Twenty-Four-Hour Intraocular Pressure Control with Omidenepag Isopropyl 0.002% in Patients with Glaucoma and Ocular Hypertension.

PURPOSE: To clarify the intraocular pressure (IOP)-lowering effect of a selective prostanoid EP2 receptor agonist, omidenepag isopropyl (OMDI) during a 24-hour period. PATIENTS AND METHODS: Subjects aged ≥20 years and with diagnosed, untreated primary open-angle glaucoma or ocular hypertension were enrolled. IOP measurements were performed every 4 hours over a 24-hour period using a Goldmann applanation tonometer (GAT) and Icare PRO tonometer (PRO). The baseline 24-hour IOP was measured in untreated subjects. After the baseline measurements, participants were given OMDI 1 drop once daily at night for 4 weeks. At week 4, the IOP measurement was repeated under the same conditions. Diurnal (9 am, 1 pm, 5 pm) and nocturnal (9 pm, 1 am, 5 am) IOP measurements were compared between baseline and treatment with OMDI. Safety measures included adverse events, slit-lamp biomicroscopy, visual acuity, heart rate and blood pressure. RESULTS: Of 27 participants enrolled, 25 patients (20 males and 5 females, average age 52.2 ± 8.5 years) completed the study. In the sitting position, the baseline diurnal and nocturnal mean IOPs (GAT) were 19.1 ± 2.1 mmHg and 18.2 ± 2.6 mmHg, respectively, the diurnal and nocturnal mean IOP reduction from baseline were -2.8 ± 2.6 mmHg (p < 0.0001) and -3.3 ± 2.9 mmHg (p < 0.0001), respectively, mean 24-hour IOP (GAT) was significantly lower with the OMDI treatment (-3.1 ± 2.5 mmHg, p < 0.0001). In the supine position, the baseline nocturnal mean IOP (PRO) was 17.99 ± 2.22 mmHg, and the nocturnal mean IOP reduction from baseline was -1.78 ± 2.37 mmHg (p = 0.0009) after 4 weeks of the treatment. Nine adverse events were observed in 8 patients including mild conjunctival hyperemia (n = 8) and mild iritis (n=1). There were no significant effects on systemic safety. CONCLUSION: Once daily OMDI treatment was able to produce stable 24-hour IOP reduction.

Predicting Lifetime Transition Risk of Severe Visual Field Defects Using Monte Carlo Simulation in Japanese Patients with Primary Open-Angle Glaucoma.

PURPOSE: To maintain visual fields and quality of life over a lifetime, medical practice must be conducted taking into consideration not only visual field progression but also future visual field changes that occur over the patients' expected lifespan. The purpose of this study is to investigate the feasibility of establishing a model that predicts prognosis, estimating the proportion of glaucoma patients with severe visual field defects. PATIENTS AND METHODS: The data of 191 patients with primary open-angle glaucoma, with a predominance of normal-tension glaucoma, were used for this study. The model was developed based on patients' backgrounds and risk factors, using Monte Carlo simulation. A "severe visual field defect" was defined as ≤-20 dB. The mean deviation (MD) value for 10,000 virtual patients in each simulation pattern (144 patterns) was calculated using a predictive formula to estimate the MD slope, and the effects of risk factors and intraocular pressure (IOP) reduction on the proportion of patients with severe visual field defects were evaluated. RESULTS: Younger age, later-stage disease, more severe glaucomatous structural abnormalities and the presence of disc hemorrhage were associated with an increase in the progression rate of patients with severe visual field defects. Conversely, lower IOP was associated with a decrease in this rate. CONCLUSION: Combining regression analysis with Monte Carlo simulation could be a useful method for developing predictive models of prognosis in glaucoma patients.

Correction to: Multicenter, Randomized, Controlled Study Comparing Tafluprost/Timolol Fixed Combination with Latanoprost/Timolol Fixed Combination in Primary Open-Angle Glaucoma and Ocular Hypertension.

In the original publication, the range to derive the P values is incorrectly represented in Table 2 and Table 3. The corrected tables are provided below.

Multicenter, Randomized, Controlled Study Comparing Tafluprost/Timolol Fixed Combination with Latanoprost/Timolol Fixed Combination in Primary Open-Angle Glaucoma and Ocular Hypertension.

