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Color vision, initiated from the cone photoreceptors, is essential for fish to obtain environmental information. Although the visual impairment of triazine herbicide prometryn has been reported, data on the effect of herbicide such as prometryn on natural color sensitivity of fish is scarce. Here, zebrafish were exposed to prometryn (0, 1, 10, and 100 μg/L) from 2 h post-fertilization to 160 days post-fertilization, to explore the effect and underlying mechanism of prometryn on color perception. The results indicated that 10 and 100 μg/L prometryn shortened the height of red-green cone cells, and down-regulated expression of genes involved in light transduction pathways (arr3a, pde6h) and visual cycle (lrata, rpe65a); meanwhile, 1 μg/L prometryn increased all-trans-retinoic acid levels in zebrafish eyes, and up-regulated the expression of genes involved in retinoid metabolism (rdh10b, aldh1a2, cyp26a1), finally leading to weakened red and green color perception of female zebrafish. This study first clarified how herbicide such as prometryn affected color vision of a freshwater fish after a long-term exposure from both morphological and functional disruption, and its hazard on color vision mediated-ecologically relevant tasks should not be ignored., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: To longitudinally evaluate the visual function and structure of patients taking ethambutol by various modalities and identify useful tests for detection of subclinical ethambutol-induced optic toxicity., Methods: This retrospective study enrolled 84 patients with newly diagnosed tuberculosis treated with ethambutol. Best-corrected visual acuity (BCVA), color vision, contrast sensitivity, fundus and retinal nerve fiber layer (RNFL) photography, automated visual field (VF) test, and optical coherence tomography (OCT) were performed: prior to starting; every month during administration, and 1 month after stoppage. We longitudinally compared visual function and structure with the baseline and identified the occurrence of subclinical toxicity., Results: BCVA, color vision, and contrast sensitivity showed no change from the baseline. Mean temporal RNFL thickness was significantly increased at 6 months (p = 0.014). Subclinical toxicity was found in 22 eyes of 14 patients (i.e., 13% of 168 eyes), in the forms of VFI decrease (VF index, 9 eyes of 6 patients), quadrant RNFL thickness increase (5 eyes of 4 patients), and VF pattern defect (12 eyes of 6 patients). 73% of the patients showed recovery to the baseline at 1 month post-stoppage. The risk factors for occurrence of subclinical toxicity were age, cumulative dose, and medication duration., Conclusion: Mean temporal RNFL thickness increased after administration. The VFI, quadrant RNFL thickness, and VF pattern defect could prove useful in assessment of subclinical toxicity. Medication duration was shown to be a strong risk factor for occurrence of subclinical toxicity., Competing Interests: The authors have declared that no competing interests exist.

The extensive usage of xenobiotic endocrine disrupting chemicals (XEDCs), such as Bisphenol A (BPA), has created obvious threat to aquatic ecosystems worldwide. Although a comprehensive understanding of the adverse effect of BPA on behaviors and physiology have been proven, the potential impact of low-dose BPA on altering the basic ability of aquatic organism in adapting to the surrounded complex environment still remains elusive. In this research, we report that treatment of adult male zebrafish with chronic (7 weeks) low-dose (0.22 nM-2.2 nM) BPA, altered the ability in adapting the complex environment by disturbing the natural color preference patterns. In addition, chronic 50 ng/L (0.22 nM) BPA exposure alleviated the anxiety behavior of male zebrafish confronted with the novel environment by enhancing the preference towards light in the light/dark preference test. This phenotype was associated with less expression of serotonin (5-TH) in the hypothalamus and the down-regulation of tyrosine hydroxylase (TH) in brain tissues. As such, our results show that low-dose BPA remnant in surface waters altered zebrafish behavior that are known to have ecological and evolutionary consequences., Highlights: Here we reported that the impact of chronic low-dose BPA exposure on the basic capability of zebrafish to adapt to the environmental complexity. Specifically, BPA at low concentration, under the environmental safety level and 3000-fold lower than the accepted human daily exposure, interfered with the ability to discriminate color and alleviate anxiety induced by the novel environment, which finally altered the capability of male zebrafish to adapt to the environmental complexity. These findings revealed the ecological effect of low-dose BPA and regular BPA concentration standard are not necessarily safe. The result also provided the consideration of retuning the hazard concentration level of BPA., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: Past studies have shown that higher macular pigment optical density (MPOD) and lutein (L) and zeaxanthin (Z) supplementation are related to improvements in glare disability, photostress recovery, and chromatic contrast. This study assessed those links using a randomized, double-blind, placebo-controlled design., Methods: The visual effects of 1 year of supplementing L (10 mg/d) and Z (2 mg/d) were investigated. One hundred fifteen young, healthy subjects were recruited and randomized into the study (58 received placebo, 57 L+Z). Several dependent measures were collected at baseline and then once every 3 months: serum L and Z measured by HPLC chromatography; MPOD measured using customized heterochromatic flicker photometry; photostress recovery assessed by measuring the time needed to recover visual acquisition of a grating target after 30 seconds of an intense xenon white flash exposure; glare disability evaluated as the energy in a surrounding annulus necessary to veil a central grating target; and chromatic contrast assessed by measuring thresholds for a yellow grating target superposed on a 460-nm background., Results: Macular pigment optical density increased significantly versus placebo at all eccentricities (10, 30, 60, and 105 minutes from the center of the macula). Serum L and Z also increased significantly by the first follow-up visit (at 3 months), and remained elevated throughout the intervention period of 1 year. Chromatic contrast and photostress recovery time improved significantly versus placebo. Glare disability was correlated with macular pigment density throughout the study period but did not increase significantly in the treated group., Conclusions: Daily supplementation with L+Z resulted in significant increase in serum levels and MPOD and improvements in chromatic contrast and recovery from photostress. These results are consistent with past studies showing that increasing MPOD leads to improved visual performance. (ClinicalTrials.gov number, NCT00909090.)., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Aims: To report the first three studies with SCH 900435, a selective glycine-1 re-uptake inhibitor in development for treating schizophrenia, using systematic evaluations of pharmacodynamics to understand the observed effects., Methods: Three double-blind, placebo-controlled studies (single, visual effect and multiple dose) were performed. In the single and multiple dose study SCH 900435 (0.5-30 mg) was given to healthy males and frequent pharmacokinetic and pharmacodynamic measurements were performed. The visual effects study incorporated visual electrophysiological measures of macular, retinal and intracranial visual pathway function., Results: In the single dose study (highest difference, 95% CI, P) increases in smooth pursuit eye movements (8, 12 mg (-6.09, 10.14, -2.04, 0.013), 30 mg), pupil : iris ratio (20 and 30 mg (-0.065, 0.09, -0.04, <0.0001)), VAS colour perception (30 mg (-9.48, 13.05, -5.91, <0.0001)) and changes in spontaneous reports of visual disturbance were found, while FSH (8 mg (0.42, 0.18, 0.66, 0.0015), 12, 20 mg), LH (8-30 mg (1.35, 0.65, 2.05, 0.0003)) and EEG alpha2 activity decreased (12, 20, 30 mg (0.27, 0.14, 0.41, 0.0002)). A subsequent dedicated visual effects study demonstrated that visual effects were transient without underlying electrophysiological changes. This provided enough safety information for starting a multiple ascending dose study, showing less visual symptoms after twice daily dosing and titration, possibly due to tolerance., Conclusions: Several central nervous system (CNS) effects and gonadotropic changes resulted from administration of 8 mg and higher, providing evidence for CNS penetration and pharmacological activity of SCH 900435. Antipsychotic activity in patients, specificity of the reported effects for this drug class and possible tolerance to visual symptoms remain to be established., (© 2012 Centre for Human Drug Research. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Aims: To study whether morphologic (foveal thickness, FT) variations of clinically significant macular oedema (CMO) in patients suffering from diabetes following intravitreal pegaptanib sodium (IVP) injection were associated with functional [macular sensitivity (MS) and colour discrimination (CD)] changes., Methods: A longitudinal, interventional, non-randomized study was performed. FT was assessed by optical coherence tomography (OCT), MS by microperimetry, best-corrected visual acuity (BCVA) by early treatment diabetic retinopathy study charts (ETDRS) and CD by Farnswoth-Munsell test. The treatment protocol consisted of three consecutive injections (0.3 mg/0.05 ml; baseline, week 6 and week 12). Follow-up checks were scheduled at 18, 24, 36 and 48 weeks, after injections., Results: Thirty eyes of 30 patients with clinically significant CMO were included for analysis. After IVP a significant decrease of FT occurred with a mean reduction from baseline of 56.9% (P= 0.0001). An improvement of functional parameters was recorded in all patients (BCVA from 18.2 ± 8.5 letters to 25.5 ± 8.4 letters, P < 0.005, MS from 8.6 ± 2.16 dB to 10.6 ± 2.61 dB, P < 0.001, colour analysis from 376.1 ± 125.6 TES to 116 ± 34.6 TES, P= 0.0001). A statistically significant correlation between FT and BCVA as well as MS and CD was also found. Neither ocular nor systemic adverse events were reported., Conclusions: Intravitreal pegaptanib significantly reduced FT, with a concomitant improvement of MS and CD. This association emphasizes the efficacy of IVP in the treatment of CMO., (© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Neuropsychological investigations of patients with Parkinson's disease, schizophrenia, or attention deficit disorder converge with psychopharmacological studies in animals and healthy volunteers to implicate dopamine (DA) pathways in timing. In parallel, single-cell recording and functional neuroimaging studies have highlighted the importance of basal ganglia, prefrontal cortex, and supplementary motor area (SMA) for timing. In a placebo-controlled, within-subject design, we combined event-related functional magnetic resonance imaging with a DA manipulation (acute phenylalanine/tyrosine depletion; APTD) in healthy volunteers to pinpoint the neuroanatomical and functional substrates of the DA modulation of timing. Behaviorally, APTD selectively impaired accuracy of perceptual timing, with no effect on performance of a color-control task matched for difficulty, working memory (WM), and attentional demands. Neurally, APTD attenuated timing-specific activity in the putamen and SMA. Notably, APTD-induced decreases in brain activity were directly correlated to APTD-induced impairments in timing performance. Moreover, APTD modulated timing-specific activity selectively during initial storage of the sample duration, but had no effect during its subsequent retrieval or comparison to a probe. Our results do not simply reflect DA modulation of WM since the color task controlled for the WM updating process necessary for timing of durations in the seconds range. Moreover, preliminary evidence indicated APTD effects on putamen and SMA were greater for subsecond (540 ms) than suprasecond (1080 ms) durations, when WM demands would actually be lower. Instead, we show for the first time in healthy humans that DA manipulation perturbs timing by attenuating the activity in putamen and SMA that mediates initial storage of temporal information into WM.

