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1.  Changes in Outer Retinal Microstructures during Six Month Period in Eyes with Acute Zonal Occult Outer Retinopathy-Complex 
PLoS ONE  2014;9(10):e110592.
To study the changes in the outer retinal microstructures during a six month period after the onset of acute zonal occult outer retinopathy (AZOOR)-complex by spectral-domain optical coherence tomography (SD-OCT).
Seventeen eyes of 17 patients with the AZOOR-complex were studied. The integrity of the external limiting membrane (ELM), ellipsoid zone (EZ; also called the inner/outer segment junction), and interdigitation zone (IDZ; also called the cone outer segment tips) were evaluated in the SD-OCT images obtained at the initial visit and at six months. The three highly reflective bands were divided into three types; continuous, discontinuous, and absent. The integrity of the outer nuclear layer (ONL) was also assessed.
Among the three highly reflective bands, the IDZ was most altered at the initial visit and least recovered at six months. Fifteen of 17 eyes (88%) had a recovery of at least one of the three bands at six months in the retinal area where the ONL was intact, and these areas showed an improvement of visual field. Three eyes (18%) had retinal areas where the ONL was absent at the initial visit, and there was no recovery in both the retinal structures and visual fields in these areas.
Our results indicate that more than 85% eyes with AZOOR-complex show some recovery in the microstructures of the outer retina during a six month period if the ONL is intact. We conclude that SD-OCT is a useful method to monitor the changes of the outer retinal microstructure in eyes with the AZOOR-complex.
PMCID: PMC4214711  PMID: 25356549
2.  Whole Exome Analysis Identifies Frequent CNGA1 Mutations in Japanese Population with Autosomal Recessive Retinitis Pigmentosa 
PLoS ONE  2014;9(9):e108721.
The purpose of this study was to investigate frequent disease-causing gene mutations in autosomal recessive retinitis pigmentosa (arRP) in the Japanese population.
In total, 99 Japanese patients with non-syndromic and unrelated arRP or sporadic RP (spRP) were recruited in this study and ophthalmic examinations were conducted for the diagnosis of RP. Among these patients, whole exome sequencing analysis of 30 RP patients and direct sequencing screening of all CNGA1 exons of the other 69 RP patients were performed.
Whole exome sequencing of 30 arRP/spRP patients identified disease-causing gene mutations of CNGA1 (four patients), EYS (three patients) and SAG (one patient) in eight patients and potential disease-causing gene variants of USH2A (two patients), EYS (one patient), TULP1 (one patient) and C2orf71 (one patient) in five patients. Screening of an additional 69 arRP/spRP patients for the CNGA1 gene mutation revealed one patient with a homozygous mutation.
This is the first identification of CNGA1 mutations in arRP Japanese patients. The frequency of CNGA1 gene mutation was 5.1% (5/99 patients). CNGA1 mutations are one of the most frequent arRP-causing mutations in Japanese patients.
PMCID: PMC4182560  PMID: 25268133
3.  Probing of congenital nasolacrimal duct obstruction with dacryoendoscope 
A congenital nasolacrimal duct obstruction (CNLDO) is a relatively common disease in infants. We evaluated the results of probing three patients with CNLDO, under direct view, with a dacryoendoscope.
Three cases of CNLDO were examined and treated by probing with a dacryoendoscope, under intravenous anesthesia. The diameter of the dacryoendoscope probe was 0.7 mm, and we were able to observe the inner walls of the lacrimal duct and able to guide the probe through the duct.
In all cases, the site of obstruction was detected, and the probe was used to remove the obstruction. At 2 weeks after the removal of the obstruction, there was no epiphora or mucopurulent discharge in any of the cases. No complications were detected intra- and postoperatively.
Although only three cases were studied, we believe that probing with a dacryoendoscope is a safe and effective method of treating a CNLDO. More cases need to be studied.
