The impact of chorioamnionitis on neurodevelopmental outcomes at 3, 8 and 18 years in low-birthweight preterm infants.

OBJECTIVE: To assess the long-term cognitive, behavioral and academic status of preterm children exposed to clinical chorioamnionitis. STUDY DESIGN: In total, 985 infants (<37 weeks and 2500 g at birth) were recruited in a multisite interventional research program. Of these, 43 case-infants were identified based on documented diagnosis of maternal clinical chorioamnionitis. Infants with chorioamnionitis were compared with the remainder of the cohort after controlling for maternal and infant variables. All infants underwent cognitive, behavioral and academic achievement assessments at 3, 8 and 18 years. Standardized cognitive and academic achievement scores were cutoff at 2 s.d.'s below the mean, behavioral scores were cutoff at a T-score >70 and examined with χ(2) statistics. Mean scores were evaluated using preliminary bivariate analysis and were followed by multiple regression models predicting child outcomes. RESULT: Overall, children with chorioamnionitis did not have lower scores on any assessment at any age. Children without chorioamnionitis performed significantly lower at 8 years on the Woodcock-Johnson reading subscore and the mean score of the Peabody Picture Vocabulary Test (PPVT). No significant difference persisted to 18-year follow-up. In logistic regression, chorioamnionitis independently predicted higher PPVT scores at 8 years, but not lower performance scores on the Woodcock-Johnson reading subscore. CONCLUSION: Clinical chorioamnionitis was not associated with adverse neurodevelopmental outcomes in this group of preterm infants <37 weeks and 2500 g.

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

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.

Macular pigment density measured by autofluorescence spectrometry: comparison with reflectometry and heterochromatic flicker photometry.

We present a technique for estimating the density of the human macular pigment noninvasively that takes advantage of the autofluorescence of lipofuscin, which is normally present in the human retinal pigment epithelium. By measuring the intensity of fluorescence at 710 nm, where macular pigment has essentially zero absorption, and stimulating the fluorescence with two wavelengths, one well absorbed by macular pigment and the other minimally absorbed by macular pigment, we can make accurate single-pass measurements of the macular pigment density. We used the technique to measure macular pigment density in a group of 159 subjects with normal retinal status ranging in age between 15 and 80 years. Average macular pigment density was 0.48 +/- 0.16 density unit (D.U.) for a 2 degrees -diameter test field. We show that these estimates are highly correlated with reflectometric (mean: 0.23 +/- 0.07 D.U.) and psychophysical (mean: 0.37 +/- 0.26 D.U.; obtained by heterochromatic flicker photometry) estimates of macular pigment in the same subjects, despite the fact that systematic differences in the estimated density exist between techniques. Repeat measurements over both short- and long-time intervals indicate that the autofluorescence technique is reproducible: The mean absolute difference between estimates was less than 0.05 D.U., superior to the reproducibility obtained by reflectometry and flicker photometry. To understand the systematic differences between density estimates obtained from the different methods, we analyzed the underlying assumptions of each technique. Specifically, we looked at the effect of self-screening by visual pigment, the effect of changes in optical property of the deeper retinal layers, including the role of retinal pigmented epithelium melanin, and the role of secondary fluorophores and reflectors in the anterior layers of the retina.

Comparing laser ray tracing, the spatially resolved refractometer, and the Hartmann-Shack sensor to measure the ocular wave aberration.

PURPOSE: To compare quantitatively three techniques to measure the optical aberrations of the human eye: laser ray tracing (LRT), the Hartmann-Shack wavefront sensor (H-S), and the spatially resolved refractometer (SRR). LRT and H-S are objective imaging techniques, whereas SRR is psychophysical. METHODS: Wave aberrations were measured in two normal subjects with all three techniques implemented in two different laboratories. RESULTS: We compared the experimental variability of the results obtained with each technique with the overall variability across the three methods. For the two subjects measured (RMS wavefront error 0.5 microm and 0.9 microm, respectively), we found a close agreement; the average standard deviation of the Zernike coefficients within a given method was 0.07 microm, whereas the average global standard deviation across techniques was 0.09 microm, which is only slightly higher. CONCLUSIONS: There is a close match between the Zernike coefficients obtained by LRT, H-S, and SRR. Thus, all three techniques provide similar information concerning wave aberration when applied to normal human eyes. However, the methods are operationally different, and each has advantages and disadvantages depending on the particular application.

