Noriko Miyamoto

Phosphatidylinositol 3-Kinase/Akt Regulates Angiotensin II–Induced Inhibition of Apoptosis in Microvascular Endothelial Cells by Governing Survivin Expression and Suppression of Caspase-3 Activity

Abstract— Angiotensin II (Ang II) plays essential roles in vascular homeostasis, neointimal formation, and postinfarct remodeling. Although Ang II has been shown to regulate apoptosis in cardiomyocytes and vascular smooth muscle cells, its role in vascular endothelial cells (ECs) remains elusive. To address this issue, we first performed TUNEL and caspase-3 activity assays with porcine microvascular ECs challenged by serum deprivation. Ang II significantly reduced the ratio of apoptotic cells and caspase-3 activity. The Ang II type 1 receptor (AT1) was responsible for these effects. Among the signaling molecules downstream of AT1, we revealed that PI3-kinase/Akt pathway plays a predominant role in the antiapoptotic effect of Ang II. Interestingly, the expression of survivin, a central molecule of cell survival, increased after Ang II stimulation. Overexpression of a dominant-negative form of Akt abolished both Ang II–induced antiapoptosis and survivin protein expression. In a murine model of hyperoxygen-induced retinal vascular regression, AT1a knockout mice showed a significant increase in retinal avascular areas. Our data indicate that Ang II plays a critical antiapoptotic role in vascular ECs by a mechanism involving PI3-kinase/Akt activation, subsequent upregulation of survivin, and suppression of caspase-3 activity.

Pars plana vitrectomy for cystoid macular edema secondary to sarcoid uveitis.

OBJECTIVE To examine the results of pars plana vitrectomy for cystoid macular edema secondary to sarcoid uveitis resistant to medical treatment. DESIGN Retrospective, interventional, noncomparative case series. SUBJECTS Fourteen consecutive subjects (18 eyes) with cystoid macular edema associated with sarcoid uveitis resistant to medical treatment. INTERVENTION All eyes underwent pars plana vitrectomy. Nine eyes also underwent peeling of the epiretinal membrane or removal of the posterior vitreous cortex. MAIN OUTCOME MEASURES Status of macular edema, visual acuity, and complications. RESULTS Ten eyes (56%) improved 2 or more lines of Snellen visual acuity within 12 months. Six eyes (33%) remained unchanged, within a line of preoperative Snellen visual acuity, and two eyes (11%) worsened by 2 or more lines of Snellen visual acuity. Slit-lamp biomicroscopy showed that cystoid macular edema had resolved in 14 eyes (78%) within 9 months postoperatively. One eye (6%) had minimal edema, whereas three eyes (17%) remained unchanged biomicroscopically at the final visit. Postoperative complications included cataract formation, glaucoma, optic nerve atrophy, epiretinal membrane formation, and tractional retinal detachment. No severe postoperative inflammation was noted. CONCLUSIONS Pars plana vitrectomy seems to have a beneficial effect on cystoid macular edema caused by sarcoidosis resistant to medical treatment.

Transcription Factor Ets-1 Mediates Ischemia- and Vascular Endothelial Growth Factor-Dependent Retinal Neovascularization

Transcription factor Ets-1 has been reported to regulate angiogenesis in vascular endothelial cells. Here, we investigated a mechanism that may regulate the expression of Ets-1 in vascular endothelial growth factor (VEGF)- and hypoxia-induced retinal neovascularization and that may have potential to inhibit ocular neovascular diseases. VEGF and hypoxia increased Ets-1 expression in cultured bovine retinal endothelial cells. The VEGF-induced mRNA increase of Ets-1 was suppressed by a tyrosine kinase inhibitor (genistein), by inhibitors of MEK (mitogen-activated protein and extracellular signal-regulated kinase kinase) (PD98059 and UO126), and by inhibitors of protein kinase C (GF109203X, staurosporine, and Gö6976). Dominant-negative Ets-1 inhibited VEGF-induced cell proliferation, tube formation, and the expression of neuropilin-1 and angiopoietin-2. In a mouse model of proliferative retinopathy, Ets-1 mRNA was up-regulated. Intravitreal injection of dominant-negative Ets-1 suppressed retinal angiogenesis in a mouse model of proliferative retinopathy. In conclusion, VEGF induces Ets-1 expression in bovine retinal endothelial cells and its expression is protein kinase C/ERK pathway-dependent. Ets-1 up-regulation is involved in the development of retinal neovascularization, and inhibition of Ets-1 may be beneficial in the treatment of ischemic ocular diseases.

