Toshikatsu Kaburaki

Plasma and whole-blood chemokine levels in patients with Behcet's disease

BackgroundChemokines are a family of chemoattractants of leukocytes that play a critical role for leukocyte recruitment in various inflammatory diseases. The purpose of this study is to investigate the involvement of chemokines, interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in the peripheral blood, with a special reference to disease activities of the patients with Behçets disease (BD).MethodsThe study population consisted of totally 55 patients with BD who had panuveitis (20 patients with active BD, 35 patients with inactive BD) as well as 19 healthy volunteers as control. Disease activity was defined according to the existence of ocular inflammation. IL-8 and MCP-1 concentration levels in the plasma and whole-blood samples were measured by enzyme-linked immunosorbent assay. Whole-blood samples were obtained by lysing cell membranes of peripheral blood cells.ResultsMost of the plasma IL-8 samples were below the detectable limit. Whole-blood IL-8 levels were readily measured. The levels in the patients with active BD were significantly higher than the other two groups. The patients with active and inactive BD showed higher plasma and whole-blood levels of MCP-1 than controls. The plasma and whole-blood MCP-1 levels of the samples collected at the same time showed a linear correlation.ConclusionA close relationship was found to exist between the cell-associated IL-8 and the disease activity, while a persistent role of MCP-1 was observed in BD. Measuring the whole-blood levels of chemokines is useful for monitoring the disease activity.

Common Variants on Chromosome 9p21 Are Associated with Normal Tension Glaucoma

Although intraocular pressure (IOP) is the most definitive cause of glaucoma, a subtype of open angle glaucoma (OAG) termed normal tension glaucoma (NTG), which occurs in spite of normal IOP, accounts for a large part of glaucoma cases, especially in Japan. To find common genetic variants contributing to NTG in Japanese patients, we conducted a genome-wide association study (GWAS). We performed the first screening for 531,009 autosomal SNPs with a discovery cohort of 286 cases and 557 controls, and then a second screening for the top 30 suggestive loci in an independent cohort of 183 cases and 514 controls. Our findings identified a significantly associated SNP; rs523096 [combined p-value = 7.40× 10−8, odds ratio (OR)  = 2.00 with 95% confidence interval (CI) 1.55–2.58] located 10 kbp upstream of CDKN2B on chromosome 9p21. Moreover, analysis of another independent case-control set successfully replicated the results of the screening studies (combined values of all 3 stages p = 4.96 × 10−11, OR  = 2.13 with 95% CI 1.69–2.68). The SNPs near rs523096 were recently reported to be associated with OAG associated with elevated IOP in primary open-angle glaucoma (POAG), the predominant subtype of glaucoma in Caucasian populations. Our results revealed that the 9p21 locus is also associated with NTG in Japanese. In addition, we identified SNPs more strongly associated with NTG.

Evaluation of the Long-Term Efficacy and Safety of Infliximab Treatment for Uveitis in Behçet's Disease: A Multicenter Study

PURPOSE To evaluate the long-term efficacy and safety of infliximab for the treatment of uveitis in Behçets disease (BD). DESIGN Retrospective multicenter study using a questionnaire. PARTICIPANTS A total of 164 consecutive patients with BD treated with infliximab for more than 1 year were studied. The mean age at initiation of infliximab treatment was 42.6±11.7 years, and the mean treatment duration was 32.9±14.4 months. METHODS Data before and at the last visit during infliximab treatment were analyzed in 4 groups divided by duration of treatment: group A (n = 43, 12-<24 months), group B (n = 62, 24-<36 months), group C (n = 42, 36-<48 months), and group D (n = 17, ≥48 months). MAIN OUTCOME MEASURES Best-corrected visual acuity (BCVA), relapse of ocular inflammation, numbers of ocular inflammatory attacks per year, and adverse effects of infliximab therapy. RESULTS The frequency of ocular attacks decreased in all groups (from 5.3±3.0 to 1.0±0.3 in group A, 4.8±4.6 to 1.4±0.3 in group B, 4.1±2.9 to 0.9±0.3 in group C, and 9.5±5.8 to 1.6±0.5 in group D; all P < 0.05). The BCVA was improved in approximately 55% of the eyes after treatment. Mean BCVA converted to logarithm of the minimum angle of resolution was improved after treatment with infliximab in groups A to C (from 0.79±1.04 to 0.59±0.94 in group A, 0.59±1.07 to 0.41±1.04 in group B, and 1.15±1.77 to 0.92±1.73 in group C; all P < 0.05) but not in group D. Uveitis relapsed in 59.1% of all patients after infliximab treatment, and no difference in duration until relapse was observed between individual groups. Approximately 80% of relapses occurred within 1 year after the initiation of infliximab treatment in all groups, 90% of which were controlled by increasing doses of topical corticosteroids and shortening the interval of infliximab infusion. Adverse effects were observed in 65 cases or 35% of all subjects. Infliximab treatment was continued in 85% of the patients, but 15% of the patients discontinued infliximab treatment because of adverse effects or insufficient efficacy. CONCLUSIONS Infliximab reduced the frequency of ocular attacks and improved visual acuity in patients with BD-related uveitis and was generally well tolerated with few serious adverse events.

