<p> <b>Overview:</b> Optical concepts as they relate to the ophthalmologic correction of vision in corneal laser vision correction and intraocular lens design was examined. </p><p> <b>Purpose:</b> The interaction between the excimer laser and residual corneal tissue in laser vision correction produces unwanted side effects. Understanding the origin of these artifacts can lead to better procedures. Furthermore, accommodating intraocular lenses offer a potential for eliminating presbyopia. Understanding the properties of a new accommodating intraocular lens incorporating a deformable interface may lead to advances in cataract surgery. </p><p> <b>Introduction:</b> Corneal surface irregularities following laser refractive procedures are commonly seen. They regularly result in a patient&rsquo;s decreased best corrected visual acuity and decreased contrast sensitivity. These changes are only seen in biologic tissue and the etiology has been elusive. A thermal response has been theorized and was investigated in this research. In addition, intraocular lenses using a mechanically deforming interface to change their power in order to duplicate natural accommodation have been developed. The deforming interface(s) induce optical aberrations due to irregular deformations. Design efforts have centered on minimizing these deformations. Both of the ophthalmic applications have been analyzed using finite element analysis (FEA) to understand their inherent optical properties. </p><p> <b>Methods:</b> FEA modeling of thermal theory has been applied to verify that excimer laser induced collagen contraction creates corneal surface irregularities and central islands. A mathematical model which indicates the viability of the theory was developed. The modeling results were compared to post ablation changes in eyes utilizing an excimer (ArF 193 nm), as well as non-ablative thermal heating in eyes with a CO₂ laser. </p><p> Addition modeling was performed on an Intraocular lens prototype measuring of actuation force, lens power, interface contour, optical transfer function, and visual Strehl ratio. Prototype verified mathematical models were utilized to optimize optical and mechanical design parameters to maximize the image quality and minimize the required force. </p><p> Results: The predictive model shows significant irregular central buckling formation and irregular folding. The amount of collagen contraction necessary to cause significant surface changes is very small (0.3%). Uniform scanning excimer laser ablation to corneal stroma produces a significant central steepening and peripheral flattening in the central 3mm diameter. Isolated thermal load from uniform CO₂ laser irradiation without ablation also produces central corneal steepening and paracentral flattening in the central 3mm diameter. </p><p> The iterative mathematical modeling based upon the intraocular lens prototype yielded maximized optical and mechanical performance through varied input mechanical and optical parameters to produce a maximized visual Strehl ratio and a minimized force requirement. </p><p> <b>Conclusions:</b> The thermal load created by laser irradiation creates a characteristic spectrum of morphologic changes on the porcine corneal stromal surface which correlates to the temperature rise and is not seen inorganic, isotropic material. The highly similar surface changes seen with both lasers are likely indicative of temperature induced transverse collagen fibril contraction and stress re-distribution. Refractive procedures which produce significant thermal load should be cognizant of these morphological changes. </p><p> The optimized intraocular lens operates within the physiologic constraints of the human eye including the force available for full accommodative amplitude using the eye&rsquo;s natural focusing feedback, while maintaining image quality in the space available. Optimized optical and mechanical performance parameters were delineated as those which minimize both asphericity and actuation pressure. The methodology combines a multidisciplinary basic science approach from biomechanics, optical science, and ophthalmology to optimize an intraocular lens design suitable for preliminary trials.</p>