Outcomes of 23- and 25-gauge transconjunctival sutureless vitrectomies for idiopathic macular holes

Background/aims: To assess the outcomes of 23-gauge sutureless transconjunctival vitrectomies (TSV), as compared with 25-gauge TSV in macular hole surgeries. Methods: A retrospective, consecutive, interventional case series of 47 eyes with idiopathic macular holes treated by 23- or 25-gauge TSV were analysed. Results: The operative time was 37.2 (SD 8.9) min with 23-gauge TSV and 34.2 (8.7) min with 25-gauge TSV (p = 0.388). The anatomical success rate was 96% with 23-gauge TSV and 92% with 25-gauge TSV (p>0.999). The logarithm of the minimum angle of resolution of best-corrected visual acuity (BCVA) at the sixth postoperative month was 0.19 (0.16) with 23-gauge TSV and 0.19 (0.25) with 25-gauge TSV (p = 0.521). Postoperative improvement in BCVA was comparable between the two TSVs. IOP on postoperative day 1 was lower with 25-gauge TSV (12.3 (4.9) mm Hg) than with 23-gauge TSV (17.4 (5.8) mm Hg) (p = 0.036). Complications included retinal break, intraoperative bleeding and slippage of the infusion cannula with 23-gauge TSV, while retinal detachment and postoperative hypotony occurred in the 25-gauge TSV group (p = 0.570). Conclusion: 23-gauge TSV appears to be as safe and effective as 25-gauge TSV in macular hole surgery.

Association between external limiting membrane status and visual acuity in diabetic macular oedema.

Aim To evaluate the association between the foveal external limiting membrane (ELM) status and visual acuity (VA) in diabetic macular oedema (DMO). Methods We retrospectively reviewed the spectral domain optical coherence tomography images of 127 eyes from 127 patients with DMO and evaluated the correlation between the logarithm of the minimal angle of resolution (logMAR) VA and the statuses of the foveal ELM, inner segment/outer segment (IS/OS) and cone outer segment tips (COST); foveal macular thickness (FMT); and presence or absence of hard exudates (HE), serous retinal detachment (SRD) and vitreous adhesion. The integrity of the ELM, IS/OS, and COST was classified into three categories (absent, disrupted and complete). Results There was a strong correlation between VA and the statuses of the ELM (r=0.699, p<0.001), IS/OS (r=0.716, p<0.001) and COST (r=0.471, p<0.001). There was no correlation between FMT and logMAR VA (r=−0.036, p=0.687). However, when we analysed the correlation between FMT and VA by dividing patients into those with FMT ≤250 μm and those with FMT >250 μm, there was a positive correlation between FMT and VA in eyes with FMT ≤250 μm (r=−0.601, p<0.0001) and a negative correlation in eyes with FMT>250 μm (r=0.290, p<0.01). Other factors HE, SRD and vitreous adhesion did not correlate with VA. Conclusions In DMO, the ELM status may be as closely related to VA as the IS/OS status.

Pars plana vitrectomy for vitreous opacity associated with ocular sarcoidosis resistant to medical treatment.

objective: To examine the results of pars plana vitrectomy for nonclearing vitreous opacities associated with ocular sarcoidosis that is resistant to corticosteroid treatment. Methods: Eight consecutive patients (11 eyes) with vitreous opacities and uveitis associated with sarcoidosis were studied. All patients were resistant to or intolerant of corticosteroid therapy. All eyes underwent pars plana vitrectomy, followed by evaluation of visual acuity and recording of the grade of inflammation and complications. Results: Seven eyes had gained two or more lines of Snellen visual acuity six months postoperatively; visual acuity remained unchanged in the other four eyes. Vitreous inflammation was reduced in all cases. Severe postoperative inflammation did not recur in any eyes. Five eyes developed visually significant cataracts and underwent cataract extraction and intraocular lens insertion within 8–30 months. Based on slit-lamp biomicroscopy and fluorescein angiography, preoperative cystoid macular edema in five eyes resolved or improved within six months after vitrectomy. Postoperative complications included elevated intraocular pressure in three eyes, cataract formation in six eyes, epiretinal membrane formation in one eye, and choroidal neovascularization in one eye. None of the patients developed cystoid macular edema postoperatively. Only three patients received systemic corticosteroids after surgery. At the final visit, only one patient required systemic corticosteroid therapy. Conclusions: Pars plana vitrectomy appears to have beneficial effects on restoring vision, stabilizing vitreous inflammation, and reducing systemic corticosteroid requirements in eyes with thick vitreous opacities associated with sarcoidosis that is resistant to medical treatment.

Suprachoroidal fluid as a complication of 23-gauge vitreous surgery.

The popularity of transconjunctival sutureless vitreoretinal surgery has been increasing recently.1 2 Eckardt designed a 23-gauge instrument system for transconjunctival sutureless vitrectomy.3 Howard et al reported on the effectiveness and safety of 23-gauge instrument for a variety of vitreoretinal conditions.4 However, the complications involving the cannula remain problematic. In the current study, we report the accumulation of suprachoroidal fluid as an intraoperative complication of vitrectomy using the 23-gauge system. We performed a retrospective, noncomparative case review of the operative reports of 392 patients (442 eyes) who underwent 23-gauge vitrectomy by one surgeon (HT) between November 2005 and March 2007 at Hyogo Prefectural Amagasaki Hospital. Institutional review board approval and complete informed consent was obtained from all patients. Vitrectomy was performed using a 23-gauge …

Intraocular gas dynamics after 20-gauge and 23-gauge vitrectomy with sulfur hexafluoride gas tamponade.