PMCID: PMC4037296  PMID: 24876765
probing; epiphora; mucoprulent discharge
4.  Choroidal atrophy in a patient with paraneoplastic retinopathy and anti-TRPM1 antibody 
The purpose of this paper is to report choroidal atrophy in a patient with cancer-associated retinopathy who had autoantibodies against the transient receptor potential cation channel, subfamily M, member 1 (TRPM1). A 69-year-old man visited our clinic in July 2010 with complaints of blurred vision and night blindness in both eyes. The full-field electroretinograms were negative type, indicating ON bipolar cell dysfunction. General physical examination revealed small cell carcinoma of the lung, and Western blot of the patient’s serum showed autoantibodies against TRPM1. We diagnosed this patient with cancer-associated retinopathy and retinal ON bipolar dysfunction due to anti-TRPM1 autoantibody. We followed him for more than 2 years from the initial visit and his symptoms have not changed. However, consistent with the choroidal hypopigmentation of the fundus, spectral domain optical coherence tomography showed a decrease in choroidal thickness of about one third over a 2-year follow-up period. We suggest that this case of gradually progressive choroidal atrophy was caused by the autoantibody against TRPM1 directly, because TRPM1 is expressed not only on ON bipolar cells but also on melanocytes. These findings indicate that we should be aware of choroidal thickness in patients with paraneoplastic retinopathy who have retinal ON bipolar dysfunction with the anti-TRPM1 antibody.
PMCID: PMC3921079  PMID: 24523577
choroidal thickness; melanocyte; TRPM1; cancer-associated retinopathy; paraneoplastic retinopathy
5.  Retinal Remodeling in the Tg P347L Rabbit, a Large-Eye Model of Retinal Degeneration 
The Journal of comparative neurology  2011;519(14):2713-2733.
Retinitis pigmentosa (RP) is an inherited blinding disease characterized by progressive loss of retinal photo-receptors. There are numerous rodent models of retinal degeneration, but most are poor platforms for interventions that will translate into clinical practice. The rabbit possesses a number of desirable qualities for a model of retinal disease including a large eye and an existing and substantial knowledge base in retinal circuitry, anatomy, and ophthalmology. We have analyzed degeneration, remodeling, and reprogramming in a rabbit model of retinal degeneration, expressing a rhodopsin proline 347 to leucine transgene in a TgP347L rabbit as a powerful model to study the pathophysiology and treatment of retinal degeneration. We show that disease progression in the TgP347L rabbit closely tracks human cone-sparing RP, including the cone-associated preservation of bipolar cell signaling and triggering of reprogramming. The relatively fast disease progression makes the TgP347L rabbit an excellent model for gene therapy, cell biological intervention, progenitor cell transplantation, surgical interventions, and bionic prosthetic studies.
PMCID: PMC3894993  PMID: 21681749
retinitis pigmentosa; retinal degeneration; retinal remodeling; neural remodeling; transgenic; electron microscopy; light microscopy; confocal microscopy; electroretinogram; computational molecular phenotyping; human; rabbit
6.  Histopathological examination of Acanthamoeba sclerokeratitis 
To report the histopathological findings in a case of severe Acanthamoeba sclerokeratitis (ASK).
Patient and methods
A 46-year-old patient was referred to the Department of Ophthalmology of Mie University Hospital because of a severe corneal ulcer of the right eye of 6 months’ duration. Our initial examination showed a ring-shaped corneal opacity with extensive epithelial defects and nodular scleritis. Cysts of Acanthamoeba were identified in cultures from corneal scrapings, and he was diagnosed with ASK. He was started on antiamoebic treatment, including topical micafungin and chlorhexidine. The corneal ulcer was debrided several times. One month later, he developed necrotizing scleritis, and the cornea suddenly perforated. The eye was enucleated because of severe pain and prepared for histopathological examination.
The histopathological examination showed an infiltration of polymorphonuclear leukocytes throughout the corneal stroma and also in the limbal area of the sclera, forming an abscess. Granulation tissue was observed in the anterior sclera close to the ciliary body, but the posterior regions of the eye were not affected by inflammation or tissue destruction. The cysts of Acanthamoeba were observed only in the cornea.
Histopathological examination of an eye with severe ASK showed that the inflammation and tissue granulation were present only in the anterior part of eye, and the posterior segment was not affected. Because the inflammation and tissue destruction were confined to the anterior segment, enucleation might not have been necessary if the severe pain was able to be controlled.
PMCID: PMC3897317  PMID: 24548999
Acanthamoeba sclerokeratitis; histopathology; acute and chronic inflammation; enucleation
7.  Degeneration of Retinal ON Bipolar Cells Induced by Serum Including Autoantibody against TRPM1 in Mouse Model of Paraneoplastic Retinopathy 
PLoS ONE  2013;8(11):e81507.
