In vivo performance of melimine as an antimicrobial coating for contact lenses in models of CLARE and CLPU

Purpose: One strategy to minimize bacteria-associated adverse responses such as microbial keratitis, contact lens–induced acute red eye (CLARE), and contact lens induced peripheral ulcers (CLPUs) that occur with contact lens wear is the development of an antimicrobial or antiadhesive contact lens. Cationic peptides represent a novel approach for the development of antimicrobial lenses.---------- Methods: A novel cationic peptide, melimine, was covalently incorporated into silicone hydrogel lenses. Confirmation tests to determine the presence of peptide and anti-microbial activity were performed. Cationic lenses were then tested for their ability to prevent CLPU in the Staphylococcus aureus rabbit model and CLARE in the Pseudomonas aeruginosa guinea pig model. ---------- Results: In the rabbit model of CLPU, melimine-coated lenses resulted in significant reductions in ocular symptom scores and in the extent of corneal infiltration (P < 0.05). Evaluation of the performance of melimine lenses in the CLARE model showed significant improvement in all ocular response parameters measured, including the percentage of eyes with corneal infiltrates, compared with those observed in the eyes fitted with the control lens (P ≤ 0.05). ---------- Conclusions: Cationic coating of contact lenses with the peptide melimine may represent a novel method of prevention of bacterial growth on contact lenses and consequently result in reduction of the incidence and severity of adverse responses due to Gram-positive and -negative bacteria during lens wear.

Cone Ratios in Myopia and Emmetropia: A Pilot Study

Purpose There is a suggestion that the long wavelength-sensitive (LWS)-to-middle wavelength-sensitive (MWS) cone ratio in the retina is associated with myopia. The aim was to measure the LWS/MWS amplitude modulation ratio, an estimate of the LWS/MWS cone ratio, in young adult emmetropes and myopes. Methods Multifocal visual evoked potentials were measured when the LWS and MWS cone systems were excited separately using the method of silent substitution. The 30 young adult participants (22 to 33 years) included 10 emmetropes (mean [±SD] refraction, +0.3 [±0.4] diopters [D]) and 20 myopes (mean [±SD] refraction, -3.4 [±1.7] D). Results The LWS/MWS amplitude modulation ratios ranged from 0.56 to 1.80 in the central 3- to 13-degree diameter ring and from 0.94 to 1.91 in the peripheral 13- to 30-degree diameter ring. Within the central ring, the mean (±SD) ratios were 1.20 (±0.26) and 1.20 (±0.33) for the emmetropic and the myopic groups, respectively. For the peripheral ring, the mean (±SD) ratios were 1.48 (±0.27) and 1.30 (±0.27), respectively. There were no significant differences in the ratios between the emmetropic and myopic groups for either the central (p = 0.99) or peripheral (p = 0.08) rings. For the latter, more myopic refractive error was associated with lower LWS/MWS amplitude modulation ratio; the refraction explained 16% (p = 0.02) of variation in ratio. Conclusions The relationship between the LWS/MWS amplitude modulation ratios and refraction at 13 to 30 degrees indicates that a large longitudinal study of changes in refraction in persons with known cone ratio is required to determine if a low LWS/MWS cone ratio is associated with myopia development.

Optics of the human eye in diabetes

This study compared optics of eyes in people with diabetes with those age-balanced controls. Relative to the control group, the diabetes group demonstrated greater lens thickness, more curved lens shapes, smaller lens diameters, higher light scatter, greater lens yellowing, and poorer focusing ability. While the optics of the people with diabetes made them appear as older eyes than those of people of the same age without diabetes, the differences did not increase significantly with age. It was concluded that age-related changes in eyes of people with diabetes need not be accelerated if the diabetes is well controlled.

3D refraction correction and extraction of clinical parameters from spectral domain optical coherence tomography of the cornea.

