Implications of retinal effects observed in chronic toxicity studies on the clinical development of a CNS-active drug candidate.

The development path described for JNJ-26489112 provides perspectives on interpretation of retinal effects observed in nonclinical studies and their implications for clinical development. JNJ-26489112 is a CNS-active investigational drug that has potential as a novel treatment for treatment-resistant and bipolar depression, epilepsy, and neuropathic/inflammatory pain. In a 6-month toxicity study in albino rats, retinal atrophy was observed at supratherapeutic exposures to JNJ-26489112. The histopathological changes and topography of the lesions were characteristic of light-induced damage specific to albino rats. The species/strain specificity is supported by an absence of any ocular effects in dogs and in pigmented and albino rats, housed under standard and reduced lighting, respectively. To further evaluate its potential to cause ocular effects, in vivo functional and structural ocular analyses were included in a 9-month monkey toxicity study. Reductions in rod- and cone-mediated electroretinograms were observed at supratherapeutic exposures but without any histopathologic changes. These data suggested that the effects of JNJ-26489112 in monkeys were neuromodulatory and not neurotoxic. Taken together, data related to the light-induced atrophy in albino rats and reversible neuromodulatory effects in monkeys, supported the safe evaluation of JNJ-26489112 in a clinical proof-of-concept study that included comprehensive functional and structural ocular monitoring.

Vision loss following snakebite in a patient with controlled aplastic anemia

Viper venoms act mainly on blood and blood vessels. Reports of ophthalmic manifestations after snakebite include ptosis and ophthalmoplegia. In the current study, we describe a case that developed bilateral retinal and subretinal hemorrhage following snakebite. Bilateral retinal hemorrhage is a rare ocular complication of snake envenomation and has not been reported with fundus photographs in the literature so far.(AU)

Effect of H-7 and Lat-B on retinal physiology.

PURPOSE: To investigate the effects of H-7 and Latrunculin B (Lat-B) on retinal vascular permeability and electrophysiology at concentrations that increase outflow facility in monkeys. METHODS: One eye of 1 rhesus and 22 cynomolgus monkeys received an intravitreal bolus injection of H-7 or Lat-B; the opposite eye received vehicle. Multifocal electroretinograms (mfERGs), and photopic and scotopic full-field electroretinograms (ffERGs, sERGs) were recorded in subsets of monkeys at baseline and at multiple time-points post-H-7 or Lat-B. Vitreous fluorophotometry (VF) and fluorescein angiography (FA) were also performed. RESULTS: No differences between the H-7 or Lat-B treated and control eyes were found in ffERGs, mfERGs, sERGs, or in FAs in any monkey. No significant difference was found in vitreous fluorescein levels between H-7 treated or Lat-B treated vs. control eyes. CONCLUSIONS: No effect on retinal vascular permeability or retinal electrophysiology was apparent after intravitreal administration of H-7 or Lat-B at doses that increase outflow facility and lower IOP when given intracamerally.

Subtherapeutic ocular penetration of caspofungin and associated treatment failure in Candida albicans endophthalmitis.

Candida endophthalmitis represents the most serious ocular complication of candidemia. The pharmacokinetics and pharmacodynamics of fluconazole, amphotericin B, and flucytosine are fairly well established in endophthalmitis therapy. There remains a paucity of clinical data regarding the utility of new antimycotic agents in the treatment of fungal chorioretinitis and endophthalmitis. We report a case of clinical failure of caspofungin in the management of Candida albicans endophthalmitis associated with poor vitreous penetration.

The effects of panretinal photocoagulation on the primary visual cortex of the adult monkey.

PURPOSE: To determine the effects of panretinal photocoagulation (PRP) on the levels of cytochrome oxidase (CO), Zif268, synaptophysin, and growth-associated protein 43 (GAP-43) in the primary visual cortex of adult monkeys. METHODS: Ten adult primates underwent unilateral argon laser PRP with instrument settings at 300 to 500 microns spot diameter, 200 to 500 mW power intensity, and 0.1 to 0.2 second duration, causing moderate to severe burns in the peripheral retina. At 20 hours, 12 days, 6 months, and 13 months after laser treatment, the visual cortex was assessed histologically for CO and immunohistochemically for Zif268, synaptophysin, and GAP-43. RESULTS: PRP resulted in transneuronal changes in the relative distributions of CO, Zif268, synaptophysin, and GAP-43 in the primary visual cortex. CO activity was relatively decreased in the lasered eye's ocular dominance columns at 12 days post-PRP, with recovery by 13 months post-PRP. The level of Zif268 was dramatically decreased in the lasered eye's ocular dominance columns at 20 hours post-PRP, with gradual recovery by 13 months post-PRP. Levels of synaptophysin and GAP-43 immunoreactivity were increased in both the lasered and the nonlasered eyes' ocular dominance columns at 6 months post-PRP. CONCLUSION: PRP treatment results in metabolic activity changes in the visual cortex of the adult monkey. These changes are followed chronologically by spatial redistribution of synaptophysin and GAP-43, neurochemicals known to play a role in cortical plasticity. This study demonstrates, for the first time, that PRP as used in the treatment of diabetic retinopathy results in a redistribution of neurochemicals in the adult monkey visual cortex. Such changes may help explain the anomalous visual functional loss often reported by patients after PRP.

