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We reported previously that enzymatic and singlet oxygen-mediated fatty acid oxidation may be major oxidation pathways in subjects with primary open angle glaucoma, based on measurement of serum levels of hydroxylinoleate (HODE) and hydroxyarachidonate (HETE) isomers after reduction and saponification. In this study, we measured serum levels of HODE and HETE isomers to investigate the pathogenesis of exfoliation syndrome (EX). In total, 311 Japanese subjects comprising EX patients (n = 192) and non-glaucomatous control subjects (n = 119) were included in this study. Patients with EX (n = 192) were divided into EX with glaucoma (EXG) and EX without glaucoma (EXS) groups (n = 128 and n = 64, respectively) depending on the intraocular pressure. Total HODE (/linoleic acid) serum levels were significantly (p = 0.0426) higher in the EX group (202.7 ± 153.2 μmol/mol) than in the controls (167.1 ± 105.3 μmol/mol). Among the HODE isomers, the levels of 9-(E,E)-HODEs (p 0.0001) and 13-(E,E)-HODEs (p 0.0001), both free radical-mediated oxidation products, were higher in the EX and EXG groups than in the controls, whereas no significant difference was observed between EXS and controls. After adjusting for differences in demographic parameters, multivariate analyses confirmed the association between 9- and 13-(E,E)-HODEs and EX. This is the first report of a dramatic increase in free radical-mediated oxidation products related to the pathogenesis of EX, and our findings suggest that free radical-mediated oxidation can be one of the causes of deterioration in EX.

Purpose To compare postsurgical anterior chamber flare (ACF) among conventional (trabeculectomy, LEC) and novel (EX-PRESS Shunt, EXP) filtration surgeries and microhook ab interno trabeculotomy (μLOT), a novel minimally invasive glaucoma surgery (MIGS). Subjects and methods This retrospective study included 125 primary open angle glaucoma eyes (89 consecutive subjects) treated with μLOT (n=38), LEC (n=12), or EXP (n=75). The intraocular pressure (IOP), numbers of antiglaucoma medication, and ACF at preoperatively and 2 weeks; 1, 3, and 6 months postoperatively were compared among the surgical groups using a mixed-effects regression model. Results The postoperative IOP (p

Background Sympathetic ophthalmia (SO) is a bilateral diffuse uveitis that can arise after ocular trauma or ocular surgery in the inciting eye. Pars plana vitrectomy (PPV) is one of the risk factors for SO. Several reports have described SO developing after 23- and 25-G PPV, but none have described SO occurring after 27-G PPV. We describe herein a case of SO after 27-G PPV for rhegmatogenous retinal detachment. Case presentation A 42-year-old woman presented with visual disturbance in the right eye. Best-corrected visual acuity (BCVA) was 6/200 in the right eye. Fundus examination revealed off-macula retinal detachment with retinal tears at both ends of retinal lattice degeneration at the temporal-oven peripheral retina of the right eye. We therefore performed 27-G sutureless PPV on the right eye. After 12 days, the retina was reattached, and BCVA improved to 6/30 in the right eye. Fifteen days postoperatively, she experienced headache and reduced vision in both eyes. Symptoms gradually worsened, and she visited our hospital 21 days postoperatively. BCVA was 6/30 in the right eye and 6/15 in the left eye. Slit-lamp examination revealed uveitis in the anterior chambers of both eyes, and fundus examination showed papillitis and subretinal detachment at the posterior poles of both eyes. Optical coherence tomography revealed subretinal fluid in the maculae of both eyes and fluorescein angiography showed multiple hyperfluorescent leakage sites in the retinal pigment epithelium. Cerebrospinal fluid examination showed pleocytosis and human leukocyte antigen testing showed expression of the DR04 phenotype; therefore, the patient was diagnosed with SO. She was treated with steroid therapy, and her visual disturbance subsided and the subretinal fluid improved as well. Her BCVA was 6/15 for the right eye and 6/5 for the left eye 93 days after the initial surgery. Conclusion The present case shows that even if the sclerotomy site of 27-G PPV is small, there is still a risk of SO occurring in the eyes of patients who underwent transconjunctival vitrectomy. Ophthalmologists should recognize SO as complication of 27-G PPV and carry out proper management as early as possible.

We report a case of saccharopinuria with hyperammonemia and hypercitrullinemia in a Japanese woman who presented with elderly-onset epilepsy, progressive cognitive decline, and gait ataxia. Blood amino acid analysis revealed an increase in citrulline, cystine, and lysine levels, and urine amino acid analysis showed increased citrulline and cystine levels. Urine metabolomics revealed an increased saccharopine level, leading to the definitive diagnosis of saccharopinuria. In western blots of liver biopsy samples, normal citrin levels were observed, suggesting that adult-onset citrullinemia type 2 (CTLN2) was not present. In addition, decreased argininosuccinate synthetase (ASS) levels were observed, and ASS1 gene, a causative gene for citrullinemia type 1 (CTLN1), was analyzed, but no gene mutations were found. Because the causes of hypercitrullinemia were not clear, it might be secondary to saccharopinuria. Muscle biopsy findings of the biceps brachii revealed diminished cytochrome c oxidase (COX) activity, mitochondrial abnormalities on electron microscopy and p62- positive structures in immunohistochemical analyses. Saccharopinuria is generally considered a benign metabolic variant, but our case showed elevated lysine and saccharopine levels causing ornithine circuit damage, mitochondrial dysfunction, and autophagy disorders. This may lead to so far unknown neurological disorders.