INTRODUCTION: This was the first exploratory randomized controlled study to compare the efficacy and safety of a preserved tafluprost/timolol fixed combination (TAF/TIM) with a preserved latanoprost/timolol fixed combination (LAT/TIM). METHODS: This prospective, randomized, open-label study was conducted in Japanese patients with primary open-angle glaucoma, including normal-tension glaucoma or ocular hypertension. Following a 4-week LAT/TIM run-in period, eligible patients entered a 12-week treatment period, during which they received either LAT/TIM or TAF/TIM. The efficacy endpoint was the change in intraocular pressure (IOP) from baseline to week 12 and the safety endpoints included the changes from baseline to week 12 in superficial punctate keratopathy (SPK) score, tear breakup time (TBUT), and hyperemia score, as well as adverse events (AEs). At week 6, ocular symptoms were evaluated using a questionnaire. RESULTS: In total, 131 patients provided informed consent. Of these, 115 completed the run-in period and were assigned to receive TAF/TIM (n = 60) or LAT/TIM (n = 55). At week 12, there were no significant differences between the TAF/TIM and LAT/TIM groups in the change from baseline in trough IOP and IOP at 4-6 h after instillation. There were no significant differences between the two groups in the change from baseline to week 12 in SPK score, TBUT, and hyperemia score. However, only in the TAF/TIM group, the total SPK score and the inferior cornea SPK score were significantly lower at week 12 compared with baseline. Eye irritation and eye pain were significantly decreased in the TAF/TIM group compared with the LAT/TIM group. Two treatment-related AEs were reported in the TAF/TIM group (3.3%) and none in the LAT/TIM group, while no serious AEs were reported in either group. CONCLUSION: TAF/TIM is as effective as LAT/TIM in terms of IOP-reducing effect, with fewer ocular symptoms. TAF/TIM was associated with a significant improvement in SPK scores. TRIAL REGISTRATION: UMIN Clinical Trials Registry Identifier, UMIN000023862. FUNDING: Santen Pharmaceutical Co., Ltd., Osaka, Japan.

Aeromedical Transport Operations Using Helicopters during the 2016 Kumamoto Earthquake in Japan.

More than 6,000 people died in the Great Hanshin (Kobe) Earthquake in 1995, and it was later reported that there were around 500 preventable trauma deaths. In response, the Japanese government developed the helicopter emergency medical service in 2001, known in Japan as the "Doctor-Heli" (DH), which had 46 DHs and 2 private medical helicopters as of April 2016. DHs transport physicians and nurses to provide pre-hospital medical care at the scene of medical emergencies. Following lessons learned in the Great East Japan Earthquake in 2011, a research group in the Ministry of Health, Labour and Welfare developed a command and control system for the DH fleet as well as the Disaster Relief Aircraft Management System Network (D-NET), which uses a satellite communications network to monitor the location of the fleet and weather in real-time during disasters. During the Kumamoto Earthquake disaster in April 2016, 75 patients were transported by 13 DHs and 1 private medical helicopter in the first 5 days. When medical demand for the DHs exceeded supply, 5 patients, 8 patients, and 1 patient were transported by Self-Defense Force, Fire Department, and Coast Guard helicopters, respectively. Of the 89 patients who were transported, 30 (34%) had trauma, 3 (3%) had pulmonary embolisms caused by sleeping in vehicles, and 17 (19%) were pregnant women or newborns. This was the first time that the command and control system for aeromedical transport and D-NET, established after the Great East Japan Earthquake in 2011, were operated in an actual large-scale disaster. Aeromedical transport by DHs and helicopters belonging to several other organizations was accomplished smoothly because the commanders of the involved organizations could communicate directly with each other in person within the Aviation Coordination Section of the prefectural government office. However, ongoing challenges in the detailed operating methods for aeromedical transport were highlighted and include improving shared knowledge and training across the organizational framework. These are particularly important issues to address given the Nankai Trough and Tokyo inland earthquakes that are predicted for the near future in Japan.

The 24-hour intraocular pressure control by tafluprost/timolol fixed combination after switching from the concomitant use of tafluprost and timolol gel-forming solution, in patients with primary open-angle glaucoma.

