Invariant natural killer T cells play dual roles in the development of experimental autoimmune uveoretinitis.

Experimental autoimmune uveoretinitis (EAU) represents an experimental model for human endogenous uveitis, which is caused by Th1/Th17 cell-mediated inflammation. Natural killer T (NKT) cells recognize lipid antigens and produce large amounts of cytokines upon activation. To examine the role of NKT cells in the development of uveitis, EAU was elicited by immunization with a peptide from the human interphotoreceptor retinoid-binding protein (hIRBP1-20) in complete Freund's adjuvant and histopathology scores were evaluated in C57BL/6 (WT) and NKT cell-deficient mice. NKT cell-deficient mice developed more severe EAU pathology than WT mice. When WT mice were treated with ligands of the invariant subset of NKT cells (α-GalCer or RCAI-56), EAU was ameliorated in mice treated with RCAI-56 but not α-GalCer. IRBP-specific Th1/Th17 cytokines were reduced in RCAI-56-treated compared with vehicle-treated mice. Although the numbers of IRBP-specific T cells detected by hIRBP3-13/I-Ab tetramers in the spleen and the draining lymph node were the same for vehicle and RCAI-56 treatment groups, RORγt expression by tetramer-positive cells in RCAI-56-treated mice was lower than in control mice. Moreover, the eyes of RCAI-56-treated mice contained fewer IRBP-specific T cells compared with control mice. These results suggest that invariant NKT (iNKT) cells suppress the induction of Th17 cells and infiltration of IRBP-specific T cells into the eyes, thereby reducing ocular inflammation. However, in sharp contrast to the ameliorating effects of iNKT cell activation during the initiation phase of EAU, iNKT cell activation during the effector phase exacerbated disease pathology. Thus, we conclude that iNKT cells exhibit dual roles in the development of EAU.

Retinal pigment epithelial atrophy over polypoidal choroidal vasculopathy lesions during ranibizumab monotherapy.

BACKGROUND: To evaluate the quantitative changes of retinal pigment epithelial (RPE) atrophy during 3-year follow-up period of ranibizumab monotherapy for polypoidal choroidal vasculopathy (PCV). METHODS: We retrospectively reviewed consecutive 100 Japanese patients with unilateral symptomatic treatment-naïve PCV who received ranibizumab monotherapy for 3 years. Color fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence were evaluated for RPE atrophy. Multiple regression analysis was performed to investigate the predictive factors found during univariate analysis to identify an association with increased RPE atrophic areas. RPE atrophic areas overlapping PCV lesions were measured. RESULTS: The mean (standard deviation) number of injections was 11.4 (4.50). RPE atrophic area enlarged to 2.91 (5.41 mm(2)) 3 years after the first injection from 1.22 (1.72 mm(2)) at baseline, which differed significantly (P = 0.012). Multiple regression analysis showed that larger PCV lesions and larger RPE atrophic areas at baseline were associated with increased RPE atrophic areas. RPE atrophic area overlapping the baseline PCV lesions significantly increased during 3-year follow-up period, whereas RPE atrophic area not overlapping the baseline PCV lesions did not increase significantly. CONCLUSION: RPE atrophy progresses in eyes with PCV during ranibizumab monotherapy and the tendency for development of RPE atrophy within the PCV lesions.

Prevention of experimental autoimmune uveoretinitis by blockade of osteopontin with small interfering RNA.

