A multicenter phase II study on the safety of rho-kinase inhibitor (ripasudil) with needling for the patients after trabeculectomy.

Background: There is no established method of maintaining or reducing intra ocular pressure after the needling procedure for failing blebs post trabeculectomy. Regarding newer antihypertensive medications, ripasudil, which is a rho-associated protein kinase inhibitor ophthalmic solution, was able to prevent excessive scarring in vitro. This study aims to evaluate the safety of glaucoma patients submitted to the needling procedure and administered ripasudil for preventing scarring after the procedure. We also investigate the efficacy of ripasudil after needling for bleb failure through suppression of fibrosis to the bleb. Methods: This study is a multicenter, open-label, single-arm, phase II trial to evaluate the safety and efficacy of ripasudil in glaucoma patients after the needling procedure. Forty patients who will undergo needling at least 3 months after trabeculectomy will be recruited in Hiroshima university hospital and Hiroshima eye clinic. All the patients will instill ripasudil two times per day for three months after the needling procedure. The primary endpoint is the safety of ripasudil. Conclusions: We plan to establish the safety of ripasudil and to collect information involving the efficacy of ripasudil widely in this study.

Safety and Efficacy of the Rho-Kinase Inhibitor (Ripasudil) in Bleb Needling after Trabeculectomy: A Prospective Multicenter Study.

Ripasudil, a rho-associated protein kinase inhibitor ophthalmic solution, shows a protective effect in preventing excessive scarring in vitro. This study aims to evaluate the safety and efficacy of ripasudil for glaucoma patients submitted to the needling procedure. In this prospective, multicenter, single-arm study, we included 20 eyes of 20 patients with glaucoma who underwent the needling procedure without antimetabolites. All patients administered ripasudil after needling for three months. The primary endpoint of this study was the safety of ripasudil in patients, and the secondary endpoint was the change in IOP at 12 weeks after the needling procedure. No serious complications were found in the patients. One eye experienced pruritus and conjunctival follicle, while another eye had conjunctival follicle. These complications were transient and resolved quickly after discontinuation of ripasudil. The mean preoperative IOP was 14.6 ± 4.6 mmHg, which decreased to 11.0 ± 4.7 mmHg (p = 0.0062) at 1 week postoperatively. The IOP reduction effect continued to 12 weeks (11.8 ± 3.1 mmHg; p = 0.0448). The administration of the ROCK inhibitor, ripasudil, after the needling procedure is safe and effective in maintaining IOP for 12 weeks.

Effect of the rho-kinase inhibitor ripasudil in needling with mitomycin C for the failure of filtering bleb after trabeculectomy: a cross-sectional study.

BACKGROUND: Rho-kinase inhibitors can inhibit fibrosis after glaucoma surgery. This study aimed to evaluate the effect of rho-kinase inhibitor after needling procedure with mitomycin C for the failure of filtering bleb with trabeculectomy. METHODS: This retrospective single-center study examined the effects of rho-kinase inhibitor after the needling procedure. We included 27 eyes of 27 patients with glaucoma who underwent needling procedure using mitomycin C and were subsequently treated with ripasudil-a rho-associated protein kinase inhibitor (ripasudil group)-or without ripasudil (control group). The ripasudil and control groups were compared in terms of intraocular pressure (IOP) and the number of antiglaucoma medications. Success at 12 months after the needling procedure was defined as a > 20% decrease in IOP from the preoperative period without surgical reintervention. RESULTS: At 12 months after the needling procedure, the mean IOP decreased from 16.9 ± 4.5 to 12.6 ± 1.1 mmHg in the control group and from 16.0 ± 5.3 to 12.2 ± 1.2 mmHg in the ripasudil group (p = 0.77). The 12-month success rates were 60.00% and 56.25% in the control and ripasudil groups (p = 0.98), respectively. In the preoperative period, the numbers of antiglaucoma drugs were 0.27 ± 0.46 and 0.92 ± 0.91 in the control and ripasudil groups (p = 0.022), respectively, and at 12 months after the needling procedure, they were 1.07 ± 1.44 and 0.73 ± 1.10 (p = 0.52), respectively. CONCLUSIONS: Treatment with ripasudil (a rho-associated protein kinase inhibitor) after the needling procedure with mitomycin C did not show better results than treatment with the mitomycin C needling procedure alone at 12 months after the procedure.

