Biomedical subjects

Nagahisa Yoshimura

Publications and source records attributed to Nagahisa Yoshimura.

At least 19 recordsLinked to original sources

PubMed2006

Three-dimensional imaging of macular holes with high-speed optical coherence tomography.

OBJECTIVE: To demonstrate the advantages of 3-dimensional imaging of macular hole pathology using new-generation high-speed optical coherence tomography (OCT). DESIGN: Prospective observational case series. PARTICIPANTS: Twenty-one eyes from 20 consecutive patients diagnosed with a macular hole. METHODS: A prototype high-speed OCT system was built based on a Fourier-domain OCT (FD OCT) technology for patient examination. The system has achieved sensitivity of approximately 98 decibels, axial resolution of approximately 4.3 mum in tissue, and an acquisition rate of approximately 18,700 axial scans per second. Three-dimensional imaging of macular hole pathology was performed based on a raster scan protocol consisting of 256x256 axial scans. All patients were imaged with 3-dimensional OCT, Stratus OCT, and OCT Ophthalmoscope C7. MAIN OUTCOME MEASURES: Images of macular hole pathologies obtained by 3-dimensional OCT and standard OCT instruments. RESULTS: The 3-dimensional OCT imaging successfully generated realistic 3-dimensional images of the vitreofoveal interface and intraretinal microstructures associated with a macular hole. The 3-dimensional overview of the vitreofoveal interface was helpful in gaining an immediate understanding of the dynamic interactions of the vitreous and fovea. Observations of consecutive en face images in combination with conventional longitudinal images and of cross-sectional images in combination with sectioned volume images enabled identification of intraretinal microstructures and their 3-dimensional extension associated with a macular hole, such as subfoveal structural changes after vitreous traction, connection of the flap to intraretinal structures, the external limiting membrane (ELM) and its disruption, and elevated photoreceptor inner and outer segments delineated by the ELM. The appearance of inner-wall images of a macular hole produced by photoreceptor inner and outer segment backreflection varied throughout macular hole stages. CONCLUSIONS: Three-dimensional imaging of macular holes with high-speed OCT based on FD OCT technology offers 3-dimensional overviews that facilitate understanding of the abnormalities in the vitreofoveal interface. It also provides consecutive orthogonal images that allow much more precise and minute observation of 3-dimensionally extending intraretinal structural changes associated with a macular hole than conventional OCT imaging, especially in the photoreceptor inner and outer segments.

Aged↗

PubMed2006

Alteration of leukocyte-endothelial cell interaction during aging in retinal microcirculation of hypertensive rats.

PURPOSE: Hypertension, one of the more common chronic diseases affecting the elderly, has been reported to influence leukocyte-endothelial cell interaction. The leukocyte-mediated inflammatory process contributes to age-related changes in vessels. This study was designed to evaluate age-related changes in leukocyte-endothelial cell interaction in the hypertensive rat retina. METHODS: Male spontaneous hypertensive rats (SHR; 1.5, 3, 6, 12, and 20 months of age) and age-matched Wistar-Kyoto rats (WKY) were used. The number of accumulated leukocytes was counted in sections of flat-mounted retinal tissue. The expression of intercellular adhesion molecule-1 (ICAM-1) and CD18 (the common beta-chain of ICAM-1 ligands) was evaluated. Retinal thickness was evaluated histologically. RESULTS: The number of accumulated leukocytes and the expression of ICAM-1 and CD18 increased in the aged retina. The number of leukocytes that accumulated and the expression of CD 18 were significantly higher in the SHR group than in the WKY group (P < 0.01). In addition, retinal thickness decreased with age. CONCLUSION: Leukocyte-endothelial cell interaction increased in the aged retina and these changes were more severe in SHR retina than in WKY retina. This increased interaction was first observed at 3 months, a relatively young age.

Aging↗

PubMed2006

Cyclic stretch-induced reactive oxygen species generation enhances apoptosis in retinal pericytes through c-jun NH2-terminal kinase activation.