The paraneoplastic retinopathies (PRs) are a group of eye diseases characterized by a sudden and progressive dysfunction of the retina caused by an antibody against a protein in a neoplasm. Evidence has been obtained that the transient receptor potential melastatin 1 (TRPM1) protein was one of the antigens for the autoantibody against the ON bipolar cells in PR patients. However, it has not been determined how the autoantibody causes the dysfunction of the ON bipolar cells. We hypothesized that the antibody against TRPM1 in the serum of patients with PR causes a degeneration of retinal ON bipolar cells. To test this hypothesis, we injected the serum from the PR patient, previously shown to contain anti-TRPM1 antibodies by westerblot, intravitreally into mice and examined the effects on the retina. We found that the electroretinograms (ERGs) of the mice were altered acutely after the injection, and the shape of the ERGs resembled that of the patient with PR. Immunohistochemical analysis of the eyes injected with the serum showed immunoreactivity against bipolar cells only in wild-type animals and not in TRPM1 knockout mice,consistent with the serum containing anti-TRPM1 antibodies. Histology also showed that some of the bipolar cells were apoptotic by 5 hours after the injection in wild type mice, but no bipolar cell death was found in TRPM1 knockout mice, . At 3 months, the inner nuclear layer was thinner and the amplitudes of the ERGs were still reduced. These results indicate that the serum of a patient with PR contained an antibody against TRPM1 caused an acute death of retinal ON bipolar cells of mice.
PMCID: PMC3840061  PMID: 24282602
8.  Uniform Suspension of the Clustered Triamcinolone Acetonide Particle 
Journal of Ophthalmology  2013;2013:315658.
Purpose. MaQaid (MaQ) is a new triamcinolone acetonide commercialised in Japan to visualize the vitreous. Because MaQ is preservative-free, it has a lower risk of ocular toxicities. However, since MaQ is only available as a powder, it needs suspenssion. Suspension does not always result uniformally, which causes poor visibility. This study reports a new MaQ suspension for better visibility. Methods. After medium addition to a MaQ vial, various methods were used. These included the use of (1) vortex mixer, (2) two syringes and a three-way stopcock, and (3) ultrasonic washer. We calculated suspended MaQ concentration (n = 5). To evaluate the reproducibility, we estimated the coefficient of variance (CV, n = 3). We used this MaQ for pig eyes, and vitreous visualization was simulated. Subsequently, we used this MaQ suspension for humans. Results. MaQ suspensions were sucessfull, and the concentrations of single particles increased significantly (P < 0.01). The CV was 36.1% for the routine method and 9.03% ffor the new method. Administration of a suspended MaQ made it possible to clearly visualize the vitreous in both pig and human eyes. Conclusions. We devised new techniques for uniformal MaQ suspension. These new methods can compensate for the MaQ disadvantages and ensure a safety surgery.
PMCID: PMC3568888  PMID: 23431418
9.  Peripheral capillary nonperfusion and full-field electroretinographic changes in eyes with frosted branch-like appearance retinal vasculitis 
We report a patient with frosted branch-like appearance retinal vasculitis associated with peripheral capillary nonperfusion and full-field electroretinographic changes. A 62-year-old man presented with sudden bilateral decreased vision accompanied by headaches. His best-corrected visual acuity was 0.01 in both eyes. Fundus examination and fluorescein angiography showed bilateral frosted branch-like appearance retinal vasculitis, and spectral-domain optical coherence tomography showed severe macular edema in both eyes. The cerebrospinal fluid analyses showed an increased lymphocyte count and protein levels. He was treated with systemic corticosteroid therapy, and his best-corrected visual acuity improved to 0.8 OD and 1.0 OS at 6 months after onset. However, fluorescein angiography showed a lack of capillary perfusion in the periphery, and the oscillatory potentials on full-field electroretinography were severely reduced in both eyes. These findings indicated extensive retinal ischemia and inner retinal dysfunction, and that fluorescein angiography and full-field electroretinograms can be useful during follow-up of eyes with frosted branch-like appearance retinal vasculitis.
PMCID: PMC3552475  PMID: 23355770
frosted branch angiitis; aseptic meningitis; optical coherence tomography; electroretinogram; oscillatory potentials
10.  Age-dependent alteration of intraocular soluble heparan sulfate levels and its implications for proliferative diabetic retinopathy 
Molecular Vision  2013;19:1125-1131.
