Anti-TNF-α Therapy for Refractory Uveitis Associated with Behçet's Syndrome and Sarcoidosis: A Single Center Study of 131 Patients.

PURPOSE: The efficacy of infliximab (IFX) and adalimumab (ADA) for treating Behçet's syndrome (BS) and sarcoidosis has not been compared adequately. METHODS: We reviewed the medical records of patients with uveitis diagnosed at Tokyo Medical University Hospital and compared the efficacy of IFX and ADA for BS and the efficacy of ADA for sarcoidosis and BS. RESULTS: 68 patients in IFX group and 63 patients in ADA group were analyzed. In BS patients, IFX and ADA were both effective in improving uveitic macular edema (UME). ADA improved UME in BS but not in sarcoidosis patients. The efficacy of ADA in reducing doses of corticosteroids and glaucoma medications was better in sarcoidosis than in the BS group. CONCLUSION: Both IFX and ADA are efficacious in improving UME in BS patients. The reason that ADA improves UME better in BS than in sarcoidosis may be due to the difference in pathogenesis between these diseases.

An unusual case of Behcet disease with posterior scleritis: A case report.

RATIONALE: Posterior scleritis is an ocular inflammatory disorder that can be associated with both infectious and non-infectious immune reactions. Behcet disease is a chronic, relapsing, multisystemic inflammatory disorder with uveitis. There are no reported cases of posterior scleritis with Bechet disease. PATIENT CONCERNS: A 50-year-old man previously diagnosed with systemic Behcet disease presented with ocular pain and decreased vision in the left eye. DIAGNOSIS: Posterior scleritis associated with Behcet disease was diagnosed based on optical coherence tomography showing choroidal folds, as well as contrast computed tomography and ultrasound sonography demonstrating thickening of the posterior sclera. INTERVENTIONS: Treatment with systemic corticosteroids was initiated. Since inflammation relapsed during steroid tapering, anti-tumor necrosis factor-alpha (TNF-α) therapy was used in combination, and tapering of steroids was possible without recurrence of inflammation for 12 months. OUTCOMES: Posterior scleritis was resolved and visual acuity improved. With the continuation of TNF-α therapy, oral prednisolone was successfully tapered and discontinued. No relapse of inflammation was observed at follow-up 1 year after discontinuation of prednisolone. LESSONS: Ophthalmologists should be aware of the possibility of rare manifestation of posterior scleritis in patients with Behcet disease, and that combined use of systemic steroids and anti-TNF-α therapy may resolve the scleritis without recurrence of inflammation.

Clinical features of anterior uveitis caused by three different herpes viruses.

PURPOSE: To compare the clinical findings in patients with anterior uveitis (AU) caused by herpes simplex virus (HSV), varicella zoster virus (VZV), and cytomegalovirus (CMV). METHODS: We retrospectively analyzed the clinical profiles of HSV-AU (14 patients), VZV sine herpete (ZSH-AU: 21 patients), and CMV-AU (17 patients) diagnosed by the detection of corresponding viral DNA in aqueous humor samples by polymerase chain reaction. Further, five patients with Posner-Schlossman (P-S) syndrome were selected as controls for CMV-AU. RESULTS: Patients with CMV-AU were predominately male or older in age, and all cases were unilateral except for three patients with CMV-AU. Mutton-fat keratic precipitates (KPs) were found mostly in patients with HSV-AU and ZSH-AU. Severities of AU and viral load were the highest in ZSH-AU, followed by HSV-AU and CMV-AU. Iris atrophy was observed in HSV-AU (50%) and ZSH-AU (76%), with typical morphology of round type and sector type, respectively. In patients with CMV-AU, a ring-shaped KP was found in 53% patients, 76% of whom showed a decreased number of corneal endothelial cells. CMV was not detected in the aqueous humor of patients with typical P-S syndrome. CONCLUSION: Clinical findings of HSV-AU and VZV-AU were similar; however, more inflammatory findings were observed in VZV-AU. Iris atrophy morphologically differed in HSV-AU and VZV-AU. Inflammatory findings in CMV-AU were mild, and clinical features of iritis differed from those of the two former groups. A difference in the etiology between CMV-AU and P-S syndrome was observed.

