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Ronald A Schachar,1 Majid Mani,2 Ira H Schachar31Department of Physics, University of Texas at Arlington, Arlington, TX, 2California Retina Associates, El Centro, 3Byers Eye Institute of Stanford University, Palo Alto, CA, USAPurpose: To evaluate anterior chamber depth, central crystalline lens thickness and lens curvature during accommodation.Setting: California Retina Associates, El Centro, CA, USA.Design: Healthy volunteer, prospective, clinical research swept-source optical coherence biometric image registration study of accommodation.Methods: Ten subjects (4 females and 6 males) with an average age of 22.5 years (range: 20–26 years) participated in the study. A 45° beam splitter attached to a Zeiss IOLMaster 700 (Carl Zeiss Meditec Inc., Jena, Germany) biometer enabled simultaneous imaging of the cornea, anterior chamber, entire central crystalline lens and fovea in the dilated right eyes of subjects before, and during focus on a target 11 cm from the cornea. Images with superimposable foveal images, obtained before and during accommodation, that met all of the predetermined alignment criteria were selected for comparison. This registration requirement assured that changes in anterior chamber depth and central lens thickness could be accurately and reliably measured. The lens radii of curvatures were measured with a pixel stick circle.Results: Images from only 3 of 10 subjects met the predetermined criteria for registration. Mean anterior chamber depth decreased, −67 µm (range: −0.40 to −110 µm), and mean central lens thickness increased, 117 µm (range: 100–130 µm). The lens surfaces steepened, anterior greater than posterior, while the lens, itself, did not move or shift its position as appeared from the lack of movement of the lens nucleus, during 7.8 diopters of accommodation, (range: 6.6–9.7 diopters).Conclusion: Image registration, with stable invariant references for image correspondence, reveals that during accommodation a large increase in lens surface curvatures is associated with only a small increase in central lens thickness and no change in lens position.Keywords: swept-source biometry, accommodation, anterior chamber depth, crystalline lens thickness, image registration, lens curvature

Age-related Macular Degeneration (AMD) is the leading cause of visual impairment and blindness in the elderly in developed countries. Neovascular/exudative (wet) AMD is the aggressive form of AMD and can involve choroidal neovascularization and vascular leakage. Anti-vascular endothelial growth factor (anti-VEGF) medications have significantly improved treatment of wet-AMD. However, only approximately 40% of patients obtain full benefit from anti-VEGF therapy and the medications are given by intravitreal injection. Axitinib, a small molecule multi-receptor tyrosine kinase inhibitor used for the treatment of advanced renal cell carcinoma, is taken orally and inhibits VEGF activity by blocking VEGF receptors. Axitinib also has the advantage of blocking platelet derived growth factor (PDGF) receptors which play a role in neovascularization. Using in vitro human retinal microvascular endothelial cells (HRMVECs), human brain vascular pericytes (HBVRs), 3D co-culture vessel sprout assay, and in vivo laser induced rat choroidal neovascularization (CNV) models, the effect of axitinib on neovascularization was evaluated. Axitinib inhibited neovascularization better than anti-VEGF and/or anti-hPDGF-B mAb in the in vitro models demonstrating that combined inhibition of both VEGF and PDGF pathways may be synergistic in treating wet-AMD. Additionally, axitinib showed good efficacy at a low dose (0.875 mg/day) in laser-induced CNV model in rats. In conclusion our data shows that axitinib, an inhibitor of VEGF and PDGF-B pathways may be useful in ameliorating wet-AMD therapy.

Lenses have an intracellular hydrostatic pressure gradient to drive fluid from central fiber cells to surface epithelial cells. Pressure is regulated by a feedback control system that relies on transient receptor potential vanilloid (TRPV)1 and TRPV4 channels. The ciliary muscle transmits tension to the lens through the zonules of Zinn. Here, we have examined if ciliary muscle tension influenced the lens intracellular hydrostatic pressure gradient.We measured the ciliary body position and intracellular hydrostatic pressures in mouse lenses while pharmacologically causing relaxation or contraction of the ciliary muscle. We also used inhibitors of TRPV1 and TRPV4, in addition to phosphoinositide 3-kinase (PI3K) p110α knockout mice and immunostaining of phosphorylated protein kinase B (Akt), to determine how changes in ciliary muscle tension resulted in altered hydrostatic pressure.Ciliary muscle relaxation increased the distance between the ciliary body and the lens and caused a decrease in intracellular hydrostatic pressure that was dependent on intact zonules and could be blocked by inhibition of TRPV4. Ciliary contraction moved the ciliary body toward the lens and caused an increase in intracellular hydrostatic pressure and Akt phosphorylation that required intact zonules and was blocked by either inhibition of TRPV1 or genetic deletion of the p110α catalytic subunit of PI3K.These results show that the hydrostatic pressure gradient within the lens was influenced by the tension exerted on the lens by the ciliary muscle through the zonules of Zinn. Modulation of the gradient of intracellular hydrostatic pressure in the lens could alter the water content, and the gradient of refractive index.

