Stem cells in the trabecular meshwork: present and future promises.

Primary open-angle glaucoma is recognized as a disease of aging, and studies show a relationship between aging and trabecular meshwork (TM) cell density. Human TM cell division occurs primarily in the anterior, non-filtering region. A commonly used glaucoma treatment, laser trabeculoplasty (LTP), triggers and increases cell division, as well as cell migration of these anterior TM cells. These freshly-divided migrating cells repopulate the burned laser sites, suggesting that they are stem cells. Several studies concerning this putative TM stem cell will be discussed.

Refining the primary open-angle glaucoma GLC1C region on chromosome 3 by haplotype analysis.

The GLC1C locus for primary open-angle glaucoma (POAG) is inherited as an autosomal dominant trait. This region on chromosome 3 is 11 cM long. DNA samples from members of a Greek and an American GLC1C family were obtained to determine whether additional typing of microsatellite markers in family members might narrow the region. GLC1C family members were evaluated clinically for POAG on the basis of open angles, intraocular pressures, cupping of discs, and visual fields. DNA samples from the Greek and Oregon GLC1C families were used to further refine the GLC1C region using microsatellite markers. A total of 22 affected members were identified in the two families. Common alleles for D3S3637 and D3S3612 were present in the disease haplotype from both families, suggesting that they may have a common founder. A newly diagnosed patient in the American family had a recombination in the distal portion of the GLC1C haplotype. This recombination narrows the GLC1C region from 11 to 4 cM.

Short wavelength automated perimetry and tamoxifen use.

BACKGROUND/AIMS: Oestrogen receptors (ORs) have been reported to be present in the retina, and the selective oestrogen receptor modulator tamoxifen has been reported to affect colour vision. This study aimed, therefore, to determine whether standard doses of tamoxifen affect visual sensitivities mediated via short wavelength sensitive (SWS) cones. METHODS: Two types of visual fields were measured for middle aged women who were being treated with 20 mg of tamoxifen daily as adjuvant therapy for early stage breast cancer. Visual fields were measured using short wavelength automated perimetry (SWAP) and frequency doubling perimetry (FDP). For SWAP, 24-2 visual fields were analysed. No subjects had tamoxifen retinopathy or other eye disease. For each type of visual field, mean deviations (MDs) were assessed as a function of the duration of tamoxifen use, using a cross sectional design. In addition, the difference between the two types of MDs was computed after standardisation of each type of MD separately, and this difference itself was evaluated as a function of the duration of tamoxifen use. Duration dependent changes for SWAP were further evaluated as a function of eccentricity within the visual field, and the visual field data were compared with foveal data obtained psychophysically. RESULTS: SWAP sensitivities depended on the duration of tamoxifen use. Subjects who used tamoxifen for about 2 years or less were significantly more likely than subjects who had longer use to have high MDs. The difference between the standardised SWAP and FDP MDs likewise was significantly related to the duration of use, whereas duration of use effects for FDP itself were reduced or absent. Although the duration of use effect observed for SWAP was strongest in the peripheral portion of the visual field, there was evidence of changes in SWS cone mediated vision even at the fovea. CONCLUSION: Standard dosages of tamoxifen can affect SWAP visual fields. The effects of tamoxifen are not equivalent for SWAP and FDP, indicating that tamoxifen affects some types of visual pathways preferentially or selectively. SWS cone pathways, in particular, are affected. SWAP appears able to reveal effects of tamoxifen occurring years before completion of the standard 5 year regimen of use.

In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome.

Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterised by short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described and a gene for AR WMS has recently been mapped to chromosome 19p13.3-p13.2. Here, we report on the exclusion of chromosome 19p13.3-p13.2 in a large AD WMS family and show that, despite clinical homogeneity, AD and AR WMS are genetically heterogeneous entities. Because two AD WMS families were consistent with linkage to chromosome 15q21.1, the fibrillin-1 gene was sequenced and a 24 nt in frame deletion within a latent transforming growth factor-beta1 binding protein (LTBP) motif of the fibrillin-1 gene was found in a AD WMS family (exon 41, 5074_5097del). This in frame deletion cosegregated with the disease and was not found in 186 controls. This study strongly suggests that AD WMS and Marfan syndrome are allelic conditions at the fibrillin-1 locus and adds to the remarkable clinical heterogeneity of type I fibrillinopathies.

Ophthalmic drops causing coma in an infant.