Purpose To investigate the reproducibility for the iridocorneal angle evaluations using the pictures obtained by a gonioscopic camera, Gonioscope GS-1 (Nidek Co., Gamagori, Japan). Methods The pragmatic within-patient comparative diagnostic evaluations for 140 GS-1 gonio-images obtained from 35 eyes of 35 patients at four ocular sectors (superior, temporal, inferior, and nasal angles) were conducted by five independent ophthalmologists including three glaucoma specialists in a masked fashion twice, 1 week apart. We undertook the observer agreement and correlation analyses of Scheie’s angle width and pigmentation gradings and detection of peripheral anterior synechia and Sampaolesi line. Results The respective Fleiss’ kappa values for the four elements between manual gonioscopy and automated gonioscope by the glaucoma specialist were 0.22, 0.40, 0.32 and 0.58. Additionally, the respective intraobserver agreements for the four elements by the glaucoma specialist each were 0.32 to 0.65, 0.24 to 0.71, 0.35 to 0.70, and 0.20 to 0.76; the Fleiss’ kappa coefficients for the four elements among the three glaucoma specialists were, respectively, 0.31, 0.38, 0.31, and 0.17; the Fleiss’ kappa coefficients for the angle width and pigmentation gradings between the two glaucoma specialists each were 0.30 to 0.35, and 0.29 to 0.43, respectively. Overall, the Kendall’s tau coefficients for the angle gradings reflected the positive correlations in the evaluations. Conclusion Our findings suggested slight-to-substantial intraobserver agreement and slight-to-fair (among the three) or fair-to-moderate (between the two each) interobserver agreement for the angle assessments using GS-1 gonio-photos even by glaucoma specialists. Sufficient training and a solid consensus should allow us to perform more reliable angle assessments using gonio-photos with high reproducibility.

Purpose. To compare the refractive status between eyes implanted with toric and nontoric intraocular lenses (IOLs) during combined cataract surgery and microhook ab interno trabeculotomy (μLOT), a minimally invasive glaucoma surgery (MIGS). Methods. Twenty eyes of 20 patients who had open-angle glaucoma, cataract, and preexisting regular corneal astigmatism exceeding 1.5 diopters (D) and underwent combined μLOT and phacoemulsification were recruited retrospectively. Ten eyes were implanted with a toric IOL and 10 eyes with a nontoric IOL. The primary outcomes were the uncorrected visual acuity (UCVA) and refractive cylinder at 3 months postoperatively. Results. The mean UCVA of the toric IOL group (logarithm of the minimum angle of resolution (logMAR), 0.23 ± 0.25) was significantly better than that of the nontoric IOL group (logMAR, 0.45 ± 0.26) at 3 months postoperatively ( p < 0.05 ). The mean absolute residual refractive cylinder of the nontoric IOL group (2.25 ± 0.62 D) was significantly greater than that of the toric IOL group (1.30 ± 0.68 D) ( p < 0.05 ). Postoperatively, 60% of eyes in the toric IOL group and 10% in the nontoric IOL group had an absolute refractive astigmatism level of 1.5 D or less. Surgically induced astigmatism (0.77 ± 0.43 D for toric group and 0.60 ± 0.32 D for nontoric group) and IOP reduction (33.9 ± 15.6% for toric group and 29.4 ± 11.7% for nontoric group) were not different between groups. Conclusions. Use of toric IOL during combined cataract surgery and μLOT is possible and better than not, but physician should prevent their patient of persisting residual astigmatism. The study was registered at https://www.umin.ac.jp/, and the clinical trial accession number is https://clinicaltrials.gov/ct2/show/UMIN000043141.

The retinal vessel narrowing may be implicated in the pathogenesis of glaucoma, however, the association between systemic oxidative stress and retinal vessel diameter remains largely unknown. We examined the relationship between serum oxidative stress markers and retinal vessel diameters in eyes with primary open-angle glaucoma (POAG) and cataract, using central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE). We included 66 eyes of 66 patients with POAG (37 men, 29 women, 65.4 &plusmn, 11.7 years) and 20 eyes of 20 patients with cataract (7 men, 13 women, 69.4 &plusmn, 9.0 years) as the controls. The CRAE (p &lt, 0.0001), CRVE (p &lt, 0.0001), and serum biological antioxidant potential (BAP) (p = 0.0419) were significantly lower in the POAG group compared to the controls. The BAP showed significant correlation both with CRAE (&rho, = 0.2148, p = 0.0471) and systolic blood pressure (&rho, = &minus, 0.2431, p = 0.0241), while neither Diacron reactive oxygen metabolites nor sulfhydryl test correlated with them. The multivariate analyses indicated that age, best corrected visual acuity, and BAP were independent factors for CRAE or CRVE. The present study suggested that lower systemic antioxidant capacity was significantly associated with the intraocular pressure-independent vascular narrowing in POAG patients. This study provided a novel insight into the pathophysiology of glaucoma and highlighted the clinical impact on systemic antioxidant treatment for patients with glaucoma.

Oxidative stress is thought to play a significant role in the development of glaucoma. However, the association between systemic and local oxidative stresses in different types of glaucoma has not been assessed fully. The current study compared the redox status in the aqueous humor (AH) and blood samples among eyes with primary open-angle glaucoma (POAG), exfoliation glaucoma (EXG), and non-glaucomatous controls to evaluate the relationship among systemic redox status, intraocular oxidative stress, and clinical backgrounds. AH and blood samples were obtained from 45 eyes of 45 Japanese subjects (15 POAG, 15 EXG, and 15 control eyes). The serum levels of lipid peroxides, ferric-reducing activity, and thiol antioxidant activity were measured by diacron reactive oxygen metabolites (dROM), biologic antioxidant potential (BAP), and sulfhydryl (SH) tests, respectively, using a free radical analyzer. The activities of cytosolic and mitochondrial forms of the superoxide dismutase (SOD) isoforms, i.e., SOD1 and SOD2, respectively, in AH and serum were measured using a multiplex bead immunoassay. In AH, SOD1 in subjects with EXG and SOD2 in those with POAG and EXG were significantly higher than in control eyes. In serum, compared to control subjects, BAP in subjects with POAG and EXG was significantly lower, SOD1 in those with EXG and SOD2 in those with POAG and EXG were significantly higher. dROM and SH did not differ significantly among the groups. The BAP values were correlated negatively with the SOD1 concentrations in AH and serum, SOD2 in the AH, intraocular pressure, and number of antiglaucoma medications. In conclusion, lower systemic antioxidant capacity accompanies up-regulation of higher local antioxidant enzymes, suggesting increased oxidative stress in eyes with OAG, especially in EXG. Determination of the systemic BAP values may help predict the redox status in AH.

