Manabu Mochizuki

Genome-wide association studies identify IL23R - IL12RB2 and IL10 as Behçet's disease susceptibility loci

Behçets disease is a chronic systemic inflammatory disorder characterized by four major manifestations: recurrent ocular symptoms, oral and genital ulcers and skin lesions. We conducted a genome-wide association study in a Japanese cohort including 612 individuals with Behçets disease and 740 unaffected individuals (controls). We identified two suggestive associations on chromosomes 1p31.3 (IL23R-IL12RB2, rs12119179, P = 2.7 × 10−8) and 1q32.1 (IL10, rs1554286, P = 8.0 × 10−8). A meta-analysis of these two loci with results from additional Turkish and Korean cohorts showed genome-wide significant associations (rs1495965 in IL23R-IL12RB2, P = 1.9 × 10−11, odds ratio = 1.35; rs1800871 in IL10, P = 1.0 × 10−14, odds ratio = 1.45).

International Criteria for the Diagnosis of Ocular Sarcoidosis: Results of the First International Workshop on Ocular Sarcoidosis (IWOS)

Aim: To report criteria for the diagnosis of intraocular sarcoidosis, taking into account suggestive clinical signs and appropriate laboratory investigations and biopsy results. Design: Concensus workshop of an international committee on nomenclature. Methods: An international group of uveitis specialists from Asia, Africa, Europe, and America met in a concensus conference in Shinagawa, Tokyo on October 28–29, 2006. Based on questionnaires that had been sent out prior to the conference, the participants discussed potential intraocular clinical signs eligible for a diagnosis of ocular sarcoidosis. A refined definition of clinical signs, which received two-thirds majority of votes, was included in the list of signs consistent with ocular sarcoidosis. Laboratory investigations were similarly discussed and those tests reaching a two-thirds majority were retained for the diagnosis of ocular sarcoidosis. Finally diagnostic criteria were proposed based on ocular signs, laboratory investigations, and biopsy results. Results: The concensus conference identified seven signs in the diagnosis of intraocular sarcoidosis: (1) mutton-fat keratic precipitates (KPs)/small granulomatous KPs and/or iris nodules (Koeppe/Busacca), (2) trabecular meshwork (TM) nodules and/or tent-shaped peripheral anterior synechiae (PAS), (3) vitreous opacities displaying snowballs/strings of pearls, (4) multiple chorioretinal peripheral lesions (active and/or atrophic), (5) nodular and/or segmental peri-phlebitis (± candlewax drippings) and/or retinal macroaneurism in an inflamed eye, 6) optic disc nodule(s)/granuloma(s) and/or solitary choroidal nodule, and (7) bilaterality. The laboratory investigations or investigational procedures that were judged to provide value in the diagnosis of ocular sarcoidosis in patients having the above intraocular signs included (1) negative tuberculin skin test in a BCG-vaccinated patient or in a patient having had a positive tuberculin skin test previously, (2) elevated serum angiotensin converting enzyme (ACE) levels and/or elevated serum lysozyme, (3) chest x-ray revealing bilateral hilar lymphadenopathy (BHL), (4) abnormal liver enzyme tests, and (5) chest CT scan in patients with a negative chest x-ray result. Four levels of certainty for the diagnosis of ocular sarcoidosis (diagnostic criteria) were recommended in patients in whom other possible causes of uveitis had been excluded: (1) biopsy-supported diagnosis with a compatible uveitis was labeled as definite ocular sarcoidosis; (2) if biopsy was not done but chest x-ray was positive showing BHL associated with a compatible uveitis, the condition was labeled as presumed ocular sarcoidosis; (3) if biopsy was not done and the chest x-ray did not show BHL but there were 3 of the above intraocular signs and 2 positive laboratory tests, the condition was labeled as probable ocular sarcoidosis; and (4) if lung biopsy was done and the result was negative but at least 4 of the above signs and 2 positive laboratory investigations were present, the condition was labeled as possible ocular sarcoidosis. Conclusion: Various clinical signs, laboratory investigations, and biopsy results provided four diagnostic categories of sarcoid uveitis. The categorization allows prospective multinational clinical trials to be conducted using a standardized nomenclature, which serves as a platform for comparison of visual outcomes with various therapeutic modalities.

