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AimsTo investigate the association between corneal hysteresis and the presence of glaucoma and its subtypes in a general Japanese population.MethodsWe analysed the data of 2338 Japanese community-dwellers aged ≥40 years (1059 men, 1279 women) who underwent an eye examination in 2018 as part of the population-based, cross-sectional Hisayama Study. Participants were divided into quartile levels of corneal hysteresis, which had been measured with an ocular response analyzer. Glaucoma was defined based on the International Society of Geographical and Epidemiological Ophthalmology criteria. We conducted a logistic regression analysis to determine the ORs and their 95% CIs for the presence of outcomes according to the corneal hysteresis quartiles.ResultsGlaucoma was diagnosed in 154 participants: primary open-angle glaucoma (POAG), n=115; primary angle-closure glaucoma, n=17; exfoliation glaucoma, n=21 and secondary glaucoma without exfoliation glaucoma, n=1. After adjustment for confounders, the OR for prevalent glaucoma was significantly increased in the participants in the first corneal-hysteresis quartile compared with those in the fourth quartile (OR: 1.80; 95% CI: 1.03 to 3.17). Regarding glaucoma subtypes, the first-quartile participants had significantly greater likelihoods of the presence of POAG (OR: 1.63; 95% CI: 1.02 to 2.61) and exfoliation glaucoma (OR: 6.49; 95% CI: 1.44 to 29.30) compared with those in the third and fourth quartiles after adjustment for potential confounders.ConclusionsThese results demonstrated a significant inverse association between corneal hysteresis and the likelihood of glaucoma, suggesting that the measurement of corneal hysteresis would provide useful information for elucidating the aetiology of glaucoma.

Background/Objectives: To identify factors associated with disc/retina deterioration in stereo fundus photographs preceding that of the visual field (VF), as determined with a Humphrey Field Analyzer (HFA) (Structure First deterioration) and factors associated with the latter preceding the former (Field First deterioration) in open-angle glaucoma (OAG) with lower normal intraocular pressure (IOP). Subjects/Methods: Prospective cohort study. Ninety eyes of 90 patients with OAG and a baseline IOP < 15 mmHg participated in a 5-year prospective study without treatment. IOP measurements and HFA 24-2 Swedish Interactive Test Algorithm Standard tests were performed every 3 months, and fundus photographs were obtained every 6 months. VF deterioration was determined by Guided Progression Analysis and deterioration of disc/retina was determined on stereophotographs by an independent committee. A multivariable Cox proportional hazard model was used to identify factors associated with Structure First deterioration, and with Field First deterioration. Results: The average baseline age and mean deviation were 53.9 ± 9.8 years and −2.8 ± 2.8 dB, respectively. During the 5-year follow-up, the probability of Field First deterioration was 49% ± 6.6% (standard error) and that of Structure First deterioration was 33% ± 6.4% (P= 0.062, log-rank test). Disc hemorrhage (DH) prior to the event (P= 0.006) was associated with Structure First deterioration, and older age was associated with Field First deterioration (P= 0.040). Conclusions: In OAG eyes with lower normal IOP, DH was significantly associated with Structure First deterioration, and age was significantly associated with Field First deterioration.

