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Biomedical subjects

R N Weinreb

Publications and source records attributed to R N Weinreb.

At least 19 recordsLinked to original sources
PubMed2001

Induction of tyrosinase gene transcription in human iris organ cultures exposed to latanoprost.

OBJECTIVE: Topical administration of latanoprost sometimes induces gradual iris darkening. The present study was undertaken to determine if latanoprost can increase transcription of the gene for tyrosinase, an important enzyme in the biosynthesis of melanin. Results from brown, hazel, and blue irides were compared. METHODS: Iris tissue was isolated from 30 pairs of postmortem human donor eyes, and 2 iris segments from each eye were incubated in tissue culture medium supplemented with 200nM latanoprost acid or vehicle for 7 days. Tyrosinase messenger RNA (mRNA) was determined using real-time polymerase chain reaction analysis (TaqMan quantitative polymerase chain reaction). Results for tyrosinase mRNA were normalized according to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA in each sample. RESULTS: Tyrosinase mRNA expression was similar in blue and hazel irides, and ranged from 0.7-fold to 12.6-fold greater than GAPDH expression. In contrast, control brown iris culture tyrosinase expression ranged from 6.4-fold to 265-fold greater than GAPDH expression. Induction of tyrosinase mRNA by latanoprost was below threshold in all the blue iris cultures (n = 8 pairs), present in 1 of 9 hazel iris cultures, and present in 5 of 13 brown iris cultures. Mean induction in the responding hazel iris cultures was 1.40-fold. Mean induction among the responding brown iris cultures was 2.97-fold. CONCLUSIONS: These observations support the view that iris darkening associated with latanoprost treatment reflects induction of tyrosinase expression. Moreover, they suggest that the probability that latanoprost will increase tyrosinase expression is directly related to the magnitude of tyrosinase expression before treatments are initiated. CLINICAL RELEVANCE: The variability of iris darkening with latanoprost may reflect natural variation in the basal transcription of tyrosinase.

Adult↗
PubMed2001

Discriminating between normal and glaucomatous eyes using the Heidelberg Retina Tomograph, GDx Nerve Fiber Analyzer, and Optical Coherence Tomograph.

OBJECTIVE: To compare the ability of 3 instruments, the Heidelberg Retina Tomograph (HRT), the GDx Nerve Fiber Analyzer (GDx), and the Optical Coherence Tomograph (OCT), to discriminate between healthy eyes and eyes with early to moderate glaucomatous visual field loss. SUBJECTS AND METHODS: Forty-one patients with early to moderate glaucomatous visual field loss and 50 healthy subjects were included in the study. The HRT, GDx, and OCT imaging and visual field testing were completed on 1 eye from each subject within a 6-month interval. Statistical differences in sensitivity at fixed specificities of 85%, 90%, and 95% were evaluated. In addition, areas under the receiver operating characteristic (ROC) curve were compared. RESULTS: No significant differences were found between the area under the ROC curve and the best parameter from each instrument: OCT thickness at the 5-o'clock inferior temporal position (mean +/- SE, 0.87 +/- 0.04), HRT mean height contour in the nasal inferior region (mean +/- SE, 0.86 +/- 0.04), and GDx linear discriminant function (mean +/- SE, 0.84 +/- 0.04). Twelve HRT, 2 GDx, and 9 OCT parameters had an area under the ROC curve of at least 0.81. At a fixed specificity of 90%, significant differences were found between the sensitivity of OCT thickness at the 5-o'clock inferior temporal position (71%) and parameters with sensitivities less than 52%. Qualitative assessment of stereophotographs resulted in a sensitivity of 80%. CONCLUSION: Although the area under the ROC curves was similar among the best parameters from each instrument, qualitative assessment of stereophotographs and measurements from the OCT and HRT generally had higher sensitivities than measurements from the GDx.

Adult↗
PubMed2001

Increased matrix metalloproteinases 1, 2, and 3 in the monkey uveoscleral outflow pathway after topical prostaglandin F(2 alpha)-isopropyl ester treatment.