Capable of three-dimensional imaging of the cornea with micrometer-scale resolution, spectral domain-optical coherence tomography (SDOCT) offers potential advantages over Placido ring and Scheimpflug photography based systems for accurate extraction of quantitative keratometric parameters. In this work, an SDOCT scanning protocol and motion correction algorithm were implemented to minimize the effects of patient motion during data acquisition. Procedures are described for correction of image data artifacts resulting from 3D refraction of SDOCT light in the cornea and from non-idealities of the scanning system geometry performed as a pre-requisite for accurate parameter extraction. Zernike polynomial 3D reconstruction and a recursive half searching algorithm (RHSA) were implemented to extract clinical keratometric parameters including anterior and posterior radii of curvature, central cornea optical power, central corneal thickness, and thickness maps of the cornea. Accuracy and repeatability of the extracted parameters obtained using a commercial 859nm SDOCT retinal imaging system with a corneal adapter were assessed using a rigid gas permeable (RGP) contact lens as a phantom target. Extraction of these parameters was performed in vivo in 3 patients and compared to commercial Placido topography and Scheimpflug photography systems. The repeatability of SDOCT central corneal power measured in vivo was 0.18 Diopters, and the difference observed between the systems averaged 0.1 Diopters between SDOCT and Scheimpflug photography, and 0.6 Diopters between SDOCT and Placido topography.

Effect of position of near addition in an asymmetric refractive multifocal intraocular lens on quality of vision

Purpose
To evaluate the impact of the position of an asymmetric multifocal near segment on visual quality.

Setting
Cathedral Eye Clinic, Belfast, United Kingdom.

Design
Retrospective comparative case series.

Methods
Data from consecutive patients who had bilateral implantation of the Lentis Mplus LS-312 multifocal intraocular lens were divided into 2 groups. One group received inferonasal near-segment placement and the other, superotemporal near-segment placement. A +3.00 diopter (D) reading addition (add) was used in all eyes. The main outcome measures included uncorrected distance visual acuity (UDVA), uncorrected near visual acuity (UNVA), contrast sensitivity, and quality of vision. Follow-up was 3 months.

Results
Patients ranged in age from 43 to 76 years. The inferonasal group comprised 80 eyes (40 patients) and the superotemporal group, 76 eyes (38 patients). The mean 3-month spherical equivalent was −0.11 D ± 0.49 (SD) in the inferonasal group and −0.18 ± 0.46 D in the superotemporal group. The mean postoperative UDVA was 0.14 ± 0.10 logMAR and 0.18 ± 0.15 logMAR, respectively. The mean monocular UNVA was 0.21 ± 0.14 logRAD and 0.24 ± 0.13 logRAD, respectively. No significant differences were observed in the higher-order aberrations, total Strehl ratio (point-spread function), or modulation transfer function between the groups. Dysphotopic symptoms measured with a validated quality-of-vision questionnaire were not significantly different between groups.

Conclusion
Positioning of the near add did not significantly affect objective or subjective visual function parameters.

Rapid, objective detection of cataract-induced blur using a bull's eye photodetector.

PURPOSE: To determine whether optical aberrations caused by cataract can be detected and quantified objectively using a newly described focus detection system (FDS). SETTING: The Wilmer Opthalmological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. METHODS: The FDS uses a bull's eye photodetector to measure the double-pass blur produced from a point source of light. To determine the range and level of focus, signals are measured with a series of trial lenses in the light path selected to span the point of best focus to generate focus curves. The best corrected visual acuity (BCVA), refractive error, lens photograph grades, and FDS signals were obtained in 18 patients scheduled to have cataract surgery. The tests were repeated 6 weeks after surgery. RESULTS: The mean FDS outcome measures improved after cataract surgery, with increased peak height (P=.001) and decreased peak width (P=.001). Improvement in signal strength (integral of signal within +/-1.5 diopters of the point of best focus) strongly correlated with improvement in peak height (R(2)=.88, P<.0001) and photographic cataract grade (R(2)=.72, P<.0001). The mean BCVA improved from 20/50 to 20/26 (P<.0001). The improvement in BCVA correlated more closely with FDS signal strength (R(2)=.44, P=.001) than with cataract grade (R(2)=.25, P=.06). CONCLUSIONS: Improvement in FDS outcome measures correlated with cataract severity and improvement in visual acuity. This objective approach may be useful in long-term studies of cataract progression.

Corneal staining and cell shedding during the development of solution-induced corneal staining

Purpose. This non-dispensing cross-over study was conducted to determine if lenses presoaked in Opti-Free RepleniSH (OFR) or ReNu MultiPlus (RMP) cause solution-induced corneal staining (SICS) and subsequent cell sloughing before the typical 2 h in vivo examination point.