Purpose: The purpose of this study was to conduct a questionnaire-based survey of subjective visual perceptions induced by intravitreous (IVT) injections of therapeutic agents., Patients and Methods: Patients undergoing an IVT injection of ranibizumab, pegaptanib sodium, or triamcinolone acetonide were administered a questionnaire in the immediate post-injection period and at 2 weeks of follow-up., Results: In the immediate post-injection period (75 IVT injections, 75 eyes, 75 patients), lights and floaters were reported after 20 (27%) and 24 (32%) IVT injections, respectively. In comparison, at the 2-week follow-up, the incidence of reported lights (11; 15%) was similar (P>0.05), but the incidence of reported floaters was higher (48; 64%; P=0.00). Subgroup analysis for various injection subgroups (no previous injection vs previous injection(s) in the study eye; injections in study eyes with good VA (logarithm of minimal angle of resolution [logMAR] ≤ 0.3) vs moderate VA (0.7 0.3) vs poor VA (logMAR ≥ 0.7); injections according to pharmacological agent (ranibizumab vs pegaptanib vs triamcinolone acetonide); injections in study eyes with choroidal neovascularization (of various causes) vs study eyes with macular edema (of various causes); and injections in phakic vs pseudophakic eyes) did not reveal any statistically significant associations. Visual perceptions experienced following 15% of IVT injections gave cause for concern to the patient (mean visual analog scale score (± SD): 4.5 (± 1.7)), and in 64% of cases, the patients believed that preoperative counseling would have averted the concern., Conclusions: Lights and floaters are frequent visual perceptions following IVT injections of therapeutic agents. They can give rise to concern that could be alleviated with preinjection counseling.

Objective: To evaluate the impact of clomiphene citrate on vision., Design: Observational study., Setting: Patients were referred to the University of Ottawa Eye Institute ophthalmology clinic from the Department of Obstetrics and Gynaecology of the Ottawa Hospital-General Campus., Patient(s): Eight adult females taking clomiphene citrate and experiencing visual disturbances., Intervention(s): Patients received a comprehensive visual evaluation twice: once during a washout period, and once during an active clomiphene citrate treatment., Main Outcome Measure(s): Ophthalmologic examination, color vision, visual acuity, contrast sensitivity, visual fields using standard automated perimetry, and foveal flicker sensitivity at high (32 Hz) and low (8 Hz) temporal frequencies., Result(s): We found no differences between the washout and clomiphene citrate conditions for color vision, visual acuity, contrast sensitivity, and visual fields. The only statistically significant difference was found for foveal flicker sensitivity at 32 Hz in the right eye, with a similar trend in the left eye and at 8 Hz in both eyes., Conclusion(s): The effect of clomiphene citrate on vision was minimal, and the visual disturbances were reversible in all patients. A bilateral reduction in flicker sensitivity was the only observed visual disturbance. Women who experience visual symptoms associated with clomiphene citrate should be monitored, but therapy can usually be maintained., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