Inhibition of hydrogen embrittlement of Ni-Ti superelastic alloy in acid fluoride solution by hydrogen peroxide addition.

Inhibition of the hydrogen embrittlement of Ni-Ti superelastic alloy in an acidulated phosphate fluoride (APF) solution has been attempted by adding various amounts of H(2)O(2). In a 0.2% APF solution, hydrogen absorption is markedly inhibited by adding H(2)O(2), although corrosion is slightly enhanced by increasing the amount of added H(2)O(2). By adding a small amount of H(2)O(2) (0.001 M), in the early stage of immersion, hydrogen embrittlement is inhibited and corrosion is only slightly enhanced. Upon adding H(2)O(2), it appears that the dominant cathodic reactions change from hydrogen evolution to H(2)O(2) reduction reactions, or the surface conditions of the alloy are changed by H(2)O(2) with a high oxidation capability, thereby inhibiting hydrogen absorption. The present study clearly indicates that infinitesimal addition of H(2)O(2) into acid fluoride solutions is effective for the inhibition of the hydrogen embrittlement of the alloy.

The structure of a new cardenolide diglycoside and the biological activities of eleven cardenolide diglycosides from Nerium oleander.

A new cardenolide diglycoside (1) was isolated from Nerium oleander together with ten known cardenolide diglycosides 2-11. The structure of compound 1 was established on the basis of their spectroscopic data. The in vitro anti-inflammatory activity of compounds 1-11 was examined on the basis of inhibitory activity against the induction of the intercellular adhesion molecule-1 (ICAM-1). Compounds 2-5 were active at an IC(50) value of less than 0.8 µM. The cytotoxicity of compounds 1-11 was evaluated against three human cell lines normal human fibroblast cells (WI-38), malignant tumor cells induced from WI-38 (VA-13), and human liver tumor cells (HepG2). Compound 3 was active toward VA-13 cells, and compounds 2-5 were active toward HepG2 cells at IC(50) values of less than 1.3 µM. The multidrug resistance (MDR)-reversal activity of compounds 1-11 was evaluated on the basis of the amount of calcein in MDR human ovarian cancer 2780AD cells in the presence of each compound. Compounds 1 and 8 showed moderate effects on calcein accumulation.

Three new cardenolides from methanol extract of stems and twigs of Nerium oleander.

Two new cardenolide monoglycosides, cardenolides B-1 (1) and B-2 (2) were isolated from Nerium oleander, together with oleagenin (3) which is the first isolated compound from natural sources. The structure of compounds 1-3 were established on the basis of their spectroscopic data.

[Pars plana vitrectomy in patients with acute retinal necrosis syndrome: surgical results in 52 patients].

PURPOSE: To analyze results of pars plana vitrectomy for acute retinal necrosis (ARN) syndrome. METHODS: We reviewed the records of 52 eyes with ARN syndrome who underwent pars plana vitrectomy at the Tokyo Medical University Hospital from 1989 to 2007. The mean age was 50.1 +/- 10.2 years and the mean follow-up duration was 75.3 months. The causative virus was herpes simplex virus in 7 cases and varicella zoster virus in 45 cases. In all cases, treatment with acyclovir and corticosteroids was started from presentation. During the follow-up period, vitrectomy was done in patients who developed retinal detachment, and in those who developed posterior vitreous detachment exerting marked traction on the retina, even though retinal detachment had not occurred. In these cases, preoperative and postoperative visual acuities were compared and reoperation, retinal detachment preventive surgery and age-stratified visual prognosis after vitrectomy were analyzed. RESULTS: Visual acuity was improved by 2 lines or more in 13 eyes (25.0%), remained unchanged in 16 eyes (30.8%), and deteriorated by 2 lines or more in 23 eyes (44.2%). Thirty-seven of 52 eyes (71.2%) required re-operation. No significant differences were detected when the patients were stratified according to whether they were treated either with or without combined use of silicon oil, or according to whether they were treated either with or without prophylactic surgery for retinal detachment, as well as by age of vitrectomy. A combination of lens extraction, silicon oil and encircling sclera buckling procedure was associated with a significantly higher frequency of final visual acuity. CONCLUSION: Despite the advances in vitrectomy achieved today, the visual prognosis of acute retinal necrosis remains unsatisfactory. The present study found no significant improvement in the prognostic relevance of prophylactic vitrectomy. Improvement in pharmacotherapy may help improve the prognosis. Further prospective large-scale studies to compare other treatment modalities are also required.