To assess the relationship between intraocular soluble heparan sulfate (HS) concentration and age in subjects with and without diabetic retinopathy.
Vitreous from subjects with idiopathic maculopathies (n=17), i.e., macula hole or epiretinal membrane, or nonproliferative diabetic retinopathy (non-PDR; n=5) and aqueous humor from subjects with PDR (n=16), non-PDR (n=7), or cataracts (n=15) was collected. The levels of HS and vascular endothelial growth factor (VEGF) were measured using enzyme-linked immunosorbent assay. Concentrations of sulfated glycosaminoglycan were determined through dimethylmethylene blue–based assay. The effect of the vitreal HS level on the binding of exogenous VEGF to surface-bound heparin was determined in vitro.
The level of HS in vitreous samples from subjects with idiopathic maculopathies increased concomitantly with age (p=0.020, R2=0.327). Meanwhile, HS levels in aqueous humor were lower in PDR subjects than in non-PDR (p=0.003) and cataract subjects (p=0.007). However, the PDR subjects were significantly younger than the non-PDR subjects (p<0.001) or cataract subjects (p<0.001). When the three groups were controlled for age, the levels of HS glycosaminoglycans were no longer different between the three (p=0.247). The increasing level of HS or sulfated glycosaminoglycan in the vitreous was associated with its increased inhibitory effect on interaction between VEGF and surface heparin in vitro (p=0.014, R2=0.377).
The HS level of the intraocular fluid increased with age. The possible link between low HS in intraocular fluid and increased localization of VEGF at the retinal surface may provide one explanation for the higher susceptibility of younger subjects with diabetes mellitus to developing PDR.
PMCID: PMC3669540  PMID: 23734081
11.  Real-Time Imaging of Rabbit Retina with Retinal Degeneration by Using Spectral-Domain Optical Coherence Tomography 
PLoS ONE  2012;7(4):e36135.
Recently, a transgenic rabbit with rhodopsin Pro 347 Leu mutation was generated as a model of retinitis pigmentosa (RP), which is characterized by a gradual loss of vision due to photoreceptor degeneration. The purpose of the current study is to noninvasively visualize and assess time-dependent changes in the retinal structures of a rabbit model of retinal degeneration by using speckle noise-reduced spectral-domain optical coherence tomography (SD-OCT).
Methodology/Principal Findings
Wild type (WT) and RP rabbits (aged 4–20 weeks) were investigated using SD-OCT. The total retinal thickness in RP rabbits decreased with age. The thickness of the outer nuclear layer (ONL) and between the external limiting membrane and Bruch's membrane (ELM–BM) were reduced in RP rabbits around the visual streak, compared to WT rabbits even at 4 weeks of age, and the differences increased with age. However, inner nuclear layer (INL) thickness in RP rabbits did not differ from that of WT during the observation period. The ganglion cell complex (GCC) thickness in RP rabbits increased near the optic nerve head but not around the visual streak in the later stages of the observation period. Hyper-reflective change was widely observed in the inner segments (IS) and outer segments (OS) of the photoreceptors in the OCT images of RP rabbits. Ultrastructural findings in RP retinas included the appearance of small rhodopsin-containing vesicles scattered in the extracellular space around the photoreceptors.
In the current study, SD-OCT provided the pattern of photoreceptor degeneration in RP rabbits and the longitudinal changes in each retinal layer through the evaluation of identical areas over time. The time-dependent changes in the retinal structure of RP rabbits showed regional and time-stage variations. In vivo imaging of RP rabbit retinas by using SD-OCT is a powerful method for characterizing disease dynamics and for assessing the therapeutic effects of experimental interventions.
PMCID: PMC3338600  PMID: 22558356
12.  Two Novel Mutations in the EYS Gene Are Possible Major Causes of Autosomal Recessive Retinitis Pigmentosa in the Japanese Population 
PLoS ONE  2012;7(2):e31036.