G-protein coupled receptors (GPCRs) are transmembrane proteins capable of recognizing an astonishing variety of biological signals, ranging from photons of light to hormones, odorants, and neurotransmitters involved in key biological signaling processes. The aim of this work is to identify how lipid-protein interactions involving the membrane bilayer ultimately affect such vital biological functions. Here the relationship between the bilayer thickness, hydrophobic mismatch, and protein aggregation are investigated by expanding the framework of membrane-receptor interactions in terms of a new flexible surface model. Previously, we have shown how coupling of the elastic stress-strain due to mismatch of the spontaneous curvature and hydrophobic thickness at the lipid/protein interface can govern the conformational transitions of membrane proteins. This approach has now been extended to include coupling of the lateral organization of the GPCR rhodopsin to the curvature and area stress and strain of the proteolipid membrane. Rhodopsin was labeled with site-specific fluorophores, and a FRET technique was employed to probe protein association in different lipid environments. Moreover, UV-visible spectroscopy was used for thermodynamic characterization of the conformational change of rhodopsin. Lastly, the deformation of the lipids with and without rhodopsin was probed in terms of acyl chain order parameters and relaxation rates by solid-state NMR methods, giving insight into the lipid deformation. The results showed that optimal receptor activation occurs in phosphatidylcholine bilayers of 20-carbon acyl chain length, hence one can say that metarhodopsin II is likely to adopt an elongated shape. Lipids promoting aggregation, or below their gel to liquid crystalline transition temperature all favor formation of metarhodopsin I. The data also showed that association and activation of rhodopsin do not always correlate. In terms of the extended flexible surface model, the stress due to hydrophobic mismatch is coupled via the effective number of lipids surrounding the protein due to the lateral organization of the membrane. The measured changes in rhodopsin-rhodopsin interactions and membrane influences on the conformation of the protein after photoisomerization may be crucial to understanding physiological regulation of the rod disk membranes. They are relevant to understanding the complexity of biomembranes involved in many cellular mechanisms, including signal transduction.

<p><b>Purpose</b>: To examine if disparities exist among US adults aged 40 and above that reported reasons for no access to eye care. </p><p> <b>Methods</b>: A secondary analysis was conducted on 14,129 US adults aged 40 and above who responded to the Vision Module of the 2007 BRFSS using cross-tabulations, logistic regression and chi square statistics. </p><p> <b>Results</b>: Respondents reporting cost/insurance as the main reason for not accessing an eye doctor was greater among adults with education level &lt; HS than with > HS (p&lt;0.001). The percentage who reported cost/insurance as the main reason was greater among adults with income &lt; $25,000 than with >$50,000 (p&lt;0.001). Similarly, a greater percentage of Black adults reported cost/insurance as the reason for not accessing an eye doctor compared to White adults. </p><p> <b>Conclusion</b>: Given that Cost/Insurance was the most frequently cited reason, making eye health/health insurance available to most or all Americans will go a long way in narrowing the gap in vision health disparities. </p>

This thesis presents results of a case-control study investigating the excess risk of ocular hypertension or open-angle glaucoma associated with the use of oral, inhaled and nasal glucocorticoids. Data on 9,793 cases and 38,325 control subjects were obtained from the computerized administrative health databases of the province of Quebec, Canada. / For oral glucocorticoids, a 40% increase in the risk of ocular hypertension or open-angle glaucoma was observed. The risk increased with higher daily doses and increasing duration of treatment. / Exposure to inhaled glucocorticoids was not associated with an elevated risk, except when they were administered in high doses over extended periods of time. No elevated risk was observed for exposure to nasal glucocorticoids. / The study results are discussed in view of pharmacological data for different forms of glucocorticoids and compared to findings for ophthalmic glucocorticoids. The database is used to illustrate empirical explorations of concerns about bias.

Fixed-vector saccades obtained upon electrical stimulation--while the eyes are steady--of any central oculomotor system structure can be derived from 2 different signals: (1) a retinal error signal, directing the eyes toward a specific location relative to the retina; (2) a motor error signal determining the movement vector itself. Theoretically, the two mechanisms can be segregated by delivering the stimulation during a naturally-triggered saccade (colliding saccade paradigm, Schlag-Rey et al., 1989), thereby creating a difference between the eyes' position at stimulation onset and their position at saccade outset. If derived from a retinal error signal, the electrically-evoked vector trajectory should be modified to compensate for the intervening change in eye position. If the saccade is derived from a motor error signal, the vector trajectory should be the same as when stimulating the same site while the eyes are immobile. This study describes the results of the application of the collision test in conjunction with the stimulation of 16 sites throughout the Superior Colliculus of 3 head-free cats. The main result of these tests--whether applied in conjunction with stimulation of superficial (where cells have visual activity) or deeper layers (where cells have motor activity) sites--is an absence of compensation indicating that the gaze saccades were derived from a motor error signal. Compensating saccades were only found in 6% of the cases with superficial layer stimulation sites while they were found in about 12% of the cases with deeper layer sites.

