Impaired atrial electromechanical function and atrial fibrillation promotion in alloxan-induced diabetic rabbits

Background: Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). However, the underlying mechanisms are still not clearly elucidated. The aim of this study was to evaluate the atrial electromechanical function, atrial electrophysiological changes and AF inducibility in alloxan-induced diabetic rabbits. Methods: In 8 alloxan-induced diabetic rabbits and 8 controls, we evaluated atrial electromechanical function by tissue Doppler imaging. Isolated Langendorff-perfused rabbit hearts were prepared to measure atrial refractory effective period (AERP) and its dispersion (AERPD), interatrial conduction time (IACT) and vulnerability to AF. Atrial interstitial fibrosis was evaluated by Sirius-Red staining. Results: Compared with controls, left atrial lateral wall Pa’-start interval (Pastart) and right atrial wall Pastart were increased in diabetic rabbits. AERPD was increased and IACT was prolonged in diabetic rabbits. Inducibility of AF in diabetic group was significant higher than controls (6/8 vs. 1/8, p < 0.05). Extensive interstitial fibrosis was observed in the DM group (p < 0.01). Correlation analysis showed that right atrial wall Pastart, Pa’-peak interval (Papeak) and total electromechanical activity (TEMA); left atrial lateral wall Papeak and TEMA, left atrial posterior wall TEMA, and IACT were correlated with atrial areas of fibrosis. Conclusions: Atrial electromechanical function is impaired in diabetic rabbits, and is associated with atrial fibrosis and interatrial electrical conduction delay

Renin–angiotensin system inhibition is associated with reduced risk of left atrial appendage thrombosis formation in patients with atrial fibrillation

Background: Inhibition of the renin–angiotensin axis can reduce the likelihood of atrial fibrillation (AF). However, the effects of angiotensin-converting-enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) on thrombogenicity in AF remain incompletely elucidated. Thisretrospective case-control study was conducted to evaluate whether the use of ACEI or ARB could reduce the incidence of left atrial appendage thrombus (LAAT) and spontaneous echocardiographic contrast (SEC) in patients with AF. Methods: A total of 199 AF patients who received both transesophageal echocardiogram (TEE) and transthoracic echocardiogram (TTE) successively on the same day from 2012 to 2016 were enrolled. Left atrial dimension, maximal left atrial volume (LAVmax), left ventricular end-diastolic dimension, left ventricular ejection fraction, and the ratio of the early transmitral flow velocity and the early mitral annular velocity (E/e’) were determined. Longitudinal LA strain was evaluated using two-dimensional speckle tracking imaging at each LA segment. Peak systolic strain was calculated by averaging total segments. LAAT, LAA emptying flow velocity (LAAeV) and SEC were evaluated by TEE. Risk factors for LAAT and usage of ACEIs or ARBs were recorded. Results: The incidence of LAAT was 27.6%. Among the patients with renin–angiotensin system (RAS) inhibitors, 20.5% were demonstrated to have LAAT, compared with 33.3% in the nonuser group (p = 0.044). LA peak systolic strain and LAAeV were significantly increased in patients with RAS inhibitors compared to the nonuser group (p = 0.002, p = 0.047, respectively). Patients with LAAT had higher CHA2DS2-VASc scores and evident SEC comparedwith those without LAAT (p = 0.000, p = 0.000, respectively). Usage of ACEIs/ARBs and antiplatelet drugs were frequent in patients with LAAT than in those without LAAT (p = 0.044, p = 0.000, respectively). Even after controlling for LAAT-related risk factors (age, body mass index, AF type, hypertension, diabetes mellitus, prior stroke or transient ischemic attack, drinking history and usage of antiplatelet drugs and LAVmax), use of RAS inhibitors remained significantly associated with a lower risk of LAAT (OR = 0.222; 95% CI 0.084–0.585, p = 0.002). Conclusions: This study shows that RAS inhibitors may be effective in reducing the risk of LAAT in patients with AF through atrial reverse remodeling

A novel three-dimensional and tissue Doppler echocardiographic index for diagnosing and prognosticating heart failure with preserved ejection fraction