ABSTRACTIn an ex vivorat glaucoma model using dissected retinas, the neurosteroid allopregnanolone (AlloP) protects retinal ganglion cells (RGCs) via GABR/GABAAreceptors. To determine the involvement of macroautophagy/autophagy in neuroprotection by AlloP, we examined the effects of autophagy activators, rapamycin and torin 2, and autophagy inhibitors, bafilomycin A1and SAR405, on retinal retinal morphology and expression of MAP1 LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) and SQSTM1 (sequestosome 1). Administration of rapamycin or torin 2 exerted partial histological neuroprotection, while combined administration of AlloP with bafilomycin A1or SAR405 induced severe degeneration in a hyperbaric condition. Electron microscopic analyses showed that the addition of AlloP significantly increased autophagosomes and degenerative autophagic vacuoles in the retinal nerve fiber layer. Immunoblotting showed that the addition of AlloP or autophagic activators increased the lipidated form of LC3B (LC3B-II) and suppressed SQSTM1. Moreover, bafilomycin A1increased LC3B-II and SQSTM1 protein levels in the presence of AlloP without changes in corresponding mRNAs compared to AlloP-treated retinas in a hyperbaric condition. These data indicate that AlloP likely induces a protective form of autophagy in this model. In an in vivorat model of glaucoma, we also observed neuroprotective effects of AlloP. Injection of polystyrene microbeads into the anterior chamber increased intraocular pressure about 3-fold and induced RGC apoptosis. A single intravitreal injection of AlloP or autophagy activators prevented apoptosis and protected RGCs with autophagy activation. We conclude that AlloP may serve as a potential therapeutic agent for the treatment of glaucoma via diverse mechanisms.Abbreviations:2HBCD: 2-Hydroxypropyl)-β-cyclodextrin; 3-MA: 3-methyladenine; AlloP: allopregnanolone; AP: autophagosome; AVd: degradative autophagic vacuoles; GCL: ganglion cell layer; INL: inner nuclear layer; IOP: intraocular pressure; IPL: inner plexiform layer; LC3B-I: cytosolic form of LC3B; LCB-II: lipidated form of LC3B; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mPTP: mitochondrial permeability transition pore; NDS: neuronal damage score; NFL: nerve fiber layer; OH: ocular hypertension; ON: optic nerve; ONL: outer nuclear layer; OPL: outer plexiform layer; p-STR: scotopic threshold response; RGC: retinal ganglion cells; RT-PCR: real-time reverse transcription polymerase chain reaction; SQSTM1: sequestosome 1; TUNEL: TdT-mediated dUTP Nick End Labeling

To study the optic disc characteristics using the Heidelberg Retina Tomograph (HRT) II in normal Japanese subjects.

In order to clarify the vasodilatory mechanism of betaxolol and timolol, we studied the effects of these drugs in isolated rabbit ciliary arteries. Rabbit ciliary artery specimens were mounted in a double myograph system, and betaxolol, timolol, or another agent was introduced into the organ chamber. The mechanical response of the arteries was studied using an isometric tension recording method. The intracellular free calcium concentration [Ca2+]i was also measured using fluorescence photometry. Betaxolol and timolol induced dose-dependent relaxation in the rabbit ciliary arteries precontracted by high-K+Krebs solution. The minimum concentrations required to cause relaxation were 10 µM of betaxolol, and 30 µM of timolol. At the maximum concentration of 1 mM, betaxolol induced almost complete relaxation of the ciliary arteries, whereas timolol induced approximately 70% relaxation. These actions were not inhibited by pretreatment with 100 µM NG-nitro-l-arginine methylester (L-NAME), a nitric oxide synthase inhibitor, or by denudation of the vascular endothelium. However, 300 µM of betaxolol or timolol decreased the [Ca2+]i of the vascular smooth muscle, an action similar to that of diltiazem, a typical L-type voltage calcium-channel blocker. Betaxolol, a selective β1-adrenoceptor antagonist, and timolol, a nonselective β-adrenoceptor antagonist, both frequently used in the medical management of glaucoma, decrease [Ca2+]i by acting as Ca2+channel blockers, thus causing relaxation of isolated rabbit ciliary artery.

To examine whether the application of immunosuppression enhances the survival of limbal allograft stem cells. Wistar (allograft) or Fischer 344 (isograft) rat limbal tissue was transplanted into superior lamellar excision sites in Fischer 344 rats. Allograft-recipient rats received an immunosuppressive agent or vehicle for 8 weeks. Graft-recipient rats were examined by slit-lamp microscopy for clinical signs of rejection, and some recipients were killed for immunohistochemical analysis during rejection. One month from the time of transplantation, other (five in each group) recipients received daily injections of 5-bromo-2-deoxyuridine (BrdU) at a dose of 5 mg/100 g for 2 weeks, followed by a 1-month BrdU-free period before death. After the rats were killed, limbal allograft eyes were removed for BrdU staining to identify label-retaining cells. The labeling index of transplanted limbal basal epithelial cells was determined. In nonimmunosuppressed allograft recipients, clinical rejection occurred between days 5 and 10 after transplantation (median, 7 days). In contrast, rejection was suppressed for more than 60 days (median value) when the immunosuppressive was administered. Numerous MHC class II+, CD4+, and CD8+T cells were identified with acute rejection. Immunosuppressive-treated allografts had significantly less inflammation compared with untreated controls. Furthermore, immunosuppressive-treated allografts showed more label-retaining basal cells in transplanted limbal epithelium compared with untreated allograft controls (P< 0.01). The survival of limbal allograft stem cells can be improved by immunosuppression. The limbal allograft procedure described here provides a useful model for evaluating a suitable alternative means of sustaining the survival of corneal stem cells.

