Masahiko Sugimoto

Macular thickness measurements in healthy subjects with different axial lengths using optical coherence tomography.

Purpose To evaluate the retinal thickness of the macula in healthy subjects with different axial lengths. Methods Included were 203 healthy subjects (116 males and 87 females). The axial length of the eyes ranged from 22.68 to 30.22 mm. Four optical coherence tomograms were obtained in a radial spoke pattern centered on the central fovea. Retinal thickness was calculated from the inner and outer retinal boundaries. The average retinal thickness in three circular areas surrounding the central fovea (350, 1,850, and 2,850 &mgr;m in diameter) was determined. Results The retinal thickness in the three circular areas was not significantly correlated with the axial length of the eye (P = 0.10, P = 0.39, and P = 0.12). There also was no statistically significant difference found between the average thickness in emmetropic and low myopic, mildly myopic, and highly myopic eyes in the three circular areas (P = 0.35, P = 0.38, and P = 0.14). Conclusion When eyes with pathologic myopia were excluded, the axial length of the eye was found not to influence the average retinal thickness in the macular area.

The keratin-binding protein Albatross regulates polarization of epithelial cells

The keratin intermediate filament network is abundant in epithelial cells, but its function in the establishment and maintenance of cell polarity is unclear. Here, we show that Albatross complexes with Par3 to regulate formation of the apical junctional complex (AJC) and maintain lateral membrane identity. In nonpolarized epithelial cells, Albatross localizes with keratin filaments, whereas in polarized epithelial cells, Albatross is primarily localized in the vicinity of the AJC. Knockdown of Albatross in polarized cells causes a disappearance of key components of the AJC at cell–cell borders and keratin filament reorganization. Lateral proteins E-cadherin and desmoglein 2 were mislocalized even on the apical side. Although Albatross promotes localization of Par3 to the AJC, Par3 and ezrin are still retained at the apical surface in Albatross knockdown cells, which retain intact microvilli. Analysis of keratin-deficient epithelial cells revealed that keratins are required to stabilize the Albatross protein, thus promoting the formation of AJC. We propose that keratins and the keratin-binding protein Albatross are important for epithelial cell polarization.

Quantitative analysis of eyelash lengthening following topical latanoprost therapy.

BACKGROUNDnThere have been several reports, mostly qualitative, of ocular side effects of latanoprost, including lengthening of eyelashes. We investigated changes in eyelash length in patients receiving topically administered latanoprost.nnnMETHODSnSeventeen patients (11 men and 6 women aged 63 to 80 years) with glaucoma or ocular hypertension were treated with latanoprost (one drop to one eye daily at bedtime). All had dark brown irises. At the start of treatment and after 2, 6 and 10 weeks of treatment, a single eyelash was removed from the centre of the upper eyelid of the treated and fellow (control) eyes and measured. Adverse events (defined as any undesirable event occurring in a subject, regardless of whether it was considered related to the latanoprost treatment) were monitored carefully. At each examination patients were asked whether they had any ocular or systemic symptoms.nnnRESULTSnFor the eyes treated with latanoprost, the mean eyelash length (and standard deviation) was 5.8 mm (0.7 mm) at baseline, 6.5 mm (0.6 mm) at 2 weeks, 6.5 mm (0.9 mm) at 6 weeks and 6.6 mm (0.7 mm) at 10 weeks (p < 0.001 for all differences from baseline). The corresponding values for the untreated eyes were 5.7 mm (0.7 mm), 5.8 mm (0.7 mm), 5.9 mm (0.7 mm) and 5.6 mm (0.7 mm); all differences were nonsignificant.nnnINTERPRETATIONnLatanoprost significantly increases eyelash length.

Inhibition of EGF signaling protects the diabetic retina from insulin-induced vascular leakage.