Introduction: The diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging. In this study, a novel echocardiography index based on three-dimensional and tissue Doppler echocardiography for diagnosing and estimating prognosis in HFpEF. Materials and Methods: Patients with symptoms and/or signs of heart failure and normal left ventricular ejection fraction (LVEF ≥50%) who underwent right heart catheterization were screened. Patients were divided based on pulmonary capillary wedge pressure (PCWP) of ≥15 mmHg and PCWP <15 mmHg. A diagnosis of HFpEF was confirmed by PCWP of ≥15 mmHg according to ESC guidelines. A novel index was calculated by the ratio between stroke volume standardized to body surface area (SVI) and tissue Doppler mitral annulus systolic peak velocity S' (SVI/S'). Its diagnostic and prognostic values were determined. Results: A total of 104 patients (mean age 64 ± 12 years) were included. Of these, 63 had PCWP ≥15 mmHg and 41 patients had PCWP <15 mmHg. Compared to the PCWP <15 mmHg group, the ≥15 mmHg group had a significantly lower SVI/S' (P < 0.001). Logistic regression showed that SVI/S' was associated with high PCWP measured invasively. The SVI/S' had an area under the curve of 0.761 for diagnosing classifying between PCWP ≥15 mmHg and <15 mmHg. Kaplan–Meier analysis showed that the lower SVI/S' group showed a poorer prognosis. Conclusions: SVI/S' is a non-invasive index calculated by three-dimensional and tissue Doppler echocardiography. It is a surrogate measure of PCWP and can be used to diagnose and determine prognosis in HFpEF

Evaluation of portable colposcopy and human papillomavirus testing for screening of cervical cancer in rural China

OBJECTIVE: To evaluate the use of a portable, rechargeable colposcope combined with human papillomavirus (HPV) testing, as compared with HPV testing alone, for screening of cervical cancer and pre-cancerous lesions. METHODS: This was a cross-sectional study among 488 women in Baoshan County, Yunnan. The women underwent HPV testing followed by Gynocular portable colposcopy with visual inspection with acetic acid. Obvious lesions were biopsied. If portable colposcopy testing was negative but HPV testing was positive, the women underwent follow-up testing with thin-prep cytology and traditional colposcopy. Cervical biopsies were performed for any abnormalities. Histopathology was followed up with diagnosis and treatment. RESULTS: Among 488 women screened with portable colposcopy, 24 women underwent biopsy based on positive colposcopy screening. Of these 24 women, three were HPV positive and 21 were HPV negative. Five women had cervical intra-epithelial neoplasia (CIN) I and one had advanced cervical cancer. Forty-six women tested positive for HPV. Three of these women had screened positive on preliminary colposcopy, with one positive for CIN III/squamous cell carcinoma and one woman with CIN I. Forty-three women underwent follow-up testing with thin-prep cytology. Two women had atypical squamous cells of undetermined significance and five had low-grade squamous intra-epithelial lesions and were biopsied; three women had CIN I, one had CIN II and one had CIN III. HPV testing and portable colposcopy was more sensitive but slightly less specific than portable colposcopy or HPV testing alone. CONCLUSION: While HPV testing has high sensitivity and specificity for the detection of pre-cancerous and cancerous lesions and portable colposcopy has lower specificity, both methods of detection have low positive predictive value and high negative predictive value. In tandem, HPV testing and portable colposcopy had higher sensitivity for detection among women who underwent biopsies. In clinical practice, portable colposcopy was an effective, easy and affordable tool to transport to villages where cytology is not currently feasible

A Novel Three-Dimensional and Tissue Doppler Echocardiographic Index for Diagnosing and Prognosticating Heart Failure With Preserved Ejection Fraction

INTRODUCTION: The diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging. In this study, a novel echocardiography index based on three-dimensional and tissue Doppler echocardiography for diagnosing and estimating prognosis in HFpEF. MATERIALS AND METHODS: Patients with symptoms and/or signs of heart failure and normal left ventricular ejection fraction (LVEF ≥50%) who underwent right heart catheterization were screened. Patients were divided based on pulmonary capillary wedge pressure (PCWP) of ≥15 mmHg and PCWP <15 mmHg. A diagnosis of HFpEF was confirmed by PCWP of ≥15 mmHg according to ESC guidelines. A novel index was calculated by the ratio between stroke volume standardized to body surface area (SVI) and tissue Doppler mitral annulus systolic peak velocity S' (SVI/S'). Its diagnostic and prognostic values were determined. RESULTS: A total of 104 patients (mean age 64 ± 12 years) were included. Of these, 63 had PCWP ≥15 mmHg and 41 patients had PCWP <15 mmHg. Compared to the PCWP <15 mmHg group, the ≥15 mmHg group had a significantly lower SVI/S' (P < 0.001). Logistic regression showed that SVI/S' was associated with high PCWP measured invasively. The SVI/S' had an area under the curve of 0.761 for diagnosing classifying between PCWP ≥15 mmHg and <15 mmHg. Kaplan–Meier analysis showed that the lower SVI/S' group showed a poorer prognosis. CONCLUSIONS: SVI/S' is a non-invasive index calculated by three-dimensional and tissue Doppler echocardiography. It is a surrogate measure of PCWP and can be used to diagnose and determine prognosis in HFpEF