The objective was to assess the long-term effect of treatment with latanoprost on ocular development and safety in pediatric patients with glaucoma and ocular hypertension.Prospective cohort study.This was a prospective 3-year cohort study conducted in 14 countries in Europe and South America. Patients aged18 years with glaucoma or ocular hypertension were enrolled into either the latanoprost or non-prostaglandin (non-PG) group in this observational study. The primary endpoint was change in best-corrected visual acuity (BCVA) from baseline to 3 years. Several secondary endpoints were evaluated, including corneal thickness and ocular hyperpigmentation. For treatment comparison, analysis of covariance (ANCOVA) was used for continuous endpoints and Fisher exact test was applied for proportion of participants with clinically significant deterioration events.A total of 175 patients were enrolled: 102 in the latanoprost group (median follow-up: 36.7 months) and 73 in the non-PG group (median follow-up: 36.1 months). There was no statistically significant difference between the latanoprost and the non-PG groups (aged 5 to18 years) in BCVA change from baseline (least square mean logMAR difference -0.03 [95% confidence interval: -0.12, 0.06]), corneal thickness, or ocular hyperpigmentation.Latanoprost had an acceptable safety profile with no evidence of inducing clinically meaningful or statistically significant changes in ocular development or ocular hyperpigmentation in pediatric patients with glaucoma and ocular hypertension.

Andrzej Grzybowski,1,2 Ronald A Schachar,3 Magdalena Gaca-Wysocka,2 Ira H Schachar,4 Barbara K Pierscionek5 1Institute for Research in Ophthalmology, Foundation for Ophthalmology Development, Poznan, 2Department of Ophthalmology, University of Warmia and Mazury, Olsztyn, Poland; 3Department of Physics, University of Texas, Arlington, TX, 4Byers Eye Institute of Stanford University, Palo Alto, CA, USA; 5School of Science and Technology, Nottingham Trent University, Nottingham, UK Purpose: To measure the maximum, objectively measured, accommodative amplitude, produced by pharmacologic stimulation.Methods: Thirty-seven healthy subjects were enrolled, with a mean age of 20.2±1.1 years, corrected visual acuity of 20/20, and mean spherical equivalent refraction (SER)=–0.83±1.60diopters. For each subject, the right pupil was dilated with phenylephrine 10%. After 30 minutes, the pupil was measured, the left eye was patched, and the right eye was autorefracted. Pilocarpine 4% was then instilled in the right eye, followed by phenylephrine. At 45 minutes after the pilocarpine, autorefraction and pupil size were again measured.Results: Mean pupil size pre- and postpilocarpine was 8.0±0.8 mm and 4.4±1.9 mm, respectively. Pre- and postpilocarpine, the mean SER was –0.83±1.60 and –10.55±4.26 diopters, respectively. The mean pilocarpine-induced accommodative amplitude was 9.73±3.64 diopters. Five subjects had accommodative amplitudes ≥14.00 diopters. Accommodative amplitude was not significantly related to baseline SER (p-value=0.24), pre- or postpilocarpine pupil size (p-values =0.13 and 0.74), or change in pupil size (p-value=0.37). Iris color did not statistically significantly affect accommodative amplitude (p-value =0.83).Conclusion: Following topically applied pilocarpine, the induced objectively measured accommodation in the young eye is greater than or equal to the reported subjectively measured voluntary maximum accommodative amplitude. Keywords: maximum, accommodative amplitude, objective, pilocarpine

Our purpose was to determine the changes in anterior chamber depth (ACD) and central lens thickness (CLT) during pharmacologically induced accommodation. Following pupillary dilation with phenylephrine 10%, baseline auto-refractions and swept-source optical coherence tomographic biometric images (Zeiss IOLMaster 700) were obtained from the right eyes of 25 subjects aged 19 to 24 years. Pilocarpine 4% and phenylephrine 10% were then instilled into these right eyes. One hour later, auto-refractions and biometric imaging were repeated. Only data from eight of 25 subjects met the following stringent criteria to be included in the study analysis: pre and post-pilocarpine biometric foveal images were registerable, the images of the corneal centers were shifted by ≤100 μm, pupils >5 mm and the pharmacologically induced refractive change was ≥ −7 diopters. The mean auto-refractive accommodative change for the eight included subjects was −12.45 diopters (± 3.45 diopters). The mean change in CLT was 81 μm (± 54 μm) and the mean change in ACD was −145 μm (± 86 μm). Superimposition of the registered pre and post-pilocarpine biometric images of the sagittal sections of the whole eye from each subject demonstrated that the position of the whole lens did not shift either anteriorly, posteriorly or vertically during pharmacologically induced accommodation. A small increase in lens thickness was associated with a large change in accommodative amplitude and no significant change in lens position as predicted by the Schachar theory.