Osteopontin (OPN) is elevated during the progression of experimental autoimmune uveoretinitis (EAU) in C57BL/6 (B6) mice. Furthermore, EAU symptoms are ameliorated in OPN knockout mice or in B6 mice treated with anti-OPN antibody (M5). Recently, OPN has been shown to promote the Th1 response not only in the extracellular space as a secretory protein but also in cytosol as a signaling component. Thus, we attempted to reduce OPN in both compartments by using a small interfering RNA (siRNA) targeting the OPN coding sequence (OPN-siRNA). EAU was induced in B6 mice by immunization with human interphotoreceptor retinoid-binding protein (hIRBP) peptide sequence 1-20. The OPN- or control-siRNA was administered with hydrodynamic methods 24 h before and simultaneously with immunization (prevention regimen). When plasma OPN levels were quantified following siRNA administration with the prevention regimen, the level in the OPN-siRNA-treated group was significantly lower than that in the control-siRNA-treated group. Accordingly, the clinical and histopathological scores of EAU were significantly reduced in B6 mice when siRNA caused OPN blockade. Furthermore, TNF-alpha, IFN-gamma, IL-2, GM-CSF and IL-17 levels in the culture supernatants were markedly suppressed in the OPN-siRNA-treated group, whereas the proliferative responses of T lymphocytes from regional lymph nodes against immunogenic peptides was not significantly reduced. On the other hand, the protection was not significant if the mice received the OPN-siRNA treatment on day 7 and day 8 after immunization when the clinical symptoms appeared overt (reversal regimen). Our results suggest that OPN blockade with OPN-siRNA can be an alternative choice for the usage of anti-OPN antibody and controlling uveoretinitis in the preventive regimen.

Retinal angiography and optical coherence tomography disclose focal optic disc vascular leakage and lipid-rich fluid accumulation within the retina in a patient with leber idiopathic stellate neuroretinitis.

A 52-year-old woman with clinical features of Leber idiopathic stellate neuroretinitis (LISN) underwent retinal fluorescein and indocyanine green angiography that revealed lipid-containing fluid leakage from a single arteriole in the superficial nerve fiber layer of the optic disc. The fluid expanded gradually into the upper half of the optic disc and the adjacent peripapillary retina. Optical coherence tomography (OCT) demonstrated fluid accumulation in two separate subretinal spaces and in the outer nuclear-plexiform layer, which extended from the optic disc margin to the fovea. These angiographic and OCT findings support the hypothesis that LISN develops from focally increased permeability of an optic disc surface arteriole from which lipid-rich fluid flows through the outer nuclear-plexiform layer space to pool in these retinal areas.

Association of heat shock protein 70 induction and the amelioration of experimental autoimmune uveoretinitis in mice.

Experimental autoimmune uveoretinitis (EAU) serves as a model of human endogeneous uveitis. In the present study we examined whether induction of heat shock protein (HSP) 70 by oral geranylgeranylacetone (GGA) administration had a therapeutic effect on murine EAU. When C57BL/6 mice that had received oral administration of GGA (500mg/kg) were immunized with interphotoreceptor retinoid-binding protein (IRBP)-derived peptide plus adjuvants, the expression levels of HSP70 mRNA and protein were rapidly and transiently upregulated in eyes of the GGA-treated mice, compared with those from vehicle-pretreated and IRBP-immunized mice. The antigen-specific T cell proliferation was partially suppressed in these mice treated with GGA. The mean EAU scores of the GGA-treated mice on day 21 and 28 (2.4+/-0.2 and 2.1+/-0.2, respectively) were significantly lower than those in the controls (3.0+/-0.1 and 2.6+/-0.2, respectively p<0.01). The histopathological severity of the GGA-treated mice (average 0.33) was markedly milder than that in the controls (average 1.63, p<0.05) at day 21. The present findings demonstrate that the pharmacological induction of HSP70 may be applicable to the amelioration of ocular autoimmune diseases.

Amelioration of experimental autoimmune uveoretinitis (EAU) with an inhibitor of nuclear factor-kappaB (NF-kappaB), pyrrolidine dithiocarbamate.

Experimental autoimmune uveoretinitis (EAU) is a T helper type 1 cell-mediated autoimmune disease, which serves as a model of human chronic uveitis. In this model, cells of a monocyte/macrophage lineage and retinal antigen (Ag)-specific T cells infiltrate into the retina and cause inflammatory lesion, where proinflammatory cytokines and various stimuli activate a transcriptional factor, nuclear factor-kappaB (NF-kappaB), which modulates inflammation and enhances immune responses. In the present study, the therapeutic effect of administration of a NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), was examined in a murine EAU model. It was shown that PDTC ameliorated the clinical symptoms of EAU mice and significantly reduced the histopathological score compared with those in untreated mice. mRNA expressions of tumor necrosis factor alpha and interleukin-1beta were suppressed in eyes of PDTC-treated EAU mice. However, when T cells from PDTC-treated EAU mice, Ag-presenting cells (APC), and the retinal Ag peptides were cocultured, these T cells showed the same level of proliferation as those from control mice. Furthermore, addition of PDTC in the culture of T cells from EAU mice, Ag, and APC completely abrogated the T cell-proliferative response and cytokine production. Pretreatment of Ag-primed T cells or APC with PDTC in vitro also reduced these responses. These results indicate that the inhibitory effect of PDTC is attributed mainly to the suppression of effector-phase responses including inflammation but not to the inhibition of T cell priming. Regulation of NF-kappaB pathway in the lesion could be a novel target for the successful control of uveoretinitis.

