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Background Myeloid differentiation protein 1 (MD1) is expressed in the human heart and is a negative regulator of Toll-like receptor 4 (TLR4) signalling. MD1 exerts anti-arrhythmic effects. Aim The aim of this study was to determine the role of MD1 in myocardial infarction (MI)-related ventricular arrhythmias (VAs). Method Myocardial infarction was induced by surgical ligation of the left anterior coronary artery in MD1 knockout (KO) mice and their wild-type littermates. Myocardial infarction-induced vulnerability to VAs and its underlying mechanisms were evaluated. Results Myeloid differentiation protein 1 was downregulated in the MI mice. Myeloid differentiation protein 1 deficiency decreased post-MI left ventricular (LV) function and increased the infarct size. The MI mice exhibited prolonged action potential duration (APD), enhanced APD alternans thresholds, and a higher incidence of VAs. Myocardial infarction-induced LV fibrosis and inflammation decreased the expression levels of Kv4.2, Kv4.3, Kv1.5, and Kv2.1, increased Cav1.2 expression, and disturbed Ca2+ handling protein expression. These MI-induced adverse effects were further exacerbated in KO mice. Mechanistically, MD1 deletion markedly enhanced the activation of the TLR4/calmodulin-dependent protein kinase II (CaMKII) signalling pathway in post-MI mice. Conclusions Myeloid differentiation protein 1 deletion increases the vulnerability to VAs in post-MI mice. This is mainly caused by the aggravated maladaptive LV fibrosis and inflammation and interference with the expressions of ion channels and Ca2+ handling proteins, which is related to enhanced activation of the TLR4/CaMKII signalling pathway.

Double sex and mab-3-related transcription factor 1 (Dmrt1), which is expressed in goat male germline stem cells (mGSCs) and Sertoli cells, is one of the most conserved transcription factors involved in sex determination. In this study, we highlighted the role of Dmrt1 in balancing the innate immune response in goat mGSCs. Dmrt1 recruited promyelocytic leukemia zinc finger (Plzf), also known as zinc finger and BTB domain-containing protein 16 (Zbtb16), to repress the Toll-like receptor 4 (TLR4)-dependent inflammatory signaling pathway and nuclear factor (NF)-κB. Knockdown of Dmrt1 in seminiferous tubules resulted in widespread degeneration of germ and somatic cells, while the expression of proinflammatory factors were significantly enhanced. We also demonstrated that Dmrt1 stimulated proliferation of mGSCs, but repressed apoptosis caused by the immune response. Thus, Dmrt1 is sufficient to reduce inflammation in the testes, thereby establishing the stability of spermatogenesis and the testicular microenvironment.雄性生殖干细胞 (male Germ Stem Cell, mGSCs)，同样被称作精原干细胞 (Spermatogonial Stem Cells, SSCs)，是位于睾丸曲细精管基底膜上，既能通过自我更新维持自身群体数量的稳定，又能在体内定向分化并最终形成精子的一类成体干细胞。雄性生殖干细胞可以作为研究精子发生、减数分裂调控和细胞重编程的一个理想体外模型。Double sex and mab-3 related transcription factor 1 (DMRT1) 基因编码的蛋白质包含一个double sex/mab-3结构域，无论是在脊椎动物或者无脊椎动物中，这个最保守的结构域都会参与个体的性别决定过程。转录因子Dmrt1在奶山羊雄性生殖干细胞（mGSCs）和支持细胞（Sertoli cells）中都存在表达。在这项研究中，我们探究了Dmrt1在奶山羊mGSCs中免疫应答作用。Dmrt1通过募集转录因子Plzf（Promyelocytic Leukemia Zinc Finger，Plzf；又称为zinc finger and BTB domain-containing protein 16，Zbtb16）以抑制Toll样受体4（Toll-like receptor 4，TLR4）依赖性的炎症信号通路和核因子NF- κB的表达，从而降低雄性生殖干细胞中炎症反应的发生。我们在曲细精管中敲低Dmrt1导致了生殖细胞和体细胞的丢失，并发现促炎因子TNFα及IL-6的表达量上调。同时我们发现Dmrt1可以促进mGSCs的自我更新和增殖，并抑制由炎症反应引起的雄性生殖干细胞的凋亡。综合以上结果表明，DMRT1在促进雄性生殖干细胞自我更新及维持睾丸内环境稳态中的重要功能，提供了治疗睾丸生殖缺陷疾病的新思路。.