OBJECTIVE: To investigate the effects of topical prostaglandin F(2 alpha)--isopropyl ester (PGF(2 alpha)-IE) administration on immunoreactivity of matrix metalloproteinases (MMPs) 1, 2, and 3 within the anterior segment tissues of monkey eyes. METHODS: Eight eyes from 4 cynomolgus monkeys were evaluated. One eye from each monkey was treated with 2 mg of PGF(2 alpha)-IE twice daily for 5 days, and intraocular pressure reduction was measured. After fixation and processing, deparaffinized sections of anterior segments were immunostained using antibodies to MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), or MMP-3 (stromelysin-1). Optical density along 2 line segments overlying the iris root, ciliary muscle, and adjacent sclera and perpendicular to their long axes was measured using imaging densitometry. RESULTS: Compared with the contralateral vehicle-treated eyes, statistically significant increases in optical density scores were observed in the iris root, ciliary muscle, and adjacent sclera for all 3 MMPs (P<.01). In these tissues, MMP-1 immunoreactivity was increased by a mean +/- SD of 89% +/- 16%, 61% +/- 8%, and 66% +/- 57%, respectively; MMP-2 immunoreactivity by 129% +/- 53%, 82% +/- 27%, and 267% +/- 210%, respectively; and MMP-3 immunoreactivity by 207% +/- 84%, 83% +/- 49%, and 726% +/- 500%, respectively. CONCLUSIONS: Treatment of monkey eyes with PGF(2 alpha)-IE induces elevation of MMP-1, MMP-2, and MMP-3 in tissues of the uveoscleral outflow pathway. These increases suggest that MMPs might play an important role in the increased uveoscleral outflow observed with topical prostaglandin treatment. CLINICAL RELEVANCE: Immunoreactivity of MMPs in tissues of the monkey uveoscleral outflow pathway is increased after topical treatment with PGF(2 alpha)-IE. This response also might be involved in the intraocular pressure--lowering effect of other prostanoids used to treat glaucoma.

Administration, Topical↗
PubMed2001

Interobserver variability of optic disk variables measured by confocal scanning laser tomography.

PURPOSE: To assess the interobserver variation of confocal laser scanning tomographic measurements of the optic nerve head and to address the question of whether the addition of clinical optic disk photographs is helpful in outlining the optic disk margin and in reducing the observer-related variation of the measurements. PATIENTS AND METHODS: Optic disk variables for 16 eyes of 16 patients with glaucoma, generated by confocal laser scanning laser tomography (Heidelberg Retina Tomograph), were independently evaluated by four experienced glaucoma specialists, and the interobserver variability was calculated. A second separate review by the same observers included the use of clinical stereoscopic color optic nerve head photographs to aid definition of the optic disk margin. RESULTS: Optic disk parameters with the smallest interobserver variation were cup shape measure, maximum cup depth, height variation contour, and mean height contour. The intraobserver variation of these parameters did not increase when clinical optic disk slides were additionally available. Parameters with the highest interobserver variation were volume below surface, volume below reference, volume above surface, and volume above reference. The observer variation of these optic disk parameters increased significantly for two of the four examiners when clinical optic disk slides were additionally available for outlining the optic disk margin. CONCLUSION: Confocal laser scanning tomography of the optic nerve head can be improved significantly if clinical optic disk photographs are additionally available to help in outlining the optic disk margin. Because interobserver variation in the tomographic optic disk measurements can be significant, even if experienced observer are involved, tomographic optic disk measurements may be centralized in reading centers in the case of multicenter studies.

Diagnostic Techniques, Ophthalmological↗
PubMed2001

Relationship between visual field testing and scanning laser polarimetry in patients with a large cup-to-disk ratio.