Comparison of patients with ocular tuberculosis in the 1990s and the 2000s.

PURPOSE: To compare clinical findings in patients with ocular tuberculosis experienced during two different decades. METHODS: Thirty-four patients with ocular tuberculosis were divided into two groups: a 1990s group (n = 18) and a 2000s group (n = 16), according to the dates of their first outpatient visit. The clinical profiles of the two groups were then compared. RESULTS: More cases of the 1990s group had complications involving extraocular tuberculosis than those of the 2000s group. While various ophthalmic manifestations were observed clinically in the 1990s group, all retinal periphlebitis cases presented in the 2000s group. The proportion of patients who received antituberculous treatment was higher in the 1990s group, but the proportion who received oral corticosteroid therapy did not differ between the two periods. However, more patients underwent laser photocoagulation in the 2000s group. The percentage of eyes with final visual acuity better than 20/20 increased in the 2000s group. CONCLUSIONS: The clinical outcome of patients with ocular tuberculosis was improved in the 2000s group, which may be attributable to the increase in active use of laser photocoagulation therapy.

Immune responses to interphotoreceptor retinoid-binding protein and S-antigen in Behcet's patients with uveitis.

PURPOSE: Immune responses to retina-specific autoantigens, including S antigen (S-Ag) and interphotoreceptor retinoid binding protein (IRBP), have been suggested to be involved in the pathogenesis of human uveitis, including Behçet's disease (BD). In this study, the authors examined whether immune responses to IRBP and S-Ag in BD patients can be characterized by cytokine production profiles. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from BD patients with uveitis and healthy controls, and each sample was cultured with IRBP, S-Ag, or purified protein derivative (PPD). At the end of culture, IL-2, IL-4, IL-6, IL-10, IL-17, IFN-gamma, and TNF-alpha concentrations in supernatants were measured. RESULTS: PBMCs from BD patients and healthy controls produced IL-6, IL-10, IL-17, IFN-gamma, and TNF-alpha on stimulation with IRBP or S-Ag, as well as PPD stimulation, immunity against which was acquired by Bacille Calmette-Guérin immunization. IL-17 and IFN-gamma production was significantly higher when PBMCs were stimulated with IRBP than with S-Ag, whereas the reverse was observed for IL-6 production. IRBP-stimulated IL-6, IFN-gamma, and IL-17 production was higher in BD patients than in healthy controls, though IL-10 production was not different between them. In particular, IRBP-stimulated IFN-gamma production was significantly higher in BD patients with active uveitis than in BD patients with uveitis in remission. CONCLUSIONS: Immune responses to both IRBP and S-Ag were observed even in PBMCs of healthy controls. However, the present results suggested that retinal autoantigen-stimulated IL-6, IL-17, and especially IFN-gamma production would be involved in the development of uveitis in BD.

Functional and morphological changes in the eyes of Behçet's patients with uveitis.