Improvements in Optical Characteristics after Excision of an Overhanging Bleb Developed following Trabeculectomy.

INTRODUCTION: To examine the corneal total higher-order aberrations before and after the excision of an overhanging bleb that developed following trabeculectomy. Case Presentation. Two patients who developed overhanging blebs following trabeculectomy with a fornix-based conjunctival flap using mitomycin C (MMC) were assessed. We measured the corneal total higher-order aberrations for a 4 mm pupil diameter using the TOPCON KR-1W wavefront analyzer and the visual acuity before and after bleb excision. The corneal total higher-order aberration (HOA) improved from 0.50 µm to 0.38 µm in case 1 and from 0.59 µm to 0.49 µm in case 2 after bleb excision. The intraocular pressure was identical before and after bleb excision in both cases. No significant changes in the best-corrected visual acuity (BCVA) were noted in case 1; however, BCVA was improved from 20/25 to 20/20 in case 2. Both cases showed improvements in the symptoms of dysesthesia. CONCLUSION: Excision of the overhanging bleb developed following trabeculectomy may have beneficial possibility in some cases where corneal total HOA is affected and reduces the symptoms of dysesthesia.

Influence of Overhanging Bleb on Corneal Higher-Order Aberrations after Trabeculectomy.

Recent advances in ocular aberrometry have revealed that ocular surgery increases ocular and corneal higher-order aberrations. This retrospective single-center study aimed to examine the effects of the overhanging bleb on corneal higher-order aberrations using a wavefront analyzer. We included 61 eyes from 50 patients with overhanging bleb after trabeculectomy with a fornix-based conjunctival flap using mitomycin C (overhanging bleb group) and 65 eyes from 54 glaucoma patients with no history of glaucoma surgery (control group). Corneal higher-order aberrations (total higher-order aberrations, coma aberrations, coma-like aberrations, spherical aberrations, and spherical-like aberrations) on a 4 mm pupil diameter were measured using the TOPCON KR-1W wavefront analyzer. Corneal coma aberrations were higher in the overhanging bleb group than in the control group (0.16 ± 0.13 µm and 0.10 ± 0.05 µm, respectively; p = 0.042). Corneal coma-like aberrations were also higher in the overhanging bleb group than in the control group (0.31 ± 0.32 µm and 0.16 ± 0.09 µm, respectively; p = 0.022). With an increasing ratio of cornea covered by the bleb to the entire cornea, all corneal higher-order aberrations increased except for corneal coma-like aberrations. Overhanging bleb after trabeculectomy with a fornix-based conjunctival flap using mitomycin C and its size influenced corneal higher-order aberrations.

Development of Pin1 Inhibitors and their Potential as Therapeutic Agents.

The prolyl isomerase Pin1 is a unique enzyme, which isomerizes the cis-trans conformation between pSer/pThr and proline and thereby regulates the function, stability and/or subcellular distribution of its target proteins. Such regulations by Pin1 are involved in numerous physiological functions as well as the pathogenic mechanisms underlying various diseases. Notably, Pin1 deficiency or inactivation is a potential cause of Alzheimer's disease, since Pin1 induces the degradation of Tau. In contrast, Pin1 overexpression is highly correlated with the degree of malignancy of cancers, as Pin1 controls a number of oncogenes and tumor suppressors. Accordingly, Pin1 inhibitors as anti-cancer drugs have been developed. Interestingly, recent intensive studies have demonstrated Pin1 to be responsible for the onset or development of nonalcoholic steatosis, obesity, atherosclerosis, lung fibrosis, heart failure and so on, all of which have been experimentally induced in Pin1 deficient mice. In this review, we discuss the possible applications of Pin1 inhibitors to a variety of diseases including malignant tumors and also introduce the recent advances in Pin1 inhibitor research, which have been reported.

Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice.

