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We have recently developed a tissue model of the human aqueous outflow pathway involving placement of the eviscerated anterior corneoscleral shell, [with lens and uveal tissue removed but trabecular meshwork (TM) attached] onto a specialized perfusion apparatus. The TM and associated outflow tissues are perfused with culture medium at a physiologically-relevant perfusion pressure in a 5% CO2 environment at 37 degrees C. Under these conditions, the perfused outflow tissues are similar for several days, to the human and/or subhuman primate outflow system in vivo with regard to morphology as well as several functional parameters. Measured facility of outflow (0.271 +/- 0.018 microliters min-1 mmHg-1, n = 79) is similar to facility values obtained by tonography in living human beings. Moreover, outflow facility decreases in a linear fashion with increased perfusion pressure by 1.4% mmHg-1. Finally the removal of the TM results in a 41% decrease in measured outflow resistance. The ability to study viable human outflow tissue for at least several days and the opportunity to establish a model which serves as an alternative to animal testing, point to the potential importance of this technique in investigating the biology of the aqueous outflow system.

Five cases of anterior ischemic optic neuropathy secondary to biopsy-proven giant cell arteritis are presented. In each case, cupping of the optic disc, which closely resembled glaucomatous cupping, was observed in the affected eye. The presence of glaucoma was ruled out on the basis of normal intraocular pressures and normal tonographic measurements of facility of outflow. These cases indicate that arteritic ischemic optic neuropathy can result in optic disc cupping, which closely resembles glaucomatous cupping. The similarities in the appearance of cupping of these discs with that seen in eyes with glaucoma suggest that the pathogenesis of cupping in glaucoma and in arteritic ischemic optic neuropathy may share some common mechanisms.

• A double-masked, randomly assigned, crossover trial of the effect of supplemental two-week 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.

Our thesis, inspired by the experience and teaching of Paul A. Chandler, is that after the optic discs have developed cupping and atrophy from elevated intraocular pressure they tend to become abnormally vulnerable and, in some cases, may continue to deteriorate even if the intraocular pressure is brought to the teens. At this stage they behave the same as in eyes with so-called low-tension glaucoma, which have developed progressive cupping and atrophy with pressures always in the teens. In either case, we find that the progression of cupping and field loss can be stopped by reducing the intraocular pressure to lower levels, preferably to 10 mm Hg or less. We have found that such low pressures are most reliably attained by surgery, using a special technique we call the shell tamponade filtration procedure, which involves the use of a glaucoma shell in conjunction with standard (full-thickness sclerostomy) filtration operations and certain specific operative and perioperative maneuvers. We present nine case reports illustrating our thesis. Glaucomatous cupping and loss of visual field were progressing relentlessly at normal pressures in each case. This progressive deterioration was shown to be arrested by reduction of the pressure to less than 12 mm Hg in 13 eyes.

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.

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.

• 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.

We examined trabeculectomy specimens obtained at the time of surgery for inadequately controlled open-angle glaucoma by scanning electron microscopy. Of the 50 specimens ten included a broad area of the trabecular meshwork. In these ten specimens the meshwork was obscured by material. We believe the degree of occlusion was significant in these specimens, which would lead to obstruction of aqueous outflow. No similar material was found in control specimens from persons of similar age.

A COROLLARY of Friedenwald's concept of bicarbonate secretion in the formation of aqueous humor is that inhibition of the enzyme carbonic anhydrase might be expected to decrease the rate of secretion and lower the intraocular pressure. Thus it was not surprising when the carbonic anhydrase inhibitor Diamox * (acetazoleamide) became available and was found safe for human beings, that several investigators should have given it a trial in glaucoma simultaneously and independently. Some of these results have been published, 1 and many others may be expected in the near future. The following is a report of our initial experience.† Preliminary trials of Diamox in rabbits produced definite lowering of intraocular pressure when 10 to 100 mg. per kilogram was injected intravenously. However, no significant effect on intraocular pressure was obtained when a saturated solution of Diamox was dropped repeatedly on the cornea or injected subconjunctivally. CLINICAL INVESTIGATION Clinical trials, in both

The importance of considering the effect of a possible flow out of the anterior chamber before inferring any mechanism of aqueous humor formation from the relative concentration of a substance in the aqueous humor and plasma under equilibrium conditions has been stressed. Several processes to account for the chemical equilibria between aqueous humor and blood based on the ultrafiltration and secretion hypotheses with a possible simultaneous loss of aqueous humor by flow have been outlined. On the basis of these processes, equations were formulated which would relate the rates of transfer into and out of the anterior chamber to the ratio of concentration of a substance in the aqueous to that in the blood at various intervals after its introduction into the blood. The explanation of equilibrium ratios above and below one for aqueous constituents is made apparent from the mathematical formulations. For each substance tested a determination was made of the best fit when the concentration in the aqueous humor is plotted against time. This fit was obtained by plotting the rate of transfer in against the rate of transfer out of the anterior chamber for all of the experimentally found concentration ratios on the basis of both the ultrafiltration and secretory hypotheses. Two sets of values were obtained from these calculations, one set for each hypothesis. The substantial agreement of all the experimental data with an assumed rate of leakage out of the anterior chamber of approximately 4 c. mm. per minute was shown to be compatible only with the idea that all the monovalent electrolytes tested entered the anterior chamber as a result of secretory process. It could not be decided from these chemical studies whether the non-electrolytes and the one multivalent electrolyte tested enter the anterior chamber by ultrafiltration or secretion. Experimental findings from other sources were cited which would suggest that non-electrolytes enter the anterior chamber as a result of ultrafiltration. The implications of the mechanism outlined in the paper with respect to intraocular pressure have been discussed. Supplementary evidence from the literature has been given in support of the conclusions presented here.