Kinetic analysis and mechanistic aspects of autoxidation of catechins

A peroxidase-based bioelectrochemical sensor of hydrogen peroxide (H(2)O(2)) and a Clark-type oxygen electrode were applied to continuous monitoring and kinetic analysis of the autoxidation of catechins. Four major catechins in green tea, (-)-epicatechin, (-)-epicatechin gallate, (-)-epigallocatechin, and (-)-epigallocatechin gallate, were used as model compounds. It was found that dioxygen (O(2)) is quantitatively reduced to H(2)O(2). The initial rate of autoxidation is suppressed by superoxide dismutase and H(+), but is independent of buffer capacity. Based on these results, a mechanism of autoxidation is proposed; the initial step is the one-electron oxidation of the B ring of catechins by O(2) to generate a superoxide anion (O(2)(*-)) and a semiquinone radical, as supported in part by electron spin resonance measurements. O(2)(*-) works as a stronger one-electron oxidant than O(2) against catechins and is reduced to H(2)O(2). The semiquinone radical is more susceptible to oxidation with O(2) than fully reduced catechins. The autoxidation rate increases with pH. This behavior can be interpreted in terms of the increase in the stability of O(2)(*-) and the semiquinone radical with increasing pH, rather than the acid dissociation of phenolic groups. Cupric ion enhances autoxidation; most probably it functions as a catalyst of the initial oxidation step of catechins. The product cuprous ion can trigger a Fenton reaction to generate hydroxyl radical. On the other hand, borate ion suppresses autoxidation drastically, due to the strong complex formation with catechins. The biological significance of autoxidation and its effectors are also discussed.

Novel mechanism for age-related macular degeneration : An equilibrium shift between the angiogenesis factors VEGF and PEDF

We investigated gene expression profiles of vascular endothelial growth factor (VEGF) and pigment epithelium‐derived factor (PEDF) in differentiated and non‐differentiated retinal pigment epithelial (RPE) cells during oxidative stress. Human RPE cells were grown in culture on laminin‐coated flasks to obtain differentiated features. Cells cultured on plastic were used as non‐differentiated controls. After confluence, hydrogen peroxide (H2O2) was added for 48 h, then, total RNA was extracted and used for RT‐PCR and Northern blot analysis. Medium conditioned by RPE was used for ELISA, Western blotting, and in vitro angiogenesis assay. As a result, differentiated RPE cells expressed significantly higher levels of VEGF protein, as compared to their non‐differentiated counterparts. The expression pattern remained consistent even after cellular exposure to H2O2. Conversely, while elevated levels of PEDF transcript and protein were seen in differentiated RPE cells, compared to non‐differentiated cells, a marked decrease at both PEDF mRNA and protein levels was seen after treatment with H2O2. Moreover, this decrease in PEDF expression was dosage dependent. In in vitro angiogenesis assay, conditioned medium from differentiated human RPE cells after exposure to H2O2 showed a dramatic increase in tubular formation and migratory activity of microvascular endothelial cells. These data suggest that, in physiological conditions, a critical balance between PEDF and VEGF exists, and PEDF may counteract the angiogenic potential of VEGF. Under oxidative stress, PEDF decreases disrupting this balance. This equilibrium shift may be significant in promoting a pathological condition of RPE cells and contributing to choroidal neovascularization in age‐related macular degeneration.

