Chang-Hao Yang

Intraocular lens position and anterior chamber angle changes after cataract extraction in eyes with primary angle-closure glaucoma

Purpose: To prospectively study the anterior chamber angle in eyes with chronic primary angle‐closure glaucoma (PACG) having posterior chamber intraocular lens (IOL) implantation and evaluate IOL position and intraocular pressure (IOP). Setting: National Taiwan University Hospital, Taipei, Taiwan. Methods: Using Scheimpflug image processing, the anterior chamber angles were studied in 20 consecutive eyes with chronic PACG and 10 control eyes before and after posterior chamber IOL implantation. Anterior chamber depth, chamber angle width, IOL position, and IOP change were evaluated. Results: Mean anterior chamber depth in the PACG group was 2.04 ± 0.29 mm preoperatively and 3.44 ± 0.16 mm postoperatively. The anterior chamber angle widened significantly in relation to the superior, inferior, temporal, and nasal quadrants after surgery. The degree of IOL tilting and decentration was the same in both the PACG and control groups. All eyes in the PACG group maintained an IOP under 21 mm Hg during the 6 month follow‐up. Eighty‐four percent maintained or decreased their antiglaucoma medication; 16% required increased medication. Conclusion: Cataract extraction with posterior chamber IOL implantation in eyes with PACG controlled IOP well in most cases.

Bevacizumab pretreatment in vitrectomy with silicone oil for severe diabetic retinopathy.

Purpose: To evaluate the effects of intravitreal bevacizumab pretreatment in vitrectomy with silicone oil infusion for severe diabetic retinopathy. Methods: Forty-one eyes (39 patients) that underwent primary vitrectomy with silicone oil tamponade for severe diabetic retinopathy were enrolled in this prospective, comparative case–control clinical study. Cases were alternately divided into the following Group 1, intravitreal bevacizumab (1.25 mg) injection 1 week before surgery; or Group 2, no bevacizumab injection. Cases were followed-up for at least 6 months. Postinjection retinal changes, intra- and postoperative findings, and outcomes were compared between groups. Results: Bevacizumab injections induced regression of neovascularization after 1 week. One case developed increased retinal detachment. In Group 1, there were significantly more cases of subretinal bleeding (P < 0.01). The severity of intraoperative and postoperative bleeding was significantly lower in Group 1. The blood reabsorption time was 11.1 ± 6.3 days in Group 1 and 34.8 ± 12.0 days in Group 2 (P < 0.01). One case in Group 1 and 2 cases in Group 2 had ultimate retinal detachment. Multiple regression analyses indicated bevacizumab significantly reduced intra- and postoperative bleeding. Conclusion: Bevacizumab may reduce intra- and postoperative hemorrhage in diabetic vitrectomy with silicone oil infusion. Increased subretinal bleeding are potential complications.

Photodynamic Therapy With or Without Intravitreal Bevacizumab for Polypoidal Choroidal Vasculopathy: Two Years of Follow-Up

PURPOSE To compare the long-term results of the efficacy of photodynamic therapy (PDT) with or without intravitreal bevacizumab (IVB) injections for polypoidal choroidal vasculopathy. DESIGN Retrospective, comparative, interventional case series. METHODS We included 69 eyes of 69 patients with macula-involved polypoidal choroidal vasculopathy. All patients were followed up for more than 2 years. We compared the treatment outcomes between groups and investigated the factors influencing visual improvement at 24 months of follow-up. RESULTS Thirty-six patients received PDT combined with IVB and 33 patients received PDT monotherapy. At 3 months, the mean logarithm of minimal angle of resolution (logMAR) best-corrected visual acuity (BCVA) improved from 0.73 to 0.53 in the combined therapy group (P < .001) and from 0.79 to 0.72 in the PDT monotherapy group (P = .02), with a significant difference in treatment efficacy between the 2 groups (P < .001). However, the improvements in BCVA were not statistically significant after 21 months in the combined therapy group and 15 months in the monotherapy group. The difference in treatment efficacy between the 2 groups was not significant after 6 months. Initial BCVA (P = .005), lesion size (P = .011), patient age (P = .018), and location of polyps (P = .006) significantly predicted the final visual outcome rather than treatment modality (P = .243). CONCLUSIONS PDT combined with IVB for symptomatic PCV was temporarily superior to PDT monotherapy, and the treatment efficacy decreased with time. Initial BCVA, lesion size, and location were more significant than treatment modality as the factors influencing final visual improvement.