Hypertension is known to exacerbate diabetic complications, such as retinopathy and nephropathy. Apoptosis of retinal vascular pericytes has been well established as the earliest conceivable change in diabetic retinopathy. In this study, we investigated the contribution of cyclic stretch, which mimics a hypertensive state to pericyte apoptosis. A 48-hour cyclic stretch induced DNA fragmentation in porcine retinal pericytes and increased the number of TUNEL+ cells at a pathophysiologically relevant extension level (10%/60 cycles per minute). Stretch also increased intracellular reactive oxygen species generation and increased c-Jun NH(2)-terminal kinase phosphorylation in a time- and magnitude-dependent manner, which were reduced by the nicotinamide-adenine dinucleotide phosphate oxidase inhibitor diphenylene iodonium or dominant-negative protein kinase C-delta. Stretch activated protein kinase C-delta and increased its association with p47phox. Stretch induced cleavage of caspase-9 and -3 and increased caspase-3 activity. Protein kinase C-delta or c-Jun NH(2)-terminal kinase inhibition normalized stretch-induced caspase-3 activity and prevented stretch-induced apoptosis. These data indicate that cyclic stretch induces apoptosis in porcine retinal pericytes by activation of the reactive oxygen species-c-Jun NH(2)-terminal kinase-caspase cascades, suggesting a novel molecular mechanism to explain the exacerbation of early diabetic retinopathy by concomitant hypertension.

Animals↗

PubMed2006

Pigment epithelial detachment in polypoidal choroidal vasculopathy.

PURPOSE: To study the morphological features of serosanguineous pigment epithelial detachments (PEDs) with accompanying polypoidal lesions in eyes with polypoidal choroidal vasculopathy (PCV). DESIGN: Retrospective observational case series. METHODS: For this observational case study, we retrospectively reviewed 93 consecutive eyes of 85 patients with PCV. The lesions in eyes with PCV were examined with indocyanine green angiography (IA) and optical coherence tomography (OCT). RESULTS: Of 93 eyes with PCV, 51 eyes (55%) had serous or hemorrhagic PEDs. Of these 51 eyes, a notch in the PED was found in 27 eyes (53%) by angiography, most of which showed polypoidal lesions by IA that corresponded in location to the notch observed by angiography. Polypoidal lesions were detected outside the PED in one eye (2%), at the margin of the PED in 33 eyes (65%), and inside the PED in 12 eyes (24%). OCT revealed that PED had a notch observed tomographically in 29 eyes (57%), most of which corresponded in location to polypoidal lesions seen by IA. In eight eyes, polypoidal lesions, which were adherent to the inner surface of the serous PED, appeared to be detached from the Bruch membrane and the choroid. CONCLUSIONS: Polypoidal lesions are located at the margin of PED and make a notch in the accompanying PED that is visible by angiography and tomographically. When the polypoidal lesions have increased exudate, the fluid from the lesions infiltrates under the polypoidal lesions themselves, which results in the lesions detaching from the Bruch membrane and appearing to be located inside the PED.

Aged↗

PubMed2006

Photoreceptor status after resolved macular edema in branch retinal vein occlusion treated with tissue plasminogen activator.

PURPOSE: To evaluate the integrity of photoreceptors in macular edema (ME) associated with branch retinal vein occlusion after intravitreal tissue plasminogen activator. DESIGN: Retrospective, interventional case series. METHODS: Nineteen eyes with ME by branch retinal vein occlusion were treated with intravitreal tissue plasminogen activator injection. We assessed visual acuity (VA) and the presence or absence in the fovea of a third high reflectance band (HRB) by optical coherence tomography at the final visit. RESULTS: No differences were found in age, preoperative VA, and foveal thickness between the groups with or without the third HRB. After treatment, the mean VA improved significantly (P < .05) in both groups. At the final visit, the mean VA in the group without HRB was significantly poorer than the group with HRB (P = .0042); foveal thickness did not differ between the groups. CONCLUSIONS: The integrity of the third HRB in the fovea is associated with VA after the resolution of ME.

Female↗

PubMed2006

No association between complement factor H gene polymorphism and exudative age-related macular degeneration in Japanese.

