Trade-Offs Between Energy and Depth of Neural Networks.

We present an investigation on threshold circuits and other discretized neural networks in terms of the following four computational resources-size (the number of gates), depth (the number of layers), weight (weight resolution), and energy-where the energy is a complexity measure inspired by sparse coding and is defined as the maximum number of gates outputting nonzero values, taken over all the input assignments. As our main result, we prove that if a threshold circuit C of size s, depth d, energy e, and weight w computes a Boolean function f (i.e., a classification task) of n variables, it holds that log( rk (f))≤ed(logs+logw+logn) regardless of the algorithm employed by C to compute f, where rk (f) is a parameter solely determined by a scale of f and defined as the maximum rank of a communication matrix with regard to f taken over all the possible partitions of the n input variables. For example, given a Boolean function CD n(ξ) =⋁i=1n/2ξi∧ξn/2+i, we can prove that n/2≤ed( log s+logw+logn) holds for any circuit C computing CD n. While its left-hand side is linear in n, its right-hand side is bounded by the product of the logarithmic factors of s,w,n and the linear factors of d,e. If we view the logarithmic terms as having a negligible impact on the bound, our result implies a trade-off between depth and energy: n/2 needs to be smaller than the product of e and d. For other neural network models, such as discretized ReLU circuits and discretized sigmoid circuits, we also prove that a similar trade-off holds. Thus, our results indicate that increasing depth linearly enhances the capability of neural networks to acquire sparse representations when there are hardware constraints on the number of neurons and weight resolution.

Genetic diversity of viruses infecting cnidium plants (Cnidium officinale) in Japan.

Cnidium vein yellowing virus (CnVYV), cnidium virus X (CnVX), cucumber mosaic virus (CMV) and cnidium virus 1 (CnV1) were detected at extremely high levels in Cnidium officinale plants showing viral symptoms collected from Iwate and Hokkaido Prefectures, Japan. The complete nucleotide sequence of the newly detected CnVYV and CnV1, and genetic diversity of the cnidium-infecting viruses (CnVYV, CnVX, and CnV1) indicated that South Korean and Japanese cnidium plants had close relationship with each other. All three viruses can infect vegetatively propagated perennials and are vertically transmitted once infection occurs. Supplementary Information: The online version contains supplementary material available at 10.1007/s13337-023-00835-w.

Live-cell imaging of septins and cell polarity proteins in the growing dikaryotic vegetative hypha of the model mushroom Coprinopsis cinerea.

The developmental biology underlying the morphogenesis of mushrooms remains poorly understood despite the essential role of fungi in the terrestrial environment and global carbon cycle. The mushroom Coprinopsis cinerea is a leading model system for the molecular and cellular basis of fungal morphogenesis. The dikaryotic vegetative hyphae of this fungus grow by tip growth with clamp cell formation, conjugate nuclear division, septation, subapical peg formation, and fusion of the clamp cell to the peg. Studying these processes provides many opportunities to gain insights into fungal cell morphogenesis. Here, we report the dynamics of five septins, as well as the regulators CcCla4, CcSpa2, and F-actin, visualized by tagging with fluorescent proteins, EGFP, PA-GFP or mCherry, in the growing dikaryotic vegetative hyphae. We also observed the nuclei using tagged Sumo proteins and histone H1. The five septins colocalized at the hyphal tip in the shape of a dome with a hole (DwH). CcSpa2-EGFP signals were observed in the hole, while CcCla4 signals were observed as the fluctuating dome at the hyphal tip. Before septation, CcCla4-EGFP was also occasionally recruited transiently around the future septum site. Fluorescent protein-tagged septins and F-actin together formed a contractile ring at the septum site. These distinct specialized growth machineries at different sites of dikaryotic vegetative hyphae provide a foundation to explore the differentiation program of various types of cells required for fruiting body formation.

(E)-7-phenyl-2-heptene-4,6-diyn-1-ol from Bidens pilosa as a repellent against isopods.