We measured visual performance in achromatic and chromatic spatial tasks of mercury-exposed subjects and compared the results with norms obtained from healthy individuals of similar age. Data were obtained for a group of 28 mercury-exposed subjects, comprising 20 Amazonian gold miners, 2 inhabitants of Amazonian riverside communities, and 6 laboratory technicians, who asked for medical care. Statistical norms were generated by testing healthy control subjects divided into three age groups. The performance of a substantial proportion of the mercury-exposed subjects was below the norms in all of these tasks. Eleven of 20 subjects (55%) performed below the norms in the achromatic contrast sensitivity task. The mercury-exposed subjects also had lower red-green contrast sensitivity deficits at all tested spatial frequencies (9/11 subjects; 81%). Three gold miners and 1 riverine (4/19 subjects, 21%) performed worse than normal subjects making more mistakes in the color arrangement test. Five of 10 subjects tested (50%), comprising 2 gold miners, 2 technicians, and 1 riverine, performed worse than normal in the color discrimination test, having areas of one or more MacAdam ellipse larger than normal subjects and high color discrimination thresholds at least in one color locus. These data indicate that psychophysical assessment can be used to quantify the degree of visual impairment of mercury-exposed subjects. They also suggest that some spatial tests such as the measurement of red-green chromatic contrast are sufficiently sensitive to detect visual dysfunction caused by mercury toxicity.

We evaluated the color vision of 24 subjects (41.6 +/- 6.5 years; 6 females) who worked in fluorescent lamp industries. They had been occupationally exposed to mercury vapor (10.6 +/- 5.2 years) and had been away from the source of exposure for 6.4 +/- 4.04 years. Mean urinary concentration of mercury was 40.6 +/- 36.4 microg/g creatinine during or up to 1 year after exposure and 2.71 +/- 1.19 microg/g creatinine at the time of color vision testing or up to 1 year thereafter. All patients were diagnosed with chronic mercury intoxication, characterized by clinical symptoms and neuropsychological alterations. A control group (N = 36, 48.6 +/- 11.9 years, 10 females, 1.5 +/- 0.47 microg mercury/g creatinine) was subjected to the same tests. Inclusion criteria for both groups were Snellen VA 20/30 or better and absence of known ophthalmologic pathologies. Color discrimination was assessed with the Farnsworth D-15 test (D-15) and with the Lanthony D-15d test (D-15d). Significant differences were found between the two eyes of the patients (P < 0.001) in both tests. Results for the worst eye were also different from controls for both tests: P = 0.014 for D-15 and P < 0.001 for D-15d. As shown in previous studies, the D-15d proved to be more sensitive than the D-15 for the screening and diagnosis of the color discrimination losses. Since color discrimination losses were still present many years after the end of exposure, they may be considered to be irreversible, at least under the conditions of the present study.

Purpose: To investigate the effects of tropicamide on chromatic and achromatic contrast sensitivities over the physiological range of spatial frequencies., Methods: A total of 26 healthy volunteers, with a mean age of 32 years, were examined with and without one drop of 1% tropicamide being administered 30 min previously. On each occasion, acuity and pupil diameter were recorded, and chromatic and achromatic contrast sensitivities were examined using the Sussex Grating Machine., Results: Following tropicamide administration mean pupil diameter increased from 4.1 mm to 7.2 mm (P<0.001), and mean BCVA was reduced by 0.07 LogMar units (P<0.001). Achromatic contrast sensitivity was significantly reduced following tropicamide administration at 2.20 cycles per degree (cpd) (P=0.01), 3.40 cpd (P=0.01), 10 cpd (P=0.04), 17 cpd (P=0.04), and 25 cpd (P<0.01). There was no difference in contrast sensitivity at lower spatial frequencies (0.33 and 0.66 cpd). Chromatic contrast sensitivity was not significantly altered when tested along the red-green and tritan confusion axes., Conclusions: Achromatic contrast sensitivity is significantly reduced following tropicamide administration at intermediate and high spatial frequencies. No significant changes were seen at low spatial frequencies and in chromatic contrast sensitivities.

In the absence of a red-sensitive visual pigment, some deep-sea fish use a chlorophyll derivative in their green-sensitive rod cells in order to see deep-red light. Here we show that living rods extracted from a salamander can also accumulate an exogenous chlorophyll derivative, chlorin e6, that renders them as sensitive to red light as they are to green. This vision enhancement by an unbleachable chlorophyll derivative might therefore be a general phenomenon in vertebrate photoreception.

Purpose: To assess the effects of sildenafil on blue-on-yellow (B/Y) and white-on-white (W/W) Humphrey perimetry in a group of men with erectile dysfunction in 3 months regular use., Methods: In this prospective study, 14 patients with erectile dysfunction received 50 mg doses of sildenafil (Viagra, Pfizer) two times per week regularly for 3 months. Patients underwent best-corrected visual acuity (BCVA), colour vision, anterior segment and fundus examination, and B/Y and W/W Humphrey perimetry in each eye before and after sildenafil treatment. Changes in mean deviations (MD) were compared separately for both eyes., Results: No significant changes from baseline were observed in BCVA and colour vision after sildenafil treatment. The anterior segment and fundus examinations revealed no abnormalities. There was no change on B/Y and W/W Humphrey visual field. MD values of B/Y and W/W Humphrey perimetry remained nonsignificant for both eyes after 3 months regular use of sildenafil (P=0.133, and 0.092, respectively, for right, and P=0.221 and 0.925, respectively, for left eyes)., Conclusion: Oral sildenafil used regularly for 3 months produced no effect on B/Y and W/W Humphrey perimetry.

Flavanols are the main flavonoids found in cocoa and chocolate, and can be especially abundant in certain cocoas. Research over the past decade has identified flavanols as showing diverse beneficial physiologic and antioxidant effects, particularly in context of vascular function. The present study employed functional magnetic resonance imaging based on blood oxygenation level-dependent (BOLD) contrast to explore the effect of flavanols on the human brain. Magnetic resonance imaging was used to measure BOLD responses to a cognitive task in 16 healthy young subjects. The data presented show an increase in the BOLD signal intensity in response to a cognitive task following ingestion of flavanol-rich cocoa (5 days of 150 mg of cocoa flavanols). This may arise either as a result of altered neuronal activity, or a change in vascular responsiveness, or both--the net effect then being dependent on which of the two effects is dominant. No significant effects were evident in behavioral reaction times, switch cost, and heart rate after consumption of this moderate dose of cocoa flavanols. A pilot study evaluated the relationship between cerebral blood flow and a single acute dose (450 mg flavanols) of flavanol-rich cocoa and showed that flavanol-rich cocoa can increase the cerebral blood flow to gray matter, suggesting the potential of cocoa flavanols for treatment of vascular impairment, including dementia and strokes, and thus for maintaining cardiovascular health.