Age-related macular degeneration (ARMD) is the leading cause of blindness in the elderly population not only Western but also Asian industrial countries. In Caucasian, a polymorphism of the complement factor H gene (CFH), the C allele of rs1061170 (Y402H), was established as the first strong genetic factor for excursively exudative type of ARMD. In this study, we performed an extensive sequencing of the 22 exons in the CFH gene by recruiting 146 exudative ARMD patients and 105 normal controls of Japanese origin and identified 61 polymorphisms. We found that the frequency of the C allele of rs1061170 (Y402H) is much lower (0.04) in Japanese controls than in Caucasians (0.45). No case disease susceptibility to exudative ARMD was noted for rs1061170 (Y402H) (chi (2) = 3.19, P (corr) = 0.423), or other 12 single nucleotide polymorphisms (SNPs) whose frequency is greater than 0.05. When haplotypes were inferred for 13 SNPs (these 12 SNPs with a frequency greater than 0.05 and rs1061170), three haplotypes whose pattern was similar to those in Caucasians were identified but with substantial difference in frequency. Again we failed to identify genetic association between Japanese exudative ARMD and any of the haplotypes including the J1 haplotype which was shown to be susceptible to ARMD in Caucasians (chi (2 )=( )3.92, P (corr) = 0.157). CFH does not appear to be a primary hereditary contributor to ARMD in Japanese. The absence of CFH contribution to ARMD in Japanese may correlate with the findings in ethnic differences of ARMD phenotypes.

Age Factors↗

PubMed2006

A rat model of glaucoma induced by episcleral vein ligation.

To establish a reliable animal model of glaucoma, we examined if episcleral vein ligation in rat eyes can induce intraocular pressure (IOP) elevation and concomitant characteristic morphological features of glaucoma. IOP elevation was detected on the next day (30.1+/-4.4 mmHg: operated eyes; 21.0+/-1.8 mmHg: control eyes) and persisted at least 7 months after the procedure (24.5+/-2.3 mmHg: operated eyes; 19.7+/-1.9 mmHg: control eyes). These results suggest that episcleral vein ligation can induce very mild IOP elevation immediately after the operation, which can last over several months. Furthermore, it appears there was little variability in the patterns of IOP elevation among the individual eyes treated with episcleral vein ligation. Morphological changes were detected selectively in the retinal ganglion cell (RGC) layer and optic disc excavation was evident in the late stage of chronic IOP elevation. RGCs were selectively lost by apoptotic death. The number of RGCs was reduced by 18% at 12 weeks and eventually by 35% at 8 months postoperatively. Müller cells downregulated the expression of p27Kip1 and appeared to be partially in a reactive state even at the advanced stages of glaucoma. The expression of basic fibroblast growth factor and ciliary neurotrophic factor, which are neurotrophic factors implicated in the control of cell survivals and neuroprotection, significantly declined at the advanced stages. Taken altogether, these observations indicate that the episcleral vein ligation model based on the simple ligation procedure reproducibly provides a reliable glaucoma model and contributes to give insights into the underlying molecular and cellular bases of human glaucoma and to devise the new medication upon the disease.

Animals↗

PubMed2006

Effects of bone marrow stromal cell injection in an experimental glaucoma model.

We investigated if bone marrow stromal cells (BMSCs) transplanted into the vitreous body of a glaucoma model eye could be integrated in the host retina and also whether they could rescue the retinal ganglion cells (RGCs) from death induced by the elevated intraocular pressure. Glaucoma was induced in the right eye of adult Wistar rats by ligating the episcleral veins. The GFP-expressing BMSCs (GFP-BMSCs) were injected into the vitreous body of both the control and the glaucomatous eyes. After transplantation, GFP-BMSCs were mostly present along with the inner limiting membrane and only a few cells were integrated into the ganglion cell layer. At 2 or 4 weeks after transplantation, GFP-BMSCs were observed to express various trophic factors. The BMSCs injected glaucoma model eyes showed less reduction in the number of RGCs compared to the glaucomatous eyes with PBS injection. This study suggests that BMSC transplantation may be worthy as a neuroprotective tool to treat glaucoma.

Animals↗

PubMed2006

Recurrent bleeding after photodynamic therapy in polypoidal choroidal vasculopathy.