PURPOSE: To determine the relationship between quantitative nerve fiber layer measurements and visual field testing in patients with large cup-to-disk ratios. METHODS: Seventy-six patients with vertical cup-to-disk ratios by contour of at least 0.8 on stereoscopic photographs and 50 normal subjects were included. One eye was randomly selected for study. All patients underwent standard achromatic automated perimetry, short-wavelength automated perimetry, and retinal nerve fiber layer measurements with scanning laser polarimetry. Analysis of variance was used to evaluate differences between the subject groups. Significance of pairwise comparisons was determined using the Tukey-Kramer multiple comparison test. RESULTS: Statistically significant differences in nerve fiber layer measurements between patients with large cup-to-disk ratios and both abnormal standard achromatic automated perimetry and short-wavelength automated perimetry (n = 22) and patients with large cup-to-disk ratios and both normal standard achromatic automated perimetry and short-wavelength automated perimetry (n = 42) were found for superior nasal ratio, maximum modulation, ellipse modulation, and the linear discriminant function (Tukey-Kramer less than.05). There was no significant difference in patients with abnormal short-wavelength automated perimetry only (n = 9) as compared with patients with both normal standard achromatic automated perimetry and short-wavelength automated perimetry and patients with both abnormal standard achromatic automated perimetry and short-wavelength automated perimetry. Statistically significant differences between the normal subjects and patients with large cup-to-disk ratios and both abnormal standard achromatic automated perimetry and short-wavelength automated perimetry were found for all retinal nerve fiber layer parameters, with the exception of symmetry, superior ratio, and inferior ratio. CONCLUSION: Our results show considerable overlap in nerve fiber layer measurements in eyes with large cup-to-disk ratio and abnormal visual fields as compared with eyes with large cup-to-disk ratios and normal visual fields. This may limit the clinical usefulness of scanning laser polarimetry for detection of early glaucoma in patients with large cup-to-disk ratios. Longitudinal studies are needed to determine if patients with large cup-to-disk ratios with normal standard achromatic automated perimetry and abnormal short-wavelength automated perimetry subsequently develop standard achromatic automated perimetry defects and if scanning laser polarimetry can concurrently detect progression of nerve fiber layer damage.

Aged↗
PubMed2001

Assessment of the retinal nerve fiber layer in clinical trials of glaucoma neuroprotection.

Assessment of the retinal nerve fiber layer (RNFL) is appealing for use in clinical trials of glaucoma neuroprotection, as it is directly correlated with loss of ganglion cells, which is assumed to be a primary event in glaucomatous damage. Qualitative assessment of the RNFL includes ophthalmoscopy, color stereophotography, and red-free monochromatic photography. In contrast, confocal scanning laser ophthalmoscopy (CSLO), scanning laser polarimetry (GDx), optical coherence tomography (OCT), and retinal thickness analysis (RTA) objectively and quantitatively measure the RNFL thickness. These latter techniques are still in evolution. Continuing meticulous objective validation is necessary to assess the usefulness and limitations of these powerful tools. Nevertheless, there are excellent prospects for using longitudinal assessment of the RNFL in clinical trials of glaucoma neuroprotection.

Cell Survival↗
PubMed2001

Using optical imaging summary data to detect glaucoma.

PURPOSE: To evaluate the sensitivity and specificity for discriminating between early to moderate glaucomatous and normal eyes using summary data reports from the Heidelberg Retina Tomograph (HRT), the GDx Nerve Fiber Analyzer (GDx), and the Optical Coherence Tomograph (OCT). DESIGN: Comparative cross-sectional study PARTICIPANTS: One eye each of 50 normal subjects and 39 glaucoma patients with early to moderate visual field damage (mean deviation, -5.04 +/- 3.32 dB; range, -0.85 to -13.2 dB). METHODS: Three experienced graders masked to patient identity and diagnosis evaluated each summary data report from the HRT, GDx, and OCT independently. MAIN OUTCOME MEASURES: Each summary report was classified as either normal or glaucomatous. Sensitivity and specificity are reported for each grader, and agreement between graders is reported. RESULTS: For the HRT, sensitivity and specificity ranged from 64% to 75% and 68% to 80%, respectively. Agreement (kappa +/- standard error [SE]) between observers one and two, two and three, and one and three was 0.73 +/- 0.07, 0.77 +/- 0.07, and 0.67 +/- 0.08, respectively. For the GDx, sensitivity and specificity ranged from 72% to 82% and 56% to 82%, respectively. Agreement (kappa +/- SE) between observers one and two, two and three, and one and three was 0.66 +/- 0.08, 0.66 +/- 0.08, and 0.50 +/- 0.09, respectively. For the OCT, sensitivity and specificity ranged from 76% to 79% and 68% to 81%, respectively. Agreement (kappa +/- SE) between observers one and two, two and three, and one and three was 0.73 +/- 0.07, 0.58 +/- 0.08, and 0.51 +/- 0.09, respectively. CONCLUSIONS: When used alone, HRT, GDx, and OCT summary data reports can differentiate between normal and glaucomatous eyes with mild to moderate visual field loss. However, none of the instruments provided sensitivity and specificity that justify summary data reports being used as a screening tool for early to moderate glaucoma.

