Introduction: A study in 2005 found that Epidermal Growth Factor Kinase Inhibitors (EGFRki) could promote Retinal Ganglion Cell (RGC) axonal regeneration in vivo when delivered to the crushed Optic Nerve (ON). The axon regenerative effects of these EGFRki were attributed to their blockade of the Epidermal Growth Factor Receptor (EGFR), and EGFR activation was hence suggested to lead to growth cone collapse and failed RGC axon regeneration. Aims: To investigate the role of EGFR in RGC axonal regenerative failure, and to elucidate the mechanisms of action by which EGFRki promote RGC axonal regeneration. Methods: Immunohistochemistry and immunocytochemistry to visualize activated EGFR (pEGFR) Primary retinal cultures to examine the actions of EGFRki such as AG1478 on RGC in vitro. ELISA to examine the conditioned media from these cultures for NeuroTrophic Factors (NTF). Intravitreal (ivit) injections of EGFRki (PD168393) into Optic Nerve Crush (ONC) recipient rats to attempt to elicit in vivo regeneration. The implantation of PD168393-impregnated collagen matrices into ONC recipient rats to attempt to elicit in vivo regeneration. PCR on retinal lysates to detect NTF mRNA. Results: No pEGFR was detected on RGC axons, either in the retina or in the ON of any treatment or control group. pEGFR was detected on almost all ON and retinal glial types prior to injury and almost all glial types exhibited increased pEGFR levels post-ONC. A sub population (~30%) of RGC cell bodies were pEGFR+ but this proportion did not change between control and treatment groups. AG1478 was shown to disinhibit RGC in Nogo-P4 inhibited primary retinal cultures but ELISA on conditioned media for various NTF detected none, however PCR detected mRNA for several of these NTF in retinal lysates. Ivit PD168393 failed to elicit RGC survival or axonal regeneration in vivo. Intra ON implantation of PD168393 impregnated collagen matrices appeared to promote significant RGC axonal regeneration post-ONC, but did not affect RGC survival. Discussion: Several models explaining the in vitro regenerative and in vivo neuritogenic actions of EGFRki were developed. These included the abrogation of various harmful glially mediated processes, the stimulation of NTF release by local glia and the stimulation or blockade of several other non-EGFR dependent signalling cascades by EGFRki. Conclusions: The axogenic and neuritogenic actions of EGFRki in vitro and in vivo were confirmed. The identification of numerous other means by which EGFRki could indirectly promote RGC axonal regeneration, including by acting on targets other than EGFR allowed the construction of a combinatorial model of how EGFRki effect axonal regeneration, and the original hypothesis positing EGFR as an intra-axonal component of a growth cone collapsing signalling cascade was disgarded.

This thesis aimed to investigate a novel way to explore changes in gaze behaviour, whilst walking, in frail populations. Initially three studies were conducted to establish how similar gaze behaviour recorded during walking was to that recorded whilst scene viewing. Duration of time and number of times different features were fixated were found to be similar in the three experiments. Older adults were assessed for falling risk and split into higher risk of falling (HROA) and lower risk of falling (LROA) groups. Their gaze behaviour was recorded whilst scene viewing along with a group of young adults. HROA were found to fixate the travel path longer than LROA and younger adults. HROA were slower at completing the incongruent Stroop task, suggesting a relationship between response inhibition and increased falling risk. A group of stroke patients were assessed for falling risk and split according to lesion location (parietal, occipital or frontal-temporal); gaze behaviour was recorded during scene viewing and compared to controls. Observable differences, which related to falling risk and lesion location, were shown in the gaze behaviour of the stroke patients compared to the controls. The findings of this thesis suggest that scene viewing could be used to better inform us about the changes in gaze behaviour which occur in frail populations that led to an increased risk of falling and the cognitive mechanisms which underlie these changes than laboratory studies.

Since Cohn’s investigation of the cause a of short-sight and the striking evidence which he brought forward as to the part which Education played in connection therewith, we have been accustomed to regard the schools as the "hot bed" of myopia. In view of the apparently conclusive nature of the statistics obtained by Cohn after an examination of over 10,000 scholars in German Schools, supplemented, as these have been, by the work of Snellen, Priestley Smith, Straub (Amsterdam) and many other eminent ophthalmologists, one reads with something of surprise the memoir or Pearson and Barrington “ A First Study of the Inheritance of Vision, and of the relative influence of Heredity and Environment on Sight “. In this memoir, which was issued in 1909 under the auspice of the Eugenic Laboratory of London University, the authors have carefully analysed, by modern statistical methods, much of the evidence adduced in support, of the generally accepted theory that short-sight is largely the result of Educational Environment.