Selective loss of S-cones in diabetic retinopathy.

OBJECTIVE: To determine whether selective cone loss could explain the acquired tritan-like color confusion found in diabetic retinopathy. METHODS: Terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine triphosphate nick end labeling (TUNEL) was employed on paraffin sections of retinas from 5 donors with diabetic retinopathy. For quantitative analysis, postmortem retinas were obtained from 13 human donors; 7 from patients with various durations and stages of diabetic retinopathy (4 background, 3 proliferative) and 6 controls. Enzyme histochemical analysis for carbonic anhydrase (CA) was used to distinguish L/M-cones (positive for CA) from S-cones (negative for CA). Cone topography was determined by sampling 360 degrees from 0.1 to 1.5 mm of foveal eccentricity and along the horizontal meridians from 1.5 to 15.0 mm. RESULTS: Rare cells in both the inner and outer nuclear layers of the diabetic eyes were positively labeled with the TUNEL method. The CA staining revealed incomplete and patchy losses of S-cones that were limited to the diabetic retinas. Statistically significant reduction in the density of S-cones was found at nearly all foveal eccentricities from 0.1 mm to 15.0 mm. This was not the case for the L/M-cones. On average, for all locations, the percentage of S-cones compared with L/M-cones was decreased by 21.0% +/- 3.4% with respect to the controls. CONCLUSION: The S-cones selectively die in diabetic retinopathy. CLINICAL RELEVANCE: Selective loss of S-cones may contribute to the tritan-like color vision deficit seen in patients with diabetic retinopathy.

Protection of ganglion cells in experimental glaucoma by retinal laser photocoagulation.

OBJECTIVE: To test a hypothesis of photoreceptor involvement in retinal ganglion cell (RGC) death in chronic glaucoma. METHODS: Laser spots were applied to 6 eyes of 3 rhesus monkeys, causing focal destruction of the outer retina, including the photoreceptors. After 3 to 4 weeks, experimental glaucoma was induced in the right eyes of each monkey using argon laser trabecular destruction (ALTD). The intraocular pressures in these eyes were elevated for 3 to 7 months. As a control, 1 additional monkey underwent retinal laser photocoagulation followed by optic nerve transection instead of ALTD. Following enucleation, the retinas were embedded and sectioned for histologic evaluation. RESULTS: There was extensive loss of RGCs in the eyes with ALTD except over the large retinal laser spots, where there was an increased survival of RGCs. The RGC protection was not observed in the monkey that had undergone optic nerve transection. CONCLUSION: Photocoagulation of the outer retina that completely destroys the photoreceptors results in survival of the overlying RGCs in experimental glaucoma in monkey eyes. CLINICAL RELEVANCE: Although this is an experimental model and not a therapeutic option, these results suggest that treatments other than lowering intraocular pressure may be potential therapies for preventing RGC death in glaucomatous eyes. Arch Ophthalmol. 2000;118:1242-1250

Swelling and loss of photoreceptors in chronic human and experimental glaucomas.