Long-term Pattern of Progression of Myopic Maculopathy: A Natural History Study

OBJECTIVE To investigate the long-term progression pattern of myopic maculopathy and to determine the visual prognosis of each progression stage. DESIGN Retrospective, observational case series. PARTICIPANTS The medical records of 806 eyes of 429 consecutive patients with high myopia (refractive error more than -8.00 diopters [D] or axial length > or =26.5 mm) who were followed for 5-32 years were reviewed. METHODS Participants had complete ophthalmological examinations including best-corrected visual acuity, axial length measurements, fluorescein angiography, and color fundus photography, at least once a year. The presence and type of posterior staphyloma was determined by binocular stereoscopic ophthalmoscopy. The types of myopic maculopathy included tessellated fundus, lacquer cracks, diffuse chorioretinal atrophy, patchy chorioretinal atrophy, choroidal neovascularization (CNV), and macular atrophy. None of the patients had received any type of treatment for the maculopathy. MAIN OUTCOME MEASURES The longitudinal long-term progression pattern and the visual prognosis of each type of fundus lesion. RESULTS During the mean follow-up of 12.7 years, 327 of the 806 highly myopic eyes (40.6%) showed a progression of the myopic maculopathy. The most commonly observed patterns were from tessellated fundus to the development of diffuse atrophy and lacquer cracks, an increase in the width and progression to patchy atrophy in eyes with lacquer cracks, an enlargement of the diffuse atrophy, and the development of patchy atrophy in eyes with diffuse atrophy, and an enlargement and fusion of patches of atrophic areas in eyes with patchy atrophy. Eyes with tessellated fundus, lacquer cracks, diffuse atrophy and patchy atrophy at the initial examination progressed to the development of CNV. Eyes with CNV developed macular atrophy. The fusion of patchy atrophy, the development of CNV, and macular atrophy all led to significant visual decreases. A posterior staphyloma was observed more frequently in eyes that showed progression from tessellated fundus, diffuse atrophy, and patchy atrophy than those without a progression. CONCLUSIONS These findings indicate that myopic maculopathy tends to progress in approximately 40% of highly myopic eyes, and the pattern of progression affects the visual prognosis. Preventive therapy targeting posterior staphyloma should be considered to prevent the visual impairment caused by the progression of myopic maculopathy.

Patchy atrophy and lacquer cracks predispose to the development of choroidal neovascularisation in pathological myopia

Aims: To determine the incidence and predisposing findings for choroidal neovascularisation (CNV) in a large series of highly myopic patients. Methods: The medical records of 218 consecutive patients (325 eyes) with myopic fundus changes in the macula were reviewed. The incidence of CNV during a follow up of at least 3 years of highly myopic patients and identification of predisposing findings for the development of myopic CNV were examined. Results: Among 325 highly myopic eyes examined, 33 eyes (10.2%) developed myopic CNV. The incidence was higher (34.8%) among the fellow eyes of patients with pre-existing CNV than among eyes of patients without pre-existing CNV (6.1%). CNV developed in 3.7% with diffuse chorioretinal atrophy, in 20.0% with patchy atrophy, and in 29.4% with lacquer cracks. Conclusion: Approximately one in 10 highly myopic eyes developed myopic CNV in average 130.2 months. Patchy atrophy and lacquer cracks were shown to be important predisposing findings for CNV development.

Prevalence and characteristics of foveal retinal detachment without macular hole in high myopia.

PURPOSE To report the prevalence of foveal retinal detachment without macular hole in a large number of highly myopic eyes using optical coherence tomography (OCT), and to clarify the demographic characteristics associated with foveal retinal detachment in these eyes. DESIGN A consecutive, prospective, observational case series. METHODS In 134 eyes of 78 consecutive patients with high myopia (refractive error of -8 diopters or more), we performed complete ophthalmic examinations and studied cross-sectional images of the macula with OCT. The patients were divided into two groups according to the presence (group 1, n = 78 eyes of 45 patients) or absence (group 2, n = 56 eyes of 33 patients) of posterior staphyloma. Slit-lamp examination with a Goldmann three-mirror lens indicated that none of the eyes had a macular hole. RESULTS In seven of 78 eyes (9.0%) with posterior staphyloma (group 1), OCT revealed foveal retinal detachment. Two of the seven eyes had foveal retinoschisis. Optical coherence tomography revealed no retinal detachment or retinoschisis in any eye without posterior staphyloma (group 2). Visual acuity of the seven eyes with foveal retinal detachment ranged from 20/40 to 20/200. Two of the seven eyes had visual acuity 20/50 or better. No patients complained of recent, progressive visual impairment. All seven eyes with foveal retinal detachment had severe myopic fundus changes (focal chorioretinal atrophy or bare sclera). CONCLUSIONS In highly myopic eyes with posterior staphyloma, the prevalence of foveal retinal detachment without macular hole was 9.0%. In eyes with this type of retinal detachment, visual acuity varies and foveal retinal detachment tends to be missed on routine examination. Periodic examination using OCT is recommended for highly myopic eyes with severe myopic degenerative changes and posterior staphyloma.