OBJECTIVE: The aim of this study was to evaluate the 24-hour intraocular pressure (IOP)-control effect of the tafluprost/timolol fixed combination (TAF/TIM-FC) in patients with primary open-angle glaucoma after they switched from the concomitant use of tafluprost and timolol gel-forming solution. PATIENTS AND METHODS: Twenty patients with primary open-angle glaucoma (12 male and 8 female; mean ± SD age, 57.0±7.1 years) were included in this study. The patients were treated for 8 weeks with the concomitant administration of tafluprost and timolol gel-forming solution (evening dosing). At the end of this period, the patients underwent 24-hour IOP monitoring (measured at 21:00, 01:00, 05:00, 09:00, 13:00 and 17:00). IOP was measured with Goldmann applanation tonometer (GAT) and Icare PRO at sitting position at all timepoints and additionally, at supine position with Icare PRO tonometer at 01:00 and 05:00. The patients were then all switched to TAF/TIM-FC treatment (evening dosing). After 8 weeks, the 24-hour IOP monitoring was repeated. RESULTS: Nineteen patients completed the study. The mean 24-hour IOPs in the concomitant and TAF/TIM-FC phases were 13.8±2.7 vs 13.3±2.8 mmHg (P=0.0033) with the GAT in the sitting position and 13.96±2.56 vs 13.48±2.56 mmHg (P=0.0120) with the Icare PRO in habitual positions. In comparison with the concomitant phase, significantly lower IOP was observed for the TAF/TIM-FC phase at 21:00 and 01:00 with the GAT and at 01:00 with the Icare PRO. In addition, the maximum IOP and fluctuations in IOP in habitual positions were lower for the TAF/TIM-FC phase than for the concomitant phase. CONCLUSION: TAF/TIM-FC showed a stable 24-hour IOP-lowering effect and was equally or more effective than the concomitant use of tafluprost and timolol gel, both when sitting and when in habitual positions.

Prediction of Visual Field Progression in Patients with Primary Open-Angle Glaucoma, Mainly Including Normal Tension Glaucoma.

An objective method to predict individual visual field progression will contribute to realise personalised medication. The purpose of this study was to establish a predictive formula for glaucomatous visual field progression in patients with Primary open-angle glaucoma, mainly including normal tension glaucoma. This study was a large-scale, longitudinal and retrospective study including 498 eyes of 312 patients visiting from June 2009 to May 2015. In this analysis, 191 eyes of 191 patients meeting all eligible criteria were used. A predictive formula to calculate the rate of glaucomatous visual field progression (mean deviation slope) was obtained through multivariate linear regression analysis by adopting "Angle of Retinal Nerve Fibre Layer Defect" at the baseline, "Vertical Cup-Disc ratio" at the baseline, "Presence or absence of Disc Haemorrhage" during the follow-up period, and "Mean IOP change (%)" during the follow-up period as predictors. Coefficient of determination of the formula was 0.20. The discriminative ability of the formula was evaluated as moderate performance using receiver operating characteristic analysis, and the area under the curve was approximately 0.75 at all cut-off values. Internal validity was confirmed by bootstrapping. The predictive formula established by this type of approach might be useful for personalised medication.

[Experience of DMAT rescue activity by doctor-helicopter in Tohoku Area after the earthquake].

We operated rescue activities in Tohoku area after the earthquake of March 11th, 2011. From our hospital, a doctor-helicopter flew to the staging care unit at Hanamaki airport with two members of the disaster medical assistance team (DMAT), one of whom was an anesthesiologist. The helicopter carried ten patients by nine flight missions, who were the victims of tsunami after the earthquake. There were seven doctor-helicopters from all over Japan and did the missions based at Hanamaki airport. The missions was quite different from our usual job as an anesthesiologist, but we could transfer the patients safely by using some knowledge of stabilizing the unstable patients as flight doctors. We report the details of our activities by our doctor-helicopters in Tohoku area.

[Report of International Medical Relief Activity for Haiti earthquake as a delegate of Japanese Red Cross Society].

The author joined the emergency health operation of the International Red Cross for Haiti earthquake as one of Japanese Red Cross delegates for about one month in May, 2010. Althought I was not expected to offer the skills and experiences as an anesthesiologist, but those of a general practicing, I learned many valuable things from seeing local people, especially about the characteristic diseases and symptoms after disasters caused by living in the camp which was not an ideal environment to be in so long. It is difficult to know much about such typical problems through our usual work as an anesthesiologist. If we want to join these kinds of mission, we have to have some extra knowledge for helping people after such disasters.