PURPOSE: Behçet's disease (BD) is a chronic, recurrent, multisystem disorder, and serious ocular involvement may lead to blindness. In some BD patients, latent tissue damage caused by recurrent ocular inflammation is not reflected by visual acuity or ophthalmoscopic findings. In this study, we evaluated the morphological and functional changes of ocular features related to duration of uveitis from onset in BD patients, and analysed their association with visual acuity. METHODS: Thirty-eight eyes of 20 patients with ocular BD were enrolled. Eyes with marked complications such as cataract, glaucoma, cystoid macular oedema, macular degeneration and optic atrophy were excluded from the study. During clinical remission of ocular inflammation, perimetric sensitivity and retinal thickness were measured by Micro Perimeter 1 (MP-1) and optical coherence tomography (OCT), respectively. The relationship between MP-1 and OCT findings, best-corrected visual acuity (BCVA) converted to logarithm of the minimum angle of resolution (logMAR) and duration from initial onset of uveitis were analysed statistically. RESULTS: logMAR correlated with perimetric sensitivity measured with MP-1 at the fovea, inner macula and outer macula, but not with retinal thickness based on OCT. The duration of uveitis correlated significantly with logMAR and with OCT-based retinal thickness at the fovea, inner macular and outer macula, but not with MP-1-derived retinal perimetric sensitivity. No correlation was found between OCT-based retinal thickness and the corresponding MP-1-derived retinal sensitivity at the fovea, inner macula or outer macula. CONCLUSION: These results demonstrate that visual acuity, retinal perimetric sensitivity and retinal thickness decrease with an increase in the duration of uveitis in BD patients, but that retinal perimetric sensitivity is relatively preserved among these factors.

Biphenylene-substituted ruthenocenylphosphine for Suzuki-Miyaura coupling of sterically hindered aryl bromides.

A highly general, active, and stable catalytic system was realized in the palladium-catalyzed Suzuki-Miyaura reactions of sterically hindered aryl bromides with arylboronic acids using biphenylene-substituted di-tert-butylruthenocenylphosphine (R-Phos) as a supporting ligand.

Presumed Vogt-Koyanagi-Harada disease with unilateral ocular involvement: report of three cases.

AIM: To report three cases of presumed Vogt-Koyanagi-Harada (VKH) disease with unilateral ocular manifestations. METHODS: This retrospective study reviewed the long-term follow-up observations of three patients who attended the uveitis clinic at Tokyo Medical University Hospital. The patients were followed for 5-16 years with systemic clinical, ophthalmologic and laboratory examinations. Ophthalmoscopic findings, extraocular manifestations, visual acuity, and response to corticosteroid administration were evaluated. RESULTS: Three patients had characteristic clinical features of VKH involving only one eye, including diffuse choroiditis, serous retinal detachment, focal areas of delayed choroidal perfusion, multifocal areas of pinpoint leakage, macular oedema, and optic nerve staining. All patients received systemic corticosteroid therapy during the acute phase of the disease. During the follow-up period (5-16 years), all three patients developed sunset-glow fundus and nummular chorioretinal depigmented scars in the affected eye only, as well as systemic complications of deafness, vitiligo, and poliosis. CONCLUSION: The clinical and laboratory features of all three patients were typical of VKH disease except for the unilateral involvement. It is important for ophthalmologists to recognize unilateral VKH disease, even though it is a rare clinical variant of the disease.

The application of the mutated acetolactate synthase gene from rice as the selectable marker gene in the production of transgenic soybeans.

We investigated selective culturing conditions for the production of transgenic soybeans. In this culturing system, we used the acetolactate synthase (ALS)-inhibiting herbicide-resistance gene derived from rice (Os-mALS gene) as a selectable marker gene instead of that derived from bacteria, which interfered with the cultivation and practical usage of transgenic crops. T(1) soybeans grown from one regenerated plant after selection of the ALS-targeting pyrimidinyl carboxy (PC) herbicide bispyribac-sodium (BS) exhibited herbicide resistance, and the introduction and expression of the Os-mALS gene were confirmed by genetic analysis. The selective culturing system promoted by BS herbicide, in which the Os-mALS gene was used as a selectable marker, was proved to be applicable to the production of transgenic soybeans, despite the appearance of escaped soybean plants that did not contain the Os-mALS transgene.

Confinement loss evaluation based on a multilayer division method in Bragg fibers.

