Effects of interactions among wave aberrations on optical image quality.

Wave aberrations degrade the optical quality of the eye relative to the diffraction limit, but there are situations in which having slightly aberrated optics can provide some relative visual benefits. This fact led us to consider whether interactions among aberrations in the eye's wavefront produce an advantage for image quality relative to wavefronts with randomized combinations of aberrations with the same total RMS error. Total ocular wave aberrations from two experimental groups and corneal wave aberrations from one group were measured and expressed as Zernike polynomial expansions through the seventh-order. In a series of Monte Carlo simulations, modulation transfer functions (MTFs) for the measured wave aberrations were compared to distributions of artificial MTFs for wavefronts created by randomizing the sign or orientation of the aberrations, while maintaining the RMS error within each Zernike order. In a control condition, "synthetic" model eyes were produced by choosing each individual aberration term at random from individuals in the experimental group, and again MTFs were compared for original and randomized signs. Results were summarized by the MTF ratio: real MTF/mean simulated MTF, as a function of spatial frequency. For a 6mm pupil, the mean MTF ratio for total ocular aberrations was greater than 1.0 up to 60 cycles per degree, suggesting that the eye's aberrations are not independent and that there may be a positive functional consequences to their interrelations. This positive relation did not hold for corneal aberrations alone, or for the synthetic eyes.

Animal models and analytical approaches for understanding the relationships between wine and cancer.

We used two approaches for studying the relationships between wine consumption, wine composition and cancer In the first approach, a transgenic mouse model of human neurofibromatosis, combined with the use of well-defined, chemically purified diets, showed that red wine contains nonalcoholic components that can delay tumor onset. In additional studies, catechin, the main monomeric polyphenol of red wine, delayed tumor onset in this mouse model in a positive, linear relationship when incorporated into the diet at levels of 0.5-4 mmol/kg diet. In the second approach, low doses of the chemical carcinogen 2-amino-1-methyl-6-phenylimidazo(4, 5-b)pyridine (PhlP) were administered to rats, and formation of DNA adducts was evaluated by accelerator mass spectrometry. Consumption of red wine solids (the residue from red wine remaining after removal of alcohol and water) and the wine polyphenol quercetin did not influence PhlP-DNA adduct levels or induce liver enzymes (glutathione-S-transferase and quinone reductase). However, quercetin did alter distribution of PhlP in the rat tissues compared to control animals and animals fed other potential dietary chemopreventive agents, including phenylethyl isothiocyanate and sulforaphane. These studies demonstrate the feasibility of these approaches for studying the chemopreventive potential of dietary components at physiologic levels in

Age-related changes in monochromatic wave aberrations of the human eye.

PURPOSE: To investigate the relations between age and the optical aberrations of the whole eye. The eye's optical quality, as measured by the modulation transfer function (MTF), degrades with age, but the MTF does not provide a means to assess the contributions of individual aberrations, such as coma, spherical aberration, and other higher order aberrations to changes in optical quality. The method used in this study provides measures of individual aberrations and overall optical quality. METHODS: Wave aberrations in 38 subjects were measured psychophysically using a spatially resolved refractometer. Data were fit with Zernike polynomials up to the seventh order to provide estimates of 35 individual aberration terms. MTFs and root mean square (RMS) wavefront errors were calculated. Subjects ranged in age from 22.9 to 64.5 years, with spherical equivalent corrections ranging from +0.5 to -6.0 D. RESULTS: Overall RMS wavefront error (excluding tilts, astigmatism, and defocus) was significantly positively correlated with age (r = 0.33, P = 0.042). RMS error for the highest order aberrations measured (fifth through seventh order) showed a strong positive correlation with age (r = 0.57, P = 0.0002). Image quality, as quantified by the MTF, also degraded with age. CONCLUSIONS: Wave aberrations of the eye increase with age. This increase is consistent with the loss of contrast sensitivity with age observed by other investigators.

Foveal cone photopigment distribution: small alterations associated with macular pigment distribution.