White Light–Emitting Diodes (LEDs) at Domestic Lighting Levels and Retinal Injury in a Rat Model

Background: Light-emitting diodes (LEDs) deliver higher levels of blue light to the retina than do conventional domestic light sources. Chronic exposure to high-intensity light (2,000–10,000 lux) has previously been found to result in light-induced retinal injury, but chronic exposure to relatively low-intensity (750 lux) light has not been previously assessed with LEDs in a rodent model. Objective: We examined LED-induced retinal neuronal cell damage in the Sprague-Dawley rat using functional, histological, and biochemical measurements. Methods: We used blue LEDs (460 nm) and full-spectrum white LEDs, coupled with matching compact fluorescent lights, for exposures. Pathological examinations included electroretinogram, hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), and transmission electron microscopy (TEM). We also measured free radical production in the retina to determine the oxidative stress level. Results: H&E staining and TEM revealed apoptosis and necrosis of photoreceptors, which indicated blue-light induced photochemical injury of the retina. Free radical production in the retina was increased in LED-exposed groups. IHC staining demonstrated that oxidative stress was associated with retinal injury. Although we found serious retinal light injury in LED groups, the compact fluorescent lamp (CFL) groups showed moderate to mild injury. Conclusion: Our results raise questions about adverse effects on the retina from chronic exposure to LED light compared with other light sources that have less blue light. Thus, we suggest a precautionary approach with regard to the use of blue-rich “white” LEDs for general lighting. Citation: Shang YM, Wang GS, Sliney D, Yang CH, Lee LL. 2014. White light–emitting diodes (LEDs) at domestic lighting levels and retinal injury in a rat model. Environ Health Perspect 122:269–276; http://dx.doi.org/10.1289/ehp.1307294

Intravitreal bevacizumab and panretinal photocoagulation for proliferative diabetic retinopathy associated with vitreous hemorrhage.

Purpose: To evaluate the efficacy of intravitreal bevacizumab with panretinal photocoagulation (PRP) in the treatment of proliferate diabetic retinopathy (PDR) with vitreous hemorrhage (VH). Methods: Forty cases (40 patients) with PDR and persistent VH were prospectively enrolled, with a follow-up period of 12 months or more. Intravitreal bevacizumab injection (1.25 mg) was given, followed by PRP when visualization of peripheral fundus could be obtained. A second injection was administered 4 weeks to 6 weeks after the first injection if no signs of VH decrease were noted. Vitrectomy was performed if VH persisted >12 weeks. The vitreous clear-up time (VCUT) and the rate of vitrectomy were compared with those in a historical control group (40 eyes in 40 patients) who were treated with conventional methods. Results: Thirty-one eyes had 1 injection and 9 eyes (22.5%) received 2 injections. Vitreous clear-up time in the study and control groups were 11.9 ± 9.5 weeks and 18.1 ± 12.7 weeks (P = 0.02), respectively. Rates of required vitrectomy were 10% in the study group and 45% in the control group (P = 0.01). Conclusion: One or 2 intravitreal injections of 1.25 mg bevacizumab with PRP are associated with rapid regression of VH and may reduce the need for vitrectomy.

Cyr61 induces the expression of monocyte chemoattractant protein-1 via the integrin ανβ3, FAK, PI3K/Akt, and NF-κB pathways in retinal vascular endothelial cells.

