Russell L. Woods

A placental clock controlling the length of human pregnancy

We report the existence of a ‘placental clock’, which is active from an early stage in human pregnancy and determines the length of gestation and the timing of parturition and delivery. Using a prospective, longitudinal cohort study of 485 pregnant women we have demonstrated that placental secretion of corticotropin-releasing hormone (CRH) is a marker of this process and that measurement of the maternal plasma CRH concentration as early as 16–20 weeks of gestation identifies groups of women who are destined to experience normal term, preterm or post-term delivery. Further, we report that the exponential rise in maternal plasma CRH concentrations with advancing pregnancy is associated with a concomitant fall in concentrations of the specific CRH binding protein in late pregnancy, leading to a rapid increase in circulating levels of bioavailable CRH at a time that coincides with the onset of parturition, suggesting that CRH may act directly as a trigger for parturition in humans.

Quantitative measurements of autofluorescence with the scanning laser ophthalmoscope.

PURPOSE To evaluate the feasibility and reliability of a standardized approach for quantitative measurements of fundus autofluorescence (AF) in images obtained with a confocal scanning laser ophthalmoscope (cSLO). METHODS AF images (30°) were acquired in 34 normal subjects (age range, 20-55 years) with two different cSLOs (488-nm excitation) equipped with an internal fluorescent reference to account for variable laser power and detector sensitivity. The gray levels (GLs) of each image were calibrated to the reference, the zero GL, and the magnification, to give quantified autofluorescence (qAF). Images from subjects and fixed patterns were used to test detector linearity with respect to fluorescence intensity, the stability of qAF with change in detector gain, field uniformity, effect of refractive error, and repeatability. RESULTS qAF was independent of detector gain and laser power over clinically relevant ranges, provided that detector gain was adjusted to maintain exposures within the linear detection range (GL < 175). Field uniformity was better than 5% in a central 20°-diameter circle but decreased more peripherally. The theoretical inverse square magnification correction was experimentally verified. Photoreceptor bleaching for at least 20 seconds was performed. Repeatability (95% confidence interval) for same day and different-day retests of qAF was ±6% to ±14%. Agreement (95% confidence interval) between the two instruments was <11%. CONCLUSIONS Quantitative AF imaging appears feasible. It may enhance understanding of retinal degeneration, serve as a diagnostic aid and as a sensitive marker of disease progression, and provide a tool to monitor the effects of therapeutic interventions.

Vision and mobility performance of subjects with age-related macular degeneration.

Purpose. To investigate the effects of age-related macular degeneration (ARMD) on mobility performance and to identify the vision determinants of mobility in subjects with ARMD. Methods. Walking speed and the number of obstacle contacts made on a 79-m indoor mobility course were measured in 21 subjects with ARMD and 11 age-matched subjects with normal vision. The mobility measures were transformed to percentage preferred walking speed and contacts score. The vision functions assessed included binocular visual acuity, contrast sensitivity, and visual field. Results. In this study, subjects with ARMD did not walk significantly slower or make significantly more obstacle contacts on the mobility course than the normally sighted subjects of similar age. Between 29% and 35% of the variance in the ARMD mobility performance was accounted for by visual field and contrast sensitivity measures. The most significant predictor of mobility performance scored as percentage preferred walking speed was the size of a binocular central scotoma. Conclusion. As the size of a binocular central scotoma increases, mobility performance decreases.

Subjective depth-of-focus of the eye.

An experiment is described in which the subjective depth-of-focus (DOF) of the eye, defined as the range of focusing errors for which the image of the target appears to have the same clarity, contrast, and form as the optimal in-focus image, was measured as a function of the size of high contrast (99%) Snellen Es for 5 trained subjects under cycloplegia. Mean DOF increased by approximately 60% as the size of the letter detail increased from −0.2 to 0.87 log min arc (Snellen equivalent: 6/3.8 to 6/45), although there were considerable intersubject variations. DOF declined with increasing pupil diameter, the mean total DOFs being 0.86, 0.59, and 0.55 D for 2-, 4-, and 6-mm pupils, respectively. In a second experiment, use of low (21%) contrast letters with a 4-mm pupil and 4 subjects marginally increased the DOF (by 0.08 ± 0.05 D); refraction also shifted in a myopic direction by a mean of 0.15 ± 0.06 D compared with the high contrast letters. A third experiment with four less-experienced subjects demonstrated the importance of instruction and training in any measurement involving judgment of just-perceptible defocus blur. The clinical implications of the results for measurements of refraction and amplitude of accommodation are discussed.