PURPOSE: To map the photopigment distribution of central foveal cones in healthy adult subjects before potential onset of age-related macular degeneration. To compare alterations in cone photopigment distribution to those of macular pigment and examine those loci for subretinal changes. METHODS: Eleven healthy subjects (age range, 31-59 years) underwent reflectometry with a scanning laser ophthalmoscope. The difference in cone photopigment density in the fovea was mapped for the long-wavelength- and middle-wavelength-sensitive cones, using 594-nm light. Macular pigment was mapped with 488-nm and 514-nm light. Subretinal changes were investigated with infrared imaging (830-860 nm). RESULTS: Most subjects had small alterations in the regularity of their foveal cone photopigment distribution. Alterations were spatially related to macular pigment alterations but not to the presence of subretinal defects. Subjects were classified into three groups according to the type of alterations in the regularity of pigment distributions: central peak of photopigment and macular pigment, small foveal alterations, and broad distribution with missing central peak of photopigment or macular pigment. The resultant groups differed significantly in age, 43, 46, and 59 years, for groups 1, 2, and 3, respectively (P < 0.05). CONCLUSIONS: Small alterations in the distributions of foveal cone photopigment or macular pigment were found that varied among the subjects. Larger alterations in older subjects may indicate changes in foveal architecture with age, including potential vulnerability of central cones before the onset of clinically significant changes in the retinal pigment epithelium.

A psychophysical technique for measuring cone photopigment bleaching.

A new, clinically applicable test has been developed to measure the bleaching of the foveal cone photopigments. This noninvasive test is called steady-state color matching. Steady-state color matching is based on the dependence of a color match on the optical density of the cone photopigments. By measuring the color match as a function of retinal illuminance, it is possible to compute the optical density of the cone photopigments at each illuminance. Thus, abnormalities of photopigment bleaching can be detected. This study demonstrates that the technique is readily performed by a clinical population. Patients with central serous retinopathy and retinitis pigmentosa are shown to have low effective optical densities.

Cone photopigment bleaching abnormalities in diabetes.

We have used a color-matching technique to obtain estimates of the optical density of cone photopigments as a function of retinal illuminance in patients with insulin-dependent diabetes mellitus (IDDM). We found that the half-bleach illuminance of some patients is abnormally high. That is, it takes more light to bleach an equivalent amount of photopigment in these patients. Since low illuminance color matches for these patients are normal, this implies that these patients have normal amounts of photopigment, but the photopigment is not bleaching normally. This result clearly points to abnormalities in the outer retina of these diabetic patients. The most likely causes of this abnormality are either decreases in the ability of the cones to absorb light, or an increased rate of regeneration of the cone photopigments.

P-selectin expression in myocardium of children undergoing cardiopulmonary bypass.

Cardiopulmonary bypass is a planned support technique that results in a period of myocardial ischemia and reperfusion. In addition, it is associated with an inflammatory response likely involving endothelial cell activation. In previous studies, we showed that E-selectin and intercellular adhesion molecule-1 (ICAM-1) messenger ribonucleic acid (mRNA) are increased in human myocardium after cardiopulmonary bypass. We have now examined the expression of P-selectin mRNA by ribonuclease protection in paired atrial biopsy specimens from 12 patients before and after cardiopulmonary bypass. By means of immunocytochemistry, we have also examined the endothelial cell surface expression of P-selectin protein, as well as that of E-selectin and ICAM-1 in three additional patients. Patient ages ranged from 1 day to 8.5 years (median 12 months), and cardiopulmonary bypass times ranged from 46 to 196 minutes (median 144 minutes). By ribonuclease protection, there was marked variability in the expression of P-selectin in biopsy specimens before bypass. However, when compared with prebypass levels, P-selectin mRNA decreased modestly in 10 of 12 patients after bypass (median decrease 1.5-fold, p = 0.016). As seen with immunocytochemistry, P-selectin protein was distributed diffusely through the vascular bed on large vessels and small vessels before bypass but was virtually absent on capillaries in specimens taken after bypass. E-selectin, which was absent in prebypass biopsy specimens, was induced in one of the three specimens after bypass, but no change in ICAM-1 protein expression above baseline was noted. We also find that cultured human endothelial cells treated with tumor necrosis factor-alpha in doses which induce ICAM-1 mRNA simultaneously decrease their expression of P-selectin mRNA as compared with untreated cells. These observations suggest that endothelial P-selectin is transcriptionally downregulated after cardiopulmonary bypass at times when E-selectin and ICAM-1 are induced. Furthermore, we find that E-selectin and ICAM-1 are expressed at times and at sites where P-selectin is absent. Although it is possible that P-selectin may have been induced and lost at early times before reperfusion, these data suggest that endothelial P-selectin plays a limited role in the inflammatory response that ensues after cardiopulmonary bypass.