A 1-month-old infant with Peters anomaly had recurrent episodes of unresponsiveness, hypotension, hypotonia, hypothermia, and bradycardia. An extensive medical evaluation determined these episodes to be caused by brimonidine, an anti-glaucoma agent. There is the potential for serious toxic effects from the systemic absorption of topically applied ophthalmic agents in children.

Flicker sensitivity and cardiovascular function in healthy middle-aged people.

OBJECTIVE: To establish normative relations between measures of visual function and cardiovascular variables that are important for age-related disease, including various forms of glaucoma. METHODS: Foveal flicker sensitivities, resting blood pressures and heart rates, and intraocular pressures were measured in 18 individuals aged 40 to 68 years. All subjects had 20/20 or better visual acuity in the test eye and no evidence of eye disease or glaucoma suspicion on clinical evaluation and medical history. No subjects were using medication to lower blood pressure. Flicker sensitivity was measured by increasing the illuminance of a fully modulated 20-Hz test stimulus until flicker was perceived. Two test-background stimulus combinations were used: a 570-nm ("yellow") test on a predominantly long-wavelength ("magenta") background and a 580-nm ("yellow") test on a 580-nm ("yellow") background. The illuminance of the yellow background was dimmer than that typically used for short-wavelength automated perimetry, whereas the illuminance of the magenta background was greater. RESULTS: The 2 flicker sensitivity measures were distinguished by the strong dependence of the magenta background measure on the ratio of mean arterial blood pressure to heart rate. Log flicker sensitivity on this background generally could be modeled as a linear combination of age, intraocular pressure, and ratio of mean arterial blood pressure to heart rate. The optimal model accounted for 84% of the variance (R = 0.92) from all but 2 outlying individuals. After age and intraocular pressure effects were partialed out, an increasing ratio of mean arterial blood pressure to heart rate was strongly associated with decreasing flicker sensitivity. CONCLUSIONS: Reduced cardiovascular function impacts the ability of the normal visual system to adapt and regulate flicker sensitivity. Elevated intraocular pressure and increased age reduce flicker sensitivity relatively uniformly across a range of stimulus conditions. Because the ratio of mean arterial blood pressure to heart rate equals total peripheral vascular resistance multiplied by cardiac stroke volume, and because total peripheral resistance is determined largely at the arterioles, it is likely that even modest changes in arteriolar function are associated with measurable alterations of visual function. Arch Ophthalmol. 2000;118:1049-1055

Mediation of laser trabeculoplasty-induced matrix metalloproteinase expression by IL-1beta and TNFalpha.

PURPOSE: Laser trabeculoplasty of the anterior uveal region of the trabecular meshwork induces sustained matrix metafloproteinase expression within the juxtacanalicular region of the meshwork. Studies were conducted to test the hypothesis that a factor mediates this response and to identify the factor. METHODS: Human anterior segment organ cultures were subjected to laser treatment using standard clinical parameters and were returned to culture for 8 hours. The resultant 8-hour-conditioned culture medium was then tested for factor activity by evaluating its ability to produce two typical trabecular responses to laser treatment, that is, to induce stromelysin expression or to trigger cell division, when applied to fresh organ cultures or to cell cultures. Confocal immunohistochemistry of the laser-treated organ cultures and western immunoblot analysis of the conditioned medium were used to evaluate changes in potential candidates for the factor activity. The ability of the interleukin (IL)-1 receptor antagonist (IL-1ra)- and of tumor necrosis factor alpha (TNFalpha)- blocking antibodies to eliminate the stromelysin induction was evaluated. RESULTS: Medium conditioned for 8 hours induced typical trabecular cell division in anterior segment organ cultures. Medium conditioned for 8 hours, but not for 30 minutes, induced typical increases in stromelysin expression in these organ cultures and in cell cultures. After 8 hours, both trabecular cells in laser-treated organ cultures and in the conditioned medium contained elevated levels of IL-1beta and TNFalpha. The laser-treated organ cultures contained elevated levels of IL-1alpha, but it was not secreted into the medium. The ability of conditioned media to induce stromelysin expression was partially blocked by either the IL-1ra- or the TNFalpha-blocking antibody. CONCLUSIONS: Laser trabeculoplasty induces the expression and secretion of both IL-1beta and TNFalpha within the first 8 hours after treatment. These cytokines then mediate increased trabecular stromelysin expression. Putatively, this initiates remodeling of the juxtacanalicular extracellular matrix, a likely site for the aqueous outflow resistance, and thus restores normal outflow facility.