Discrepant effects of drugs on behavior maintained by temporal-discrimination procedures make conclusive statements about the neuropharmacological bases of timing difficult. The current experiment examined the possible contribution of a general, drug-induced disruption of stimulus control. Four pigeons responded on a three-component multiple schedule that included a fixed-interval 2-min, temporal discrimination, and color-matching component. Under control conditions, response rates and choice responses during the first two components showed evidence of control by time, and accuracy for color matching was high in the third component. Morphine administration flattened the distribution of fixed-interval responding and produced a general disruption of accuracy in the temporal-discrimination component, whereas accuracy in the color-matching component was relatively unaffected. Analysis of the psychophysical functions from the temporal-discrimination component indicated that morphine decreased accuracy of temporal discrimination by decreasing overall stimulus control, rather than by selectively affecting timing. These results suggest the importance of determining the neurophysiological bases of stimulus control as it relates to temporal discrimination.

Purpose: To investigate whether initial valproate (VPA) monotherapy for the treatment of epilepsy causes visual field defects and visual dysfunction., Methods: In a cross-sectional study, visual fields were examined with the kinetic Goldmann and automated Humphrey perimeters, contrast sensitivity function with the Pelli-Robson letter chart and colour vision with the Standard Pseudoisochromatic Plates Part 2 (SPP 2) and Farnsworth-Munsell 100 Hue test (FM 100) in eighteen epilepsy patients (aged 18--50 years, 30.2.+/-10 years, mean+/-S.D.) treated with initial valproate monotherapy for 2--20 years (8.4+/-5.1 years)., Results: None had vigabatrin-type, concentric visual field defect with the kinetic Goldmann or automated Humphrey perimetries. In the Humphrey perimetry, the mean deviation for the group was within normal limits varying from -2.53 to 0.59 dB (-0.74+/-0.80 dB) in the right eye and from -2.66 to 0.67 dB (-0.78+/-0.82 dB) in the left eye. In the FM 100 test, acquired colour vision deficiency was found in two out of 18 patients (11%, 95% CI: 0--25%). However, the mean total error score was lower in the patient group than in the control group. All patients had normal contrast sensitivity function., Conclusions: The use of VPA in the treatment of epilepsy is not associated with visual field defects similar to vigabatrin, but may induce abnormalities in colour vision.

Many reports in the literature suggest that long-term exposure to styrene may exert a variety of effects on the nervous system, including increased choice reaction time and decreased performance of color discrimination and color arrangement tasks. Sufficient information exists to perform a meta-analysis of these observations quantifying the relationships between exposure (estimated from biomarkers) and effects on two measures of central nervous system function: reaction time and color vision. To perform the meta-analysis, we pooled data into a single database for each end point. End-point data were transformed to a common metric of effect magnitude (percentage of baseline). We estimated styrene concentration from biomarkers of exposure and fitted linear least-squares equations to the pooled data to produce dose-effect relationships. Statistically significant relationships were demonstrated between cumulative styrene exposure and increased choice reaction time as well as increased color confusion index. Eight work-years of exposure to 20 ppm styrene was estimated to produce a 6.5% increase in choice reaction time, which has been shown to significantly increase the probability of automobile accidents. The same exposure history was predicted to increase the color confusion index as much as 1.7 additional years of age in men.

Background: Previous research has been inconclusive regarding the impact of glucose ingestion and gluco-regulatory control on cognitive performance in healthy older adults. The aim of this research was to determine whether glucose specifically enhanced episodic memory in an older population. In addition, the link between individual differences in glucose regulation and the magnitude of the enhancement effect was examined., Design and Subjects: A within subjects, counterbalanced, crossover design was used with 20 participants (60-80 year olds), each serving as his/her control., Methods: Episodic memory was tested by presenting unrelated paired associates followed by immediate and delayed cued recall, and delayed recognition, under single and dual task conditions. In addition, a battery of cognitive tests was administered, including tests of semantic memory, working memory and speed of processing., Results: Glucose ingestion was found to largely facilitate performance of episodic memory. Furthermore, subsidiary analyses found that gluco-regulatory efficiency predicted episodic memory performance in both control and glucose conditions., Conclusions: A boost in performance after glucose ingestion was particularly seen in the episodic memory domain. Notably, strong evidence was provided for the utility of gluco-regulatory control measures as indicators of cognitive decline in the elderly.

Visual disturbances are a common side-effect of many antiepileptic drugs. Non-specific retino- and neurotoxic visual abnormalities, that are often reported with over-dosage and prolonged AED use, include diplopia, blurred vision and nystagmus. Some anticonvulsants are associated with specific visual problems that may be related to the mechanistic properties of the drug, and occur even when the drugs are administered within the recommended daily dose. Vigabatrin, a GABA-transaminase inhibitor, has been associated with bilateral concentric visual field loss, electrophysiological changes, central visual function deficits including reduced contrast sensitivity and abnormal colour perception, and morphological alterations of the fundus and retina. Topiramate, a drug that enhances GABAergic transmission, has been associated with cases of acute closed angle glaucoma, while tiagabine, a GABA uptake inhibitor, has been investigated for a potential GABAergic effect on the visual field. Only mild neurotoxic effects have been identified for patients treated with gabapentin, a drug designed as a cyclic analogue of GABA but exhibiting an unknown mechanism while carbamazepine, an inhibitor of voltage-dependent sodium channels, has been linked with abnormal colour perception and reduced contrast sensitivity. The following review outlines the visual disturbances associated with some of the most commonly prescribed anticonvulsants. For each drug, the ocular site of potential damage and the likely mechanism responsible for the adverse visual effects is described.

Purpose: To report that acute phenytoin toxicity may result in acute visual dysfunction., Methods: A 19-year old man with cryptogenic simple partial and secondary generalized epilepsy developed blurred vision and xanthopsia after phenytoin loading for status epilepticus. Color blindness was found on testing with Ishihara's pseudo-isochromatic charts and visual fields (Goldmann perimeter) showed gross concentric constriction in both eyes. Flash visually evoked potentials showed prolonged P1 latency in both the eyes. Serum free-phenytoin concentration revealed toxic levels of phenytoin and no other etiology for retinopathy or optic neuropathy., Results: Phenytoin was withheld and the patient experienced a partial recovery in conjunction with reduced serum levels of phenytoin. Ten months later flash visually evoked potentials were normal but electroretinogram confirmed diffuse bilateral cone and rod dysfunction., Conclusion: Phenytoin toxicity may result in acute visual dysfunction a previously unreported phenomenon.