Objective Reproductive factors are female-specific coronary artery disease (CAD) risk factors. However, the importance of reproductive factors in angiographic obstructive CAD in postmenopausal women remains uncertain. This study aimed to compare reproductive factors between postmenopausal women with no apparent CAD, nonobstructive CAD, and obstructive CAD and identify reproductive risk factors for obstructive CAD. Methods In this hospital-based cross-sectional study, 1,474 postmenopausal women, admitted with chest pain and referred for invasive coronary angiography were enrolled between April 2013 and October 2018. Results Adjusted odds ratio (95% CI) for obstructive CAD were 1.81 (1.03-3.17) for multigravidity (three or more pregnancies), 1.77 (1.14-2.76) for early menopause (≤40 y old), and 1.72 (1.26-2.35) for short reproductive life span (≤30 y). Each additional year in age at menopause or reproductive life span was associated with a 4% reduction in obstructive CAD risk in postmenopausal women (odds ratio, 0.96; 95% CI, 0.94-0.99; P = 0.011). The other reproductive factors, including parity, age at first birth, spontaneous abortion, induced abortion, stillbirth, hypertensive disorders of pregnancy, gestational diabetes mellitus, and age at menarche, were not correlated with obstructive CAD risk in postmenopausal women. Conclusions Multigravidity (three or more pregnancies), early menopause, and a shorter reproductive life span were independent risk factors of angiographic obstructive CAD among postmenopausal women, which suggested that pregnancy and ovarian function may be important for the early identification and prevention of increased risk of female angiographic obstructive CAD.

Objective The purpose of this study was to examine the efficacy and safety of catheter-directed thrombolysis (CDT) for first-line treatment of popliteal and infrapopliteal acute limb ischemia. Methods A total of 28 consecutive patients (30 limbs) who underwent CDT for treatment of popliteal and infrapopliteal acute limb ischemia of thromboembolic origin between March 2012 and December 2017 were enrolled in this study. Per the Society for Vascular Surgery, limbs were classified into three runoff score groups: 10, poor. The primary end points were primary patency and limb salvage assessed by Kaplan-Meier survival analysis. Secondary end points were technical success and clinical success. The Society for Vascular Surgery-recommended scale for gauging changes in clinical status was used to assess clinical success. Safety of the procedure was evaluated on the basis of periprocedural complications according to the Society of Interventional Radiology classification system. Results Technical success was achieved in 25 (83.33%) treated limbs. Improved clinical status (grade +3/+2) was achieved in 93.33% of limbs. Primary patency and limb salvage for the entire cohort were 76.67% and 90% at 6 months and 60.0% and 76.67% at 12 months, respectively. The patency rate at 6 months and 12 months was 91.67% and 83.33% for the good runoff group, 80% and 60% for the compromised runoff group, and 50% and 25% for the poor runoff group, respectively. The patency rate of the good runoff group was significantly higher compared with that of the poor runoff group (P = .004). Major amputation rate and mortality rate were 16.67% and 7.14%, respectively, at 12 months. The reintervention rate was 3.57% at 6 months and 21.42% at 12 months. Conclusions CDT is safe and effective for revascularization of smaller vessel acute arterial thromboembolism as a primary therapy. However, more studies with a larger sample are warranted.

Aims Myeloid differentiation protein 1 (MD1) is expressed in the mammalian heart and exerts an anti‐arrhythmic effect. Atrial fibrillation (AF) is closely related to heart failure with preserved ejection fraction (HFpEF). The potential impact of MD1 on AF vulnerability in an HFpEF model is not clear. Methods and results MD1 knock‐out and wild‐type (WT) mice were subjected to uninephrectomy and continuous saline or d‐aldosterone infusion and given 1% sodium chloride drinking water for 4 weeks. Echocardiographic and haemodynamic measurements, electrophysiological studies, Masson staining, and molecular analysis were performed. Aldosterone‐infused WT mice develop HFpEF with left ventricular hypertrophy, moderate hypertension, pulmonary congestion, and diastolic dysfunction. Aldosterone infusion increased the vulnerability of WT mice to AF, as shown by a prolonged interatrial conduction time, shortened effective refractory period, and higher incidence of AF. In addition, aldosterone infusion increased myocardial fibrosis and inflammation, decreased sarcoplasmic reticulum Ca2+‐ATPase 2a protein expression and the phosphorylation of phospholamban at Thr17, and increased sodium/calcium exchanger 1 protein expression and the phosphorylation of ryanodine receptor 2 in WT mice. All of the above adverse effects of aldosterone infusion were further exacerbated in MD1 knock‐out mice compare with WT mice. Mechanistically, MD1 deletion increased the activation of the toll‐like receptor 4/calmodulin‐dependent protein kinase II signalling pathway in in vivo and in vitro experiments. Conclusions MD1 deficiency increases the vulnerability of HFpEF mice to AF. This is mainly caused by aggravated maladaptive left atrial fibrosis and inflammation and worsened dysregulation of calcium handling, which is induced by the enhanced activation of the toll‐like receptor 4/calmodulin‐dependent protein kinase II signalling pathway.

