[Show abstract][Hide abstract] ABSTRACT: Leber's hereditary optic neuropathy (LHON) refers to an optic nerve dysfunction due to mutations in the mitochondrial DNA, resulting in visual loss by apoptosis of retinal ganglion cells (RGC). In 20% of LHON cases, their fundus examination looks entirely normal at early stage. There are some reports regarding the circumpapillary retinal nerve fiber layer (cpRNFL) and the ganglion cell analysis around the macula in LHON patients and carriers by using optical coherence tomography.
A 40-year-old female complained of acute visual loss in both eyes. Her best-corrected visual acuity was 0.3 in the right eye and 0.2 in the left eye at the initial visit. Goldmann perimetry revealed bilateral central scotomas. Fundus examination and fluorescein angiography findings were normal, but decreased retinal inner layer thickness was detected around the macular area on spectral domain optical coherence tomography (SD-OCT). One month later, her visual acuity deteriorated to counting fingers in both eyes, and the thinning area of retinal inner layer spread rapidly. Suspected progressive RGC loss led us to check the possibility of LHON, with which the patient was diagnosed due to a positive result for the mitochondrial DNA (mtDNA) 11778 mutation. The ganglion cell complex (GCC) and cpRNFL thicknesses were observed for 24 months by using SD-OCT. The GCC thickness plunged sharply within 3 months followed by gradual decline until 6 months, thereafter showing a plateau up to 24 months. On the cpRNFL map, the temporal quadrant also showed the earliest thinning as seen in the macular area of the GCC map. The thicknesses of the superior, nasal, and inferior quadrants decreased gradually, keeping their normal ranges up to 6 months.
SD-OCT was a useful tool in the diagnosis and follow-up of LHON. The macular GCC thickness map may detect the earliest morphological changes in LHON, as well as the temporal area of cpRNFL, before funduscopic examination reveals optic nerve atrophy.
[Show abstract][Hide abstract] ABSTRACT: To investigate the alteration of vitreal N-glycans in patients with proliferative diabetic retinopathy (PDR).
Plasma and vitreous samples were collected from 17 patients (10 females and 7 males) with PDR (PDR group) and 17 nondiabetic patients (8 females and 9 males) with epiretinal membrane (ERM) and idiopathic macular hole (MH) (non-diabetes mellitus [DM] group). Profiles of N-glycans were analyzed by a glycoblotting-based high-throughput protocol that we recently developed. Human retinal microvascular endothelial cells (HRMECs) were cultivated with culture media containing either low glucose (5 mM) or high glucose (25 mM), and expression levels of sialyltransferases were analyzed by real-time PCR and ELISA.
Amount of N-glycans in the vitreous fluid of the PDR group was significantly higher than that of the non-DM group (495.5 ± 37.4 vs. 142.7 ± 30.8 pmol/100 μg protein, P < 0.005), whereas there was no significant difference in the plasma samples between the PDR and the non-DM group. In addition, profile analysis showed that N-glycans with sialic acids increased in the vitreous of the PDR group (328.4 ± 25.8 pmol/100 μg protein) compared to the non-DM group (92.1 ± 21.2 pmol/100 μg protein, P < 0.0005). Expression levels of sialyltransferases ST3GAL1 and ST3GAL4 were upregulated in the HRMECs after high-glucose stimulation. Consistent with the real-time PCR data, high-glucose stimulation elevated the protein levels of ST3GAL1 (117.4 ± 14.9 pg/mg, P < 0.01) and ST3GAL4 (6.1 ± 0.9 pg/mg, P < 0.05) in the HRMECs compared with the cells cultured with low-glucose culture media (ST3GAL1, 64.4 ± 5.8 pg/mg; ST3GAL4, 3.8 ± 0.3 pg/mg).
Our data demonstrate distinct changes in the N-glycan profile and an increase in sialylated N-glycans in eyes with PDR.
[Show abstract][Hide abstract] ABSTRACT: To investigate the alteration of N-glycans in the vitreous fluid of patients with neovascular glaucoma (NVG) secondary to proliferative diabetic retinopathy (PDR).
Vitreous samples were collected from 18 patients with PDR (including 7 with NVG and 11 without NVG), and 17 patients without diabetes. Profiles of N-glycans were analyzed by glycoblotting-based high throughput protocol, which we recently developed. Protein levels of vascular endothelial growth factor (VEGF)-A were measured by ELISA.
