Cigarette toxicity triggers Leber's hereditary optic neuropathy by affecting mtDNA copy number, oxidative phosphorylation and ROS detoxification pathways.

Leber's hereditary optic neuropathy (LHON), the most frequent mitochondrial disease, is associated with mitochondrial DNA (mtDNA) point mutations affecting Complex I subunits, usually homoplasmic. This blinding disorder is characterized by incomplete penetrance, possibly related to several genetic modifying factors. We recently reported that increased mitochondrial biogenesis in unaffected mutation carriers is a compensatory mechanism, which reduces penetrance. Also, environmental factors such as cigarette smoking have been implicated as disease triggers. To investigate this issue further, we first assessed the relationship between cigarette smoke and mtDNA copy number in blood cells from large cohorts of LHON families, finding that smoking was significantly associated with the lowest mtDNA content in affected individuals. To unwrap the mechanism of tobacco toxicity in LHON, we exposed fibroblasts from affected individuals, unaffected mutation carriers and controls to cigarette smoke condensate (CSC). CSC decreased mtDNA copy number in all cells; moreover, it caused significant reduction of ATP level only in mutated cells including carriers. This implies that the bioenergetic compensation in carriers is hampered by exposure to smoke derivatives. We also observed that in untreated cells the level of carbonylated proteins was highest in affected individuals, whereas the level of several detoxifying enzymes was highest in carriers. Thus, carriers are particularly successful in reactive oxygen species (ROS) scavenging capacity. After CSC exposure, the amount of detoxifying enzymes increased in all cells, but carbonylated proteins increased only in LHON mutant cells, mostly from affected individuals. All considered, it appears that exposure to smoke derivatives has a more deleterious effect in affected individuals, whereas carriers are the most efficient in mitigating ROS rather than recovering bioenergetics. Therefore, the identification of genetic modifiers that modulate LHON penetrance must take into account also the exposure to environmental triggers such as tobacco smoke.

Electroretinography in dogs using a fiber electrode prototype.

We compared two electroretinography (ERG) electrodes in dogs using ERG standards of the International Society for Clinical Electrophysiology of Vision (ISCEV). Ten healthy Yorkshire terrier dogs (mean age, 2.80 ± 1.42 years; 6 females) weighing 5.20 ± 1.56 kg were evaluated using an ERG system for veterinary use. Dark- and light-adapted ERG responses were recorded using an ERG-Jet electrode and a fiber electrode prototype. The examinations were performed during 2 visits, 3 weeks apart. Both electrodes (ERG-Jet or fiber prototype) were used on each animal and the first eye to be recorded (OD × OS) was selected randomly. Three weeks later the examination was repeated on the same animal switching the type of electrode to be used that day and the first eye to be examined. The magnitude and waveform quality obtained with the two electrode types were similar for all ERG responses. ERG amplitudes and implicit times obtained from dogs using the fiber electrode prototype were comparable to those obtained with the ERG-Jet electrode for rod, maximal rod-cone summed, cone, and 30-Hz flicker responses. The fiber electrode prototype is a low-cost device, available as an alternative instrument for clinical veterinary ERG recording for retinal function assessment.

Electroretinography in dogs using a fiber electrode prototype

We compared two electroretinography (ERG) electrodes in dogs using ERG standards of the International Society for Clinical Electrophysiology of Vision (ISCEV). Ten healthy Yorkshire terrier dogs (mean age, 2.80 ± 1.42 years; 6 females) weighing 5.20 ± 1.56 kg were evaluated using an ERG system for veterinary use. Dark- and light-adapted ERG responses were recorded using an ERG-Jet electrode and a fiber electrode prototype. The examinations were performed during 2 visits, 3 weeks apart. Both electrodes (ERG-Jet or fiber prototype) were used on each animal and the first eye to be recorded (OD × OS) was selected randomly. Three weeks later the examination was repeated on the same animal switching the type of electrode to be used that day and the first eye to be examined. The magnitude and waveform quality obtained with the two electrode types were similar for all ERG responses. ERG amplitudes and implicit times obtained from dogs using the fiber electrode prototype were comparable to those obtained with the ERG-Jet electrode for rod, maximal rod-cone summed, cone, and 30-Hz flicker responses. The fiber electrode prototype is a low-cost device, available as an alternative instrument for clinical veterinary ERG recording for retinal function assessment.