Taprenepag isopropyl (PF-04217329) is a highly selective EP2 receptor agonist that reduces intraocular pressure (IOP) in animals and humans.1-3 In a 2-stage, phase 2 clinical trial of taprenepag, 28 days of monotherapy reduced IOP by approximately 6.5 mm Hg, comparable with 0.005% latanoprost in ocular hypertensive and open-angle glaucoma subjects.1 However, this positive efficacy was accompanied by treatment-related adverse events of conjunctival hyperemia, photophobia, and an increase in corneal thickness of mild to moderate severity within 7 days of dosing. The increased corneal thickness did not seem to be related to the dose of taprenepag or whether it was monotherapy or combination therapy. The cornea returned to its baseline thickness within approximately 1 month of discontinuing the medication.1 The formulation of taprenepag in these studies contained benzalkonium chloride, which has been shown to increase corneal thickness4; however, taprenepag vehicle and 0.005% latanoprost controls contained equivalent concentrations of benzalkonium chloride and did not induce significant changes in corneal thickness.1 In addition, these formulations of taprenepag did not induce increased corneal thickness in rabbits or dogs.2 Only at doses approximately 10 times the taprenepag dose tested clinically was an increase in corneal thickness observed in monkeys.3 This increase in corneal thickness in monkeys resolved within 2 weeks after discontinuation of taprenepag. Neither in vivo specular microscopy nor in vitro histological or transmission electron microscopic examination of the corneas of the monkeys that were killed revealed any taprenepag toxicity to the cornea or its endothelium.3 Confocal microscopy has emerged as an invaluable tool in the evaluation and diagnosis of many ocular surface disorders because it allows for a noninvasive, high-magnification evaluation of the corneal layers. Due to its ability to produce images in vivo at a microstructural level, it is increasingly used in both laboratory and clinical settings. Multiple in vivo animal and human studies have demonstrated that confocal microscopy is a reliable and effective method for detecting microscopic corneal abnormalities of the ocular surface.5-8 However, this technology has had limited use for the assessment of a topical medication on other layers of the cornea. The purpose of this study was to determine the etiology of taprenepag-related increase in corneal thickness with standard clinical testing along with analysis of in vivo confocal microscopic scan of the entire cornea. In particular, the measurement of changes in stromal reflectivity, as an indirect indicator of changes in corneal hydration, was explored to detect possibly subtle changes in this parameter that could provide an insight into the change in corneal thickness not clinically notable. The plan was to assess quantitatively and qualitatively confocal images of the corneal epithelium, midstromal keratocytes, and endothelium. In addition, the average light intensity reflected from the anterior stroma and midstroma was compared to determine whether the increased corneal thickness was due to a disturbance of the corneal epithelium or endothelium affecting this light intensity. If the epithelium was the origin, the anterior stroma should be excessively hydrated and scatter more light than the midstroma. If the endothelium was the origin, then the reverse should be true. By measuring the average light intensity, reflectivity, of the anterior stromal and midstromal images, the etiology of the increase in corneal thickness, and therefore hydration, should be suggested. Assessment of stromal reflectivity is more sensitive to subtle changes in corneal hydration than reflectivity of the superficial and/or basal corneal epithelium because of the normal increased light scattering from these layers and the potential confounding effect of cellular morphological change.

Accurate mathematical descriptions of the human crystalline lens surface shape are required to properly understand the nature of functional adaptations that occur when the lens shape alters to changes in refractive power. Using least squares method, the total mean normal distance, smoothness, rate of change of the transverse and sagittal radii of curvatures and continuity at the lens equator between eight mathematical functions: conic, figuring conicoid, generalized conic, Hermans conic patch, Urs polynomial, Urs 10th order Fourier series, Chien, and Giovanzana, and 17 human crystalline lenses were evaluated. The mean differences of the fits of all the equations to the whole lens and to the central 8 mm of the lens surfaces were >24 μm with comparable standard deviations. When considering fit smoothness and continuity at the equator, the Giovanzana and Chien functions are most representative of the lens surface.

Aim To determine the viscoelastic properties of fresh human lenses obtained from cadavers under 40 years of age. Methods 52 intact clear, human lenses were obtained from 26 donors (mean age of 27.5±9.2 years) within 9±4 h of death. The viscoelastic properties of the lens nuclei and 16 of the lens cortices were quantified within 42±10 h of death using a controlled-strain, linear, simple-shear rheometer. Results The means (±SD) of the viscoelastic properties of the lens nuclei at a frequency of 75 Hz were: elastic shear modulus, G′=11.00±4.67 Pa, viscous shear modulus, G′′=24.91±10.98 Pa, magnitude of the complex shear modulus, |G*|=27.23 Pa, dynamic viscosity, η′=0.33 Pa.s, damping ratio, ζ=2.26 and phase shift, δ=66.17°. There was no statistical difference in these measures between the lens cortices and their respective lens nuclei. There was a small age-related statistically significant increase in G′, p=0.003, but not G′′ or |G*|. Conclusions The observed age-related increase in tissue stiffness of the lens nucleus, ∼0.4 Pa/year, is too small to account for the 10 dioptre decline in accommodative amplitude in this age group.