Diabetes causes a number of metabolic and physiological abnormalities in the retina. Many of the molecular and physiological abnormalities that develop during diabetic retinopathy are due to inflammation. Monocyte chemoattractant protein-1 (MCP-1) is an important factor involved in diabetic retinopathy. In a previous study, we found that cysteine-rich 61 (Cyr61), an important angiogenic factor, also plays an important role in diabetic retinopathy. In addition to the direct effects of Cyr61, we observed that Cyr61 can induce the expression of MCP-1. However, the mechanism through which this occurs is not completely understood in chorioretinal vascular endothelial cells. We therefore investigated the effects of Cyr61 on MCP-1 expression in this cell type. Cyr61 stimulated the expression of MCP-1 at the mRNA, protein, and secreted protein levels in a dose-dependent and time-dependent manner. Both total MCP-1 levels and secreted MCP-1 levels were attenuated during the response to Cyr61 stimulation by pretreatment with integrin ανβ3-blocking antibodies, a FAK inhibitor (PF573228), a PI3K inhibitor (LY294002), and an Akt inhibitor (A6730). Electrophoretic mobility shift assays revealed that the above inhibitors suppressed the activation of NF-κB. Additionally, deletion of the NF-κB-binding element in the MCP-1 gene promoter led to a decrease in expression in luciferase reporter assays. These results show that the induction of MCP-1 by Cyr61 is mediated through the activation of the integrin ανβ3, FAK, PI3K/Akt, and IKK/NF-κB pathways in chorioretinal vascular endothelial cells.

Cysteine-rich 61, a member of the CCN family, as a factor involved in the pathogenesis of proliferative diabetic retinopathy.

PURPOSE Cysteine-rich 61 (Cyr61/CCN1) is reported to mediate angiogenesis. In this study, its role in ocular angiogenesis and proliferative diabetic retinopathy (PDR) was investigated. METHODS The effects of Cyr61 were evaluated by determining proliferation and chemotaxis and in an assay of capillary tube formation in synthetic matrix by chorioretinal endothelial cells (RF/6A). In the same cells, Cyr61 expression under hypoxic conditions was then investigated. Interactions between Cyr61 and vascular endothelial growth factor (VEGF) were examined using endothelial cell chemotaxis, tube-formation assay, and cross-stimulation assay. A mouse model of oxygen-induced retinopathy (OIR) and a rat model of streptozocin-induced diabetes were used to evaluate Cyr61 expression in the retina. Cyr61 levels were also measured and chemotactic effects were evaluated in vitreous samples from patients with PDR. RESULTS Cyr61 significantly induced proliferation, migration, and synthetic matrix tube formation of RF/6A cells. Hypoxia significantly induced Cyr61 mRNA and protein expression. Cyr61 induced expression of VEGF and vice versa. Anti-Cyr61 or anti-VEGF could inhibit the effects of both Cyr61 and VEGF. Intravitreal injection of anti-Cyr61 antibody significantly inhibited retinal neovascularization in the mouse OIR model. Cyr61 mRNA and protein were significantly expressed in the retina of streptozocin-induced diabetic rats. Vitreous levels of Cyr61 were elevated in patients with PDR when compared with nondiabetic patients. CONCLUSIONS Cyr61 acts as an angiogenic mediator of ocular neovascularization in vitro and in vivo. It may interact with VEGF in a synergetic manner. Vitreous levels of Cyr61 are elevated in PDR, and it may play an important role in the diseases pathogenesis.

Overexpression of integrin α6 and β4 enhances adhesion and proliferation of human retinal pigment epithelial cells on layers of porcine Bruch's membrane

Transplantation of retinal pigment epithelium (RPE) following removal of choroidal neovascular membranes has been attempted in patients with age-related macular degeneration (AMD). However, inability of transplanted RPE to initially attach and subsequently proliferate on Bruchs membrane may lead to failure of RPE transplants and poor visual outcomes. Integrin alpha(6)beta(4) functions as a receptor for laminin, the major component of Bruchs membrane, and mediates the stable attachment of most epithelial cells to the underlying basement membrane. To improve adhesion and proliferation of transplanted RPE on Bruchs membrane, we elucidated the roles of integrin alpha(6)beta(4) in RPE adhesion to extracellular matrix and investigated whether ex vivo gene transfer of integrin alpha(6) and beta(4) in RPE could promote adhesion and proliferation of transplanted RPE on Bruchs membrane. The expression of integrin alpha(6) and beta(4) mRNA and surface protein in ARPE-19 cells was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometric analysis. We generated point mutation in the ligand binding domain of integrin alpha(6) and beta(4) by using site-directed mutagenesis and transfected these mutated constructs into ARPE-19 cells. Adhesion assay was used to determine the roles of integrin alpha(6) and beta(4) in RPE adhesion to extracellular matrix. In addition, we transfected full-length alpha(6) cDNA or beta(4) cDNA into ARPE-19 cells. The reattachment and proliferation ratios of alpha(6)-cDNA- or beta(4)-cDNA-transfected ARPE-19 cells on different layers of Bruchs membrane were determined by cell adhesion and proliferation assays. Cell morphology and surface coverage were evaluated by scanning electron microscopy 7 days after plating on various layers of Bruchs membrane. We found that integrin alpha(6) and beta(4) mRNA and proteins were constitutively expressed in ARPE-19 cells. Decreased endogenous integrin alpha(6) and beta(4) expression by selective mutation of amino acid residues caused a significant reduction in adhesion of ARPE-19 cells to laminin 5. Modification of integrin expression by transfection of alpha(6) cDNA into ARPE-19 cells induced a significant increase in cell adhesion to laminin 5, fibronectin, whereas transfection with beta(4) cDNA caused increased adhesion only to laminin 5. alpha(6)-cDNA-transfectants increased cell attachment and proliferation on all layers of Bruchs membrane, whereas beta(4)-cDNA-transfectants enhanced adhesion and proliferation on basal lamina and inner collagenous layers. These data indicate that integrin alpha(6) and beta(4) play a role in adhesion of ARPE-19 cells to extracellular matrix. Modification of integrin expression by ex vivo genetic manipulation in RPE might be an alternative strategy to increase the success of RPE transplantation.