Cardiac dysfunction is a common complication of sepsis, and is attributed to severe inflammatory responses. Ferroptosis is reported to be involved in sepsis-induced cardiac inflammation. Therefore, we speculated that ferrostatin-1 (Fer-1), a ferroptosis inhibitor, improves cardiac dysfunction caused by sepsis. An intraperitoneal injection of lipopolysaccharide (LPS) was performed to induce a rat cardiac dysfunction model. Echocardiography, cardiac histopathology, biochemical and western blot results were analyzed. Twelve hours after the LPS injection, LPS-treated rats exhibited deteriorating cardiac systolic function, increased levels of cardiac injury markers and levels of ferroptosis markers prostaglandin endoperoxide synthase 2 (PTGS2). Additionally, LPS increased iron deposition in the myocardium, with downregulating ferroportin (FPN, SLC40A1) and transferrin receptor (TfR)expression, and upregulating ferritin light chain (FTL) and ferritin heavy chain (FTH1) expression. Meanwhile, LPS also increased lipid peroxidation in the rat heart by decreasing the expression of glutathione peroxidase 4 (GPX4). Moreover, the expression of inflammatory cytokines, such as tumor necrosis-alpha (TNF-α), interleukin-1 (IL-1β), and interleukin-6 (IL-6), and inflammatory cell infiltration were also increased following LPS challenge. Finally, the abovementioned adverse effects of LPS were relieved by Fer-1 except for TfR expression. Mechanistically, Fer-1 significantly reduced the levels of toll-like receptor 4 (TLR4), phospho-nuclear factor kappa B (NF-κB), and phospho-inhibitor of kappa Bα (IκBα) in LPS-treated rats. In summary, these findings imply that Fer-1 improved sepsis-induced cardiac dysfunction at least partially via the TLR4/NF-κB signaling pathway.

Background Knee osteoarthritis (KOA) is one of the most common musculoskeletal disorders. Acupotomy may be effective for KOA, but the evidence is limited. This trial aims to determine the effectiveness and safety of acupotomy for KOA. Methods/design This is a parallel-group, assessor-blinded randomized controlled trial. Two hundred patients with KOA will be recruited and randomly assigned to two groups (group A or group D) in a 1:1 ratio. Patients in group A will receive acupotomy and topical diclofenac diethylamine for 4 weeks, while patients in group D will receive topical diclofenac diethylamine alone for 4 weeks. The primary outcome will be the response rate—the proportion of patients who achieve the minimal clinically important improvement in pain and function at week 4 compared with baseline. Secondary outcomes will include pain, function, quality of life, the use of rescue medicine (loxoprofen sodium), and adverse events at weeks 4, 8, and 24 after randomization. Besides, joint fluid and serum will be collected to assess the level of inflammatory cytokines, like TNF-α, IL-1β, and MMP-3. Discussion This study will contribute to a better understanding of the effectiveness and safety of acupotomy in combination with topical nonsteroidal anti-inflammatory drugs. If the hypothesis is confirmed, acupotomy may be recommended as adjunctive therapy for patients with KOA. Results of the study will be of great importance for the guidelines of clinical therapy. Trial registration Chinese Clinical Trial Registry ChiCTR2100043005 Registered on 4 February 2021.

Myeloid differentiation 1 (MD‐1) is a secreted protein that regulates the immune response of B cell through interacting with radioprotective 105 (RP105). Disrupted immune response may contribute to the development of cardiac diseases, while the roles of MD‐1 remain elusive. Our studies aimed to explore the functions and molecular mechanisms of MD‐1 in obesity‐induced cardiomyopathy. H9C2 myocardial cells were treated with free fatty acid (FFA) containing palmitic acid and oleic acid to challenge high‐fat stimulation and adenoviruses harbouring human MD‐1 coding sequences or shRNA for MD‐1 overexpression or knockdown in vitro. MD‐1 overexpression or knockdown transgenic mice were generated to assess the effects of MD‐1 on high‐fat diet (HD) induced cardiomyopathy in vivo. Our results showed that MD‐1 was down‐regulated in H9C2 cells exposed to FFA stimulation for 48 hours and in obesity mice induced by HD for 20 weeks. Both in vivo and in vitro, silencing of MD‐1 accelerated myocardial function injury induced by HD stimulation through increased cardiac hypertrophy and fibrosis, while overexpression of MD‐1 alleviated the effects of HD by inhibiting the process of cardiac remodelling. Moreover, the MAPK and NF‐κB pathways were overactivated in MD‐1 deficient mice and H9C2 cells after high‐fat treatment. Inhibition of MAPK and NF‐κB pathways played a cardioprotective role against the adverse effects of MD‐1 silencing on high‐fat stimulation induced pathological remodelling. In conclusion, MD‐1 protected myocardial function against high‐fat stimulation induced cardiac pathological remodelling through negative regulation for MAPK/NF‐κB signalling pathways, providing feasible strategies for obesity cardiomyopathy.

