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The mechanism by which platelet-derived growth factor (PDGF) regulates vascular smooth muscle cell (SMC) DNA synthesis is unknown, but may involve isoprenoid intermediates of the cholesterol biosynthetic pathway. Inhibition of isoprenoid synthesis with the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, simvastatin (Sim, 1-10 microM), inhibited PDGF-induced SMC DNA synthesis by >95%, retinoblastoma gene product hyperphosphorylation by 90%, and cyclin-dependent kinases (cdk)-2, -4, and -6 activity by 80 +/- 5, 50 +/- 3, and 48 +/- 3%, respectively. This correlated with a 20-fold increase in p27(Kip1) without changes in p16, p21(Waf1), or p53 levels compared with PDGF alone. Since Ras and Rho require isoprenoid modification for membrane localization and are implicated in cell cycle regulation, we investigated the effects of Sim on Ras and Rho. Up-regulation of p27(Kip1) and inhibition of Rho but not Ras membrane translocation by Sim were reversed by geranylgeranylpyrophosphate, but not farnesylpyrophosphate. Indeed, inhibition of Rho by Clostridium botulinum C3 transferase or overexpression of dominant-negative N19RhoA mutant increased p27(Kip1) and inhibited retinoblastoma hyperphosphorylation. In contrast, activation of Rho by Escherichia coli cytotoxic necrotizing factor-1 decreased p27(Kip1) and increased SMC DNA synthesis. These findings indicate that the down-regulation of p27(Kip1) by Rho GTPase mediates PDGF-induced SMC DNA synthesis and suggest a novel direct effect of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors on the vascular wall.

Background Reflectance confocal microscopy (RCM) has been used for over 10 years for in vivo skin imaging. However, to date no standard RCM terminology has been published. Objective To establish a glossary of terms for RCM evaluation of melanocytic lesions. Methods Prominent RCM researchers were presented with RCM images of melanocytic lesions. Reviewers evaluated RCM images for image quality, lesion architecture, and cellular details. Reviewers could utilize published descriptors or contribute unpublished terminology to describe lesion attributes. An online meeting was conducted to reach consensus that integrates and defines existing and new RCM descriptive terms. Results We present a glossary with descriptors of image quality, normal skin morphology, lesion architecture, and cellular details for RCM evaluation of melanocytic lesions. Limitations Usefulness of the glossary in RCM diagnosis of melanocytic lesions needs to be assessed. Conclusion Standardization of terminology is important toward implementation of RCM in the clinical setting.

Background Topical anesthetics, unlike injectable anesthetics, can be applied painlessly and can provide sufficient pain control to maintain patient comfort throughout a variety of laser procedures. Although the use of topical lidocaine is considered relatively safe, instances of cardiotoxic and neurotoxic adverse events have been reported to occur. Observations A 52-year-old woman underwent fractional photothermolysis for management of severe hypopigmentation and scarring of several years' duration. Shortly after termination of treatment to her face and neck, which required prolonged exposure to a 30% lidocaine gel compound both before and during surgery, she developed clinical signs and symptoms consistent with systemic lidocaine toxicity. The results of laboratory studies confirmed serum lidocaine levels within the toxic range. We postulate that the combination of the high concentration of topical lidocaine required to achieve sufficient anesthesia, together with the laser-induced disruption in epidermal barrier function, may have been responsible for this phenomenon. Conclusions Application of a 30% topical lidocaine gel to a limited area in conjunction with fractional photothermolysis may generate serum lidocaine levels high enough to elicit systemic toxicity. Laser surgeons should be alert to this phenomenon, particularly in patients with underlying hepatic, endocrine, cardiac, or central nervous system/psychiatric dysfunction; in patients with a low body mass index; and in patients who are taking medications that may interfere with hepatic lidocaine metabolism.

Background —Salicylates may have direct vascular effects by mechanisms that are independent of platelet inhibition. Methods and Results —We investigated the effect of salicylates on vascular smooth muscle cell (SMC) proliferation in response to platelet-derived growth factor (PDGF) in vitro. Salicylate concentrations of 5 and 10 mmol/L inhibited serum- or PDGF-induced SMC cell count and [ 3 H]thymidine incorporation by 62% and 81%, respectively. There was no evidence of cellular toxicity or apoptosis as determined by trypan blue exclusion and FACS analyses. Because cell cycle progression is regulated by hyperphosphorylation of the retinoblastoma (Rb) protein, we examined the effects of salicylate on Rb hyperphosphorylation. Treatment with salicylate, but not indomethacin, inhibited nuclear factor-κB activation and completely abolished Rb hyperphosphorylation in PDGF-treated SMCs. This effect was associated with a decrease in cyclin-dependent kinase (Cdk)-2 and, to a lesser extent, Cdk-6, but not Cdk-4 activity, without changes in Cdk-2, -4, and -6 and cyclin D and E protein levels. Because Cdk-2 activity is regulated by the Cdk inhibitors p21 Waf1 and p27 Kip1 , we studied the effects of salicylate on p21 Waf1 and p27 Kip1 expression. Treatment with salicylate prevented PDGF-induced downregulation of p21 Waf1 and p27 Kip1 but not of the Cdk-4/-6 inhibitor p16 Ink4 . Conclusions —These findings indicate that high doses of salicylates inhibit SMC proliferation by cell cycle arrest at the G 1 -S phase and suggest a beneficial role for high-dose salicylates in the treatment of vascular proliferative disorders.