Introduction Neovascular glaucoma is characterized by neovascularization of the iris and anterior angle chamber. Intravitreal anti-vascular endothelial growth factor agents may decrease intraocular pressure (IOP) and improve neovascularization. The VENERA study assessed the efficacy and safety of intravitreal aflibercept (IVT-AFL) in patients with neovascular glaucoma. Methods This was a 5-week, single-arm, nonrandomized, open-label, phase 3 study performed at 7 study sites in Japan that enrolled Japanese patients with anterior segment neovascularization and IOP > 25 mmHg who had not undergone (within 30 days prior), nor were imminently scheduled to undergo (within 8 days following) intraocular surgeries, including panretinal photocoagulation (PRP). Patients received background therapy plus 2 mg IVT-AFL at baseline. Background therapy with systemic IOP-lowering drugs was prohibited for 3 days before day 1 and until IOP evaluation at week 1. The primary endpoint was the change in IOP from baseline to week 1 and the secondary endpoint was the proportion of patients with an improvement of ≥ 1 grade of neovascularization of the angle (NVA) from baseline to week 1. Results Sixteen patients received treatment (full analysis set); the per-protocol set comprised 15 patients. The mean IOP decreased from 34.1 mmHg at baseline to 25.8 mmHg at week 1 (mean change, −8.3 mmHg [95% confidence interval; CI −12.2 to −4.4; P = 0.0004]). At week 1, 81.3% of patients had an improvement in the grade of neovascularization of the iris (NVI) and 50.0% of patients had an improvement in NVA grade. The proportion of patients with controlled IOP (≤ 21 mmHg) was 43.8% (95% CI 19.8–70.1) at week 1, and increased to 56.3% at week 2 and 86.7% at week 5. The most common ocular treatment-emergent adverse event was eye pain, which occurred in 4 patients (25.0%). Conclusions IVT-AFL was associated with statistically significant and clinically meaningful IOP reductions, without concomitant use of systemic IOP-lowering drugs or PRP. The safety profile was consistent with the known safety profile of IVT-AFL. These findings supplement those from the previous VEGA study, and suggest that IVT-AFL may be a potential treatment option for patients with neovascular glaucoma. Trial Registration Clinicaltrials.gov identifier NCT03639675. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-020-01580-y.

Prcis Use of toric intraocular lenses is a reasonable option for better visual outcomes when a combined minimally invasive glaucoma surgery (MIGS) and cataract surgery is performed in eyes with corneal astigmatism. Purpose To assess the efficacy of toric intraocular lenses (IOLs) in combined cataract and MIGS, visual and refractive outcomes were compared between eyes implanted with nontoric and toric IOLs during microhook ab interno trabeculotomy triple procedures. Methods Glaucomatous eyes with preexisting corneal astigmatism exceeding -1.5 D implanted with nontoric (n=10) or toric (n=10) IOLs were evaluated retrospectively. The uncorrected visual acuity (UCVA) and refractive astigmatism preoperatively and 3 months postoperatively were compared. Results Preoperatively, the groups had similar logarithm of the minimum angle of resolution (logMAR) UCVAs and refractive astigmatism. Postoperatively, the logMAR UCVA (toric, 0.07±0.07; nontoric, 0.33±0.30; P=0.0020) was significantly better and the refractive astigmatism (toric, -0.63±0.56 D; nontoric, -1.53±0.74 D; P=0.0110) significantly less in the toric group. The toric group had postoperative improvements in the logMAR UCVA (-0.58, P=0.0039) and refractive astigmatism (+1.45 D, P=0.0195). Vector analyses showed the postoperative centroid magnitude of refractive astigmatism was less in the toric group (0.23 D at 83 degrees) than the nontoric group (1.03 D at 178 degrees). Postoperatively, 70% of eyes in the toric group had 1.0 D or less refractive astigmatism compared with 10% in the nontoric group. Surgically induced astigmatism (nontoric group, 0.62 D at 10 degrees; toric group, 0.50 D at 113 degrees) and intraocular pressure reduction (22% in both groups) did not differ between groups. Conclusions Better visual outcomes may be achieved with toric IOLs when a combined MIGS/cataract surgery is performed in eyes with corneal astigmatism.

Background The role of B cells in the pathogenesis of multiple sclerosis (MS) is a subject of much research. We report a case of a MS patient who presented with subacute diffuse lesions in the limbic system and short-term memory loss. Case presentation A male patient had experienced numbness in the left upper extremity at the age of 17 years, but this disappeared without treatment. At 19 years-of-age, he developed subacute short-term memory loss followed by paralysis and sensory disturbance in the left upper and lower extremities. Magnetic resonance brain fluid-attenuated/T2-weighted imaging showed diffuse high-intensity lesions in the medial parts of both temporal lobes, and spotty multiple lesions in the periventricular and subcortical white matter. Twenty days later, a new lesion was observed around the right putamen, and the temporal lesions had disappeared. A symptomatic cervical lesion with gadolinium enhancement was observed at C3. This lesion involved just one vertebral segment. Cerebrospinal fluid analysis showed no pleocytosis or elevated protein levels, but did show oligoclonal immunoglobulin G bands. No antibodies against aquaporin-4 or myelin oligodendrocyte glycoprotein were detected in the serum, and anti-N-methyl-D-aspartate receptor was not detected in the cerebrospinal fluid. We diagnosed the patient with MS despite the atypical diffuse lesions in the limbic system and the short-term memory loss. Corticosteroid medication effectively treated the symptoms in his extremities and his impaired memory. Conclusions The present case shows that cortical lesions can occur in MS patients and might be induced by B cell-mediated mechanisms.

An 87-year-old woman with primary open-angle glaucoma presented to our hospital. Although the combined cataract and minimally invasive glaucoma surgeries (MIGS) were an appropriate surgical option, the presence of band keratopathy made it difficult to perform ab interno glaucoma surgery in her right eye (OD); therefore, the corneal opacity was removed using ethylenediaminetetraacetic acid (EDTA) chelation procedure. One month after chelation, microhook ab interno trabeculotomy and cataract surgery were performed successfully. Clear intraoperative visualization of the angle structures is critical for the success of these MIGS procedures. In glaucomatous eyes that require MIGS, EDTA chelation is a good neoadjuvant therapy for coexisting band keratopathy.

