In several disease states, abnormal growth of blood vessels is associated with local neuronal degeneration. This is particularly true in ocular diseases such as retinal angiomatous proliferation (RAP) and macular telangiectasia (MacTel), in which, despite the absence of large-scale leakage or hemorrhage, abnormal neovascularization (NV) is associated with local neuronal dysfunction. We describe here a retinal phenotype in mice with dysfunctional receptors for VLDL (Vldlr -/-mice) that closely resembles human retinal diseases in which abnormal intra-and subretinal NV is associated with photoreceptor cell death. Such cell death was evidenced by decreased cone and, to a lesser extent, rod opsin expression and abnormal electroretinograms. Cell death in the region of intraretinal vascular abnormalities was associated with an increased presence of markers associated with oxidative stress. Oral antioxidant supplementation protected against photoreceptor degeneration and preserved retinal function, despite the continued presence of abnormal intra-and subretinal vessels. What we believe to be novel, Müller cell-based, virally mediated delivery of neurotrophic compounds specifically to sites of NV was also neuroprotective. These observations demonstrate that neuronal loss secondary to NV can be prevented by the use of simple antioxidant dietary measures or cell-based delivery of neurotrophic factors, even when the underlying vascular phenotype is not altered.

Glial cell line-derived neurotrophic factor (GDNF) or its naturally occurring analog, neurturin (NTN), can potentially improve the function and delay the rate of degeneration of dopaminergic neurons in Parkinson's disease (PD). However, their delivery to the central nervous system has proven to be a significant challenge. Viral vector-mediated gene transfer offers a practical means to continuously supply neurotrophic factors in targeted areas of the brain. CERE-120 is an adeno-associated viral vector encoding NTN, developed for the treatment of PD. We found that the kinetics and pattern of NTN expression in the rat striatum following injection of CERE-120 is rapid, increases significantly up to 4 weeks, and exhibits a stable volume of distribution thereafter for at least 1 year, the longest time-point evaluated. Quantitative enzyme-linked immunosorbent assay confirmed that steady-state levels are maintained from 4 weeks onward. We demonstrated that NTN volume of distribution can be controlled by varying the dose of vector injected and that NTN delivered via CERE-120 was bioactive, as evidenced by the neuroprotection of DA neurons in the rat 6-hydroxydopamine lesion model. These data provided the foundation for further non-clinical development of CERE-120, leading to an ongoing clinical trial in PD patients.

Rotaviruses were prospectively studied in 51 rural Costa Rican children from birth to two years. Samples of feces were collected weekly over a 33-month period. Rotavirus was detected in 45 (1.04%) of 4,317 fecal specimens; 39 infections were documented (an incidence of 0.5 infection per child-year), only five of which were associated with diarrhea (a pathogenicity of 12.8%). Secretory antibody in fecal extracts, detected in six of 39 infections, was short lived and did not protect against reinfection. Serum antibody was present in 69.6% of two-year-old children, but was not detected in 18.8% with documented infections. On the other hand, serum antibody was present in six of 14 children in whom rotavirus was not detected, thus increasing the overall incidence to 0.6 infection per child-year. The combination of prolonged breast-feeding, exposure to a lower infecting dose (compared with urban children), and a higher standard of hygiene than expected may explain the low incidence and low pathogenicity of rotavirus among these rural children.The epidemiology of rotavirus infection in populations observed in their own environment needs further elucidation, particularly in less-developed countries where diarrheal disease takes its highest toll. In Costa Rica, rotavirus was demonstrated as the most important etiologic agent of acute diarrhea among outpatients at the National Children's Hospital in San Jose [1]. Hospital-based studies are of limited epidemiological value, however, because they are cross-sectional in nature; cover, by definition, the most serious cases that require hospital treatment; and thus, do not reflect the situation in the general population. Consequently, a cohort study was designed in order to study patterns of infection and immunity to rotavirus under natural conditions. This longitudinal study permitted investigation of the

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