Hyperuricemia has been recognized as a risk factor for insulin resistance as well as one of the factors leading to diabetic kidney disease (DKD). Since DKD is the most common cause of end-stage renal disease, we investigated whether febuxostat, a xanthine oxidase (XO) inhibitor, exerts a protective effect against the development of DKD. We used KK-Ay mice, an established obese diabetic rodent model. Eight-week-old KK-Ay mice were provided drinking water with or without febuxostat (15 µg/mL) for 12 weeks and then subjected to experimentation. Urine albumin secretion and degrees of glomerular injury judged by microscopic observations were markedly higher in KK-Ay than in control lean mice. These elevations were significantly normalized by febuxostat treatment. On the other hand, body weights and high serum glucose concentrations and glycated albumin levels of KK-Ay mice were not affected by febuxostat treatment, despite glucose tolerance and insulin tolerance tests having revealed febuxostat significantly improved insulin sensitivity and glucose tolerance. Interestingly, the IL-1ß, IL-6, MCP-1, and ICAM-1 mRNA levels, which were increased in KK-Ay mouse kidneys as compared with normal controls, were suppressed by febuxostat administration. These data indicate a protective effect of XO inhibitors against the development of DKD, and the underlying mechanism likely involves inflammation suppression which is independent of hyperglycemia amelioration.

Prolyl isomerase Pin1 binds to and stabilizes acetyl CoA carboxylase 1 protein, thereby supporting cancer cell proliferation.

The prolyl isomerase Pin1 expression level is reportedly increased in most malignant tissues and correlates with poor outcomes. On the other hand, acetyl CoA carboxylase 1 (ACC1), the rate limiting enzyme of lipogenesis is also abundantly expressed in cancer cells, to satisfy the demand for the fatty acids (FAs) needed for rapid cell proliferation. We found Pin1 expression levels to correlate positively with ACC1 levels in human prostate cancers, and we focused on the relationship between Pin1 and ACC1. Notably, it was demonstrated that Pin1 associates with ACC1 but not with acetyl CoA carboxylase 2 (ACC2) in the overexpression system as well as endogenously in the prostate cancer cell line DU145. This association is mediated by the WW domain in the Pin1 and C-terminal domains of ACC1. Interestingly, Pin1 deficiency or treatment with Pin1 siRNA or the inhibitor juglone markedly reduced ACC1 protein expression without affecting its mRNA level, while Pin1 overexpression increased the ACC1 protein level. In addition, chloroquine treatment restored the levels of ACC1 protein reduced by Pin1 siRNA treatment, indicating that Pin1 suppressed ACC1 degradation through the lysosomal pathway. In brief, we have concluded that Pin1 leads to the stabilization of and increases in ACC1. Therefore, it is likely that the growth-enhancing effect of Pin1 in cancer cells is mediated at least partially by the stabilization of ACC1 protein, corresponding to the well-known potential of Pin1 inhibitors as anti-cancer drugs.

Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16.

Non-shivering thermogenesis in adipocytes provides defense against low temperatures and obesity development, but the underlying regulatory mechanism remains to be fully clarified. Based on both markedly increased Pin1 expression in states of excess nutrition and resistance to obesity development in Pin1 null mice, we speculated that adipocyte Pin1 may play a role in thermogenic programs. Adipose-specific Pin1 knockout (adPin1 KO) mice showed enhanced transcription of thermogenic genes and tolerance to hypothermia when exposed to cold. In addition, adPin1 KO mice were resistant to high-fat diet-induced obesity and glucose intolerance. A series of experiments revealed that Pin1 binds to PRDM16 and thereby promotes its degradation through the ubiquitin-proteasome system. Consistent with these results, Pin1 deletion in differentiated adipocytes showed enhancement of thermogenic programs in response to the ß3 agonist CL316243 through the upregulation of PRDM16 proteins. These observations indicate that Pin1 is a negative regulator of non-shivering thermogenesis.

A comparative study of transscleral suture-fixated and scleral-fixated intraocular lens implantation.