We previously reported that lower systemic antioxidant capacity is involved in primary open-angle glaucoma (POAG) and exfoliation syndrome pathogeneses as measured by ferric-reducing activity. In the present study, we measured hydroxylinoleate (HODE) and hydroxyarachidonate (HETE) isomer serum levels after sample reduction and saponification to investigate POAG pathogenesis. POAG patients (n = 198) were recruited and divided into normal- and high-tension glaucoma groups (n = 84 and 114, respectively) depending on intraocular pressure. Total HODE (/linoleic acid) and HETE (/arachidonic acid) serum levels were significantly higher in the POAG group (211.9 ± 143.0 and 181.0 ± 164.1 µmol/mol, respectively) than in controls (167.1 ± 105.2 and 132.5 ± 139.7 µmol/mol, p = 0.0025 and 0.0101, respectively). The associations between HODEs/HETEs and glaucoma were further confirmed by multivariate analyses after adjusting for differences in demographic parameters. Among the HODE isomers, the levels of 9- and 13-(Z,E)-HODEs (p = 0.0014) and singlet oxygen-specific products (i.e., 10- and 12-(Z,E)-HODEs, p = 0.0345) were higher in the POAG group than in controls, while free radical-mediated oxidation-specific products (i.e., 9- and 13-(E,E)-HODEs, p = 0.0557) demonstrated a marginal difference. Enzymatic and singlet oxygen-mediated fatty acid oxidation may be major pathways of oxidation process in glaucoma subjects.

Purpose. To assess the safety and effectiveness of the single-layered inverted internal limiting membrane (ILM) flap technique for treating chronic, large, or highly myopic macular holes (MHs). Methods. The medical records of 20 eyes of 20 consecutive Japanese patients with large MHs n=6 (minimal diameter, >400 μm), chronic MHs n=2 (symptom duration, >24 months), MHs in high myopia n=11 (axial length, >26 mm), and MHs in a patient unable to maintain prone positioning postoperatively n=1 were reviewed retrospectively. All patients underwent 25-gauge pars plana vitrectomy and the temporal inverted ILM flap technique. A semicircular ILM notch was made temporally two disc diameters from the MH using a 25-gauge knife, and the ILM was peeled temporally to create a semicircular ILM flap using a 25-gauge forceps. The single-layered ILM flap was inverted in a nasal direction to cover the MH. When an epiretinal membrane (ERM) was present, it was peeled before the ILM flap was inverted. Results. The MHs closed successfully in all (100%) eyes postoperatively. In the MHs associated with an ERM, after hole closure, gradual foveal deformation occurred in both the area from which the ILM was not peeled and the ILM flap inverted side. Conclusions. The single-layered inverted ILM flap technique, a simple surgery to treat MHs, provides scaffolding for retinal gliosis and may facilitate bridge formation between the walls of the MH under the flap. Considering the 100% success rate of MH closure, this technique seems to be effective and safe for treating chronic, large, or highly myopic MHs and MHs in patients unable to maintain postoperative prone positioning. In the MHs associated with ERMs, gradual foveal deformation was observed after ERM peeling. Further studies are needed to minimize surgical complications and understand the mechanism of this technique. This trial is registered with UMIN000035091.

The temporal inverted internal limiting membrane flap technique, which is a simple surgical strategy to treat macular holes, provides scaffolding for retinal gliosis and may facilitate bridge formation between the walls of the macular hole beneath the flap. The procedure may be a good option to achieve macular hole closure without postoperative prone positioning., Purpose: To report the surgical technique and efficacy of the temporal inverted internal limiting membrane (ILM) flap technique for a patient with an idiopathic macular hole (MH) who is unable to maintain postoperative prone positioning. Methods: Case report. Results: A 73-year-old man with a Stage III MH in his left eye was scheduled to undergo surgery. Owing to his inability to maintain postoperative prone positioning for continuous placement of a transdermal bladder catheter after radical cystoprostatectomy to treat urinary bladder cancer, he underwent pars plana vitrectomy combined with the temporal inverted ILM flap technique and intraocular sulfur hexafluoride gas tamponade. The technique included ILM peeling at a temporal area of the macula to create one 2-disk-diameter semicircular ILM flap and inversion of the ILM flap nasally to cover the MH. Optical coherence tomography showed that MH closure started from the top of the MH just beneath the covered ILM flap; the closure process gradually extended toward the bottom of the MH. The well-aligned fovea recovered in 5 weeks postoperatively. The visual acuity was 20/200 preoperatively and improved to 20/50 postoperatively. Conclusion: The temporal inverted ILM flap technique, a simple surgery to treat MHs, provides scaffolding for retinal gliosis and may facilitate bridge formation between the walls of the MH beneath the flap. The procedure may be a good option to achieve MH closure without postoperative prone positioning.

Purpose To compare changes in macular pigment optical density (MPOD) and serum lutein concentration between free lutein and lutein esters supplements in healthy Japanese individuals. Methods Twenty healthy subjects (age range, 22–47 years) were recruited into this prospective, randomized, doubled-blind comparative study. Individuals were evenly divided into two groups: free lutein group, supplementation with 10 mg of free lutein; or lutein esters group, supplementation with 20 mg of lutein esters equivalent to 10 mg of free lutein. Each participant took either type of oral lutein daily for 3 months. The serum lutein concentrations and MPOD levels were measured at baseline and 3 and 6 months after the start of supplementation. Results There were no significant differences in the serum lutein concentrations and MPOD levels at baseline between the groups. The increased serum lutein concentration and MPOD levels at 3 months were respectively, 89% and 38% in the free lutein group and 97% and 17% in the lutein esters group. The serum lutein concentrations in both groups and MPOD levels in the free lutein group increased significantly (p