OBJECTIVE: To determine whether outer retinal changes occur in chronic, presumed primary open-angle glaucoma (POAG). METHODS: The outer retinas from 128 human eyes with a diagnosis of chronic glaucoma (presumably POAG in most cases) and 90 control eyes were examined histologically by 3 masked observers for photoreceptor swelling and loss. Retinas from 9 rhesus monkeys with glaucoma induced experimentally by laser trabecular destruction were compared with 7 fellow (control) eyes. The mean pressure elevations in the eyes with laser trabecular destruction ranged from 26.6 to 53.6 mm Hg with durations varying from 7 to 33 weeks. RESULTS: Swelling of the red- and green-sensitive cones was observed in a statistically significantly greater proportion of human eyes with presumed POAG compared with the control eyes. Patchy loss of red/green cones and rods was also found in some of the glaucomatous retinas. In a subset of the human eyes with end-stage disease, cone swelling was a variable finding. Although no photoreceptor loss was found in the 9 monkey eyes with experimental glaucoma, 8 had swelling of their red/green cones that was remarkably similar to that seen in the human eyes. Swelling was not present in any of the control monkey eyes. CONCLUSIONS: The photoreceptors are affected by chronically elevated intraocular pressure. CLINICAL RELEVANCE: These findings may explain some of the abnormalities of color vision and the electrophysiological effects that have been observed in patients with POAG.

Relative contributions of the neurosensory retina and retinal pigment epithelium to macular hypofluorescence.

OBJECTIVE: To determine quantitatively the relative contributions of the neurosensory retina (NR) and retinal pigment epithelium (RPE) to the macular hypofluorescence observed during routine fundus fluorescein angiography. METHODS: Macular and peripheral buttons of neurosensory retina and retinal pigment epithelium were obtained from 10 postmortem human eyes. A well was created to simulate a fluorescein-filled choroid. The fluorescence of each tissue and combinations of tissue atop the well was determined using a fluorescence microscope. The percent reduction in the fluorescence of each, relative to the baseline fluorescence of the well alone, was calculated. RESULTS: Macular RPE demonstrated substantially lower fluorescence than peripheral RPE in all subjects. Macular NR demonstrated lower fluorescence than peripheral NR in all but one subject. The addition of macular NR to macular RPE caused significantly less fluorescence in all cases. Macular RPE caused a much greater percent reduction in fluorescence than macular NR in all subjects. CONCLUSIONS: Hypofluorescence of the macula relative to the peripheral retina is a well-known feature of fluorescein angiography. This phenomenon is predominantly owing to the RPE and minimally to the NR, which cause 90.6 and 13.6 mean percent reductions in fluorescence, respectively.

Acquired color vision loss and a possible mechanism of ganglion cell death in glaucoma.

PURPOSE: First, to study the cellular mechanisms of acquired color vision loss in retinal detachment and diabetic retinopathy. Second, to learn why, in glaucoma, the type of color vision deficit that is observed is more characteristic of a retinal injury than it is of an optic neuropathy. Third, to test a hypothesis of photoreceptor-induced, ganglion cell death in glaucoma. METHODS: Various histologic techniques were employed to distinguish the L/M-cones (long/medium wavelength-sensitive cones, or red/green sensitive cones) from the S-cones (short wavelength-sensitive cones, or blue sensitive cones) in humans and monkeys with retinal detachment, humans with diabetic retinopathy, and both humans and monkeys with glaucoma. To test if the photoreceptors were contributing to ganglion cell death, laser photocoagulation was used in a experimental model of glaucoma to focally eliminate the photoreceptors. As a control, optic nerve transection was done following retinal laser photocoagulation in one animal. RESULTS: Selective and widespread loss of the S-cones was found in retinal detachment as well as diabetic retinopathy. By contrast, in human as well as experimental glaucoma, marked swelling of the L/M-cones was the predominant histopathologic feature. Retinal laser photocoagulation followed by experimental glaucoma resulted in selective protection of ganglion cells overlying the laser spots. This was not seen with retinal laser photocoagulation by optic nerve transection. CONCLUSIONS: In retinal detachment and diabetic retinopathy, acquired tritan-like color vision loss could be caused, or contributed to, by selective loss of the S-cones. Both L- and M-cones are affected in glaucoma, which is also consistent with a tritan-like deficit. Although not a therapeutic option, protection of ganglion cells by retinal laser in experimental glaucoma is consistent with an hypothesis of anterograde, photoreceptor-induced, ganglion cell death.

Treatment and histopathology of a congenital vitreous cyst.