Methods. Study lenses (PureVision) were worn bilaterally by 13 participants for periods of 15, 30, 60, and 120 min using two different contralateral care regimen pairings. The lens worn on the test eye was soaked overnight in either OFR or RMP and the control eye in Clear Care (CC). After lens removal, corneal staining was rated on a scale of 0 (negligible) to 100 (severe) for four peripheral quadrants and the central region, and the differential global staining score was calculated by subtracting baseline staining scores. Following the staining assessment, corneal cells were collected from the ocular surface using a non-contact irrigation system to determine ocular cell shedding rates.

Results. Differential global staining score with OFR was greater than CC with the differences being statistically significant at 30 and 60 min (p < 0.01). Maximum staining with RMP was significantly greater than OFR and peaked after 60 and 120 min of lens wear (p < 0.01). On average, 710 ± 470 ocular cells were collected after lens wear, with similar shedding seen independent of solution or lens wear duration (p > 0.05).

Conclusions. SICS occurred earlier but to a significantly lower degree when PureVision lenses were presoaked in OFR compared with RMP, while lenses presoaked in CC did not cause SICS. Ocular surface cell shedding after lens removal was not impacted by lens wear durations of <=2 h.

In vivo chromatic aberration in eyes implanted with intraocular lenses

Purpose. To measure in vivo and objectively the monochromatic aberrations at different wavelengths, and the chromatic difference of focus between green and infrared wavelengths in eyes implanted with two models of intraocular lenses (IOL).


Methods. Eighteen eyes participated in this study: nine implanted with Tecnis ZB99 1-Piece acrylic IOL and nine implanted with AcrySof SN60WF IOL. A custom-developed laser ray tracing (LRT) aberrometer was used to measure the optical aberrations, at 532 nm and 785 nm wavelengths. The monochromatic wave aberrations were described using a fifth-order Zernike polynomial expansion. The chromatic difference of focus was estimated as the difference between the equivalent spherical errors corresponding to each wavelength.


Results. Wave aberration measurements were highly reproducible. Except for the defocus term, no significant differences in high order aberrations (HOA) were found between wavelengths. The average chromatic difference of focus was 0.46 ± 0.15 diopters (D) in the Tecnis group, and 0.75 ± 0.12 D in the AcrySof group, and the difference was statistically significant (P < 0.05). Chromatic difference of focus in the AcrySof group was not statistically significantly different from the Longitudinal chromatic aberration (LCA) previously reported in a phakic population (0.78 ± 0.16 D). The impact of LCA on retinal image quality (measured in terms of Strehl ratio) was drastically reduced when considering HOA and astigmatism in comparison with a diffraction-limited eye, yielding the differences in retinal image quality between Tecnis and AcrySof IOLs not significant.


Conclusions. LRT aberrometry at different wavelengths is a reproducible technique to evaluate the chromatic difference of focus objectively in eyes implanted with IOLs. Replacement of the crystalline lens by the IOL did not increase chromatic difference of focus above that of phakic eyes in any of the groups. The AcrySof group showed chromatic difference of focus values very similar to physiological values in young eyes.

Clinical and quality of life data correlation with a single-optic accommodating intraocular lens

Purpose: To examine a single-optic accommodating intraocular lens (IOL) visual performance by correlating IOL implanted eyes’ defocus curve with the intraocular aberrometric profile and the impact on the quality of life (QOL). Methods: Prospective consecutive case series study including a total of 25 eyes of 14 patients with ages ranging between 52 and 79 years old. All cases underwent cataract surgery with implantation of the single-optic accommodating IOL Crystalens HD (Bausch & Lomb). Distance and near visual acuity outcomes, intraocular aberrations, the defocus curve and QOL (NEI VFQ-25) were evaluated 3 months after surgery. Results: A significant improvement in distance visual acuity was found postoperatively (p = 0.02). Mean postoperative LogMAR uncorrected near visual acuity was 0.44 ± 0.23 (20/30). 60% of eyes had a postoperative addition between 0 and 1.5 diopters (D). The defocus curve showed an area of maximum visual acuity for the levels of defocus corresponding to distance and intermediate vision (−1 to +0.5 D). Postoperative intermediate visual acuity correlated significantly some QOL indices (r ≥ 0.51, p ≤ 0.03; difficulty in going down steps or seeing how people react to things that patient says) as well as with J0 component of manifest cylinder. Postoperative distance-corrected near visual acuity correlated significantly with age (r = 0.65, p < 0.01). Conclusions: This accommodating IOL seems to be able to restore the distance visual function as well as to provide an improvement in intermediate and near vision with a significant impact on patient's QOL, although limited by age and astigmatism. Future studies with larger sample sizes should confirm all these trends.

