Surgical Treatment of Acute Submacular Hemorrhages and Advanced Exudative Age-related Macular Degeneration

__Abstract__ Located behind the cornea, iris and lens, the vitreous is a clear gel in the center of the eye (figure 1). The inner surface of the eye is lined with retina, a multi-layered sensory tissue. In the retina the photoreceptors, rods and cones, are capable of phototransduction; light is converted into signals that will stimulate neuronal impulse transmission.1 The nerve impulses then travel through axons of the retinal ganglion cells, via the optic nerve to the visual cortex of the brain where these signals are processed. Under the retina are the retinal pigment epithelium (RPE) and Bruch’s membrane. The RPE is a monolayer of highly pigmented hexagonal cells which forms the outer blood-retinal barrier of the eye. The RPE is highly specialized in nutrient and waste transport, and in the synthesis and secretion of the proteins needed for retinal function.2 The retina is also protected from light damage by the RPE, as the RPE melanosomes absorb excess incoming light.1 The basement membrane of the RPE is the innermost layer of the five layers of Bruch’s membrane, and the basement membrane of the choriocapillaris forms the bottom layer of Bruch’s membrane. Bruch’s membrane further consists of fine collagen and elastic fiber layers through which nutrients pass from the choriocapillaris to the RPE, and through which cellular waste products pass from the RPE to the choriocapillaris.3 The choroid, which contains the choriocapillaris, supplies oxygen to the outer layers of the retina, whereas the retinal vessels supply the inner retina. The outermost layer of the eye is the sclera, which gives support and protects the eye, and to which the eye musculature is attached

Oncolytic adenoviruses for treatment of oral cancer and precancer in sporadic and genetically predisposed patients

Brakenhoff, R.H. [Promotor]Leemans, C.R. [Promotor]Beusechem, V.W. van [Copromotor

Visual acuity of 20/32, 13.5 years after a retinal pigment epithelium and choroid graft transplantation

Purpose: To present the 13.5-year-survival of an autologous retinal pigment epithelium (RPE) and choroid graft transplantation with good visual acuity results. Observations: A 72-year old patient presented with a 5-weeks-old visual acuity deterioration to excentric finger counting at half a meter. Fundoscopy showed a fibrotic macular scar, a large subretinal hemorrhage, partly recent, combined with intraretinal fluid, blood, and hard exudates. RPE-choroid graft surgery was performed, and visual acuity improved to 20/32, and maintained up until 13.5 years postoperative. Microperimetry performed at the same time revealed a 3.4 dB sensitivity, with fixation on the graft. During the postoperative years glaucoma developed, an uveitis anterior was treated, and to treat a small Coats' like lesion; one bevacizumab injection was administered. Conclusions and importance: A best corrected visual acuity of 20/32 could be achieved and maintained up to 13.5 years after an RPE-choroid graft transplantation, despite an unfavorable preoperative presentation and some early and late complications. This case is a proof of principle that an RPE-choroid graft harvested from the midperiphery can support the macular metabolism up to 13.5 after surgery in a patient with severe exudative AMD. It also represents a rationale for pursuing stem cell derived RPE replacement. Anti-vascular endothelial growth factor injections are nowadays the mainstay of therapy for choroidal neovascularization and/or small hemorrhages and offer good results. Nevertheless, selected patients that cannot benefit from this therapy may profit from an autologous RPE-choroid graft transplantation

Phase-stabilized optical frequency domain imaging at 1-mu m for the measurement of blood flow in the human choroid

In optical frequency domain imaging (OFDI) the measurement of interference fringes is not exactly reproducible due to small instabilities in the swept-source laser, the interferometer and the data-acquisition hardware. The resulting variation in wavenumber sampling makes phase-resolved detection and the removal of fixed-pattern noise challenging in OFDI. In this paper this problem is solved by a new post-processing method in which interference fringes are resampled to the exact same wavenumber space using a simultaneously recorded calibration signal. This method is implemented in a high-speed (100 kHz) high-resolution (6.5 μm) OFDI system at 1-μm and is used for the removal of fixed-pattern noise artifacts and for phase-resolved blood flow measurements in the human choroid. The system performed close to the shot-noise limit (<1dB) with a sensitivity of 99.1 dB for a 1.7 mW sample arm power. Suppression of fixed-pattern noise artifacts is shown up to 39.0 dB which effectively removes all artifacts from the OFDI-images. The clinical potential of the system is shown by the detection of choroidal blood flow in a healthy volunteer and the detection of tissue reperfusion in a patient after a retinal pigment epithelium and choroid transplantation. © 2011 Optical Society of America