Human T-cell leukemia virus type I (HTLV-1) proviral load and disease progression in asymptomatic HTLV-1 carriers: a nationwide prospective study in Japan

Definitive risk factors for the development of adult T-cell leukemia (ATL) among asymptomatic human T-cell leukemia virus type I (HTLV-1) carriers remain unclear. Recently, HTLV-1 proviral loads have been evaluated as important predictors of ATL, but a few small prospective studies have been conducted. We prospectively evaluated 1218 asymptomatic HTLV-1 carriers (426 males and 792 females) who were enrolled during 2002 to 2008. The proviral load at enrollment was significantly higher in males than females (median, 2.10 vs 1.39 copies/100 peripheral blood mononuclear cells [PBMCs]; P < .001), in those 40 to 49 and 50 to 59 years of age than that of those 40 years of age and younger (P = .02 and .007, respectively), and in those with a family history of ATL than those without the history (median, 2.32 vs 1.33 copies/100 PBMCs; P = .005). During follow-up, 14 participants progressed to overt ATL. Their baseline proviral load was high (range, 4.17-28.58 copies/100 PBMCs). None developed ATL among those with a baseline proviral load lower than approximately 4 copies. Multivariate Cox analyses indicated that not only a higher proviral load, advanced age, family history of ATL, and first opportunity for HTLV-1 testing during treatment for other diseases were independent risk factors for progression of ATL.

The potential role of amyloid βin the pathogenesis of age-related macular degeneration

Drusen are extracellular deposits that lie beneath the retinal pigment epithelium (RPE) and are the earliest signs of age-related macular degeneration (AMD). Recent proteome analysis demonstrated that amyloid beta (Abeta) deposition was specific to drusen from eyes with AMD. To work toward a molecular understanding of the development of AMD from drusen, we investigated the effect of Abeta on cultured human RPE cells as well as ocular findings in neprilysin gene-disrupted mice, which leads to an increased deposition Abeta. The results showed that Abeta treatment induced a marked increase in VEGF as well as a marked decrease in pigment epithelium-derived factor (PEDF). Conditioned media from Abeta-exposed RPE cells caused a dramatic increase in tubular formation by human umbilical vein endothelial cells. Light microscopy of senescent neprilysin gene-disrupted mice showed an increased number of degenerated RPE cells with vacuoles. Electron microscopy revealed basal laminar and linear deposits beneath the RPE layer, but we did not observe choroidal neovascularization (CNV). The present study demonstrates that Abeta accumulation affects the balance between VEGF and PEDF in the RPE, and an accumulation of Abeta reproduces features characteristic of human AMD, such as RPE atrophy and basal deposit formation. Some other factors, such as breakdown of integrity of Bruch membrane, might be necessary to induce CNV of AMD.

Epidemiological Survey of Intraocular Inflammation in Japan

PurposeTo report the frequency and trend of intraocular inflammation based on a survey of new ophthalmology patient visits to university hospitals throughout Japan during 2002.MethodsA questionnaire was sent to the departments of ophthalmology in 110 university hospitals nationwide to survey the total number of new patients who visited the outpatient clinics for the first time between 1 January and 31 December 2002, and also the number of patients diagnosed with intraocular inflammation during this period.ResultsThe surveys completed by 41 university hospitals were analyzed in this study. During 2002, a total of 151 299 new ophthalmological patients presented at the 41 institutions, and 3060 (2.2%) of the new patients were diagnosed as having intraocular inflammation. The most frequent intraocular inflammatory disease identified was sarcoidosis (13.3%), followed by Vogt-Koyanagi-Harada (VKH) disease (6.7%), Behçet disease (6.2%), bacterial endophthalmitis (3.8%), herpetic iridocyclitis (3.6%), diabetic iritis (1.6%), human leukocyte antigen-B27-associated uveitis (1.5%), acute retinal necrosis (1.3%), ocular toxoplasmosis (1.1%), ocular toxocariasis (1.1%), uveitis associated with human T lymphotropic virus-1 (also known as HAU) (1.1%), and others. Infectious intraocular inflammation accounted for 16% of all uveitis cases.ConclusionsThrough the collaboration of a large number of institutions, some aspects of the epidemiology of intraocular inflammation in Japan were elucidated. However, the disease concept and diagnostic criteria remain ambiguous for a considerable number of diseases within the spectrum of intraocular inflammation, and the possibility that such factors may bias the present findings cannot be denied. In the future, a prospective survey based on well-defined, common diagnostic criteria is required to obtain more precise epidemiological data. Jpn J Ophthalmol 2007;51:41–44