The goals of this study were to investigate the role of the Notch1/PDGFRβ/ROCK1 signaling pathway in the pathogenesis of pulmonary fibrosis and to explore the possibility of treating fibrosis by targeting Notch1. Lung tissues from patients with pulmonary fibrosis were examined for the expression of Notch1/PDGFRβ/ROCK1 using RT-qPCR, western blotting, and immunostaining. Cultured mouse lung pericytes were transfected with Notch1-overexpressed vectors or shRNA targeting PDGFRβ/ROCK1 to examine cell behaviors, including proliferation, cell cycle arrest, and differentiation toward myofibroblasts. Finally, a mouse pulmonary fibrosis model was prepared, and a Notch1 inhibitor was administered to observe tissue morphology and pericyte cell behaviors. Human pulmonary fibrotic tissues presented with overexpression of Notch1, PDGFRβ, and ROCK1, in addition to a prominent transition of pericytes into myofibroblasts. In cultured mouse lung pericytes, overexpression of Notch1 led to the accelerated proliferation and differentiation of cells, and it also increased the expression of the PDGFRβ and ROCK1 proteins. The knockdown of PDGFRβ/ROCK1 in pericytes remarkably suppressed pericyte proliferation and differentiation. As further substantiation, the administration of a Notch1 inhibitor in a mouse model of lung fibrosis inhibited the PDGFRβ/ROCK1 pathway, suppressed pericyte proliferation and differentiation, and alleviated the severity of fibrosis. Our results showed that the Notch1 signaling pathway was aberrantly activated in pulmonary fibrosis, and this pathway may facilitate disease progression via mediating pericyte proliferation and differentiation. The inhibition of the Notch1 pathway may provide one promising treatment strategy for pulmonary fibrosis., Pulmonary fibrosis: Moving signals down a notch might help A cell membrane protein called Notch1, which binds to signaling molecules outside cells and then alters the activity of genes inside the cells, might be a promising target for drugs to treat the lung damage of pulmonary fibrosis. This condition, generally of unknown cause, involves thickening, stiffening and scarring of lung tissue. It can lead to serious breathing difficulties and eventually death, especially in people aged over 70. Hui Wang and colleagues at Central South University, Changsha, investigated the significance of the Notch1 signaling pathway by examining lung tissue from patients and manipulating the activity of the pathway in mouse cells. They conclude that Notch1 signaling is activated in pulmonary fibrosis. Drugs that could inhibit the pathway, for example by binding to the Notch1 protein, might open a promising new avenue toward treatment.

Background/Aims: Daphnetin (7,8-dihydroxycoumarin, DAP) exhibits various bioactivities, such as anti-inflammatory and antioxidant activities. However, the role of DAP in myocardial ischaemia/reperfusion (I/R) injury and I/R-related arrhythmia is still uncertain. This study aimed to investigate the mechanisms underlying the effects of DAP on myocardial I/R injury and electrophysiological properties in vivo and in vitro. Methods: Myocardial infarct size was measured by triphenyltetrazolium chloride staining. Cardiac function was assessed by echocardiographic and haemodynamic analyses. The levels of creatine kinase-MB, lactate dehydrogenase, malondialdehyde, superoxide dismutase, interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-α) were detected using commercial kits. Apoptosis was measured by terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labelling staining and flow cytometry. The viability of H9c2 cells was determined by the Cell Counting Kit-8 assay. In vitro, the levels of IL-6 and TNF-α were measured by quantitative PCR. The expression levels of proteins associated with apoptosis, inflammation, and the Toll-like receptor 4/myeloid differentiation factor 88/nuclear factor kappa B (TLR4/MyD88/NF-κB) signalling pathway were detected by Western blot analysis. The RR, PR, QRS, and QTc intervals were assessed by surface ECG. The 90% action potential duration (APD90), threshold of APD alternans, and ventricular tachycardia inducibility were measured by the Langendorff perfusion technique. Results: DAP preconditioning decreased myocardial I/R injury and hypoxia/reoxygenation (H/R) injury in cells. DAP preconditioning improved cardiac function after myocardial I/R injury. DAP preconditioning also suppressed apoptosis, attenuated oxidative stress, and inhibited inflammatory responses in vivo and in vitro. Furthermore, DAP preconditioning decreased the susceptibility to ventricular arrhythmia after myocardial I/R. Finally, DAP preconditioning inhibited the expression of TLR4, MyD88, and phosphorylated NF-κB (p-NF-κB)/P65 in mice subjected to I/R and cells subjected to H/R. Conclusions: DAP preconditioning protected against myocardial I/R injury and decreased susceptibility to ventricular arrhythmia by inhibiting the TLR4/MyD88/NF-κB signalling pathway.