Retinitis pigmentosa (RP) is a highly heterogeneous genetic disease including autosomal recessive (ar), autosomal dominant (ad), and X-linked inheritance. Recently, arRP has been associated with mutations in EYS (Eyes shut homolog), which is a major causative gene for this disease. This study was conducted to determine the spectrum and frequency of EYS mutations in 100 Japanese arRP patients. To determine the prevalence of EYS mutations, all EYS exons were screened for mutations by polymerase chain reaction amplification, and sequence analysis was performed. We detected 67 sequence alterations in EYS, of which 21 were novel. Of these, 7 were very likely pathogenic mutations, 6 were possible pathogenic mutations, and 54 were predicted non-pathogenic sequence alterations. The minimum observed prevalence of distinct EYS mutations in our study was 18% (18/100, comprising 9 patients with 2 very likely pathogenic mutations and the remaining 9 with only one such mutation). Among these mutations, 2 novel truncating mutations, c.4957_4958insA (p.S1653KfsX2) and c.8868C>A (p.Y2956X), were identified in 16 patients and accounted for 57.1% (20/35 alleles) of the mutated alleles. Although these 2 truncating mutations were not detected in Japanese patients with adRP or Leber's congenital amaurosis, we detected them in Korean arRP patients. Similar to Japanese arRP results, the c.4957_4958insA mutation was more frequently detected than the c.8868C>A mutation. The 18% estimated prevalence of very likely pathogenic mutations in our study suggests a major involvement of EYS in the pathogenesis of arRP in the Japanese population. Mutation spectrum of EYS in 100 Japanese patients, including 13 distinct very likely and possible pathogenic mutations, was largely different from the previously reported spectrum in patients from non-Asian populations. Screening for c.4957_4958insA and c.8868C>A mutations in the EYS gene may therefore be very effective for the genetic testing and counseling of RP patients in Japan.
PMCID: PMC3281914  PMID: 22363543
13.  Identification of Autoantibodies against TRPM1 in Patients with Paraneoplastic Retinopathy Associated with ON Bipolar Cell Dysfunction 
PLoS ONE  2011;6(5):e19911.
Paraneoplastic retinopathy (PR), including cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR), is a progressive retinal disease caused by antibodies generated against neoplasms not associated with the eye. While several autoantibodies against retinal antigens have been identified, there has been no known autoantibody reacting specifically against bipolar cell antigens in the sera of patients with PR. We previously reported that the transient receptor potential cation channel, subfamily M, member 1 (TRPM1) is specifically expressed in retinal ON bipolar cells and functions as a component of ON bipolar cell transduction channels. In addition, this and other groups have reported that human TRPM1 mutations are associated with the complete form of congenital stationary night blindness. The purpose of the current study is to investigate whether there are autoantibodies against TRPM1 in the sera of PR patients exhibiting ON bipolar cell dysfunction.
Methodology/Principal Findings
We performed Western blot analysis to identify an autoantibody against TRPM1 in the serum of a patient with lung CAR. The electroretinograms of this patient showed a severely reduced ON response with normal OFF response, indicating that the defect is in the signal transmission between photoreceptors and ON bipolar cells. We also investigated the sera of 26 patients with MAR for autoantibodies against TRPM1 because MAR patients are known to exhibit retinal ON bipolar cell dysfunction. Two of the patients were found to have autoantibodies against TRPM1 in their sera.
Our study reveals TRPM1 to be one of the autoantigens targeted by autoantibodies in at least some patients with CAR or MAR associated with retinal ON bipolar cell dysfunction.
PMCID: PMC3096646  PMID: 21611200
14.  Regression of macular edema secondary to branch retinal vein occlusion during anti-TNF-α therapy for rheumatoid arthritis 
A patient with macular edema secondary to a branch retinal vein occlusion (BRVO) was treated with intravenous injections of infliximab, an antitumor necrosis factor (TNF)-α antibody, for her rheumatoid arthritis (RA). Before the injection, the thickness of the right fovea, determined by optical coherent tomography, was 629 μm and the best-corrected visual acuity (BCVA) was 20/50. After eight injections of infliximab and 10 months after the first injection, her foveal thickness was decreased to 293 μm and the visual acuity improved to 20/20. There was no recurrence of macular edema during the infliximab injections. However, the infliximab injection was stopped because the patient developed pneumonia. Eight months after stopping the infliximab injection, her foveal thickness increased to 494 μm. To treat the RA, her orthopedists began weekly subcutaneous injections of etanercept, a fusion protein of a section of the TNF receptor and immunoglobulin. Five months later, the foveal thickness had decreased to 260 μm, and the visual acuity remained at 20/25+. Because TNF-α is known to break down the blood–retinal barrier, the improvements in our case suggest that TNF-α plays a role in the pathogenesis of macular edema in some patients with BRVO.