A prospective multicenter study on genome wide associations to ranibizumab treatment outcome for age-related macular degeneration.

We conducted a genome-wide association study (GWAS) on the outcome of anti-VEGF treatment for exudative age-related macular degeneration (AMD) in a prospective cohort. Four hundred and sixty-one treatment-naïve AMD patients were recruited at 13 clinical centers and all patients were treated with 3 monthly injections of ranibizumab followed by pro re nata regimen treatment for one year. Genomic DNA was collected from all patients for a 2-stage GWAS on achieving dry macula after the initial treatment, the requirement for an additional treatment, and visual acuity changes during the 12-month observation period. In addition, we evaluated 9 single-nucleotide polymorphisms (SNPs) in 8 previously reported AMD-related genes for their associations with treatment outcome. The discovery stage with 256 patients evaluated 8,480,849 SNPs, but no SNPs showed genome-wide level significance in association with treatment outcomes. Although SNPs with P-values of <5 × 10-6 were evaluated in replication samples of 205 patients, no SNP was significantly associated with treatment outcomes. Among AMD-susceptibility genes, rs10490924 in ARMS2/HTRA1 was significantly associated with additional treatment requirement in the discovery stage (P = 0.0023), and pooled analysis with the replication stage further confirmed this association (P = 0.0013). ARMS2/HTRA1 polymorphism might be able to predict the frequency of injection after initial ranibizumab treatment.

Comparative study of two sets of criteria for the diagnosis of Vogt-Koyanagi-Harada's disease.

PURPOSE: The Vogt-Koyanagi-Harada's (VKH) Disease Committee established the "Revised diagnostic criteria for VKH disease" in 2001. The purpose of the present study was to assess the concordance between these criteria and the traditional Sugiura's diagnosis system. DESIGN: Observational case series. METHODS: The medical records of patients previously diagnosed with VKH disease based upon Sugiura's criteria at the Uveitis Survey Clinic of the Hokkaido University Hospital between 1991 and 2003 were retrospectively reevaluated using the VKH Committee's revised diagnostic criteria for VKH disease. RESULTS: Sugiura's criteria were used to identify 169 patients with VKH disease. All patients were Japanese, and 95 cases (56%) were women. Mean age at the time of their first visit to our clinic was 44.7 +/- 13.9 years (range, 9 to 74 years). Using the VKH Committee's new criteria, 91.7% of the previously diagnosed VKH patients were classified as having the disease. Of this group, 11.8% were classified as complete, 71% incomplete, and 8.9% as probable VKH disease. CONCLUSIONS: The VKH Committee's revised diagnostic criteria proved useful for VKH disease diagnosis, as the concordance rate for the two criteria was more than 90%. However, patients who had prior cataract surgery or who lacked signs of serous retinal detachment were not classified as having VKH disease because of exclusion by the VKH Committee's new criteria.

Prognostic factors of 2-year outcomes of ranibizumab therapy for polypoidal choroidal vasculopathy.

PURPOSE: To determine predictors of 2-year outcomes after three, monthly, intravitreal ranibizumab (IVR) injections followed by as-needed injections for treatment-naive polypoidal choroidal vasculopathy (PCV). METHODS: This trial included 85 Japanese patients with symptomatic treatment-naive PCV who received one 0.5 mg IVR injection monthly for 3 months followed by as-needed retreatments. PCV with subfoveal leakage on fluorescein angiography with or without actual choroidal neovascularisation were included. Analyses evaluated independent baseline predictors of better and improved visual acuity (VA) and need for fewer reinjections 2 years after the first injection. RESULTS: After the three monthly injections, 1.3±1.4 and 1.5±2.0 (mean±SD) as-needed injections were administered during years 1 and 2, respectively. The baseline logarithm of the minimum angle of resolution, VA (0.60±0.49) improved significantly (p=0.001) (0.41±0.47) 2 years after the first injection. Younger patients' eyes with a better baseline VA and no cluster of grape-like polypoidal lesions were significant independent predictors of better VA 2 years after treatment. No baseline factors predicted fewer ranibizumab reinjections during 2 years. At 2 years, resolution of polypoidal lesions 1 month after the three monthly injections did not affect VA and number of reinjections during 2 years. CONCLUSIONS: Patient age, baseline VA and clusters of grape-like polypoidal lesions predicted VA outcomes 2 years after treatment with IVR for PCV.