Confinement loss is comprehensively evaluated for TE, TM, and hybrid modes of Bragg fibers using a multilayer division method newly developed. We show the loss dependence on the core radius, wavelength, cladding index contrast, and the number of cladding pairs. The confinement loss is reduced in proportion to (a/b)(2N) and (n(2) (b)b/n(2) (a)a)(2N) for the TE and other three modes, respectively, with respect to cladding pairs N under the quarter-wave stack condition, with cladding high na and low indices nb and their corresponding thicknesses a and b. For sufficiently large core radius, the confinement loss decreases in inverse proportion to the third and first powers of core radius for the TE and other three modes, respectively. Low loss modes are the TE(01), TE(02), HE(13), and TE(03) modes in order of increasing confinement loss.

Biphenylene-substituted ruthenocenylphosphine for Suzuki-Miyaura coupling of aryl chlorides.

High activity in the palladium-catalyzed Suzuki-Miyaura reactions of aryl chlorides with arylboronic acids was furnished using biphenylene-substituted di- tert-butylruthenocenylphosphine (R-Phos) as a supporting ligand. Substrate combinations even for the construction of highly hindered tetra- ortho-substituted biaryls can be achieved in good to excellent yields with low catalyst loadings in short reaction times.

Bid truncation mediated by caspases-3 and -9 in vinorelbine-induced apoptosis.

Vinorelbine is a chemotherapeutic vinca alkaloid clinically prescribed for non-small cell lung cancer and breast cancer. Here we studied the mechanism for vinorelbine-induced apoptosis in a human T-cell lymphoma. Although vinorelbine induces DNA fragmentation that is inhibited by specific peptide inhibitors for caspases-9 and -3 in Jurkat cells, caspase-8 deficiency retards vinorelbine-induced apoptosis. Activation of caspase-8 is also observed in vinorelbine-treated cells, and the activity is diminished when the caspase-3 activity is blocked by a specific peptide inhibitor, Ac-DNLC-CHO. Blocking of the Fas receptor with an antagonistic anti-Fas antibody does not affect vinorelbine-induced DNA fragmentation. These results suggest that vinorelbine-induced apoptosis is enhanced by the activation of caspase-8 via caspase-9-mediated activation of caspase-3, but not through a Fas-triggered signal. Western blotting suggests that vinorelbine cleaves caspase-3, -9 and -8 and reduces the amount of mitochondrial cytochrome c. Caspase-8 deficiency suppresses all of these events. A downstream substrate for caspase-8, Bid, is also cleaved in vinorelbine-treated cells, but the Bid truncation is also observed in caspase-8-deficient Jurkat cells. Importantly, recombinant caspases-3 and -9, as well as caspase-8, directly cleaves recombinant Bid in vitro. These results suggest that caspases-3 and -9 participate in Bid truncation, indicating a new mechanism for vinorelbine-induces apoptosis.

Bioactive triterpene saponins from the roots of Phytolacca americana.

Five new triterpene saponins named phytolaccasaponins N-1 (1), N-2 (2), N-3 (3) N-4 (4), and N-5 (5) were isolated from the roots of Phytolacca americana together with seven known triterpene saponins (6-12). The structures of the five new saponins were established as shown in structures 1-5 on the basis of their spectroscopic data. The MDR-reversal activity of 1-12 was evaluated on the basis of the amount of calcein accumulated in MDR human ovarian cancer 2780 AD cells in the presence of each compound. The most effective compound was 8 (155% of control at 25 microg/mL).

Circulating neutrophils in Behçet disease is resistant for apoptotic cell death in the remission phase of uveitis.