PMCID: PMC2915850  PMID: 20689780
branch retinal vein occlusion; macular edema; tissue necrosis factor-alpha; rheumatoid arthritis; infliximab; etanercept; foveal thickness
15.  Paraneoplastic retinopathy associated with retroperitoneal liposarcoma 
We report a case of paraneoplastic retinopathy associated with a retroperitoneal liposarcoma. A 42-year-old man was referred to our hospital with complaints of night blindness and blurred vision in the peripheral field. Electroretinograms showed a progressive amplitude reduction in his both eyes. Abdominal magnetic resonance imaging showed a large retroperitoneal mass, and pathologic examination revealed a dedifferentiated liposarcoma. Western blot analysis showed an antiretinal antibody in the serum of our patient, and his serum reacted with the photoreceptors of a bovine retina. To the best of our knowledge, this is the first case of paraneoplastic retinopathy associated with a liposarcoma.
PMCID: PMC2861929  PMID: 20463790
paraneoplastic retinopathy; retroperitneal liposarcoma; electroretinogram; cancer-associated retinopathy
16.  Analyses of ERG in a patient with intraocular lymphoma 
To follow the changes in the electroretinograms (ERGs) in a patient with primary intraocular lymphoma (PIOL) who had a complete remission after chemotherapy.
ERGs were recorded in a 41-year-old woman with PIOL during and after complete remission with chemotherapy. The patient was diagnosed with PIOL from both the ocular signs and the medical history of cranial lymphoma.
The ERGs were depressed in the subject. The amplitudes of the bright white flash b-waves were smaller than the a-waves, resulting in a “negative type” ERG. Six weeks after the beginning of chemotherapy, the ocular changes had resolved, and the ERGs, although not of the “negative type”, still showed signs that the amplitude had not returned to normal levels.
The negative type ERGs indicated that the inner retina had been damaged to a greater extent than the outer retina. In the convalescent stage, when the ocular manifestations were resolved, the ERGs were still not fully recovered. Although only one case was studied, we suggest that ERGs can be used to evaluate and follow patients with a PIOL.
PMCID: PMC2861936  PMID: 20463797
electroretinogram; primary intraocular lymphoma; uveitis masquerade syndrome
17.  TRPM1 mutations are associated with the complete form of congenital stationary night blindness 
Molecular Vision  2010;16:425-437.
To identify human transient receptor potential cation channel, subfamily M, member 1 (TRPM1) gene mutations in patients with congenital stationary night blindness (CSNB).
We analyzed four different Japanese patients with complete CSNB in whom previous molecular examination revealed no mutation in either nyctalopin (NYX) or glutamate receptor, metabotropic 6 (GRM6). The ophthalmologic examination included best-corrected visual acuity, refraction, biomicroscopy, ophthalmoscopy, fundus photography, Goldmann kinetic perimetry, color vision tests, and electroretinography (ERG). Exons 2 through 27 and the exon-intron junction regions of human TRPM1 were sequenced.
Five different mutations in human TRPM1 were identified. Mutations were present in three unrelated patients with complete CSNB. All three patients were compound heterozygotes. Fundus examination revealed no abnormalities other than myopic changes, and the single bright-flash, mixed rod-cone ERG showed a “negative-type” configuration with a reduced normal a-wave and a significantly reduced b-wave amplitude. Our biochemical and cell biologic analyses suggest that the two identified IVS mutations lead to abnormal TRPM1 protein production, and imply that the two identified missense mutations lead to the mislocalization of the TRPM1 protein in bipolar cells (BCs).
Human TRPM1 mutations are associated with the complete form of CSNB in Japanese patients, suggesting that TRPM1 plays an essential role in mediating the photoresponse in ON BCs in humans as well as in mice.
PMCID: PMC2838739  PMID: 20300565
18.  Functional Roles of Otx2 Transcription Factor in Postnatal Mouse Retinal Development▿ † 
Molecular and Cellular Biology  2007;27(23):8318-8329.