GLC1F, a new primary open-angle glaucoma locus, maps to 7q35-q36.

BACKGROUND: A large family with adult-onset primary open-angle glaucoma (POAG) was identified. OBJECTIVE: To initiate a genome-wide scan to map the POAG locus in this family. METHODS: Blood samples or buccal swabs were obtained from 25 members of a large family with POAG after informed consent was obtained. Members and their spouses were evaluated clinically for POAG on the basis of intraocular pressures, cupping of discs, and visual fields. DNA samples were used for a genome-wide screen using microsatellite markers. RESULTS: Ten affected family members in 4 generations showed evidence of POAG including intraocular pressures of 22 mm Hg or more, and/or optic cup-disc ratios of 0.6 or more, and/or visual field defects consistent with glaucomatous damage. Primary open-angle glaucoma segregated as an autosomal dominant trait, with the disease locus mapping to 7q35-q36 between markers D7S2442 and D7S483 with a multipoint lod score of 4.06. CONCLUSION: A sixth gene for POAG (GLC1F) has been mapped to 7q35-q36 in a family with at least 4 generations affected. CLINICAL RELEVANCE: The mapping of this locus further confirms that primary open-angle glaucoma is a heterogeneous group of diseases with at least 6 different loci resulting in a similar phenotype. The eventual ability to classify which major POAG gene an affected person carries could have ramifications for selecting the most effective treatment regimen for that person.

Effect of matrix metalloproteinases activity on outflow in perfused human organ culture.

PURPOSE: To test the hypothesis that extracellular matrix turnover, mediated by the matrix metalloproteinases, modulates aqueous humor outflow facility in a human outflow model. METHODS: Matrix metalloproteinase activity was manipulated and outflow facility evaluated using perfused human anterior segment organ culture. Purified matrix metalloproteinases, tissue inhibitors of metalloproteinases (TIMPs), and several families of synthetic inhibitors of matrix metalloproteinases were added to the perfusion medium. Matrix metalloproteinase expression was increased by adding recombinant interleukin (IL)-1alpha. Kinetic inhibition analysis was conducted for stromelysin, gelatinase A, and gelatinase B with the various inhibitors. Live-dead staining was used to evaluate culture viability. RESULTS: Increasing metalloproteinase activity, by adding purified metalloproteinases or by inducing their expression by IL-1alpha treatment, increased outflow facility. Inhibition of endogenous trabecular metalloproteinase activity using TIMP or several families of synthetic metalloproteinase inhibitors reduced outflow rates. The elevation and the reduction of outflow rates were reversible, with changes requiring 1 to 3 days. Kinetic enzyme inhibition analysis produced 50% inhibitory concentration values for these inhibitors that were compatible with the concentration ranges for outflow inhibition. CONCLUSIONS. The ability of several specific matrix metalloproteinase inhibitors to reduce outflow facility implies that endogenous extracellular matrix turnover by these enzymes was required for the maintenance of trabecular outflow resistance, at least in this human culture model. These observations provide support for the hypothesis that controlled extracellular matrix turnover is important in the regulation of aqueous humor outflow facility.

Prospects for genetic intervention in primary open-angle glaucoma.

Recent advances in glaucoma genetics hold potential for dramatically changing the clinical care of glaucoma patients. To date, 5 primary open-angle glaucoma genes and 2 congenital glaucoma genes have been mapped. As more glaucoma genes are identified, earlier diagnosis for glaucoma should become more readily available. Progress in molecular genetics holds considerable promise for both current and future therapy of glaucoma. Glaucoma classification will be tailored to each individual based upon that person's family history, i.e. family glaucoma genotype. In the future, the optimum treatment for a specific glaucoma patient might rely on the knowledge of the phenotype of that person's causal gene, without having to resort to 'trial and error'. At this time, glaucoma treatment is restricted to lowering intraocular pressure. In the near future, with the knowledge of the pathophysiology caused by the defective glaucoma gene, more traditional drug treatments may be used to bypass the gene defect. Ultimately, gene therapy would replace the mutant gene with a normal one before visual loss has occurred as has been done with a model for retinitis pigmentosa, the retinal degeneration mouse.

Growth factor and cytokine modulation of trabecular meshwork matrix metalloproteinase and TIMP expression.

