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Objective: To determine whether previous phacoemulsification adversely affects surgical prognosis of trabeculectomy with mitomycin for open-angle glaucoma., Methods: The study is a retrospective, consecutive, comparative case series. At 2 clinical centers, we reviewed 226 medical records of eyes with open-angle glaucoma undergoing initial trabeculectomy, including 175 phakic eyes (phakic group) and 51 pseudophakic eyes that had previously undergone phacoemulsification with superior conjunctival incision (pseudophakic group). Primary outcome was the probability of success after trabeculectomy. Surgical failure was defined as an additional glaucoma surgery or 1 of the following 3 criteria: intraocular pressure (IOP) of 21 mm Hg or greater (A); IOP of 18 mm Hg or greater (B); and IOP of 15 mm Hg or greater (C). Multivariable analysis was performed using the Cox proportional hazards model., Results: The mean follow-up period was 37.5 months. The probability of success for criteria A, B, and C at 1 and 3 years in the phakic vs the pseudophakic group was 97.8% and 92.6%, respectively, vs 78.6% and 65.1%, respectively, for criterion A (P < .001); 92.9% and 81.3%, respectively, vs 72.8% and 63.7%, respectively, for criterion B (P = .004); and 73.1% and 54.2%, respectively, vs 53.1% and 38.4%, respectively, for criterion C (P = .009). The multivariable model confirmed that pseudophakia independently contributes to surgical failure (criterion A relative risk, 4.59 [P < .001]; criterion B, 2.88 [P = .004]; and criterion C, 2.02 [P = .009]). The pseudophakic group required more postoperative laser suture lysis (P = .01)., Conclusion: Previous phacoemulsification is a prognostic factor for surgical failure of trabeculectomy with mitomycin for open-angle glaucoma.

Objective: To evaluate the long-term impact of liver transplantation on ocular manifestations of familial amyloid polyneuropathy (FAP) in Japanese patients., Methods: Medical records were retrospectively reviewed in a long-term follow-up study. Of 52 patients with FAP amyloidogenic transthyretin Val30Met, 22 patients underwent liver transplantation. We assessed ocular manifestations, including amyloid deposition at the pupillary border, pupillary border with irregularity, vitreous opacities, and glaucoma, in patients who underwent liver transplantation. In addition, we compared the clinical characteristics of vitreous opacities-the most common ocular manifestation of FAP-in patients who underwent liver transplantation and those who did not to determine the effect of transplantation on the progression of ocular amyloidosis., Results: Mean time after FAP onset was 10 years and after liver transplantation was 7 years in patients who underwent liver transplantation. All ocular manifestations increased with time after transplantation. Eight patients (36%) developed vitreous opacities and 4 patients (18%) developed glaucoma during follow-up. Mean time from FAP onset to vitreous opacities onset was significantly shorter in patients with early-onset disease who underwent liver transplantation than in those who did not., Conclusions: Patients with FAP who undergo liver transplantation continue to have a long-term risk of severe ocular manifestations, especially vitreous opacities and glaucoma, which can restrict their daily lives, even after liver transplantation.

Objective: To investigate the effects and safety of topical administration of an ophthalmic solution of a selective Rho-associated coiled coil-forming protein kinase (ROCK) inhibitor, SNJ-1656, 0.003% to 0.1%, in healthy male adult volunteers., Design: Randomized, double-masked, group-comparison, phase 1 clinical study. In the initial single-instillation trial, 45 healthy volunteers were randomly subdivided into 5 groups and treated with SNJ-1656 in concentrations of 0.003%, 0.01%, 0.03%, 0.05%, and 0.1% in stepwise fashion. In the repeated-instillation trial, 36 healthy volunteers were assigned to receive SNJ-1656 ophthalmic solution at the following concentrations and dosages: 0.05% once daily, 0.1% once daily, 0.05% twice daily, or 0.1% twice daily. In our studies, the administration of the solution and subsequent examinations (including intraocular pressure [IOP] measurements) were performed in a double-masked fashion., Results: After single instillation of placebo or SNJ-1656, in concentrations of 0.003%, 0.01%, 0.03%, 0.05%, and 0.1%, the changes in IOP from the baseline were -0.91, -1.18, -1.48, - 2.20 (P = .04 vs placebo), -1.48, and -1.98 mm Hg, respectively, at 2 hours, and -0.63,-0.95, -1.79, -2.26 (P = .01 vs placebo), -1.95, and -3.00 mm Hg (P < .001 vs placebo) respectively, at 4 hours. Significant IOP reductions after repeated instillation were also found. On slitlamp examination during the trial, there were no significant adverse findings except hyperemia of the bulbar and palpebral conjunctiva after instillation., Conclusion: This clinical study demonstrated that SNJ-1656 is a safe topical agent effective in reducing IOP in human eyes.