Material properties of cornea and sclera are important for maintaining the shape of the eye and the requisite surface curvatures for optics. They also need to withstand the forces of external and internal musculature and fluctuations in intraocular pressure (IOP). These properties are difficult to measure and variable results have been reported. A previously published experimental procedure, from which the material properties of the eyeball coats were obtained, has been modelled in this paper using Finite Element Analysis, in order to test the accuracy of the experiment. Material parameters were calculated from the model and the resulting relationships between stress and strain for the cornea and sclera compared to their experimentally obtained counterparts. The comparison between model and experiment was close for the sclera but more varied for the cornea. The pressure vessel model can be applied for measuring the material properties of the sclera but is less accurate for the cornea.

Purpose Ligands for the proinflammatory C-C chemokine receptor types 2 and 5 (CCR2 and CCR5) are elevated in the eyes of patients with diabetic macular edema (DME). We evaluated the efficacy and safety of PF-04634817, an oral CCR2/5 dual antagonist, versus intravitreal ranibizumab, in adult subjects with DME. Methods In this phase II, randomized, placebo-controlled, double-masked study, eligible subjects (≥18 years of age) had type 1 or 2 diabetes and DME with best-corrected visual acuity (BCVA) of 20/32 or worse (letter score ≤ 78), and up to 20/320 or better (≥24 letter score), in the study eye. Subjects were assigned randomly 1:1 to once-daily (QD) oral PF-04634817 200 mg plus masked sham therapy as placebo or monthly intravitreal ranibizumab 0.3/0.5 mg plus QD oral placebo. The primary objective was to evaluate the efficacy of PF-04634817 compared with ranibizumab in change from baseline in BCVA after 12 weeks in a noninferiority design. Noninferiority was based on BCVA 80% confidence interval (CI): there had to be a less than three letter loss in the PF-04634817 arm compared with the ranibizumab arm. Results A total of 199 subjects were randomized. Least squares mean difference in change in BCVA from baseline to week 12 in the study eye for the PF-04634817 arm was -2.41 letters (80% CI: -3.91, -0.91; P = 0.04) compared with ranibizumab. PF-04634817 was well tolerated. Conclusions Treatment with oral CCR2/5 receptor dual antagonist PF-04634817 was associated with a modest improvement in BCVA, but did not meet the predefined noninferiority criteria compared with intravitreal ranibizumab.

The transparency of the eye lens is vital for maintenance of good image quality to the eye. This is lost when the lens develops a cataract which is a manifestation of changes to the structural proteins and their organisation. Understanding the complex arrangements and interactions of proteins in the lens and how these alter with opacification requires a means of probing the intact tissue. Nanoparticles offer such potential but need to be tested on lens cells and proteins to see whether they cause any detrimental changes. Cerium oxide nanoparticles (nanoceria) of around 5-6nm were prepared and characterised. A concentration of 10μg/ml was introduced into cell cultures from porcine eye lens epithelial cells and from a commercially available human cell line. Transmission electron microscopy of treated samples showed nanoparticles within cells. Proteins extracted from the cultured cells were subjected to chromatography and electrophoresis. Chromatographs and electrophoresis gels showed no difference between treated and control samples from human lens cell cultures. Some slight differences, between treated and control samples, were noted in porcine samples. The results suggest that introduction of nanoceria into cultured cells from the eye lens do not manifest any significant effects on chromatographic or electrophoretic profiles of eye lens proteins.

Aims. According to Hubble’s classification scheme, lenticular galaxies represent an intermediate evolutionary step between elliptical and spiral galaxies. This evolutionary path predicts that the aspect ratios of both lenticular and spiral galaxies should be smaller than the aspect ratios of their E6 or E7 elliptical predecessors. In contradiction to this prediction, observation has demonstrated that the aspect ratio of lenticular galaxies is larger than its immediate elliptical predecessor. In this paper, we suggest a novel explanation for this inconsistency. Methods. The approach described in this paper is primarily based on analytical methods; however, some numerical methods are also used. Results. Our idea comes from theoretical and experimental results, which show that a small increase in the equatorial diameter of an oblate spheroid with an aspect ratio ≤0.6 surprisingly causes its minor axis to also increase. We demonstrate that the same phenomenon occurs in the isodensity contours of elliptical galaxies given by Miyamoto & Nagai (Miyamoto M., & Nagai R., 1975, PASJ, 27, 533) and in a Maclaurin spheroidal mass in response to the gravitational force generated by a circumferential equatorial disk. Conclusions. The result of this paper is our explanation for the transformation of a disky elliptical galaxy into a lenticular galaxy which in response to rotation and equatorial diameter expansion evolves into a red spiral galaxy. This evolutionary path is consistent with the common environmental location of disky ellipticals, lenticular and red spiral galaxies and explains why elliptical galaxies are generally ≤E4. The proposed evolutionary path is opposite to the generally accepted formation of lenticular galaxies from the merger of spiral galaxies.