Retinal ganglion cell (RGC) apoptosis and failure of optic nerve (ON) axon regeneration contribute to profound visual loss after traumatic optic neuropathy (TON), for which clinically effective treatments are lacking. Experimental manipulations of cellular signalling have identified phosphoinositide-3-kinase (PI3K) and its downstream mediators mTOR and GSK3\(\beta\) as important regulators of neuronal survival and axon regeneration in an animal model of TON, using targeted siRNA to knock-down key negative regulators of cellular signalling, and to investigate underlying mechanisms using retinal cultures. Intravitreal treatment with siRNA targeting RTP801, a stress-induced inhibitor of mTOR, promoted RGC survival and axon elongation after ON crush (ONC), and potentiated reactive gliosis. In vitro, siRTP801- induced neuroprotection was direct, but required GFAP\(^+\) activated retinal glia to stimulate neurite elongation. siRTP801 also potentiated levels of glial-derived Trk-dependent neurotrophic factors. Knock-down of the axon growth cone/apoptosis regulator GSK3\(\beta\) was also neuroprotective, promoted modest axon elongation after ONC, and increased neurite sprouting in vitro. GSK3\(\beta\) suppression counteracted neurite growth-inhibition induced by CNS myelin-derived Nogo. Combined treatment with siRTP801/siGSK3\(\beta\) augmented axon regeneration after ONC. These findings support a clinically translatable siRNA approach targeting PI3K/mTOR signalling as the basis for development of novel neuroprotective/axogenic therapies.

No description available.

The retina is a specialized part of the central nervous system adapted to encoding images into electrical signals. Images are formed on the back of the eye by the lens and cornea, and photons that make up those images are absorbed by light sensitive pigments in the photoreceptors. Photon absorptions by these pigments generate a current, the photocurrent, which is modified by voltage-gated ion channels and electrical connections to adjacent photoreceptors. A voltage change in the photoreceptor is transformed into a chemical signal to downstream cells by its modulatory effect on the calcium concentration at the synapse. This thesis examines two important elements in photoreceptor function other than the photocurrent: the Ih current and electrical coupling between rods. Here, using the tiger salamander (Ambystoma tigrinum) as a model, we investigate the kinetic properties of the HCN channels responsible for the Ih current in photoreceptors, and show that they are similar in rods and cones, which in turn are similar to the known properties of the HCN1 isoform. With western blot and immunostaining, we show that the HCN1 isoform is present in retina. We also demonstrate how HCN channels modify the kinetics of the rod and cone light response to make it faster. This thesis integrates this and other data from photoreceptor ion channels into physiology-based models of rod and cone photoreceptors. Through simulation, the model of the rod demonstrates that conductance changes from the h and Kx currents largely cancel one another during the rod light response. The cone model is used to demonstrate the feasibility of two proposed mechanisms for horizontal cell to cone negative feedback. Finally, this work presents measurements of electrical coupling between rod photoreceptors in the salamander retina using both light and electrical stimuli. Using measured parameters for the coupling resistance, a model of the electrically coupled network of rod photoreceptors is developed. We use this model to demonstrate how rod-rod coupling decreases noise at the expense of attenuating sharp contrasts in visual scenes. The model predicts the tradeoff between these two factors results in an overall improvement in the signal-to-noise ratio for most perceptible stimuli. Results suggest that photoreceptor coupling is especially helpful in the perception of images with statistical qualities similar to natural scenes.

Purpose: This study asks whether active horizontal angular Vestibulo-Ocular Reflex (VOR) gain is capable of monocular adaptation after 4 hours of wearing 10 dioptres (D) of induced anisometropia in healthy human adults. Method: The participants (average age 28 years) wore a contact lenses/spectacles combination for 4 hours. The power of the spectacle was +5. 00D (magnified images 8. 65%) in front of the right eye and ?5. 00D (minified images 5. 48%) for the left eye, while the power of the contact lenses was equal to the subjects? habitual correction, summed with the opposite power of the spectacle lens. Eye and head position data was collected in complete darkness, in one-minute trials before adaptation and every 30 minutes for 2 hours after adaptation. Eye and head position data obtained using a video-based eye tracking system, was analyzed offline using Fast Fourier Transform in MATHCADTM 11. 1 software to calculate VOR gain. The VOR gain was compared between the right eyes and left eyes for the trials before and after adaptation. Results: In the first post-adaptation trial, a significant decrease in VOR gain (? 6%) occurred in the left eye in response to the miniaturizing lens. The right eye VOR gain did not show a significant change in the first post-adaptation trial (?2% decrease). During the remaining trials in the 2 hour follow-up time, both eyes showed a significant decrease compared to the baseline trial. This might indicate habituation of the VOR from repeated testing, or fatigue. Conclusion: There was monocular adaptation of VOR in response to the combined contact lenses/spectacles, but it was not complete and it was not as we expected. However, trying different amounts of anisometropia in one or two directions, a longer adaptation period (more than 4 hours) or monitoring the gain for more than 2 hours after adaptation with a longer separation between trials, might show different results.

Die Augenheilkunde stellt eine der medizinischen Fachdisziplinen dar, die Laserstrahlung schon sehr früh einsetzten und heute bei verschiedenen Erkrankungen anwenden. Zur Diagnostik und Therapie der Glaukome, bei Netzhauterkrankungen, aber auch zur Behandlung von Fehlsichtigkeiten werden verschiedene Lasertypen erfolgreich eingesetzt. / Ophthalmology represents a medical field where laser technology was established very early and where lasers are nowadays frequently used. In the diagnosis and treatment of glaucoma, for treatment of retinal disorders as well as for refractive surgery different types of lasers are used.

Thesis (Ph. D.)--University of Texas at Austin, 2001. / Vita. Includes bibliographical references (leaves 237-244). Available also in a digital version from Dissertation Abstracts.

<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>