Mesenchymal Stem Cells from Bone Marrow Enhance Neovascularization and Stromal Cell Proliferation in Rat Ischemic Limb in the Early Phase after plantation

Accumulating evidence from animal studies shows that the administration of mesenchymal stem cells (MSCs) from adult bone marrow ameliorates tissue damage after ischemic injury. In the present study we investigated the efficacy of MSC implantation into a hindlimb ischemia model over a short-term period to elucidate the effects conferred within the early phase after treatment. MSCs from rats expressing green fluorescence protein (GFP) were injected into rat ischemic limbs. Laser Doppler perfusion imaging revealed significantly higher blood perfusion recovery in the MSC group than in the control group on days 3 and 7 after the treatment. The capillary / muscle fiber ratio in ischemic muscle was also significantly higher in the MSC group than in the controls in a histological study. In spite of these benefits, we found no evident engraftment of the GFP-positive cells, and instead, the MSC treatment induced a proliferation of resident stromal cells in the perivascular area of the ischemic muscle, some of which produced vascular endothelial growth factor. The present study suggested that MSC therapy promotes neovascularization even in the early phase, both directly through endothelial proliferation and indirectly through activation of the resident stromal cells

Changes in Atrial Size Following PVI: Comparison of the Right and Left Atria

Background: Pulmonary vein isolation (PVI) is expected to cure atrial fibrillation (AF) and to improve atrial remodeling. However, the effects of PVI on the right atrial (RA) size have not been fully examined. We studied the effects of PVI on RA size in comparison that with the effects on LA size. Method: We studied 17 patients with drug-refractory AF (11 paroxysmal, 6 persistent). Two-dimensional echocardiography was performed at baseline and at follow-up to measure and compare RA and LA size.Results: Despite a short duration of AF in 7 patients after the PVI, all cases were maintained in sinus rhythm during the follow-up. LA and RA size were both reduced after the PVI compared with baseline measurements (LA 25.5 ± 2.9cm2 vs. 23.2 ± 3.6cm2, P < 0.05, RA 21.2 ± 2.9cm2 vs. 18.1 ± 3.0cm2, P < 0.01). The reduction ratio was more prominent in RA size (14.9%) than in LA size (8.7%)(P < 0.05). Conclusion: Atrial size was reduced following PVI for both the LA and RA, although the rate of reduction was more prominent in the RA

Tuberculosis infection among homeless persons and caregivers in a high-tuberculosis-prevalence area in Japan: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Tuberculosis (TB) is a major public health problem. The Airin district of Osaka City has a large population of homeless persons and caregivers and is estimated to be the largest TB-endemic area in the intermediate-prevalence country, Japan. However, there have been few studies of homeless persons and caregivers. The objective of this study is to detect active TB and to assess the prevalence and risk factors for latent TB infection among homeless persons and caregivers.</p> <p>Methods</p> <p>We conducted a cross-sectional study for screening TB infection (active and latent TB infections) using questionnaire, chest X-ray (CXR), newly available assay for latent TB infection (QuantiFERON-TB Gold In-Tube; QFT) and clinical evaluation by physicians at the Osaka Socio-Medical Center Hospital between July 2007 and March 2008. Homeless persons and caregivers, aged 30-74 years old, who had not received CXR examination within one year, were recruited. As for risk factors of latent TB infection, the odds ratios (OR) and 95% confidence intervals (95% CI) for QFT-positivity were calculated using logistic regression model.</p> <p>Results</p> <p>Complete responses were available from 436 individuals (263 homeless persons and 173 caregivers). Four active TB cases (1.5%) among homeless persons were found, while there were no cases among caregivers. Out of these four, three had positive QFT results. One hundred and thirty-three (50.6%) homeless persons and 42 (24.3%) caregivers had positive QFT results. In multivariate analysis, QFT-positivity was independently associated with a long time spent in the Airin district: ≥10 years versus <10 years for homeless (OR = 2.53; 95% CI, 1.39-4.61) and for caregivers (OR = 2.32; 95% CI, 1.05-5.13), and the past exposure to TB patients for caregivers (OR = 3.21; 95% CI, 1.30-7.91) but not for homeless persons (OR = 1.51; 95% CI, 0.71-3.21).</p> <p>Conclusions</p> <p>Although no active TB was found for caregivers, one-quarter of them had latent TB infection. In addition to homeless persons, caregivers need examinations for latent TB infection as well as active TB and careful follow-up, especially when they have spent a long time in a TB-endemic area and/or have been exposed to TB patients.</p

Population Attributable Fraction of Smoking and Metabolic Syndrome on Cardiovascular Disease Mortality in Japan: a 15-Year Follow Up of NIPPON DATA90