Abstract The purpose of this histological study was to determine the effects of photodynamic treatment, using a hematoporphyrin derivative and argon laser, on normal retinas of monkeys. Ten cynomolgus monkeys were treated with a hematoporphyrin derivative, given intravenously at a dose of 2.5 mg/kg. Forty minutes or 1 or 3 days after the injection, argon laser photoradiation was given over a 2.0-mm-diameter with a 10-min exposure and at an intensity of 40, 100, or 200 mW. The eyes were enucleated 1, 3, 4, 15, 18, 21, 35, or 38 days after the photoradiation and tissue samples were observed under a transmission electron microscope. The most fragile regions in the retina were the retinal nerve fibers, the outer segments of the visual cells, and the retinal pigment epithelium. Vascular endothelial cells were also fragile. The retinal capillary was easily obstructed, and the choriocapillaris was also occluded in an animal with severe retinal damage. The Mueller cells had the highest tolerance to the photodynamic treatment. Thus, exposing the normal part of the retina to light during photodynamic therapy should be avoided.

Abstract. Background: Latanoprost is a prostaglandin (PG)F_2α analogue widely recognized in the treatment of glaucoma. To investigate the action of this drug on the ocular circulation, we have studied its effects on isolated rabbit ciliary artery. The data obtained on this drug are compared with the data from PGE₂ and PGF_2α. Methods: Under the microscope, ciliary artery specimens were prepared from rabbit eyes and mounted in a myograph system. The effects of latanoprost, PGE₂, and PGF_2α on the isolated rabbit ciliary artery were investigated in vitro using isometric tension recording methods. Results: Exogenously applied PGF_2α, but not latanoprost, evoked contraction in the rabbit ciliary artery. After precontraction with excess-[K]₀ solution, latanoprost evoked relaxation dose-dependently. Latanoprost at a concentration of 100µM induced maximum relaxation, which was not blocked by 10 µM L-nitro-L-arginine methylester (L-NAME), 1 µM 8-37 calcitonin gene-related peptide (CGRP) or 10 µM indomethacin. Moreover, latanoprost induced relaxation even in preparations without endothelium. The maximum relaxation obtained with PGE₂ was somewhat less than 50% of that with latanoprost. Conclusions: These results indicate that latanoprost and PGE₂ relaxed rabbit ciliary artery to different degrees. The relaxation provoked by latanoprost was not dependent on endothelium and was not caused by intrinsic PG, CGRP or nitric oxide. The mechanism of this relaxation is not yet clear.

Purpose:Ciliary muscle tone is considered to be an important factor for control of uveoscleral outflow. In an attempt to clarify the functional roles of the ciliary muscle in uveoscleral outflow, the effects of latanoprost, prostaglandin (PG)F 2α or nipradilol, all of which are known to increase uveoscleral outflow, were investigated, using the bovine ciliary muscle.

The effect of insertion of an exogenous gene on smooth muscle function in rabbit iris sphincter muscle was investigated. An adenoviral vector encoding the bacterial LacZ gene (AdLacZ, 107 pfu) and viscoelastics were injected into the posterior chamber of eyes of albino rabbits. Three days after injection, the effects of acetylcholine (Ach), carbachol (Carb), substance P (SP) and electrical field stimuli on isolated iris sphincter were investigated using isometric tension-recording methods. X-Gal histostaining showed that iris sphincter smooth muscle cells were transfected in 7 of 11 muscle strips. Contraction-response curves for Ach, Carb or SP were not different from control. We conclude that the iris sphincter muscle can be gene-transfected by posterior chamber infusion of an adenoviral vector with viscoelastics. Adenovirus-mediated gene transfer per se had no measurable effect on tension development.

• Background and methods: In an attempt to clarify the functional action of histamine and substance P on atropine-resistant miosis, we isolated rabbit and human iris sphincter muscles and investigated their mechanical properties using the isometric tension recording method. • Results: Substance P dose-dependently contracted the rabbit iris sphincter, but had no effect on the human iris sphincter. In the rabbit iris sphincter, histamine reduced the amplitude of twitch contraction evoked by field stimulation but had no effect on carbachol-induced contraction. Thioperamide, but not mepyramine or cimetidine, partially antagonized the histamine-induced reduction in the amplitude of twitch contractions. In the human iris sphincter, on the other hand, histamine dose-dependently provoked contraction and the amplitude of histamine-induced contraction was affected neither by atropine nor by indomethacin. • Conclusions: These results provide evidence that histamine has strong contractile effect on the human iris sphincter muscle; the rabbit iris sphincter muscle, however, apparently lacks functional histamine receptors. In rabbits, exogenously applied histamine only activates H3 receptors located on the cholinergic nerve terminal, hence the excitatory neuro-effector transmission is suppressed. Thus, histamine may have an important roles in atropine-resistant miosis in humans, but not in rabbits.

