Background —We initiated a phase 1 clinical study to determine the safety and bioactivity of direct myocardial gene transfer of vascular endothelial growth factor (VEGF) as sole therapy for patients with symptomatic myocardial ischemia. Methods and Results —VEGF gene transfer (GTx) was performed in 5 patients (all male, ages 53 to 71) who had failed conventional therapy; these men had angina (determined by angiographically documented coronary artery disease). Naked plasmid DNA encoding VEGF (phVEGF 165 ) was injected directly into the ischemic myocardium via a mini left anterior thoracotomy. Injections caused no changes in heart rate (pre-GTx=75±15/min versus post-GTx=80±16/min, P =NS), systolic BP (114±7 versus 118±7 mm Hg, P =NS), or diastolic BP (57±2 versus 59±2 mm Hg, P =NS). Ventricular arrhythmias were limited to single unifocal premature beats at the moment of injection. Serial ECGs showed no evidence of new myocardial infarction in any patient. Intraoperative blood loss was 0 to 50 cm 3 , and total chest tube drainage was 110 to 395 cm 3 . Postoperative cardiac output fell transiently but increased within 24 hours (preanesthesia=4.8±0.4 versus postanesthesia=4.1±0.3 versus 24 hours postoperative=6.3±0.8, P =0.02). Time to extubation after closure was 18.4±1.4 minutes; average postoperative hospital stay was 3.8 days. All patients had significant reduction in angina (nitroglycerin [NTG] use=53.9±10.0/wk pre-GTx versus 9.8±6.9/wk post-GTx, P <0.03). Postoperative left ventricular ejection fraction (LVEF) was either unchanged (n=3) or improved (n=2, mean increase in LVEF=5%). Objective evidence of reduced ischemia was documented using dobutamine single photon emission computed tomography (SPECT)-sestamibi imaging in all patients. Coronary angiography showed improved Rentrop score in 5 of 5 patients. Conclusions —This initial experience with naked gene transfer as sole therapy for myocardial ischemia suggests that direct myocardial injection of naked plasmid DNA, via a minimally invasive chest wall incision, is safe and may lead to reduced symptoms and improved myocardial perfusion in selected patients with chronic myocardial ischemia.
Although lymphedema is a common clinical condition, treatment for this disabling condition remains limited and largely ineffective. Recently, it has been reported that overexpression of VEGF-C correlates with increased lymphatic vessel growth (lymphangiogenesis). However, the effect of VEGF-C–induced lymphangiogenesis on lymphedema has yet to be demonstrated. Here we investigated the impact of local transfer of naked plasmid DNA encoding human VEGF-C (phVEGF-C) on two animal models of lymphedema: one in the rabbit ear and the other in the mouse tail. In a rabbit model, following local phVEGF-C gene transfer, VEGFR-3 expression was significantly increased. This gene transfer led to a decrease in thickness and volume of lymphedema, improvement of lymphatic function demonstrated by serial lymphoscintigraphy, and finally, attenuation of the fibrofatty changes of the skin, the final consequences of lymphedema. The favorable effect of phVEGF-C on lymphedema was reconfirmed in a mouse tail model. Immunohistochemical analysis using lymphatic-specific markers: VEGFR-3, lymphatic endothelial hyaluronan receptor-1, together with the proliferation marker Ki-67 Ab revealed that phVEGF-C transfection potently induced new lymphatic vessel growth. This study, we believe for the first time, documents that gene transfer of phVEGF-C resolves lymphedema through direct augmentation of lymphangiogenesis. This novel therapeutic strategy may merit clinical investigation in patients with lymphedema
A pilot study was performed to measure head impact accelerations in collegiate men’s ice hockey during the 2005–2007 seasons using helmets instrumented with Head Impact Telemetry System technology to monitor and record linear head accelerations and impact locations in situ. The objectives of this study were (1) to quantify the relationship between resultant peak linear head acceleration and impact location for in situ head impacts in collegiate men’s ice hockey, (2) to quantify the frequency and severity of impacts to the facemask, and (3) to determine if in situ impacts occurred such that the peak resultant linear head acceleration was higher than the peak resultant linear headform acceleration from a 40-in. linear drop (as in ASTM F1045–99) on the same helmet at a similar impact location. Voluntary participants (n=5 and 7 for years 1 and 2, respectively) wore instrumented helmets which monitored head impact accelerations sustained by each player during all games and practices. Head impact data were grouped by impact location into five bins representing top, back, side, forehead, and facemask. Forehead impacts represented impacts to the helmet shell as distinguished from facemask impacts. Additionally, a sample instrumented helmet was impacted in the laboratory at forehead, side, rear, and top impact locations (40-in. drop, three trials per location, test setup as specified in ASTM F1045-99). The mean peak resultant linear headform acceleration for each impact location was determined for analysis. Of the 4,393 recorded head impacts, 33.2 % were to the back of the helmet. This percentage increased to 59.2 % for impacts above 70 g. Facemask impacts accounted for 12.2 % of all impacts but only 2.4 % of impacts above 70 g. Over two seasons, five in situ impacts occurred such that the peak resultant linear head acceleration was greater than the mean peak resultant linear headform acceleration for a corresponding impact location in the laboratory. This study found that the most common impact location in ice hockey, particularly for impacts with higher peak linear accelerations, was the back of the head and demonstrated that facemask impacts were typically of a lower magnitude. The five impacts or ∼0.4 per player/season that exceeded the peak linear acceleration associated with 40-in. laboratory drops suggested that the impact energy specified in ASTM F1045 may not reflect the highest energy impacts seen in situ.
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