Diabetes mellitus is a disease with considerable morbidity and mortality worldwide. Breakdown of the blood-retinal barrier and leakage from the retinal vasculature leads to diabetic macular edema, an important cause of vision loss in patients with diabetes. Although epidemiologic studies and randomized clinical trials suggest that glycemic control plays a major role in the development of vascular complications of diabetes, insulin therapies for control of glucose metabolism cannot prevent long-term retinal complications. The phenomenon of temporary paradoxical worsening of diabetic macular edema after insulin treatment has been observed in a number of studies. In prospective studies on non-insulin-dependent (type 2) diabetes mellitus patients, a change in treatment from oral drugs to insulin was often associated with a significant increased risk of retinopathy progression and visual impairment. Although insulin therapies are critical for regulation of the metabolic disease, their role in the retina is controversial. In this study with diabetic mice, insulin treatment resulted in increased vascular leakage apparently mediated by betacellulin and signaling via the epidermal growth factor (EGF) receptor. In addition, treatment with EGF receptor inhibitors reduced retinal vascular leakage in diabetic mice on insulin. These findings provide unique insight into the role of insulin signaling in mediating retinal effects in diabetes and open new avenues for therapeutics to treat the retinal complications of diabetes mellitus.

Increased Neovascularization in Mice Lacking Tissue Inhibitor of Metalloproteinases-3

PURPOSEnTissue inhibitor of metalloproteinases-3 (TIMP-3) is a matrix-bound inhibitor of matrix metalloproteinases (MMPs). The authors have previously determined a novel function of TIMP-3 to inhibit vascular endothelial growth factor (VEGF)-mediated angiogenesis. Here, the authors examined the in vivo angiogenic phenotype of ocular vessels in mice deficient in TIMP-3.nnnMETHODSnVEGF-mediated corneal neovascularization and laser-induced choroidal neovascularization (CNV) were examined in TIMP-3-null mice. The effects of the absence of TIMP-3 on the phosphorylation status of the VEGF-receptor-2 (VEGFR-2) and the downstream signaling pathways were evaluated biochemically. In addition, the activation state of MMPs in the retina of TIMP-3-deficient mice was examined by in situ zymography.nnnRESULTSnThe results of these studies determine an accentuation of pathologic VEGF-mediated angiogenesis in the cornea and laser-induced CNV in mice lacking TIMP-3. In the absence of the MMP inhibitor, pathophysiological changes were observed in the choroidal vasculature concomitantly with an increase in gelatinolytic activity. These results suggest that an imbalance of extracellular matrix homeostasis, together with a loss of an angiogenesis inhibitor, can prime vascular beds to be more responsive to an angiogenic stimulus.nnnCONCLUSIONSnIn light of the recent studies suggesting that genetic variants near TIMP-3 influence susceptibility to age-related macular degeneration, these results imply that TIMP-3 may regulate the development of the choroidal vasculature and is a likely contributor to increased susceptibility to choroidal neovascularization.

Betacellulin Induces Increased Retinal Vascular Permeability in Mice

Background Diabetic maculopathy, the leading cause of vision loss in patients with type 2 diabetes, is characterized by hyper-permeability of retinal blood vessels with subsequent formation of macular edema and hard exudates. The degree of hyperglycemia and duration of diabetes have been suggested to be good predictors of retinal complications. Intervention studies have determined that while intensive treatment of diabetes reduced the development of proliferative diabetic retinopathy it was associated with a two to three-fold increased risk of severe hypoglycemia. Thus we hypothesized the need to identify downstream glycemic targets, which induce retinal vascular permeability that could be targeted therapeutically without the additional risks associated with intensive treatment of the hyperglycemia. Betacellulin is a 32 kD member of the epidermal growth factor family with mitogenic properties for the retinal pigment epithelial cells. This led us to hypothesize a role for betacellulin in the retinal vascular complications associated with diabetes. Methods and Findings In this study, using a mouse model of diabetes, we demonstrate that diabetic mice have accentuated retinal vascular permeability with a concomitant increased expression of a cleaved soluble form of betacellulin (s-Btc) in the retina. Intravitreal injection of soluble betacellulin induced retinal vascular permeability in normoglycemic and hyperglycemic mice. Western blot analysis of retinas from patients with diabetic retinopathy showed an increase in the active soluble form of betacellulin. In addition, an increase in the levels of A disintegrin and metalloproteinase (ADAM)-10 which plays a role in the cleavage of betacellulin was seen in the retinas of diabetic mice and humans. Conclusions These results suggest that excessive amounts of betacellulin in the retina may contribute to the pathogenesis of diabetic macular edema.