Psychophysical analysis of contrast processing segregated into magnocellular and parvocellular systems in asymptomatic carriers of 11778 Leber's hereditary optic neuropathy.

We examined achromatic contrast discrimination in asymptomatic carriers of 11778 Leber's hereditary optic neuropathy (LHON 18 controls) and 18 age-match were also tested. To evaluate magnocellular (MC) and Parvocellular (PC) contrast discrimination, we used a version of Pokorny and Smith's (1997) pulsed/steady-pedestal paradigms (PPP/SPP) thought to be detected via PC and MC pathways, respectively. A luminance pedestal (four 1 degree x 1 degree squares) was presented on a 12 cd/m2 surround. The luminance of one of the squares (trial square, TS) was randomly incremented for either 17 or 133 ms. Observers had to detect the TS, in a forced-choice task, at each duration, for three pedestal levels: 7, 12, 19 cd/m2. In the SPP, the pedestal was fixed, and the TS was modulated. For the PPP, all four pedestal squares pulsed for 17 or 133 ms, and the TS was simultaneously incremented or decremented. We found that contrast discrimination thresholds of LHON carriers were significantly higher than controls' in the condition with the highest luminance of both paradigms, implying impaired contrast processing with no evidence of differential sensitivity losses between the two systems. Carriers' thresholds manifested significantly longer temporal integration than controls in the SPP, consistent with slowed MC responses. The SPP and PPP paradigms can identify contrast and temporal processing deficits in asymptomatic LHON carriers, and thus provide an additional tool for early detection and characterization of the disease.

Pupil size following dark adaptation in patients with retinitis pigmentosa

According to the equivalent light hypothesis, molecular defects in the photoreceptor lead to a continuous activation of the photoreceptor cascade in a manner equivalent to real light. The consequences in diseases such as retinitis pigmentosa (RP) are as disruptive to the cells as real light. Two forms of the equivalent light hypothesis can be distinguished: strong - mutations in rhodopsin or other cascade proteins in some forms of RP continuously excite the visual phototransduction cascade; weak - disruption of outer segments in all patients with RP eliminates circulating dark current and blocks neurotransmitter release in a manner similar to real light. Both forms of the equivalent light hypothesis predict that pupils of patients with RP will be constricted like those of normal subjects in the light. The purpose of this study was to test the equivalent light hypothesis by determining whether steady-state pupil diameter following full dark adaptation is abnormally small in any of a sample of patients with RP. Thirty-five patients with RP and 15 normal subjects were tested. Direct steady-state pupillometric measures were obtained from one eye in a full-field dome after 45 min of dark adaptation by videotaping the pupil with an infrared camera. Mean pupil diameter in the dark was comparable (t = -0.15, P = 0.88) between patients with RP (6.85 Ý 0.58 mm) and normal subjects (6.82 Ý 0.76 mm). The results of the present study are clearly counter to the prediction of the second (weaker) form of the equivalent light hypothesis

Pupil size following dark adaptation in patients with retinitis pigmentosa.

According to the equivalent light hypothesis, molecular defects in the photoreceptor lead to a continuous activation of the photoreceptor cascade in a manner equivalent to real light. The consequences in diseases such as retinitis pigmentosa (RP) are as disruptive to the cells as real light. Two forms of the equivalent light hypothesis can be distinguished: strong - mutations in rhodopsin or other cascade proteins in some forms of RP continuously excite the visual phototransduction cascade; weak - disruption of outer segments in all patients with RP eliminates circulating dark current and blocks neurotransmitter release in a manner similar to real light. Both forms of the equivalent light hypothesis predict that pupils of patients with RP will be constricted like those of normal subjects in the light. The purpose of this study was to test the equivalent light hypothesis by determining whether steady-state pupil diameter following full dark adaptation is abnormally small in any of a sample of patients with RP. Thirty-five patients with RP and 15 normal subjects were tested. Direct steady-state pupillometric measures were obtained from one eye in a full-field dome after 45 min of dark adaptation by videotaping the pupil with an infrared camera. Mean pupil diameter in the dark was comparable (t = -0.15, P = 0.88) between patients with RP (6.85 +/- 0.58 mm) and normal subjects (6.82 +/- 0.76 mm). The results of the present study are clearly counter to the prediction of the second (weaker) form of the equivalent light hypothesis.