Adult↗
PubMed2001

Latanoprost and matrix metalloproteinase-1 in human choroid organ cultures.

PURPOSE: Latanoprost, a prostaglandin F2a analogue and ocular hypotensive agent, alters extracellular matrix and matrix metalloproteinases (MMPs), including MMP-1, within tissues of the uveoscleral outflow pathway. In addition to these tissues, the anterior choroid also is exposed to fluid within the uveoscleral outflow pathway. The present study was undertaken to compare MMP-1 expression in the choroid with other uveoscleral pathway tissues and to determine the effect of latanoprost on MMP-1 expression in human choroid organ cultures. METHODS: Choroid tissue explant cultures were generated and incubated with PhXA85, the biologically active form of latanoprost, or vehicle for 12 or 18 hours. Explant cultures from iris and ciliary body also were generated and exposed to PhXA85. Protein extracts of theses cultures, as well as from fresh tissues, were then probed for MMP-1 by Western blotting. All samples were normalized for protein content and reletive expression was evaluated by densitometry. Also, total RNA was harvested from fresh tissues or from cultures treated with PhXA85. The amount of MMP-1 mRNA in these samples was measured using real time polymerase chain reaction. These results were normalized according to simultaneous measurements of glyceraldehyde-3-phosphate dehydrogenase mRNA within the same samples. RESULTS: Compared to the ciliary body, in which specific MMP-1 concentration (/total mg protein) was greatest, the specific MMP-1 concentrations within iris, anterior choroid, and posterior choroid were less by 24.7 +/- 0.69%, 40.7 +/- 1.04%, and 64.5 +/- 0.52%, respectively (mean +/- SD). The order of MMP-1 mRNA expression among these tissues from fresh eyes was ciliary body < anterior choroid < posterior choroid < iris. Treatment of ciliary body explant cultures with 200 nM PhXA85 for 12 hours increased MMP-1 protein content by 154 +/- 34% (P = 0.004, students t test, N = 3). In contrast, similar treatment of anterior choroid, posterior choroid, or iris explant cultures minimally changed MMP-1 protein content (23 +/- 22+/-, P = 0.124; 14 +/- 8%, P = 0.462; 27 +/- 16%, P = 0.037, respectively). Increased MMP-1 was observed in choroid cultures incubated for 18 hrs with 200 nM or 500 nM PhXA85. MMP-1 mRNA in 12 hour PhXA85-treated choroid cultures was the same or less than vehicle-treated cultures from 7 of 9 donors. In contrast, MMP-1 mRNA was increased in PhXA85-treated ciliary body cultures from 2 of 2 donors. CONCLUSIONS: These results suggest that the capacity for latanoprost-mediated induction of MMP-1 within the choroid is less than within the ciliary muscle. Hence, it is unlikely that induction of MMP-1 in choroid plays as important a role in uveoscleral outflow modulation as induction of MMP-1 in the ciliary muscle.

Adult↗
PubMed2001

Exogenous vasopressin influences intraocular pressure via the V(1) receptors.

PURPOSE: To compare central, peripheral, and ocular effects of exogenously given vasopressin on intraocular pressure (IOP) and to identify the related receptor mechanisms of action in rabbits. METHODS: Young adult New Zealand albino rabbits were entrained under a daily 12-hour light and 12-hour dark cycle. In the early light period, bolus injections of vasopressin or desmopressin (a specific V(2) receptor agonist) were given either to the central nervous system (CNS) through an implanted cannula to the 3(rd) ventricle or to the systemic circulation via the ear vein in conscious rabbits. Changes in IOP and pupil size were monitored for up to 6 hours and dose-response curves were generated. Effects of centrally and peripherally given vasopressin on IOP were further examined following pretreatments with a selective V(1) receptor antagonist administered into the 3(rd) ventricle and into the ear vein, respectively. In order to clarify whether or not exogenously given vasopressin can alter IOP by mechanisms inside the eye, vasopressin was injected into the anterior chamber or the vitreous chamber unilaterally in conscious rabbits. Changes in IOP and pupil size were monitored. After an anterior chamber or intravitreal injection of the V(1) receptor antagonist, changes in IOP and pupil size due to an intravenous injection of vasopressin were determined to study the involvement of the related receptor mechanism. RESULTS: A dose-dependent elevation of IOP appeared after injections of vasopressin into the 3(rd) ventricle. There was no pupillary change. This IOP elevation was blocked by the pretreatment with the V(1) receptor antagonist. Following intravenous injections of vasopressin, significant reductions of IOP and pupil size occurred. These reductions were blocked by the pretreatment with the V(1) receptor antagonist. Intracerebroventricular or intravenous injection of desmopressin had no effect on IOP or pupil size. Injection of vasopressin into the anterior chamber or the vitreous chamber caused significant reductions of IOP and pupil size. Pretreatment with the V(1) receptor antagonist into the anterior chamber or the vitreous chamber prevented the reductions of IOP and pupil size following an intravenous injection of vasopressin. CONCLUSIONS: Intracerebroventricular and intravenous injections of vasopressin cause opposite effects on IOP. The central effect of vasopressin on IOP and the peripheral effects of vasopressin on IOP and pupil size are due to stimulations of the V(1) receptors. Reductions of IOP and pupil size following intravenous injections of vasopressin are at least partially due to stimulations of the V(1) receptors inside the eye.