A nonlinear axisymmetric finite element method (FEM) analysis was employed to determine the critical geometric and material properties that affect human accommodation. In this model, commencing at zero, zonular traction on all lens profiles resulted in central lenticular surface steepening and peripheral surface flattening, with a simultaneous increase in central lens thickness and central optical power. An age-related decline in maximum zonular tension appears to be the most likely etiology for the decrease in accommodative amplitude with age.

Purpose To measure the radii of curvature of postmortem, whole, encapsulated human crystalline lenses, free of all zonular attachments, and to calculate their corresponding optical powers. Design Experimental study. Participants Thirty human crystalline lenses from donors with a mean age of 33.6±14.4 years. Methods Intact clear human crystalline lenses were obtained within an average of 21 hours of death. The lenses were removed from the eye by the contributing eye bank and shipped in Optisol-GS, a physiologic preservative storage medium. These lenses, with intact capsules, were freed of all zonular attachments. The lenses were stored at 7° C and were maintained in the same storage medium during the period that they were held for evaluation. Using a portable Keratron Scout corneal topographer (Eyequip, Ponte Vedra Beach, FL) fixed to an optical bench, the radii of curvatures of the anterior and posterior surfaces of the crystalline lens were measured daily for 10 days after receipt of the tissue. The capsules of the crystalline lenses remained intact, and the lenses were clear throughout the study. Measurements were made at room temperature after removing the lens from storage. Eight repetitions of the topography were made from each surface on each day to determine the accuracy and stability of the measurement. Profile photographs were taken daily to establish the central crystalline lens thickness. The corresponding optical power of each physiologically maintained crystalline lens was calculated. Main outcome measures The main outcome measures were the central anterior radius of curvature, the central posterior radius of curvature, the central thickness of each crystalline lens, and the amount of change in these parameters over 10 days. Results The means ± standard deviations of the central anterior and posterior radii of curvatures of the 30 adult lenses were 10.5±0.6 mm and 7.1±1.0 mm, respectively. The mean ± standard deviation of the central thickness, as measured from profile photographs, was 3.9±0.5 mm. These mean measurements remained stable for up to 5 days after receipt of the tissue. The mean and standard deviation of the calculated optical power of these postmortem, physiologically maintained, intact human crystalline lenses from donors with a mean age of 33.6 years was 19.8±1.7 diopters. Conclusions Lenses free of zonular tension are at an optical power that would be associated with optimal distance acuity.

A closed shell structured eyeball model was developed for predicting the displacements and curvatures in an eyeball due to radial keratotomy. Both the cornea and sclera are modeled as an ellipsoidal cap, and the two caps are connected at the limbus to form a closed shell. The analysis of the number of corneal collagen laminae required for the tissue to be theoretically transversely isotropic was presented. The cornea, as well as the limbus and sclera, is considered as macroscopically homogeneous and isotropic in this study. A procedure to obtain the principal curvature at a point on the exterior surface was established. In the basic formulation, large displacements are contemplated. However, the FORTRAN computer program that was prepared to implement the procedure considers small displacements, and the resulting equations are linear. Although the results from this shell structured eyeball model are fairly good quantitatively, they do show vividly the following qualitative corneal behavior after the operation is performed: The opening of an incision has a V-shape, the radial displacements through the corneal thickness are nearly the same, and the largest in-plane displacement is only one-tenth of the largest radial displacement. [S0148-0731(00)00705-6]

Aim: To determine the viscoelastic properties of the porcine lens Methods: Linear viscoelastic shear properties of the stroma of four porcine lenses were measured within 5 hours post-mortem, using sinusoidal oscillatory shear deformation. The elastic shear modulus, viscous shear modulus, dynamic viscosity, damping ratio, and phase shift of the lenses were quantified by a controlled-strain, linear simple-shear rheometer at frequencies of 10–50 Hz. Results: The mean viscoelastic properties and their standard deviations across the frequencies examined were: the elastic shear modulus, G′ = 6.2±4.0 Pa, the viscous shear modulus, G″ = 19.2±2.5 Pa, the dynamic viscosity, η′ = 0.16±0.1 Pa•sec, the damping ratio ζ = 4.06±1.25, and the phase shift, δ = 76°± 5.6°. Conclusions: The measured viscoelastic shear properties of the porcine lens reflect a low dynamic viscosity with a high damping ratio. The porcine lens is viscoelastic and is more viscous than elastic. The magnitude of the complex shear modulus of the porcine lens, |G*|, is similar to the shear modulus of the young human lens. Understanding these viscoelastic properties of the natural lens may provide guidance in developing a lens substitute capable of accommodation in the post cataract patient.