This review covers the effect of drugs affecting anxiety using four psychological procedures for inducing experimental anxiety applied to healthy volunteers and patients with anxiety disorders. The first is aversive conditioning of the skin conductance responses to tones. The second is simulated public speaking, which consists of speaking in front of a video camera, with anxiety being measured with psychometric scales. The third is the Stroop Color-Word test, in which words naming colors are painted in the same or in a different shade, the incongruence generating a cognitive conflict. The last test is a human version of a thoroughly studied animal model of anxiety, fear-potentiated startle, in which the eye-blink reflex to a loud noise is recorded. The evidence reviewed led to the conclusion that the aversive conditioning and potentiated startle tests are based on classical conditioning of anticipatory anxiety. Their sensitivity to benzodiazepine anxiolytics suggests that these models generate an emotional state related to generalized anxiety disorder. On the other hand, the increase in anxiety determined by simulated public speaking is resistant to benzodiazepines and sensitive to drugs affecting serotonergic neurotransmission. This pharmacological profile, together with epidemiological evidence indicating its widespread prevalence, suggests that the emotional state generated by public speaking represents a species-specific response that may be related to social phobia and panic disorder. Because of scant pharmacological data, the status of the Stroop Color-Word test remains uncertain. In spite of ethical and economic constraints, human experimental anxiety constitutes a valuable tool for the study of the pathophysiology of anxiety disorders.

Purpose: To investigate visual function in the central 10 degrees in patients who have undergone vigabatrin (VGB) antiepileptic drug (AED) therapy with the aim of identifying a clinical regimen for assessing central visual function., Methods: The sample comprised 12 epilepsy patients (mean age, 38.6 +/- 11.7 years) who had been treated with VGB (either as monotherapy or polytherapy). A number of central visual-function tests were carried out for each eye, including high-contrast LogMAR visual acuity, short-wavelength automated perimetry (SWAP 10-2), spatial contrast sensitivity (CSV-1000), and Farnsworth-Munsell (FM) 100-hue colour discrimination., Results: The group mean cumulative VGB dose was 5,086 +/- 3,245 g. The average SWAP 10-2 mean deviation (MD) for the group was -3.24 +/- 3.23 dB; 14 eyes of eight patients showed defects (range, -1.62 to -9.46 dB). The square root of the group mean total error score for FM 100-hue was 7.42 +/- 3.84; nine eyes of five patients were classified as abnormal with an unsolved colour axis suggestive of complex drug interactions. For contrast sensitivity, 15 eyes of eight patients yielded abnormal results in one or more spatial frequencies. Defects were more prominent at higher spatial frequencies. Overall, four patients had defects in all three visual-function tests, six patients had mixed defects, and two patients were normal., Conclusions: Visual-function deficits in epilepsy patients treated with VGB are present in the central 10 degrees of the retina. We recommend a battery of investigations, including SWAP 10-2 and spatial contrast sensitivity testing, to assess central visual function.

Aims: To evaluate possible differences between men and women in acute health effects after controlled short term chamber exposure to vapours of two common organic solvents., Methods: Fifty six healthy volunteers (28 per sex) were exposed to 150 ppm 2-propanol, 50 ppm m-xylene, and clean air for two hours at rest. The subjects rated symptoms on a visual analogue scale before, during, and after the exposure. Blinking frequency was measured continuously during exposure. Pulmonary function, nasal swelling, inflammatory markers (lysozyme, eosinophilic cationic protein, myeloperoxidase, albumin) in nasal lavage and colour vision (Lanthony D-15 desaturated panel) were measured before and at 0 and 3 hours after the exposure., Results: There were no significant sex differences in response to solvent exposure with respect to blinking frequency, lung diffusing capacity, nasal area and volume, inflammatory markers in nasal lavage, and colour vision. Increased symptoms were rated by both sexes for nearly all 10 questions during exposure to 2-propanol or m-xylene, most increases being significant at one time point at least. The rating of "discomfort in the throat or airways" increased more in women during exposure to 2-propanol or m-xylene. During exposure to 2-propanol the rating of "fatigue" was more increased in men after one hour, but more increased in women after two hours of exposure. With regard to pulmonary function, women had small but significant decreases in FVC, FEV(1)/FVC, and FEF(75) three hours after exposure to m-xylene, but only the decrease in FVC was significantly different from that in men., Conclusion: Our results suggest that women are slightly more sensitive than men to the acute irritative effects of 2-propanol and m-xylene vapours.

Purpose: To study if flecainide has ocular adverse effects., Methods: Both eyes of 38 flecainide medicated patients were thoroughly examined including colour vision, contrast sensitivity and visual fields., Results: 10.5% of the patients had blurred vision on lateral gaze lasting for a couple of seconds. Small corneal deposits were found in 14.5% of the patients. All visual function tests were normal., Conclusion: Flecainide seems to be a safe drug with minimal ocular adverse effects.

To investigate the threshold effects of chronic low-level occupational exposure to styrene on color vision, we examined color discrimination in 105 male workers exposed to styrene (mean age 37.7 years; mean length of exposure 6.2 years; mean urinary concentration of mandelic acid 0.21 g/L) and in 117 referents (mean age 37.7 years). We also assessed the effects of styrene by examination of the nature of the relation between disorders of nervous function and age, alcohol consumption, and other variables. A standardized questionnaire was adopted to collect information about work history, occupational or nonoccupational solvent exposure, alcohol consumption, and drug use. Color vision was evaluated by the Lanthony desaturated panel D-15 test. The results of the test were expressed as the color confusion index (CCI). There was a dose-dependent relationship between the urinary concentration of mandelic acid and color vision loss. The CCIs of the subgroups whose urinary mandelic acid levels were 0.1-0.2 and >0.2 g/L were significantly higher than those of each referent group (P<0.05 and P<0.01, respectively), but not in the subgroup whose urinary mandelic acid level was lower than 0.1 g/L. Our study suggests that a low level of styrene, presumably 0.1-0.2 g/L, involves the risk of inducing adverse effects on color vision. After confounding factors were adjusted for, the urinary mandelic acid level had a significant positive relationship with color vision., (Copyright 2001 Academic Press.)

Purpose: To report on a unilateral optic nerve reaction appearing 9-10 hours after vaccination against hepatitis B., Methods: To describe the case and discuss the underlying mechanisms. There was a scintillating scotoma leaving a permanent inferior notch in the visual field, but central vision was left normal and with only a slight affection of colour perception. Shortly the optic nervehead appeared engorged, then slightly ischaemic, but was hardly left with evidence of atrophy., Results: Immune-based reactions could hardly be held responsible, multiple sclerosis was unlikely, and ultrasonography excluded optic nervehead drusen. An optic nerve migraine mechanism is probable, possibly with the vaccination having acted as the trigger.

