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H-7 disrupts the actin cytoskeleton and increases outflow facility.

OBJECTIVES: To determine the effects of the serine-threonine kinase inhibitor H-7 on (1) cell junctions and the attached actin-based cytoskeleton in cultured bovine aortic endothelial cells, and (2) outflow facility in living monkeys. METHODS: Bovine aortic endothelial cells were cultured by standard techniques. The architecture and distribution of actin filaments, vinculin, and beta-catenin in bovine aortic endothelial cells were studied by immunolabeling before and after exposure to H-7 at various concentrations and durations. Outflow facility (perfusion) and intraocular pressure (Goldmann tonometer) were determined before and after the intracameral or topical administration of H-7 or a vehicle. RESULTS: In bovine aortic endothelial cells, exposure to H-7 produced a reversible time- and concentration-dependent disruption of actin microfilaments and an alteration in the organization of cell-cell and cell-matrix adhesions. In monkeys, intracameral and topical administration of H-7 dose dependently and reversibly doubled facility, and topical H-7 reduced intraocular pressures. CONCLUSION: H-7 increases outflow facility in monkeys, probably by inhibiting cell contractility, cytoskeletal support, and cell-cell adhesions in the trabecular meshwork.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

Anterior chamber depth measurement as a screening tool for primary angle-closure glaucoma in an East Asian population.

OBJECTIVE: To evaluate anterior chamber depth measurement as a method of screening for primary angle-closure glaucoma in an East Asian population. DESIGN: Two-phase, cross-sectional, community-based study. SETTING: Rural and urban locations in the Hovsgol and Omnogobi provinces, Mongolia. PARTICIPANTS: Nine hundred forty-two (94.2%) of 1000 individuals in Hovsgol(1995) and 775 (96.9%) of 1000 individuals in Omnogobi (1997) aged 40 years or older were examined. MAIN OUTCOME MEASURES: Anterior chamber depth was measured by optical pachymetry, slitlamp-mounted A-mode ultrasound, and handheld ultrasound. Gonioscopy was used to detect occludable angles, defined as one in which the trabecular meshwork was visible for less than 90 degrees of angle circumference. Primary open-angle glaucoma was diagnosed in subjects with an occludable angle and glaucomatous optic neuropathy with visual morbidity. The area under the curve in a receiver operating characteristic plot was used to compare test performance. RESULTS: Optical pachymetry outperformed the slitlamp-mounted ultrasound method of anterior chamber depth measurement (area under the curve, 0.93 and 0.90, respectively; z test, P = .001). Handheld ultrasound (area under the curve, 0.86) was inferior to optical measurement (z test, P = .001) but did not differ significantly from slitlamp ultrasound (z test, P = .06). The optical method gave sensitivity of 85% and specificity of 84% at a screening cutoff of less than 2.22 mm for detecting occludable angles. CONCLUSIONS: Measurement of axial anterior chamber depth can detect occludable angles in this Asian population and therefore may have a role in population screening for primary angle-closure glaucoma.

Adult↗

Essential iris atrophy. Report of a case.

The clinicopathologic findings in an eye from a 40-year-old man with essential iris atrophy are reported. Noteworthy is the proliferation of corneal endothelium and a laying down of a new Descemet (cuticular) membrane over the trabecular meshwork and in areas of anterior peripheral synechiae formation over the pseudoangle. The histologic characteristics favor a vascular cause for the condition, but the evidence is circumstantial.

Adolescent↗

Aqueous humor ascorbate concentration and open-angle glaucoma.

The mean value for aqueous concentration in 35 patients with open-angle glaucoma was 22.4 +/- 12.9 mg/100 ml. The mean value for aqueous ascorbate in four patients with uncomplicated senile cataract was 11.55 +/- 3.01 mg/100 ml. The results indicate that the majority of open-angle glaucomatous eyes do not involve a deficiency of ascorbate, and suggest that ascorbate has no therapeutic value in the management of primary open-angle glaucoma. The magnitude of aqueous ascorbate variation among glaucoma eyes is probably related to the factors that influence the patency of trabecular meshwork, not the metabolic activity of the ciliary processes.