Intraoperative endoscopic observation of sclerotomy site after cannula removal for 23-gauge vitrectomy.

BACKGROUND: The purpose of this study was to determine the incidence of vitreous incarceration in sclerotomy after cannula removal during 23-gauge vitrectomy. METHODS: Thirty-seven eyes underwent 23-gauge sutureless vitrectomy. Oblique sclerotomies were made parallel to the limbus and tangentially to the sclera. Once past the trocar sleeve, the angle was changed to 90 degrees perpendicular to the surface and the trocar and cannula inserted. Vitreous gel was removed until the intraocular edge of the infusion cannula was free from the gel. The cannula was extracted with insertion of a light probe. The sclerotomy site was evaluated endoscopically through another cannula in 32 eyes; in five eyes, another infusion tube was inserted into the cannula to maintain intraocular pressure, the original infusion was removed, and the sclerotomy site observed. RESULTS: No vitreous incarceration occurred in 30 (94%) eyes when one cannula was removed with insertion of a light probe, and minimal incarceration occurred in two (6%) eyes. No incarceration occurred in five eyes with observation of the infusion site. CONCLUSION: The incidence of vitreous incarceration is low when a light probe or vitreous cutter is inserted. Inserting the light probe through the cannula during its removal and creating an oblique sclerotomy may reduce vitreous incarceration.

Two-year outcomes of intravitreal bevacizumab therapy for macular oedema secondary to branch retinal vein occlusion.

AIM: To determine the 2-year outcomes of intravitreal bevacizumab (IVB) injections in eyes with macular oedema (ME) following branch retinal vein occlusion (BRVO). METHODS: Of 105 consecutive eyes (105 treatment-naïve patients) with ME following BRVO, 89 eyes were followed for 2 years after the first injection. During the 2-year follow-up period, patients were examined at least every 3 months and received an IVB injection (1.25 mg/0.05 mL) if they met prespecified retreatment criteria. Rescue grid laser was permitted based on the findings of the Branch Vein Occlusion Study. RESULTS: The baseline logarithm of the minimum angle of resolution visual acuity (VA) was 0.64±0.24 (mean±SD), which significantly (p=0.001) improved 1 month after the first injection to 0.39±0.22. One year after the first injection, VA improved significantly (p=0.001) to 0.33±0.21 and remained 0.34±0.21 until 2 years after the first injection (p=0.001). The changes in foveal thickness were correlated with those of VA during the 2-year follow-up period with a mean of 3.8±1.5 injections (including the first injection). CONCLUSIONS: This relatively large case series study showed favourable 2-year outcomes using bevacizumab to treat ME following BRVO. Bevacizumab provides substantial long-term benefits in the treatment of ME following BRVO.

Relation between changes in foveal choroidal thickness and 1-year results of ranibizumab therapy for polypoidal choroidal vasculopathy.

AIM: To determine a correlation between changes in the subfoveal choroidal thickness and outcomes 1 year after ranibizumab therapy for polypoidal choroidal vasculopathy (PCV). METHODS: We prospectively studied 89 consecutive eyes with treatment-naïve symptomatic PCV and 1 year of follow-up after treatment. The choroidal thickness was measured monthly by optical coherence tomography using enhanced-depth imaging and the correlation between the changes in the choroidal thickness and outcomes 1 year after treatment was analysed. RESULTS: 86 eyes followed for 1 year were ultimately analysed. The mean logarithm of the minimum angle of resolution visual acuity (0.33±0.35) 1 year after the first injection significantly (p=0.001) improved compared to baseline (0.42±0.37). The mean choroidal and foveal retinal thicknesses decreased significantly (p=0.001 for both comparisons) from 271 and 347 µm to 212 and 203 µm, respectively. The amplitude of the change in the subfoveal choroidal thickness during the 1-year follow-up in eyes in which the polypoidal lesions resolved 1 year after the first injection (89±94 µm) was significantly (p=0.022) greater than in eyes in which the polypoidal lesions remained (45±109 µm). CONCLUSIONS: The subfoveal choroidal thickness decreased during ranibizumab therapy, which was associated with resolved polypoidal lesions and foveal retinal thickness, and may be associated with PCV activity.

