Spaceflight Effects and Molecular Responses in the Mouse Eye: Observations After Shuttle Mission STS-133

Microgravity-induced cephalad fluid shift and radiation exposure are some of the stressors seen in space exploration. Ocular changes leading to visual impairment in astronauts are of occupational health relevance. Therefore, we analyzed the effects of space flight in the eyes of mice. Six mice were assigned to Flight (FLT), Animal enclosure Module (AEM), or vivarium (VIV) group, respectively. Mice were sacrificed at 1, 5 or 7 days after landing from space. One eye was used for histological and immunohistoche-mistry analysis and the other eye for gene expression profiling. 8-OHdG and caspase-3 immunoreactivity were increased in the retina in FLT samples at return(R+1) compared to AEM/VIV groups, and decreased at day 7 (R+7). beta-amyloid was seen in the nerve fibers at the post-laminar region of the optic nerve in the flight samples (R+7). In addition, oxidative and cellular stress response genes were upregulated in the retina of FLT samples upon landing, and decreased by R+7. According to the results, a reversible molecular damage may occur in the retina of mice exposed to spaceflight followed by protective cellular response

Hindlimb Suspension (HLS) in Rodents for the Study of Intracranial Pressure, Molecular and Histologic Changes in the Eye, and CSF Production Regulation and Resorption: A Status Report of Two Studies

This status report corresponds to two studies tied to an animal experiment being executed at the University of California Davis (Charles Fuller's laboratory). The animal protocol uses the well-documented rat hindlimb suspension (HLS) model, to examine the relationship between cephalic fluid shifts and the regulation of intracranial (ICP) and intraocular (IOP) pressures as well as visual system structure and function. Long Evans rats are subjected to HLS durations of 7, 14, 28 and 90 days. Subgroups of the 90-day animals are studied for recovery periods of 7, 14, 28 or 90 days. All HLS subjects have age-matched cage controls. Various animal cohorts are planned for this study: young males, young females and old males. In addition to the live measures (ICP by telemetry, IOP and retinal parameters by optical coherence tomography) which are shared with the Fuller study, the specific outcomes for this study include: -Gene expression analysis of the retina -Histologic analysis - Analysis of the microvasculature of retina flat mounts by NASA's VESsel GENeration Analysis (VESGEN) Software. To date, the young male and female cohorts are being completed. Due to the need to keep technical variation to a minimum, the histologic and genomic analyses have been delayed until all samples from each cohort are available and can be processed in a single batch per cohort. The samples received so far correspond to young males sacrificed at 7,14, 28 and 90 days of HLS and at 90 days of recovery; and from young females sacrificed at 7, 14 and 28 of HLS. A complementary study titled: "A gene expression and histologic approach to the study of cerebrospinal fluid (CSF) production and outflow in hindlimb suspended rats" seeks to study the molecular components of CSF production and outflow modulation as a result of HLS, bringing a molecular and histologic approach to investigate genome wide expression changes in the arachnoid villi and choroid plexus of HLS rats compared to rats in normal posture

A Non Membrane-Targeted Human Soluble CD59 Attenuates Choroidal Neovascularization in a Model of Age Related Macular Degeneration

Age related macular degeneration (AMD) is the most common cause of blindness amongst the elderly. Approximately 10% of AMD patients suffer from an advanced form of AMD characterized by choroidal neovascularization (CNV). Recent evidence implicates a significant role for complement in the pathogenesis of AMD. Activation of complement terminates in the incorporation of the membrane attack complex (MAC) in biological membranes and subsequent cell lysis. Elevated levels of MAC have been documented on choroidal blood vessels and retinal pigment epithelium (RPE) of AMD patients. CD59 is a naturally occurring membrane bound inhibitor of MAC formation. Previously we have shown that membrane bound human CD59 delivered to the RPE cells of mice via an adenovirus vector can protect those cells from human complement mediated lysis ex vivo. However, application of those observations to choroidal blood vessels are limited because protection from MAC- mediated lysis was restricted only to the cells originally transduced by the vector. Here we demonstrate that subretinal delivery of an adenovirus vector expressing a transgene for a soluble non-membrane binding form of human CD59 can attenuate the formation of laser-induced choroidal neovascularization and murine MAC formation in mice even when the region of vector delivery is distal to the site of laser induced CNV. Furthermore, this same recombinant transgene delivered to the intravitreal space of mice by an adeno-associated virus vector (AAV) can also attenuate laser-induced CNV. To our knowledge, this is the first demonstration of a non-membrane targeting CD59 having biological potency in any animal model of disease in vivo. We propose that the above approaches warrant further exploration as potential approaches for alleviating complement mediated damage to ocular tissues in AMD

Compressive Optic Neuropathy from Salivary Gland Tumor of Sphenoid Sinus (.pdf)

We present compressive optic neuropathy from salivary duct carcinoma of minor salivary gland origin, arising primarily from the sphenoid sinus

Ocular toxicity of intravitreous adalimumab (Humira) in the rabbit

Purpose To evaluate the ocular toxicity of escalating doses of intravitreous adalimumab (Humira) in the rabbit eye. Methods Twelve New Zealand albino rabbits received unilateral intravitreous injections of 0.1 ml of adalimumab 0.25 mg (three eyes), 0.50 mg (three eyes), 1.0 mg (three eyes) or 0.1 ml balanced salt solution (BSS, threeeyes). Slit-lamp biomicroscopy and fundoscopy were carried out at baseline, day 1, 7 and 14 following intravitreous injection, while electroretinography (ERG) was carried out at baseline and day 14. Animals were euthanized on day 14, and histopathological examination of the eyes was performed. Results Slit-lamp biomicroscopy and fundoscopy were normal in eyes having received BSS, 0.25 mg or 0.50 mg adalimumab; however, inflammation was present in two of three eyes having received 1.0 mg adalimumab. Similarly, comparison of scotopic and photopic ERG light at baseline and day 14 demonstrated no changes in eyes receiving BSS, 0.25 mg or 0.50 mg adalimumab, but two of three eyes having received 1.0 mg adalimumab showed a greater than 30% reduction in a and b wave. Finally, histopathology demonstrated no differences between eyes receiving BSS, 0.25 mg or 0.50 mg of adalimumab, but two of three eyes injected with 1.0 mg demonstrated inflammatory cell infiltration of the vitreous and anterior chamber, with one of these eyes demonstrating retinal necrosis. Conclusions Escalating doses of intravitreous adalimumab in rabbit eyes caused no detectable functional or structural ocular toxicity up to a dose of 0.50 mg. Administration of 1.0 mg in 0.1 ml was associated with an inflammatory reaction and retinal necrosis