Background-Bone marrow implantation (BMI) was shown to enhance angiogenesis in a rat ischemic heart model. This preclinical study using a swine model was designed to test the safety and therapeutic effectiveness of BMI. Methods and Results-BM-derived mononuclear cells (BM-MNCs) were injected into a zone made ischemic by coronary artery ligation. Three weeks after BMI, regional blood flow and capillary densities were significantly higher (4.6-and 2.8-fold, respectively), and cardiac function was improved. Angiography revealed that there was a marked increase (5.7-fold) in number of visible collateral vessels. Implantation of porcine coronary microvascular endothelial cells (CMECs) did not cause any significant increase in capillary densities. Labeled BM-MNCs were incorporated into Ϸ31% of neocapillaries and corresponded to Ϸ8.7% of macrophages but did not actively survive as myoblasts or fibroblasts.There was no bone formation by osteoblasts or malignant ventricular arrhythmia. Time-dependent changes in plasma levels for cardiac enzymes (troponin I and creatine kinase-MB) did not differ between the BMI, CMEC, and medium-alone implantation groups. BM-MNCs contained 16% of endothelial-lineage cells and expressed basic fibroblast growth factorӷvascular endothelial growth factorϾangiopoietin 1 mRNAs, and their cardiac levels were significantly upregulated by BMI. Cardiac interleukin-1␤ and tumor necrosis factor-␣ mRNA expression were also induced by BMI but not by CMEC implantation. BM-MNCs were actively differentiated to endothelial cells in vitro and formed network structure with human umbilical vein endothelial cells. Conclusions-BMI may constitute a novel safety strategy for achieving optimal therapeutic angiogenesis by the natural ability of the BM cells to secrete potent angiogenic ligands and cytokines as well as to be incorporated into foci of neovascularization.

BackgroundLittle research addresses how medical students develop their choice of specialty training in Japan. The purpose of this research was to elucidate factors considered by Japanese medical students when formulating their specialty choice.MethodsWe conducted qualitative interviews with 25 Japanese medical students regarding factors influencing specialty preference and their views on roles of primary versus specialty care. We qualitatively analyzed the data to identify factors students consider when developing specialty preferences, to understand their views about primary and subspecialty care, and to construct models depicting the pathways to specialization.ResultsStudents mention factors such as illness in self or close others, respect for family member in the profession, preclinical experiences in the curriculum such as labs and dissection, and aspects of patient care such as the clinical atmosphere, charismatic role models, and doctor-patient communication as influential on their specialty preferences. Participating students could generally distinguish between subspecialty care and primary care, but not primary care and family medicine. Our analysis yields a "Two Career" model depicting how medical graduates can first train for hospital-based specialty practice, and then switch to mixed primary/specialty care outpatient practice years later without any requirement for systematic training in principles of primary care practice.ConclusionPreclinical and clinical experiences as well as role models are reported by Japanese students as influential factors when formulating their specialty preferences. Student understanding of family medicine as a discipline is low in Japan. Students with ultimate aspirations to practice outpatient primary care medicine do not need to commit to systematic primary care training after graduation. The Two Career model of specialization leaves the door open for medical graduates to enter primary care practice at anytime regardless of post-graduate residency training choice.

Objective-This study was performed to evaluate the angiogenic effect of implantation of peripheral blood mononuclear cells (PB-MNCs) compared with bone marrow mononuclear cells (BM-MNCs) into ischemic hibernating myocardium. Methods and Results-A NOGA electromechanical system was used to map the hibernating region and to inject cells.PB-MNCs and BM-MNCs contained similar levels of vascular endothelial growth factor and basic fibroblast growth factor, whereas contents of angiogenic cytokines (interleukin-1␤ and tumor necrosis factor-␣) were larger in PB-MNCs. Numbers of endothelial progenitors were Ϸ500-fold higher in BM-MNCs. In BM-MNC-implanted myocardia of pigs, an increase in systolic function (ejection fraction from 33% to 52%) and regional blood flow (2.1-fold) and a reduction of the ischemic area (from 29% to 8%) were observed. PB-MNC implantation reduced the ischemic area (from 31% to 17%), the extent of which was less than that seen with BM-MNCs. In saline-implanted myocardium, the ischemic area expanded (from 28% to 38%), and systolic function deteriorated. Angiography revealed an increase in collateral vessel formation by PB-MNC or BM-MNC implantation. Capillary numbers were increased 2.6-and 1.7-fold by BM-MNC and PB-MNC implantation, respectively. BM-MNCs but not PB-MNCs were incorporated into neocapillaries. Conclusions-Catheter-based implantation of PB-MNCs can effectively improve collateral perfusion and regional function in hibernating ischemic myocardium by its ability to mainly supply angiogenic factors and cytokines. T herapeutic angiogenesis is a new and promising strategy to revascularize ischemic myocardium by stimulation of the growth of new blood vessels or maturation of preexisting collaterals. 1 Angiogenesis is induced by surgical or catheterbased delivery of angiogenic molecules, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). 2,3 Double-blind placebo-controlled clinical studies have indicated that intracoronary infusion of VEGF 4 or FGF2 5 does not improve myocardial perfusion, whereas catheter-based gene transfer of VEGF produces an increase in regional perfusion in patients with ischemic myocardium. 6 Myogenic cell grafting into the damaged myocardium is a promising approach for the treatment of heart failure. We and others have shown previously that intramyocardial transplantation of bone marrow (BM) mononuclear cells (MNCs) improves regional perfusion and systolic function in animal models of ischemic heart failure. [7][8][9][10] Marked increase in cardiac function after BM-MNC implantation may be due not only to neovascularization but also to cardiomyogenesis derived from marrow hematopoietic cells (see review 11 ) and/or marrow mesenchymal cells. 12 Hamano et al 13 reported the clinical efficacy and safety of BM-MNC implantation in 5 patients with ischemic heart disease in combination with bypass surgery. Thus, BM-MNC implantation may be feasible to salvage myocardial ischemia, although this procedure requires a minithoracotomy to exp...