EXPRESSION OF TGF-BETA TYPE I AND TYPE II RECEPTORS IN RAT EYES

Transforming growth factor beta (TGF-beta) transduces signals through mediation of type I and type II serine/threonine kinase receptors. The expression of TGF-beta type I (T beta R-I) and II (T beta R-II) receptors in rat eyes was investigated immunohistochemically. T beta R-I and T beta R-II immunoreactivity was detected in corneal and conjunctival epithelial cells, corneal endothelial cells, ciliary epithelial cells, lens epithelial cells, retinal pigment epithelial cells, and choroidal vessels. This co-expression of T beta R-I and T beta R-II indicates that the above cells respond to TGF-beta and, because TGF-beta is reported to be produced in ocular tissues, that it may have important autocrine and/or paracrine roles in the growth and metabolism of ocular tissues in situ.

Genetic characterization and susceptibility for sarcoidosis in Japanese patients: risk factors of BTNL2 gene polymorphisms and HLA class II alleles.

PURPOSE Sarcoidosis is a heterogeneous and multisystem granulomatous disorder. The etiology still is uncertain, but the disease currently is thought to be triggered by various genetic as well as environmental factors. Recently, an association between sarcoidosis and the butyrophilin-like 2 (BTNL2) gene located in close proximity to the HLA-DRB1 gene was reported. The purpose of our study was to verify the relationship between BTNL2 and HLA risk alleles for the susceptibility to sarcoidosis, and to assess whether the BTNL2 association is independent of the HLA risk alleles. METHODS In our study, 11 single nucleotide polymorphisms (rs28362677, rs2076533, rs2076530, rs2076529, rs2294881, rs3763304, rs2076523, rs28362682, rs3806156, rs9268499, rs3763317), including the functional rs2076530 (G > A) of the BTNL2 gene, and HLA-DRB1 and -DQB1 alleles, were genotyped in 237 Japanese patients diagnosed with sarcoidosis and 287 healthy Japanese control subjects. RESULTS In the patient group, the HLA-DRB1*08:03 (P = 6.15 × 10(-5), odds ratio [OR] = 2.43) and BTNL2 rs2076530_A (P = 6.90 × 10(-6), OR = 1.84) were associated with disease susceptibility. Upon stratification analysis in search for a synergistic effect given the extensive linkage disequilibrium between BTNL2 rs2076530_A and HLA-DRB1*08:03, our results suggested that the risk-bearing allele of these two loci interact negatively. No significant differences were observed in allele frequencies for alleles in patients with ocular and other systemic sarcoidosis. CONCLUSIONS Our studies implicated that the HLA-DRB1 allele is a major contributing genetic factor in the development of sarcoidosis in Japan. However, further studies are needed to verify how HLA or BTNL2 alleles confer the disease phenotype, severity of sarcoidosis.

Angiostatic effect of CXCR3 expressed on choroidal neovascularization.

PURPOSE Several recent studies suggest that some chemokines/chemokine receptors are involved in choroidal neovascularization (CNV). CXCR3 was the focus of the present study because microarray analysis for murine laser-induced CNV model showed the increased expression of CXCR3. The purpose of this study was to evaluate the effect of CXCR3 on CNV. METHODS Microarray analysis was performed for the mouse eyes with laser-induced CNV. CXCR3 expressions on the CNV were evaluated by immunohistochemistry and real-time RT-PCR. CNV was compared between CXCR3-deficient mice and wild-type mice, between mice treated with anti-CXCR3/anti-IP-10 neutralizing antibody and mice treated with control IgG. Macrophage recruitment into CNV was also investigated. Ocular expressions of vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), C-C chemokine ligand-2 (CCL2), and complement component-3 (C3) were evaluated by real-time PCR. RESULTS Microarray analysis and real-time RT-PCR revealed the elevation of CXCR3 and IP-10 in laser-treated mouse eyes compared with control eyes. Immunohistochemistry showed CXCR3 expression on the endothelial cells of CNV. Laser-induced CNV of CXCR3-deficient mice was significantly larger, with greater leakage in fluorescein angiography, and with greater macrophage-infiltration compared with wild-type mice (P < 0.01). Intravitreal injection of anti-CXCR3/anti-IP-10 neutralizing antibody exacerbated CNV. The CCL2 expression in the laser-treated eyes of CXCR3-deficient mice was higher than in those of wild-type mice (P < 0.05), whereas VEGF, PEDF, and C3 showed no differences. CONCLUSIONS These results suggested that CXCR3 expressed on CNV could have an angiostatic effect on it.