The development of repellents as alternatives to insecticides has expanded in recent years. However, their use in isopod pest control is limited. To develop an isopod repellent, a plant extract library from wild plants native to the Kochi Prefecture was screened for repellent activity against pillbugs, and 82 samples (87%) exhibited repellent activity. Among them, (E)-7-phenyl-2-heptene-4,6-diyn-1-ol was isolated and identified as a repellent from the root of Bidens pilosa. It had a half-maximal effective concentration of 0.20 µm, with a strong repellency. A study of the structure-activity relationship to (E)-7-phenyl-2-heptene-4,6-diyn-1-ol revealed that the presence of a hydroxyl group and an aromatic at both ends of the length of the seven-carbon chain is important for the expression of repellency. These results can potentially lead to a new repellent of phenylalkyl alcohol.

A review of food poisoning caused by local food in Japan.

Increasingly popular worldwide, Japanese cuisine includes several raw preparations such as sashimi and sushi; however, limited information on food poisoning from Japanese local food is available in English literature. Without appropriate knowledge, physicians may underdiagnose traveler's diarrhea among people returning from Japan. To provide accurate information to primary care physicians worldwide, we conducted a narrative review on food poisoning research published in Japanese and English over the past four years, considering the frequency and clinical importance of various presentations.

Refraction and pupil diameter in 3-year- and 1-month-old children as measured by Spot Vision Screener.

Spot Vision Screener (SVS) can conduct refraction tests for both eyes within a short period. This study aims to evaluate the refraction and pupil diameters of 3-year- and 1-month-old Japanese children using SVS in regular medical checkup. We examined 2438 eyes of 1219 children (age: 3-year- and 1-month) in Fujieda (Shizuoka, Japan) to assess their refraction and pupil diameters and eye-position screening conducted by SVS. SVS successfully measured 1217 children (99.8%). Regarding the right eye refraction, the spherical power was +0.70 ± 0.55 D (median, +0.75 D), and the cylindrical power was -0.67 ± 0.49 D (median, -0.50 D). The pupil diameter of the right eyes was 5.57 ± 0.79 (median, 5.60) mm. we could obtain a large number of basic data for 3-year- and 1-month-old Japanese children. However, refraction and pupil diameter of children were not normally distributed, so careful handling of children's basic data on the eye is necessary.

SLC1A1 Gene Variants and Normal Tension Glaucoma: An Association Study.

BACKGROUND: It has been hypothesized that dysfunction of the solute carrier family 1, member1 gene (SLC1A1), which encodes the glutamate aspartate transporter, may play a role in normal tension glaucoma. In this study we investigate whether SLC1A1 is associated with normal tension glaucoma in Japanese patients. METHODS: A total of 292 Japanese patients with normal tension glaucoma and 500 healthy control subjects were recruited. We genotyped 12 single-nucleotide polymorphisms in SLC1A1. We also performed an imputation analysis to evaluate the potential association of un-genotyped SLC1A1 single-nucleotide polymorphisms, and 165 single-nucleotide polymorphisms were imputed. RESULTS: We observed an increased frequency of the G allele of rs10739062 in patients compared to controls (p = 0.043, OR = 1.25). The rs10739062 polymorphism exhibited a dominant effect: individuals with genotype GG and GC showed a 1.91-fold increase in risk compared to genotype CC (p = 0.0082). However, the statistical significance disappeared after Bonferroni correction for multiple testing (pc > 0.05). We did not find any significant association between any of the remaining 176 single-nucleotide polymorphisms and disease risk. CONCLUSIONS: Our study showed a lack of association between SLC1A1 variants and normal tension glaucoma in Japanese patients, suggesting that the SLC1A1 gene does not play a critical role in the development of the disorder in this patient population. However, further genetic studies with larger sample sizes are needed to clarify whether SLC1A1 may make some contribution that affects the risk of developing normal tension glaucoma.

One-year clinical evaluation of 0.4% ripasudil (K-115) in patients with open-angle glaucoma and ocular hypertension.