Background Cardiac remodeling predisposes individuals to heart failure if the burden is not solved, and heart failure is a growing cause of morbidity and mortality worldwide. The cardiac extracellular matrix not only provides structural support, but also is a core aspect of the myocardial response to various biomechanical stresses and heart failure. MFAP4 (microfibrillar‐associated protein 4) is an integrin ligand located in the extracellular matrix, whose biological functions in the heart remain poorly understood. In the current study we aimed to test the role of MFAP4 in cardiac remodeling. Methods and Results MFAP4‐deficient (MFAP4 −/− ) and wild‐type mice were subjected to aortic banding surgery and isoproterenol to establish models of cardiac remodeling. We also evaluated the functional effects of MFAP4 on cardiac hypertrophy, fibrosis, and cardiac electrical remodeling. The expression of MFAP4 was increased in the animal cardiac remodeling models induced by pressure overload and isoproterenol. After challenge of 8 weeks of aortic banding or 2 weeks of intraperitoneal isoproterenol, MFAP4 −/− mice exhibited lower levels of cardiac fibrosis and fewer ventricular arrhythmias than wild‐type mice. However, there was no significant effect on cardiomyocyte hypertrophy. In addition, there was no significant difference in cardiac fibrosis severity, hypertrophy, or ventricular arrhythmia incidence between wild‐type‐sham and knockout‐sham mice. Conclusions These findings are the first to demonstrate that MFAP4 deficiency inhibits cardiac fibrosis and ventricular arrhythmias after challenge with 8 weeks of aortic banding or 2 weeks of intraperitoneal isoproterenol but does not significantly affect the hypertrophy response. In addition, MFAP4 deficiency had no significant effect on cardiac fibrosis, hypertrophy, or ventricular arrhythmia in the sham group in this study.

Aims Microfibrillar-associated protein 4 (MFAP4) is associated with atrial fibrillation (AF). Nevertheless, the specific role and underlying mechanism of MFAP4 in atrial fibrosis, the hallmark of AF, remain undefined. This study aims to elucidate the role of MFAP4 in the regulation of atrial fibrosis and to explore the underlying mechanism. Methods and results This study used MFAP4 knockout (MFAP4-KO) mice and their wild-type (WT) littermates to investigate the effect of angiotensin II (Ang II) (2000 ng/kg/min for 3 weeks) on atrial fibrosis and susceptibility to AF in terms of morphology, histology, electrophysiology, and molecular biology. MFAP4 deletion in mice did not alter cardiac structure and function at baseline. After treatment with Ang II, the MFAP4-KO mice showed a decreased left atrial enlargement and fibrosis, slowed atrial conduction, and reduced susceptibility to AF compared with the WT mice. Regarding the mechanism, we found that MFAP4 deletion markedly inhibited activated focal adhesion kinase (FAK)-mediated PI3K-AKT signalling and MEK1/2-ERK1/2 signalling after Ang II treatment. Conclusions Overall, our study showed that loss of MFAP4 attenuates Ang II-mediated left atrial fibrosis and dilation and decreases susceptibility to AF by decreasing the phosphorylation of FAK and inhibiting the activation of the PI3K-AKT and MEK1/2-ERK1/2 signalling pathways. These findings further indicate that targeting MFAP4 may be a potential upstream therapeutic option for atrial fibrosis and AF.