MiR-4319 Suppress the Malignancy of Triple-Negative Breast Cancer by Regulating Self-Renewal and Tumorigenesis of Stem Cells

Background/Aims: High levels of cancer stem cells (CSCs) in patients with triple-negative breast cancer (TNBC) correlate with risk of poor clinical outcome and possibly contribute to chemoresistance and metastasis in patients with highly malignant TNBC. Aberrant microRNA expression is associated with the dysfunction of self-renewal and proliferation in cancer stem cells, while there is little information about the TNBC-specific microRNAs in regulating CSC ability. Methods: Solexa deep sequencing was performed to detect the expression levels of TNBC or non-TNBC stem cells (CSCs) microRNAs. Mammosphere formation assay, qRT-PCR and the xenograft model in nude mice were performed. Bioinformatic analysis and microarray were used to select the target gene, and luciferase reporter assays were used to confirm the binding sites. Results: Solexa sequencing data exhibited differential expression of 193 microRNAs between TNBC and non-TNBC stem cells. The gene ontology analysis and pathways analyses showed that genes were involved in the maintenance of stemness. MiR-4319 could suppress the self-renewal and formation of tumorspheres in TNBC CSCs through E2F2, and also inhibited tumor initiation and metastasis in vivo. Moreover, increased E2F2 could reverse the effect of miR-4319 on the self-renewal in TNBC CSCs. Conclusions: MiR-4319 suppresses the malignancy of TNBC by regulating self-renewal and tumorigenesis of stem cells and might be a remarkable prognostic factor or therapeutic target for patients with TNBC

Curing hemophilia A by NHEJ-mediated ectopic F8 insertion in the mouse

BACKGROUND: Hemophilia A, a bleeding disorder resulting from F8 mutations, can only be cured by gene therapy. A promising strategy is CRISPR-Cas9-mediated precise insertion of F8 in hepatocytes at highly expressed gene loci, such as albumin (Alb). Unfortunately, the precise in vivo integration efficiency of a long insert is very low (~ 0.1%). RESULTS: We report that the use of a double-cut donor leads to a 10- to 20-fold increase in liver editing efficiency, thereby completely reconstituting serum F8 activity in a mouse model of hemophilia A after hydrodynamic injection of Cas9-sgAlb and B domain-deleted (BDD) F8 donor plasmids. We find that the integration of a double-cut donor at the Alb locus in mouse liver is mainly through non-homologous end joining (NHEJ)-mediated knock-in. We then target BDDF8 to multiple sites on introns 11 and 13 and find that NHEJ-mediated insertion of BDDF8 restores hemostasis. Finally, using 3 AAV8 vectors to deliver genome editing components, including Cas9, sgRNA, and BDDF8 donor, we observe the same therapeutic effects. A follow-up of 100 mice over 1 year shows no adverse effects. CONCLUSIONS: These findings lay the foundation for curing hemophilia A by NHEJ knock-in of BDDF8 at Alb introns after AAV-mediated delivery of editing components

Research on stabilized pressure hydraulic fluid supply technology adapted to hydraulic support actio

In order to improve ability of hydraulic support following shearer in working face, coupling relationship among support action velocity, hydraulic system pressure and flow rate of hydraulic fluid supply was revealed by theory analysis of support hydraulic fluid supply process. Simulation model of hydraulic system on working face was established and correctness of the model was verified. Effect of hydraulic system pressure and flow rate on support action velocity was analyzed, and a stabilized pressure hydraulic fluid supply technology adapted to support action was proposed. The technology takes support action type and hydraulic system pressure limitation as criterion, and realizes slow and steady changing process of hydraulic system pressure with slight rise during support action by adjusting flow rate, so as to improve support action velocity. The technology was tested by use of multi-pump and multi-frequency hydraulic fluid supply system, and validity of the technology was verified