PURPOSE: To investigate the intra-ocular pressure (IOP)-lowering effects and safety of 0.4% ripasudil (K-115), a Rho kinase inhibitor, twice daily for 52 weeks, in patients with open-angle glaucoma or ocular hypertension (OHT). METHODS: In this multicentre, prospective, open-label study, 388 patients with primary open-angle glaucoma, OHT or exfoliation glaucoma were enrolled and 354 of them were subdivided into four cohorts (monotherapy, 173; additive therapy to prostaglandin analogs, 62; ß-blockers, 60; or fixed combination drugs, 59). The IOP reduction at trough and peak from baseline and adverse events was investigated. RESULTS: Ripasudil showed IOP-lowering effects over 52 weeks in all the analyses of monotherapy, additive therapy and both subgroups (baseline IOP ≥21 mmHg and <21 mmHg) of monotherapy. The mean IOP reductions at trough and peak at week 52 were -2.6 and -3.7 mmHg for monotherapy, and -1.4 and -2.4, -2.2 and -3.0, and -1.7 and -1.7 mmHg, respectively, for additive therapy described above. The most frequently observed adverse events were conjunctival hyperaemia (n = 264, 74.6%), blepharitis (n = 73, 20.6%) and allergic conjunctivitis (n = 61, 17.2%). Most of the conjunctival hyperaemia findings were mild (97.0%), transient and resolved spontaneously (78.0%). Although 51 patients discontinued from the study due to blepharitis and/or allergic conjunctivitis (blepharitis, 28; allergic conjunctivitis, 17; both, 6), all the events resolved with or without treatment after the discontinuation of ripasudil administration. CONCLUSION: Fifty-two week administration of 0.4% ripasudil revealed IOP-lowering effects and an acceptable safety profile when administered as monotherapy or as additive therapy, in patients with open-angle glaucoma or OHT.

Additive Intraocular Pressure-Lowering Effects of the Rho Kinase Inhibitor Ripasudil (K-115) Combined With Timolol or Latanoprost: A Report of 2 Randomized Clinical Trials.

IMPORTANCE: Ripasudil hydrochloride hydrate (K-115), a novel rho kinase inhibitor, provides statistically significant intraocular pressure (IOP)-lowering effects and has a tolerable safety profile. However, no studies have evaluated ripasudil combined with ß-blockers and prostaglandin analogues. OBJECTIVE: To evaluate the additive IOP-lowering effects and the safety of ripasudil, 0.4%, combined with timolol, 0.5%, or latanoprost, 0.005%, in patients with primary open-angle glaucoma or ocular hypertension. DESIGN, SETTING, AND PARTICIPANTS: We conducted 2, multicenter, randomized, double-masked, parallel group comparison studies of ripasudil-timolol and ripasudil-latanoprost in 29 and 36 Japanese clinical centers, respectively. Analyses were performed on an intention-treat-treat basis. After appropriate run-in periods with timolol or latanoprost, 208 and 205 patients whose IOP levels were 18 mm Hg or higher were enrolled in the ripasudil-timolol and ripasudil-latanoprost groups, respectively. Enrollment began December 1, 2011, and follow-up was completed on September 7, 2012, in the ripasudil-timolol study. Enrollment began December 1, 2011, and follow-up was completed on September 27, 2012, in the ripasudil-latanoprost study. INTERVENTIONS: Patients were subdivided into 2 groups in each study and were treated with ripasudil or placebo twice daily for 8 weeks. MAIN OUTCOMES AND MEASURES: The IOP reductions in the ripasudil and placebo groups were analyzed with a repeated-measures analysis of variance model at weeks 4, 6, and 8, at trough (before instillation [9 am]) and peak (2 hours after instillation [11 am]) levels. RESULTS: In the ripasudil-timolol study, the mean IOP reductions from baseline in the ripasudil and placebo groups were -2.4 and -1.5 mm Hg at 9 am for a difference of 0.9 mm Hg (95% CI, 0.4-1.3 mm Hg; P < .001) and -2.9 and -1.3 mm Hg at 11 am for a difference of 1.6 mm Hg (95% CI, 1.1-2.1 mm Hg; P < .001), respectively. In the ripasudil-latanoprost study, those IOP reductions were -2.2 and -1.8 mm Hg at 9 am for a difference of 0.4 mm Hg (95% CI, -0.0 to 0.9 mm Hg; P = .06) and -3.2 and -1.8 mm Hg at 11 am for a difference of 1.4 mm Hg (95% CI, 0.9-1.9 mm Hg; P < .001), respectively. The most frequently reported adverse event was conjunctival hyperemia, which was mild and in most cases resolved without treatment before the next instillation. CONCLUSIONS AND RELEVANCE: These clinical trials found additive IOP-lowering effects of ripasudil from placebo at trough and peak levels in combination with timolol and at peak level in combination with latanoprost. However, a definitive difference in the addition of placebo to latanoprost was not identified in the trough level. TRIAL REGISTRATION: clinicaltrials.jp Identifiers: JAPIC111700 and JAPIC111701.