Purpose Pseudoexfoliation syndrome (PEX), the most common identifiable cause of open-angle glaucoma, might affect the retinal hemodynamics. To test this, we compared retinal vessel diameter and glaucoma-related parameters between eyes with pseudoexfoliation material (PE+) and fellow unaffected (PE-) eyes of patients with clinically unilateral PEX. Methods The medical records of 30 consecutive Japanese subjects were reviewed retrospectively. The retinal vessel diameters were measured and expressed as the central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) using standardized software. During the chart review, we recorded glaucoma-related parameters including intraocular pressure (IOP), visual field mean deviation (MD) value, planimetrically measured vertical cup-to-disc (C/D) ratio, circumpapillary retinal nerve fiber layer thickness (cpRNFLT) and macular inner retinal thickness (mIRT) measured by spectral-domain optical coherence tomography, anterior chamber flare (ACF), corneal endothelial cell density (CECD), and number of antiglaucoma medications. Results Compared with PE- eyes, the CRAE, CRVE, MD, cpRNFLT and mIRT, and CECD were significantly lower in PE+ eyes; the IOP, vertical C/D ratio, number of antiglaucoma medications, and ACF were significantly higher in PE+ eyes (P

Local and systemic oxidative stress in intraocular pressure (IOP) elevation and optic nerve damage may be involved in the pathogenesis of glaucoma. We reported previously that a lower level of systemic antioxidative capacity is associated with IOP elevation in open-angle glaucoma (OAG). We assessed the correlation between the visual field sensitivity value, i.e., mean deviation (MD) and systemic levels of prooxidants and antioxidants by analyzing the blood biochemistry in 202 patients with glaucoma. Serum levels of lipid peroxides, ferric-reducing activity and thiol antioxidant activity were measured using the diacron reactive oxygen metabolite (dROM), biological antioxidant potential (BAP) and sulfhydryl (SH) tests, respectively, using a free-radical analyzer. Univariate and multivariate analyses suggested a positive correlation between MD and BAP (R = 0.005 and P = 0.0442 by a multiple regression model adjusted for seven demographic parameters), but no significant associations between the MD and the dROM (R = 0.002 and P = 0.8556) and SH tests (R = −0.001 and P = 0.8280). Use of more antiglaucoma medication and primary OAG rather than normal tension glaucoma also were associated significantly with worse visual field damage. This large and comprehensive assessment of the association between systemic redox status and visual field damage in OAG suggests that lower systemic antioxidant capacity measured by ferric-reducing activity is associated with more severe visual field damage in OAG that partly explained its roles in IOP elevation.

Background The involvement of local and systemic oxidative stress in intraocular pressure (IOP) elevation and optic nerve damage has been hypothesized in the pathogenesis of glaucoma. We reported previously that the level of systemic antioxidative capacity is lower in patients with open-angle glaucoma than controls without glaucoma. Here, we assessed the correlation between IOP and systemic levels of prooxidants and antioxidants by analyzing the blood biochemistry in patients with glaucoma. Methods Peripheral blood samples were collected from Japanese patients with primary open-angle glaucoma (n = 206), exfoliation syndrome (n = 199), and controls (n = 126). Serum levels of lipid peroxides, ferric-reducing activity, and thiol antioxidant activity were measured by diacron reactive oxygen metabolite (dROM), biological antioxidant potential (BAP), and sulfhydryl (SH) tests, respectively, using a free radical analyzer. To test the possible effect of oxidative stress on IOP levels, the patients were classified into one of four groups (Q1, Q2, Q3, and Q4, with Q1 having the lowest IOP) based on the quartile value of IOP. For this classification, the known highest IOP value in both the right and left eyes was regarded as each subject’s IOP. For comparisons among the IOP groups, the differences were calculated using one-way analysis of variance followed by post-hoc unpaired t-tests. To adjust for differences in demographic characteristic distributions, the dROM, BAP, and SH test values were compared among the IOP groups using multiple logistic regression analysis; the odds ratio (OR) of each variable was calculated with the Q1 group as the reference. Results The dROM and the SH levels did not differ significantly (p = 0.6704 and p = 0.6376, respectively) among the four IOP groups. The BAP levels differed significantly (p = 0.0115) among the four IOP groups; the value was significantly lower in the Q4 group (1,932 μmol/L) compared with the Q1 (2,023 μmol/L, p = 0.0042) and Q2 (2,003 μmol/L, p = 0.0302) groups and significantly lower in the Q3 group (1,948 μmol/L) than the Q1 (p = 0.0174) group. After adjustment for differences in various demographic characteristics, lower BAP values were significantly associated with the classification into higher IOP groups (Q3 group, p = 0.0261 and OR = 0.06/range; Q4 group, p = 0.0018 and OR = 0.04/range). The dROM and SH values did not reach significance in any comparisons. Conclusions Lower systemic antioxidant capacity measured by ferric-reducing activity is involved in the pathogenesis of open-angle glaucoma via its roles in IOP elevation.

Purpose To report the efficacy of systemic prostaglandin E1 (PGE1) monotherapy for treating acute central retinal artery occlusion (CRAO). Methods The best-corrected visual acuity (BCVA) and side effects were evaluated retrospectively in 10 consecutive eyes (nine patients; mean age, 61.3 years) with acute CRAO treated with PGE1 monotherapy. The protocol included intravenous injection of 40 μg PGE1 twice daily (80 μg per day) for 5 days then oral PGE1 three times daily (30 μg per day) for at least 1 month. In four eyes, the retinal vessel diameters were assessed on serial fundus photographs. Results The mean time to treatment was 7.1 hours (range, 1-18 hours). The mean ± SD logarithm of the minimum angle of resolution (logMAR) BCVAs at baseline and 1 month after initiation of therapy were 2.67 ± 0.54 (range, 3.00-1.70) and 0.52 ± 0.62 (range, 2.00 to -0.18), respectively (P = 0.005); the BCVA improved by 1.0 or more logMAR unit at 1 month in all eyes. The BCVA improvement was correlated negatively with the time to treatment (ρ = -0.655, P = 0.0492), but was not correlated with age (ρ = -0.473, P = 0.156) and did not differ between sexes (P = 0.0871). Compared with baseline, the mean changes in the vessel diameters in four cases were 151.1% (range, 115.1%-188.0%) in the arteries and 191.0% (range, 127.2%-246.4%) in the veins 1 day after initiation of therapy. Angialgia during injection was the only side effect. Conclusions Systemic administration of PGE1 for acute CRAO rapidly restores retinal blood flow by its vasodilatory effects, improves VA, is well tolerated with few side effects, and requires no special training.