The concentration of total N-glycans and the concentration of N-glycans with sialic acids were significantly higher in NVG group compared with those in non-NVG group or control group, whereas there was no significant difference in concentrations of high-mannose N-glycans among three groups. There was a moderate correlation between the concentrations of sialylated N-glycans and VEGF-A.
Our data demonstrate the distinct changes of N-glycan profile and the increase of sialylated N-glycans in eyes with NVG secondary to PDR.
Current eye research 07/2015; DOI:10.3109/02713683.2015.1068816 · 1.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Excessive angiogenesis contributes to numerous diseases, including cancer and blinding retinopathy. Antibodies against vascular endothelial growth factor (VEGF) have been approved, and are widely used in the clinical treatment. Our previous studies using SRPIN340, a small molecule inhibitor of SRPK1 (Serine-Arginine Protein Kinase 1), demonstrated that SRPK1 is a potential target for development of anti-angiogenic drug. In this study, we solved the structure of SRPK1 bound to SRPIN340 by X-ray crystallography. Using pharmacophore docking models followed by in vitro kinase assays, we screened a large-scale chemical library, and thus identified a new inhibitor of SRPK1. This inhibitor, SRPIN803, prevented VEGF production more effectively than SRPIN340 due to the dual inhibition of SRPK1 and CK2 (Casein Kinase 2). In a mouse model of age-related macular degeneration, topical administration of eye ointment containing SRPIN803 significantly inhibited choroidal neovascularization, suggesting a clinical potential of SRPIN803 as a topical ointment for ocular neovascularization. Thus SRPIN803 merits further investigation as a novel inhibitor of VEGF.
The American Society for Pharmacology and Experimental Therapeutics.
[Show abstract][Hide abstract] ABSTRACT: The pathogenesis of unilateral acute idiopathic maculopathy (UAIM) is unknown. The aim of this study was to quantitatively examine changes in choroidal circulation hemodynamics in patients with UAIM.
This was a retrospective observational case-series which included five eyes of four patients with UAIM. All UAIM eyes and the fellow eyes in remaining three patients were studied using laser speckle flowgraphy (LSFG) to evaluate the mean blur rate (MBR), a quantitative index of relative blood flow velocity. The changes in MBR between the initial visit and after 1 and 3 months were statistically analyzed. Subfoveal choroidal thickness was measured in three UAIM eyes by enhanced depth imaging optical coherence tomography.
The mean logMAR value of best-corrected visual acuity in the UAIM eyes significantly improved (P = 0.04) with recovery of outer retinal morphology. The average MBR of the UAIM eyes significantly increased at 1 (+21.7 % baseline value; P = 0.003) and 3 months (+32.5 % baseline value; P = 0.001), whereas the fellow eyes did not show this tendency. The mean values of subfoveal choroidal thickness decreased with time (316.0 µm at baseline, 186.6 µm at 1 month, and 167.3 µm at 3 months).
These results reveal that there is a significant elevation of choroidal blood flow velocity and substantial reduction of choroidal thickness with regression of UAIM, suggesting that impaired choroidal circulation may be involved in the pathogenesis of UAIM.
Japanese Journal of Ophthalmology 04/2015; DOI:10.1007/s10384-015-0380-6 · 1.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the relationship between circulation hemodynamics and morphology in the choroid during systemic corticosteroid therapy for patients with Vogt-Koyanagi-Harada (VKH) disease.
This retrospective case series includes 18 eyes of nine patients with VKH disease (two men and seven women; average age, 40.8 years) who received systemic corticosteroid therapy. Laser speckle flowgraphy (LSFG) and enhanced-depth imaging optical coherence tomography (EDI-OCT) were performed before treatment and at 1 week and 1 and 3 months after treatment. The average values of the mean blur rate (MBR) at the macula and the central choroidal thickness (CCT) were compared at each stage.
The changing rates of the average MBR significantly increased at all examinations after the start of treatment compared with the pre-treatment value with resolution of serous retinal detachment (SRD) (P = 0.0002 for all). The CCT decreased significantly at all examinations after the start of treatment compared with the pre-treatment value (P = 0.0002 for all). Changes in MBR and CCT during the 3-month follow-up period correlated significantly (R = -0.5913, P = 0.0097). The best-corrected visual acuity at pre-treatment correlated significantly with the changing rate of the MBR from 0 to 3 months (R = 0.5944, P = 0.0093) but not with CCT.