Objective: To elucidate long-term outcome of trabeculotomy in primary and secondary developmental glaucoma., Methods: One hundred forty-nine eyes of 89 patients with developmental glaucoma who underwent trabeculotomy were retrospectively studied. Intraocular pressure (IOP), success probabilities, visual acuities, and visual field were determined during follow-up and at the final visit., Results: The mean +/- SD IOP of 112 eyes with primary developmental glaucoma at the final visit with an mean +/- SD follow-up period of 9.5 +/- 7.1 years was 15.6 +/- 5.0 mm Hg. The average IOP for 37 eyes with secondary developmental glaucoma was 16.7 +/- 4.2 mm Hg. One hundred eyes (89.3%) with primary developmental glaucoma were defined as achieving success at the final visit. Complete and qualified successes were achieved in 71 eyes (63.4%) and 29 eyes (25.9%), respectively. Visual acuities were 20/40 or better in 78 (59.5%) of 131 eyes examined and were poorer than 20/200 in 32 eyes (24.4%). The causes of poor visual acuities were mainly progression of glaucoma, including delay of detection of onset or surgery and amblyopia. Eyes with glaucoma that existed before 2 months of age or eyes that needed several trabeculotomies were considered to have poor visual acuity. Visual fields were classified as normal or almost normal in 21 (44.7%) of 47 eyes., Conclusions: Trabeculotomy for developmental glaucoma is effective over a long time. There is a fairly good prognosis for visual function of eyes with developmental glaucoma with early detection of the onset, proper treatment, and proper management after trabeculotomy.

Objective: To elucidate the clinical features and surgical outcomes of the treatment of secondary glaucoma associated with transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP)., Design: Retrospective case study., Participants: Forty-nine Japanese patients with FAP., Methods: For all patients, measurement of best-corrected visual acuity, intraocular pressure, and visual fields as well as slitlamp and ocular fundus examinations were conducted and compared. In addition, the exact mutation of the amyloidogenic TTR variants was analyzed for all 49 patients with FAP. The TTR mutations included amyloidogenic TTR (ATTR) Val30Met in 41 patients, ATTR Tyr114Cys in 6, ATTR Ser50Ile in 1, and a compound heterozygous mutation of ATTR Val30Met + Arg104His in 1., Results: The onset of secondary glaucoma was defined as elevation of intraocular pressure and glaucomatous changes in visual field defects. Secondary glaucoma was detected in 12 (24%) of the 49 patients. The incidence of secondary glaucoma in patients with the Val30Met mutation (17%) was lower than for the other FAP genotypes (P =.02 using the chi(2) test). Of 20 glaucomatous eyes, amyloid deposition on the pupil and anterior surface of the lens was found in 18 eyes. Amyloid deposition was found prior to glaucoma in 11 eyes and at the first visit to our clinic in another 7 eyes. In the 11 eyes in which the onset of glaucoma occurred following amyloid deposition along the pupil, the mean +/- SD period between the onsets of pupillary amyloid deposition and glaucoma was 2.55 +/- 1.43 years (range, 0.2-4.0 years). Further statistical analyses revealed significant relationships between the onset of secondary glaucoma and both amyloid deposition (P<.001) and vitreous opacity (P<.001). Surgical treatment was required in 15 (75%) of the 20 glaucomatous eyes. In 9 (81%) of the 11 eyes that underwent trabeculectomy, the intraocular pressure was well controlled at or lower than 20 mm Hg during the follow-up period. In the eyes that underwent combined trabeculotomy and sinusotomy (2 eyes), nonpenetrating trabeculectomy (1 eye), or a cyclodestructive procedure (1 eye), the intraocular pressure was poorly controlled., Conclusions: Glaucoma is not a rare condition in patients with FAP, especially because liver transplantation now enables patients with FAP to live longer. Careful observation of amyloid deposition along the pupil allows the prediction of glaucoma onset.