PURPOSE: To report a case of recurrent bleeding after photodynamic therapy (PDT) in an eye with polypoidal choroidal vasculopathy (PCV). DESIGN: Interventional case report. METHODS: A 73-year-old man was treated in the left eye for PCV with PDT. RESULTS: Two weeks after PDT, his left eye showed extensive subretinal hemorrhage, with a slight vision loss. Three months after PDT, subretinal hemorrhage was almost absorbed. He received a second session of PDT to the remaining choroidal neovascularization. Two weeks thereafter, his left eye showed massive suprachoroidal hemorrhage with further vision loss. One month after the second PDT, visual acuity was decreased to no light perception as a result of massive vitreous hemorrhage. Although the patient underwent pars plana vitrectomy, visual acuity in the left eye remained hand motion as a result of massive suprachoroidal hemorrhage. CONCLUSIONS: Ophthalmologists and patients should be aware of the risk of massive bleeding after PDT in eyes with PCV.

Aged↗

PubMed2006

Intravitreal tissue plasminogen activator to treat macular edema associated with branch retinal vein occlusion.

PURPOSE: To evaluate the efficacy of intravitreal tissue plasminogen activator (tPA) injection for branch retinal vein occlusion (BRVO). DESIGN: Retrospective, interventional case series. METHODS: Seventeen eyes presenting with macular edema caused by BRVO were treated with an intravitreal tPA (Monteplase, 40 k IU) injection. We assessed the visual acuity (VA) and foveal thickness measured with optical coherence tomography. RESULTS: The mean duration of symptoms before surgery was 3.6 +/- 3.8 weeks. The mean logMAR VA significantly improved from 0.603 +/- 0.327 at baseline to 0.388 +/- 0.248 (P < .01) at one month and 0.359 +/- 0.319 (P < .05) at six months. The mean foveal thickness significantly decreased from 738 +/- 156 microm at baseline to 454 +/- 213 microm (P < .001) at one month and 253 +/- 164 microm (P < .001) six months. CONCLUSION: Intravitreal tPA injection may be an effective treatment for resolving macular edema and improving the VA in BRVO.

Aged↗

PubMed2006

Scanning laser polarimetry with variable corneal compensation and optical coherence tomography in tilted disk.

PURPOSE: To determine whether scanning laser polarimetry with variable corneal compensation (GDx-VCC) or optical coherence tomography (OCT) is helpful for the analysis of the retinal nerve fiber layer (RNFL) thickness in glaucoma subjects with tilted disk. DESIGN: Retrospective case-control study. METHODS: We included 21 glaucomatous eyes with tilted disk and 35 glaucomatous eyes without tilted disk. Peripapillary RNFL thickness measurement by GDx-VCC and OCT, and also visual field testing with a Humphrey Field Analyzer program 30-2 (HFA) were performed in all subjects. RESULTS: In the group without tilted disk, the RNFL thickness values obtained with GDx-VCC and OCT analysis had a good correlation with mean deviation (MD), and clearly showed stage-dependent reduction. Conversely, in the group with tilted disk, a discrepancy in the RNFL measurement between GDx-VCC and OCT was observed. The correlation of RNFL measurement to the visual field was further examined at each hemifield (superior and inferior). In the group without tilted disk, the measurements of both instruments at each hemifield were in good correlation with the mean pattern deviation values. However, in the group with tilted disk, the GDx-VCC derived values did not correlate with the visual field defect in both hemifields, whereas OCT was in good association with both mean pattern deviation values. Infrared images acquired with a wavelength of nearly 780 nm revealed a high reflex from the sclera in the tilted disk. CONCLUSIONS: Our study has suggested that RNFL analysis by OCT is more suitable for the glaucoma assessment in the tilted disk compared with GDx-VCC.

Birefringence↗

PubMed2006

Polypoidal choroidal vasculopathy with choroidal vascular hyperpermeability.