PURPOSE: We hypothesize that regulated trabecular extracellular matrix (ECM) turnover, initiated by the matrix metalloproteinases, is critical for the maintenance of normal aqueous humor outflow rates. However, very little is known about the regulation of trabecular ECM turnover. To identify candidate trabecular regulators, we evaluated the effects of several growth factors and cytokines on trabecular matrix metalloproteinase and TIMP expression. METHODS: Porcine trabecular meshwork cells were treated with several doses of a variety of growth factors and cytokines and culture media was analyzed after 24, 48, and 72 h. Zymograms were used to evaluate stromelysin, gelatinase A and B activity levels, while immunoblots of Western transfers were used to evaluate stromelysin, collagenase, TIMP-1 and TIMP-2 protein levels. RESULTS: A phorbol mitogen (TPA), and TNF alpha and beta, interleukin-1 alpha and PDGF BB stimulate gelatinase B, stromelysin, interstitial collagenase and TIMP-1 expression, while having negligible effects on gelatinase A expression; TIMP-2 levels are reduced by TNF but not affected by the other treatments. Acidic and basic FGF, IL-1 beta, TGF beta and PDGF AB produce similar but smaller effects, while HGF, VEGF, EGF, KGF, and LIF produce small to moderate elevations in stromelysin with minimal other responses. PDGF AA, gamma INF, oncostatin-M and endothelin-1 produce negligible changes in these proteinases and inhibitors. CONCLUSIONS: In addition to providing potential ways to modulate trabecular metalloproteinase and TIMP levels, the responsiveness of these cells to some of these growth factors and cytokines suggests possible roles in normal or pathogenic trabecular cell regulation and some may affect aqueous humor outflow.

Proteoglycan expression by human trabecular meshworks.

PURPOSE: Proteoglycans may serve important roles in trabecular meshwork structure or function. Detailed molecular characterization and identification of specific trabecular proteoglycan core proteins has been limited. METHODS: Radiolabeled proteoglycans were extracted from cultured human trabecular meshworks and subjected to ion exchange and molecular sieve chromatography. Peaks were subjected to glycosaminoglycan content analysis. Reverse transcription with polymerase chain reaction was used to identify trabecular mRNAs of several common proteoglycan core proteins. Western immunoblots of trabecular extracts were also utilized to identify these proteoglycan core proteins. RESULTS: The proteoglycans elute from ion exchange columns at high salt and molecular sieve column profiles, and they exhibit broad peaks typical of the proteoglycan microheterogeneity seen in other tissues. The four common glycosaminoglycan side-chains were identified on these proteoglycans. Trabecular cells in organ or cell culture contain mRNAs coding for decorin, biglycan, versican, perlecan and a basement membrane glycoprotein, SPARC. Syndecan-1 transcripts were present at very low levels, while aggrecan transcripts were not detectable. Decorin, biglycan, versican and perlecan core proteins were also identified by immunoblots of trabecular cell extracts. CONCLUSIONS: Several common proteoglycans are expressed by trabecular cells in organ explant or cell culture. Their general characteristics are not unlike those found in other tissues. These proteoglycans may serve important functions in the trabecular outflow pathway.

Mapping a gene for adult-onset primary open-angle glaucoma to chromosome 3q.

Glaucoma is the third-leading cause of blindness in the world, affecting >13.5 million people. Adult-onset primary open-angle glaucoma (POAG) is the most common form of glaucoma in the United States. We present a family in which adult-onset POAG is inherited as an autosomal dominant trait. Twelve affected family members were identified from 44 at-risk individuals. The disease-causing gene was mapped to chromosome 3q21-24, with analysis of recombinant haplotypes suggesting a total inclusion region of 11.1 cM between markers D3S3637 and D3S1744. This is the first report of mapping of an adult-onset POAG gene to chromosome 3q, gene symbol GLC1C.

Weill-Marchesani syndrome--possible linkage of the autosomal dominant form to 15q21.1.

Weill-Marchesani syndrome comprises short stature, brachydactyly, microspherophakia, glaucoma, and ectopia lentis is regarded as an autosomal recessive trait (McKusick 277600). We present two families each with affected individuals in 3 generations demonstrating autosomal dominant inheritance of Weill-Marchesani syndrome. Linkage analysis in these 2 families suggests a gene for Weill-Marchesani syndrome maps to 15q21.1. The dislocated lenses and connective tissue disorder in these families suggests that fibrillin-1 and microfibril-associated protein 1, which both map to 15q21.1, are candidate genes for Weill-Marchesani syndrome. Immunohistochemistry staining of skin sections from family 1 showed an apparent decrease in fibrillin staining compared to control individuals.