Visual field defects in children with congenital glaucoma.

PURPOSE: To determine visual field defects in a cohort of children with congenital glaucoma. METHODS: Monocular visual fields were measured in 24 meridians for targets V4e, I4e, I2e, and I1e, using a Goldmann perimeter in a group of 13 children between the ages of 4 and 14 years with congenital glaucoma and 10 age-matched healthy children. Localized visual field defects (eg, paracentral scotoma, nasal step, and arcuate scotoma) were determined by abnormal findings or shape of the eye in at least one of each of the targets presented. RESULTS: Visual field extent for target 12e was significantly constricted for unilateral and bilateral cases of congenital glaucoma when compared with control eyes. A post-hoc procedure (Tukey Test) showed significant differences between unilateral cases and normal control eyes, and between bilateral cases (best outcome eye) and normal control eyes. Stimuli V4e and 14e results were comparable for patients and normals. Stimulus I1e showed significantly different total extent visual field for bilateral and normal controls. Specific visual field defects were found only in bilateral cases. Paracentral scotoma was found in 1 of 12 eyes with bilateral congenital glaucoma. Nasal steps were found in 6 of 12 eyes with bilateral congenital glaucoma. Arcuate scotoma were found in 4 of 12 eyes with bilateral congenital glaucoma. CONCLUSION: Localized visual fields were found in 37.5% of eyes with congenital glaucoma. Early treatment for congenital glaucoma provided better visual field outcome.

Large sample population age norms for visual acuities obtained with Vistech-Teller Acuity Cards.

PURPOSE: To determine population age norms in the first three years of life for binocular and monocular grating visual acuity (VA) obtained with Vistech-Teller Acuity Cards (TAC). METHODS: TAC was used to estimate grating acuity in 646 healthy infants and children born at due date +/- 2 weeks, all of whom underwent ophthalmologic and orthoptic evaluation. The sample consisted of 20 age groups from 0 to 36 months. Sixty-nine percent of the children attended day care centers in the city of São Paulo. The sample was composed of white (63.0%), mulatto (25.2%), African-Brazilian (11.0%), and Asian (0.8%) infants and children, most of whom (97%) were from low-income families. Tests were conducted by eight highly trained testers, six of whom were orthoptists. RESULTS: Binocular and monocular norms for grating VA are presented in terms of tolerance limits for 90% of the population with 95% probability. The range of tolerance limits is approximately 2.5 octaves at most ages. There were no statistical differences among scores obtained by the different testers. There were no differences in VA due to race, sex, and first or second eye tested. The results on binocular (99.3%) and monocular (96.2%) testability and on mean test duration (13 minutes for one binocular and two monocular measurements) confirm the clinical applicability of TAC. CONCLUSIONS: The binocular and monocular grating VA norms obtained in this large-sample study are different from the preliminary norms published with the TAC. Results from this and other studies (see Mayer et al, page 671, this issue) strongly point to a need for redefinition of the preliminary VA norms.

Glaucoma congenito. Aspectos clinicos e importancia de ambliopia. / Congenital glaucoma. Clinical aspectos and the importance of amblyopia

O glaucoma congenito e uma das principais causas de cegueira na infancia. A suspeita diagnostica pode ser estabelecida por todos aqueles que cuidam da crianca desde o seu nascimento. O tratamento deve ser precoce e sempre e cirurgico. O tratamento da ambliopia, presente nestas criancas, deve ser sempre considerado