The movement of the human lens equator during accommodation was examined in vivo. High-resolution ultrasound images of the lens equator were obtained from young human subjects whose amplitude of accommodation was controlled with 1% tropicamide and 2% pilocarpine. To avoid errors that otherwise arise from eye rotation or other movement, the cornea and sclera were used as positional references in comparative studies of the video images obtained from the unaccommodated and accommodated states. During accommodation, the movement at the lens equator involved small displacement; i.e., < 100 microns, and the equator did not move anteriorly or posteriorly but peripherally toward the sclera. These results indicate that the lens equator is under increased zonular tension during accommodation, in contradiction to Helmholtz's widely accepted theory of accommodation.

Objective To evaluate the efficacy of different dosing paradigms of PF-04523655 (PF) versus ranibizumab (comparator) in subjects with neovascular age-related macular degeneration (AMD). Design Multicenter, open-label, prospective, randomized, comparator-controlled exploratory study. Participants A total of 151 patients with subfoveal choroidal neovascularization (CNV) secondary to neovascular AMD who were naive to AMD therapy. Methods In this phase 2 study, patients were randomized to 1 of 5 treatment groups with equal ratio. All groups received ranibizumab 0.5 mg at baseline and (a) PF 1 mg every 4 weeks (Q4W) from week 4 to week 12; (b) PF 3 mg Q4W from week 4 to week 12; (c) PF 3 mg every 2 weeks (Q2W) from week 4 to week 12; (d) PF 1 mg + ranibizumab (combination) Q4W from baseline to week 12; and (e) ranibizumab Q4W to week 12. All study treatments were given as intravitreal injections. Main Outcome Measures The primary end point was the mean change in best-corrected visual acuity (BCVA) from baseline at week 16; secondary end points included the percentage of patients gaining ≥10 and ≥15 letters in BCVA and mean change in retinal central subfield thickness, lesion thickness, and CNV area. Results At week 16, the PF 1 mg + ranibizumab combination group achieved numerically greater improvement in mean BCVA from baseline (9.5 letters) than the ranibizumab group (6.8 letters). The difference was not statistically significant. The BCVA improvement in the PF monotherapy groups was less than in the ranibizumab group. Similar trends were observed in the percentage of patients who gained ≥10 and ≥15 letters. From baseline to week 16 (last observed carried forward), the combination and ranibizumab groups had similar mean reductions in central subfield retinal thickness and total CNV area, which were greater than in all PF monotherapy groups. There were no clinically meaningful differences in reduction of lesion thickness among treatment groups. Conclusions In this early, underpowered study evaluating treatments for neovascular AMD, the combination of PF with ranibizumab led to an average gain in BCVA that was more than with ranibizumab monotherapy. No safety concerns were identified. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

To evaluate the safety of escalating doses of taprenepag isopropyl (PF-04217329), a selective EP(2) receptor agonist administered as a topical ophthalmic solution, versus its vehicle (Stage I), and dose-response of taprenepag isopropyl alone and in unfixed combination with latanoprost ophthalmic solution 0.005% versus latanoprost alone (Stage II).Randomized, vehicle- and active-controlled, double-masked, two-stage, dose-finding trial in primary open-angle glaucoma (POAG) or ocular hypertension; first taprenepag isopropyl study in patients (NCT00572455). Study eye: 26 mmHg ≤ intraocular pressure (IOP)36 mmHg at 8 am and 22 mmHg ≤ IOP36 mmHg at 10 am, 1 pm, 4 pm. Stage I: 3 cohorts (total n = 67) received 1 drop of taprenepag isopropyl unit dose formulation qPM/eye for 14 days: low dose: 0.0025%, 0.005%, vehicle; middle dose: 0.01%, 0.015%, vehicle; high dose: 0.02%, 0.03%, vehicle. Stage II: 7 groups (total n = 250) received 1 drop of taprenepag isopropyl multidose formulation qPM/eye for 28 days: 0.005%, 0.01%, 0.015% monotherapy; each in unfixed combination with latanoprost 0.005%, or latanoprost monotherapy.mean change in diurnal IOP, baseline to last visit; adverse events.Stage I at day 14: statistically significantly greater IOP reductions were observed at all taprenepag isopropyl doses versus vehicle. Stage II at day 28: statistically significantly greater IOP reductions were observed at all doses of the unfixed combination versus latanoprost monotherapy. At least 1 treatment-emergent adverse event reported for 29/67 (43.3%) subjects in Stage I and 158/250 (63.2%) in Stage II.Taprenepag isopropyl significantly reduces IOP in POAG and ocular hypertension. Taprenepag isopropyl monotherapy is comparable to latanoprost 0.005% in reducing IOP. As demonstrated in this report, the activity of taprenepag isopropyl is additive to that of latanoprost 0.005%. Further studies are required to determine whether it shows similar additivity when administered with other ocular antihypertensive medications.