Purpose: The purpose of this study was to evaluate the intraocular gas dynamics after 23-gauge transconjunctival sutureless vitrectomy (TSV) as compared with 20-gauge pars plana vitrectomy (PPV). Methods: A consecutive series of 290 eyes that experienced 20-gauge or 23-gauge vitrectomy with 25% sulfur hexafluoride (SF6) gas tamponade were retrospectively reviewed. Intraocular gas bubble size on postoperative Day 1 and Gas50, the interval to dissipate to a 50% gas fill, were evaluated. Results: The mean intraocular bubble size on postoperative Day 1 was 92.0 ± 8.3% in the 20-gauge PPV cases and 83.8 ± 13.7% in the 23-gauge TSV cases (P < 0.001). The mean Gas50 was 8.6 ± 1.6 days in the 20-gauge PPV cases and 6.6 ± 2.2 days in the 23-gauge TSV cases (P < 0.001). Thorough peripheral vitrectomy and 23-gauge TSV were significantly associated with Gas50 ≤4 days (odds ratio, 4.62 and 16.8; P = 0.036 and P = 0.007, respectively). Among thoroughly vitrectomized eyes, 13 eyes treated with 23-gauge PPV with intraoperative suture placement at the sclerotomy sites had gas longevity comparative to those with 20-gauge PPV. Conclusion: Eyes treated with 23-gauge TSV tend to have earlier gas disappearance or incomplete gas fill. Intraoperative suture placement would be a solution.

Response of eyes with age-related macular degeneration to anti-VEGF drugs and implications for therapy planning

Purpose To evaluate the response to and dependence on aflibercept or ranibizumab in patients with age-related macular degeneration (AMD). Methods We retrospectively reviewed AMD patients who received induction therapy with aflibercept or ranibizumab for the following parameters: whether complete resolution of the retinal fluid (“good response”) was achieved and whether recurrence was observed within 3 months (“dependent”) after the induction treatment. With aflibercept treatment, treatment-naïve eyes with a good response/non-dependence were recommended a pro re nata regimen, and other eyes were recommended a proactive bimonthly regimen, followed by monitoring of visual acuity (VA) for 12 months. The measured values of the groups were compared using one-way analysis of variance with Tukey’s test to evaluate the difference between baseline and postinjection VA. Results Among the treatment-naïve eyes, 76% had a good response to aflibercept and 37% of these were aflibercept-dependent, while 58% had a good response to ranibizumab but 51% of these were ranibizumab-dependent. Among the eyes that converted from ranibizumab treatment, 92% of the good responders to ranibizumab with dependence and 76% of the poor responders on ranibizumab had a good response to aflibercept. With aflibercept treatment, the mean VA of treatment-naïve patients was significantly better than the baseline VA over 12 months (P<0.001), and the VA of the converted group improved significantly with proactive treatment and the improvement was continuously maintained from 6 to 12 months. Conclusion The evaluation of response to and dependence on anti-vascular endothelial growth factor therapies in AMD was useful and practical in managing therapeutic protocols to obtain a good VA.

Long-term results of photodynamic therapy or ranibizumab for polypoidal choroidal vasculopathy in LAPTOP study

Background/aim We previously reported that ranibizumab performed better on visual prognosis than photodynamic therapy (PDT) in a Ranibizumab (Lucentis) And Photodynamic Therapy On Polypoidal choroidal vasculopathy (LAPTOP) study. To determine if the first-choice treatment, either PDT or intravitreal ranibizumab, has a long-term effect in patients with polypoidal choroidal vasculopathy (PCV). Methods We reviewed medical records of patientsrandomised to either PDT (29 eyes) or ranibizumab (27 eyes) from July 2009 to June 2011 in LAPTOP study. Retreatment or switching to other treatments were at the investigator’s discretion after release from the 2-year LAPTOP study up to 5years. We evaluated visual acuity (VA), continuity of initial treatment, percentage of dry macula achievement and macular atrophy at 5 years. Results The logarithm of minimal angle of resolution VA was 0.56 in the PDT and 0.44 in the ranibizumab groups at baseline (p=0.101) and was 0.55 and 0.28 at 5years, respectively (p<0.05). More than 70% of the patients converted to aflibercept in following years. Achievement percentages of dry macula were 74% (PDT) and 63% (ranibizumab) at 5years, and macular atrophy was detected in 78% (PDT) and 60% (ranibizumab) with a mean area of 7.7 and 3.5 mm2, respectively (p=0.155). Conclusions The better VA in the initial ranibizumab group compared with the PDT group at 2 years was retained at the 5-year follow-up.