Retinal Nerve Fiber Layer Decrease during Glycemic Control in Type 2 Diabetes.

Purpose. To assess an effect of glycemic control on retinal nerve fiber layer (RNFL) in type 2 diabetes mellitus. Methods. Thirty-eight eyes of 38 patients with type 2 diabetes undergoing blood glucose regulation were enrolled. All patients were examined at (1) initial visit, (2) 1 month, (3) 2 months, and (4) 4-month after the initial examination. On each occasion, glycosylated hemoglobin (HbA1c) levels and optical coherence tomography (OCT) scanning for RNFL thickness were evaluated. 360 degree circular OCT scans with a diameter of 3.4u2009mm centered on the optic disc were performed. Results. Significant RNFL decrease was seen in the superior area between initial and 4 months examination (P = .043). The relationship between the changes in HbA1c and the changes in RNFL thickness was observed in superior, temporal, and inferior area (P < .05) at 4 months. Conclusions. This study suggests that the glycemic control affects RNFL within 4 months.

Screening for diabetic retinopathy using new mydriasis-free, full-field flicker ERG recording device

Diabetic retinopathy (DR) is a leading cause of blindness among working-age adults. Therefore, it is important to detect DR accurately during mass screening. The purpose of this study was to determine whether a small, hand-held, mydriasis-free, full-field flicker electroretinographic (ERGs) device called RETeval can be used to screen for DR. To accomplish this, we recorded full-field flicker ERGs with this device from 48 normal eyes and 118 eyes with different severities of DR in patients with diabetes mellitus (DM). This system delivered a constant flash retinal luminance by adjusting the flash luminance that compensated for changes in the pupil size. Our results showed that there were significant correlations between the severity of DR and the implicit times (Pu2009<u20090.001; ru2009=u20090.55) and the amplitudes (Pu2009=u20090.001; ru2009=u2009−0.29). When the implicit time was used for the index, the area under the receiver operating characteristic curve was 0.84 for the detection of DR, and was 0.89 for the detection of DR requiring ophthalmic treatments. These results suggest that the implicit times of the flicker ERGs recorded by the small, mydryasis-free ERG system can be used as an adjunctive tool to screen for DR.

Effect of topical rebamipide on conjunctival goblet cell recovery after vitrectomy.

In vitro and in vivo experiments have shown that topical rebamipide will increase the number of goblet cells in the bulbar conjunctiva. The purpose of this study was to determine whether topical rebamipide will enhance the recovery of conjunctival goblet cells that were damaged during vitrectomy. Forty patients who underwent vitrectomy surgery were studied. The 40 patients consisted of 20 with diabetes mellitus (DM) and 20 patients without DM. They were randomized in a 1:1 ratio into groups that were treated or not treated with topical 2% rebamipide after the surgery. Impression cytology was performed at the end of surgery and at 14 days after the surgery. The mean goblet cell density of each specimen was determined by averaging the total number of goblet cells obtained from three consecutive high magnification microscopic images. In patients without DM, the mean goblet cell density at 14 days after the vitrectomy was significantly higher in eyes with topical rebemipide than in eyes without rebemipide (Pu2009<u20090.01). In patients with DM, a similar tendency was observed but the difference was not significant (Pu2009=u20090.09). These results suggest that topical rebamipide can be helpful in patients with globlet cell damage that occur during and after vitrectomy.

Ultrasound biomicroscopy for membranous congenital cataract.

376 CAN J OPHTHALMOL—VOL. 43, NO. 3, 2008 thalmic arterial occlusions in children younger than 12 years old.4,5,6 The first describes the case of an 11-yearold girl with unilateral visual field loss due to a branch retinal artery occlusion in the right eye and no underlying cause found after extensive investigations.4 The second describes the case of a 7-year-old girl with spontaneous occlusion of the right ophthalmic artery and a negative systemic work-up.5 The third describes the case of an 8-yearold boy with a CRAO and no definite etiology, but a 4-day history of flu-like symptoms led the authors to attribute the pathology to a postviral vasculitis.6 In our instance, we hypothesize that the prolonged retinal occlusion led to both macular and disc edema, resulting in severe ischemic damage. Though retinal arterial obstruction is rare in children, our case highlights the importance of including this in the differential diagnosis of acute vision loss.