Animals↗

Recurrent traumatic hyphema. A sequel of injury to the Schlemm canal.

A patient with recurrent hyphema following blunt trauma to the left eye was found to have an angle recession with a laceration of the trabecular meshwork and Schlemm canal. Active bleeding from the Schlemm canal proved to be the cause of the recurrent hyphema. Repeated trials of bed rest and bilateral eye patching provided only temporary control of the bleeding. Cessation of the active bleeding and subsequent resolution of the hyphema was achieved following argon laser photocoagulation to the traumatized portion of the Schlemm canal. While hyphema is a common manifestation of blunt ocular trauma, visible rupture of the Schlemm canal is most unusual. This paper describes the gonioscopic findings of a rupture of the Schlemm canal in a patient who had a traumatic hyphema and recurrent bleeding.

Adult↗

Proliferative endotheliopathy with iris abnormalities. The iridocorneal endothelial syndrome.

Sixteen cases of essential iris atrophy and two of iris nevus (Cogan-Reese) syndrome were reviewed retrospectively by light and electron microscopy. Varying degrees of corneal endothelial proliferation onto the trabecular meshwork and anterior iris were seen in all cases. The demonstration of an endothelial-abnormal basement membrane complex on the anterior iridic surface, deep to synechias in over half the cases, indicates that endothelialization may be primary, since it precedes the formation of anterior synechias. Pathologic and clinical evidence suggests that the iris nevus syndrome, Chandler's syndrome, and essential iris atrophy represent a continuum of clinical manifestations of a single disease process involving proliferation of the corneal endothelial and characteristic iris abnormalities; the latter may be secondary to variations in the pattern, rate, and extent of endothelial proliferation. We suggest the term "proliferative endotheliopathy" to emphasize the common pathogenetic role of corneal endothelial proliferation in all three entities (iris nevus syndrome, Chandler's syndrome, and essential iris atrophy). A more succinct alternate term is "the iridocorneal endothelial (ICE) syndrome."

Adult↗

Are most iris "melanomas' really nevi? A clinicopathologic study of 189 lesions.

A retrospective clinicopathologic study of 189 iris and iris and ciliary body lesions originally diagnosed as melanomas led to a nine-part histopathologic classification. Eighty-seven percent of lesions were reassigned to six benign categories and 13% were assigned to three malignant ones (spindle-B and epithelioid cell melanomas). There were no tumor deaths. The benign lesions were so classified if the constituent cells displayed bland cytologic characteristics, even though they might have produced a surface plaque or growth onto the trabecular meshwork and peripheral cornea. No clinical features were found to distinguish the benign from malignant tumors, including diffuse spread and the presence of glaucoma. The six recurrent tumors were equally divided between benign and malignant lesions. Thirty-six of 42 patients with incompletely excised lesions did not show further clinical problems on follow-up, establishing the inherently benign nature of most of the tumors.

Adolescent↗

Clearance from the anterior chamber of RBCs from human diabetics.

Erythrocytes from diabetic patients manifest decreased deformability and increased adherence. These abnormal membrane properties may diminish the ability of erythrocytes (RBCs) from diabetics to undergo deformation in passage through the trabecular meshwork. Using sodium chromate Cr 51-labeled RBCs from type I diabetic patients with proliferative retinopathy and normal control subjects, we studied RBC clearance from the rabbit anterior chamber. The mean time for 50% clearance (T50) of RBCs from diabetics (76 hours) was significantly longer than that for RBCs from normal subjects (19.5 hours). In this model, RBCs from diabetics have a slower clearance from the anterior chamber than do RBCs from normal subjects.

Adult↗

Intraocular pressure effects of multiple doses of drugs applied to glaucomatous monkey eyes.

The effects of multiple dosing with 0.5% timolol maleate, 2% epinephrine hydrochloride, 4% pilocarpine hydrochloride, 1% vanadate, 1% forskolin (nonproprietary name, colforsin), or 0.5% prostaglandin F2 alpha on intraocular pressure (IOP) were each tested on eight cynomolgus monkey eyes in which glaucoma was induced by photocoagulating the trabecular meshwork with the argon laser. The week prior to drug therapy, baseline IOP measurements were carried out at hourly intervals from 9:30 am to 3:30 pm on three days. One to two days later, therapy was initiated. Each drug was applied topically to both eyes of each monkey twice daily for at least four days. The IOP was measured with a calibrated pneumatonometer at the same hourly intervals on treatment days as on the baseline days. The IOP at each time of day on treatment days was compared with the average baseline IOP measured at the corresponding time of day. Topical application of timolol, epinephrine, pilocarpine, vanadate, and prostaglandin F2 alpha significantly reduced IOP without evidence of tolerance or tachyphylaxis during the course of therapy. Forskolin did not significantly decrease IOP after the second day of treatment.

Animals↗

Pathogenesis of epidemic dropsy glaucoma.

Thirty-one cases of epidemic dropsy with raised intraocular pressure were studied. Glaucoma was bilateral in all, with open angles and no signs of anterior segment inflammation. The outflow facility was unimpaired (C value, 0.24 +/- 0.09 microL/min/mm Hg). Aqueous bioassays revealed significantly elevated prostaglandin E2 level (23.33 +/- 4.32 ng/mL) and histamine activity (13.0 +/- 2.76 ng/mL) in all samples from patients with epidemic dropsy glaucoma as compared with negligible levels in control samples from patients with open angle glaucoma. Aqueous biochemical analysis revealed increased total protein level (1.03 +/- 0.10 g/L) with a normal globulin pattern as compared with controls (0.26 +/- 0.08 g/L). On histopathologic and histochemical testing, a normal trabecular meshwork was found in 11 of the 12 trabeculectomy specimens. It is concluded that dropsy glaucoma is hypersecretory in nature; prostaglandin and histamine release may have significant roles in its pathogenesis.

Alkaloids↗

Malignant melanoma of the iris in xeroderma pigmentosum.

Xeroderma pigmentosum is an autosomal recessive, precancerous dermatosis caused by defective repair of ultraviolet-damaged DNA. Characterized clinically by progressive cutaneous pigmentary alterations and tumorigenesis, it serves as a model for ultraviolet carcinogenesis. We describe the clinical and histopathologic findings in a 31-year-old woman with xeroderma pigmentosum and a massive iris melanoma of the left eye. Histologic examination following enucleation revealed diffuse iris replacement by spindle and epithelioid cells with extension into the trabecular meshwork. Evidence of direct extraocular extension was absent, and a metastatic evaluation showed no abnormalities. To our knowledge, this is the first reported case of xeroderma pigmentosum complicated by melanoma of the iris. It provides further evidence suggesting a role for sunlight exposure in the pathogenesis of uveal melanoma.

Adult↗

Effect of sulcus vs capsular fixation on YAG-induced pressure rises following posterior capsulotomy.

Neodymium-YAG capsulotomy for secondary cataracts can induce acute intraocular pressure rises, possibly by a blocking of the trabecular meshwork by debris. To test a hypothesis that bag-fixated intraocular lenses may act as a barrier to debris, thus reducing pressure rises after YAG capsulotomy, we conducted a study comparing pressures (at 1, 2, 3, 6, and 24 hours after YAG capsulotomy) between bag-fixated and sulcus-fixated cases. There were substantial and statistically significant intraocular pressure rises in the sulcus-fixated group starting at 1 and 2 hours after YAG capsulotomy, and peaking at 3 hours (mean rise, 7.83 mm Hg). There were no such peaks of intraocular pressure rise among bag-fixated cases (mean change, -0.32 mm Hg at 3 hours). There was a weak but significant (r = -.18) correlation between the change 1 hour after YAG capsulotomy in intraocular pressure and percent of enclosure of the intraocular lens optic among bag-fixated cases. Higher proportions (fourfold to fivefold) of cases with sulcus-fixated lenses had significant flare and particulate matter in the anterior chamber, compared with bag-fixated cases.

Adolescent↗

Argon laser trabeculoplasty controls one third of cases of progressive, uncontrolled, open angle glaucoma for 5 years.

Seventy-eight patients (109 eyes) with progressive glaucoma had argon laser trabeculoplasty as a substitute for filtration surgery and were then followed up for a minimum of 5 years. One hundred spots were placed at the anterior margin of the posterior trabecular meshwork over 360 degrees. Consecutive cases between 1980 and 1985 were reviewed, 95% of treated cases being included in the final analysis. Eighty-two eyes had primary open angle glaucoma. If only the group with primary open angle glaucoma is considered, the failure rate the first year was 19%. After that, the failure rate was approximately eight per year. At the end of 5 years, 65% of all eyes had failed. At the end of 10 years, data were available on 84 of the original 109 treated eyes; in 80 treatment had failed, and four were still receiving medical therapy.

Adult↗

Juxtacanalicular tissue in pigmentary and primary open angle glaucoma. The hydrodynamic role of pigment and other constituents.

We tested the hypothesis that obstruction of the juxtacanalicular tissues, by melanin granules in pigmentary glaucoma and by other impermeable material in primary open angle glaucoma, leads to the development of a chronic glaucomatous condition. The distribution and concentration of melanin and other impermeable materials in the juxtacanalicular tissues and elsewhere in the trabecular meshwork was determined in 13 specimens. Six specimens were from patients with pigmentary glaucoma, two from patients with pigment dispersion syndrome, and three from patients with primary open angle glaucoma, as well as two from normal subjects. The effect of these materials on flow resistance was estimated using two hydrodynamic models. In model A, the electron-lucent spaces of the juxtacanalicular tissue were assumed to be open spaces, while in model B, these spaces and spaces filled with ground substance were assumed to be gel filled. In pigmentary glaucoma, 3.5% of the pigment was found in the juxtacanalicular tissue, while 96.5% was found in the corneoscleral and uveoscleral tissues. Permeabilities calculated according to model A were much higher than those expected from estimates of outflow facility in all groups, in agreement with the previous report of Ethier et al. The gel-filled spaces available for fluid flow, as determined by model B, showed no statistically demonstrable differences (pigmentary glaucoma, 32.9%; primary open angle glaucoma, 36.6%; pigment dispersion syndrome, 43.4%; normal, 44.1%). Furthermore, the amount of pigment present in the juxtacanalicular tissue was determined to have a negligible influence on permeability. Thus, the development of the chronic glaucomatous condition cannot be directly attributed to pigment accumulation in the juxtacanalicular tissue in pigmentary glaucoma.

Adult↗

Cutaneous malignant melanoma with diffuse intraocular metastases.

A 63-year-old man with a history of cutaneous melanoma and a 3-month history of visual loss in his right eye presented with marked pigmentation of the anterior-segment structures, including trabecular meshwork, iris, and lens surface, with pigment dispersion in the aqueous and anterior vitreous in the right eye. Clinical examination and echography showed no evidence of an intraocular tumor although metastatic melanoma was suspected. Pathologic examination revealed numerous heavily pigmented melanoma cells throughout the anterior segment of the eye, mainly concentrated in the anterior vitreous near the ciliary body. No discrete tumor was found on multiple sections through the globe.

Anterior Eye Segment↗

Phalloidin inhibits epinephrine's and cytochalasin B's facilitation of aqueous outflow.

OBJECTIVE: To determine whether phalloidin, a fungal peptide that inhibits actin filament depolymerization, could inhibit the ability of cytochalasin B and epinephrine to increase the facility of aqueous outflow in the eyes of living cynomolgus monkeys. METHODS: Outflow facility was determined by two-level constant-pressure perfusion of the anterior chamber. After measurement of baseline facility in both eyes, one eye of each animal received intracameral phalloidin (1.3, 13, or 130 mumol/L); the opposite eye received vehicle. Both eyes then received either epinephrine (0.3 mmol/L) or cytochalasin B (0.2 mmol/L), and facility was again measured. RESULTS: Cytochalasin B and epinephrine increased facility by 120% to 190% and 100% to 180%, respectively (uncorrected for 15% resistance washout caused by perfusion itself). Phalloidin itself (13 or 130 mumol/L) did not affect facility, but it inhibited up to 50% of the facility-increasing effect of cytochalasin B and epinephrine. CONCLUSIONS: We conclude that (1) the aqueous humor outflow facilitating effects of cytochalasin B or epinephrine depend in some manner on depolymerization of actin filaments within trabecular meshwork cells, and (2) actin filaments may help regulate aqueous outflow.

Animals↗

Collagen metabolism in human aqueous humor from primary open-angle glaucoma. Decreased degradation and increased biosynthesis play a role in its pathogenesis.

OBJECTIVE: To explore the influence of aqueous humor from patients with glaucoma on collagen turnover. METHODS: The aqueous humor of patients with primary open-angle glaucoma (POAG), chronic angle-closure glaucoma, congenital glaucoma, neovascular glaucoma, and senile cataract (control group) was analyzed for its capacity to induce fibroblast proliferation, collagen synthesis, collagenolytic activity, and production of tissue inhibitor of metalloproteinase-1. All data were analyzed using the Mann-Whitney U test. RESULTS: Aqueous humor derived from patients with POAG induced a significant decrease of functional collagenase activity (mean +/- SE, 9.12 +/- 1.33 microgram of degraded collagen per milligram of incubated protein vs 20.94 +/- 4.14 micrograms from the control group, P < .05). The enzymatic activity in the other types of glaucoma was similar to that of controls. The POAG samples had a significantly higher concentration of tissue inhibitor of metalloproteinase-1 (mean +/- SE, 3.11 +/- 0.58 vs 0.91 +/- 0.13 micrograms/mL from controls; P < .05). The amount of immunoreactive tissue inhibitor of metalloproteinase-1 found in the other three groups was not significantly different from the control. Aqueous humor stimulated fibroblast proliferation in all cases, but significant differences were not observed between the POAG samples (mean +/- SE, 20,285 +/- 4642 cpm/mg of incubated protein) and the control group samples (26,550 +/- 3688 cpm/mg of incubated protein). Primary open-angle glaucoma fluids increased collagen synthesis significantly compared with the control group (mean +/- SD, 3352 +/- 630 vs 985 +/- 285, P < .05), and the other groups. CONCLUSIONS: An increase of collagen synthesis and a decrease of collagen degradation may contribute to an excessive deposit of collagen with loss of the trabecular cells during the development of POAG, and aqueous humor must be considered as a microenvironment that affects the metabolism or function of the trabecular meshwork or both.

Adult↗

Aging effects on accommodation and outflow facility responses to pilocarpine in humans.

OBJECTIVE: To determine the relationships among age, outflow facility, and refractive and facility responses to pilocarpine in humans. METHODS: Refraction, intraocular pressure, and outflow facility were determined in 30 normal volunteers aged 20 to 75 years, by coincidence refractometry, applanation tonometry, and Schiøtz tonography, respectively, before and 1 hour after a 30-microL drop of 2% or 6% pilocarpine. Simple regression of baseline facility, postpilocarpine facility, and facility change, on age and refractive change singly and jointly, was performed. Stepwise regression models and graphic conditioning plots were used to determine, for each facility variable, its relationship to age or refractive change specifically. RESULTS: Baseline outflow facility and maximum pilocarpine-induced refractive change (ie, accommodation) declined with age, but the decrease in intraocular pressure and the facility response to pilocarpine did not. After adjusting for age, for baseline facility, there was no further relationship to 6% pilocarpine-induced accommodation, and a slight residual relationship to 2% pilocarpine-induced accommodation. After adjusting for both 2% or 6% pilocarpine-induced accommodation, the relationship to age was still significant. The facility increase after 2% or 6% pilocarpine did not depend on age and/or accommodative amplitude. CONCLUSIONS: In humans, as previously described in rhesus monkeys, an age-related loss of ciliary muscle mobility may compromise the basal function of the trabecular meshwork. However, unlike monkeys, humans exhibit no loss of the intraocular pressure or outflow facility response to pilocarpine with age.

Accommodation, Ocular↗