Lentiviral delivery of glial cell line-derived neurotrophic factor (lenti-GDNF) was tested for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson's disease (PD). We injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive GDNF expression with anterograde and retrograde transport was seen in all animals. In aged monkeys, lenti-GDNF augmented dopaminergic function. In MPTP-treated monkeys, lenti-GDNF reversed functional deficits and completely prevented nigrostriatal degeneration. Additionally, lenti-GDNF injections to intact rhesus monkeys revealed long-term gene expression (8 months). In MPTP-treated monkeys, lenti-GDNF treatment reversed motor deficits in a hand-reach task. These data indicate that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients.

A developmental role for the Ahr locus has been indicated by the observation that mice harboring a null allele display a portocaval vascular shunt throughout life. To define the ontogeny and determine the identity of this shunt, we developed a visualization approach in which three-dimensional (3D) images of the developing liver vasculature are generated from serial sections. Applying this 3D visualization approach at multiple developmental times allowed us to demonstrate that the portocaval shunt observed in Ahr-null mice is the remnant of an embryonic structure and is not acquired after birth. We observed that the shunt is found in late-stage wild-type embryos but closes during the first 48 h of postnatal life. In contrast, the same structure fails to close in Ahr-null mice and remains open throughout adulthood. The ontogeny of this shunt, along with its 3D position, allowed us to conclude that this shunt is a patent developmental structure known as the ductus venosus (DV). Upon searching for a physiological cause of the patent DV, we observed that during the first 48 h, most major hepatic veins, such as the portal and umbilical veins, normally decrease in diameter but do not change in Ahr-null mice. This observation suggests that failure of the DV to close may be the consequence of increased blood pressure or a failure in vasoconstriction in the developing liver.

No abstract

Mechanisms of acute retroviral pathogenesis have been examined during primary infection of rhesus macaques with simian-human immunodeficiency virus 89.6PD (SHIV(89.6PD)). During acute infection, between initial exposure and establishment of antigen-specific immune responses that stabilize the virus burden, rapid immune system changes influence the viral set-point and dictate subsequent steps in disease progression. In a previous study, we described specific patterns of lymphocyte activation during acute SHIV(89.6PD) infection. We now extend these studies to describe lymphoid tissue activation, using whole body positron emission tomography (PET) and the radioactive tracer 2-[(18)F]fluorodeoxyglucose (FDG). Within a few days after primary infection by intravenous, intrarectal, or intravaginal routes, PET-FDG imaging revealed a distinct pattern of lymphoid tissue activation centered on axillary, cervical, and mediastinum lymph nodes. Increased tissue FDG uptake preceded fulminant virus replication at these sites, suggesting that a diffusible factor of host or viral origin was responsible for lymphoid tissue changes. These data show that activation of lymphoid tissues in the upper body is an early response to virus infection and that diffusible mediators of activation might be important targets for vaccine or therapeutic intervention strategies.

MRI volumetric TLE studies show inconsistent evidence of hippocampal involvement in memory. Prior studies have not dissociated hippocampal and temporal lobe contributions to memory. We measured hippocampal and temporal lobe volumes and immediate/delayed memory performances in 64 TLE patients. Regression was used to dissociate hippocampal from temporal lobe contributions to memory. Results revealed reliable evidence for dominant hippocampal involvement in delayed verbal recall across three separate measures and less consistent evidence for nondominant hippocampal involvement. The findings point to a consistent relationship of dominant hippocampal volumes to delayed verbal recall but no involvement of the temporal lobe or nondominant hippocampus in memory.