Shensong Yangxin (SSYX) is a traditional Chinese medicine, which has been proven to improve the clinical symptoms of arrhythmia. However, the role of SSYX in metabolic syndrome (MetS)-induced electrical remodeling remains to be fully elucidated. Here, we sought to clarify whether SSYX can alter the electrophysiological remodeling of cardiac myocytes from MetS rats by regulating transient outward potassium current (I to) and calcium current (I Ca-L). Male Wistar rats were subjected to 16 weeks of high-carbohydrate, high-fat to produce a MetS model group. SSYX (0.4 g/kg) was administrated by daily gavage 8 weeks following high-carbohydrate, high-fat for 8 weeks. In vivo electrophysiological study was performed to evaluated ventricular arrhythmias (VA) vulnerability and electrophysiological properties. The potential electrical mechanisms were estimated by whole-cell patch-clamp and molecular analysis. The H9C2 cells were used to verify the protective role of SSYX in vitro. After 16-week high-carbohydrate, high-fat feeding, MetS model rats showed increased body weight (BW), blood pressure (BP), blood sugar (BS), heart rate (HR) and heart weights to tibia length (HW/TL) ratio. Furthermore, MetS rats depicted increased VA inducibility, shortened effective refractory period (ERP) and prolonged action potential duration (APD). Lower I Ca-L and I to current densities were observed in MetS rats than CTL rats. Additionally, MetS rats exhibited significantly increased cardiac fibrosis, decreased Cx43 expression and protein levels of Cav1.2, Kv4.2, Kv4.3 than CTL group. As expected, these MetS-induced effects above were reversed when SSYX was administrated. Mechanistically, SSYX administrated significantly down-regulated the TLR4/MyD88/CaMKII signaling pathway both in vivo and in vitro. Collectively, our data indicated that the electrical remodeling induced by MetS contributed to the increased VA susceptibility. SSYX protects against MetS-induced VA by inhibiting electrical remodeling through TLR4/MyD88/CaMKII signaling pathway.

Myeloid differentiation protein 1 (MD1) is exerted an anti-arrhythmic effect in obese mice. Therefore, we sought to clarify whether MD1 can alter the electrophysiological remodeling of cardiac myocytes from obese mice by regulating voltage-gated potassium current and calcium current. MD1 knock-out (KO) and wild type (WT) mice were given a high-fat diet (HFD) for 20 weeks, starting at the age of 6 weeks. The potential electrophysiological mechanisms were estimated by whole-cell patch-clamp and molecular analysis. After 20-week HFD feeding, action potential duration (APD) from left ventricular myocytes of MD1-KO mice revealed APD20, APD50, and APD90 were profoundly enlarged. Furthermore, HFD mice showed a decrease in the fast transient outward potassium currents (Ito,f), slowly inactivating potassium current (IK, slow), and inward rectifier potassium current (IK1). Besides, HFD-fed mice showed that the current density of ICaL was significantly lower, and the haft inactivation voltage was markedly shifted right. These HFD induced above adverse effects were further exacerbated in KO mice. The mRNA expression of potassium ion channels (Kv4.2, Kv4.3, Kv2.1, Kv1.5, and Kir2.1) and calcium ion channel (Cav1.2) was markedly decreased in MD1-KO HFD-fed mice. MD1 deletion led to down-regulated potassium currents and slowed inactivation of L-type calcium channel in an obese mice model.

Background Trimethylamine N-oxide, a gut microbe-dependent metabolite of dietary choline and other trimethylamine-containing nutrients, has been associated with a poor prognosis for patients with cardiovascular disease. However, the role and underlying mechanisms of trimethylamine N-oxide in the cardiac function of patients with heart failure with preserved ejection fraction (HFpEF) have not been elucidated. Methods and Results C57BL/6 mice were fed a normal diet, high-choline (1.2%) diet, and/or 3-dimethyl-1-butanol diet 3 weeks before the operation (uninephrectomy followed by a continuous saline or aldosterone infusion). Mice were assessed for 4 weeks after the operation. Echocardiographic and hemodynamic measurements were performed. Blood samples were evaluated for choline, trimethylamine N-oxide, and inflammatory factor levels. Left ventricular tissues were collected to assess myocardial fibrosis and inflammation. Left ventricular hypertrophy, pulmonary congestion, and diastolic dysfunction were markedly exacerbated in HFpEF mice fed high-choline diets compared with mice fed the control diet. Myocardial fibrosis and inflammation were markedly increased in HFpEF mice fed high-choline diets compared with animals fed the control diet. Additionally, 3,3-dimethyl-1-butanol DMB markedly ameliorated cardiac diastolic dysfunction, myocardial fibrosis and inflammation in the choline-fed HFpEF mice. Conclusions A high-choline diet exacerbates cardiac dysfunction, myocardial fibrosis, and inflammation in HFpEF mice, and 3,3-dimethyl-1-butanol ameliorates the high-choline diet-induced cardiac remodeling.