Repair of double aortic arch associated with D-transposition of the great arteries.

D-transposition of the great arteries is infrequently associated with anomalies of the aortic arch. We report a rare case of double aortic arch associated with D-transposition of the great arteries. The diagnosis was made by angiography and transthoracic echocardiography. The patient underwent a successful simultaneous arterial switch operation and division of the vascular ring through a median sternotomy incision.

The spatially resolved refractometer.

PURPOSE: To investigate factors controlling the aberrations of the eye, including accommodation, wavelength, and the apodization of the optics of the eye by cone directional selectivity. METHODS: We constructed a new implementation of the Spatially Resolved Refractometer (SRR). This is an instrument, based on the Scheiner principle, that allows the rapid psychophysical measurement of the complete wavefront aberrations of the eye. We have investigated both the reproducibility of the measurements, and the effect of static accommodation and wavelength on the wavefront aberrations of the eye. In addition we combined the wave front aberrations with cone photoreceptor directionality to compute the modulation transfer function of the eye, at the retinal level. RESULTS: The SRR measurements were rapid (4 minutes per measurements, 12 minutes per patient) and reproducible. There are significant changes in wavefront quality with accommodation, with optimal image quality near the resting point of accommodation. Image quality for polychromatic (white) light is strongly affected by both longitudinal and transverse chromatic aberration. Finally, we find that incorporating the effects of cone directionality into the calculation of image quality can increase image quality by up to 50%. CONCLUSION: Calculation of a simple "optimal surgical shape" for wave-front guided refractive surgery will depend on improved understanding of the interplay between the biological and physical properties of the eye.

On the symmetry between eyes of wavefront aberration and cone directionality.

There are two optical processes that control the retinal image sampled by the photoreceptor array: aberrations of the ocular optics and cone directionality (Stiles-Crawford effect). The shape of wavefront aberration and Stiles-Crawford functions are known to vary markedly across subjects. In this study we investigate in twelve subjects the symmetry between right and left eyes of wavefront aberration (measured using a spatially resolved refractometer) and cone directionality (measured using an imaging reflectometric technique). The pattern of aberrations is in general non-symmetric, suggesting that the development of aberrations follow independent paths in many right and left eye pairs. Cone directionality is in most cases mirror-symmetric (with one case of direct symmetry), suggesting some systematic process underlying cone orientation. Except in two subjects, symmetry in these two functions seems to be unrelated. Cone directionality apodization improves optical quality, but not optimally in all eyes, and it does not tend to increase symmetry in the optical performance of left and right eyes.

Monochromatic aberrations in the accommodated human eye.

The wave-front aberration of the human eye was measured for eight subjects using a spatially resolved refractometer (a psychophysical ray-tracing test). The eyes were undilated and presented with accommodative stimuli varying from 0 to -6 diopters. Monochromatic wave-front aberrations tend to increase with increasing levels of accommodation, although there are substantial individual variations in the actual change in the wave-front aberration. While spherical aberration always decreased with increasing accommodation, it did not change from positive to negative for every observer. The direction and amount of change in fourth order aberrations varied between observers. Aberrations with orders higher than fourth are at a minimum near the resting state of accommodation. The accommodation induced change in wavefront aberration was not strongly related to the total amount of aberration in the eight eyes studied.

Effects of flicker adaptation and temporal gain control on the flicker ERG.