PURPOSE: To describe the incidence and clinical characteristics of polypoidal choroidal vasculopathy (PCV) associated with choroidal vascular hyperpermeability. DESIGN: Retrospective observational case series. METHODS: We reviewed the medical records of 122 consecutive eyes with PCV and 106 consecutive eyes with exudative age-related macular degeneration (AMD). Fluorescein angiography and indocyanine green (ICG) angiography were performed using a confocal scanning laser system. In the midphase of ICG angiography, we evaluated choroidal vascular hyperpermeability, which is recognized as one of the characteristic findings in central serous chorioretinopathy (CSC). Choroidal vascular hyperpermeability appeared as multifocal patchy areas of hyperfluorescence with blurred margins within the choroid that increased in intensity with time after injection of the dye. RESULTS: Of 122 eyes with PCV, 12 (9.8%) eyes of 10 patients exhibited multifocal choroidal hyperfluorescence in the midphase of ICG angiography, whereas two (1.9%) of 106 eyes with exudative AMD showed a similar appearance (P = .013). Of the 12 eyes in 10 patients with PCV that demonstrated multifocal choroidal hyperfluorescence, we also noted that the early phase of ICG angiography showed choroidal filling delay in seven eyes (58%) and venous dilation in 12 eyes (100%). Four of these 12 eyes (33%) had a medical history of CSC, and nine (90%) of the 10 patients revealed multifocal choroidal hyperfluorescence bilaterally. CONCLUSIONS: Multifocal choroidal hyperfluorescence seen by ICG angiography occurs more frequently in eyes with PCV than in those with AMD. Choroidal vascular hyperpermeability, reportedly a characteristic finding in CSC, might be one of the risk factors of PCV.

Aged↗

PubMed2006

Photopsia as a manifestation of digitalis toxicity.

CASE REPORT: To present a case of photopsia resulting from digoxin intoxication brought about by dehydration in a 72-year-old woman. COMMENTS: Ophthalmologists may be the first clinicians to notice the symptoms of digitalis intoxication, which is potentially a life-threatening condition.

Aged↗

PubMed2006

Time-lapse imaging of vitreoretinal angiogenesis originating from both quiescent and mature vessels in a novel ex vivo system.

PURPOSE: Diabetic retinopathy (DR) is an angiogenic disease that leads to severe visual loss. However, adequate animal models of vitreoretinal neovascularization in proliferative diabetic retinopathy (PDR) have not yet been described. The purpose of this study was to develop a novel ex vivo system for assessing vitreoretinal angiogenic processes that originate from both quiescent and mature vessels that could be observed with time-sequential imaging. METHODS: The retinas of 7- to 8-week-old mice were cultured for 4 days, with or without several growth factors with novel procedures, and immunohistochemistry was performed. The retinas from Tie2-GFP mice were cultured with vascular endothelial growth factor (VEGF), and time-sequential imaging of vitreoretinal angiogenesis was acquired. RESULTS: Vascular sprouts were induced by both VEGF and placenta growth factor, but not by insulin-like growth factor-1, basic fibroblast growth factor or angiopoietin-2. In explants with or without VEGF, perivascular mural cells were dissociated from endothelial cells, which is an important step during angiogenesis and in the progression of DR. Furthermore, use of time-lapse observations of retinal neovascularization events visualized that the first step in vascular sprout emergence from quiescent vessels was a single cell extension. The leading edges of a sprouting endothelial cell extended and retracted in a sequential manner. From newly formed vessels, additional vascular sprouts then emerged and new vessels fused to each other, resulting in vascular branching. CONCLUSIONS: Time-lapse imaging of this system visualized the dynamic process in vitreoretinal neovascularization from quiescent and mature vessels.

Animals↗

PubMed2006

The simultaneous treatment of MMP-2 stimulants in retinal transplantation enhances grafted cell migration into the host retina.

The success of functional retinal cell transplantation has been limited by the low efficiency of the transplanted cell integration into the host retina. Given that the extracellular matrix (ECM) is thought to inhibit entry and axonal outgrowth of grafted neural cells into the host retina, modulation of the ECMs in the host environment may overcome this limitation. Here, we demonstrate that matrix metalloprotease-2 (MMP-2) expression is associated with the high migratory potential of adult rat hippocampus-derived neural stem cells compared with retinal progenitor cells. In addition, MMP-2, as well as its reported inducers concanavalin A and 17beta-estradiol, can trigger the migration of retinal progenitor cells into explanted retinas. Inhibitors of MMP-2 suppressed these effects. Intense cell migration is not required for photoreceptor transplantation; however, the environment that allows the transplanted cells to integrate is most important. Migration of the transplanted cells is a good index of the acceptance of grafted cell of the host tissue. Strategies modulating the environment by MMP-2 stimulation may provide an advance in the development of retinal transplantation.

Adult Stem Cells↗

PubMed2006

EphrinA1 inhibits vascular endothelial growth factor-induced intracellular signaling and suppresses retinal neovascularization and blood-retinal barrier breakdown.

