Genetic deletion of TNFR2 augments inflammatory response and blunts satellite-cell-mediated recovery response in a hind limb ischemia model.

We have previously shown that TNF-tumor necrosis factor receptor-2/p75 (TNFR2/p75) signaling plays a critical role in ischemia-induced neovascularization in skeletal muscle and heart tissues. To determine the role of TNF-TNFR2/p75 signaling in ischemia-induced inflammation and muscle regeneration, we subjected wild-type (WT) and TNFR2/p75 knockout (p75KO) mice to hind limb ischemia (HLI) surgery. Ischemia induced significant and long-lasting inflammation associated with considerable decrease in satellite-cell activation in p75KO muscle tissue up to 10 d after HLI surgery. To determine the possible additive negative roles of tissue aging and the absence of TNFR2/p75, either in the tissue or in the bone marrow (BM), we generated 2 chimeric BM transplantation (BMT) models where both young green fluorescent protein (GFP)-positive p75KO and WT BM-derived cells were transplanted into adult p75KO mice. HLI surgery was performed 1 mo after BMT, after confirming complete engraftment of the recipient BM with GFP donor cells. In adult p75KO with the WT-BMT, proliferative (Ki67(+)) cells were detected only by d 28 and were exclusively GFP(+), suggesting significantly delayed contribution of young WT-BM cell to adult p75KO ischemic tissue recovery. No GFP(+) young p75KO BM cells survived in adult p75KO tissue, signifying the additive negative roles of tissue aging combined with decreased/absent TNFR2/p75 signaling in postischemic recovery.

Right ventricular dilatation on bedside echocardiography performed by emergency physicians aids in the diagnosis of pulmonary embolism.

STUDY OBJECTIVE: The objective of this study was to determine the diagnostic performance of right ventricular dilatation identified by emergency physicians on bedside echocardiography in patients with a suspected or confirmed pulmonary embolism. The secondary objective included an exploratory analysis of the predictive value of a subgroup of findings associated with advanced right ventricular dysfunction (right ventricular hypokinesis, paradoxical septal motion, McConnell's sign). METHODS: This was a prospective observational study using a convenience sample of patients with suspected (moderate to high pretest probability) or confirmed pulmonary embolism. Participants had bedside echocardiography evaluating for right ventricular dilatation (defined as right ventricular to left ventricular ratio greater than 1:1) and right ventricular dysfunction (right ventricular hypokinesis, paradoxical septal motion, or McConnell's sign). The patient's medical records were reviewed for the final reading on all imaging, disposition, hospital length of stay, 30-day inhospital mortality, and discharge diagnosis. RESULTS: Thirty of 146 patients had a pulmonary embolism. Right ventricular dilatation on echocardiography had a sensitivity of 50% (95% confidence interval [CI] 32% to 68%), a specificity of 98% (95% CI 95% to 100%), a positive predictive value of 88% (95% CI 66% to 100%), and a negative predictive value of 88% (95% CI 83% to 94%). Positive and negative likelihood ratios were determined to be 29 (95% CI 6.1% to 64%) and 0.51 (95% CI 0.4% to 0.7%), respectively. Ten of 11 patients with right ventricular hypokinesis had a pulmonary embolism. All 6 patients with McConnell's sign and all 8 patients with paradoxical septal motion had a diagnosis of pulmonary embolism. There was a 96% observed agreement between coinvestigators and principal investigator interpretation of images obtained and recorded. CONCLUSION: Right ventricular dilatation and right ventricular dysfunction identified on emergency physician performed echocardiography were found to be highly specific for pulmonary embolism but had poor sensitivity. Bedside echocardiography is a useful tool that can be incorporated into the algorithm of patients with a moderate to high pretest probability of pulmonary embolism.

Cardiovascular risks associated with low dose ionizing particle radiation.

Previous epidemiologic data demonstrate that cardiovascular (CV) morbidity and mortality may occur decades after ionizing radiation exposure. With increased use of proton and carbon ion radiotherapy and concerns about space radiation exposures to astronauts on future long-duration exploration-type missions, the long-term effects and risks of low-dose charged particle irradiation on the CV system must be better appreciated. Here we report on the long-term effects of whole-body proton ((1)H; 0.5 Gy, 1 GeV) and iron ion ((56)Fe; 0.15 Gy, 1GeV/nucleon) irradiation with and without an acute myocardial ischemia (AMI) event in mice. We show that cardiac function of proton-irradiated mice initially improves at 1 month but declines by 10 months post-irradiation. In AMI-induced mice, prior proton irradiation improved cardiac function restoration and enhanced cardiac remodeling. This was associated with increased pro-survival gene expression in cardiac tissues. In contrast, cardiac function was significantly declined in (56)Fe ion-irradiated mice at 1 and 3 months but recovered at 10 months. In addition, (56)Fe ion-irradiation led to poorer cardiac function and more adverse remodeling in AMI-induced mice, and was associated with decreased angiogenesis and pro-survival factors in cardiac tissues at any time point examined up to 10 months. This is the first study reporting CV effects following low dose proton and iron ion irradiation during normal aging and post-AMI. Understanding the biological effects of charged particle radiation qualities on the CV system is necessary both for the mitigation of space exploration CV risks and for understanding of long-term CV effects following charged particle radiotherapy.