Our data suggest that circulatory disturbances and increased thickness of the choroid relate to the pathogenesis of VKH disease with link mutually. LSFG is useful as an index for evaluating the choroiditis activity of VKH disease as well as EDI-OCT.
Albrecht von Graæes Archiv für Ophthalmologie 01/2015; 253(4). DOI:10.1007/s00417-014-2927-5 · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tuberculous endophthalmitis is very rare with only 18 reports published worldwide and only a few cases in Japan. We report a case of tuberculous endophthalmitis successfully treated with vitrectomy followed by antituberculous agents.
An 81-year-old man was referred to us due to the exacerbation of vitreous opacity on his left eye(OS) after he had received the corticosteroid therapy. His best corrected visual acuity was light perception OS, and he had severe intraocular inflammation with fibrin formation in the anterior chamber and dense vitreous opacity. A chest CT showed miliary nodules indicating miliary tuberculosis, and pars plana vitrectomy was performed. Intraoperative observation showed that the vitreous cavity was filled by fibrin, and large elevated subretinal yellow-white lesions were present at the mid-periphery. The patient immediately received triple antituberculous agents orally, and Mycobacterium tuberculosis was detected in vitreous fluids. The intraocular inflammation gradually decreased, and the subretinal mass regressed within 2 weeks.
We encountered a case of tuberculous endophthalmitis successfully treated with vitrectomy followed by antituberculous agents. If endophthalmitis is suspected in a patient with systemic tuberculosis infection, prompt vitrectomy along with the administration of antituberculous agents may be necessary.
[Show abstract][Hide abstract] ABSTRACT: To investigate sequential post-operative thickness changes in inner and outer retinal layers in eyes with an idiopathic macular hole (MH).
Retrospective case series. Twenty-four eyes of 23 patients who had received pars plana vitrectomy (PPV) for the closure of MH were included in the study. Spectral domain optical coherence tomography C-scan was used to automatically measure the mean thickness of the inner and outer retinal layers pre-operatively and up to 6 months following surgery. The photoreceptor outer segment (PROS) length was measured manually and was used to assess its relationship with best-corrected visual acuity (BCVA).
Compared with the pre-operative thickness, the inner layers significantly thinned during follow-up (P = 0.02), particularly in the parafoveal (P = 0.01), but not perifoveal, area. The post-operative inner layer thinning ranged from the ganglion cell layer to the inner plexiform layer (P = 0.002), whereas the nerve fiber layer was unaltered. Outer layer thickness was significantly greater post-operatively (P = 0.002), and especially the PROS lengthened not only in the fovea but also in the parafovea (P < 0.001). Six months after surgery, BCVA was significantly correlated exclusively with the elongated foveal PROS (R = 0.42, P = 0.03), but not with any of the other thickness parameters examined.
Following PPV for MH, retinal inner layers other than the nerve fiber layer thinned, suggestive of subclinical thickening in the inner layers where no cyst was evident pre-operatively. In contrast, retinal outer layer thickness significantly increased, potentially as a result of PROS elongation linking tightly with favorable visual prognosis in MH eyes.
PLoS ONE 01/2015; 10(8):e0135925. DOI:10.1371/journal.pone.0135925 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To describe a level of vascular endothelial growth factor (VEGF) in the subretinal fluid obtained from a case with vasoproliferative retinal tumors (VPRTs).
A 30-year-old male patient presented with VPRTs subsequent to long-standing rhegmatogenous retinal detachment.
The patient was treated with encircling scleral buckling, cryopexy, and intravitreal bevacizumab injection. The protein level of VEGF in the subretinal fluid was measured and compared with those in the subretinal fluid obtained from patients with rhegmatogenous retinal detachment. Vascular endothelial growth factor level in the subretinal fluid from a patient with VPRTs was 12,997.9 pg/mL, whereas the mean VEGF concentration in the subretinal fluid from 4 patients with rhegmatogenous retinal detachment was 2.1 ± 2.8 pg/mL.
The current data provide the evidence that VEGF production has increased in eyes with VPRTs and anti-VEGF therapy is theoretically effective for the treatment of VPRTs.
[Show abstract][Hide abstract] ABSTRACT: The mechanism underlying focal choroidal excavation (FCE) remains largely unknown. We evaluated the sequential progression of FCE generation using enhanced depth imaging optical coherence tomography (EDI-OCT) in a patient with multiple evanescent white dot syndrome (MEWDS).