Characteristics of primary rhegmatogenous retinal detachment in Taiwan

PurposeTo investigate the epidemiological characteristics and related risk factors for primary rhegmatogenous retinal detachment (RRD) in Taiwan.MethodsThe case–control study was based on retrospective chart review of hospital patients treated for primary RRD from 1995 to 2001, inclusively. The preoperative fundus findings and refractive status were collected for each patient. Controls were selected from a nationwide survey of visual impairment in the adult population during the same period. Risk factors for RRD were analysed by logistic regression. A total of 1032 RRD cases and 3537 controls were enrolled for the study.ResultsA pronounced bipeak pattern was evident in the age distribution for primary RRD in the third and sixth decades of life. Atrophic hole with lattice degeneration was preferential to younger (20–30 years) and highly myopic individuals (−7.4±5 D), whereas the flap tear tended to occur in middle-aged individuals (50–60 years) and those with moderate myopia (−4.1±5 D). The odds ratio for primary RRD with myopia, male gender, and older age (>40 years) were 1.33/D, 2.15, and 1.69, respectively.ConclusionsMyopia is an important RRD risk factor for young Taiwanese. The increasing prevalence of myopia has predisposed the young population to RRD.

Anti-Inflammatory Effect of the Proteasome Inhibitor Bortezomib on Endotoxin-Induced Uveitis in Rats

PURPOSE We evaluated the anti-inflammatory effect of bortezomib (Velcade), a proteasome inhibitor, on endotoxin-induced uveitis (EIU) in rats and lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. METHODS EIU was induced by footpad injection of LPS into Lewis rats. MG-132 (10 mg/kg), or high-dose (0.2 mg/kg) or low-dose (0.05 mg/kg) bortezomib was given 30 minutes before LPS injection in each treatment group. The rats were sacrificed 24 hours later to observe the inflammatory response in tissues. The expression levels of fractalkine, MCP-1, ICAM-1, and iNOS were evaluated by PCR and Western blot analysis. Immunohistochemical (IHC) studies were used to demonstrate the expression of pro-inflammatory mediators and nuclear factor-kappa B (NF-κB) p65 in the iris and ciliary body. The DNA-binding activity of NF-κB was evaluated using an electrophoretic mobility shift assay (EMSA). An in vitro study using RAW 264.7 cells was performed to verify the results. RESULTS Pretreatment with high-dose bortezomib significantly attenuated the inflammatory response of EIU. Reduced expression of inflammatory mediators always was observed in the high-dose bortezomib and MG-132 groups, but invariably was not noted in the low-dose bortezomib group. Decreased DNA-binding activity of NF-κB was noted in those rats pretreated with high-dose bortezomib or MG-132. In vitro study demonstrated the dose-dependent anti-inflammatory effects of bortezomib in LPS-stimulated RAW cells, consistent with the results obtained in vivo. CONCLUSIONS Bortezomib inhibits EIU, probably by inhibiting the activation of NF-κB, which in turn, down-regulates the expression of the associated inflammatory genes. Proteasome inhibition may be a potential treatment strategy for uveitis.