Photodynamic therapy combined with intravitreal bevacizumab and sub-tenon triamcinolone acetonide injections for age-related macular degeneration.

PURPOSE: To report the results of triple therapy with photodynamic therapy (PDT) (PDT combined with intravitreal injection of bevacizumab (IVB) and sub-tenon injection of triamcinolone acetonide (STTA)) for the treatment of age-related macular degeneration (AMD) in Japanese patients. METHODS: This retrospective case series included 38 eyes of 38 patients with exudative AMD treated with PDT combined with IVB (1.25 mg) and STTA (40 mg). Retreatment was performed in the same manner with intervals of at least 3 months. All patients had been treatment naïve, with a follow-up period of 12 months. Best-corrected visual acuity (BCVA), macular retinal thickness (MRT) on optical coherence tomography, and the number of treatments were analyzed. RESULTS: The mean logarithm of the minimum angle of resolution BCVA in patients treated with PDT triple therapy was 0.86 ± 0.55 at baseline and 0.62 ± 0.55 at 12 months (p < 0.001). The mean MRT was 554.0 ± 202.6 µm at baseline and 205.1 ± 78.6 µm at 12 months (p < 0.001). During the 1-year follow-up, the average number of PDT triple therapy (treatments per patient) was 1.1. No complications, for example increase in intraocular pressure, cataract, or endophthalmitis, were observed. CONCLUSIONS: In AMD patients, PDT triple therapy significantly improved visual acuity with a minimum number of treatments and a low risk of complications during the 1-year follow-up.

Results of 2 years of treatment with as-needed ranibizumab reinjection for polypoidal choroidal vasculopathy.

PURPOSE: To investigate the 2-year outcomes of three monthly intravitreal ranibizumab injections followed by as-needed reinjections to treat polypoidal choroidal vasculopathy (PCV). METHODS: Seventy-five consecutive eyes with naïve symptomatic PCV with 2 years of follow-up after treatment were studied prospectively. RESULTS: The mean (±SD) numbers of injections were 4.2±1.3 that included three monthly injections in the loading phase and 1.6±1.7 during years 1 and 2, respectively (mean 2-year total, 5.6±1.9). The baseline logarithm of the minimum angle of resolution visual acuity (VA) was 0.59±0.51 that improved significantly (p=0.001 for both comparisons) to 0.37±0.33 and 0.41±0.40 at 1 and 2 years, respectively, after the first injection. Although no significant difference was found between years 1 and 2 after the first injection, the VA tended to decrease slightly during year 2. The improved foveal thickness was maintained during year 2. Thirty (40%) eyes and 19 (25%) eyes, respectively, at years 1 and 2 after the first injection had no polypoidal lesions on indocyanine green angiography. A branching vascular network (BVN) remained in all eyes 2 years after the first injection and tended to increase in size during year 2. CONCLUSIONS: The 2-year outcomes showed significant VA and foveal thickness improvements in eyes with PCV. During year 2, the magnitude of the improvement was lower compared with year 1. An as-needed reinjection schedule might not prevent polypoidal lesions or BVNs from regrowing. Further investigations should establish a treatment strategy for PCV.

Chickenpox chorioretinitis with retinal exudates and periphlebitis.