Two cases of frosted branch angiitis with central retinal vein occlusion.

BACKGROUND Frosted branch angiitis usually occurs in children, and has a good prognosis. We report two cases of unilateral frosted branch angiitis in adults. Both had poor visual outcomes because of associated central retinal vein occlusion and neovascular glaucoma. CASES Case 1 was a 36-year-old woman. Almost all retinal veins and some retinal arteries showed vasculitis in her right eye, and veins were slightly dilated and sheathed. Case 2 was a 23-year-old woman. Angle hypopyon was observed in her left eye. Retinal veins were dilated, meandering, and sheathed. Retinal hemorrhages were also observed. In both cases, after systemic steroid therapy the retinal vasculitis gradually decreased, but central retinal vein occlusions gradually developed. Despite systemic administration of urokinase and panretinal photocoagulation, neovascular glaucoma developed, and visual acuity diminished in both cases. CONCLUSIONS Two cases of frosted branch angiitis complicated by retinal vein occlusion are reported. Careful observation of retinal blood flow is necessary in frosted branch angiitis in adults.

Statistical Analysis of Endogenous Uveitis at Tokyo University Hospital (1998-2000)

eye drops was 0.2 ± 0.6, at 1 month after switching (P < 0.0001).At 1 month after switching, 50 patients (89.3%) preferred brinzolamide. Adverse events are shown in Table 1. Eleven patients were excluded from the evaluation of hypotensive effects; eight could not continue brinzolamide treatment owing to adverse events, and three patients had not come to our hospital during the 6-month study for nonmedical reasons. There were no statistically significant differences in the IOP before or after switching (Table 2).

Case of Optic Nerve Involvement in Metastasis of a Gastrointestinal Stromal Tumor

BackgroundThe gastrointestinal stromal tumor (GIST) belongs to the leiomyosarcoma or leiomyoma group, and metastasis of leiomyosarcoma to the orbit is extremely rare. The most common sign of the metastasis of leiomyosarcoma to the orbit is proptosis; the primary lesion is usually found in skin or soft tissue.CaseA 60-year-old man, who had a history of multiple metastases of GIST, suffered sudden unilateral blindness.ObservationsHis history and computed tomographic scans suggested that the lesion was a metastasis of GIST to the cavernous sinus around the root of the optic nerve.ConclusionTo the best of our knowledge, this is the first case of metastasis of GIST to the orbit. Jpn J Ophthalmol 2004;48:166–168

Frequency of Uveitis in the Central Tokyo Area (2010–2012)

ABSTRACT Purpose: To investigate the frequency of conditions of newly arrived patients with uveitis from 2010 to 2012 and compare this frequency with that since 2004. Methods: We retrospectively analyzed clinical records of patients who visited the outpatient clinic from January 2010 to December 2012, and compared them with those from 2004–2009. Results: From 2010 to 2012, 695 new patients with uveitis visited Tokyo University Hospital, with a definite diagnosis made in 431 (62.0%). The most common diagnosis was scleritis (8.3%), followed by sarcoidosis (8.1%); herpetic iridocyclitis (5.5%); Behçet disease (4.6%); Vogt–Koyanagi–Harada disease (4.0%); acute anterior uveitis (3.7%); Posner–Schlossman syndrome (3.6%); intraocular malignant lymphoma (3.0%); and bacterial endophthalmitis (1.9%). The most frequent unclassified type of uveitis was sarcoidosis-suspected (14.8%). Conclusions: When compared with years 2004–2009, the present series showed an increasing trend of intraocular malignant lymphoma, bacterial endophthalmitis, and chronic iridocyclitis, and a notable increase in chronic iridocyclitis in young girls, with decreasing trends of scleritis and Vogt–Koyanagi–Harada disease.