We have previously shown that chronic treatment with the monoclonal antibody m266, which is specific for amyloid beta-peptide (Abeta), increases plasma concentrations of Abeta and reduces Abeta burden in the PDAPP transgenic mouse model of Alzheimer's disease (AD). We now report that administration of m266 to PDAPP mice can rapidly reverse memory deficits in both an object recognition task and a holeboard learning and memory task, but without altering brain Abeta burden. We also found that an Abeta/antibody complex was present in both the plasma and the cerebrospinal fluid of m266-treated mice. Our data indicate that passive immunization with this anti-Abeta monoclonal antibody can very rapidly reverse memory impairment in certain learning and memory tasks in the PDAPP mouse model of AD, owing perhaps to enhanced peripheral clearance and (or) sequestration of a soluble brain Abeta species.

Several lines of evidence suggest that both sweet and bitter tastes are transduced via receptors coupled to heterotrimeric guanine-nucleotide-binding proteins (G proteins). Gustducin is a taste receptor cell (TRC)-specific G protein that is closely related to the transducins. Gustducin and rod transducin, which is also expressed in TRCs, have been proposed to couple bitter-responsive receptors to TRC-specific phosphodiesterases to regulate intracellular cyclic nucleotides. Here we investigate gustducin's role in taste transduction by generating and characterizing mice deficient in the gustducin alpha-subunit (alpha-gustducin). As predicted, the mutant mice showed reduced behavioural and electrophysiological responses to bitter compounds, whereas they were indistinguishable from wild-type controls in their responses to salty and sour stimuli. Unexpectedly, mutant mice also exhibited reduced behavioural and electrophysiological responses to sweet compounds. Our results suggest that gustducin is a principal mediator of both bitter and sweet signal transduction.

CorrectionsNEUROBIOLOGY. For the article ''Phototransduction in transgenic mice after targeted deletion of the rod transducin ␣-subunit'' by

Olanzapine plus fluoxetine demonstrated superior efficacy for treating resistant depression compared to either agent alone.

Presently, there are no effective treatments for several diseases involving the CNS, which is protected by the blood-brain, blood-CSF and blood-arachnoid barriers. Traversing any of these barriers is difficult, especially for macromolecular drugs and particulates. However, there is significant experimental evidence that large molecules can be delivered to the CNS through the cerebro-spinal fluid (CSF). The flux of the interstitial fluid in the CNS parenchyma, as well as the macro flux of CSF in the leptomeningeal space, are believed to be generally opposite to the desirable direction of CNS-targeted drug delivery. On the other hand, the available data suggest that the layer of pia mater lining the CNS surface is not continuous, and the continuity of the leptomeningeal space (LMS) with the perivascular spaces penetrating into the parenchyma provides an unexplored avenue for drug transport deep into the brain via CSF. The published data generally do not support the view that macromolecule transport from the LMS to CNS is hindered by the interstitial and CSF fluxes. The data strongly suggest that leptomeningeal transport depends on the location and volume of the administered bolus and consists of four processes: (i) pulsation-assisted convectional transport of the solutes with CSF, (ii) active “pumping” of CSF into the periarterial spaces, (iii) solute transport from the latter to and within the parenchyma, and (iv) neuronal uptake and axonal transport. The final outcome will depend on the drug molecule behavior in each of these processes, which have not been studied systematically. The data available to date suggest that many macromolecules and nanoparticles can be delivered to CNS in biologically significant amounts (>1% of the administered dose); mechanistic investigation of macromolecule and particle behavior in CSF may result in a significantly more efficient leptomeningeal drug delivery than previously thought.

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Pulmonary arterial hypertension (PAH) is a life-threatening disease that results in right ventricular failure. 5- pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorobenzonitrile monofumarate (PRX-08066) is a selective 5-hydroxytryptamine receptor 2B (5-HT2BR) antagonist that causes selective vasodilation of pulmonary arteries. In the current study, the effects of PRX-08066 were assessed by using the monocrotaline (MCT)-induced PAH rat model. Male rats received 40 mg/kg MCT or phosphate-buffered saline and were treated orally twice a day with vehicle or 50 or 100 mg/kg PRX-08066 for 5 weeks. Pulmonary and cardiac functions were evaluated by hemodynamics, heart weight, magnetic resonance imaging (MRI), pulmonary artery (PA) morphology, and histology. Cardiac MRI demonstrated that PRX-08066 (100 mg/kg) significantly (P Ͻ 0.05) improved right ventricular ejection fraction. PRX-08066 significantly reduced peak PA pressure at 50 and 100 mg/kg (P Ͻ 0.05 and Ͻ 0.01, respectively) compared with MCT control animals. PRX-08066 therapy also significantly reduced right ventricle (RV)/body weight and RV/left ventricle ϩ septum (P Ͻ 0.01 and Ͻ 0.001, respectively) compared with MCT-treated animals. Morphometric assessment of pulmonary arterioles revealed a significant reduction in medial wall thickening and lumen occlusion associated with both doses of PRX-08066 (P Ͻ 0.01). The 5-HT2BR antagonist PRX-08066 significantly attenuated the elevation in PA pressure and RV hypertrophy and maintained cardiac function. Pulmonary vascular remodeling was also diminished compared with MCT control rats. PRX-08066 prevents the severity of PAH in the MCT rat model. Pulmonary arterial hypertension (PAH)is an elevation in pulmonary vascular resistance caused by vasoconstriction and pulmonary vascular remodeling, resulting in increased pulmonary arterial pressure. Idiopathic PAH has no known underlying cause. PAH can also develop as a consequence of coexisting disease, such as chronic obstructive pulmonary disease, hypoxia, portal hypertension, or HIV infection (Archer and Rich, 2000;Li et al., 2006). PAH is usually progressive and invariably fatal. The median survival without treatment in adult patients with PAH was 2.8 years after diagnosis, and in children the median survival was only 10 months (D'Alonzo et al., 1991). Recent advances in PAH therapies, specifically epoprostenoltreated patients, have resulted in the median survival reaching more than 6 years in adults (Barst et al., 1994) and significant improvement in survival for children with reported rates at 1, 5, and 10 years being 94, 81, and 61%, respectively (Yung et al., 2004). Although survival rates have improved with new therapeutic modalities, the prognosis is still poor and development of more effective therapies is clearly needed.Serotonin or 5-hydroxytryptamine (5-HT) was recognized for playing a role in the development of PAH because a relationship between PAH patients and diet pills such as aminorex, dexfenfluramine (DF), and fenfluramine was observed (Kew, 1970; ...