Rescue of replication failure by Fanconi anaemia proteins

Chromosomal aberrations are often associated with incomplete genome duplication, for instance at common fragile sites, or as a consequence of chemical alterations in the DNA template that block replication forks. Studies of the cancer-prone disease Fanconi anaemia (FA) have provided important insights into the resolution of replication problems. The repair of interstrand DNA crosslinks induced by chemotherapy drugs is coupled with DNA replication and controlled by FA proteins. We discuss here the recent discovery of new FA-associated proteins and the development of new tractable repair systems that have dramatically improved our understanding of crosslink repair. We focus also on how FA proteins protect against replication failure in the context of fragile sites and on the identification of reactive metabolites that account for the development of Fanconi anaemia symptoms

Surface-Based Analyses of Anatomical Properties of the Visual Cortex in Macular Degeneration

INTRODUCTION: Macular degeneration (MD) can cause a central visual field defect. In a previous study, we found volumetric reductions along the entire visual pathways of MD patients, possibly indicating degeneration of inactive neuronal tissue. This may have important implications. In particular, new therapeutic strategies to restore retinal function rely on intact visual pathways and cortex to reestablish visual function. Here we reanalyze the data of our previous study using surface-based morphometry (SBM) rather than voxel-based morphometry (VBM). This can help determine the robustness of the findings and will lead to a better understanding of the nature of neuroanatomical changes associated with MD. METHODS: The metrics of interest were acquired by performing SBM analysis on T1-weighted MRI data acquired from 113 subjects: patients with juvenile MD (JMD; n = 34), patients with age-related MD (AMD; n = 24) and healthy age-matched controls (HC; n = 55). RESULTS: Relative to age-matched controls, JMD patients showed a thinner cortex, a smaller cortical surface area and a lower grey matter volume in V1 and V2, while AMD patients showed thinning of the cortex in V2. Neither patient group showed a significant difference in mean curvature of the visual cortex. DISCUSSION: The thinner cortex, smaller surface area and lower grey matter volume in the visual cortex of JMD patients are consistent with our previous results showing a volumetric reduction in their visual cortex. Finding comparable results using two rather different analysis techniques suggests the presence of marked cortical degeneration in the JMD patients. In the AMD patients, we found a thinner cortex in V2 but not in V1. In contrast to our previous VBM analysis, SBM revealed no volumetric reductions of the visual cortex. This suggests that the cortical changes in AMD patients are relatively subtle, as they apparently can be missed by one of the methods

Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration

Age-related macular degeneration (AMD) remains a major cause of blindness, with dysfunction and loss of retinal pigment epithelium (RPE) central to disease progression. We engineered an RPE patch comprising a fully differentiated, human embryonic stem cell (hESC)-derived RPE monolayer on a coated, synthetic basement membrane. We delivered the patch, using a purpose-designed microsurgical tool, into the subretinal space of one eye in each of two patients with severe exudative AMD. Primary endpoints were incidence and severity of adverse events and proportion of subjects with improved best-corrected visual acuity of 15 letters or more. We report successful delivery and survival of the RPE patch by biomicroscopy and optical coherence tomography, and a visual acuity gain of 29 and 21 letters in the two patients, respectively, over 12 months. Only local immunosuppression was used long-term. We also present the preclinical surgical, cell safety and tumorigenicity studies leading to trial approval. This work supports the feasibility and safety of hESC-RPE patch transplantation as a regenerative strategy for AMD

Cell replacement and visual restoration by retinal sheet transplants

Retinal diseases such as age-related macular degeneration (ARMD) and retinitis pigmentosa (RP) affect millions of people. Replacing lost cells with new cells that connect with the still functional part of the host retina might repair a degenerating retina and restore eyesight to an unknown extent. A unique model, subretinal transplantation of freshly dissected sheets of fetal-derived retinal progenitor cells, combined with its retinal pigment epithelium (RPE), has demonstrated successful results in both animals and humans. Most other approaches are restricted to rescue endogenous retinal cells of the recipient in earlier disease stages by a ‘nursing’ role of the implanted cells and are not aimed at neural retinal cell replacement. Sheet transplants restore lost visual responses in several retinal degeneration models in the superior colliculus (SC) corresponding to the location of the transplant in the retina. They do not simply preserve visual performance – they increase visual responsiveness to light. Restoration of visual responses in the SC can be directly traced to neural cells in the transplant, demonstrating that synaptic connections between transplant and host contribute to the visual improvement. Transplant processes invade the inner plexiform layer of the host retina and form synapses with presumable host cells. In a Phase II trial of RP and ARMD patients, transplants of retina together with its RPE improved visual acuity. In summary, retinal progenitor sheet transplantation provides an excellent model to answer questions about how to repair and restore function of a degenerating retina. Supply of fetal donor tissue will always be limited but the model can set a standard and provide an informative base for optimal cell replacement therapies such as embryonic stem cell (ESC)-derived therapy