Nanotechnology has the potential for treating diseases and conditions of ageing. The eye is particularly vulnerable, because chronic pathologies can lead to sight loss. Human lens epithelial cells were exposed to 10, 20, and 100 μg/mL of negatively charged nanoceria for 48 and 72 hours; DNA damage and cell growth were assessed. Concentrations up to 100 μg/mL for 48 hours did not cause measurable genotoxic effects. For exposures of 72 hours, concentrations above 10 μg/mL showed small but statistically significant differences in DNA damage from negative controls. All treated samples were less damaged than positive controls. Cell growth, monitored for up to 7 days, did not show deviations in cell morphology or growth between treated and untreated samples. Whereas time of exposure may have greater effect than dosage, indicating potential for genotoxicity at higher exposures, human lens epithelial cells can sustain normal growth when exposed to concentrations of nanoceria of up to 100 μg/mL. From the Clinical Editor Human lens epithelial cells were exposed to various concentrations of negatively charged nanoceria for 48 and 72 hours to assess DNA damage and cell growth. The authors demonstrate that epithelial cells can sustain normal growth when exposed to concentrations of up to 100 μg/mL, with time of exposure having a greater effect than dosage, indicating potential genotoxicity at higher exposures.

In order to obtain the curvature changes of the exterior surface of a shell subjected to an internal pressure, it is necessary to evaluate the displacement derivatives up to the second order. To this end, a hexahedronal element is developed with three-dimensional elastic properties utilized. At a nodal point on the surface of the shell, the first-order derivatives of the three displacement components are used as degrees of freedom (d.o.f.) in addition to the components themselves. However, at a nodal point not on the surface, only the three displacement components are used. Therefore, an element with aii exterior surface has a total of 48 d.o.f. and other elements have 24 d.o.f. The stiffness matrix of the 8-node subparametric hexahedronal high-order element is derived from the strain energy consideration. The cubic shape functions in the surface co-ordinates and linear shape functions through the shell thickness are used. The second derivatives of displacement components are continuous at any point on the exterior surface of the element, although they may not be continuous across the nodal line of two adjacent elements.

The scleral expansion band procedure (SRP) reverses presbyopia and increses the baseline tension of the ciliary muscle, which increases the trabecular meshwork pore size. By increasing the pore size, SRP is a new therapeutic and preventive modality for ocular hypertension and primary open-angle glaucoma.

Inclusion of nonchanging positional references I read with interest the correspondence concerning Marchini et al.’s ultrasound biomicroscopic (UBM) observations of anterior movement of monofocal intraocular lenses (IOLs) during accommodation in pseudophakic eyes. Unfortunately, Marchini et al. did not incorporate unchanging positional references in the compared images to ensure image correspondence. Examination of the compared figures in Marchini et al.’s article reveals perspective distortion that precludes an objective measure of the change in position of themonofocal IOL during accommodation. Asnoted inFigures 1 to 3,which are reproductions of Marchini et al.’s Figures 3 to 5, the center of the

Corneal and scleral thickness and anterior chamber dimensions are required for understanding developmental and pathological processes. Parameters of the eyeball are also required to calculate optical and material properties. As the eyeball resembles a pressure vessel, it has been suggested that elasticity of the cornea and sclera could be calculated from the measurements of thickness. Baseline corneal and scleral thicknesses and anterior chamber dimensions and how these change with incremental increases of intraocular fluid are measured in fresh porcine eyes using the Visante OCT (optical coherence tomography). At baseline, corneal thickness is almost constant. Anterior scleral thickness is variable, decreasing from 0.91 +/- 0.07 mm near the limbus to a minimum of 0.58 +/- 0.13. Posterior scleral thickness is more constant with an average of 0.78 +/- 0.09 mm. Near the optic nerve the thickness increases to 1.00 +/- 0.09 mm. Average baseline anterior chamber angle, diameter, and depth were found to be 33.15 +/- 4.91 deg, 13.60 +/- 0.38 mm, and 2.13 +/- 0.22 mm, respectively. After fluid injections, maximum changes in corneal and scleral thicknesses were 9 to 10 and 1 to 3%, respectively. Anterior chamber angle and depth decreased slightly but significantly. Changes in the eyeball coats with fluid injections, indicate that the pressure vessel model can be applied to the eye to calculate corneal and scleral elasticities. (C) 2008 Society of Photo-Optical Instrumentation Engineers.