New findings What is the central question of this study? Can targeted ablation of cardiac sympathetic neurons suppress myocardial infarction-induced adverse cardiac remodelling and left ventricular dysfunction? What is the main finding and its importance? Targeted ablation of cardiac sympathetic neurons significantly alleviated sympathetic remodelling and neuroendocrine activation, attenuated cardiac hypertrophy and fibrosis and improved left ventricular function. Thus, targeted ablation of cardiac sympathetic neurons might have a beneficial effect on adverse postinfarction remodelling and left ventricular dysfunction. Abstract Sympathetic overactivation is crucial in the development and progression of adverse cardiac remodelling and dysfunction. Targeted ablation of cardiac sympathetic neurons (TACSN) is an effective approach to inhibit overactivation of the sympathetic nervous system. The aim of this study was to investigate whether TACSN could suppress myocardial infarction (MI)-induced adverse cardiac remodelling and dysfunction, thereby producing protective effects. Thirty-eight dogs were randomly assigned into the sham-operated, MI or MI-TACSN group. The TACSN was induced by injecting cholera toxin B subunit-saporin compound into the stellate ganglia 1 week after MI. Five weeks after MI surgery, echocardiographic and haemodynamic parameters of cardiac function were significantly improved in the TACSN group compared with the MI group. In addition, TACSN attenuated the extent of cardiac hypertrophy and fibrosis and suppressed the increase in the plasma concentrations of noradrenaline, nerve growth factor, atrial natriuretic peptide, brain natriuretic peptide, angiotensin II and aldosterone. Furthermore, TACSN alleviated the growth associated protein-43-positive and tyrosine hydroxylase-positive nerve densities in the infarcted border zone and restored protein expression of the β1 -adrenergic receptor in the left ventricular myocardium. These findings indicate that TACSN might have a beneficial effect on adverse postinfarction remodelling and left ventricular dysfunction, which might be attributable, at least in part, to the attenuation of both sympathetic remodelling and the cardiac neuroendocrine system.

Aims The purpose of this study was to evaluate the cardiac electrophysiologic effects of targeted ablation of cardiac sympathetic neurons (TACSN) in a canine model of chronic myocardial infarction (MI). Methods and results Thirty-eight anaesthetized dogs were randomly assigned into the sham-operated, MI, and MI-TACSN groups, respectively. Myocardial infarction-targeted ablation of cardiac sympathetic neuron was induced by injecting cholera toxin B subunit-saporin compound in the left stellate ganglion (LSG). Five weeks after surgery, the cardiac function, heart rate variability (HRV), ventricular electrophysiological parameters, LSG function and neural activity, serum norepinephrine (NE), nerve growth factor (NGF), and brain natriuretic peptide (BNP) levels were measured. Cardiac sympathetic innervation was determined with immunofluorescence staining of growth associated protein-43 (GAP43) and tyrosine hydroxylase (TH). Compared with MI group, TACSN significantly improved HRV, attenuated LSG function and activity, prolonged corrected QT interval, decreased Tpeak-Tend interval, prolonged ventricular effective refractory period (ERP), and action potential duration (APD), decreased the slopes of APD restitution curves, suppressed the APD alternans, increased ventricular fibrillation threshold, and reduced serum NE, NGF, and BNP levels. Moreover, the densities of GAP43 and TH-positive nerve fibres in the infarcted border zone in the MI-TACSN group were lower than those in the MI group. Conclusion Targeted ablation of cardiac sympathetic neuron attenuates sympathetic remodelling and improves ventricular electrical remodelling in the chronic phase of MI. These data suggest that TACSN may be a novel approach to treating ventricular arrhythmias.

Sepsis is a known risk factor for new-onset atrial fibrillation (AF), and previous studies have demonstrated that ferroptosis participates in sepsis-induced organ injury development. Nevertheless, the role of ferroptosis in new-onset AF with sepsis remains largely unknown. This study aims to investigate the underlying mechanisms linking ferroptosis and AF caused by sepsis. LPS-induced endotoxemia is often used to model the acute inflammatory response associated with sepsis. Herein, we reported that ferroptosis was significantly activated in LPS-induced endotoxemia rat model. We also observed that ferroportin (Fpn), the only identified mammalian non-heme iron exporter, was downregulated in the atrium of endotoxemia model. Vulnerability to AF was also significantly increased in a endotoxemia rat model. Additionally, Fpn knockdown by shFpn further increased intracellular iron concentration and oxidative stress and exaggerated the AF vulnerability, which was alleviated by ferroptosis inhibition. Mechanistically, silencing Fpn worsened the alterations in calcium handling proteins expression in a endotoxemia rat model. These findings suggest that Fpn-mediated ferroptosis is involved in the new-onset AF with LPS-induced endotoxemia via worsening the calcium handling proteins dysregulation and provides a novel and promising strategy for preventing AF development in sepsis.