The flicker electroretinogram (ERG) to stimuli varying in temporal frequency and modulation depth was recorded to investigate retinal gain control. With increasing modulation of a sinusoidal flickering stimulus, the flicker ERG shows an amplitude compression and a phase retardation (of the fundamental component) at 16 Hz, an amplitude expansion and a phase advance around 40-48 Hz, and an approximately linear response at 72 Hz. With sum-of-two-sinusoids stimuli, the second stimulus enhances the fundamental response to a 40 or 48 Hz test stimulus at low modulations, and reduces the variation in phase with modulation. This interaction depends primarily on the amplitude of the response to the second stimulus, but not its frequency. With temporally alternating stimuli, a similar but smaller interaction effect is measured. The results suggest that there is an active nonlinear gain control mechanism in the outer retina and this gain control works by adjusting the phase delay of the retinal response. The phase control mechanism is set by the amplitude of the outer retinal response integrated over time.

The inverse electro-oculogram.

An electro-oculogram ratio of less than one was found to be caused by limited ocular excursions under photopic conditions in a patient with a rod-cone dystrophy. Because this inverse electro-oculogram ratio was not caused by a decrease in standing potential under photopic conditions, it should be considered an artefact.

The Abney effect: chromaticity coordinates of unique and other constant hues.

We compared unique and other constant hue loci measured at a fixed retinal illuminance for the same observers. When expressed in Judd chromaticity coordinates, unique hue and constant hue data agreed. Unique blue loci were curved, and unique red and green loci were noncollinear. These data imply that unique hues are not a linear transformation of color matching functions. Linear models are only an approximation, even at a single luminance level.

Retinal toxicity of amphotericin B in vitrectomised versus non-vitrectomised eyes.

The retinal toxicity of intravitreally administered amphotericin B was compared in non-vitrectomised versus vitrectomised rabbit eyes. Doses of 5 and 10 micrograms in both groups resulted in transient vitritis but had no effect on electroretinograms. Histopathological examination four weeks after injection showed vitreous cells and minimal areas of retinal necrosis in both groups at 5 or 10 micrograms doses. At these doses vitrectomy did not modify the retinotoxic effects of intravitreally administered amphotericin B. At higher doses marked toxicity was found in both vitrectomised and non-vitrectomised groups.

Flicker brightness enhancement and visual nonlinearity.

The purpose of this study was to investigate the nonlinear mechanism underlying brightness enhancement, in which a flickering stimulus appears brighter than a steady stimulus of equal mean luminance. The flickering and matching stimuli were temporally alternated. Both were cosine windowed to minimize the potential effects of temporal transients. Subjects adjusted the amplitude of the matching stimulus to match it in brightness to the flickering stimulus. The temporal frequency, modulation, and waveform of the flickering stimulus were varied. With sinusoidal flicker, brightness enhancement increased with increasing modulation at all frequencies, peaking at about 16 Hz at full modulation. The results were modeled by a broad temporal filter followed by a single accelerating nonlinearity. The derived temporal sensitivity of the early filter inferred from brightness enhancement decreased more slowly at high frequencies than the filter(s) inferred from flicker modulation thresholds. With low frequency sawtooth flicker, brightness enhancement was phase-dependent at low, but not at high modulations, suggesting that multiple neural mechanisms may also be involved in addition to an early nonlinearity.

A new approach to the study of ocular chromatic aberrations.

We measured the ocular wavefront aberration at six different visible wavelengths (between 450 and 650 nm) in three subjects, using a spatially resolved refractometer. In this technique, the angular deviation of light rays entering the pupil at different locations is measured with respect to a target viewed through a centered pupil. Fits of the data at each wavelength to Zernike polynomials were used to estimate the change of defocus with wavelength (longitudinal chromatic aberration, LCA) and the wavelength-dependence of the ocular aberrations. Measured LCA was in good agreement with the literature. In most cases the wavefront aberration increased slightly with wavelength. The angular deviations from the reference stimulus measured using a magenta filter allowed us to estimate the achromatic axis and both optical and perceived transverse chromatic aberration (TCA), (including the effect of aberrations and Stiles-Crawford effect). The amount of TCA varied markedly across subjects, and between eyes of the same subject. Finally, we used the results from these experiments to compute the image quality of the eye in polychromatic light.