BACKGROUND: Chickenpox is rarely associated with posterior segment inflammation. We report on a case of unilateral chickenpox chorioretinitis with retinal exudates and periphlebitis. CASE PRESENTATION: A 21-year-old healthy man, who suffered from chickenpox 2 weeks prior to symptom development, exhibited mild anterior chamber cells, vitreous opacity, sheathing of retinal veins, and yellow-white exudates in his right eye. Varicella zoster virus DNA was detected by polymerase chain reaction in the aqueous humor. He was treated with intravenous acyclovir followed by oral prednisolone and valaciclovir. Aqueous cells quickly disappeared and retinal exudates diminished within 1 month, leaving faint retinal scarring. Retinal arteritis had never been observed in this patient. CONCLUSIONS: ALTHOUGH THE OCULAR FINDINGS IN THIS CASE WERE SIMILAR TO ACUTE RETINAL NECROSIS (ARN), THE CLINICAL FEATURES DIFFERED FROM ARN IN THE FOLLOWING POINTS: (1) mild anterior chamber inflammation, (2) absence of retinal arteritis, and (3) prompt resolution of inflammatory findings. The distinctive clinical features indicated that chorioretinitis associated with chickenpox may not have the same pathological conditions as ARN.

Clinical features of intraocular inflammation in Hokkaido, Japan.

PURPOSE: We aimed to investigate the clinical features of intraocular inflammation/uveitis in Hokkaido, Japan. METHODS: We retrospectively reviewed the medical records of 1240 uveitis patients (511 men, 729 women) who visited Hokkaido University Hospital, Sapporo, Japan between 1994 and 2003. RESULTS: Mean age at disease onset was 41.7 +/- 17.8 years in men and 45.7 +/- 18.3 years in women. Anterior, posterior and combined anterior and posterior segment intraocular inflammation accounted for 45.1%, 4.7% and 50.2% of cases, respectively. Sarcoidosis was the most frequent aetiology (14.9%), followed by Vogt-Koyanagi-Harada (VKH) disease (9.7%) and Behçet's disease (6.7%). Aetiologies in 49.8% patients were unknown. In sarcoidosis, women represented 72.4% of patients, and disease onset occurred at 35.1 +/- 19.0 years of age in men and 50.3 +/- 16.5 years in women. In VKH disease, 54.2% of patients were women, and disease onset took place at 45.9 +/- 15.8 years in men and 46.4 +/- 14.1 years in women. In Behçet's disease, men accounted for 56.6% of patients, and disease onset occurred at 35.5 +/- 8.5 years in men and 44.5 +/- 11.5 years in women. CONCLUSIONS: Women were more prone to developing sarcoidosis compared with men. By contrast, men were more prone to developing Behçet's disease. The mean age at disease onset in both sarcoidosis and Behçet's disease was significantly lower in men than in women.

Osteopontin aggravates experimental autoimmune uveoretinitis in mice.

Human endogenous uveitis is a common sight-threatening intraocular inflammatory disease and has been studied extensively using a murine model of experimental autoimmune uveoretinitis (EAU). It is possibly mediated by Th1 immune responses. In the present study, we investigated the role of osteopontin (OPN), a protein with pleiotropic functions that contributes to the development of Th1 cell-mediated immunity. Accompanying EAU progression, OPN was elevated in wild-type (WT) mice that had been immunized with human interphotoreceptor retinoid-binding protein (hIRBP) peptide 1-20. OPN-deficient (OPN-/-) mice showed milder EAU progression in clinical and histopathological scores compared with those of WT mice. The T cells from hIRBP-immunized OPN-/- mice exhibited reduced Ag-specific proliferation and proinflammatory cytokine (TNF-alpha and IFN-gamma) production compared with those of WT T cells. When hIRBP-immunized WT mice were administered M5 Ab reacting to SLAYGLR sequence, a cryptic binding site to integrins within OPN, EAU development was significantly ameliorated. T cells from hIRBP-immunized WT mice showed significantly reduced proliferative responses and proinflammatory cytokine production upon stimulation with hIRBP peptide in the presence of M5 Ab in the culture. Our present results demonstrate that OPN may represent a novel therapeutic target to control uveoretinitis.

Granulocytapheresis in patients with refractory ocular Behcet's disease.

