Human glia can both induce and rescue aspects of disease phenotype in Huntington disease.

The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells (hGPCs), derived from either human embryonic stem cells or mHTT-transduced fetal hGPCs. Here we show that mHTT glia can impart disease phenotype to normal mice, since mice engrafted intrastriatally with mHTT hGPCs exhibit worse motor performance than controls, and striatal neurons in mHTT glial chimeras are hyperexcitable. Conversely, normal glia can ameliorate disease phenotype in transgenic HD mice, as striatal transplantation of normal glia rescues aspects of electrophysiological and behavioural phenotype, restores interstitial potassium homeostasis, slows disease progression and extends survival in R6/2 HD mice. These observations suggest a causal role for glia in HD, and further suggest a cell-based strategy for disease amelioration in this disorder.

Neuronal transgene expression in dominant-negative SNARE mice.

Experimental advances in the study of neuroglia signaling have been greatly accelerated by the generation of transgenic mouse models. In particular, an elegant manipulation that interferes with astrocyte vesicular release of gliotransmitters via overexpression of a dominant-negative domain of vesicular SNARE (dnSNARE) has led to documented astrocytic involvement in processes that were traditionally considered strictly neuronal, including the sleep-wake cycle, LTP, cognition, cortical slow waves, depression, and pain. A key premise leading to these conclusions was that expression of the dnSNARE was specific to astrocytes. Inconsistent with this premise, we report here widespread expression of the dnSNARE transgene in cortical neurons. We further demonstrate that the activity of cortical neurons is reversibly suppressed in dnSNARE mice. These findings highlight the need for independent validation of astrocytic functions identified in dnSNARE mice and thus question critical evidence that astrocytes contribute to neurotransmission through SNARE-dependent vesicular release of gliotransmitters.

Sustained mobilization of endogenous neural progenitors delays disease progression in a transgenic model of Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disease characterized in part by the loss of striatopallidal medium spiny projection neurons (MSNs). Expression of BDNF and noggin via intracerebroventricular (ICV) delivery in an adenoviral vector triggers the addition of new neurons to the neostriatum. In this study, we found that a single ICV injection of the adeno-associated viruses AAV4-BDNF and AAV4-noggin triggered the sustained recruitment of new MSNs in both wild-type and R6/2 mice, a model of HD. Mice treated with AAV4-BDNF/noggin or with BDNF and noggin proteins actively recruited subependymal progenitor cells to form new MSNs that matured and achieved circuit integration. Importantly, the AAV4-BDNF/noggin-treated R6/2 mice showed delayed deterioration of motor function and substantially increased survival. In addition, squirrel monkeys given ICV injections of adenoviral BDNF/noggin showed similar addition of striatal neurons. Induced neuronal addition may therefore represent a promising avenue for disease amelioration in HD.

Changes in landing mechanics after cold-water immersion.

The purpose of this study was to investigate the influence of cold-water immersion on kinematics and kinetics during a drop-landing task. On four separate occasions, 9 men performed drop-landings from a 0.6-m platform to a force platform following 30-min immersion to the hip-joint in thermoneutral water (control; 34 degrees C) and in cold water (20 degrees C) to the ankle (low level), knee (medium level), and hip (high level) joints. Sagittal plane kinematics and kinetics were determined. One-way repeated measures multivariate analysis of variance was used for statistical analysis. Compared to the control, the low-level condition had similar joint mechanics, the medium level showed 26% less ankle mechanical work (p = .003), and the high level showed 9% less vertical ground reaction force (p = .025) and 23% less ankle mechanical work (p = .023) with 18% greater trunk flexion (p = .024). In summary, the low-level cold-water immersion had no effect on landing mechanics. The medium- and high-level cold-water immersion resulted in a reduction in impact absorption at the ankle joint during landing. The increased trunk flexion after high-level immersion helped dissipate landing impact.

Dislodgeable copper, chromium and arsenic from CCA-treated wood surfaces.

Chromated copper arsenate (CCA) is commonly used to preserve wood, but its use poses risk of arsenic exposure. In order to evaluate the extent of exposure to As from physical contact with CCA-treated wood, dislodgeable As from treated wood surfaces (as well as Cu and Cr) was determined as a function of weathering time using dampened polyester wipe materials. Six sets of 2.5-m-long CCA-treated boards, three-four boards per set, were purchased from lumber yards and cut into 30- or 60-cm coupons. A total of 44 such coupons were placed outdoors and the dislodgeable CCA components from the surfaces of the wooden coupons were periodically determined over a 1- or 2-year period by a systematic wipe method followed by nitric acid extraction of the CCA components from the cloth. In all 316 samples, appreciable amounts of the three elements, Cu, Cr and As, were detected. The amounts of surface-dislodgeable As, the most potentially hazardous element and the one of major concern in this study, varied from 5 to 122 microg/100 cm(2) with an average value of 37+/-22 microg/100 cm(2). There was considerable variation in As dislodged among coupons, boards, sets and time. Test coupons that tended to release relatively higher (or lower amounts) over time initially, continued to do so over time. However, the amounts of arsenic dislodged over time did not follow a simple pattern. While the As dislodged tended to decrease with time during the first year, it approached the initial value or increased somewhat during the second year, presumably due to surface rejuvenation effects caused by erosion and weathering. When all the data were normalized to the initial values, no trend emerged, as indicated by the average normalized value of 1.0+/-0.4 for As dislodged over time. Apparently, on installations constructed with CCA-treated wood, arsenic may remain available for a number of years.