OBJECTIVE: This study aimed to evaluate the treatment efficacy of a congenital vitreous cyst and to examine the cyst histopathologically to determine its cellular makeup and possible origin. STUDY DESIGN: The study design was a case report, including a clinicopathologic correlation. INTERVENTION: A 35-year-old woman with a known vitreous cyst since childhood became increasingly troubled by its symptoms. The cyst was treated initially with argon laser photocoagulation. Vitrectomy subsequently was performed because the deflated cyst remained near the visual axis. Histopathologic studies included light and electron microscopy; immunocytochemistry for actin and glial fibrillary acidic protein (GFAP); and enzyme histochemistry for carbonic anhydrase (CA). RESULTS: The cyst was composed of a single layer of heavily pigmented cells with a thick basement membrane along the internal borders of the cells. Ultrastructurally, the cells were connected with tight junctions, had microvillous processes at their apices, and contained numerous large melanosomes in various stages of maturity, including premelanosomes. Immunochemistry showed the cells were positive for actin but negative for GFAP. Enzyme histochemical staining for CA also was strongly positive. CONCLUSIONS: The confinement of this cyst to the region of Cloquet's canal, the presence of a Mittendorf's dot, the cyst's existence for many years, and the finding of pigment epithelial-type cells having immature melanosomes (a feature not seen after birth in normal pigment epithelium) lead the authors to believe that this cyst was a congenital remnant of the primary hyaloidal system. Because pigmented cells are not normally present in this part of the eye, the cyst was a choristoma of the primary hyaloidal system.

Nuclear exclusion of wild-type p53 in immortalized human retinoblastoma cells.

BACKGROUND: Retinoblastoma is the most common childhood tumor of the eye, arising from cells that are defective in both copies of the retinoblastoma susceptibility gene (RB1). Most retinoblastoma tumor cells eventually undergo programmed cell death (i.e., apoptosis); however, some cells can acquire the ability to metastasize and become immortal. Transfection of immortal retinoblastoma cells with DNA sequences encoding wild-type p53 protein induces cell death, suggesting that the loss of both RB1 and p53 functions may be required for cell immortalization. We have examined this possibility by characterizing the p53 protein and messenger RNA in six independently isolated, immortalized retinoblastoma cell lines. METHODS: Western blotting methods were used to assess p53 protein level in each cell line, and Cleavase Fragment-Length Polymorphism analysis of complementary DNAs was used to screen for mutations in p53 messenger RNA. Localization of p53 protein in cells of the immortalized lines and in specimens of retinoblastoma tumors was achieved by means of indirect immunofluorescence and immunocytochemistry, respectively. RESULTS: All six immortalized cell lines expressed wild-type p53 messenger RNA and high levels of p53 protein. Although p53 is normally a nuclear protein, the p53 in four of the six cell lines was located predominately in the cytoplasm; in the remaining two cell lines, p53 was localized in both the nucleus and the cytoplasm. Cytoplasmic localization of p53 in retinoblastoma tumor specimens was rare and usually restricted to cells that had invaded adjacent ocular tissues, indicative of the early stages of metastasis. CONCLUSIONS: Some immortalized retinoblastoma cells may exhibit p53 dysfunction through nuclear exclusion of wild-type p53 protein.

Retinoblastoma in a dog.

OBJECTIVE: To describe and classify a retinal tumor found in a dog that histologically resembles human retinoblastoma and to discuss the molecular mechanisms of retinal oncogenesis. METHODS: A dog eye with a retinal tumor was examined histologically. Studies including immunocytochemical analysis for retinal S-antigen and glial fibrillary acidic protein, enzyme histochemical analysis for carbonic anhydrase, and nick-end DNA labeling were used to characterize the tumor. Normal retina from another dog and other tumors from dogs, including 2 ciliary body medulloepitheliomas and a brain medulloepithelioma, were examined as controls. RESULTS: The retinal tumor disclosed characteristics typical of human retinoblastoma, including Flexner-Wintersteiner rosettes. It showed strong immunoreactivity with S-antigen and glial fibrillary acidic protein. Carbonic anhydrase activity also could be shown in the tumor. Apoptosis was found to be the predominant method of cell death as shown by nick-end DNA labeling. In contrast to the other tumors examined, this tumor contained areas with retinal photoreceptor and glial differentiation. CONCLUSIONS: The histopathologic findings and differential staining characteristics in this retinal tumor are compatible with retinoblastoma, making this, to our knowledge, the first documented case of spontaneous retinoblastoma in an animal.

p53 regulates apoptosis in human retinoblastoma.