Among the commonest and most devastating chemical injuries of the eye are those caused by strong alkalies, such as calcium hydroxide, sodium hydroxide, and potassium hydroxide. Contact with these substances may render the corneal stroma opaque, and vision may be lost. In combating the effects of these alkalies, copious emergency irrigation with water is important for decontamination, but thereafter the treatment available is nonspecific, save in the instance of the most superficial opacification from lime, which may be eliminated by means of sodium ethylenediaminetetraacetate or other solubilizing agent for calcific deposits.1General anti-inflammatory measures, including the application of cortisone and hydrocortisone, appear to be beneficial; but, unfortunately, the mode of action of alkalies on the corneal stroma is at present too poorly understood to provide a logical basis for devising specific chemical antidotes. Owing to the complexity of the chemistry involved, there is unlikely to be any speedy solution

We have recently had the opportunity of studying an unusual type of corneal lesion, presumably due to butanol (n-butyl alcohol), which affected a considerable proportion of the workers in a local rubber factory. The only previous report in the literature of ocular disturbances that may have had a similar cause is the description of conjunctivitis in 11 workers, 3 of whom had keratitis, employed in a straw hat factory where butyl alcohol and butyl acetate were used as solvents. 1 Ocular irritation has, however, been recently noted in five local factories in addition to the one here referred to, and a survey of all six outbreaks, showing the relation between butanol concentration in the air and the incidence of ocular irritation will shortly be published by Tabershaw, Fahey and Skinner. 2 INDUSTRIAL BACKGROUND The ocular disturbances with which this report is concerned occurred in a plant engaged in making Army

Growth was obtained in rats on synthetic diets in which the ten essential amino acids were the sole source of amino acid nitrogen. The growth rate was dependent upon the quantity of amino acids fed and appeared to compare favorably with that obtained when a similar quantity of nitrogen was fed in the form of casein. No increase in growth was observed when nitrogen in addition to that given in the form of the essential amino acids was supplied as glycine. Our experiments would not support the contention that the unnatural forms of the amino acids are toxic. We wish to acknowledge and thank Phyllis Robison for technical assistance, and Dr. D. Mark Hegsted for helpful suggestions.

Summary Clinical and investigative evidence indicated a glaucoma caused mainly by degenerated red blood cells, or ghost cells. These ghost cells, with altered shape, color, and pliability, accumulated in the vitreous cavity after hemorrhage. Following disruption of the anterior hyaloid face, they passed into the anterior chamber and caused severe glaucoma. In the anterior chamber, the tiny, khakicolored cells, circulating slowly, were frequently mistaken for white blood cells. They covered the trabecular meshwork or filled the inferior angle with a pathognomonic khaki-colored layer. They were identified by phase-contrast microscopic examination of anterior chamber aspirates. The decreased pliability of these degenerated cells seemed to account for their inability to pass easily through the human trabecular meshwork and, therefore, to cause severe glaucoma.

Enucleated eyes were perfused alternately via the anterior and vitreous chambers. At low intraocular pressure (IOP), vitreous humor presented considerable resistance to forward flow of perfusion fluid in calf eyes, but not in human eyes. In human eyes when the perfusion pressure was increased to 60 mm Hg, the resistance to flow forward from the vitreous body increased, but became practically nil again when the IOP was decreased. At high pressure the volume of the vitreous body apparently increases and the anterior hyaloid membrane probably presses against the ciliary body, reducing the area of hyaloid membrane through which fluid can flow. Whether increased perfusion pressure can in some other manner change the permeability of human vitreous to resemble that of the calf remains unanswered. Our results suggest that factors other than, or in addition to, simple diversion of aqeous humor must be important in malignant glaucoma.

• A new device makes it much easier and more satisfactory to compare different sets of stereophotographs of an optic disc than is possible with ordinary stereo viewers that accept only one stereopair at a time. Two ordinary stereophotographic transparencies of the optic disc are inserted and viewed simultaneously through a single pair of eyepieces. By means of a pair of mirrors in the device, the two stereophotographs are made to appear close to one another so that with very small eye movements one can look from one to the other and make a very satisfactory comparison. It is desirable that the sensitivity for detection of glaucomatous change in the optic disc by this simple means be compared with the results of more complex and costly methods of analysis of the optic cup.