<p> PAMAM dendrimers are a class of well-defined, hyperbranched polymeric nanocarriers that are being investigated for ocular drug and gene delivery. Their favorable properties such as small size, multivalency and water solubility can provide significant opportunities for many biologically unstable drugs and allows potentially favorable ocular biodistribution. This work exploits hydroxyl terminated dendrimers (G4-OH) as drug/gene delivery vehicles that can target retinal microglia and pigment epithelium via systemic delivery with improved efficacy at much lower concentrations without any side effects. </p><p> Two different drugs Triamcinolone acetonide (TA) and N-Acetyl Cysteine (NAC) conjugated to G4-OH dendrimers showed tailorable sustained release in physiological relevant solutions and were evaluated in-vitro and in-vivo. Dendrimer-TA conjugates enhanced the solubility of TA and were 100 fold more effective at lower concentrations than free TA in its anti-inflammatory activity in activated microglia and in suppressing VEGF production in hypoxic RPE cells. Dendrimers targeted activated microglia/macrophages and RPE and retained for a period of 21 days in I/R mice model. The relative retention of intravitreal and intravenous dendrimers was comparable, if a 30-fold intravenous dose is used; suggesting intravenous route targeting retinal diseases are possible with dendrimers. D-NAC when injected intravenously attenuated retinal and choroidal inflammation, significantly reduced (&sim;73%) CNV growth at early stage of AMD in rat model of CNV. A combination therapy of D-NAC + D-TA significantly suppressed microglial activation and promoted CNV regression in late stages of AMD without causing side-effects. </p><p> G4-OH was modified with linker having minimal amine groups and incorporation of TA as a nuclear localization enhancer resulted in compact gene vectors with favorable safety profile and achieved high levels of transgene expression in hard to transfect human retinal pigment epithelial cells (hRPE). Prepared dendrimer-gene complexes were non-toxic and achieved significant cell uptake and safe delivery of gene in to the nucleus. Further, polyethylene glycol (PEG) surface coating enhanced colloidal stability in physiological relevant solutions without affecting its transfection efficacy.</p>

The ophthalmopathy associated with Graves' hyperthyroidism (GH) and Hashimoto's thyroiditis is an autoimmune-mediated inflammation of extraocular muscle and orbital connective tissue. The association of thyroid-associated ophthalmopathy (TAO) with autoimmune thyroid disease (ATD) can be explained by the expression on thyroid and eye muscle of shared or cross-reactive Ag(s) targeted by autoimmunity. The best candidate for such Ag(s), at present, are 64 kDa membrane molecules. When incubated with cultured human eye muscle, thyroid, and skeletal muscle cells in vitro, autoAbs in TAO patient sera immunoprecipitated a 64 kDa Ag from the first two tissues, but not from skeletal muscle. In dot blot experiments using D1 fusion protein, a fragment of a cloned 64 kDa protein, autoAbs were detected in the sera of 47% of patients with TAO and 57% of those with GH without ophthalmopathy but in only 5% of normal subjects. Short random fragments (100 to 200 bp) of 1D cDNA, a cloned 64 kDa protein, were cloned an expressed in E. coli as fusion proteins using the pUEX1 vector. Four antigenic peptides recognized by TAO sera were cloned and sequenced. When a panel of sera was screened for recognition of each peptides, sera from TAO patients reacted to one or more peptides significantly more frequently than sera from normal controls. A quantitative reverse transcriptase polymerase chain reaction (RT-PCR) methodology was used to investigate the tissue distribution of 1D mRNA and quantitate the levels of expression of transcripts of this specificity from a variety of human tissues. Expression of 1D was highest in thyroid and eye muscle, consistent with a high level of expression of this protein in these tissues. These studies indicate that 64 kDa proteins are expressed in eye muscle and thyroid, and that autoAbs reactive with the Ag(s) are present in the early stages of thyroid eye disease.