OBJECTIVES: To determine whether apoptosis is a significant mode of cell death in human retinoblastoma (RB) and if it is regulated by the expression of p53. METHODS: Apoptosis was analyzed using the criterion of internucleosomal DNA degradation as determined by agarose gel electrophoresis of DNA isolated from tumor specimens. Individual cells undergoing apoptosis were identified using terminal transferase-mediated biotin-dUTP nick end labeling (TUNEL) of fragmented DNA. The expression of p53 and WAF1 (a protein involved in p53-mediated cell cycle arrest) in human RB was determined by immunocytochemical analysis. The function of p53 in human RB cell lines was tested by transfecting them with a complementary DNA encoding a temperature-sensitive isoform of murine p53 under the control of a strong viral promoter. RESULTS: DNA from RB tumor specimens showed a strong nucleosomal ladder of DNA fragments typical of apoptosis. The TUNEL staining indicated that poorly and moderately differentiated cells in tumors were undergoing DNA fragmentation. Immunoreactivity for p53 was variable. Cells expressing low levels of p53 seemed viable and expressed WAF1. Cells expressing high levels of p53 were found immediately adjacent to cells undergoing apoptosis. Human RB cells in culture that were expressing a murine temperature-sensitive isoform of p53 died at temperatures that allow this protein to assume a wild-type conformation. CONCLUSIONS: Apoptotic cell death is prevalent in RB. The close association of p53-immunoreactive cells and cells undergoing apoptosis in human tumors, and the ability of exogenous p53 to stimulate cell death in cultured human RB cells, suggests that p53 plays a role in regulating cell death in RB.

Immunocytochemical features of retinoblastoma in an adult.

OBJECTIVE: To describe the clinical course and immunocytochemical characteristics of an unusual intraocular tumor. METHODS: Immunocytochemical analysis of the enucleated eye with an intraocular mass that markedly waxed and waned in size during 1 year of close observation of a 29-year-old woman. RESULTS: Most of the tumor was composed of either dying or rapidly proliferating cells. One area located near the retina consisted mostly of well-differentiated cells in uniform sheets (bacillettes) with lacelike glial processes between the tumor cells. Almost all of the differentiated tumor cells were positive for S antigen. In particular, the dominant cell type stained positively for both antibodies known to be specific for those isoforms of S antigen found only in blue cones and rods but not in red or green cones. Only a few of these cells labeled positively with an anti-rhodopsin antibody. CONCLUSIONS: This is the first case of adult retinoblastoma to be confirmed immunocytochemically. The tumor was unusual because the differentiated regions contained bacillettes composed mostly of blue cones. It is possible that this and other adult retinoblastomas may arise from previously existing retinocytomas.

Acetazolamide affects performance on the Nagel II anomaloscope.

BACKGROUND: Recent reports have indicated that acetazolamide alters human electroretinograms. We wished to determine the effects of administering acetazolamide on performance on the Nagel II anomaloscope. METHODS: We tested 15 subjects matches of blue-green light to a mixture of blue and green lights (luminance match) on a Nagel type II anomaloscope 2.5 h after ingesting 500 mg of acetazolamide or a placebo. RESULTS: The mean of the luminance settings for the subjects was 54.4 for the placebo condition and 58.5 for the acetazolamide condition. The mean difference of 4.1 was statistically significant, indicating that following ingestion of acetazolamide subjects were less sensitive to a blue-green light. In two supplementary experiments we tested (1) a second group of four normal subjects using the Nagel type II anomaloscope and (2) the previously untreated eyes of four patients with primary open-angle glaucoma before and after placing them on acetazolamide therapy. In both groups, more blue-green light was needed to make the match after ingestion of acetazolamide. CONCLUSIONS: Acetazolamide alters the sensitivity of one or more cone populations, probably the carbonic anhydrase-containing cones. The sensitivity loss is reversible and does not appear to be clinically significant. However, the results suggest that patients administered acetazolamide should be excluded from studies which compare the color vision of glaucomatous patients to that of normals.

Selective loss of blue cones and rods in human retinal detachment.

OBJECTIVE: To determine if there are histopathologic changes in the outer retina that could explain the blue-yellow color confusion previously described following rhegmatogenous retinal detachment in humans. METHODS: Ten eyes with traumatic retinal detachments were studied. Eight of the eyes were removed from 2 1/2 to 11 days following trauma. In the remaining two eyes, the retinas were successfully reattached. Enzyme histochemical studies for carbonic anhydrase and immunochemical studies for S antigen were performed to distinguish blue cones from red/green cones. RESULTS: With the 2 1/2- to 4-day-old detachments, nearly all of the carbonic anhydrase-negative (blue-sensitive) cones and many of the rods were seen to have signs of irreversible necrosis, including extreme swelling of the inner segments and mitochondria, loss of the outer segments, and pyknotic and displaced nuclei. In the 6- and 11-day-old detachments, almost all of the carbonic anhydrase-negative cones and many rods were missing. Blue cones were essentially absent from the reattached retinas, and there were only about half the normal number of rods. CONCLUSIONS: Rhegmatogenous retinal detachment results in rapid and almost total loss of the blue cones. Significant rod loss also occurs in this type of detachment but the red/green cones are comparatively resistant to damage. These findings could explain the observed blue-yellow color confusion in such patients. We discuss other clinical implications.