Intraocular inflammation (uveoretinitis) is one major complication of Behcet's disease (BD) and responds poorly to drug therapy. This open prospective study was to assess the efficacy of selective granulocytapheresis in patients with refractory uveoretinitis of BD. Fourteen patients aged 20-56 years were treated. Granulocytapheresis was done with an Adacolumn filled with cellulose acetate leucocyte carries or beads that adsorb granulocytes and monocytes from the blood in the column. Each patient received 5 Adacolumn sessions at one session/week over 5 consecutive weeks. The study was designed to allow each patient to serve as his or her own control. The total numbers of ocular attacks (OA) were monitored for 6 months before and after 5 Adacolumn sessions. The number of OA (mean +/- SD) per patient for the 6 months before Adacolumn was 4.21 +/- 1.6 and for the 6 months post Adacolumn was 2.93 +/- 1.39 ( P = 0.0275). Nine patients (64%) improved and 5 did not change or worsened. Further, for a sub-group (n = 7) with duration of BD > or =5 years, the number of OA were 4.71 +/- 1.89 for the first 6 months and 2.29 +/- 1.38 for the second 6 months ( P = 0.0054). The corresponding values for a sub-group (n = 7) with duration of BD<5 years were 3.71 +/- 1.25 and 3.57 +/- 1.13, indicating that patients with long duration of BD are better responders. We conclude that granulocytapheresis might be effective and safe for patients with refractory ocular BD. Further studies are necessary to fully evaluate the clinical efficacy of granulocytapheresis for BD.

Retinal neovascularization during treatment with IGF-1 for insulin resistance syndrome.

BACKGROUND: Leprechaunism is a rare congenital syndrome and the most severe form of insulin resistance syndrome, with mutations in the insulin receptor gene. Recombinant human insulin-like growth factor-1 (rhIGF-1) is currently applicable to the treatment for insulin resistance syndrome by its insulin-like effect. Although IGF-1 is thought to promote tissue proliferation and neovascularization, it is uncertain how it acts on the development of diabetic retinopathy. METHODS: Interventional case report. RESULTS: A 12-year-old girl with leprechaunism has been treated with IGF-1 since she was 6 months old. She presented with neovascular glaucoma in the left eye, but with no serious changes in the right fundus except for tortuosity and dilatation of retinal veins. Thereafter, retinal neovascularization in the right eye developed in 6 months to form a loop-shaped vascular network in the vitreous cavity despite panretinal photocoagulation. CONCLUSIONS: Characteristics of retinal neovascularization and clinical course suggest that IGF-1 treatment was closely associated with the development of diabetic retinopathy in this case.

The effects of Ginkgo biloba extract on lipopolysaccharide-induced inflammation in vitro and in vivo.

PURPOSE: Ginkgo biloba extract (GBE) contains many different flavone glycosides and terpenoides. Several previous studies have demonstrated that GBE exhibits a wide variety of biological activities, including an antioxidant action, on which we focused our attention. The aim of the present study was to investigate the efficacy of GBE on endotoxin induced uveitis in rats. The anti-inflammatory potency of GBE in vivo was compared with that of prednisolone. In addition, we also investigated nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha) and the expression of iNOS in a mouse macrophage cell line (RAW 264.7) treated with GBE in vitro to clarify the anti-inflammatory effect. METHODS: EIU was induced in male Lewis rats by a footpad injection of lipopolysaccharide (LPS). Immediately after the LPS inoculation, either 1, 10 or 100 microg of GBE were injected intravenously. 24hr later, the aqueous humor was collected from both eyes, and the number of infiltrating cells, protein concentration and NO level in the aqueous humor was determined. The RAW 264.7 cells were pretreated with various concentrations of GBE for 24hr and subsequently incubated with LPS for 24hr. Levels of NO, PGE2 and TNF-alpha were determined by enzyme-linked immunosorbent assay. The expression of iNOS protein was analyzed by Western blotting method. RESULTS: GBE treatment in vivo decreased the concentrations of protein and NO in the aqueous humor of EIU rats. The anti-inflammatory effect of 1 mg GBE was as strong as that of same dose prednisolone. It also significantly reduced the concentration of PGE2, TNF-alpha and NO production in the medium of RAW 264.7 cells compared to that of the LPS group in vitro. The expression of iNOS protein in the 1000 microg ml(-1) of GBE treated cells decreased significantly. CONCLUSION: The present results indicate GBE suppresses the inflammation of EIU by blocking the iNOS protein expression and its anti-inflammatory effect on eye is comparable with the effect of prednisolone used in similar doses.