<p>Abstract</p> <p>Background</p> <p>Smoking and metabolic syndrome are known to be related to cardiovascular diseases (CVD) risk. In Asian countries, prevalence of obesity has increased and smoking rate in men is still high. We investigated the attribution of the combination of smoking and metabolic syndrome (or obesity) to excess CVD deaths in Japan.</p> <p>Methods</p> <p>A cohort of nationwide representative Japanese samples, a total of 6650 men and women aged 30-70 at baseline without history of CVD was followed for 15 years. Multivariate-adjusted hazard ratio for CVD death according to the combination of smoking status and metabolic syndrome (or obesity) was calculated using Cox proportional hazard model. Population attributable fraction (PAF) of CVD deaths was calculated using the hazard ratios.</p> <p>Results</p> <p>During the follow-up period, 87 men and 61 women died due to CVD. The PAF component of CVD deaths in non-obese smokers was 36.8% in men and 11.3% in women, which were higher than those in obese smokers (9.1% in men and 5.2% in women). The PAF component of CVD deaths in smokers without metabolic syndrome was 40.9% in men and 11.9% in women, which were also higher than those in smokers with metabolic syndrome (7.1% in men and 3.9% in women).</p> <p>Conclusion</p> <p>Our results indicated that a large proportion of excess CVD deaths was observed in smokers without metabolic syndrome or obesity, especially in men. These findings suggest that intervention targeting on smokers, irrespective of the presence of metabolic syndrome, is still important for the prevention of CVD in Asian countries.</p

Clinical Application of Vascular Regenerative Therapy for Peripheral Artery Disease

Prognosis of peripheral artery disease (PAD), especially critical limb ischemia, is very poor despite the development of endovascular therapy and bypass surgery. Many patients result in leg amputation and, therefore, vascular regenerative therapy is expected in this field. Gene therapy using vascular endothelial growth factor is the first step of vascular regenerative therapy, but did not confirm effectiveness in a large-scale randomized comparative study. Based on animal experiments, bone marrow mononuclear cells (MNCs), peripheral blood MNCs were used as the cell source for regenerative therapy. Those cells were confirmed to be effective to decrease rest pain and ulcer size, but its effect was not fully satisfied. Mesenchymal stem cells (MSCs) are expected as an effective cell source for vascular regeneration and clinical studies are ongoing, because the cells are able to differentiate into various cell types and produce a significant amount of vascular growth factors. Of vascular regeneration therapy, peripheral MNCs and bone marrow MNCs were recognized as advanced medical technology but do not attain to the standard therapy. However, clinical use of MSCs have already started, and induced pluripotent stem cells are surely promising tool for vascular regeneration therapy although further basic studies are required for clinical application

Mesenchymal Stem/Stromal Cells in Skeletal Muscle Are Pro-Angiogenic, and the Effect Is Potentiated by Erythropoietin

The aim of this study was to investigate the angiogenic potential of skeletal muscle mesenchymal stem/stromal cells (mMSCs). Platelet-derived growth factor receptor (PDGFR)-α positive mMSCs secreted vascular endothelial growth factor (VEGF) and hepatocyte growth factor when cultured in an ELISA assay. The mMSC-medium significantly induced endothelial tube formation in an in vitro angiogenesis assay. The mMSC implantation promoted capillary growth in rat limb ischemia models. Upon identifying the erythropoietin receptor (Epo-R) in the mMSCs, we examined how Epo affected the cells. Epo stimulation enhanced the phosphorylation of Akt and STAT3 in the mMSCs and significantly promoted cellular proliferation. Next, Epo was directly administered into the rats’ ischemic hindlimb muscles. PDGFR-α positive mMSCs in the interstitial area of muscles expressed VEGF and proliferating cell markers. The proliferating cell index was significantly higher in the ischemic limbs of Epo-treated rats than in untreated controls. Investigations by laser Doppler perfusion imaging and immunohistochemistry demonstrated significantly improved perfusion recovery and capillary growth in the Epo-treated groups versus the control groups. Taken together, the results of this study demonstrated that mMSCs possessed a pro-angiogenic property, were activated by Epo, and potentially contributed to capillary growth in skeletal muscle after ischemic injury

Bone marrow-derived mesenchymal stem cells inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia after arterial injury in rats

We investigated whether mesenchymal stem cell (MSC)-based treatment could inhibit neointimal hyperplasia in a rat model of carotid arterial injury and explored potential mechanisms underlying the positive effects of MSC therapy on vascular remodeling/repair. Sprague-Dawley rats underwent balloon injury to their right carotid arteries. After 2 days, we administered cultured MSCs from bone marrow of GFP-transgenic rats (0.8 × 106 cells, n = 10) or vehicle (controls, n = 10) to adventitial sites of the injured arteries. As an additional control, some rats received a higher dose of MSCs by systemic infusion (3 × 106 cells, tail vein; n = 4). Local vascular MSC administration significantly prevented neointimal hyperplasia (intima/media ratio) and reduced the percentage of Ki67 + proliferating cells in arterial walls by 14 days after treatment, despite little evidence of long-term MSC engraftment. Notably, systemic MSC infusion did not alter neointimal formation. By immunohistochemistry, compared with neointimal cells of controls, cells in MSC-treated arteries expressed reduced levels of embryonic myosin heavy chain and RM-4, an inflammatory cell marker. In the presence of platelet-derived growth factor (PDGF-BB), conditioned medium from MSCs increased p27 protein levels and significantly attenuated VSMC proliferation in culture. Furthermore, MSC-conditioned medium suppressed the expression of inflammatory cytokines and RM-4 in PDGF-BB-treated VSMCs. Thus, perivascular administration of MSCs may improve restenosis after vascular injury through paracrine effects that modulate VSMC inflammatory phenotype. Keywords: Mesenchymal stem cells, Vascular smooth muscle cells, Neointimal hyperplasia, Stem cell-secreted factor