In goldfish it has been shown that ethambutol shifts the threshold for wavelength discrimination without affecting the absolute sensitivity of the cones. In this study we demonstrate that a similar colour vision disturbance occurs in tuberculosis patients treated with ethambutol. After 2 months of ethambutol treatment, chromatic discrimination was measured with a computerized forced two choice (CD) test with isoluminant coloured stimuli and with three other colour vision tests: the Ishihara, the Oscar and the Lanthony Desaturated 15 Hue tests. The scores of the patient group (n = 19) on these four colour vision tests were compared with the scores of a group of control subjects (n = 33) and a group of congenital red/green colour-blind subjects (n = 5). A reduction of the stimulus intensity of 1 log unit caused a significant reduction in red/green chromatic discrimination, measured with the CD test in both, control subjects and patients. This intensity dependent reduction was significantly greater for patients than for controls. In this respect, man and goldfish behave similarly. Furthermore, the CD test showed the same ethambutol-induced reduction in chromatic discrimination at low intensity for the blue/green part of the spectrum. This has not been measured in goldfish. The origin of this ethambutol-induced colour vision disturbance must be at a post-photoreceptor site, because the Ishihara and Oscar tests, both designed to screen for photoreceptor-based, or primary red/green colour vision disturbances, did not discriminate between patients and control subjects. Thus, as in goldfish, we find that in patients ethambutol shifts the threshold for chromatic discrimination without changing the absolute sensitivity.

To date, sildenafil citrate (Viagra) gives every evidence of being a safe drug for the eye despite a series of expressed concerns. A review of how its ocular safety profile has been identified offers insights into the strengths and weaknesses of present systems and resources for judging the ocular safety of Viagra or, for that matter, of any new drug. Such insights include: The great value of careful, informed assessment of preclinical information gleaned from laboratory experiments. By and large, such assessments point the way toward appropriate clinical evaluation. For Viagra, early in its development it was noted that besides exerting a major inhibitory effect on the intended target, the vascular-associated enzyme phosphodiesterase 5 (PDE5), the drug also exerts a lesser but definite inhibitory effect on the closely related PDE6, located in the retina. For this reason, preclinical evaluation of the drug included electroretinography plus postmortem histology. In addition, an extended eye examination was incorporated into clinical protocols. The often chaotic but invaluable information stream that becomes available once marketing approval has been gained and large populations begin to use a drug. False alarms, misattribution, and erroneous information are the order of the day. Nevertheless, as information accumulates, patterns of response clarify and the true nature of special susceptibility for subpopulations, if any, becomes apparent. A role for the astute clinician remains: Subtle changes or unusual risks for subpopulations can be missed entirely for long periods of time. A manifest need for improvement in evaluation of postmarketing side-effects. This need has led to the establishment of a new discipline: pharmacoepidemiology. In ophthalmology, the National Registry of Drug Induced Ocular Side-Effects maintains a constant and invaluable surveillance. Examples are supplied to illustrate each of these major points: Our presentation will include data gleaned from clinical trials plus postmarketing information on the incidence, duration, and type of color vision defects observed at different doses of Viagra.

Juvenile rainbow trout (Oncorhynchus mykiss) were given ethambutol (900 mg kg-1 body mass per day) for 4 weeks to examine its effects on vision. Using multi-unit recording from the optic nerve, spectral sensitivity of the on-responses were significantly affected in two regions, 340-440 nm and 600-660 nm. Off-responses were statistically unaffected. Changes in sensitivity to polarised light were also observed with on-responses to vertically-polarized light decreasing relative to horizontally-polarised light. In contrast, off-responses were less affected. The treatment effects were attributed to changes in the relative contribution of the photoreceptor channels as recorded at the level of the optic nerve.

Color vision was evaluated in twenty-one mercury exposed workers and referents matched for sex, age, tobacco smoking, and alcohol habits. The Lanthony 15 Hue desaturated panel (D-15 d) was applied. In the workers, mean urinary Hg (HgU) was 115+/-61.5 microg/g creatinine; in all but one the values exceeded the biological limit (BEI) proposed by the American Conference of Governmental Industrial Hygienists. A dose-related subclinical color vision impairment was observed in Hg-exposed workers compared to the referents. Just after the survey, working conditions were improved. Twelve months later the workers were reexamined. Mean HgU was 10.0 microg/g creatinine and in no subjects was the BEI exceeded. Color perception was significantly improved compared to the first examination and, furthermore, no differences were observed between exposed workers and referents. The results add evidence that the color vision loss observed during the first part of the study was related to Hg exposure and, moreover, show that this effect is reversible. These data indicate that metallic Hg can induce a reversible impairment in color perception. This suggests that color vision testing should be included in studies on the early effects of Hg. The possibility of applying the D-15 d as an early effect index in the biological monitoring of Hg exposed workers should also be entertained., (Copyright 1998 Academic Press.)

Purpose: To document the experience of patients driving after drops to dilate the pupils. There are no documented guidelines on driving after pupillary dilatation. This is a study of patients who drove a car after attending the eye casualty for an ocular examination during which their pupils were dilated., Methods: Thirty patients were identified who felt confident to drive after their pupils were dilated. Distant visual acuities, colour vision and confrontation visual fields were assessed before and after pupillary dilatation with 2.5% phenylephrine and 1% tropicamide. These patients met the legal requirements for driving after pupillary dilatation. The patients completed a questionnaire that recorded their subjective experiences of driving while their pupils were dilated., Results: The mean age of the patients was 51.9 +/- 19.7 years (range 20-73 years). Twenty-seven of the 30 patients undertook the journey on familiar roads, and 14 of 30 wore spectacles. The mean spherical equivalent was +2.00 dioptre sphere for distance and a mean additional spherical equivalent of 1.75 dioptre sphere for near. Twenty patients experienced glare, which was severe enough to cause difficulty driving in three cases. Two of these patients drove in sunny weather conditions and one in light (not sunny) weather. Six patients had difficulty with road signs, two had difficulty judging distances and one reported difficulty with traffic lights., Conclusions: Dilating the pupils did not reduce distance visual acuity. However, it would seem appropriate to warn patients of the problems associated with glare and, if driving is their only option for transport home, recommend that they allow sufficient time to adapt to a dilated pupillary state, drive only on familiar roads and avoid driving in sunny weather.

Ethambutol is a useful first line antituberculous drug, but can cause significant visual impairment. In order to determine the clinical manifestations of optic neuropathy associated with ethambutol, and the margin of drug safety in Koreans, we investigated ten men and four women, diagnosed between 1995 and 1997 at Seoul Municipal Boramae Hospital as suffering from ethambutol toxicity. After determining their history, including the period during which ethambutol had been administered, and its dose, a complete eye examination was performed, including measurement of best-corrected visual acuity, pupillary examination, color vision, fundus examination and a test of visual field. Ocular ethambutol toxicity was observed at a dose as low as 12.3 mg/kg. Abnormal ophthalmic findings include decreased visual acuity and abnormal visual field, especially in the central scotoma, and abnormal color perception. In conclusion, ethambutol at a low dose can cause optic neuropathy, and for the early detection of this, a color vision test is important.