Purpose: To determine the qualitative change in stress on the lens capsule during in vivo human accommodation. Methods: Nine subjects (mean age: 30 years; range: 25–38 years) were studied, each of whom had undergone a phakic refractive intraocular lens (PRL) surgical procedure. The change, during accommodation, of stress on the surface of the anterior lens capsule (ALS) was determined by employing high-resolution anterior segment optical coherence tomography (OCT). This was done by comparing the ratio of the intensity of the image from the anterior surface of the natural lens (ALS) to the images of the anterior corneal surface (ACS), posterior corneal surface (PCS) and the posterior surface of the phakic refractive intraocular lens (PPRLS) before and during accommodation. Results: The intensities of the OCT images of the ACS and PPRLS did not significantly change during accommodation when compared with their respective baselines, while the intensity ratios: ALS/ACS, ALS/PCS and ALS/PPRLS all significantly increased during accommodation (p Conclusions: The stress on the anterior lens capsule is increased during in vivo human accommodation. This observation is consistent with a mechanism of accommodation in which zonular tension increases with accommodation, which is opposite to the predictions of the Helmholtz theory.

Aim: To determine the effect of human in vivo accommodation on the stability of the crystalline lens. Methods: Using a dual Purkinje image (DPI) eyetracker, the phase-time difference and amplitudes of Purkinje images I (P-I) and IV ( P-1V) were measured in 37 normal emmetropic subjects ( 34 women and 3 men; mean age 19.8, range 18-22 years) when they changed focus from 70 to 15 cm and simultaneously rotated their heads horizontally from side to side or made horizontal saccades between two targets 6.8 apart. Results: When the subjects changed focus from 70 to 15 cm and rotated their heads or made eye saccades, the phase-time difference between P-I and P-IV decreased. During saccades, the amplitude of both PI and PIV overshoots significantly increased with focus at 15 cm; however, their ratio (P-IV overshoot amplitude/P-I overshoot amplitude) significantly declined. Conclusions: The lens is stable during accommodation. The implications of these findings on the mechanism of accommodation are discussed.

Aim: To measure corneal and scleral radii of curvature in response to intraocular pressure (IOP). Methods: Using digital photographic profile images of 16 fresh porcine eyes, the curvatures of the cornea and sclera were determined in response to five consecutive incremental 100 mu l saline intravitreal injections. IOP was measured and ocular rigidity calculated. Elastic moduli of the cornea and sclera were estimated. Results: Intraocular pressure and the radius of curvature of the sclera increased linearly with increasing volume. There was no statistical change in corneal curvature. The elasticity of the cornea and sclera was constant during the 15-50 mm Hg increase in IOP. The estimated range of the elastic moduli of the cornea and sclera were, respectively 0.07-0.29 MPa and 0.2 MPa to 0.5 MPa. The scleral rigidity ranged from 0.0017 to 0.0022. Conclusions: The elastic moduli of the cornea and sclera are independent of IOP. The modulus of elasticity of the sclera is higher than that of the cornea. Elevation of IOP changes the curvature of the sclera but not that of the cornea. Porcine scleral rigidity is similar to human scleral rigidity. Scleral curvature could be a novel method for measuring IOP.

Aim: To determine the relationship between accommodative amplitude and central lens thickness/equatorial lens diameter (CLT/ELD) ratio in vertebrates. Methods: Midsagittal sections of lenses from fixed, post mortem eyes from 125 different vertebrate species were photographed. Their CLT/ELD ratios were correlated with independently published measurements of their accommodative amplitudes. Using the non-linear finite element method (FEM), the efficiency of zonular traction (the absolute change in central radius of curvature per unit force [|ΔCR|/F]) for model lenses with CLT/ELD ratios from 0.45 to 0.9 was determined. Results: Vertebrates with CLT/ELD ratios ⩽0.6 have high accommodative amplitudes. Zonular traction was found to be most efficient for those model lenses having CLT/ELD ratios ⩽0.6. Conclusions: Vertebrates with lenses that have CLT/ELD ratios ⩽0.6 – i.e. “long oval” shapes – have the greatest accommodative amplitudes; e.g. primates, diving birds and diurnal birds of prey. Vertebrates that have oval or spherical shaped lenses, like owls and most mammals, have low accommodative amplitudes. Zonular traction was found to be most efficient when applied to model lenses with CLT/ELD ratios ⩽0.6. The implications of these findings on the mechanism of accommodation are discussed.

Aim: To understand the effect of the geometric and material properties of the lens on the age-related decline in accommodative amplitude. Methods: Using a non-linear finite-element model, a parametric assessment was carried out to determine the effect of stiffness of the cortex, nucleus, capsule and zonules, and that of thickness of the capsule and lens, on the change in central optical power (COP) associated with zonular traction. Convergence was required for all solutions. Results: Increasing either capsular stiffness or capsular thickness was associated with an increase in the change in COP for any specific amount of zonular traction. Weakening the attachment between the capsule and its underlying cortex increased the magnitude of the change in COP. When the hardness of the total lens stroma, cortex or nucleus was increased, there was a reduction in the amount of change in COP associated with a fixed amount of zonular traction. Conclusions: Increasing lens hardness reduces accommodative amplitude; however, as hardness of the lens does not occur until after the fourth decade of life, the age-related decline in accommodative amplitude must be due to another mechanism. One explanation is a progressive decline in the magnitude of the maximum force exerted by the zonules with ageing.