Kenichi Kimoto

Retinal circulatory disturbances following intracameral injection of bevacizumab for neovascular glaucoma.

acizumab injection affected the outcome in this case (TCVOS 1997). This is because ischaemic CRVO occurred 3 weeks after the injection, when bevacizumab has its peak effect and relatively good initial visual acuity and perfusion status. There were no other patient factors that might cause the ischaemic conversion of CRVO except diabetes. The causes and mechanisms of treatment failure associated with bevacizumab administration must be elucidated further in vitro and by clinical studies. Furthermore, the possibility that bevacizumab has a negative long-term effect on collateral vessel formation because of its anti-VEGF action requires investigation.

Anti-VEGF Agents for Ocular Angiogenesis and Vascular Permeability.

We review articles describing intravitreal injection of anti-VEGF drug trials, while discussing the mechanisms of the action of anti-VEGF antibodies, and also evaluating their outcomes. Intraocular injections of anti-VEGF drug are considered to be an effective treatment for macular edema after retinal vein occlusion, however, recurrent/persistent edema is common. The recent reports may lead to a shift in treatment paradigm for DME, from laser photocoagulation, to newer approaches using anti-VEGF drugs. There have been several well-publicized prospective, randomized studies that demonstrated the efficacy of intravitreal injection of anti-VEGF drugs for patients with AMD. Adjuvant bevacizumab for neovascular glaucoma may prevent further PAS formation, and it is likely to open up a therapeutic window for a panretinal photocoagulation and trabeculectomy. Intravitreal injection of bevacizumab (IVB) results in a substantial decrease in bleeding from the retinal vessels or new vessels during a standard vitrectomy. IVB has also been reported to be effective for inducing the regression of new vessels in proliferative diabetic retinopathy. The use of bevacizumab in stage 4 or 5 retinopahty of permaturity (ROP) is to reduce the plus sign to help reduce hemorrhage during the subsequent vitrectomy. Some authors reported cases of resolution of stage 4 A ROP after bevacizumab injection.

The PI3K/Akt pathway mediates the expression of type I collagen induced by TGF-β2 in human retinal pigment epithelial cells.

PurposeTransforming growth factor (TGF)-β is a key mediator of proliferative vitreoretinopathy, but the cellular mechanisms by which TGF-β induces extracellular matrix protein (ECM) synthesis are not fully understood. This study examined whether the PI3K/Akt pathway is involved in TGF-β2-induced collagen expression in human retinal pigment epithelial cells.MethodsHuman retinal pigment epithelial cells ARPE-19 were cultured and stimulated with TGF-β2. The role of the PI3K/Akt pathway was evaluated using the biochemical inhibitor, wortmannin. The effect of wortmannin on the expression of type I collagen mRNA (COL1A1, COL1A2) induced by TGF-β2 was evaluated by real-time RT-PCR. The effect of wortmannin on the synthesis of type I collagen induced by TGF-β2 was assessed by an immunocytochemical analysis with anti-type I collagen antibody. Luciferase reporter assays were performed to examine the effect of wortmannin on the transcriptional activities of COL1A2. A luciferase assay using a mutation construct of the Smad binding site in COL1A2 promoter (Smad-mut/Luc) was also performed to examine the crosstalk between the Smad pathway and the PI3K/Akt pathway. The effects of wortmannin on the transcriptional activity of Smad3 were also examined using CAGA12-Luc. Moreover, the effect of wortmannin on TGF-β2-induced Smad7 mRNA expression was evaluated.ResultsThe biochemical blockade of PI3K/Akt activation inhibited TGF-β2-induced type I collagen mRNA expression and type I collagen synthesis. The blockade of PI3K/Akt pathway inhibited the increase in COL1A2 promoter activities when induced by TGF-β2 and reduced TGF-β2 induction of Smad-mut/Luc promoter activity and CAGA12-Luc activity. Moreover, wortmannin increased the TGF-β2-induced Smad7 mRNA expression levels.ConclusionsThe PI3K/Akt pathway plays a role in relaying the TGF-β2 signal to induce type I collagen synthesis in the retinal pigment epithelium through Smad-dependent and Smad-independent pathways.

Diagnosis of an isolated retinal astrocytic hamartoma aided by optical coherence tomography

girl was referred for evaluation of a retinal tumour in her left eye. Her visual acuity was 20 ⁄ 20 bilaterally. A solitary translucent retinal tumour measuring 1.5 · 3.0 disc diameters was seen inferior to the optic disc (Fig. 1A). The retinal arteries passing through the tumour appeared white. The sensitivity over the tumour was not altered in Humphrey visual field tests (Fig. 1B). Fluorescein fundus angiography (FA) showed retinal circulation to be intact with only weak staining of a section of the tumour (Fig. 1C,D). An ultrasound B-mode echography showed a mass inferior to the optic disc; no calcifications were observed (Fig. 1E). The fundus was scanned with optical coherence tomography (OCT) (3D OCT-1000; Topcon, Tokyo, Japan). The measurement beam was focused on the macular area with a system

p38 MAP kinase inhibitor suppresses transforming growth factor-β2-induced type 1 collagen production in trabecular meshwork cells.