PURPOSE: To compare short-term clinical outcomes between scleral-fixated and transscleral suture-fixated intraocular lens (IOL) implantation. SEETING: Hiroshima Prefectural Hospital, Japan. DESIGN: A retrospective, nonrandomized, comparative case series. METHODS: Eighty-nine eyes of 87 patients were included in this study; 45 eyes underwent transscleral suture-fixated IOL implantation (group 1), and 44 eyes underwent scleral-fixated IOL implantation (group 2) between February 2009 and June 2017 in the department of Ophthalmology, Hiroshima Prefectural Hospital, Japan. The postoperative best corrected visual acuity (BCVA), degree of astigmatism, IOL astigmatism (total astigmatism-corneal astigmatism), and refractive error were all measured at 1-week and 1-month intervals. RESULTS: The mean preoperative BCVA in logarithm of minimum angle of resolution (log MAR) was 0.39 ± 0.56 and 0.46 ± 0.51 in groups 1 and 2, respectively, and the mean postoperative BCVA was 0.25 ± 0.41 and 0.34 ± 0.49 at 1 month. The postoperative degree of astigmatism in group 2 was significantly less than that in group 1 at 1 week and 1 month (p = 0.0046 and p = 0.021, respectively). The postoperative IOL astigmatism in group 2 was significantly less than that in group 1 at 1 week (p = 0.021), while the refractive error between the two groups was not significantly different at 1 week or 1 month. CONCLUSIONS: Scleral-fixated IOL implantation has equivalent BCVA and refractive error outcomes as transscleral suture-fixated IOL implantation during the early postoperative period without serious complications. Scleral-fixated IOL implantation appears to provide more stable fixation than suture-fixated IOL implantation.

Ocular hypotensive effects of a Rho-associated protein kinase inhibitor in rabbits.

PURPOSE: Ripasudil is a novel Rho-associated protein kinase inhibitor that is used to treat ocular hypertension. However, the comparison of the intraocular pressure (IOP)-lowering effects between ripasudil alone and other ocular hypotensive drugs has not been studied thoroughly. The purpose of this study is to examine the ocular hypotensive effects of 0.4% ripasudil, 2% pilocarpine, 0.5% timolol and 0.1% dorzolamide in rabbits. We also studied the IOP changes when 0.4% ripasudil was combined with 2% pilocarpine, 0.5% timolol or 0.1% dorzolamide. METHODS: One drop of saline solution, 0.4% ripasudil, 0.5% timolol, 2% pilocarpine or 1% dorzolamide or a combination of these agents was applied topically to the left eyes of eight healthy albino rabbits. Posttreatment changes in the IOP of albino rabbits were monitored using a rebound tonometer over a 5-h time course. Changes in IOP after application of saline served as the control. One-way analysis of variance and Dunnett's post hoc tests were used for statistical analyses. RESULTS: After topical instillation, 0.4% ripasudil resulted in significant decreases in IOP at 0.5 and 1 h compared with the control group. Treatment with timolol, pilocarpine or dorzolamide had no significant effect on IOP. Treatment with timolol, pilocarpine or dorzolamide in combination with ripasudil resulted in significant reductions in IOP at 1 h. However, none of these agents enhanced the IOP-lowering effects of ripasudil. CONCLUSION: Ripasudil has stronger IOP-lowering effects than timolol, pilocarpine or dorzolamide hypotensive agents in our rabbit model. Addition of timolol, pilocarpine or dorzolamide did not enhance the IOP-lowering effects of ripasudil alone.

Delayed leukoencephalopathy after carbon monoxide poisoning presenting as subacute dementia.

We herein report the case of a 65-year-old woman who presented with the subacute onset of dementia and subsequently developed abnormal behavior and a gait disturbance. Her condition transiently improved; however, within one month, she became drowsy and poorly responsive, with limb chorea and urinary incontinence. Her history of frequently using charcoal led us to diagnose her with carbon monoxide (CO) poisoning. The findings of this case and a literature review suggest that subacute dementia due to CO poisoning recovers late, after a year or more, in patients above sixty years of age, and both hyperbaric oxygen and corticosteroid pulse therapy should be considered in such cases, even after one month.

Numerical morphological analysis of fungal growth based on a reaction-diffusion model.

The objective of this study was to develop a numerical, reaction-diffusion based model that predicted colony formation by taking into account the influence of nutrients, moisture (water activity), temperature, and the surface characteristics of building materials for various fungi. First, the results of fundamental experiments that measure the growth responses of colony size on culture media under various environmental conditions are presented. Second, the mathematical models that reproduce colony formation on the PDA medium and the numerical simulation intended for the experimental conditions are discussed. Fitting of the model coefficients was performed using the data of the fundamental experiments, and sensitivity analysis was executed. The mathematical models proposed depended on the nutrient concentration and the substrate softness of the surface of the construction materials, and were in reasonable agreement with the experimental data.