ABSTRACT
Background: CXCL12/CXCR4 signaling is essential in cardiac development and repair, however, its contribution to aortic valve stenosis (AVS) remains unclear. In this study, we tested the role of endothelial CXCR4 on the development of AVS. Materials and methods: We generated CXCR4 endothelial cell-specific knockout mice (EC CXCR4 KO) by crossing CXCR4fl/fl mice with Tie2-Cre mice to study the role of endothelial cell CXCR4 in AVS. CXCR4fl/fl mice were used as controls. Echocardiography was used to assess the aortic valve and cardiac function. Heart samples containing the aortic valve were stained using Alizarin Red for detection of calcification. Masson's trichrome staining was used for the detection of fibrosis. The apex of the heart samples was stained with wheat germ agglutinin (WGA) to visualize ventricular hypertrophy. Results: Compared with the control group, the deletion of CXCR4 in endothelial cells led to significantly increased aortic valve peak velocity and aortic valve peak pressure gradient, with decreased aortic valve area and ejection fraction. EC CXCR4 KO mice also developed cardiac hypertrophy as evidenced by increased diastolic and systolic left ventricle posterior wall thickness (LVPW), cardiac myocyte size, and heart weight (HW) to body weight (BW) ratio. Our data also confirmed increased microcalcifications, interstitial fibrosis, and thickened valvular leaflets of the EC CXCR4 KO mice. Conclusion: The data collected throughout this study suggest the deletion of CXCR4 in endothelial cells is linked to the development of aortic valve stenosis and left ventricular hypertrophy. The statistically significant parameters measured indicate that endothelial cell CXCR4 plays an important role in aortic valve development and function. We have compiled compelling evidence that EC CXCR4 KO mice can be used as a novel model for AVS.
ABSTRACT
This systematic review determines the efficacy and safety of duloxetine for chronic low back pain (CLBP). We queried the PubMed, SCOPUS, and Ovid MEDLINE databases. All level I and II randomized controlled studies published in the English language investigating the efficacy of duloxetine for chronic low back pain were included. Five studies (832 duloxetine-treated patients, 667 placebo-treated patients, and 41 duloxetine and placebo crossover analysis patients) were analyzed. One study was level I evidence and four studies were level II evidence. All five studies reported statistically significant improvements in more than one back-pain-specific clinical outcome score with duloxetine versus placebo. Four studies found that duloxetine 60 mg daily leads to one or more statistically significant improvements versus placebo in Brief Pain Inventory Severity (BPI-S) scores. All five studies found no significant difference in serious adverse events (AEs) between the duloxetine and placebo groups. One study found a higher rate of total AEs among the duloxetine 120 mg group versus the placebo group; however, the same study did not find a significant difference in total AEs among duloxetine 20 mg and 60 mg groups versus placebo. Duloxetine is a safe and effective first-line option for the treatment of CLBP. Current studies demonstrate that 60 mg taken once daily has the highest efficacy for reducing pain and disability while minimizing minor adverse effects. Further randomized controlled trials with long-term follow-up are necessary to determine its long-term effects.