Laser trabeculoplasty induces stromelysin expression by trabecular juxtacanalicular cells.

PURPOSE: The mechanism by which laser trabeculoplasty reduces elevated intraocular pressure in primary open-angle glaucoma has been established. To test the hypothesis that trabecular extracellular matrix turnover is involved, stromelysin expression after laser treatment of anterior segment organ cultures was evaluated. METHODS: Argon laser trabeculoplasty, using typical clinical treatment parameters, was applied to anterior segment organ cultures. Stromelysin levels and activity were then evaluated at various times by immunoblots of Western transfers and by zymography. Stromelysin mRNA levels were evaluated by dot blot and by reverse transcription, followed by polymerase chain reaction amplification. Stromelysin protein was localized by immunohistochemistry, and image analysis was used for quantitation. Stromelysin mRNA was localized by in situ hybridization. RESULTS: Trabecular stromelysin protein, activity, and mRNA levels were detectably elevated by 8 hours and were several-fold higher by 24 hours after treatment. Stromelysin immunostaining was elevated dramatically in the juxtacanalicular and insert regions of the meshwork, but only modestly in other regions. Stromelysin mRNA increases also were localized primarily to these regions. The juxtacanalicular stromelysin immunostaining increase was sustained for at least 1 week, whereas the insert levels declined somewhat after day 2. CONCLUSIONS: A stromelysin increase, localized primarily to the juxtacanalicular region of the meshwork, the putative site of the aqueous humor outflow resistance, should degrade trabecular proteoglycans, the putative outflow resistance source, and allow their uptake and further degradation by the juxtacanalicular cells. If diminished juxtacanalicular extracellular matrix turnover is responsible for the glaucomatous reduction in aqueous humor outflow, an increase in stromelysin in this specific area of the meshwork should ameliorate the problem. Thus, the observations support the working hypothesis and may explain the efficacy of this treatment for glaucoma.

Foveal adaptation abnormalities in early glaucoma.

Foveal sensitivities were measured after onset of adapting background fields for each of the following four groups of subjects aged 40-70 years: (1) low-tension glaucoma subjects with minimal field loss in the test eye, (2) primary open-angle glaucoma subjects with minimal field loss in the test eye, (3) normal control subjects, and (4) subjects originally enrolled as control subjects but subsequently found, on the basis of masked clinical evaluation, to be suspect for glaucoma despite ostensibly normal intraocular pressures. We found that the desensitization of a short-wavelength-sensitive-cone-mediated response after onset of a 580-nm background field was diminished from that of normal observers for low-tension glaucoma subjects but not for primary open-angle glaucoma subjects. The desensitization was also diminished for a glaucoma-suspect subjects aged 60-70 years. In contrast, the flicker sensitivity instabilities that persisted after onset of a long-wavelength background field for the majority of subjects with primary open-angle glaucoma [J. Glaucoma Suppl. 3, S19 (1994)] occurred only infrequently among the other subject groups. These results imply that glaucoma often involves the fovea, probably by affecting retinal subtractive adaptation processes, although with different consequences for different types of glaucoma. The results also suggest that undiagnosed low-tension glaucoma may not be rare in the general aging population.

Early changes in matrix metalloproteinases and inhibitors after in vitro laser treatment to the trabecular meshwork.

Extracellular matrix turnover in the trabecular meshwork may play a role in regulating aqueous humor outflow. Laser trabeculoplasty is a common treatment for open-angle glaucoma. The mechanism of this treatment is not understood. We investigated changes in the levels and expression of the matrix metalloproteinases and their tissue inhibitors (TIMPs) in this tissue using cultured human anterior segment explants and standard clinical-parameter laser treatment. Medium gelatinase A activity levels are relatively high for sham-treated controls and are not changed dramatically following laser treatment. Medium gelatinase B and stromelysin activity levels are low in sham-treated explants and increase significantly by 24 h after treatment. TIMP1 levels, as assessed by immunoblots of Western transfers, are initially low. However, by 24 h TIMP1 levels have increased significantly. Using semi-quantitative reverse transcription and the polymerase chain reaction, mRNA levels of stromelysin, gelatinase B and TIMP1 are shown to increase after laser treatment, while gelatinase A and TIMP2 remain relatively constant. The increases in trabecular stromelysin and gelatinase B in response to laser trabeculoplasty may have important implications for the mechanism of action of this treatment for open-angle glaucoma.