To investigate the inhibitory effects of chlorogenic acid on pulmonary fibrosis and the internal mechanisms in vivo and in vitro. 30 male BALB/C mice were randomized into 5 groups: control group, pulmonary fibrosis model group, low, middle and high dose of chlorogenic acid groups. Mice in pulmonary fibrosis model group were administered 5.0 mg/kg bleomycin with intracheal instillation and mice in 3 chlorogenic acid groups were treated with chlorogenic acid every day for 28 days after bleomycin administration. Lung tissue histology was observed using HE staining. Primary pulmonary fibroblasts were isolated and cultured. The expressions of fibrosis related factors (α-SMA and collagen I), as well as ER stress markers (CHOP and GRP78) were determined by both real-time PCR assay and Western blotting, while the expressions of other ER stress signaling pathway factors PERK, IRE-1, ATF-6 and protein levels of caspase-12, caspase-9, caspase-3, PARP were determined by Western blotting. RLE-6TN cell line induced by TGF-β1 was also used to verify the amelioration effects in vitro study. In both in vivo and in vitro studies, TUNEL staining was used to evaluate cell apoptosis. Expressions of collagen I, α-SMA, GRP78, and CHOP were significantly inhibited by chlorogenic acid in dose-dependent manner. Similarly, decreasing levels of cleaved caspase-12, caspase-9, caspase-3 and increasing level of uncleaved PARP were observed in chlorogenic acid groups compared with those in the fibrosis group both in vivo and in vitro. Chlorogenic acid could also significantly down-regulate the level of phosphorylation of PERK and cleaved ATF-6 in vivo study. Moreover, MTT assay demonstrated chlorogenic acid could enhance proliferation of RLE-6TN cells induced by TGFβ1 in vitro. And the apoptosis assays indicated that chlorogenic acid could significantly inhibit cell apoptosis both in vivo and in vitro studies. Chlorogenic acid could inhibit the pulmonary fibrosis through endoplasmic reticulum stress inhibition in vivo and in vitro.

// Yichun Wang 1 , Ying Liang 2 , Junming Luo 1 , Jing Nie 1 , Huiming Yin 3 , Qiong Chen 1 , Jing Dong 1 , Jixiang Zhu 1 , Jiamei Xia 1 and Wei Shuai 1 1 Critical Care Medicine Department, Hunan Cancer Hospital, Changsha, China 2 Department of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, China 3 Respiratory Medicine Department, The First Affiliated Hospital of Hunan University of Medicine, Changsha, China Correspondence to: Huiming Yin, email: 1976841746@qq.com Keywords: XIST/miR-139, pulmonary fibrosis (PF), fibroblast, β-catenin, extracellular matrix (ECM) Received: April 05, 2017 Accepted: May 04, 2017 Published: May 31, 2017 ABSTRACT Pulmonary fibrosis (PF), characterized by the destruction of lung tissue architecture and the abnormal deposition of extracellular matrix (ECM) proteins, currently has no satisfactory treatment. In the present study, we investigated the hypothesis that XIST play a promotive role in bleomycin (BLM)-induced ECM and pulmonary fibrosis; XIST exerts its effect through miR-139 regulation. XIST expression was upregulated in lung tissues derived from BLM-induced mouse model of PF, and was positively correlated with β-catenin and ECM protein levels, respectively. LV-sh-XIST-induced XIST knockdown led to decreased PF, reduced β-catenin and ECM protein levels in lung tissues. XIST knockdown suppressed the proliferation of IMR-90 (human fibroblast) and murine lung fibroblasts (MLFCs) and ECM protein expression. Moreover, miR-139 could directly bind to XIST and the 3’UTR of β-catenin; XIST competed with β-catenin for miR-139 binding both in IMR-90 and MLFCs. In MLFCs, miR-139 inversely regulated XIST, and could partially reverse the effect of XIST on β-catenin and ECM proteins. In lung tissues of PF mice, miR-139 expression was downregulated, whereas β-catenin expression was upregulated. In conclusion, XIST exerts positive effects on BLM-induced PF through inhibiting miR-139 to promote human/mouse fibroblast proliferation and ECM proteins.

To evaluate whether the mean pulse rate (PR) from three oscillometric blood pressure (BP) measurements provides an accurate estimation of electrocardiogram ventricular rate (HR) in patients with permanent atrial fibrillation (AF).BP and PR were measured with an oscillometric BP device for three times with one-minute interval. Simultaneously, one-minute electrocardiogram was also recorded for three times. The first PR and HR values were recorded as PR1 and HR1, and the averages of three PR and HR values as mean PR (mPR) and mean HR (mHR). Meanwhile, the differences between the highest and lowest values among the three PR and HR were calculated as ΔPR and ΔHR. Furthermore, the patients were stratified on ΔPR into the 0-15 and15 subgroups.A moderate positive correlation existed between PR1 and HR1 or mPR and mHR, and Bland-Altman plot also showed quite wide 95% limits between them. Meanwhile, ