High fetal estrogen concentrations: correlation with increased adult sexual activity and decreased aggression in male mice.

In the house mouse (Mus musculus), fetuses may develop in utero next to siblings of the same or opposite sex. The amniotic fluid of the female fetuses contains higher concentrations of estradiol than that of male fetuses. Male fetuses that developed in utero between female fetuses had higher concentrations of estradiol in their amniotic fluid than males that were located between other male fetuses during intrauterine development. They were also more sexually active as adults, less aggressive, and had smaller seminal vesicles than males that had developed between other male fetuses in utero. These findings raise the possibility that during fetal life circulating estrogens may interact with circulating androgens both in regulating the development of sex differences between males and females and in producing variation in phenotype among males and among females.

Obstruction of aqueous outflow by lens particles and by heavy-molecular-weight soluble lens proteins.

Enucleated human eyes were perfused via the anterior chamber at 25 mm Hg pressure with lens particles (whole lens homogenates) in one series of experiments and with soluble lens proteins from human cataractous lenses in another series. Adding 1% of a homogenate of a single cataractous lens to the anterior chamber induced a 68% decrease in outflow. Perfusion with HMW soluble lens proteins (1 mg/ml; MW more than 150 million) caused a 60% decrease in outflow in 1 hr. In neither series was the obstruction to outflow relieved by subsequent irrigation of the anterior chamber with balanced salt solution or alpha-chymotrypsin. The results show that both lens particles and soluble lens proteins can directly obstruct the aqueous outflow pathways of human eyes. Such obstruction may be a significant factor in certain lens-induced glaucomas.

Identification of heavy-molecular-weight soluble protein in aqueous humor in human phacolytic glaucoma.

Aqueous humor was obtained by paracentesis at the time of cataract surgery from six patients with phacolytic glaucoma, diagnosed on the basis of acute unilateral open-angle glaucoma associated with an apparently leaking hypermature or mature cataract, and from six control patients with immature cataracts. Three of the latter had primary open-angle glaucoma. Quantities of heavy-molecular-weight (HMW) protein (MW greater than 150 X 10(6)) sufficient to obstruct aqueous outflow were identified in all six phacolytic aqueous humor specimens but in none of the controls. Three of the hypermature cataractous lenses from the cases of phacolytic glaucoma were also examined and were found to have 14-fold greater quantities of HMW protein in their liquefying cortex than were present in the cortex of immature cataractous lenses. These findings, correlated with experimental HMW protein perfusion studies in excised human eyes that we have already reported, strongly suggest that direct obstruction of the aqueous outflow channels by liberated HMW soluble lens protein may be a significant and previously unappreciated factor in the pathogenesis of phacolytic glaucoma.

Effect of iodoacetamide perfusion on outflow facility and metabolism of the trabecular meshwork.

Freshly enucleated eyes were quantitatively perfused via the anterior chamber with varying dosages of iodoacetamide at constant pressure. Iodoacetamide caused a significant increase in facility of outflow in a dose-response manner in calf and monkey eyes. Almost complete inhibition of glycolysis in the calf trabecular meshwork was produced by a dosage of iodoacetamide that was too low to appreciably alter the facility. A similar response was produced by a higher dosage, which did significantly increase the facility. Our results, taken together with what is known of the properties of iodoacetamide, suggest that cellular sulfhydryl groups may be involved in a mechanism for aqueous flow through the trabecular meshwork and that iodoacetamide probably acts directly on cellular permeability rather than by inhibition of glycolysis or interference with the production of energy in the trabecular meshwork.

The flow of aqueous humor through micro-porous filters.

Flow resistance was measured as bovine and primate aqueous humor was passed through Nuclepore polycarbonate filters having flow dimensions similar to those found within the juxtacanalicular meshwork of the aqueous outflow network. The results indicate that aqueous humor has a greater flow resistance than isotonic saline; this greater resistance is attributable to proteins or glycoproteins in aqueous humor that obstruct the filters. If the same phenomenon is operative in the aqueous outflow network, it would help to explain discrepancies between calculated and measured aqueous outflow resistance.

Effect of delta 9-tetrahydrocannabinol on monoamine oxidase activity in bovine eye tissues, in vitro.

An investigation was undertaken to analyze the effects of delta 9-tetrahydrocannabinol (THC) on monoamine oxidase (MAO) activity from calf ocular tissues. Ciliary processes, retina, trabecular meshwork, choroid, and iris all demonstrated significant MAO activity in decreasing order of magnitude. THC in concentrations from 10(-8)M to 10(-12)M stimulated MAO activity in extracts from all five tissues, except for iris at 10(-8)M. Maximum stimulation of MAO activity occurred at the 1 x 10(-12)M level for all tissues. Retina, followed next by trabecular meshwork and then ciliary processes, exhibited the largest increase in MAO activity at 10(-12)M THC. This latter effect could possibly by related to the influence of THC on intraocular pressure.

Carbonic anhydrase inhibitor side effects. Serum chemical analysis.

Multiple serum chemical values were examined in 92 patients with chronic glaucoma who were treated with the carbonic anhydrase inhibitors (CAIs) acetazolamide or methazolamide, seeking relationships between serum composition and symptomatic side effects. Of the 92 patients, 44 complained of a symptom-complex of malaise, fatigue, weight loss, depression, anorexia, and loss of libido, which we have found most commonly to threaten continuation of therapy. Patients who had this symptom complex were significantly more acidotic than those without it. Ten of 24 patients who had chemical evidence of excessive acidosis reported a dramatic alleviation of symptoms when sodium bicarbonate was administered, although their serum CO2-combining power changed little. There was no correlation of the symptom complex with serum potassium concentration, except in a few patients who were simultaneously receiving chlorothiazide diuretics for systemic hypertension and who became frankly hypokalemic.

Thymoxamine test. Differentiating angle-closure glaucoma form open-angle glaucoma with narrow angles.

To help differentiate mild angle-closure glaucoma from open-angle glaucoma in patients with elevated intraocular pressure (IOP) and angles so narrow that the structures cannot be seen adequately, we used a thymoxamine hydrochloride eyedrop that induces miosis and tends to widen the angle. Thymoxamine does not contract the ciliary muscle and does not alter the IOP or facility of outflow in open-angle glaucoma, but it can relieve angle-closure glaucoma. A test with thymoxamine was performed in 26 patients because of this differential diagnostic dilemma. When gonioscopic, tonometric, and tonographic findings appeared to indicate a diagnosis of angle-closure glaucoma, a peripheral iridectomy was done. Subsequent (one to 27 months) observations have substantiated that testing with thymoxamine is a helpful aid in this differential diagnosis, and merits more widespread evaluation.

The outflow tract in pigmentary glaucoma: a light and electron microscopic study.

Buttons obtained by trephination from both eyes of a 44-year-old myopic man with pigmentary glaucoma were studied by light and electron microscopy. Although clinically both eyes exhibited heavy pigmentation of the trabecular meshwork in the whole circumference, microscopically the trabecular meshwork of the left eye contained more pigment granules than that of the right eye, which appeared relatively acellular with collapse of the trabecular sheets. In both eyes endothelial cells covering the trabecular sheets were filled with pigment and showed various stages of degeneration. The intertrabecular spaces contained free pigment granules as well as cell debris. These observations suggest that plugging of the trabecular spaces by pigment and cell debris together with fragmentation and collapse of trabecular sheets contribute to the decrease in the facility of outflow that occurs in pigmentary glaucoma.

The influence of supplemental sodium acetate on carbonic anhydrase inhibitor-induced side effects.

A double-masked, randomly assigned, crossover trial of the effect of supplemental two-weak courses of sodium acetate (90 mEq/day) and placebo on carbonic anhydrase inhibitor (CAI)-induced side effects of malaise, fatigue, and others ("malaise symptom complex") was performed in 28 patients. Fifteen patients (54%) experienced significant improvement while receiving supplemental sodium acetate compared with five (18%) receiving a placebo. A relationship was observed between the clinical efficacy of the acetate supplementation and the measured improvement in serum carbon dioxide combining power. No changes in intraocular pressure were observed when supplemental sodium acetate was given. The results confirm the beneficial effect of supplemental alkalinization for such CAI-induced symptoms in somewhat less than half of the affected patients and suggest the need for long-term studies in which the dosage of sodium acetate is titrated in relation to measured changes in the level of metabolic acidosis.

Pigmentary dispersion syndrome and pigmentary glaucoma. A prospective study of the natural history.

The natural evolution of pigmentary dispersion syndrome and pigmentary glaucoma was studied in 55 patients for six to 43 months (mean, 27 months). Active dispersion of pigment was observed in 45 eyes in 31 patients and was associated with worsening of glaucoma in 32 eyes. Dispersion of pigment was defined as active when there was increase in iris transillumination, increase in corneal pigmentation, or appearance of pigment granules on the surface of the lens in the pupil. There were no differences in the frequency of active dispersion of pigment and worsening of glaucoma comparing patients aged less than 44, 45 to 64, and 65 or more years. This study demonstrates that active dispersion of pigment is clinically detectable, is correlated with elevation of intraocular pressure, and continues to occur in older patients.

Acetazolamide dosage forms in the treatment of glaucoma.

Patients with chronic glaucoma had a carefully scheduled series of intraocular pressure measurements before and after taking acetazolamide for one week at the following dosages: none, 500 mg of sustained-release capsules once a day, 500 mg of capsules twice a day, and 250 mg of tablets four times a day. A capsule taken once a day, which is better tolerated than one taken twice a day by some patients, offers a substantial pressure-lowering effect that lasts at least 23 hours, although the magnitude of the pressure lowering is less than with higher dosages. One capsule twice a day appears to be as effective in the regulation of IOP as one tablet four times a day. The 45% reduction in outflow pressure is achieved with an acetazolamide serum concentration in the range of 15 to 20 micrograms/mL.

A repeated dose-response study of methazolamide in glaucoma.

Twenty-two patients with open-angle glaucoma were given weekly courses of methazolamide at different dosages. Mean intraocular pressure reductions of 3.3, 4.3, and 5.6 mm Hg were achieved at dosages of 25 mg, 50 mg, and 100 mg of methazolamide every eight hours, respectively. Maximal intraocular pressure lowering was still present nine to ten hours after administration. The mean reduction in outflow pressure for all eyes receiving a daily dosage of 300 mg was only 31%, but this included eyes (17% of the total) that demonstrated less than 13% reduction in outflow pressure, despite similar methazolamide serum levels. Eight patients subsequently received acetazolamide, 250 mg four times a day for a week. The effect of this dosage of acetazolamide on pressure was between the effects of 50 and 100 mg of methazolamide three times daily.

Thymoxamine hydrochloride: an alpha-adrenergic blocker.

Thymoxamine is an alpha-adrenergic blocking agent which works by competitive antagonism of norepinephrine. It is the only alpha-adrenergic blocker available which has tolerable side effects when used as an ophthalmic solution. When used as a 0.5% solution it consistently produces miosis without affecting the intraocular pressure or the ciliary muscle-controlled facility of outflow. The only regularly reported side-effects at this concentration are transient burning and conjunctival hyperemia. Potential applications of thymoxamine include reversal of phenylephrine mydriasis, treatment of angle-closure glaucoma, treatment of persistent mydriasis after penetrating keratoplasty for keratoconus, reversal of lid retraction in thyroid ophthalmopathy, testing to differentiate angle-closure glaucoma from open-angle glaucoma with narrow angles, aiding in repositioning and maintaining the position of intraocular lenses, treatment of pigmentary glaucoma. Thymoxamine may also contribute to a better understanding of the adrenergic nervous system on aqueous dynamics.

Late glaucoma after interstitial keratitis.

In a systematic study of 45 patients who had syphilitic interstitial keratitis early in life and, many years later, were discovered to have glaucoma, there was evidence of two different but equally common mechanisms. In one group of patients, a deep-chamber type of glaucoma was superimposed on old inflammatory changes, was characteristically refractory to medical treatment, but did well with filtering surgery. The other group of patients had reversible angle-closure glaucoma associated with anatomically small anterior segments, and typically responded well to iridectomy. The late, refractory, deep-chamber type of glaucoma may involve endothelialization and formation of glass membrane in the angle, as seen in one excised eye. Occurrence of the shallow-chamber, reversible angle-closure type of glaucoma after interstitial keratitis may be coincidental, since no other evidence supports the idea that small anterior segments might be particularly prevalent among patients who have had congenital syphilis or interstitial keratitis.

Cyclocryotherapy of chronic open-angle glaucoma in aphakic eyes.

Twenty-six eyes of 25 patients with chronic open-angle glaucoma and surgical aphakia with inadequate control of intraocular pressure (IOP) despite maximal medical treatment were treated with cyclocryotherapy, according to a prospective protocol and specific technique. (Neovascular and synechial glaucoma were excluded from this series.) In most cases topical medications were resumed after cyclocryotherapy. During follow-up of seven to 95 months (average, 46 months), IOP was reduced to 19 mm Hg or lower in 24 out of 26 eyes (92%). In two eyes, persistent decrease in visual acuity, unrelated to reduction of IOP, occurred after cyclocryotherapy. On the basis of the long-term benefits obtained by this procedure, we concluded that cyclocryotherapy should be considered the procedure of choice in the treatment of primary open-angle glaucoma in surgically aphakic eyes when pressure cannot be adequately reduced by maximally tolerated medical treatment.

Secondary open-angle glaucoma in histiocytosis X.

A 9 month-old boy developed secondary open-angle glaucoma associated with fever and multiple lytic bone lesions 2 1/2 months after cataract aspiration. An open bone biopsy provided a diagnosis of histiocytosis X. Hisiocytes similar to those in the bone were identified in a specimen of aqueous humor from the affected eye. No other cells were found. The abnormal histiocytes may have caused the glaucoma by infiltrating the trabecular angle structures and mechanically obstructing aqueous outflow from the eye.

Phenylephrine provocative testing in the pigmentary dispersion syndrome.

Forty-nine patients with bilateral pigmentary dispersion syndrome (abnormal accumulation of pigment in the anterior chamber, principally from the posterior layers of the iris), including 31 patients with pigmentary glaucoma, underwent 10% phenylephrine testing in one eye for evaluation of liberation of pigment floaters into the anterior chamber and the influence of phenylephrine on the intraocular pressure. Ten patients with pigmentary glaucoma developed a 3+ to 4+ pigment response, but only two demonstrated a pressure rise greater than 2 mm Hg. The highest pressure rise observed was 7 mm Hg. Nine patients with pigmentary dispersion syndrome but without glaucoma also developed a 3+ to 4+ pigment response, but none of these had a pressure rise. The incidence of pigment liberation was higher in older patients and in pigmentary glaucoma patients receiving topical antiglaucoma therapy at the time of testing. The extent of iris transillumination did not correlate with the grade of phenylephrine-induced pigment liberation. Two pigmentary glaucoma patients, who did not liberate pigment or have a pressure rise when tested with phenylephrine, did exhibit spontaneous or exercise-induced liberations of pigment into the anterior chamber, with marked rises of intraocular pressure and obstruction of aqueous outflow.

Serum obstruction of aqueous outflow in enucleated eyes.

We perfused enucleated human eyes via the anterior chamber by the constant pressure technique. Infusion of human serum into the anterior chamber of enucleated human eyes for 30 minutes at 23 mm Hg pressure induced a 42% decrease in facility of outflow, which was not relieved by irrigation of the anterior chamber with balanced salt solution or alpha-chymotrypsin. Diluted serum also reduced the facility of outflow. Measured in a glass viscometer, diluted serum had less viscosity than undiluted, but interfered with outflow from the eye more than anticipated on the basis of viscosity alone. When we used lens depression to induce tension on the iridocorneal angle to simulate the effects of contraction of the ciliary muscle, outflow facility increased in control eyes that had not been exposed to serum and in serum-perfused eyes. However, the partial obstruction to outflow that had been induced by serum persisted. Normal serum components may become adsorbed or entrapped in the aqueous outflow system so as to obstruct outflow, and this may result in secondary glaucoma in eyes with chronic uveitis.

Effects of panretinal photocoagulation on rubeosis iridis, angle neovascularization, and neovascular glaucoma.

Ninety-three patients received ruby laser panretinal photocoagulation in one eye for diabetic retinopathy and we examined them at an average time of 7.1 years later. In 14 patients, the untreated eye developed rubeosis iridis and the contralateral treated eye did not. In seven patients, the untreated eye developed angle neovascularization and the contralateral eye did not. The untreated eye developed neovascular glaucoma and the contralateral treated eye did not in four patients. Our findings suggest that eyes with proliferative retinopathy that received panretinal photocoagulation are less likely to develop rubeosis iridis, angle neovascularization, and probably neovascular glaucoma, than those eyes not receiving panretinal photocoagulation.