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.

Detecting AMD with multiply scattered light tomography.

PURPOSE: to use a novel technique, Multiply Scattered Light Tomography (MSLT), to provide a comfortable, rapid, and noninvasive method for detection and management of Age-related Macualar Degeneration. METHODS: two patient groups were studied in clinical settings with MSLT and confocal scanning laser tomography. In Poway, CA, 21 retinal patients underwent tomography, and the 17 patients with suspicion of exudation also had ICG. An Angio-Scan (Laser Diagnostic Technologies, Inc.) was used to provide simultaneous fundus reflectance and ICG imaging. In Methuen, MA, 20 retinal patients underwent tomography with fluorescein angiography for suspicion of exudation. The MSLT was based on the TopSS (Laser Diagnostic Technologies, Inc.), with a Vertical Cavity Surface Emitting Laser array at 850 mm as the illumination source. The central laser produced confocal images. The surrounding lasers produced multiply scattered light images. RESULTS: MSLT emphasized structures beneath the retina such as drusen, choroidal new vessel membranes, and pigment epithelial detachments. Exudation seen on angiography was visualized by MSLT as topographical structures with distinct borders. Superficial structures, e.g., cysts and epiretinal membranes, were visualized in 850 nm images. DISCUSSION: confocal tomography and MSLT provided a rapid, noninvasive method to detect and localize macular degeneration and pathological structures found in eyes of older patients.

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.

Comparison of cone directionality determined by psychophysical and reflectometric techniques.

We measured the directionality of the cones with both a psychophysical (Stiles-Crawford I) technique and an optical technique. The two sets of measurements were made in the same subjects, with stimuli as similar as possible used. The two types of measurements gave similar estimates of the location in the pupil toward which the cones were optimally aligned. However, the two measurements gave quite dissimilar estimates of the width of the directional sensitivity. On average, optical measurements were half as broad as psychophysical measurements in the fovea, but there were substantial individual differences. At 2-deg retinal eccentricity the difference between techniques was even more marked.

Cone spacing and waveguide properties from cone directionality measurements.

Reflectometric techniques estimate the directionality of the retinal cones by measuring the distribution of light at the pupil plane of light reflected off the bleached retina. The waveguide-scattering model of Marcos et al. [J. Opt. Soc. Am. A 15, 2012 (1998)] predicts that the shape of this intensity distribution is determined by both the waveguide properties of the cone photoreceptors and the topography of the cone mosaic (cone spacing). We have performed two types of cone directionality measurement. In the first type, cone directionality estimates are obtained by measuring the spatial distribution of light returning from the retina with a single-entry pupil position (single-entry measurements). In the second type, estimates are obtained by measuring the total amount of light guided back through the pupil as a function of entry pupil position (multiple-entry measurements). As predicted by the model, single-entry measurements provide narrower distributions than the multiple-entry measurements, since the former are affected by both waveguides and scattering and the latter are affected primarily by waveguides. Measurements at different retinal eccentricities and at two different wavelengths are consistent with the model. We show that the broader multiple-entry measurements are not accounted for by cone disarray. Results of multiple-entry measurements are closer to results from measurements of the psychophysical Stiles-Crawford effect (although still narrower), and the variation with retinal eccentricity and wavelength is similar. By combining single- and multiple-entry measurements, we can estimate cone spacing. The estimates at 0- and 2-deg retinal eccentricities are in good agreement with published anatomical data.

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.

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.

Measurement of the wave-front aberration of the eye by a fast psychophysical procedure.

We used a fast psychophysical procedure to determine the wave-front aberrations of the human eye in vivo. We measured the angular deviation of light rays entering the eye at different pupillary locations by aligning an image of a point source entering the pupil at different locations to the image of a fixation cross entering the pupil at a fixed location. We fitted the data to a Zernike series to reconstruct the wave-front aberrations of the pupil. With this technique the repeatability of the measurement of the individual coefficients was 0.019 micron. The standard deviation of the overall wave-height estimation across the pupil is less than 0.3 micron. Since this technique does not require the administration of pharmacological agents to dilate the pupil, we were able to measure the changes in the aberrations of the eye during accommodation. We found that administration of even a mild dilating agent causes a change in the aberration structure of the eye.

