (P=0.0309). The mean central retinal thickness did not change before or after the switch to aflibercept (295±55 μm with ranibizumab vs 276±25 μm with aflibercept; P=0.12). The mean visual acuity also remained at an improved level after the switch. No systemic or ocular side effects were evident during the study period. Conclusion Switching therapy from ranibizumab to aflibercept in Japanese patients with ME secondary to BRVO prolonged the intravitreal injection interval without anatomical or functional degradation.

A surviving case of papillorenal syndrome with the phenotype of Potter sequence.

Papillorenal syndrome (PRS, OMIM #120330), also known as renal coloboma syndrome, is a rare autosomal dominant disorder caused by PAX2 gene mutations and is characterized by renal hypoplasia and optic disc anomalies. The renal phenotypic feature of PRS is known to have a wide variation from only mild proteinuria without renal dysfunction to end-stage renal disease (ESRD) at school age to adulthood, even in patients with the same PAX2 gene mutations. The spectrum of clinical symptoms varies even among affected family members. To date, there are no reports of surviving patients with PRS who developed oligohydramnios and ESRD during the fetal and neonatal periods; these conditions can cause Potter sequence, which is a lethal condition due to bilateral renal hypoplasia and pulmonary hypoplasia. We report here a case of PRS with Potter sequence who survived by cardiopulmonary intensive care including peritoneal dialysis (PD).