Glaucoma is an age-related neurodegenerative disease of retinal ganglion cells, and appropriate turnover of the extracellular matrix in the trabecular meshwork is important in its pathology. Here, we report the effects of Rho-associated kinase (ROCK) and p38 MAP kinase on transforming growth factor (TGF)-β2–induced type I collagen production in human trabecular meshwork cells. TGF-β2 increased RhoA activity, actin polymerization, and myosin light chain 2 phosphorylation. These effects were significantly inhibited by Y-27632, but not SB203580. TGF-β2 also increased promoter activity, mRNA synthesis, and protein expression of COL1A2. These effects were significantly inhibited by SB203580, but not Y-27632. Additionally, Y-27632 did not significantly inhibit TGF-β2–induced promoter activation, or phosphorylation or nuclear translocation of Smad2/3, whereas SB203580 partially suppressed these processes. Collectively, TGF-β2–induced production of type 1 collagen is suppressed by p38 inhibition and accompanied by partial inactivation of Smad2/3, in human trabecular meshwork cells.

Mitomycin C modulates the circadian oscillation of clock gene period 2 expression through attenuating the glucocorticoid signaling in mouse fibroblasts.

Clock gene regulates the circadian rhythm of various physiological functions. The expression of clock gene has been shown to be attenuated by certain drugs, resulting in a rhythm disorder. Mitomycin C (MMC) is often used in combination with ophthalmic surgery, especially in trabeculectomy, a glaucoma surgical procedure. The purpose of this study was to investigate the influence of MMC on clock gene expression in fibroblasts, the target cells of MMC. Following MMC treatment, Bmal1 mRNA levels was significantly decreased, whereas Dbp, Per1, and Rev-erbα mRNA levels were significantly increased in the mouse fibroblast cell line NIH3T3 cells. Microarray analysis was performed to explore of the gene(s) responsible for MMC-induced alteration of clock gene expression, and identified Nr3c1 gene encoding glucocorticoid receptor (GR) as a candidate. MMC suppressed the induction of Per1 mRNA by dexamethasone (DEX), ligand of GR, in NIH3T3 cells. MMC also modulated the DEX-driven circadian oscillations of Per2::Luciferase bioluminescence in mouse-derived ocular fibroblasts. Our results demonstrate a previously unknown effect of MMC in GR signaling and the circadian clock system. The present findings suggest that MMC combined with trabeculectomy could increase the risk for a local circadian rhythm-disorder at the ocular surface.

Two Cases of Endogenous Endophthalmitis Caused by Gram-Positive Bacteria with Good Visual Outcome

Background: Endogenous endophthalmitis is a rare disease and its visual prognosis is poor. Case Reports: We present two patients, a 60-year-old man and a 53-year-old man, who developed endogenous endophthalmitis caused byGram-positive organismsbut recovered good vision after antibiotics and vitrectomy. Results: The first patient complained of ocular pain and visual decrease in his right eye. Ophthalmoscopy showed inflammation in the anterior chamber and vitreous opacities. Antibiotic was administrated systemically, and blood culture detected Streptococcus anginosus. He underwent successful heart surgery for endocarditis and total dental extraction for severe gingivitis. Vitrectomy was performed 36 days after the onset and vision improved from 0.02 to 0.7. The second patient was referred for acute visual decrease in his left eye. Severe iritis and vitreous opacities were observed, and systemic examination showed acute pyelitis and prostatic abscesses. Blood cultures detected Staphylococcus sp., and systemic antibiotics were given. Vitrectomy was performed 12 days after the onset, and vision improved from 0.06 to 1.2. Conclusions: We conclude that the rapid treatment with systemic antibiotics for the organisms at the primary site, and the vitrectomy, even though delayed, can lead to a good recovery of vision.

One-Year Outcomes following Intravitreal Aflibercept for Polypoidal Choroidal Vasculopathy in Japanese Patients: The APOLLO Study

Purpose: To evaluate 1-year outcomes of intravitreal injections of aflibercept (IVA) in Japanese polypoidal choroidal vasculopathy (PCV) patients. Methods: In this prospective, open-label, single-arm multicenter clinical trial, treatment-naïve PCV patients received IVA (2.0 mg) every 2 months, after 3 initial monthly doses. The primary endpoint assessed was the proportion of patients maintaining baseline best-corrected visual acuity (BCVA) at 1 year. Results: Fifty eyes with PCV were included in the study. BCVA was maintained or improved in 97.6% of the patients. Mean logMAR BCVA at baseline was 0.33, and had improved to 0.12 logMAR 1 year after the initiation of aflibercept treatment (p < 0.001). Mean central foveal thickness decreased from 356 to 239 μm (p < 0.001). Complete regression of polypoidal lesions was seen in 72.5% after 1 year of treatment. Conclusions: One year of IVA resulted in stabilization of BCVA and anatomical improvement in Japanese PCV patients.