The posterior chamber phakic refractive lens (PRL): a review

Implantation of phakic intraocular lenses (pIOLs) is a reversible refractive procedure, preserving the patient’s accommodative function with minimal induction of higher order aberrations compared with corneal photoablative procedures. Despite this, as an intraocular procedure, it has potential risks such as cataracts, chronic uveitis, pupil ovalization, corneal endothelial cell loss, pigmentary dispersion syndrome, pupillary block glaucoma, astigmatism, or endophthalmitis. Currently, only two models of posterior chamber pIOLs are commercially available, the implantable collammer lens (STAAR Surgical Co.) and the phakic refractive lens (PRL; Zeiss Meditec). The number of published reports on the latter is very low, and some concerns still remain about its long-term safety. The present article reviews the published literature on the outcomes after PRL implantation in order to provide a general overview and evaluate its real potential as a surgical refractive option.

Fixed Mydriatic Pupil Associated with an Intraocular Pressure Rise as a Complication of the Implant of a Phakic Refractive Lens (PRL)

We describe a case report of a patient that was implanted with a posterior chamber phakic intraocular lens (Phakic Refractive Lens, PRL) for the correction of moderate myopia and who developed postoperatively a fixed mydriasis compatible with an Urrets-Zavalia Syndrome (UZS). Specifically, a sudden acute increase of IOP in the left eye was observed in the immediate postoperative period. After IOP stabilization, the refractive result was good, but a fixed and mydriatic pupil appeared. This condition led the patient to experience visual discomfort, halos, and glare associated with high levels of higher-order aberrations in spite of the good visual result. A tinted-contact lens was fitted in order to minimize those symptoms. The UZS should be considered as a possible complication after implantation of posterior chamber phakic intraocular lenses.

Anterior segment anomalies and effects on visual quality

The tear film, cornea and lens dictate the refractive power of the eye and the retinal image quality is principally defined by diffraction, whole eye wavefront error, scatter, and chromatic aberration. Diffraction and wave aberration are fundamentally pupil diameter dependent; however scatter can be induced by refractive surgery and in the normal ageing eye becomes an increasingly important factor defining retinal image quality. The component of visual quality most affected by the tear film, refractive surgery and multifocal contact and intraocular lenses is the wave aberration of the eye. This body of work demonstrates the effects of each of these anomalies on the visual quality of the eye. When assessing normal or borderline self-diagnosed dry eye subjects using aberrometry, combining lubricating eye drops and spray does not offer any benefit over individual products. However, subjects perceive a difference in comfort for all interventions after one hour. Total higher order aberrations increase after laser assisted sub-epithelial keratectomy performed using a solid-state laser on myopes, but this causes no significant decrease in contrast sensitivity or increase in glare disability. Mean sensitivity and reliability indices for perimetry were comparable to pre-surgery results. Multifocal contact lenses and intraocular lenses are designed to maximise vision when the patient is binocular, so any evaluation of the eyes individually is confounded by reduced individual visual acuity and visual quality. Different designs of aspheric multifocal contact lenses do not provide the same level of visual quality. Multifocal contact lenses adversely affect mean deviation values for perimetry and this should be considered when screening individuals with multifocal contact or intraocular lenses. Photographic image quality obtained through a multifocal contact or intraocular lens appears to be unchanged. Future work should evaluate the effect of these anomalies in combination; with the aim of providing the best visual quality possible and supplying normative data for screening purposes.