Reduction of wavelength discrimination ability in the 560-640 nm range, but not in the 404-540 nm range, has been demonstrated in goldfish after intravitreal injection of D1-dopamine receptor antagonists. Intravitreal injection of the dopaminergic neurotoxin 6-OH-dopamine severely reduced wavelength discrimination ability in the 540-661 nm range within 3 days. Discrimination ability could be reconstituted by the D1-agonist SKF 38393. Animals recovered from injection of 6-OH-dopamine within 14-16 days. No change of wavelength discrimination was induced by 6-OH-dopamine in the 461-540 nm range. We conclude that under photopic conditions dopamine modulates retinal mechanisms involved in red-green colour coding via D1-dopamine receptor-like binding sites.

Colour vision was examined by the Lanthony-D-15 desaturated test in 41 women exposed to toluene and in 29 non-exposed referents. Toluene exposure was evaluated by methods of environmental and biological monitoring. In the exposed group the median value of toluene in air was 35 ppm (range 11.2-49.9 ppm). Quantitative colour vision impairment was expressed as colour confusion index and colour confusion index corrected for alcohol intake. Qualitative impairment was expressed as normal, yellow-blue, red-green range or complex impairment. Statistical analysis showed the index values to be significantly correlated with age in both groups. In the exposed group they were significantly higher than in the non-exposed group. There was no significant difference in the prevalence of impairment in the blue-yellow range between the examined groups, although the prevalence of impairment in the exposed group was higher than in the non-exposed one. Results suggest that exposure to low toluene concentrations may induce colour vision impairment in women.

We investigated the influence of the antiepileptic drugs carbamazepine (CBZ), phenytoin (PHT) and valproic acid (VPA) on different aspects of visual perception in patients with epilepsy by three different methods. (i) The colour arrangement test Farnsworth Munsell D100. (ii) A monitor system generating 24 different Gaussian dots and 24 different vertical sinusoidal gratings. Luminance increments and decrements for achromatic discrimination and four different colours for chromatic discrimination were investigated with four different sizes each adding up to 24 stimuli. (iii) A Maxwellian view system providing a foveal blue test light either superimposed on a yellow adaptation field (increment threshold) or after switching off this field (postadaptation threshold). Five different adaptation levels were investigated. Patients on PHT offered the most abnormalities, particularly in the D100 and in all Gaussian dots recordings. The individual differences between increment and postadaptation threshold (transient tritanopia effect) were significantly elevated at the four higher adaptation levels, whereas no change was found in the increment thresholds and only for the highest luminance level in the postadaptation thresholds. With VPA, chromatic and achromatic increment discrimination was impaired particularly for larger Gaussian stimuli on the monitor system. Valproic acid also induced a consistent increment threshold increase on the Maxwellian view system, an increase of the postadaptation threshold at the highest luminance level and, like PHT, an increase of the threshold differences at level 3 and 4, but not at the highest background level 5. Patients on CBZ provided normal results in all investigations, with the exception of a slight but significant increase in the D100 error score. Sinusoidal gratings turned out to be much less sensitive than Gaussian dots since they remained unchanged in patients on all three drug groups.

Purpose: Ethambutol can cause optic neuropathy and deficiencies in color-opponent visual processing in patients treated for tuberculosis. In fish, Ethambutol induces color vision deficiencies similar to those observed in humans and affects color coding in retinal ganglion cells. Color opponency in fish is mainly mediated by a horizontal cell feedback onto cones thought to be provided by spinules. The authors examined whether Ethambutol affects spinules and is, therefore, able to alter color processing at a distal stage, that is, at the first synaptic connection within the retina., Methods: Ethambutol was injected into the vitreous of either dark- or light-adapted fish. After drug application, fish were held under different illumination conditions. Thereafter, the retinas were dissected and prepared for electron microscopy. Ultrathin tangential sections of retinas were examined at the level of the outer plexiform layer., Results: In already light-adapted retinas, a high dose of Ethambutol (10 mM) reduced the number of spinules by 30%. Ethambutol application in the dark with subsequent light adaptation resulted in severe dose-related inhibition of light-induced spinule formation. In these experiments, low doses (0.1 mM) of Ethambutol caused 40% inhibition, and high doses (10 mM) caused 70% inhibition. Besides affecting spinules, Ethambutol occasionally induced a degeneration of cone pedicles. This neurotoxicity only occurred in cones exposed to light., Conclusions: Results show that Ethambutol alters synaptic connections between horizontal cells and cones in a dose-related fashion; Ethambutol treatment can be toxic for cone pedicles and can cause their degeneration; and the rod pathway is not affected by the drug. This indicates that Ethambutol influences the color-coding process already at the level of the cone-horizontal cell synapse.

Ophthalmic examinations and selected tests of visual function were performed on 64 patients with rheumatoid arthritis who had received daily doses of 200 mg chloroquine sulphate for periods ranging from 3 to 11 months. Visual fields were determined by Humphrey automated perimetry and Amsler grids and a further battery of four tests of macular function (visual evoked potentials, critical flicker fusion threshold, Cambridge contrast sensitivity and the macular dazzle test) were administered. No case of retinal pigmentary abnormalities plus visual loss was found, but 2 patients were advised to cease chloroquine therapy on the basis of funduscopic findings. A small group of patients with relatively poor scores on one or more tests had normal visual fields and ophthalmic findings. There were no significant partial correlations between test results and the cumulative dose of chloroquine. These results support the opinion that currently recommended doses of chloroquine pose a minimal risk of retinal toxicity.

Three pigeons were studied under a multiple schedule in which pecks in each component were reinforced according to a variable-interval 120-s second-order schedule with fixed-interval 60-s units. In the first component of the multiple schedule, the completion of a fixed interval produced either food or a 4-s change in key color plus houselight illumination. In the second component an identical schedule was in effect, but the stimulus was a 0.3-s change in key color. Both long and short brief stimuli were not paired with food presentations in Conditions 1 and 3 and were paired with food in Condition 2. There were no consistent differences in response patterns under paired and nonpaired brief-stimulus conditions when the stimulus was a 4-s change in key color accompanied by houselight illumination. However, pairing the 0.3-s key-color change with food presentations resulted in higher indices of curvature and lower response rates in the early segments of the fixed interval than when the stimulus was not paired with food presentations. Low doses of d-amphetamine (0.3 and 1 mg/kg) produced small and inconsistent increases in overall response rates, and higher doses (3 and 10 mg/kg) decreased overall response rates. d-Amphetamine altered response patterns within fixed intervals by decreasing the indices of curvature and increasing response rates in the early segments of the fixed interval. Response rates and patterns under paired and nonpaired brief-stimulus conditions were not differentially affected by d-amphetamine. Thus, evidence for the enhancement of the conditioned reinforcement effects of psychomotor stimulant drugs was not found with the second-order schedules used in the present study.

