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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.

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.

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.

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. To test this, we measured the 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 (PG) (n = 206), exfoliation syndrome (EX) (n = 199), and controls (n = 126). Plasma levels of lipid peroxides, ferric-reducing activity, and thiol antioxidant activity were measured by diacron reactive oxygen metabolites (dROM), biological antioxidant potential (BAP), and sulfhydryl (SH) tests, respectively, using a free radical analyzer. RESULTS: In the PG, EX, and control groups, the mean ± standard deviation values were 355±63, 357±69, and 348±56 (U. Carr), respectively, for dROM; 1,951±282, 1,969±252, and 2,033±252 (µmol/L), respectively, for BAP (µmol/L); and 614±98, 584±91, and 617±99 (µmol/L), respectively, for SH. The differences in the BAP values were significant between the PG and control groups (p = 0.0062), for SH between the EX and control groups (p = 0.0017), and for SH between the PG and EX groups (p = 0.0026). After adjustment for differences in age and sex among groups using multiple regression analysis, lower BAP values were correlated significantly with PG (p = 0.0155) and EX (p = 0.0049). Higher dROM values with and without glaucoma were correlated with female gender, and lower SH values with older age. There were no significant differences between the higher (≥21 mmHg) and lower (