Investigating sources of variability of monochromatic and transverse chromatic aberrations across eyes.

Schematic eye models have typically been used to explain the average monochromatic and chromatic imaging properties of the eye. Both monochromatic aberrations and transverse chromatic aberration are known to vary widely across subjects. However, to our knowledge, the ability of schematic eye models to predict these individual variations has not been tested experimentally. We used a spatially resolved refractometer to measure the monochromatic aberrations and the optical transverse chromatic aberration (oTCA) in a group of 15 eyes. By recording the 1st and 4th Purkinje images for five directions of gaze, we also estimated the tilt, misalignment of ocular surfaces (front surface of the cornea and back surface of the lens) and off-axis position of the fovea (angle alpha), as well as pupil centration. We conclude that, contrary to expectations none of those factors are major contributors to the variability in monochromatic aberrations and oTCA in this group of eyes. Simulations show that corneal curvature and corneal conicity are also unlikely to account for the observed relation between monochromatic aberrations and oTCA. Our results suggest an important contribution of corneal irregularities to those aberrations.

Infrared imaging of sub-retinal structures in the human ocular fundus.

The interaction of infrared light with the human ocular fundus, particularly sub-retinal structures, was studied in vivo. Visible and infra-red wavelengths and a scanning laser ophthalmoscope were used to acquire digital images of the human fundus. The contrast and reflectance of selected retinal and sub-retinal features were computed for a series of wavelengths or modes of imaging. Near infrared light provides better visibility than visible light for sub-retinal features. Sub-retinal deposits appear light and thickened; the optic nerve head, retinal vessels, and choroidal vessels appear dark. Contrast and visibility of features increases with increasing wavelength from 795 to 895 nm. Optimizing the mode of imaging improves the visibility of some structures. This new quantitative basis for near infrared imaging techniques can be applied to a wide range of imaging modalities for the study of pathophysiology and treatment in diseases affecting the retinal pigment epithelium and Bruch's membrane, such as age-related macular degeneration.

Organochlorines, including chlordane compounds and their metabolites, in peregrine-falcon, prairie-falcon, and clapper-rail eggs from the USA.

Four compounds present in technical chlordane (trans- and cis-nonachlor, and tentatively MC-2 and MC-5) and three metabolites of chlordane (heptachlor epoxide, oxychlordane, and U-4) were identified by GC/MS in peregrine-falcon (Falco peregrinus anatum) eggs. Levels of Heptachlor epoxide, oxychlordane, trans- and cis-chlordane, trans- and cis-nonachlor, MC-2, and MC-5 were quantified by GC/ECD in peregrine-falcon eggs from the US east coast, Colorado, and California; and in prairie-falcon (Falco mexicanus) and light-footed-clapper-rail (Rallus longirostris levipes) eggs from California. The eggs were collected between 1986 and 1989. Oxychlordane, heptachlor epoxide, trans- and cis-nonachlor, MC-2, and MC-5 were detected in every egg analyzed. Heptachlor, trans-, and cis-chlordane were either not detected, or present at low levels in the eggs. The highest Sigmachlordane levels were found in the East Coast peregrine-falcon eggs at a geometric mean (geom. mean) concentrations of 1800 microg/kg (ppb); the lowest levels of Sigmachlordane were found in the prairie-falcon eggs at a concentration of 120 microg/kg (geom. mean). Of the technical chlordane compounds measured, MC-2 bioaccumulated to the greatest degree. SigmaDDT levels in the falcons ranged from 11 000 microg/kg (geom. mean) in the Colorado samples to 8800 microg/kg (geom. mean) in the East Coast and California peregrines. SigmaDDT levels in the rail eggs were 3000 microg/kg (geom. mean). The highest SigmaPCB levels were found in the East Coast peregrine-falcon eggs at a concentration of 14 000 microg/kg (geom. mean); the lowest levels of SigmaPCB were found in the prairie-falcon eggs at a concentration of 350 microg/kg (geom. mean).