Background-The purpose of this study was to determine the efficacy of stent-based delivery of sirolimus (SRL) alone or in combination with dexamethasone (DEX) to reduce in-stent neointimal hyperplasia. SRL is a potent immunosuppressive agent that inhibits SMC proliferation by blocking cell cycle progression. Methods and Results-Stents were coated with a nonerodable polymer containing 185 g SRL, 350 g DEX, or 185 g SRL and 350 g DEX. Polymer biocompatibility studies in the porcine and canine models showed acceptable tissue response at 60 days. Forty-seven stents (metal, nϭ13; SRL, nϭ13; DEX, nϭ13; SRL and DEX, nϭ8) were implanted in the coronary arteries of 16 pigs. The tissue level of SRL was 97Ϯ13 ng/artery, with a stent content of 71Ϯ10 g at 3 days. At 7 days, proliferating cell nuclear antigen and retinoblastoma protein expression were reduced 60% and 50%, respectively, by the SRL stents. After 28 days, the mean neointimal area was 2.47Ϯ1.04 mm 2 for the SRL alone and 2.42Ϯ1.04 mm 2 for the combination of SRL and DEX compared with the metal (5.06Ϯ1.88 mm 2 , PϽ0.0001) or DEX-coated stents (4.31Ϯ3.21 mm 2 , PϽ0.001), resulting in a 50% reduction of percent in-stent stenosis. Conclusions-Stent-based delivery of SRL via a nonerodable polymer matrix is feasible and effectively reduces in-stent neointimal hyperplasia by inhibiting cellular proliferation.

Preclinical studies in animal models and early results of clinical trials in patients suggest that intramuscular injection of naked plasmid DNA encoding vascular endothelial growth factor (VEGF) can promote neovascularization of ischemic tissues. Such neovascularization has been attributed exclusively to sprout formation of endothelial cells derived from preexisting vessels. We investigated the hypothesis that VEGF gene transfer may also augment the population of circulating endothelial progenitor cells (EPCs). In patients with critical limb ischemia receiving VEGF gene transfer, gene expression was documented by a transient increase in plasma levels of VEGF. A culture assay documented a significant increase in EPCs (219%, P<0.001), whereas patients who received an empty vector had no change in circulating EPCs, as was the case for volunteers who received saline injections (VEGF versus empty vector, P<0.001; VEGF versus saline, P<0.005). Fluorescence-activated cell sorter analysis disclosed an overall increase of up to 30-fold in endothelial lineage markers KDR (VEGF receptor-2), VE-cadherin, CD34, alpha(v)beta(3), and E-selectin after VEGF gene transfer. Constitutive overexpression of VEGF in patients with limb ischemia augments the population of circulating EPCs. These findings support the notion that neovascularization of human ischemic tissues after angiogenic growth factor therapy is not limited to angiogenesis but involves circulating endothelial precursors that may home to ischemic foci and differentiate in situ through a process of vasculogenesis.

We have detected sub-TeV gamma-ray emission from the direction of the Galactic center (GC) using the CANGAROO-II Imaging Atmospheric Cerenkov Telescope. We detected a statistically significant excess at energies greater than 250 GeV. The flux was 1 order of magnitude lower than that of the Crab Nebula at 1 TeV with a soft spectrum proportional to . The signal centroid is consistent with the GC direction, and the Ϫ4.6‫5.0ע‬E observed profile is consistent with a pointlike source. Our data suggest that the GeV source 3EG J1746Ϫ2851 is identical to this TeV source, and we study the combined spectra to determine the possible origin of the gammaray emission. We also obtain an upper limit on the cold dark matter density in the Galactic halo.

We have detected gamma-ray emission at the 6 σ level at energies greater than 500 GeV from the supernova remnant RX J0852.0−4622 (G266.2−1.2) using the

We made stereoscopic observations of the Vela Pulsar region with two of the 10 m diameter CANGAROO-III imaging atmospheric Cherenkov telescopes in January and February, 2004, in a search for sub-TeV gamma-rays from the pulsar and surrounding regions. We describe the observations, provide a detailed account of the calibration methods, and introduce the improved and bias-free analysis techniques employed for CANGAROO-III data. No evidence of gamma-ray emission is found from either the pulsar position or the previously reported position offset by 0.13 degree, and the resulting upper limits are a factor of five less than the previously reported flux from observations with the CANGAROO-I 3.8 m telescope. Following the recent report by the H.E.S.S. group of TeV gamma-ray emission from the Pulsar Wind Nebula, which is ∼0.5 degree south of the pulsar position, we examined this region and found supporting evidence for emission extended over ∼0.6 degree.