THE IMPORTANCE OF MHC-INDEPENDENT NATURAL KILLER CELL RECEPTORS IN THE IMMUNOREGULATION OF MURINE PREGNANCY

Numerous leukocyte populations are essential for pregnancy success. Uterine natural killer (uNK) cells are chief amongst these leukocytes and represent a unique lineage with limited cytotoxicity but abundant angiokine production. They possess a distinct phenotype of activating and inhibitory receptors that recognize major histocompatibility complex (MHC) molecules, such as the killer immunoglobulin like receptors (KIRs; mouse Ly49), and MHC-independent activating receptors, including the aryl hydrocarbon receptor (AHR) and natural cytotoxicity receptor 1 (NCR1). While the roles of MHC-dependent receptors are widely addressed in pregnancy, MHC-independent receptors are relatively unstudied. This thesis investigated the roles of MHC-independent receptors in promotion of mouse pregnancy and characterized early leukocyte interactions in the presence and absence of NCR1. It was hypothesized that loss of MHC-independent receptors impairs uNK cell development resulting in aberrations in leukocyte function and decidual vasculature. Implantation sites from Ahr-/- and Ncr1Gfp/Gfp mice were assessed using whole mount in situ immunohistochemistry (WM-IHC) and histochemical techniques. Leukocyte interactions identified during preliminary WM-IHC studies were confirmed as immune synapses. The novel identification of immune synapses in early mouse pregnancy compelled further examination of leukocyte conjugates in wildtype C57BL/6 and Ncr1Gfp/Gfp mice. In Ahr-/- and Ncr1Gfp/Gfp mice, receptor loss resulted in reduced uNK cell diameters, impaired decidual vasculature, and failures in spiral artery remodeling. Ahr-/- mice had severe fertility deficits whereas Ncr1Gfp/Gfp mice had increased fetal resorption indicating differing receptor requirements in pregnancy success. NCR1 loss primarily affected uNK cell maturation and function as identified by alterations in granule ultrastructure, lytic protein expression, and angiokine production. Leukocyte conjugates were frequent in early C57BL/6 decidua basalis and included uNK cells conjugating first with antigen presenting cells and then with T cells. Overall conjugate formation was reduced in the absence of NCR1, but specific uNK cell conjugations were unaffected by receptor loss. While KIR-MHC interactions are associated with numerous pregnancy complications in humans, the role of other uNK cell receptors are not well characterized. These results illustrate the importance of MHC-independent receptors in uNK cell activation during early pregnancy in mice and encourage further studies of pregnancy complications that may occur independently of maternal KIR-MHC contributions.

Biomimetic accommodating intraocular lens

The crystalline lens allows the eye to focus on near and far objects. During the aging process, it loses its ability to focus and often becomes cloudy during cataract formation. At this point, traditional medical therapy replaces the lens with an artificial replacement lens. Although replacement lenses for the crystalline lens have been implanted since 1949 for cataract surgery, none of the FDA-approved lenses mimic the anatomy of the natural lens. Hence, they are not able to focus in a manner similar to the youthful lens. Instead, they function in a manner similar to the aged lens and only provide vision at a single distance or at a very limited range of focal distances. Patients with the newest implants are often obliged to use reading glasses when using near vision, or suffer from optical aberrations, halos, or glare. Therefore, there is a need to provide youthful vision after lens surgery in terms of focusing ability, accurate optical power, and sharp focus without distortion or optical aberrations.

This thesis presents an approach to restoring youthful vision after lens replacement. An intraocular lens (IOL) that can provide accurate visual acuity along with focusing ability is proposed. This IOL relies on the natural anatomy and physiology of the eye, and therefore is actuated in a manner identical to the natural lens. In addition, the lens has the capability for adjustment during or after implantation to provide high-acuity vision throughout life.

The natural anatomy and physiology of the eye is described, along with lens replacement surgery. A lens design is proposed to address the unmet need of lens-replacement patients. Specific care in the design is made for small surgical incisions, high visual acuity, adjustable acuity over years, and the ability to focus similar to the natural lens. Methods to test the IOL using human donor tissue are developed based upon prior experiments on the ex vivo natural lens. These tools are used to demonstrate efficacy of the newly developed accommodating intraocular lens.

To further demonstrate implant feasibility, materials and processes for building the lens are evaluated for biocompatibility, endurance, repeatable manufacture, and stability. The lens biomechanics are determined after developing an artificial anatomy testing setup inspired by the natural anatomy of the human focusing mechanism. Finally, based upon a mechanical and optical knowledge of the lens, several improved lens concepts are proposed and demonstrated for efficacy.