A 37-year-old woman suffered MEWDS in the right eye. EDI-OCT showed the loss of photoreceptor inner segment/outer segment junction line, detachment between the retinal pigment epithelium (RPE) and Bruch's membrane, and dome-shaped, moderately reflective, focal photoreceptor-layer lesions corresponding to perifoveal white dots. The region with pigment epithelium detachment involved RPE/Bruch's membrane ruptures. After 1 month, almost all white dots spontaneously resolved together with improvements of the perifoveal OCT findings. Interestingly, perifoveal region developed a conforming-type FCE. An abnormal hyper-reflective lesion on OCT, regarded as fibrosis formation, simultaneously appeared within the choroid below the FCE and subsequently increased in size.
These results suggest that the RPE/Bruch's membrane disruption due to chorioretinal abnormalities and subsequent intrachoroidal scar formation play a role in the pathogenesis on an acquired FCE.
[Show abstract][Hide abstract] ABSTRACT: Purpose
On the basis of angiographic features, it is suggested that choroidal circulation disturbance may be involved in the pathogenesis of multiple evanescent white dot syndrome (MEWDS). The aim of this study is to quantitatively evaluate changes in choroidal circulation hemodynamics using laser speckle flowgraphy (LSFG) in patients with MEWDS.
Twelve eyes of 12 patients with MEWDS and 12 unaffected fellow eyes as controls were included. The macular mean blur rate (MBR), a quantitative index of relative blood flow velocity in the choroid, was measured by LSFG. Sequential changes in the average MBR values at the macula with granular changes and the lesion area with white dots were analysed. Moreover, correlations between the MRR changing rate and initial visual functions were examined.
Visual functions significantly improved 3 months after initial visit with accompanying improvements in outer retinal morphology. When compared with the baseline measurements, the MBR significantly increased at the macula of the affected eyes by 20.2 % and 13.0 % at 1 and 3 months respectively (P
Albrecht von Graæes Archiv für Ophthalmologie 10/2014; DOI:10.1007/s00417-014-2831-z · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AGEs are permanently modified macromolecule derivatives that form through nonenzymatic glycation of amino groups of proteins. Glycer-AGEs are highly toxic and play an important role in the pathogenesis of chronic inflammatory diseases. However, the contribution of glycer-AGEs to the pathogenesis of uveitis is unclear. In this study, we measured serum levels of glycer-AGEs in 100 patients with endogenous uveitis (22 with HLA-B27-associated uveitis, 20 with VKH disease, 14 with Behçet's disease, and 44 with sarcoidosis) and 33 healthy volunteers. We then examined the effect of the AGE inhibitor in a mouse model of human endogenous uveitis (EAU) by continuous oral administration of pyridoxamine at 200 or 400 mg/kg/day. Regardless of the etiology, serum glycer-AGE levels were significantly higher in patients with uveitis than in healthy subjects. Treatment with 400 mg/kg pyridoxamine significantly reduced the clinical and histological severity of EAU and was accompanied by a significant decrease in serum and retinal glycer-AGE levels and suppression of translocation of NF-κB p65 into the nucleus of retinal cells. Serum glycer-AGE levels may therefore serve as a biomarker of human uveitis, as well as systemic inflammation, and may contribute to the progression of uveitis, including diabetic iritis, via the activation of NF-κB.
[Show abstract][Hide abstract] ABSTRACT: Genistein is a dietary-derived flavonoid abundantly present in soybeans and known to possess various biological effects including anti-inflammation and anti-angiogenic activity. To investigate the effects of genistein on intraocular neovascularization, we used an animal model of laser-induced choroidal neovascularization (CNV). Male C57BL/6J mice were treated in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. CNV was induced by laser photocoagulation. The animals were fed a mixture diet containing 0.5% genistein or a control diet ad libitum for 7 days before laser photocoagulation and the treatment was continued until the end of the study. Seven days after laser injury, the size of CNV lesions was quantified. Retinal pigment epithelium (RPE)-choroid complex was also harvested 1 or 3 days after laser injury and the level of monocyte chemoattractant protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, and matrix metalloproteinase (MMP)-9 were measured by enzyme-linked immunosorbent assay. Expression levels of Ets-1 and F4/80 were examined by real-time PCR. A significant decrease in CNV size was observed in animals treated with genistein (15441.9±1511.8 μm(2)) compared to control mice (21074.0±1940.7μm(2), P<.05). Genistein significantly reduced the protein level of MCP-1, ICAM-1, and MMP-9 in the RPE-choroid complex (P<.05). In addition, genistein suppressed the expression levels of Ets-1 and F4/80 (P<.05). The current data indicate the anti-angiogenic property of genistein during CNV formation.