Purpose To test the safety and efficacy of topical 1.5% dexamethasone aqueous eye drops with cyclodextrin microparticles for diabetic macular edema (DME). Methods Nineteen eyes of 19 consecutive patients with DME were administered dexamethasone-cyclodextrin eye drops three or six times a day for 4 weeks and then observed for 4 weeks without treatment. Visual acuity, intraocular pressure, and spectral domain optical coherent tomography-measured central macular thickness recordings at weeks 0 (baseline), 4, and 8. These parameters were compared using Bonferroni-corrected paired t-tests. Results At weeks 0, 4, and 8, logMAR visual acuity (mean ± SD) was 0.52 ± 0.41, 0.37 ± 0.40 (P = 0.0025 vs. baseline), and 0.45 ± 0.41, respectively; central macular thickness (μm) was 512 ± 164, 399 ± 154 (P = 0.0016 vs. baseline), and 488 ± 172 (P = 0.0116 versus week 4), respectively; and intraocular pressure (mm Hg) was 15.2 ± 3.1, 17.4 ± 4.2 (P = 0.0015 vs. baseline) and 15.8 ± 4.0, respectively. At week 4, in 12 (63%) of 19 eyes, central macular thickness had decreased more than 10%, and the mean change was -20% (-65% to +10%). In 14 of 19 eyes (74%) visual acuity (logMAR) had improved more than 0.1 at week 4. No subjects showed severe adverse effects related to the eye drops. Conclusions Based on this short pilot study, topical dexamethasone-cyclodextrin eye drops are well tolerated, decrease central macular thickness, and improve visual acuity in DME. The results encourage comparative studies between dexamethasone cyclodextrin microparticle eye drops and other treatments for DME. (http://www.umin.ac.jp/ctr number, UMIN000001790.).

PURPOSE Toevaluate the effect of removing epiretinal membranes (ERMs) on visual function and vision-related quality of life (VR-QOL) for 12 months postoperatively. METHODS Idiopathic ERMs were removed during vitrectomy in 26 eyes. The VR-QOL was evaluated using a self-administered 25-item National Eye Institute Visual Function Questionnaire before (baseline) and 3 and 12 months postoperatively. During the same periods, the best-corrected visual acuity (BCVA), central macular thickness (CMT), and metamorphopsia score were recorded. RESULTS At baseline and months 3 and 12, the logMAR BCVAs (mean ± SEM) were 0.41 ± 0.05, 0.17 ± 0.04 (P = 0.0001 versus baseline), and 0.10 ± 0.03 (P < 0.0001 versus baseline, P = 0.0016 versus month 3), respectively; the CMTs (μm) were 402 ± 18, 312 ± 9 (P < 0.0001 versus baseline), and 300 ± 7 (P < 0.0001 versus baseline, P = 0.0544 versus month 3); and the metamorphopsia scores were 202 ± 29, 137 ± 27 (P = 0.0186 versus baseline), and 108 ± 26 (P = 0.0005 versus baseline, P = 0.0218 versus month 3). In 23 (88%) of 26 eyes, the BCVA improved more than 0.1 logMAR unit at month 12. The improved BCVA was correlated with improvements in two subscales (r = -0.405 to -0.574, P = 0.0041-0.0427) at month 3; the improved metamorphopsia score was correlated with the improved composite score (r = -0.552, P = 0.0058) and three subscales (r = -0.458 to -0.507, P = 0.0113-0.0219) at month 12. CONCLUSIONS Removing ERMs improved visual function, anatomy, and the VR-QOL. Three months postoperatively, the improved BCVA was the most important factor related to the improved VR-QOL, although the simultaneous cataract surgery might have had a confounding effect. The improved metamorphopsia was the important factor associated with improved VR-QOL 12 months postoperatively.(www.umin.ac.jp/ctr number, UMIN000000617).

PURPOSE. To measure levels of various inflammatory cytokines in the aqueous humor of patients with primary open-angle glaucoma (POAG), exfoliation glaucoma (EXG), and senile cataract. METHODS. Aqueous humor samples were obtained from 64 eyes of 64 Japanese subjects (POAG, 20 eyes; EXG, 23 eyes; and cataract, 21 control eyes). The levels of eight cytokines including interleukin (IL)1-, IL-6, IL-8, transforming growth factor (TGF)-1, tumor necrosis factor (TNF)-, serum amyloid A (SAA), migration inhibitory factor (MIF), and vascular endothelial growth factor (VEGF)-A were estimated using the multiplex bead immunoassay technique. RESULTS. Compared with the cataract group, the levels of TGF1, IL-8, and SAA were significantly higher in aqueous humor samples from the POAG (5.0-fold, 2.3-fold, and 11.9-fold, respectively) and EXG (12.5-fold, 4.0-fold, and 18.3-fold, respectively) groups. Except for a significant decrease in the IL-6 level in the POAG (0.23-fold) group, no other cytokine levels differed in the POAG and EXG groups compared with the cataract group. The levels of TGF-1, IL-8, and SAA were positively correlated with each other ( 0.723‐0.786; P 0.0001), the intraocular pressure (IOP) ( 0.392‐0.662; P 0.0001‐ 0.0019), and the number of glaucoma medications ( 0.478‐ 0.659; P 0.0001‐0.0001). CONCLUSIONS. Cytokine networks including TGF-1, IL-8, and SAA in aqueous humor may have critical roles in IOP elevations in patients with open-angle glaucoma. (Invest Ophthalmol Vis Sci. 2012;53:241‐247) DOI:10.1167/iovs.11-8434

Previous work indicated that a CTL response can be generated by the combination of IL-2 plus IL-6 or IL-4 alone. Because of the ubiquitous production of IL-6 and its apparent ability to induce IL-2, we explored the interdependence of these lymphokines in supporting a CTL response from murine thymocytes. For thymocytes cultured in IL-4, further addition of IL-6 enhanced thymocyte proliferation. In addition, a role for IL-6 in thymocyte activation was indicated by the ability of anti-IL-6 mAb to block both IL-4-directed proliferation and the cytotoxic response found in the presence of IL-4. The addition of IL-2 to limiting doses of IL-4 augmented the CTL response; however, the response to high levels of IL-4 was not augmented by addition of IL-2. Consistent with this apparent involvement of IL-2 in the IL-4-mediated response we found: (a) that mAb to IL-2 significantly reduced the CTL response generated in the presence of IL-4; (b) that IL-2 activity was present in culture supernatant following incubation of thymocytes with high levels of IL-4; and (c) that enhanced IL-2 receptor expression found in the presence of IL-4 was blocked with the addition of anti-IL-2 antibody to the thymocyte culture. In contrast to the data for proliferation, anti-IL-4 mAb had no effect on the generation of CTL in the presence of IL-2 + IL-6 but readily blocked the CTL response to IL-4. These results indicate that, for thymocyte responders, the CD8+ CTL generated in the presence of IL-4 require both IL-2 and IL-6.

A thymic stromal cell clone, MRL104.8a, expresses class I as well as class II H-2k antigens after exposure to gamma-interferon. This clone also produces thymic stroma-derived T-cell growth factor (TSTGF), which is distinct from other known interleukins and is capable of promoting the growth of various antigen-specific helper T cell (Th) clones without requiring a specific antigen or interleukin 2. When the keyhole limpet hemocyanin (KLH)-specific, I-Ek-restricted Th clone 9-16 was cultured on an Ia (I-Ak and I-Ek)-expressing MRL104.8a monolayer, potent proliferation of the 9-16 cells was induced by TSTGF produced by the monolayer. In contrast, the addition of KLH resulted in lethal growth inhibition of Th clone 9-16 cells. Another Th clone that is KLH-specific but I-Ab-restricted was capable of proliferating on the Iak-expressing MRL104.8a monolayer whether or not KLH was present. More importantly, death of Th clone 9-16 cells cultured on a MRL104.8a monolayer in the presence of KLH was almost completely prevented by the addition of anti-I-Ek or anti-CD3 monoclonal antibodies, which are capable of blocking antigen recognition by the T-cell receptor. However, when Th clone 9-16 cells were cultured in the presence of KLH but on a monolayer of MRL28.8a cells, another thymic stromal clone that expresses a comparable amount of I-Ek antigen but produces a marginal amount of TSTGF, cells did not die; a lethal effect was induced by adding TSTGF. These results indicate that the TSTGF-producing and Ia-expressing thymic stromal cells induce the continuous proliferation or selective elimination of each T-cell clone, depending on whether the T-cell receptor is stimulated by the relevant antigen associated with Ia molecules expressed on the stromal cell surface.

A new haptenic compound, a muramyl dipeptide (MDP) derivative (designated as L4-MDP-ONB) cross-reactive with Bacillus Calmette Guerin (BCG) was synthesized. The cross-reactivity of L4-MDP hapten to BCG was demonstrated from the following evidence; (a) lymph node cells from BCG-primed C3H/HeN mice exhibited appreciable L4-MDP-specific proliferative responses to the in vitro stimulation of L4-MDP-modified syngeneic cells (L4-MDP-self); (b) inoculation of L4-MDP-self into footpads of BCG-primed C3H/HeN mice elicited ample delayed type-hypersensitivity (DTH) responses in vivo as measured by footpad swelling; and (c) BCG-primed mice contained L4-MDP-reactive helper T cell activity which functions to augment the generation of effector T cell responses to cell surface antigens. This crossreactivity between L4-MDP hapten and BCG as measured by the helper T cell activity was applied to enhanced induction of tumor-specific immunity. When BCG-primed C3H/HeN mice were immunized with L4-MDP-modified syngeneic X5563 tumor cells, these mice could generate augmented tumor-specific in vivo protective (tumor neutralizing) immunity as well as in vitro cytotoxic T cell responses. These results indicate the effectiveness of L4-MDP hapten in augmenting tumor-specific immunity. The present approach is discussed in the context of potential advantages of this new hapten for its future application to clinical tumor systems.

Thymic stromal cell lines, termed MRL104 and MRL28, have been isolated from long-term liquid cultures of thymic stromal cells from MRL/1 mice. The capacities of these parental lines and derived clones to express la antigens and to produce cytokines involved in T-cell proliferation and/or differentiation were investigated. Parental lines and their clones did not exhibit a typical fibroblastic, macrophage-like, or epithelial appearance in electron as well as phase-contrast micrographs. These thymic stromal cells seemed to differ from established fibroblast lines in that these thymic stromal cells expressed la antigens after exposure to interferon-γ (IFN-γ), whereas fibroblast lines did not They also appeared to differ from macrophage cell lines in that they lacked the expression of Mac-1 antigens on their cell surface and produced no detectable level of interteukin-1 (IL1) before or even after exposure to lipopolysaccharide. When these parental lines and its clones were tested for their ability to produce various types of cytokines, it was revealed that they were capable of producing colony-stimulating factor (CSF), IL6, and thymic stroma-derived T cell growth factor (TSTGF). which was recently described, but were unable to generate other lymphokines and IFNs. Thus these cell lines and clones represent unique features in that they have potentials to express la antigens and to produce CSF, IL6, and TSTGF. The biological significance for the expression of these features is discussed in the context of intrathymic T-cell maturation and T-cell repertoire selection.

The role of vaccinia virus-reactive helper T cells (Th) in augmenting in vivo generation of antitumor protective immunity and the Ly phenotype mediating the enhanced in vivo tumor immunity were investigated. C3H/HeN mice were inoculated i.p. with viable vaccinia virus to generate vaccinia virus-reactive Th activity. The mice were subsequently immunized i.p. with virus-infected syngeneic X5563 and MH134 tumor cells, and spleen cells from these mice were tested for in vivo tumor neutralizing activity. Immunization of virus-primed mice with virus-uninfected tumor cells and of virus-unprimed mice with virus-infected tumor cells failed to result in in vivo protective immunity. In contrast, spleen cells from mice immunized with virus-infected tumor cells subsequent to virus-priming exhibited potent tumor-specific neutralizing activities. Such an augmented generation of in vivo protective immunity was accompanied by enhanced induction of tumor-specific cytotoxic T lymphocyte (CTL) and antibody activities in X5563 and MH134 tumor systems, respectively. However, analysis of the effector cell type responsible for in vivo tumor neutralization revealed that enhanced in vivo immunity was mediated by Lyt-1+2- T cells in both tumor systems. Moreover, the Lyt-1+2- T cells exerted their function in vivo under conditions in which anti-X5563 tumor-specific CTL or anti-MH134 tumor-specific antibody activity was not detected in recipient mice. These results indicate that augmenting the generation of a tumor-specific Lyt-1+2- T cell population is essential for enhanced tumor-specific immunity in vivo.

C3H/HeN mice were inoculated i.p. with viable vaccinia virus to generate virus- reactive helper T cell activity. 850R X-irradiated spleen cells from vaccinia virus-primed or unprimed mice as helper cells were stimulated in vitro with either trinitrophenyl (TNP)-modified syngeneic spleen cells (TNP-self), vaccinia virus-infected spleen cells (virus-self), or cells modified with TNP subsequent to virus infection (virus-self-TNP) in the presence of normal C3H/HeN spleen cells (responding cells). After 5 days of culture, effector cells were tested for anti-TNP delayed-type hypersensitivity (DTH) responses by adoptive transfer into footpads of syngeneic C3H/HeN recipient mice together with TNP-self. The results demonstrate that spleen cells from virus-primed mice failed to enhance anti-TNP DTH responses when in vitro stimulation was provided by either virus-self or TNP-self alone. In contrast, spleen cells from vaccinia virus- primed mice, but not from unprimed mice, could augment anti-TNP DTH responses when stimulated by virus-self-TNP. Such a helper activity provided by vaccinia virus-primed mice was shown to be antigen-specific, and mediated by Lyt-1+2−T cells. DTH effector cells enhanced by helper cells were also antigen-specific and Lyt-1 +2−T cells. Furthermore, vaccinia virus-reactive helper T cell activity could be applied to augmented induction of anti-tumor DTH responses by stimulation with virus-infected syngeneic fibrosarcoma tumor cells. Thus, these results provide evidence for the role of antigen-specific helper T cells in augmenting the development of DTH responses to cell surface antigens including tumor antigens.

Investigations have attempted to delineate the consequences of malignant transformation of cells by the appearance of new cell surface structures [tumor-associated antigens (TAA) or tumor-associated transplantation antigens (TATA)] that could be identified by specific antiserum or by their ability to induce a specific cellular immune response. Considerable efforts have been undertaken to establish the significance of these tumor cell surface structures by correlating their cell surface expression with changes that take place during the course of neoplastic disease. The most compelling evidence for the existence of TATA comes from the study of chemically induced tumors of inbred rodents. These tumors express neoantigens capable of immunizing syngeneic or autochthonous hosts against subsequent challenge with the same tumor.(1–4)

We established an interleukin-6 (IL-6)-dependent cell line from murine plasmacytoma MOPC-104E cells. This cell line (designated PIL-6) was found to respond to murine and to human IL-6, but not to any other cytokines. We used this cell line to investigate the involvement of IL-6 production in type II collagen-induced arthritis in DBA/1 mice. Only marginal IL-6 activity was detected in sera from DBA/1 mice inoculated with Freund's complete adjuvant (FCA) alone, with an unrelated protein (bovine serum albumin) plus FCA, or with type II collagen plus Freund's incomplete adjuvant. However, enhanced IL-6 activity was observed in DBA/1 mice that had been injected with type II collagen plus FCA to induce arthritis. The elevated level of serum IL-6 activity was associated with high levels of IL-6 produced when lymph node cells from arthritic mice were stimulated in vitro with type II collagen. We also found that the L3T4+ T cell subset is responsible for the enhanced production of IL-6 in arthritic mice. The results are discussed in the context of potential roles of IL-6 in the induction and/or expression of chronic, progressive arthritis.

C3H/He mice were immunized to vaccinia virus by inoculating i.p. viable virus. Their spleen cells (SC) were tested for vaccinia virus-reactive helper T cell activity capable of augmenting (a) anti-trinitrophenyl (TNP) cytotoxic T lymphocyte (CTL) response generated from unprimed C3H/He SC (responding cells) or (b) anti-TNP antibody response generated from TNP-primed C3H/He SC (responding cells) by the stimulation with syngeneic SC infected with vaccinia virus and subsequently modified with TNP (virus-self-TNP). The results demonstrate that cultures of responding cells plus 850 rds X-irradiated vaccinia virus-primed SC failed to enhance anti-TNP CTL or plaque-forming cell (PFC) responses when in vitro stimulation was provided by either virus-self or TNP-self alone. In contrast, these cultures resulted in appreciable augmentation of CTL and PFC responses when stimulated by virus-self-TNP. Such a helper activity provided by vaccinia virus-primed SC was revealed to be T cell mediated and antigen specific. These results are discussed in the context of (a) nature of virus helper antigens, (b) mechanism of help and (c) potential of virus help in augmenting CTL and antibody responses to tumor antigens.

The genetic control of hapten-reactive helper T-cell activity involved in cytotoxic T-lymphocyte (CTL) responses and its implications for augmenting tumor-specific immunity were studied. C57BL/6N mice were immunized to trinitrophenyl (TNP) or N-iodoacetyl-N'-(5-sulfonic l-naphthyl)ethylenediamine (AED) hapten by inoculation of hapten-modified syngeneic spleen cells. Spleen cells from these hapten-immunized mice were tested for hapten-reactive helper T-cell activity for generation of CTL. TNP-primed spleen cells resulted in only marginal help for the generation of anti-TNP-modified syngeneic spleen cell (TNP-self) CTL response when cocultured with normal C57BL/6N spleen cells (responding cells) in the presence of TNP-self. In contrast, AED-primed spleen cells exhibited appreciable help for AED-induced CTL responses. Furthermore, AED-helper, but not TNP-helper, T-cell activity was demonstrated to augment the generation of antitumor (RBL-5 leukemia) CTL responses from normal syngeneic spleen cells when stimulated with the corresponding hapten-self plus RBL-5 tumor cells. These results indicate that the successful augmentation of syngeneic tumor immunity through T-T-cell interaction with the use of hapten-reactive helper T-cells can depend on selection of the appropriate haptenic reagent in an individual expressing a given major histocompatibility haplotype.