BACKGROUND: Behçet disease (BD) is manifested by recurrent acute iridocyclitis with hypopyon in the active phase, which regresses spontaneously. Hypopyon consists of inflammatory cells infiltrating the eye, with polymorphonuclear cells (PMNs) as the main component. The present study was conducted to investigate the apoptosis property of PMNs in BD patients with uveitis. METHODS: PMNs were purified from peripheral blood cells of BD patients with uveitis in the active or remission phase and were cultured for 12 hours. In some cultures, lipopolysaccharide (LPS), antagonistic anti-TNFalpha antibody, agonistic anti-Fas antibody, or Fas:Fc fusion protein was added. At the end of cultures, apoptotic cells were evaluated by Annexin V expression using flow cytometry. RESULTS: Spontaneous apoptosis of PMNs showed lower levels in the remission phase of BD-related uveitis compared with the active phase or healthy controls. The lower level of PMN apoptosis in the remission phase of uveitis in BD remained even by stimulation with LPS, anti-TNFalpha antibody, or Fas:Fc fusion protein, which was abolished in the presence of agonistic anti-Fas antibody. CONCLUSIONS: In BD patients, the apoptosis of PMNs was reduced in the remission phase of uveitis and restored in the active phase, which arose from the apoptotic cell death in part via Fas-Fas ligand interaction.

A case of hypertensive keratouveitis with endotheliitis associated with cytomegalovirus.

AIM: While cytomegalovirus is well known as a pathogenic organism of retinitis, especially associated with human immunodeficiency virus infection, there are few reports of anterior uveitis associated with cytomegalovirus. METHODS: The authors present a case of keratouveitis associated with cytomegalovirus. RESULTS: A 70-year-old Japanese man was referred to the authors because of poorly controlled hypertensive keratouveitis in the left eye. The patient had a history of recurrent hypertensive anterior uveitis. At presentation, the corneal stroma was edematous, with Descemet's folds and pigmented keratic precipitates. The anterior chamber angle was depigmented compared to the fellow eye. Even though pupil dilation and posterior synechiae were absent, iris atrophy was not evident. His right eye appeared normal except for moderate cataract. Funduscopy of the left eye was hazy, with the optic disc showing a normal color but poorly defined details, and no apparent exdative retinitis. The best-corrected decimal visual acuity of the right and left eyes was 0.4 and 0.02, respectively. Intraocular pressure was 11 mmHg in the right eye and 35 mmHg in the left, despite maximum medical therapy. Systemic acyclovir and prednisolone for a month did not improve the hypertensive keratouveitis. The aqueous humor was investigated for herpes simplex virus, varicella-zoster virus and cytomegalovirus. Cytomegalovius genome was detected by polymerase chain reaction analysis. Oral valganciclovir rapidly reduced ocular hypertension within a week. CMV DNA disappeared 3 months after the initiation of valganciclovir. CONCLUSION: The authors reported a case of hypertensive keratouveitis with endotheliitis associated with cytomegalovirus.

Bioactive cardenolides from the stems and twigs of Nerium oleander.

Four new cardenolide monoglycosides, cardenolides N-1 (1), N-2 (2), N-3 (3), and N-4 (4), were isolated from Nerium oleander, together with two known cardenolides, 5 and 12, and seven cardenolide monoglycosides, 6-11 and 13. The structures of compounds 1-4 were established on the basis of their spectroscopic data. The in vitro anti-inflammatory activity of compounds 1-13 was examined on the basis of inhibitory activity against the induction of the intercellular adhesion molecule-1 (ICAM-1). Compounds 1, 5, 6, and 11-13 were active at an IC50 value of less than 1 microM. The cytotoxicity of compounds 1-13 was evaluated against three human cell lines, normal human fibroblast cells (WI-38), malignant tumor cells induced from WI-38 (VA-13), and human liver tumor cells (HepG2). Compounds 1, 4, 6, and 11-13 were active toward V-13 cells, and compounds 1, 11, and 12 were active toward HepG2 cells at IC50 values of less than 1 microM. Compounds 4, 5, 10, and 12 showed selective cell growth inhibitory activity toward V-13 tumor cells compared with that of parental normal WI-38 cells. The MDR-reversal activity of compounds 1-13 was evaluated on the basis of the amount of calcein accumulated in MDR human ovarian cancer 2780AD cells in the presence of each compound. Compounds 4, 9, and 10 showed significant effects on calcein accumulation, compound 4 showing stronger activity than that of verapamil.