The Eph receptor/ephrin system is a recently discovered regulator of vascular development during embryogenesis. Activation of EphA2, one of the Eph receptors, reportedly suppresses cell proliferation and adhesion in a wide range of cell types, including vascular endothelial cells. Vascular endothelial growth factor (VEGF) plays a primary role in both pathological angiogenesis and abnormal vascular leakage in diabetic retinopathy. In the study described herein, we demonstrated that EphA2 stimulation by ephrinA1 in cultured bovine retinal endothelial cells inhibits VEGF-induced VEGFR2 receptor phosphorylation and its downstream signaling cascades, including PKC (protein kinase C)-ERK (extracellular signal-regulated kinase) 1/2 and Akt. This inhibition resulted in the reduction of VEGF-induced angiogenic cell activity, including migration, tube formation, and cellular proliferation. These inhibitory effects were further confirmed in animal models. Intraocular injection of ephrinA1 suppressed ischemic retinal neovascularization in a dose-dependent manner in a mouse model. At a dose of 125 ng/eye, the inhibition was 36.0 +/- 14.9% (P < 0.001). EphrinA1 also inhibited VEGF-induced retinal vascular permeability in a rat model by 46.0 +/- 10.0% (P < 0.05). These findings suggest a novel therapeutic potential for EphA2/ephrinA1 in the treatment of neovascularization and vasopermeability abnormalities in diabetic retinopathy.

Animals↗

PubMed2005

Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy.

BACKGROUND: Although vascular endothelial growth factor (VEGF) is a primary mediator of retinal angiogenesis, VEGF inhibition alone is insufficient to prevent retinal neovascularization. Hence, it is postulated that there are other potent ischemia-induced angiogenic factors. Erythropoietin possesses angiogenic activity, but its potential role in ocular angiogenesis is not established. METHODS: We measured both erythropoietin and VEGF levels in the vitreous fluid of 144 patients with the use of radioimmunoassay and enzyme-linked immunosorbent assay. Vitreous proliferative potential was measured according to the growth of retinal endothelial cells in vitro and with soluble erythropoietin receptor. In addition, a murine model of ischemia-induced retinal neovascularization was used to evaluate erythropoietin expression and regulation in vivo. RESULTS: The median vitreous erythropoietin level in 73 patients with proliferative diabetic retinopathy was significantly higher than that in 71 patients without diabetes (464.0 vs. 36.5 mIU per milliliter, P<0.001). The median VEGF level in patients with retinopathy was also significantly higher than that in patients without diabetes (345.0 vs. 3.9 pg per milliliter, P<0.001). Multivariate logistic-regression analyses indicated that erythropoietin and VEGF were independently associated with proliferative diabetic retinopathy and that erythropoietin was more strongly associated with the presence of proliferative diabetic retinopathy than was VEGF. Erythropoietin and VEGF gene-expression levels are up-regulated in the murine ischemic retina, and the blockade of erythropoietin inhibits retinal neovascularization in vivo and endothelial-cell proliferation in the vitreous of patients with diabetic retinopathy in vitro. CONCLUSIONS: Our data suggest that erythropoietin is a potent ischemia-induced angiogenic factor that acts independently of VEGF during retinal angiogenesis in proliferative diabetic retinopathy.

Animals↗

PubMed2005

Generation of Rx+/Pax6+ neural retinal precursors from embryonic stem cells.

We report directed differentiaion of retinal precursors in vitro from mouse ES cells. Six3+ rostral brain progenitors are generated by culturing ES cells under serum-free suspension conditions (SFEB culture) in the presence of Wnt and Nodal antagonists (Dkk1 and LeftyA), and subsequently steered to differentiate into Rx+ cells (16%) by treatment with activin and serum. Consistent with the characteristics of early neural retinal precursors, the induced Rx+ cells coexpress Pax6 and the mitotic marker Ki67, but not Nestin. The ES cell-derived precursors efficiently generate cells with the photoreceptor phenotype (rhodopsin+, recoverin+) when cocultured with embryonic retinal cells. Furthermore, organotypic culture studies demonstrate the selective integration and survival of ES cell-derived cells with the photoreceptor phenotype (marker expression and morphology) in the outer nuclear layer of the retina. Taken together, ES cells treated with SFEB/Dkk1/LeftyA/serum/activin generate neural retinal precursors, which have the competence of photoreceptor differentiation.

Activins↗