Quantitative fundus autofluorescence in recessive Stargardt disease.

PURPOSE To quantify fundus autofluorescence (qAF) in patients with recessive Stargardt disease (STGD1). METHODS A total of 42 STGD1 patients (ages: 7-52 years) with at least one confirmed disease-associated ABCA4 mutation were studied. Fundus AF images (488-nm excitation) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to account for variable laser power and detector sensitivity. The gray levels (GLs) of each image were calibrated to the reference, zero GL, magnification, and normative optical media density to yield qAF. Texture factor (TF) was calculated to characterize inhomogeneities in the AF image and patients were assigned to the phenotypes of Fishman I through III. RESULTS Quantified fundus autofluorescence in 36 of 42 patients and TF in 27 of 42 patients were above normal limits for age. Young patients exhibited the relatively highest qAF, with levels up to 8-fold higher than healthy eyes. Quantified fundus autofluorescence and TF were higher in Fishman II and III than Fishman I, who had higher qAF and TF than healthy eyes. Patients carrying the G1916E mutation had lower qAF and TF than most other patients, even in the presence of a second allele associated with severe disease. CONCLUSIONS Quantified fundus autofluorescence is an indirect approach to measuring RPE lipofuscin in vivo. We report that ABCA4 mutations cause significantly elevated qAF, consistent with previous reports indicating that increased RPE lipofuscin is a hallmark of STGD1. Even when qualitative differences in fundus AF images are not evident, qAF can elucidate phenotypic variation. Quantified fundus autofluorescence will serve to establish genotype-phenotype correlations and as an outcome measure in clinical trials.

Mobility performance with retinitis pigmentosa

Purpose: Reduced mobility can have a serious impact on quality of life. Though previous studies have demonstrated that some vision measures relate to the mobility of subjects with simulated and true low vision, the relationship between residual vision and mobility is not clear. We investigated the relationship between clinical vision measures and mobility performance under different illumination levels for subjects with retinitis pigmentosa (RP).

How red is a white eye? Clinical grading of normal conjunctival hyperaemia

PurposeTo quantify the level of normal bulbar conjunctival hyperaemia using the Cornea and Contact Lens Research Unit (CCLRU) grading scale, and to investigate inter-observer agreement.MethodsBulbar conjunctival hyperaemia was assessed by two trained observers, using the CCLRU grading scale (zero to four units) interpolated into 0.1 increments, on the right eye of 121 healthy, non-contact lens-wearing subjects (male=58, female=63, median age=28 years, range 16–77). The eye was observed using a slit-lamp bio-microscope (× 10 magnification) under diffuse, white illumination. The subjects position of gaze was directed to allow grading of four quadrants: superior, nasal, inferior, and temporal conjunctiva. Bulbar redness was defined as the average of those four grades of conjunctival hyperaemia. A further twenty subjects were recruited to assess inter-observer agreement (male=8, female=12, median age=23 years).ResultsThe average bulbar redness was 1.93 (±0.32 SD) units. The nasal (2.3±0.4) and temporal (2.1±0.4) quadrants were significantly redder than the superior (1.6±0.4) and inferior (1.7±0.4) quadrants (P<0.0001). Males had redder eyes than females by 0.2 units. Inter-observer 95% limits of agreement for bulbar redness was 0.38 units.ConclusionsThe average bulbar redness of 1.9 units was higher than expected, reflecting the design of the grading scale. A bulbar redness of greater than 2.6 units may be considered abnormal, and a change in bulbar redness of ≥0.4 units may be significant.