Intra-ocular pressure-lowering effects of a Rho kinase inhibitor, ripasudil (K-115), over 24 hours in primary open-angle glaucoma and ocular hypertension: a randomized, open-label, crossover study.

PURPOSE: To investigate the intra-ocular pressure (IOP)-lowering effects of a selective Rho kinase inhibitor, ripasudil (K-115), over 24 hr in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). METHODS: In this multicenter, prospective, randomized, open-label, 3-period, Latin-square crossover clinical study, 28 patients with POAG or OHT whose IOP level was 21 mmHg or higher were subdivided into three groups. Each patient was treated with placebo and ripasudil in concentrations of 0.2 and 0.4%, at 9:00 and 21:00 on day 1 through a total of 3 periods separated by washout periods. IOP was measured at 9:00, 10:00, 11:00, 13:00, 16:00, 19:00, 21:00, 22:00 and 23:00 on day 1, and 1:00, 4:00, 7:00 and 9:00 on day 2 in sitting position using Goldmann applanation tonometer. Main outcome measure was the IOP reduction of placebo and ripasudil from baseline. RESULTS: The mean IOP reduction was -5.2 mmHg for 0.2%, -6.4 mmHg for 0.4% and -2.0 mmHg for placebo at 2 hr after the first instillation. Also, the corresponding values were -6.8 mmHg for 0.2%, -7.3 mmHg for 0.4% and -4.1 mmHg for placebo at 2 hr after the second instillation. Statistically significant IOP reduction, compared with placebo, was found for both 0.2 and 0.4% from 1 through 7 hr after each instillation. In safety, conjunctival hyperaemia was observed in 22 patients (79%) for 0.2%, 27 patients (96%) for 0.4% and three patients (11%) for placebo. CONCLUSION: Ripasudil is a promising new topical medication to lower IOP for at least 7 hr after instillations in patients with POAG or OHT.

Secondary glaucoma associated with bilateral complete ring cysts of the ciliary body.

PURPOSE: To report a case of acute glaucoma due to complete ring cyst of the ciliary body. PATIENTS AND METHODS: A 33-year-old woman experienced blurred vision in her left eye. Intraocular pressure of the left eye was elevated accompanied with a very shallow anterior chamber. Anterior segment-optical coherence tomography and ultrasound biomicroscopy detected ring-shaped ciliary masses in the both eyes. Myopic change and contact between the ciliary mass and lens in the left eye suggested the presence of aqueous misdirection resulting in forward displacement of the lens-iris diaphragm. Because elevated intraocular pressure was refractory to conservative management, the left eye underwent clear lens aspiration and implantation of intraocular lens. RESULTS: Although the anterior chamber became deep in the left eye initially after lens extraction in conjunction with core vitrectomy, possible aqueous misdirection recurred. Second vitrectomy in the left eye together with posterior and anterior capsulotomies, to establish humoral communication between the anterior and posterior chambers, deepened the anterior chamber and lowered the intraocular pressure. The anterior chamber in the fellow right eye remained deep a year after the episode. CONCLUSIONS: This is the first reported case of bilateral ring cysts of the ciliary body. The manifestation caused secondary glaucoma, which was resolved by lensectomy and vitrectomy.