Seven pigeons were studied in two experiments in which key pecks were reinforced under a second-order schedule wherein satisfaction of variable-interval schedule requirements produced food or a brief stimulus. In the second part of each session, responses produced only the brief stimulus according to a variable-interval schedule (food extinction). For the 4 pigeons in Experiment 1, the response key was red throughout the session. In separate phases, the brief stimulus was either paired with food, not paired with food, or not presented during extinction. d-Amphetamine (0.3 to 10.0 mg/kg) dose-dependently reduced food-maintained responding during the first part of the session and, at intermediate dosages, increased responding during the extinction portion of the session. The magnitude of these increases, however, did not consistently depend on whether the brief stimulus was paired, not paired, or not presented. It was also true that under nondrug conditions, response rates during extinction did not differ reliably depending on pairing operations for the brief stimulus. In Experiment 2, 3 different pigeons responded under a procedure wherein the key was red in the component with food presentations and blue in the extinction component (i.e., multiple schedule). Again, d-amphetamine produced dose-related decreases in responding during the first part of a session and increases in responding in the second part of the session. These increases, however, were related to the pairing operations; larger increases were observed when the brief stimulus was paired with food than when it was not or when it was not presented at all. Under nondrug conditions, the paired brief stimulus controlled higher response rates during extinction than did a nonpaired stimulus or no stimulus. These findings suggest that d-amphetamine can enhance the efficacy of conditioned reinforcers, and that this effect may be more robust if conditioned reinforcers occur in the context of a signaled period of extinction.

The neurotoxicity of methylene chloride (MC) is of special interest because of its acute effects on the central nervous system (CNS) and its metabolic conversion to carbon monoxide. A cohort study of retired airline mechanics was conducted to examine the hypothesis that long term exposure to MC results in lasting effects on the CNS. Retirees were studied to eliminate effects of current occupational exposures. The total retiree population (n = 1758) was surveyed to identify mechanics who met specific occupational, demographic, and medical criteria. A group of eligible retirees having long term exposure to MC and another group with low probability of exposure to solvents were given a comprehensive battery of physiological and psychological tests. The exposure groups were similar for all potential confounders that were measured. No statistically significant differences between groups were detected on outcome measures, although subtle differences in attention and memory were identified. Thus no firm evidence was found to support the hypothesis of lasting CNS effects in retired mechanics with long term exposure to MC.

Certain functions of the peripheral and autonomic nervous systems, and colour discrimination were examined in 45 workers (mean age 49; mean exposure to carbon disulphide (CS2) 20 years) and 37 controls (mean age 48). Conduction velocity and refractory period of the peroneal and sural nerves were determined. The conduction velocity of the slower fibres of the peroneal nerve was measured by means of an improved method that makes use of the refractory period. Function of autonomic nerves was assessed by measuring the variation in heart rate during rest, during deep breathing, and during isometric muscle contraction. Colour discrimination was evaluated by the Lanthony desaturated test. Individual cumulative exposure to CS2 was calculated on the basis of exposure in the past and individual job history. Mean cumulative exposure was 165 ppm-years. The peroneal nerves of exposed workers showed a decrease (-1.0 m/s) in conduction velocity of the slow fibres and a prolongation (0.1 ms) of the refractory period (mean 1.6 ms) compared with controls. These effects were related to cumulative exposure. No impairment of function of the sural nerve or of colour discrimination was found. The muscle heart reflex was decreased in the exposed group, but this was not related to cumulative exposure. This study has established more firmly that a decrease in conduction velocity of slow motor fibres occurs at low levels of exposure to CS2. Extrapolation of the results suggests that small effects may occur after 40 years of exposure to concentrations below the present threshold limit value (10 ppm).

Color discrimination ability of 53 patients with congestive heart failure and 32 healthy volunteers treated with digoxin, digitoxin, or pengitoxin was determined with the Farnworth's Munsell 100 hue test. The patients had been treated with digitalis glycosides for several months prior to color vision testing. The volunteers received glycosides until a steady-state plasma concentration was reached. Glycoside plasma levels were measured by radioimmunoassay on the 3 days prior to color vision testing. The total error scores, indices of color discrimination, increased with the glycoside plasma levels. Subjects treated with digitoxin or pengitoxin exhibited no marked elevation in total error score at therapeutic concentrations, whereas 17 of 28 subjects with therapeutic digoxin plasma concentrations (less than 2.0 ng/ml) showed disturbed color discrimination. At toxic plasma levels all 5 digoxin-treated subjects, 7 of 13 digitoxin-treated subjects, and 3 of 8 pengitoxin-treated subjects showed impairment of color discrimination. The greater tendency of digoxin to impair color vision in comparison with digitoxin and pengitoxin may be related to a higher uptake or different distribution in the retina.

The effects of pentobarbital and d-amphetamine were studied in pigeons responding under several concurrent fixed-ratio variable-interval and concurrent fixed-ratio fixed-interval schedules of food presentation. Drug effects were compared with different fixed ratios, fixed and variable intervals, changeover delays, and with the schedules operating singly. Doses of d-amphetamine that increased or did not affect responding under the interval schedules decreased responding under the fixed-ratio schedule, whereas doses of pentobarbital that increased responding under the fixed-ratio schedule decreased or eliminated responding under the interval schedules. These effects depended both on the schedule of food delivery and the parameters of schedules arranged concurrently. Pentobarbital increased responding under the fixed-ratio schedule with 4-minute and 10-minute interval schedules arranged concurrently, but not with 1.5-minute schedules. d-Amphetamine decreased concurrent ratio and interval responding with the 1.5-minute interval schedules, but either increased or did not affect responding with the longer intervals. Changes in the parameter of one schedule altered responding controlled by that schedule and also other concurrent performances. As a consequence, the effects of drugs on each behavior were altered.

Pigeons acquired a different four-response chain each session by responding sequentially on three keys in the presence of four colors. When the fixed-ratio requirement for food presentation was five completions of the chain, d-amphetamine and cocaine disrupted the behavior. As the dose of each drug was increased, the overall response rate decreased, the overall accuracy was impaired (i,e., percent errors increased), and there was less within-session error reduction (acquisition). In contrast, when the fixed-ratio requirement was either 20 or 50 completions of the chain, certain doses of both drugs produced large increases in the overall response rate by eliminating the extended pausing (ratio strain) that was characteristic of the control sessions. These rate-increasing effects were accompanied by error-decreasing effects, both during acquisition and after the response chain had been acquired. Taken together, the results show that the effects of d-amphetamine and cocaine on behavior in a repeated-acquisition task can be modulated by manipulating the value of the fixed-ratio schedule maintaining the behavior.