Frosted branch angiitis associated with streptococcal infection: optical coherence tomography as a follow-up tool.

7-year-old boy presented withdecreased vision and conjuncti-vitis in both eyes. He had a flu-likeepisode with fever about 2 weeks ear-lier, and the skin of both palms hadpeeled off. His visual acuity (VA) was0.15 OD and 0.1 OS. Slit-lamp exami-nation showed conjunctival and ciliaryinjection, cells in the anterior cham-ber, flare and fine keratic precipitatesbilaterally. Ophthalmoscopy revealeddiffuse, white perivascular sheathingof the arteries and veins, tortuous anddilatated veins, scattered retinal haem-orrhages and papilloedema in botheyes (Fig. 1A). Fluorescein angiogra-phy demonstrated extensive dye leak-age from almost all vessels (Fig. 1B)and both optic discs were hyperfluo-rescent in the late phase. Indocyaninegreen angiography (ICGA) showed amottled background pattern, stainingof the vessels especially in the poster-ior pole, and hypofluorescence of thediscs with blurred margins (Fig. 1C).Optical coherence tomography (OCTModel 2000; Carl Zeiss Meditec, Inc.,Dublin, CA, USA) showed a clear ser-ous detachment and oedema in themacula (Fig. 1D, E). Goldmann peri-metry showed an enlarged blind spot.The amplitudes of the a- and b-wavesand the oscillatory potentials of theelectroretinograms (ERGs) elicited bya bright flash were significantlyreduced (Fig. 1F).Systemic examinations disclosed noabnormal findings except for high titresof anti-streptolysin O (ASO, 1830·)and anti-streptokinase (ASK, 5120·).From these findings, the subject wasdiagnosed with frosted branch angiitis(FBA). He was treated with topical0.1% betamethasone and 1.0% atro-pine along with i.v. prednisolone(580 mg⁄day) for 3 days and subse-quently oral prednisolone for 15 days(total 165 mg). Three days later, theaqueous inflammation and the peri-vascular sheathing were markedlyreduced. Thereafter, OCT and oph-thalmoscopy of the macular areashowed a resolution of the oedemafollowed by the appearance of a star-shaped figure (Fig. 1G, H). The sub-ject’s ERGs were markedly improvedbut were still not normal (Fig. 1I).The serous detachment (Fig. 1J, K)and finally exudates disappeared.Despite the rapid improvement inthe appearance of the retina, thepatient’s VA improved much moreslowly and attained 1.0 only after3 months. Fundus angiography at thattime demonstrated the complete reso-lution of all abnormal findings.The increase in the number of casesdiagnosed as FBA raises questionsabout whether this disorder representsa distinct clinical syndrome or merelya clinical sign of eyes with inflamma-tory conditions. From their descrip-tions in the literature, cases diagnosedas FBA are characterized by bilat-eral, perivascular retinal blood vesselsheathing, retinal haemorrhages andoedema of different degrees, panuveitisand papilloedema (Walker et al. 2004).Our case had diffuse angiitis involvingthe vessels of the macular and periph-eral retina and the choroid. Anterioruveitis and papilloedema were alsopresent. The abnormal ICGA findingssuggested that the choroid was alsoaltered, which probably accounts forthe decreased a-waves on ERG. Thereduced b-waves indicated alterationsto the inner retina. Whether thesefindings are also found in other chori-oretinal inflammatory diseases is yet tobe determined. The prevalence of FBAis reported to be higher in Asians thanin White populations (Walker et al.2004).Despite the marked panophthalmicinflammation, the eye responded wellto steroids. Our subject’s VA recov-ered to normal levels, but some FBAsubjects suffer a permanent loss ofvision caused by macular scarring(Kleiner et al. 1988; Walker et al.2004).

Optical coherence tomographic findings of vitreomacular traction syndrome with macular hole retinal detachment

We report on two patients with the vitreomacular traction (VMT) syndrome whose vitreoretinal interface had a unique morphology. Case 1 was a 70-year-old woman who was referred to treat a macular hole retinal detachment (MHRD) in her right eye. Her visual acuity was 0.2, and ophthalmoscopy detected a MHRD of approximately three disc diameters (Fig. 1). Her refractive error (spherical equivalent) was +4.25 dioptres and the axial length was 21.02 mm. Optical coherence tomography (OCT) showed a perifoveal vitreous detachment with focal vitreal adhesions to the fovea, an incomplete posterior vitreous detachment (PVD), and two low reflective lines in the vitreous cavity (Fig. 1). Vitrectomy was performed with phacoemulsification and implantation of an intraocular lens. After a complete PVD was created, the internal limiting membrane (ILM) in the area of the detached retina was peeled off (Fig. 1). The vitreous cavity was