Primary open-angle glaucoma in a population associated with high prevalence of primary angle-closure glaucoma: the Kumejima Study.

PURPOSE: To evaluate the prevalence of and risk factors for primary open-angle glaucoma (POAG) in a rural population of southwestern Japan. DESIGN: Population-based cross-sectional study. PARTICIPANTS: All residents 40 years of age and older in Kumejima, Okinawa, Japan. METHODS: Of the eligible 4632 residents 40 years of age and older, 3762 subjects (participant rate, 81.2%) underwent screening examinations, including visual acuity (VA) measurement, slit-lamp examination, Goldmann applanation tonometry, gonioscopy, undilated stereoscopic fundus photographs, autorefractometry, noncontact specular microscopy, pachymetry, and visual field (VF) testing using frequency-doubling technology. If glaucoma or other related ocular disorders were suspected, subjects were referred for definitive examinations including VF testing with the Humphrey Field Analyzer. The diagnosis of POAG was based on the criteria of the International Society for Geographical and Epidemiological Ophthalmology. MAIN OUTCOME MEASURES: Prevalence and risk factors of POAG. RESULTS: The prevalence of POAG was 4.0% (95% confidence interval [CI], 3.4%-4.7%); 82% of patients had an intraocular pressure (IOP) less than 22 mmHg, resulting in a prevalence of 3.3% (95% CI, 2.8%-3.9%). Because of POAG, 3 subjects had a VA worse than 20/400 in only 1 eye, and 1 subject had VA loss of worse than 20/400 bilaterally. The average IOP values (mean ± standard deviation) were 14.9 ± 3.2 and 14.6 ± 3.3 mmHg in the right and left eyes, respectively; the IOP values were higher in patients with POAG (15.4 ± 3.3 and 15.2 ± 3.3 mmHg, respectively) than in subjects without glaucoma (14.8 ± 3.1 and 14.4 ± 3.1 mmHg, respectively; P<0.045, Student t test). Multivariate analysis showed that male gender (P = 0.003), older age (P<0.001), higher IOP (P<0.001), longer axial length (P<0.001), and thinner central cornea (P = 0.006) were associated with POAG. CONCLUSIONS: High prevalence rates of POAG (4.0%) and POAG with normal IOP levels (3.3%), which were comparable with those on the Japanese mainland, were found in a southwestern rural island of Japan, where the prevalence of primary angle-closure glaucoma (previously reported as 2.2%) was considerably higher than on the Japanese mainland (0.6% in the Tajimi Study) or other countries. The risk factors for POAG included male gender, older age, higher IOP, myopia, and a thinner cornea.

Assessment of the vision-specific quality of life using clustered visual field in glaucoma patients.

PURPOSE: To investigate the significance of vision-specific quality of life (QOL) in glaucoma patients based on the location of visual field defects. PATIENTS AND METHODS: We examined 336 eyes of 168 patients. The 25-item National Eye Institute Visual Function Questionnaire was used to evaluate patients' QOL. Visual field testing was performed using the Humphrey Field Analyzer; the visual field was divided into 10 clusters. We defined the eye with better mean deviation as the better eye and the fellow eye as the worse eye. A single linear regression analysis was applied to assess the significance of the relationship between QOL and the clustered visual field. RESULTS: The strongest correlation was observed in the lower paracentral visual field in the better eye. The lower peripheral visual field in the better eye also showed a good correlation. Correlation coefficients in the better eye were generally higher than those in the worse eye. For driving, the upper temporal visual field in the better eye was the most strongly correlated (r=0.509). For role limitation and peripheral vision, the lower peripheral visual field in the better eye had the highest correlation coefficients at 0.459 and 0.425, respectively. CONCLUSIONS: Overall, clusters in the lower hemifield in the better eye were more strongly correlated with QOL than those in the worse eye. In particular, the lower paracentral visual field in the better eye was correlated most strongly of all. Driving, however, strongly correlated with the upper hemifield in the better eye.