We previously reported that Otx2 is essential for photoreceptor cell fate determination; however, the functional role of Otx2 in postnatal retinal development is still unclear although it has been reported to be expressed in retinal bipolar cells and photoreceptors at postnatal stages. In this study, we first examined the roles of Otx2 in the terminal differentiation of photoreceptors by analyzing Otx2; Crx double-knockout mice. In Otx2+/−; Crx−/− retinas, photoreceptor degeneration and downregulation of photoreceptor-specific genes were much more prominent than in Crx−/− retinas, suggesting that Otx2 has a role in the terminal differentiation of the photoreceptors. Moreover, bipolar cells decreased in the Otx2+/−; Crx−/− retina, suggesting that Otx2 is also involved in retinal bipolar-cell development. To further investigate the role of Otx2 in bipolar-cell development, we generated a postnatal bipolar-cell-specific Otx2 conditional-knockout mouse line. Immunohistochemical analysis of this line showed that the expression of protein kinase C, a marker of mature bipolar cells, was significantly downregulated in the retina. Electroretinograms revealed that the electrophysiological function of retinal bipolar cells was impaired as a result of Otx2 ablation. These data suggest that Otx2 plays a functional role in the maturation of retinal photoreceptor and bipolar cells.
PMCID: PMC2169187  PMID: 17908793
19.  ISCEV guidelines for clinical multifocal electroretinography (2007 edition) 
The clinical multifocal electroretinogram (mfERG) is an electrophysiological test of local retinal function. With this technique, many local ERG responses, typically 61 or 103, are recorded from the cone-driven retina under light-adapted conditions. This document specifies guidelines for performance of the test. It also provides detailed guidance on technical and practical issues, as well as on reporting test results. The main objective of the guidelines is to promote consistent quality of mfERG testing and reporting within and among centers. These 2007 guidelines, from the International Society for Clinical Electrophysiology of Vision (ISCEV:, replace the ISCEV guidelines for the mfERG published in 2003.
PMCID: PMC2235911  PMID: 17972125
Clinical guidelines; Electroretinogram; Multifocal electroretinogram
20.  Abnormalities Caused by Carbohydrate Alterations in Iβ6-N-Acetylglucosaminyltransferase-Deficient Mice 
Molecular and Cellular Biology  2005;25(17):7828-7838.
Iβ6-N-acetylglucosaminyltransferase (IGnT) catalyzes the branching of poly-N-acetyllactosamine carbohydrate chains. In both humans and mice, three spliced forms of IGnT have been identified, and a common exon is present in all of them. We generated mice deficient in the common exon to understand the physiological function of poly-N-acetyllactosamine branching. IGnT activity was abolished in the stomach, kidney, bone marrow, and cerebellum of the deficient mice, while a low level of the activity persisted in the small intestine. Immunohistochemical analysis confirmed the loss of I antigen from the lung, stomach, and kidney. The deficient mice had reduced spontaneous locomotive activity. The number of peripheral blood lymphocytes was also reduced and renal function decreased in the deficient mice. Furthermore, in aged mice, vacuolization occurred in the kidney, and epidermoid cysts were frequently formed. However, cataracts did not develop earlier in the deficient mice. Decreased levels of lysosomal proteins, LAMP-2 and synaptotagmin VII, were found in the kidney of the deficient mice and correlated with renal abnormalities.
PMCID: PMC1190280  PMID: 16107727
21.  Changes in angle of optic nerve and angle of ocular orbit with increasing age in Japanese children 
To study changes in the opening angle of the optic nerve and the angle of the ocular orbit with increasing age in normal Japanese children.
We studied 147 normal children (aged 6 months to 18 years) who had undergone CT as a diagnostic procedure. Measurements were performed on axial CT images that included the entire optic nerve of both eyes. The opening angle of the optic nerve was defined as the angle formed by the intersection of a line running through the left optic nerve and a vertical line passing through the centre of the nose. The opening angle of the orbit was defined as the angle formed by the intersection of a line running tangentially along the deep lateral wall of the left orbit and a vertical line passing through the centre of the nose. The relationship between age and these opening angles was analysed by regression analysis.
The correlation between age and opening angle of the optic nerve was not significant. In contrast, the opening angle of the orbit decreased relatively rapidly until about 2–3 years of age, and then it stabilised. The decrease in the opening angle of the orbit with increasing age was significant (p<0.001). The relationship between these two parameters was best fitted by a logarithmic regression curve.
Because the opening angle of the orbit decreased significantly with increasing age, this factor must be considered when diagnosing and treating strabismus in children.
PMCID: PMC4316938  PMID: 25147368
Anatomy; Orbit; Optic Nerve

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