Lateral interactions: size does matter

Usually a high-contrast, co-local mask increases contrast threshold (inhibition). Interestingly, a laterally displaced mask (flanker) can facilitate contrast detection (Vision Research 33 (1993) 993; 34 (1994) 73). When spatial scaling of these flanker effects was implied, stimulus bandwidth was confounded with spatial frequency (lambda(-1)). Under conditions where at lower spatial frequencies, the size (standard deviation, sigma) of the Gabor patch was smaller (sigma<lambda) than higher spatial frequencies (sigma=lambda), the effect appeared scale invariant. We replicated the original results for all conditions. However, when Gabor size was fixed (sigma=lambda), facilitation changed with spatial frequency (range 2--13 cycles/deg). When Gabor size was varied (sigma=0.5-2 lambda), usually the combination of larger patch sizes and lower spatial frequencies caused inhibition. We were unable to find any conditions that demonstrated spatial scaling. The size, both lambda and sigma, of both stimulus and flankers, influenced contrast threshold. Also, facilitation reduced as contrast of the flankers was reduced to detection threshold. Some facilitation was apparent with sub-threshold flankers. These results need to be reconciled with current models of lateral interactions.

Quantitative Fundus Autofluorescence in Healthy Eyes

PURPOSE Fundus autofluorescence was quantified (qAF) in subjects with healthy retinae using a standardized approach. The objective was to establish normative data and identify factors that influence the accumulation of RPE lipofuscin and/or modulate the observed AF signal in fundus images. METHODS AF images were acquired from 277 healthy subjects (age range: 5-60 years) by employing a Spectralis confocal scanning laser ophthalmoscope (cSLO; 488-nm excitation; 30°) equipped with an internal fluorescent reference. For each image, mean gray level was calculated as the average of eight preset regions, and was calibrated to the reference, zero-laser light, magnification, and optical media density from normative data on lens transmission spectra. Relationships between qAF and age, sex, race/ethnicity, eye color, refraction/axial length, and smoking status were evaluated as was measurement repeatability and the qAF spatial distribution. RESULTS qAF levels exhibited a significant increase with age. qAF increased with increasing eccentricity up to 10° to 15° from the fovea and was highest superotemporally. qAF values were significantly greater in females, and, compared with Hispanics, qAF was significantly higher in whites and lower in blacks and Asians. No associations with axial length and smoking were observed. For two operators, between-session repeatability was ± 9% and ± 12%. Agreement between the operators was ± 13%. CONCLUSIONS Normative qAF data are a reference tool essential to the interpretation of qAF measurements in ocular disease.

Clinical and Laboratory Evaluation of Peripheral Prism Glasses for Hemianopia

Purpose. Homonymous hemianopia (the loss of vision on the same side in each eye) impairs the ability to navigate and walk safely. We evaluated peripheral prism glasses as a low vision optical device for hemianopia in an extended wearing trial. Methods. Twenty-three patients with complete hemianopia (13 right) with neither visual neglect nor cognitive deficit enrolled in the 5-visit study. To expand the horizontal visual field, patients’ spectacles were fitted with both upper and lower Press-On Fresnel prism segments (each 40 prism diopters) across the upper and lower portions of the lens on the hemianopic (“blind”) side. Patients were asked to wear these spectacles as much as possible for the duration of the study, which averaged 9 (range: 5 to 13) weeks. Clinical success (continued wear, indicating perceived overall benefit), visual field expansion, perceived direction, and perceived quality of life were measured. Results. Clinical success: 14 of 21 (67%) patients chose to continue to wear the peripheral prism glasses at the end of the study (two patients did not complete the study for non-vision reasons). At long-term follow-up (8 to 51 months), 5 of 12 (42%) patients reported still wearing the device. Visual field expansion: expansion of about 22° in both the upper and lower quadrants was demonstrated for all patients (binocular perimetry, Goldmann V4e). Perceived direction: two patients demonstrated a transient adaptation to the change in visual direction produced by the peripheral prism glasses. Quality of life: at study end, reduced difficulty noticing obstacles on the hemianopic side was reported. Conclusions. The peripheral prism glasses provided reported benefits (usually in obstacle avoidance) to 2/3 of the patients completing the study, a very good success rate for a vision rehabilitation device. Possible reasons for long-term discontinuation and limited adaptation of perceived direction are discussed.