Modified ab externo method for introducing 2 polypropylene loops for scleral suture fixation of intraocular lenses.

We describe a method that enables the introduction of 2 suture loops for scleral fixation of an intraocular lens (IOL) by a single ab externo procedure. A long needle carrying a polypropylene suture loop is inserted through the scleral fixation site and docked with a hollow needle inserted through the opposite fixation site. The hollow needle pulls the suture needle out, but the suture loop end is left external. Another polypropylene suture loop is placed through the first loop. As the first (leading) suture is pulled, the second (trailing) suture is drawn into the eye. The suture loops are retrieved through the main incision. The IOL haptics are secured with a polypropylene loop by cow hitches. After the IOL is placed in the eye, the sutures are fixated to the sclera. This technique enhances efficiency and control during the introduction of suture loops for scleral fixation of IOLs.

Phase 2 randomized clinical study of a Rho kinase inhibitor, K-115, in primary open-angle glaucoma and ocular hypertension.

PURPOSE: To identify the optimal dose of a novel Rho kinase inhibitor, K-115, by assessing dose dependency of the intraocular pressure (IOP)-lowering effects and the safety in patients with primary open-angle glaucoma or ocular hypertension. DESIGNS: Multicenter, prospective, randomized, placebo-controlled, double-masked, parallel group comparison clinical study. METHODS: After appropriate washout periods, 210 patients with primary open-angle glaucoma or ocular hypertension were subdivided into 4 groups and were treated with K-115 in concentrations of 0.1%, 0.2%, and 0.4% or placebo twice daily for 8 weeks. The dose response of IOP reduction and the incidence of adverse events by K-115 or placebo were investigated. RESULTS: The mean baseline IOP was between 23.0 and 23.4 mm Hg. The mean IOP reductions of the last visit from baseline were -2.2 mm Hg, -3.4 mm Hg, -3.2 mm Hg, and -3.5 mm Hg, respectively, in the placebo, 0.1%, 0.2%, and 0.4% groups at before instillation (9:00); -2.5 mm Hg, -3.7 mm Hg, -4.2 mm Hg, and -4.5 mm Hg at 2 hours after instillation (11:00); and -1.9 mm Hg, -3.2 mm Hg, -2.7 mm Hg, and -3.1 mm Hg at 8 hours after instillation (17:00). The dose-dependent IOP-lowering effect of K-115 was statistically significant at all time points. Also, conjunctival hyperemia was found in 7 (13.0%) of 54 patients for placebo, 23 (43.4%) of 53 patients for the 0.1% group, 31 (57.4%) of 54 patients for the 0.2% group, and 32 (65.3%) of 49 patients for the 0.4% group. CONCLUSIONS: On the basis of this dose-response study, K-115 0.4% has been selected to be the optimal dose and has the potential to be a promising new agent for glaucoma to control 24-hour IOP by twice-daily dosing.

Reading performance in patients with glaucoma evaluated using the MNREAD charts.