The effect of melatonin on aqueous humor flow in humans during the day.

BACKGROUND: Aqueous humor flow through the anterior chamber of the eye undergoes a circadian cycle. The rate of flow during the day is twice as high as the rate of flow at night. The pineal hormone, melatonin, also undergoes a circadian cycle. Melatonin levels are high at night, whereas aqueous humor flow is low. The authors studied the effect of oral melatonin on aqueous humor flow in humans. METHODS: The effect of melatonin on aqueous humor flow was evaluated in 19 healthy human volunteers in a randomized, masked crossover study with a placebo control. The hormone or placebo was administered orally during the day when endogenous levels of melatonin are low. Aqueous flow was measured by fluorophotometry for 8 hours. RESULTS: The mean rate of flow during melatonin treatment was 2.71 +/- 0.64 microliters/minute (+/- standard deviation). The rate of flow during placebo treatment was 2.80 +/- 0.66 microliters/minute. There is no statistically significant difference between these two rates (P = 0.4). With a sample size of 19, the study has a power of 92% to detect at least a 15% difference in the rate of flow under the two conditions. Measurement of plasma concentration of melatonin in five subjects confirmed that concentrations after oral dosage reached peaks comparable with the normal endogenous nocturnal peaks. CONCLUSIONS: The authors conclude that melatonin concentrations during the day, comparable with plasma concentrations that occur spontaneously during sleep, do not suppress aqueous humor formation. The authors find no support for the idea that plasma melatonin, per se, can suppress aqueous formation or that the circadian rhythm of plasma melatonin is primarily responsible for the circadian rhythm of aqueous humor flow.

DNA replication in the cat trabecular meshwork after laser trabeculoplasty in vivo.

The in vivo response to laser trabeculoplasty (LTP) was evaluated by measuring the incorporation of thymidine into DNA in the nuclei of trabecular meshwork cells. incorporation into DNA was analyzed by light microscopic autoradiography and by scintillation counting of trabecular extracts. Sixteen cats received argon LTP at a power setting of either 0.3 or 1.0 watt with the contralateral eye serving as a control; a 48-h exposure to HT began 1, 5, or 12 days later. The level of HT incorporation into DNA for LTP-treated eyes was significantly higher than controls for the earliest labeling period, but not at the later time points. This pattern was observed for both 0.3-and 1.0-watt treatments. In a second experiment, LTP was performed on six animals; a power setting of 0.3 watt was used in the left eye, and a power setting of 1 watt was used in the right eye. All 12 eyes were radiolabeled for 48 h with HT beginning 1 day after LTP. A small but significant difference in incorporation levels was found between these two power settings. Trabecular cell division may play a role in the therapeutic efficacy of LTP in glaucoma patients.

Foveal flicker sensitivity abnormalities in early glaucoma: associations with high blood pressure.

This study tested the hypothesis that (a) evidence of foveal visual dysfunction could be elicited in glaucoma subjects by measuring flicker sensitivity as a function of time after onset of an adapting field for a suitably chosen set of test and adaptation parameters and that (b) such dysfunction would be related to high blood pressure. Three groups of subjects were tested: (a) subjects with primary open-angle glaucoma but only minimal field loss, (b) normal control subjects, and (c) control subjects found to be suspect for glaucoma. The protocol included measurement of pulse rate and blood pressure, administration of Humphrey 30-2 visual fields and optic nerve head photography, and administration of a battery of psychophysical tests in Maxwellian view. This battery included a test of flicker sensitivity measured at middle wavelengths as a dynamic function of time after onset of a long-wavelength adapting field. The dynamic light-adaptation functions of subjects with glaucoma were much more likely to be unstable than were the corresponding functions of normal subjects. In addition, the dynamic light-adaptation functions of subjects with high blood pressure for their pulse rate were significantly less stable than the correspond ing functions of subjects without high blood pressure for their pulse rate. Moreover, the ratio of mean arterial pressure to pulse rate was significantly less for normal subjects than for either glaucoma subjects or for glaucoma-suspect subjects. We infer that among people with primary open-angle glau coma but with only minimal field loss, there often is foveal dysfunction associated with cardiovascular disease. Evidence of such dysfunction appears to require the use of stimulus conditions that tax the ability of the visual system to respond appropriately.