Background: Retinal ishchemia-induced neuronal death is believed to be a direct causal process in the development of many ocular diseases. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, statin, is known to improve endothelial function in proinflammatory conditions., Objective: To investigate the effects of statin on leukocyte accumulation during ischemia-reperfusion injury and on subsequent retinal damage., Methods: Transient retinal ischemia was induced in Long-Evans rats for 60 minutes using temporal ligation of the optic nerve. Leukocyte-endothelial interactions in the postischemic retina were evaluated in vivo with a scanning laser ophthalmoscope. Statin was administered 5 minutes before the induction of retinal ischemia. P-selectin and intercellular adhesion molecule-1 (ICAM-1) gene expression in the postischemic retina were studied with the semiquantitative polymerase chain reaction. Histologic studies were carried out to evaluate retinal damage., Results: The preadministration of statin attenuated the rolling and accumulation of leukocytes, decreased P-selectin and ICAM-1 expression, and reduced the number of apoptotic cells in the retina. Furthermore, histologic evaluation 168 hours after reperfusion showed that statin significantly diminished the resultant retinal tissue damage. The neuroprotective effect of statin was abolished when it was administered along with a nitric oxide synthase inhibitor, nitroglycerine-nitro-L-arginine methyl ester., Conclusion: Statin may exert neuroprotective effects by inhibiting leukocyte-endothelial interaction through the release of nitric oxide from the endothelium., Clinical Relevance: As a result of its efficacy in preventing retinal neuronal death, statin may be developed into a novel therapeutic modality for many ocular ischemic diseases.

Objective: To elucidate the roles of protein kinase in regulating the intraocular pressure (IOP) and outflow facility in rabbit eyes., Materials and Methods: A protein kinase inhibitor, 1-(5-isoquinolinesulfonyl)-homopiperazine (HA1077), was used. The IOP and the outflow facility were measured before and after topical, intracameral, or intravitreal administration of HA1077 in rabbits. Western blot analysis was performed to detect the 20-kd light chain of myosin in human trabecular meshwork (TM) cells and bovine ciliary muscle (CM) tissues. The cell morphologic condition and distribution of actin filaments and vinculin in TM cells were studied using cell biology techniques. Carbachol-induced contraction of isolated bovine CM strips following administration of HA1077 was examined in a perfusion chamber., Results: In rabbit eyes, the administration of HA1077 resulted in a significant decrease in IOP in a dose-dependent manner. An increased outflow facility was also observed. Western blot analysis revealed the presence of 20-kd light chain of myosin in human TM cells and bovine CM tissues. In cultured human TM cells, exposure to HA1077 disrupted actin bundles and impaired focal adhesion formation. In addition HA1077 showed relaxation of bovine CM strips., Conclusions: Use of HA1077 caused a reduction in IOP and an increase in the outflow facility. The results of in vitro experiments suggest that the IOP-lowering effects of HA1077 may be related to the altered cellular behavior of TM cells and relaxation of CM contraction. The results of these studies suggested that protein kinase inhibitors have the potential to be developed into a treatment modality for glaucoma.

Objectives: To determine the fate of phosphorothioate oligonucleotides (S-ODNs), which are commonly used for antisense strategy, in murine retina in vivo with the use of fluorescein isothiocyanate (FITC)-labeled S-ODNs, and to evaluate our fusogenic liposome system that may facilitate the delivery of S-ODNs., Methods: The FITC-labeled S-ODNs were encapsulated in liposomes, which were then coated with the envelope of inactivated hemagglutinating virus of Japan (HVJ; Sendai virus) by fusion (HVJ liposomes). Intravitreal injection of naked FITC-labeled S-ODNs or of the HVJ liposomes was done in ICR mice. After fixation, cryosections and flat-mounted retinas were prepared and examined by fluorescence microscopy., Results: Injection of naked FITC-labeled S-ODNs at 3 micromol/L exhibited weak fluorescence in 13% of the cells in the ganglion cell layer. When the concentration was increased to 30 micromol/L, high fluorescence was seen in 59% of cells in the ganglion cell layer at this time. This fluorescence diminished within a day. In contrast, injection of HVJ liposomes containing FITC-labeled S-ODNs at 3 micromol/L resulted in high fluorescence in 44% of the cells in the ganglion cell layer at 1 hour, and this fluorescence lasted for up to 3 days. This treatment also resulted in high fluorescence within retinal vessel walls, and weak fluorescence in photoreceptor cells., Conclusions: Intravitreally injected S-ODNs were rapidly eliminated from neural retina, and the use of HVJ liposomes could improve the delivery of S-ODNs. This method may be a potentially useful system for the antisense-based therapies for retinal diseases.

