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Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs
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Russell KE Olsen EH Raymer RA Merricks EP Bellinger DA Read MS Rup BJ Keith JC McCarthy KP Schaub RG Nichols TC 《Blood》2003,102(13):4393-4398
Intravenous administration of recombinant human factor IX (rhFIX) acutely corrects the coagulopathy in hemophilia B dogs. To date, 20 of 20 dogs developed inhibitory antibodies to the xenoprotein, making it impossible to determine if new human FIX products, formulations, or methods of chronic administration can reduce bleeding frequency. Our goal was to determine whether hemophilia B dogs rendered tolerant to rhFIX would have reduced bleeding episodes while on sustained prophylactic rhFIX administered subcutaneously. Reproducible methods were developed for inducing tolerance to rhFIX in this strain of hemophilia B dogs, resulting in a significant reduction in the development of inhibitors relative to historical controls (5 of 12 versus 20 or 20, P <.001). The 7 of 12 tolerized hemophilia B dogs exhibited shortened whole blood clotting times (WBCTs), sustained detectable FIX antigen, undetectable Bethesda inhibitors, transient or no detectable antihuman FIX antibody titers by enzyme-linked immunosorbent assay (ELISA), and normal clearance of infused rhFIX. Tolerized hemophilia B dogs had 69% reduction in bleeding frequency in year 1 compared with nontolerized hemophilia B dogs (P =.0007). If proven safe in human clinical trials, subcutaneous rhFIX may provide an alternate approach to prophylactic therapy in selected patients with hemophilia B. 相似文献
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Dwight W. Reynolds MD Peng-Sheng Chen MD Barbara J. Deal MD J. Kevin Donahue MD Kenneth A. Ellenbogen MD Andrew E. Epstein MD Paul A. Friedman MD Stephen C. Hammill MD Stefan H. Hohnloser MD Ronald J. Kanter MD Bruce D. Lindsay MD Andrea Natale MD Jeffrey Saffitz MD PhD William G. Stevenson MD 《Heart rhythm》2005,2(9):1025-1033
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Noninvasive assessment of coronary vasodilation using magnetic resonance angiography 总被引:1,自引:0,他引:1
Terashima M Meyer CH Keeffe BG Putz EJ de la Pena-Almaguer E Yang PC Hu BS Nishimura DG McConnell MV 《Journal of the American College of Cardiology》2005,45(1):104-110
OBJECTIVES: The purpose of this study was to investigate the use of coronary magnetic resonance angiography (MRA) for assessing human epicardial coronary artery vasodilation. BACKGROUND: Coronary vasodilation plays a vital role in the human coronary circulation. Previous studies of epicardial coronary vasodilation have used invasive coronary angiography. Coronary MRA may provide an alternative noninvasive method to directly assess changes in coronary size. METHODS: Thirty-two subjects were studied: 12 patients (age 55 +/- 18 years) and 20 healthy subjects (age 34 +/- 4 years). High-resolution multi-slice spiral coronary MRA (in-plane resolution of 0.52 to 0.75 mm) was performed before and after sublingual nitroglycerin (NTG). Quantitative analysis of coronary vasodilation was performed on cross-sectional images of the right coronary artery (RCA). A time-course analysis of coronary vasodilation was performed in a subset of eight subjects for 30 min after NTG. Signal-to-noise ratio was also measured on the in-plane RCA images. RESULTS: Coronary MRA demonstrated a 23% increase in cross-sectional area after NTG (16.9 +/- 7.8 mm2 to 20.8 +/- 8.9 mm2, p <0.0001), with significant vasodilation between 3 and 15 min after NTG on time-course analysis. The MRA measurements had low interobserver variability (< or =5%) and good correlation with X-ray angiography (r=0.98). The magnitude of vasodilation correlated with baseline cross-sectional area (r=0.52, p=0.03) and age (r=0.40, p=0.019). Post-NTG images also demonstrated a 31% improvement in coronary signal-to-noise ratio (p = 0.002). CONCLUSIONS: Nitroglycerin-enhanced coronary MRA can noninvasively measure coronary artery vasodilation and is a promising noninvasive technique to study coronary vasomotor function. 相似文献
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Type I interferons (IFN-αβ) are immunoregulatory cytokines that promote both innate and adaptive immune responses. Although they have been implicated in human SLE, recent studies in mice have helped solidify this connection. By using lupus-prone mice with knockout of the IFN-αβ receptor, we and others have documented that lack of IFN-αβ leads to a marked reduction in disease manifestations, including autoantibody production, target organ damage and mortality. Furthermore, IFN-αβ was found to potentially contribute to several levels of disease pathogenesis. These included the differentiation and activation of dendritic cells, the activation and proliferation of T cells, T cell survival and the activation and survival of autoantibody-producing B cells. These findings strongly support the targeting of IFN-αβ in SLE and suggest that definition of the specific pathways critical for disease induction will be important for optimal intervention. 相似文献