Hypercapnia, elevated carbon dioxide (CO2), is an established vasodilator, is present during ischemic episodes, and is a risk factor for retinopathy of prematurity, a disease of the retinal vasculature. Retinopathy of prematurity is an ischemic retinopathy, which like other ischemic pathologies, regresses with the reparation of existing blood vessels and the formation of new ones. However, the potential role of CO2 in this process has been relatively overlooked, particularly in comparison to the numerous studies examining hypoxia in ischemia. Therefore, the central aim of this work was to elucidate how hypercapnia affects the retinal vasculature, impacting blood flow and neovascularization. / Retinal blood flow (RBF) studies in hypercapnia-exposed piglets, and rodent models of CO2-induced retinopathy, demonstrate that hypercapnia leads to initial increases in prostaglandin (PG) E2, which mediates an early elevation in RBF, and subsequently augments the endothelial nitric oxide (NO) synthase expression and activity responsible for a later rise in RBF. Ex vivo retinal organ bath experiments and in vitro studies on retinal endothelial cells (ECs) confirmed these findings and revealed that PGE2 increases via EC calcium entry triggered by hypercapnia's accompanying acidosis. While the elevation in RBF creates an oxidative stress, which is detrimental in and of itself, the NO exacerbates this by generating a nitrative stress, resulting in diminished neovascularization. The mechanisms implicated in this include: (1) an altered EC/astrocyte interaction vital to vascularization; (2) the downregulation of the angiogenic PGE 2 receptor EP3; and (3) the direct loss of ECs and microglia, the latter of which we unveil for the first time to have a role in blood vessel development. / Collectively the data suggests that CO2, despite typically being considered rather innocuous, can be detrimental in certain circumstances. In the neonatal retina hypercapnia inappropriately augments RBF via a sequence of events, culminating in a free radical-mediated stress that impairs key players required for proper neovascularization. These findings impart several novel avenues for future research as not only do they improve our understanding of developmental, pathological, and therapeutic retinal neovascularization, but they convey a seminal perspective of CO2 creating a framework within which to examine hypercapnia in other tissues.

Thesis (Ph.D.)--Pacific Graduate School of Psychology, 2004. / Source: Dissertation Abstracts International, Volume: 64-09, Section: B, page: 4673. Adviser: Charles E. Baker.

Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in older Americans. There has been a long standing interest in the role of diet in the development of AMD. As early as the first National Health and Nutrition Examination Survey in the 1970s, higher intakes of fruits and vegetables were inversely correlated with the prevalence of AMD. Carotenoids and omega3 fatty acids are the most studied dietary factors due to strong biological plausibility. However, evidence from epidemiologic studies and clinical trials on the relations has been inconsistent. Chapter I prospectively examined the intakes of lutein/zeaxanthin and other common carotenoids in relation to the risk of AMD over more than two decades of follow-up among two large US cohorts, the Nurses’ Health Study and Health Professionals Follow-Up Study. We assessed nutrient intakes by repeated food frequency questionnaires. We also computed bioavailable plasma carotenoid scores directly from food intake using validated regression models. Cox proportional hazards models were used to compute the associations. Higher intakes of bioavailable carotenoids (except lycopene) were inversely associated with advanced AMD but not intermediate AMD. Analyses based on bioavailable intakes resulted in stronger associations than conventional nutrient intakes. Chapter II prospectively evaluated the marine long-chain omega3 fatty acids. We found that long-chain omega3 fatty acids were inversely associated with visually significant intermediate AMD. There was no association with advanced AMD; however, the totality of current evidence for advanced AMD is also discordant. Chapter III further investigated the plant-derived omega3 fatty acids, α-linolenic acid (ALA). We found that higher intake of ALA was associated with intermediate AMD before 2002 but not after. This coincides with the same time period when trans ALA was found in our participants’ blood and in mayonnaise, a primary food source of ALA. Whether trans ALA mediates this positive association warrants further studies. Although randomized trials are usually believed as the “gold standard”, dietary factors are hard to be adequately studied by randomized trials due to the complexities of diet and disease relations. Thus, findings in this thesis from large long-term prospective cohort studies provide the next best form of evidence.