Spatial and functional heterogeneity of sphingolipid-rich membrane domains.

Little is known about the organization of lipids in biomembranes. Lipid rafts are defined as sphingolipid- and cholesterol-rich clusters in the membrane. Details of the lipid distribution of lipid rafts are not well characterized mainly because of a lack of appropriate probes. Ganglioside GM1-specific protein, cholera toxin, has long been the only lipid probe of lipid rafts. Recently it was shown that earthworm toxin, lysenin, specifically recognizes sphingomyelin-rich membrane domains. Binding of lysenin to sphingomyelin is accompanied by the oligomerization of the toxin that leads to pore formation in the target membrane. In this study, we generated a truncated lysenin mutant that does not oligomerize and thus is non-toxic. Using this mutant lysenin, we showed that plasma membrane sphingomyelin-rich domains are spatially distinct from ganglioside GM1-rich membrane domains in Jurkat T cells. Like T cell receptor activation and cross-linking of GM1, cross-linking of sphingomyelin induced calcium influx and ERK phosphorylation in the cell. However, unlike CD3 or GM1, cross-linking of sphingomyelin did not induce significant protein tyrosine phosphorylation. Combination of lysenin and sphingomyelinase treatment suggested the involvement of G-protein-coupled receptor in sphingomyelin-mediated signal transduction. These results thus suggest that the sphingomyelin-rich domain provides a functional signal cascade platform that is distinct from those provided by T cell receptor or GM1. Our study therefore elucidates the spatial and functional heterogeneity of lipid rafts.

[Anesthetic management of two patients with amyotrophic lateral sclerosis (ALS)].

We experienced anesthetic management of two cases of amyotrophic lateral sclerosis (ALS). Case 1. A 46-year-old woman underwent emergency operation for ileus. Abdominal muscle relaxation and analgesia were obtained by combined spinal and epidural anesthesia. To avoid prolongation of muscle relaxation, awake intubation without muscle relaxants was performed. After the operation, she awoke smoothly and was extubated without any complications. Case 2. A 65-year-old woman underwent emergency operation for gastric fistula malfunction. We performed anesthetic management only with epidural anesthesia. During and after the operation, she was in good general condition and had no pain. For the patients with ALS, prolongation of muscle relaxation and residual neuromuscular block effect may cause difficult tracheal extubation and postoperative respiratory complications. We observed carefully the condition of the patients with ALS, and were able to choose the minimum invasive anesthetic methods for each case.

[Anesthetic management for non-cardiac operation with transesophageal echocardiography in a patient with left atrial myxoma].

A 68-year-old female with left atrial myxoma underwent osteosynthesis of the night tibia. During the operation we observed the motion of the tumor continuously by transesophageal echocardiography (TEE). The operation was finished successfully without any cardiovascular complications. We think that TEE was useful for observation of left atrial myxoma during this non-cardiac surgery.

Recognition of sphingomyelin by lysenin and lysenin-related proteins.

Lysenin is a sphingomyelin (SM)-specific toxin isolated from the coelomic fluid of the earthworm Eisenia foetida. Lysenin comprises a family of proteins together with lysenin-related protein 1 (LRP-1, lysenin 2) and LRP-2 (lysenin 3). In the present study, we characterized LRP-1 and LRP-2 together with lysenin using maltose-binding-protein-tagged recombinant proteins. LRP-2 specifically bound SM and induced hemolysis like lysenin. In contrast the binding and hemolytic activities of LRP-1 were 10 times less than those of lysenin and LRP-2. Lysenin and LRP-2 share 30 common sites of aromatic amino acids. Among them, only one position, phenylalanine 210, is substituted for isoleucine in LRP-1. The activity of LRP-1 was dramatically increased by introducing a single amino acid substitution of isoleucine 210 to phenylalanine, suggesting the importance of this aromatic amino acid in biological activities of lysenin and LRPs. The importance of aromatic amino acids was further indicated by a systematic tryptophan to alanine mutation of lysenin. Lysenin contains six tryptophan residues of which five are conserved in LRP-1 and -2. We showed that the conserved tryptophans but not the nonconserved one were required both in the recognition of SM and in the hemolytic activity of lysenin. Our results suggest the importance of tryptophan in the toxin function likely due to a direct recognition of SM or in maintaining the protein structure.