The Journal of Nutritional Biochemistry 07/2014; 25(11). DOI:10.1016/j.jnutbio.2014.06.004 · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose: To study the retinal degeneration caused by decreased proteasomal activity in β5t transgenic (β5t-Tg) mice, an animal model of senescence acceleration. Methods: β5t-Tg mice and age-matched littermate control (WT) mice were used. Proteasomal activities and protein level of poly-ubiquitinated protein in retinal extracts were quantified. Fundus images of β5t-Tg mice were taken and their features were assessed. For histological evaluation, the thicknesses of inner nuclear layer (INL), outer nuclear layer (ONL) and photoreceptor outer segment were measured. For functional analysis, electroretinogram (ERG) was recorded under scotopic and photopic illumination conditions. Immunofluorescence (IF) staining and TdT-mediated dUTP nick end labeling (TUNEL) were performed to investigate the mechanism of photoreceptor degeneration. Results: Chymotrypsin-like activity was partially suppressed in retinal tissues of β5t-Tg mice. Retinal degenerative changes with arterial attenuation were present in β5t-Tg, but not in WT mice. INL thickness showed no significant change between β5t-Tg and WT mice at 1, 3, 6 and 9 months-of-age. By contrast, thicknesses of ONL and outer segment in β5t-Tg mice were significantly decreased at 3, 6 and 9 months compared with those in WT mice. ERGs showed decrease of scotopic a-wave amplitude in β5t-Tg mice. The number of TUNEL-positive cells in ONL were significantly increased in β5t-Tg mice and co-localized with apoptosis-inducing factor, but not with cleaved caspase-3 and cleaved caspase-9, indicating that the photoreceptor cell death was induced via a caspase-independent pathway. Conclusions: The current data showed that impaired proteasomal function causes photoreceptor degeneration.
[Show abstract][Hide abstract] ABSTRACT: A case of retinoschisis associated with peripapillary intrachoroidal cavitation (ICC) was successfully treated with pars plana vitrectomy. A 70-year-old woman developed macular elevation and peripapillary ICC in her right eye. Optical coherence tomography revealed retinoschisis with retinal detachment in the macula. A microhole was observed within the myopic conus. A narrow passage was observed linking the ICC with the schisis cavity, complicated by a peripapillary epiretinal membrane tissue adjacent to the passage. The patient underwent vitrectomy with removal of the membrane tissue. Complete regression of the retinoschisis was observed with closure of the connection channel between the ICC and schisis cavity. These findings suggest that the communication channel between the vitreous and schisis cavities was formed due to the traction exerted by the membrane tissue on the ICC that had generated a connecting path to the schisis cavity. [Ophthalmic Surg Lasers Imaging Retina. 2014;45:xxx-xxx.].
[Show abstract][Hide abstract] ABSTRACT: To investigate the concentration and composition of N-glycans in plasma and vitreous samples obtained from patients with non-proliferative vitreoretinal diseases. Plasma and vitreous samples were collected from 11 patients with idiopathic macular hole (MH) and 9 patients with epiretinal membrane (ERM). The samples were pretreated for enzymatic cleaving, and subsequently glycans released from proteins were captured on BlotGlyco H beads. Sialic acids were methyl-esterified. Processed glycans were tagged with aminooxy-functionalized peptide reagent (aoWR) and released from the beads, followed by detection by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The concentration and composition of N-glycans in the samples were assessed. Concentration of N-glycans in vitreous samples (132 +/- 29 pmol/100 mu g protein) was significantly lower compared with those in plasma samples (714 +/- 29 pmol/100 mu g protein, p < 0.001). Predominant N-glycan in both plasma (39.7 +/- 1.1 %) and vitreous fluid (37.2 +/- 3.1 %) was identical, and the composition was presumed as [(Hex)2(HexNAc)2(NeuAc)2+ (Man)3(GlcNAc)2]. By contrast, the second-ranked N-glycan in vitreous samples (15.6 +/- 1.5 %) was the seventh in plasma (2.3 +/- 0.2 %). The current data provide useful information on N-glycan profile in the vitreous fluid, which is distinct from that in the plasma.
Albrecht von Graæes Archiv für Ophthalmologie 06/2014; 252(8). DOI:10.1007/s00417-014-2671-x · 2.33 Impact Factor