Takeshi Iwase

Digoxin inhibits retinal ischemia-induced HIF-1α expression and ocular neovascularization

Digoxin and other cardiac glycosides in‐hibit hypoxia‐inducible factor‐1 (HIF‐1) transcriptional activity in cultured cells and suppress tumor xenograft growth. We tested the hypothesis that digoxin reduces HIF‐1 levels in ischemic tissue in vivo and suppresses neovascularization. Well‐established murine models of ocular neovascularization were used to test our hypothesis. In mice with ischemic retinopathy, intraocular or intraperitoneal injection of digoxin markedly reduced retinal levels of HIF‐1α protein and mRNAs encoding multiple hypoxia‐regulated proangiogenic proteins and their receptors. Daily intraperitoneal injection of 2 mg/kg starting at postnatal day (P) 12 or a single intravitreous injection of 100 ng of digoxin at P12 reduced retinal neovascularization by >70% at P17. Digoxin also reduced the number of CXCR4+ cells and F4/80+ macrophages in ischemic retina and significantly reduced choroidal neovascularization at Bruchs membrane rupture sites. Digoxin suppresses retinal and choroidal neovascularization by reducing HIF‐1α levels, which blocks several proangiogenic pathways. Since digoxin suppresses multiple pathways in addition to VEGF signaling, it may provide advantages over specific VEGF antagonists for treatment of patients with retinal and choroidal diseases complicated by neovascularization and/or excessive vascular permeability. It may also be useful for treatment of neovascular diseases in other tissues.—Yoshida, T., Zhang, H., Iwase, T., Shen, J., Semenza, G. L., Campochiaro, P. A. Digoxin inhibits retinal ischemia‐induced HIF‐1α expression and ocular neovascularization. FASEB J. 24, 1759–1767 (2010). www.fasebj.org

Overexpression of SOD in retina: need for increase in H2O2-detoxifying enzyme in same cellular compartment.

In retinitis pigmentosa (RP), various mutations cause rod photoreceptor cell death leading to increased oxygen levels in the outer retina, progressive oxidative damage to cones, and gradual loss of cone cell function. We have been exploring the potential of overexpressing components of the endogenous antioxidant defense system to preserve cone cell function in rd10(+/+) mice, a model of RP. rd10(+/+) mice deficient in superoxide dismutase 1 (SOD1) showed increased levels of superoxide radicals and carbonyl adducts (a marker of oxidative damage) in the retina and more rapid loss of cone function than rd10(+/+) mice with normal levels of SOD1. This suggests that SOD1 is an important component of the antioxidant defense system of cones, but increased expression of SOD1 in rd10(+/+) mice increased oxidative damage and accelerated the loss of cone function. Coexpression of SOD1 with glutathione peroxidase 4 (Gpx4), which like SOD1 is localized in the cytoplasm, but not with catalase targeted to the mitochondria, reduced oxidative damage in the retina and significantly slowed the loss of cone cell function in rd10(+/+) mice. Gene transfer resulting in increased expression of SOD2, but not coexpression of SOD2 and mitochondrial Gpx4, resulted in high levels of H(2)O(2) in the retina. These data suggest that to provide benefit in RP, overexpression of an SOD must be combined with expression of a peroxide-detoxifying enzyme in the same cellular compartment.

Constituents of bile, bilirubin and TUDCA, protect against oxidative stress-induced retinal degeneration

J. Neurochem. (2011) 116, 144–153.

Clear corneal vitrectomy combined with phacoemulsification and foldable intraocular lens implantation.

We have developed a technique for the treatment of cataract and epiretinal membrane using a 25‐gauge vitrectomy system through corneal ports.

Inherent possibility of refraction error for phacovitrectomy

In cases of coexistent cataract and macular diseases, smallincision phaco-emulsification with implantation of foldable intraocular lenses (IOLs) and pars plana vitrectomy (phacovitrectomy) has become a preferable procedure, resulting in better intraoperative visualization of the posterior segment and earlier visual rehabilitation. On the other hand, there is an inherent possibility of refraction error for phacovitrectomy surgery. There have been several reports regarding the postoperative refractive error in phacovitrectomy. However, those studies included additional procedures, including gas tamponade or several kinds of disease, indicating that those results could be affected by selection bias. It was postulated that the myopic shift with phacovitrectomy was secondary to anterior displacement of the IOL by the pressure of the gas used during vitrectomy. The postoperative macular thickness and change of macular thickness are different depending on retinal diseases. We wanted to determine a more precise and accurate way to achieve minimum refractive prediction error. Thus, we performed the same procedures only for epiretinal membrane (ERM) cases. This is the first report performing phacovitrectomy only for ERM without gas tamponade. The refractive results in 67 patients who had successful uneventful phacovitrectomy with IOL implantation in the capsule without fluid-gas exchange for cataract and ERM from June 2003 to May 2007 were retrospectively reviewed (Table 1). Fifty patients who underwent cataract surgery alone were the control. The preoperative clinical data obtained included age, macular thickness as measured by ocular coherence tomography, and ultrasound axial length (AXL). IOL power was calculated using the SRK/T formula.

Needle-assisted fixation with a necktie knot of one dislocated haptic of an intraocular lens

Capsular instability or the absence of intraocular lens (IOL) support can sometimes be repaired with a fi xation suture, applied either during or after surgery. Either one or both haptics of the IOL can be inserted into the vitreous cavity even after fi xation. There are many techniques for repairing complete IOL dislocation, including conventional IOL removal and fi xation. However, few useful techniques exist for the repair of only one dislocated haptic. In this case report, we introduce a new technique for fi xation of one dislocated haptic: needle-assisted fi xation with a necktie knot.