Model for cone directionality reflectometric measurements based on scattering.

Reflectometric measurements provide an objective assessment of the directionality of the photoreceptors in the human retina. Measurements are obtained by imaging the distribution at the pupil plane of light reflected off the human fundus in a bleached condition. We propose that scattering as well as waveguides must be included in a model of the intensity distribution at the pupil plane. For scattering, the cone-photoreceptor array is treated as a random rough surface, characterized by the correlation length T (related to the distance between scatterers, i.e., mean cone spacing) and the roughness standard deviation sigma (assuming random length variations of the cone outer-segment lengths that produce random phase differences). For realistic values of T and sigma we can use the Kirchhoff approximation for computing the scattering distribution. The scattered component of the distribution can be fitted to a Gaussian function whose width depends only on T and lambda. Actual measurements vary with experimental conditions (exposure time, retinal eccentricity, and lambda) in a manner consistent with the scattering model. However, photoreceptor directionality must be included in the model to explain the actual location of the peak of the intensity distribution in the pupil plane and the total angular spread of light.

Variations in photoreceptor directionally across the central retina.

Cones show a differential sensitivity to light coming from different portions of the pupil, typically being most sensitive to light from the center of the pupil. We measured the directional properties of the cones across the central 6 deg of the retina, using an optical imaging technique. We find that the cones in the center of the fovea have the broadest tuning. The width of the angular tuning changes rapidly from 0 deg to 1 deg retinal eccentricity, with cones at 1 deg being much more narrowly tuned that the cones in the center of the fovea. Directional tuning of the cones remains relatively constant from 1 deg to 3 deg retinal eccentricity. Receptoral disarray contributes minimally to the measured directional properties of the foveal cones, and there is no evidence of asymmetry between horizontal and vertical retinal locations. There are only small differences among the five subjects in the change in angular tuning of the cones with retinal location. We find that at the foveal center the directional tuning of the cones is limited by the diameter of the cone apertures.

Rapid sensitivity changes on flickering backgrounds: tests of models of light adaptation.

To investigate mechanisms underlying sensitivity changes that are capable of following rapid variations in intensity of the background field, we measured the threshold radiance needed to detect a 2-ms probe flash presented at various phases relative to a sinusoidally flickering background. The temporal frequency, mean luminance, and modulation of the background were systematically varied. The sensitivity change consisted of two components: a phase-insensitive increase in threshold that occurs at all the phases of the background field (a change in the dc level of the threshold), and a phase-dependent variation in threshold. Both components can reliably be measured at temporal frequencies up to approximately 50 Hz. On a 30-Hz background, the threshold varied with phase over roughly 0.5 log unit within a half-cycle (17 ms). For background flicker rates of 20-40 Hz the probe threshold increased with increasing instantaneous background radiance, following a typical threshold-versus-radiance template, and approaching Weber-law behavior during the peak of the background flicker. This pattern of threshold elevation was measured at mean background illuminances from 580 to 9100 Td (trolands), with the dimmer backgrounds being slightly less effective in producing threshold elevations. The measured increase in the dc level commenced as soon as the modulation of the background flicker began, and the amount of threshold elevation followed the envelope of the background flicker, ruling out modulation gain control explanations for the change in sensitivity on flickering backgrounds. The threshold elevations measured on a 30-Hz, 25% modulation background were lower than those measured on a 30-Hz, 100% modulation background at all phases. The measured changes in threshold with changes in background modulation rule out all adaptation models consisting of a multiplicative and a subtractive adaptation processes followed by a single, late, static nonlinearity.

The reemergence of the hospital-based laboratory.

The Reference Laboratory Alliance (RLA) in Pittsburgh is an example of multiple hospital laboratories integrated for the purpose of delivering competitive outpatient laboratory services in a managed-care environment. Developed in 1994, the RLA model includes a "virtual" core laboratory (comprising four tertiary care centers of excellence) and a distributed network of more than 30 community hospitals. Linked through information systems, logistics, and an extensive committee structure, the RLA is capable of delivering a "seamless" service to the region's managed-care organizations. In its first full year of operation, the RLA is expected to shift between $12 and $15 million worth of laboratory activity back into the community's hospitals. Through its pathology component, the RLA is now actively engaged in redefining the role of the clinical laboratory in the managed-care environment.