Objective: To identify molecular mechanisms of retinal responses to intraocular pressure elevation in primate experimental glaucoma., Methods: An experimental glaucoma model was created by repeated laser trabeculophotocoagulation. After the preparation of complementary DNAs from extracted total RNAs in the retinas, polymerase chain reaction (PCR) experiments were performed for the following screening target genes: beta-tubulin beta 2 and beta 5 and glial fibrillary acidic protein (GFAP). To investigate the amplified sequences derived from the PCR experiments, sequencing, subcloning, and Southern blot analysis of PCR products were performed. In addition, an immunohistochemical analysis was performed in an attempt to show the distribution of the target gene products in the retinas., Results: A series of PCR experiments suggested up-regulation of gene expression for GFAP but not for beta-tubulins. Sequencing of the PCR products and results of the Southern blot analysis showed that the amplified sequences were derived mainly from the target gene, GFAP, and that increased expression of GFAP was found despite the severity of glaucoma. Immunohistochemical studies also demonstrated increased expression of GFAP proteins in Müller cells and astrocytes in the retinas of primate eyes with experimental glaucoma., Conclusions: Our study showed up-regulation of GFAP at gene and protein levels, which suggests that glial components in the retina may contribute to the pathologic processes induced by elevated intraocular pressure.

Objective: To elucidate long-term surgical outcome of trabeculotomy ab externo in the treatment of developmental glaucoma., Patients: Included in this retrospective study are 116 eyes of 71 patients with developmental glaucoma. We classified patients into three groups based on their age: congenital (33 eyes), existing before age 2 months; infantile (31 eyes), occurring from ages 2 months to 2 years; and juvenile (52 eyes), age 2 years or older., Results: A life-table analysis showed that the total success probabilities at 5 and 10 years with one or more trabeculotomy ab externo operations were, respectively, 92.5% +/- 2.7% and 76.5% +/- 6.2%. The success probability of patients with congenital glaucoma (60.3% +/- 15.9%) was significantly lower than it was for those with infantile (96.3% +/- 3.6%) or juvenile (76.4% +/- 7.5%) glaucoma (P < .01 for both)., Conclusions: Surgical results of trabeculotomy ab externo remain effective for a long time. Congenital glaucoma has the worst prognosis, and infantile glaucoma has a better prognosis than does juvenile glaucoma.

Objectives: Retrospective and prospective studies examined the surgical effects in lowering intraocular pressure levels of trabeculotomy ab externo in adult eyes with either primary open angle glaucoma or pseudoexfoliation syndrome. We report the results of primary trabeculotomy as an intervention for glaucoma., Patients: Included in the retrospective study were 357 eyes of 227 patients with primary open angle glaucoma and 82 eyes of 65 patients with pseudoexfoliation syndrome, each of which underwent trabeculotomy ab externo alone and none of which had a history of laser or surgical treatment for ocular disease. Included in the prospective study were 33 eyes of 22 patients with primary open angle glaucoma and 17 eyes of 15 patients (older than 40 years) with pseudoexfoliation syndrome., Results: A life-table analysis for the retrospective study showed that the final success probability (mean +/- SE) at 5 years after surgery was 73.5% +/- 6.3% in eyes with pseudoexfoliation syndrome, which is significantly better than 58.0% +/- 3.1% in eyes with primary open angle glaucoma (P < .05). Also, the higher the preoperative intraocular pressure levels are, the less likely that the postoperative intraocular pressure levels will be brought under control (P < .01). Surgical outcome in the prospective study demonstrated success in 27 (79%) of 34 eyes after 3 years and in 16 (64%) of 25 eyes after 5 years, with medication. Complications included Descemet's membrane detachment (one eye), cyclodialysis (one eye), and decreased visual acuity due to progression of cataract (four eyes)., Conclusion: The surgical results of trabeculotomy ab externo remain effective in controlling intraocular pressure levels for a long time in selected patients. It thus appears that trabeculotomy ab externo can be considered as an alternative choice of surgical treatment in some cases of glaucoma.