Animals↗
PubMed2001

Increased human scleral permeability with prostaglandin exposure.

PURPOSE: To investigate the effect of prostaglandins (PGs) on the permeability of human sclera in vitro. METHODS: Twenty-three pairs of human eye bank eyes were studied. Circular pieces of sclera were cultured in low-serum DMEM/F-12 media. Scleral hydration was assessed by measuring wet and dry weight of scleral cultures incubated with medium for 3 days and with Hanks' buffered saline solution (HBSS) for 4 hours. To assess scleral permeability, organ-cultured scleral tissues were exposed to 100 to 500 nM PGF(2alpha), 17-phenyltrinor PGF(2alpha), or PhXA85 (the active form of latanoprost) for 1, 2, and 3 days. Scleral permeability was measured using a two-chamber Ussing apparatus and rhodamine-dextran polymers dissolved in HBSS (MW = 10,000, 40,000, and 70,000). The movement of each rhodamine-dextran across the cultured sclera was measured using a spectrofluorometer. To understand the biological basis of the permeability change, the media were collected from the treated cultures, and the concentration of MMP-1, 2, and 3 was measured using an enzyme-linked immunosorbent assay. RESULTS: There was no difference in scleral hydration among fresh sclera and sclera incubated with medium for 3 days, with HBSS for 4 hours, or with medium for 3 days followed by HBSS for 4 hours. Compared to tracer movement across untreated scleral cultures (1.5 x 10(-6) cm/sec for 10 kDa dextran, 0.7 x 10(-6) cm/sec for 40 kDa dextran, and 0.4 x 10(-6) cm/sec for 70 kDa dextran), exposure to PGF(2alpha), 17-phenyltrinor PGF(2alpha), or PhXA85 each increased scleral permeability in a dose- and time-dependent manner. Increases in permeability were greater with the10 kDa dextran than with the 40 or 70 kDa dextran. The magnitude of these effects was greatest with exposure to PhXA85 and similar with exposure to PGF(2alpha) or 17-phenyltrinor-PGF(2alpha). MMP expression also was significantly increased after PG exposure. These increases were generally time and dose dependent and greater with MMP-2 and -3 than with MMP-1. CONCLUSIONS: There is increased permeability of human sclera exposed to various PGs in organ culture. This increased permeability is accompanied by increased expression of MMPS:

Aged↗
PubMed2001

Reduced TIGR/myocilin protein in the monkey ciliary muscle after topical prostaglandin F(2alpha) treatment.