Retinoblastoma. Cell of origin.

OBJECTIVES: To apply modern techniques of molecular cell biology and to revisit the old question of the cell of origin for retinoblastoma in hopes of gaining a better understanding of the retinoblastoma gene's antioncogenic mechanisms. METHODS: Twenty-two consecutively accessed retinoblastomas were examined with immunocytochemical techniques for numerous retinal proteins. Both single and double labeling were used. Enzyme histochemistry for carbonic anhydrase was used as well. RESULTS: Differentiated areas of the tumors contained abundant Müllerlike cells. Fleurettes stained mostly for red and green cone-specific antibodies while features of blue cones and rods predominated in areas with high cytoplasmic-to-nuclear ratios but no fleurettes. All of the differentiated neoplastic cells were either photoreceptors or Müller's cells. No other retinal cell types were found. CONCLUSIONS: The cells of retinoblastoma are capable only of bipotential differentiation, ie, Müller's cells and photoreceptors. Given this and recent findings concerning retinal embryogenesis, we argue for the rod photoreceptor as the cell of origin. A possible role for the retinoblastoma gene product is discussed.

Immunolocalization of the retinoblastoma protein in the human eye and in retinoblastoma.

PURPOSE: To determine whether, by employing recent advances in immunocytochemical technique, it is possible to identify reliably the product of the retinoblastoma (RB) susceptibility gene, p110RB1, in formalin-fixed, paraffin-embedded eyes with commercially available primary antibodies. If so, the authors sought to determine the distribution of p110RB1 in normal human eyes and retinoblastomas in hopes of better understanding its function. METHODS: Four antibodies to p110RB1 were tested on normal human and monkey eyes, as well as on six human retinoblastomas. The human tissue was formalin-fixed and paraffin-embedded. Free antigen was used for an absorbed control. The monkey eye had been injected with tritiated (H3) thymidine 24 hours before enucleation. RESULTS: Three of the four antibodies had acceptable reactivity (a polyclonal against the carboxyl-terminal epitope and two monoclonals against epitopes near the amino-terminus). Staining was confined to nucleated cells of the normal eyes and was strongest in the cycling cells of the lenticular and corneal epithelia. Somewhat weaker reactivity was seen in those corneal epithelial cells in S phase as determined by autoradiography for H3-thymidine. Of the six retinoblastomas, three had strong nuclear and cytoplasmic staining and one showed weaker staining in the tumor cells than in the adjacent vascular endothelial cells. Two of the tumors had positive cytoplasmic and negative nuclear staining with an amino-terminal antibody but were completely negative for carboxyl-terminal p110RB1 reactivity. CONCLUSIONS: Using appropriate immunocytochemical techniques, p110RB1 can be identified in paraffin-embedded tissues with commercially available antibodies. The observed staining pattern in retinoblastoma suggests that RB1 transcripts are commonly produced in the tumor cells and that they are sometimes, but not always, capable of nuclear binding. Thus, nuclear binding by the RB1 gene product per se is not sufficient to prevent tumor growth, nor does it indicate the presence of a normal transcript.

The effects of acetazolamide in albino rabbits, pigmented rabbits, and humans.

In three separate experiments albino rabbits, pigmented rabbits, and humans were tested following administration of acetazolamide and without acetazolamide. In all three experiments, we recorded electroretinograms (ERGs) under dark adapted and light adapted conditions and measured the b-wave amplitudes. Dark adapted ERG b-wave amplitudes were increased following administration of acetazolamide as compared to control conditions, in albino rabbits, pigmented rabbits and humans. Light adapted b-wave amplitudes showed no statistically significant changes as a function of acetazolamide administration although in all three experiments there was a trend toward light adapted b-wave amplitude reduction following administration of acetazolamide. In the human experiments, ERG a-wave amplitudes were also measured. Light adapted a-wave amplitudes were reduced following administration of acetazolamide. In the human experiments, several behavioral tests were performed, including L'Anthony desaturated D-15, Farnsworth-Munsell 100 hue, Cogan-Gunkel chromatograph, Nagel anomaloscope, Goldmann-Weekers dark adaptometry. There were no consistent changes in the human dark adaptation thresholds or color discrimination, although several measures approached significance.