BACKGROUND: Reading performance in glaucoma patients has yet to be studied. We hypothesized that glaucomatous visual field loss affects reading performance even in patients with good acuity and evaluated their reading performance quantitatively. METHODS: A cross-sectional, comparative, non-interventional study. Forty-nine patients with early-moderate glaucomatous visual field loss OU with visual acuity better than 1.0 in the better and 0.7 in the worse eye. Reading performance in glaucoma patients was examined by the Japanese version of the Minnesota Reading Acuity Chart (MNREAD) were compared to that of age-matched normal subjects (n = 30). RESULTS: The study subjects consisted of the 21 men and 28 women. The mean age was 53.3 ± 12.6 years. Diagnosis included primary open-angle glaucoma (n = 22), normal-tension glaucoma (n = 22), developmental glaucoma (n = 4) and exfoliation glaucoma (n = 1). Reading parameters of glaucoma patients examined by MNREAD were: maximum reading speed (MRS), 329.9 ± 55.4 characters per min.; critical print size (CPS), 0.24 ± 0.14 logMAR; reading acuity (RA), 0.02 ± 0.12 log MAR, significantly lower than those of normal subjects (MRS 363.0 ± 42.9, CPS 0.09 ± 0.13 logMAR, RA -0.13 ± 0.10 logMAR, P < 0.01 for three parameters by unpaired t test). CPS in glaucoma subjects was negatively correlated with mean deviation of Humphrey Field Analyzer 10-2 and 30-2 programs in the better eye (r = -0.402, P < 0.005; r = -0.304, P < 0.05; respectively, by linear regression analysis). CONCLUSIONS: The reading performance deteriorated even in glaucoma patients with good acuity.

The relationship between the mean deviation slope and follow-up intraocular pressure in open-angle glaucoma patients.

PURPOSE: The purpose of this study was to analyze the relationship between the mean deviation (MD) slope as the progressive rate of visual field defects and the follow-up intraocular pressure (IOP) in open-angle glaucoma (OAG) patients. METHODS: This study was a retrospective, nonrandomized comparative study. A total of 287 eyes from 287 Japanese OAG patients were examined. The MD slope of the Humphrey Field Analyzer was calculated and compared with the follow-up IOP. OAG was classified into the high-tension group (>21 mm Hg) and the normal-tension group (≤ 21 mm Hg) on the basis of the highest recorded IOP without treatment, and then the 2 groups were compared. After setting a threshold for the progression rate at -0.3 dB/y, related factors were compared between the fast-progression and slow-progression eyes in each group. RESULTS: The correlation line between the follow-up IOP and the MD slope was statistically significant in the high-tension group but not in the normal-tension group. Compared with eyes with slow progression, eyes with fast progression in the high-tension group were older and had a higher mean IOP, greater highest and lowest IOPs, and a smaller mean IOP reduction ratio, whereas eyes with fast progression in the normal-tension group had a greater SD of the mean IOP, a larger IOP range, and a greater highest IOP. CONCLUSIONS: Eyes with a faster visual field progression tended to have a higher follow-up IOP in the high-tension group and larger IOP fluctuations in the normal-tension group of OAG patients. We should monitor both the follow-up IOP and fluctuations in IOP to provide a safer and more reliable visual field prognosis for OAG.

Phase 1 clinical trials of a selective Rho kinase inhibitor, K-115.

IMPORTANCE: We conducted a series of phase 1 clinical trials to elucidate the efficacy and safety of the selective Rho kinase inhibitor K-115 as a candidate drug for the treatment of glaucoma. We report the intraocular pressure (IOP)-lowering effects and safety of K-115 based on our results. OBJECTIVE: To study the IOP-lowering effects and safety of topical administration of a selective Rho kinase inhibitor, K-115, in healthy male adult volunteers. DESIGN AND SETTING: Randomized, placebo-controlled, double-masked, group comparison phase 1 clinical trial. PARTICIPANTS: In the initial single-instillation trial, 50 healthy volunteers were subdivided into groups and treated with placebo or K-115 in concentrations of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8% in a stepwise manner. In the repeated-instillation trial, another 50 healthy volunteers were subdivided into groups and treated with placebo or K-115 in concentrations of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8% twice daily for 7 days in a stepwise manner. MAIN OUTCOMES AND MEASURES: In these clinical trials, the administration of eyedrops and associated examinations (including IOP measurements) were performed in a double-masked manner. RESULTS: After single instillation of placebo or K-115 in concentrations of 0.05%, 0.1%, 0.2%, 0.4%, and 0.8%, the changes in IOP from baseline were -1.6 mm Hg for placebo and -3.4, -2.2, -2.6, -4.0, and -4.3 mm Hg, respectively, for the different concentrations 2 hours after instillation. Similar to the single-instillation trial, IOP reductions in the repeated-instillation trial were found after each instillation, with maximal reduction 1 to 2 hours after instillation. In the safety trial, slight to mild conjunctival hyperemia was found in more than half of the participants treated with K-115; it was found after each instillation and spontaneously resolved within 1½ hours. CONCLUSIONS AND RELEVANCE: K-115 is a promising drug for lowering IOP in healthy adult eyes, with tolerable adverse events during at least short-term administration.