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.

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.

Retrospective analysis of patients blinded by glaucoma has revealed a need to educate patients to the significance of premonitory symptoms, to investigate a higher incidence of blindness from open-angle glaucoma among blacks than whites, and to define the goals of therapy in relation to presenting pathology. Responding to this third need, circumstances of patients followed for 20 to 40 years with extensive documentation relating to open-angle glaucoma were analyzed. Some eyes with normal discs and fields were found to tolerate a tension of 30 mm Hg for many years without need of treatment. But, when abnormalities ranging from early glaucomatous cupping to advanced visual field defects were present on initial evaluation, progressive loss of field tended to occur at lower tensions. It appears that the worse the initial condition of the eye, the lower the tension needs to be to prevent further loss or blindness.

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.

• 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.

Ophthalmologic literature relating to ethyl alcohol consists of many reports of influences on eye movements, nystagmus, visual physiology, and on so-called alcohol amblyopia, but very little is to be found concerning influence on intraocular pressure. A systematic search of textbooks and the periodical literature has disclosed only one previous study on this subject in human beings, and very little additional in animals. This is surprising when one considers how common is the drinking of alcohol, how many other effects of alcohol have been studied in great detail, and how often glaucomatous patients themselves raise questions about the possible influence of alcoholic beverages on their glaucoma. It seems to us that one of the most frequent questions asked by patients whose condition has been diagnosed as glaucoma is whether it is safe for them to continue to take their customary alcoholic beverages. Ascher, in a compendium prepared in 1937 on substances

NEW DRUGS for the treatment of pediculosis ciliaris cannot be said to be especially needed. The time-honored ammoniated mercury has proved itself effective when used liberally enough. Yet it is of considerable interest, and may be of some practical usefulness, to know that the common physostigmine in the standard concentrations used for the treatment of glaucoma is just as effective as ammoniated mercury, if not more so. Tetraethylpyrophosphate, and presumably many other anticholinesterase compounds, are also effective. A case in which we had an opportunity to study the effect of physostigmine and tetraethylpyrophosphate is reported. REPORT OF CASE E. B., a woman aged 49, during routine refraction, was noted to have blepharitis. In reply to questioning, she stated she had had severe itching of the lids, especially at night. Gross examination showed black discoloration of the eyelashes and loose, tiny black dots on the cheeks below the lashes. The first

THE OCULAR effects of a new anticholinesterase chemical, tetraethyl pyrophosphate, have been investigated in several subjects with normal eyes and in several patients with glaucomatous eyes. Although the number of observations is small, the information obtained appears to be adequate for a qualitative characterization of the actions of this compound. A more quantitative experimental comparison of tetraethyl pyrophosphate with physostigmine and di-isopropyl fluorophosphate (DFP) and a clinical comparison with di-isopropyl fluorophosphate in glaucomatous and in atropinized eyes are to be reported subsequently.1 Tetraethyl pyrophosphate is a colorless, water-soluble and lipidsoluble, hygroscopic liquid of low volatility. It is the principal active ingredient of a more complex substance, commercial hexaethyl tetraphosphate (tri-diethyl phosphophosphate), which, because of strong nicotine-like action, was used in Germany during the war as an insecticide, substituting for natural nicotine, under the name of ``bladan.''2Tetraethyl pyrophosphate is being used increasingly in this country for the same

In 44 patients with open-angle glaucoma under treatment with echothiophate, tensions were compared with and without simultaneous treatment with pilocarpine. In most cases, echothiophate is as effective alone as in combination with pilocarpine. This finding is described with reference to current views on the nature of the cholinergic receptor.

Acidic and basic dyes react preferentially with the mucoproteins of beef corneal stroma. Free carboxyl groups of the mucoproteins can combine readily with cations; additional reaction with ions seems to involve an unmasking of charged groups in these proteins. Most of the dyes studied apparently react as aggregates in 0.02 M solution, and are fully dissociated only in much more dilute solution. The state of aggregation of methylene blue has a pronounced effect on the affinity with which this dye combines with the tissue, but the chemical reaction is limited, nevertheless, to the corneal mucoproteins.

THE ACCIDENTAL injuries of the eye produced by liquefied sulfur dioxide which have been reported by myself 1 and others have usually been severer than those produced by other substances with similar moderately acidic properties. To account for the greater toxicity of sulfur dioxide, previous observers have proposed some rather unusual mechanisms based on the physical and chemical peculiarities of the noxious agent. Experiments carried out in this laboratory indicate that a relatively simple mechanism, different from those previously proposed, is responsible in large measure for the peculiar toxicity of sulfur dioxide. The following two hypotheses have previously been advanced to explain the severity of ocular injury produced by liquid sulfur dioxide. It has been assumed by some investigators that injury of the eye is due to freezing produced by the rapid evaporation of the liquefied gas (Kennon, 2 Clark 3 ), while others have assumed that injury is caused by