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Cholesterol amphiphiles containing positively charged groups (pyridinium, N-methylimidazolium, N-methylmorpholinium, and N-methylpiperidinium) linked via β-glucosyl spacer were prepared by alkylation of the corresponding bases with 6-О-mesyl-β-D-cholesteryl glucopyranoside. IC(50) values were in the range 20-35μM for the series of compounds and liposomal formulations with DOPE (1:1) were significantly less toxic. The liposomal formulations provided the accumulation of FITC-labeled oligonucleotide in cells, and the efficiency of this process was comparable to that of Lipofectamine 2000. Cationic liposomes were able to deliver siRNA into the cells, and the liposomal formulation 7d/DOPE provided the most pronounced down-regulation of EGFP expression both in the presence and in the absence of serum (up to 30%)., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Sensorimotor gating, the ability to automatically filter sensory information, is deficient in a number of psychiatric disorders, yet little is known of the biochemical mechanisms underlying this critical neural process. Previously, we reported that mice expressing a constitutively active isoform of the G-protein subunit Galphas (Galphas(*)) within forebrain neurons exhibit decreased gating, as measured by prepulse inhibition of acoustic startle (PPI). Here, to elucidate the biochemistry regulating sensorimotor gating and to identify novel therapeutic targets, we test the hypothesis that Galphas(*) causes PPI deficits via brain region-specific changes in cyclic AMP (cAMP) signaling. As predicted from its ability to stimulate adenylyl cyclase, we find here that Galphas(*) increases cAMP levels in the striatum. Suprisingly, however, Galphas(*) mice exhibit reduced cAMP levels in the cortex and hippocampus because of increased cAMP phosphodiesterase (cPDE) activity. It is this decrease in cAMP that appears to mediate the effect of Galphas(*) on PPI because Rp-cAMPS decreases PPI in C57BL/6J mice. Furthermore, the antipsychotic haloperidol increases both PPI and cAMP levels specifically in Galphas(*) mice and the cPDE inhibitor rolipram also rescues PPI deficits of Galphas(*) mice. Finally, to block potentially the pathway that leads to cPDE upregulation in Galphas(*) mice, we coexpressed the R(AB) transgene (a dominant-negative regulatory subunit of protein kinase A (PKA)), which fully rescues the reductions in PPI and cAMP caused by Galphas(*). We conclude that expression of Galphas(*) within forebrain neurons causes PPI deficits because of a PKA-dependent decrease in cAMP and suggest that cAMP PDE inhibitors may exhibit antipsychotic-like therapeutic effects.

Background: Different types of barriers are used in guided tissue regenerative procedures., Aim: This prospective study compared resorbable citric acid ester softened polylactic acid membranes (RM) and non-resorbable expanded polytetrafluoroethylene (ePTFE) barriers (NRM) in GTR treatment of intrabony defects., Methods: 29 subjects were randomly assigned to the RM group or NRM group. Each patient received one GTR procedure. An open flap debridement (FD) was performed at another site 2 weeks later to evaluate healing potential. Clinical treatment outcomes were finally evaluated 12 months after surgery for changes of pocket depth PD, probing attachment level PAL, and probing bone level PBL, and radiographically for bone change using standardised radiographs., Results: No differences in healing patters after surgery were found between patients in the 2 study groups as evaluated from the FD surgical procedures. NRM treated sites showed less signs of post-surgical inflammation during the 1st 4 weeks of healing than did RM treated sites (p<0.05). GTR-treated defects in the RM group, initially 7.0+/-2.2 mm deep, showed PD reduction of 3.3+/-2.2 mm, PAL gain of 2.4+/-1.8 mm, PBL gain of 2.4+/-3.7 mm (28%) and a radiographic bone fill of 2.3+/-2.4 mm. Defects treated with the NRM exhibited PD reduction of 3.1+/-2.1 mm, PAL gain of 2.4+/-0.8 mm, PBL gain of 2.2+/-1.7 mm (25%) and a radiographic bone fill of 3.3+/-2.2 mm. All improvements were statistically significant (p<0.01) but there was no difference between RM and NRM treatments for any of the efficacy variables. The results of this study indicated that there was no clinically significant difference in treatment outcomes following GTR treatment of intrabony defects with citric acid ester softened polylactic acid membranes as compared to ePTFE barriers. The overall mean inter-proximal vertical bone defect fill at 12 months as assessed from intra-oral radiographs was 44% of the original mean defect depth., Conclusions: Thus, no clinically significant difference in treatment outcomes was observed following GTR treatment of intrabony defects with citric acid ester softened polylactic acid membranes or ePTFE barriers.

We have examined the expression of factors associated with the growth, differentiation, and chemotaxis of cells of the monocyte/macrophage series in the central nervous system of Lewis rats sensitized to develop experimental allergic encephalomyelitis. CSF-1 mRNA increased significantly over that found in control animals (sensitized with OVA in CFA or CFA alone). The elevation in the levels of this growth factor commenced immediately before the onset of early clinical signs and peaked immediately before maximal clinical incidence of disease. Expression of CSF-1 message declined to base-line values with resolution of the disease process. CSF-1 protein was also detected in the central nervous system at the height of clinical disease. Expression of the receptor for CSF-1, the proto-oncogene c-fms, also paralleled the early disease process. Elevated levels of c-fms mRNA were detected immediately before the onset and peaked at the height of clinical signs of disease. In contrast to CSF-1 levels, elevated c-fms message expression persisted after resolution of the acute phase of experimental allergic encephalomyelitis. Levels of macrophage chemotactic factor-1 message were also elevated immediately before the onset of clinical signs, peaked with the height of clinical disease, and declined with resolution of the disease. Unlike CSF-1 or c-fms, no endogenous macrophage chemotactic factor-1 message was detected in control animals. Macrophage chemotactic factor-1 protein was demonstrated by Western blot in the central nervous system at the height of clinical disease. The results support the conclusion that expression of factors that specifically target cells of the monocyte/macrophage series are an important component of the disease process in experimental allergic encephalomyelitis.