To investigate the functional innervation pattern in smooth muscle of bovine ophthalmic artery, we studied the effect of electrical stimulation and various drugs on the mechanical responses of this muscle using isometric tension recording methods. Electrical stimulation evoked phasic contractions which were abolished by guanethidine and tetrodotoxin (TTX), suggesting that the responses were neurogenic in origin. Phentolamine (10-5M) and 10-5M timolol did not affect this contractions, but 10-5M phentolamine and 10-6M prazosin markedly reduced the amplitude of contraction evoked by exogenously applied phenylephrine (10-5M). Electrical stimulation applied during sustained contraction evoked by 5-hydroxytryptamine in the presence of guanethidine and atropine evoked relaxation which was markedly suppressed by TTX. These results indicate that bovine ophthalmic artery is innervated by adrenergic nerve fibers, and an unidentified neurotransmitter, other than noradrenaline, may play an important role in the excitatory neuroeffector transmission, and that the tissue is also innervated by non-adrenergic non-cholinergic inhibitory nerve fibers.

Histological and immunohistochemical studies of a granular cell tumor involving the lower lid are described. Histological examination showed it to have typical features of a granular cell tumor. Nervous-system-specific protein (S-100 protein) was detected in both the nuclei and cytoplasm of granular cells using the peroxidase-anti-peroxidase method. This result further supports the concept of the neurogenic origin of granular cell tumors.

In an attempt to clarify the functional role of adrenoceptors in accommodation, the effects of various adrenergic agents on the state of accommodation were studied. Fifty-two emmetropic, visually normal subjects (24.6 ± 0.42 years old) participated in this study. Using an infrared optometer, the far and near points of accommodation were measured by a quasistatic method. Tonic accommodation and accommodative adaptation were also investigated. All these parameters were measured before and after topical application of various adrenergic agents. Both bunazosin hydrochloride (0.1%) and phenylephrine hydrochloride (5%) had no effect on tonic accommodation and accommodative adaptation. However, bunazosin hydrochloride increased the near point of accommodation. Timolol maleate (0.5%) and isoproterenol hydrochloride (3.0%) did not affect tonic accommodation. Isoproterenol hydrochloride evoked a hyperopic shift of the far point of accommodation by 0.23 ± 0.42 diopters (D). Additionally, accommodative adaptation was increased by timolol maleate (0.36 ± 0.62 D) and decreased by isoproterenol hydrochloride (0.18 ± 0.48 D). These results indicate that both α and β adrenoceptors affect accommodation. Activation of α adrenoceptors increased the near point of accommodation and activation of β adrenoceptors decreased accommodative adaptation, which suggests that activation of adrenoceptors may modify parasympathetic activity; hence, affecting the state of accommodation.

The contractile activity of endothelins (ETs) and their effect on twitch contraction evoked by electrical field stimulation were studied in the isolated rabbit iris sphincter and dilator muscles using the isometric tension recording method. ET-1, ET-2 and ET-3 caused slow contractile response of the sphincter as well as the dilator muscles, with sphincter muscle EC50 values of 37.3, 58.0 and 84.3 nM, and dilator muscle values of 31.7, 69.0 and 224.4 nM, respectively. These contractile responses were not affected by atropine (1 μM), prazosin (1 μM) or indomethacin (1 μM).ET-1 and ET-3 slightly but significantly inhibited the fast cholinergic component of twitch contraction of the sphincter muscle evoked by field stimulation, without affecting the response to carbachol. However, ET-1 did not affect the slow substance P-ergic component of twitch contraction of this preparation. In the dilator muscle, ET-1 and ET-3 had little effect on the contraction induced by phenylephrine but reduced the amplitude of the twitch contraction evoked by the field stimulation. The inhibitory effect of ETs on the dilator muscle was antagonized by pretreatment with BQ-123 (100 nM), which is a selective ETA receptor antagonist. Pretreatment with indomethacin (1 μM) also attenuated the inhibitory effect of ETs on the twitch contraction.These results suggest that ETs may have two sites of action, pre- and post-synaptic effects, on the rabbit iris sphincter muscle as well as the dilator muscle. All three ET isopeptides may have direct contractile activity on the smooth muscles of the sphincter as well as the dilator without mediation by prostaglandins or neuronal mechanisms. Furthermore, ETs may act on nerve endings to inhibit adrenergic and cholinergic neurotransmission in the iris dilator and sphincter, respectively.

Pharmacological profiles of endothelin (ET) receptors in the isolated rabbit iris sphincter were characterized. ET isopeptides caused dose-dependent contraction of the preparation. The respective EC50 values for ET-1, ET-2 and ET-3 were 39.4, 58.0 and 84.3 nM, so that ET-1 was twice as potent as ET-3. Sarafotoxin (SRTX) -b, an ETA/ETB non-selective agonist, caused very potent contraction with an EC50 of 1.13 nM. However, selective ETB receptor agonists SRTX-c and IRL 1620 showed no contractile activity up to 1 μM.BQ-123, a selective ETA receptor antagonist, shifted the dose-response curves of ET isopeptides to the right. The pA2 value for ET-I was 5.52 with a slope of 1.06, which is not different from unity, and the pKB value for ET-2 was 5.06. Interestingly, very low doses of BQ-123 antagonized responses to ET-3 and SRTX-b, with a Schild plot slope of approximately 0.7 which is significantly different from unity, suggesting receptor heterogeneity. The abscissal intercepts of the Schild plots were -9.29 for ET-3 and -8.53 for SRTX-b. FR 139317, another ETA receptor antagonist, also preferentially antagonized responses to ET-3. RES 701-1, a selective ETB receptor antagonist, did not shift dose-response curves for ET-1 and ET-3.These results suggest that ET receptors in the rabbit iris sphincter muscle cannot be classified into the ETA, ETB or ETc receptor subtypes, so far established. When compared to the established receptor subtypes, ET receptors in this preparation were quite different from the ETB receptor, but apparently showed a pharmacological profile most similar to the ETA receptor, suggesting the presence of heterogeneous and atypical ETA receptors.

Calcitonin gene-related peptide (CGRP) and Substance P (SP)-immunoreactive nerves have been found in the anterior uvea of various mammalian species. Although SP is known to play a major role in control of pupil motility in rabbits, little is known about the effect of CGRP on the iris smooth muscles. We isolated iris sphincter and dilator muscles from rabbit eyes and investigated the mechanical responses and intracellular cyclic AMP (cAMP) levels in these muscles. CGRP (up to 0.1 μM) had no effect on either the resting muscle tone or the amplitude of contraction evoked by field stimulation of the sphincter. On the other hand, CGRP (0.1 μM) relaxed dilator muscle which had been pre-contracted by phenylephrine and reduced the amplitude of contraction evoked by field stimulation. These responses were antagonized by CGRP (8-37), a CGRP antagonist. The phosphodiesterase inhibitor, 3-isobutyl-l-methylxanthine (IBMX), dose-dependently inhibited the contraction evoked by field stimulation. However, 3 μM IBMX had no effect on CGRP inhibition of twitch contraction in this preparation. CGRP had little effect on cAMP production in dilator muscle either with or without IBMX. In conclusion, the miosis which occurs during an ocular inflammatory response, when both CGRP and SP are thought to be released from terminals of sensory neurons, results from CGRP relaxation of the dilator and from the strong contractile effect of SP on the sphincter. Adenylate cyclase activation does not seem to be involved in the relaxant effect of CGRP on the dilator.

Purpose. To describe the first case of multiple retinal holes in the macular region successfully treated with vitrectomy. Method. A single case report. A 44-year-old man was treated for impaired vision caused by multiple macular holes in the right eye. Results. Fundus examinations detected six retinal holes in the right macula and a giant macular hole in the left eye. Optical coherence tomography disclosed multiple vitreoretinal adhesions in the right macula. We vitrectomized the right eye to produce posterior vitreous detachment and then tamponaded the vitreous cavity with 20% SF6gas, resulting in closure of holes and improvement of the vision. Conclusion. Multiple macular holes may be treated by surgical posterior detachment combined with gas tamponade. Vitreoretinal adhesions are a possible cause of these holes. Similar multiple holes may have coalesced into one giant hole in this patient's left eye.