Association of HK2 and NCK2 with normal tension glaucoma in the Japanese population.

Although family studies and genome-wide association studies have shown that genetic factors play a role in glaucoma, it has been difficult to identify the specific genetic variants involved. We tested 669 single nucleotide polymorphisms (SNPs) from the region of chromosome 2 that includes the GLC1B glaucoma locus for association with primary open-angle glaucoma (POAG) and normal tension glaucoma (NTG) in the Japanese population. We performed a two-stage case-control study. The first cohort consisted of 123 POAG cases, 121 NTG cases and 120 controls: the second cohort consisted of 187 POAG cases, 286 NTG cases, and 271 controls. Out of six SNPs showing significant association with POAG in the first round screening, seven SNPs were tested in the second round. Rs678350 in the HK2 gene coding sequence showed significant allelic (p=0.0027 in Stage Two, 2.7XE-4 in meta-analysis) association with POAG, and significant allelic (p=4.7XE-4 in Stage Two, 1.0XE-5 in meta-analysis) association with NTG. Although alleles in the TMEM182 gene did not show significant association with glaucoma in the second round, subjects with the A/A allele in TMEM182 rs869833 showed worse visual field mean deviation (p=0.01). Even though rs2033008 in the NCK2 gene coding sequence did not show significant association in the first round, it had previously shown association with NTG so it was tested for association with NTG in round 2 (p=0.0053 in Stage Two). Immunohistochemistry showed that both HK2 and NCK2 are expressed in the retinal ganglion cell layer. Once multi-testing was taken into account, only HK2 showed significant association with POAG and NTG in Stage Two. Our data also support previous reports of NCK2 association with NTG, and raise questions about what role TMEM182 might play in phenotypic variability. Our data suggest that HK2 may play an important role in NTG in the Japanese population.

[Comparison between binocular and monocular reading ability and its relation with central visual field sensitivity in glaucoma patients].

PURPOSE: To evaluate binocular and monocular reading ability in glaucoma patients with good visual acuity and to examine its relationship with central visual field sensitivity. METHODS: Glaucoma patients(35 individuals, mean +/- SD : 51.8 +/- 12.9 years) with a decimal visual acuity in each eye of >or=1.0, reading ability was tested both binocular and monocular using Japanese version of Minnesota Reading Acuity Chart (MNREAD-J). Reading ability parameters were calculated for maximum reading speed (MRS), critical print size (CPS), and reading acuity (RA). The results were compared with those of people with normal vision; differences in reading ability under varied testing conditions and correlations between visual field sensitivity and each parameter were examined. RESULTS: Under binocular reading conditions, MRS, CPS, and RA were decreased significantly in glaucoma patients compared with normal controls (p = 0.00044, p = 0.00004, p = 0.00028, respectively). Under monocular reading conditions, glaucoma patient MRS and RA were decreased significantly in comparison with normal controls (p=0.00155, p= 0.00142). In glaucoma patients undergoing binocular reading tests, MRS was greatest in the paracentral bottom right quadrant of the worse eye (r = 0.41709, p= 0.04447). The CPS decreased in proportion to the extent of the difference between both eyes in the mean deviation value and the visual field sensitivity of the paracentral bottom left (r = 0.40693, p = 0.02699 and r=0.41478, p=0.02384). RA improved in proportion to the extent of the difference between both eyes in the visual field sensitivity of the upper left (r = 0.33557, p=0.04799). CONCLUSION: In glaucoma patients, binocular reading is not necessarily useful in cases of visual field sensitivity differences.