PURPOSE: Mutations in the trabecular meshwork inducible glucocorticoid response (TIGR) gene, also known as myocilin, have recently been linked to some forms of glaucoma. Recent studies have shown that TIGR protein also is expressed in the ciliary muscle. Because uveoscleral outflow, which traverses the ciliary muscle, is increased by prostaglandins (PGs), the present study assessed whether topical PGs alter the amount of TIGR protein within the ciliary muscle. METHODS: Vehicle was topically applied to one eye, and 2 microg PGF(2alpha)-isopropyl ester (PGF(2alpha)-IE) was applied to the other eye of cynomolgus monkeys twice daily for 5 days. Pressure reductions of 5 mm Hg in the PGF(2alpha)-IE-treated eyes were confirmed. The eyes were then fixed and paraffin sections were cut from each eye. The distribution of TIGR protein in the ciliary muscle was determined by confocal scanning laser microscopy. Additional sections were immunostained with a polyclonal antibody to recombinant TIGR protein or with a polyclonal antibody to a synthetic peptide corresponding to the leucine zipper region within the TIGR protein. Staining intensity in the ciliary muscle was assessed by measuring optical density (OD) along two line segments overlying the ciliary muscle, by using a high-resolution imaging densitometer. RESULTS: TIGR protein immunoreactivity was observed in ciliary muscle fibers throughout the ciliary muscle. Extracellular TIGR immunoreactivity colocalized with collagen type IV immunoreactivity. Intracellular staining also was present. Immunoreactivity was less intense in the sections from the PGF(2alpha)-IE-treated eyes compared with the vehicle-treated eyes. This was reflected in the reduction of mean OD scores in each monkey. Overall, the reduction of mean OD scores in the treated eyes was 42.1% +/- 9.9% (P < 0.005) with the anti-recombinant TIGR antibody and 27.3% +/- 10.4% with the anti-TIGR peptide antibody (P < 0.005). CONCLUSIONS: TIGR protein immunoreactivity was present both intracellularly and extracellularly in the ciliary muscle of the cynomolgus monkey. This suggests that extracellular TIGR protein is in contact with aqueous humor in the uveoscleral outflow pathway. Moreover, IOP-lowering topical PGF(2alpha)-IE treatment decreases the amount of TIGR protein in the ciliary muscle.

Administration, Topical↗
PubMed2001

Detecting early glaucoma by assessment of retinal nerve fiber layer thickness and visual function.

PURPOSE: To compare the abilities of scanning laser polarimetry (SLP), optical coherence tomography (OCT), short-wavelength automated perimetry (SWAP), and frequency-doubling technology (FDT) perimetry to discriminate between healthy eyes and those with early glaucoma, classified based on standard automated perimetry (SAP) and optic disc appearance. To determine the agreement among instruments for classifying eyes as glaucomatous. METHODS: One eye of each of 94 subjects was included. Healthy eyes (n = 38) had both normal-appearing optic discs and normal SAP results. Glaucoma by SAP (n = 42) required a repeatable abnormal result (glaucoma hemifield test [GHT] or corrected pattern standard deviation [CPSD] outside normal limits). Glaucoma by disc appearance (n = 51) was based on masked stereoscopic photograph evaluation. Receiver operating characteristic (ROC) curve areas, sensitivities, and specificities were calculated for each instrument separately for each diagnosis. RESULTS: The largest area under the ROC curve was found for OCT inferior quadrant thickness (0.91 for diagnosis based on SAP, 0.89 for diagnosis based on disc appearance), followed by the FDT number of total deviation plot points of < or =5% (0.88 and 0.87, respectively), SLP linear discriminant function (0.79 and 0.81, respectively), and SWAP PSD (0.78 and 0.76, respectively). For diagnosis based on SAP, the ROC curve area was significantly larger for OCT than for SLP and SWAP. For diagnosis based on disc appearance, the ROC curve area was significantly larger for OCT than for SWAP. For both diagnostic criteria, at specificities of > or =90% and > or =70%, the most sensitive OCT parameter was more sensitive than the most sensitive SWAP and SLP parameters. For diagnosis based on SAP, the most sensitive FDT parameter was more sensitive than the most sensitive SLP parameter at specificities of > or =90% and > or =70% and was more sensitive than the most sensitive SWAP parameter at specificity of > or =70%. For diagnosis based on disc appearance at specificity of > or =90%, the most sensitive FDT parameter was more sensitive than the most sensitive SWAP and SLP parameters. At specificity > or = 90%, agreement among instruments for classifying eyes as glaucomatous was poor. CONCLUSIONS: In general, areas under the ROC curve were largest (although not always significantly so) for OCT parameters, followed by FDT, SLP, and SWAP, regardless of the definition of glaucoma used. The most sensitive OCT and FDT parameters tended to be more sensitive than the most sensitive SWAP and SLP parameters at the specificities investigated, regardless of diagnostic criteria.

Diagnostic Techniques, Ophthalmological↗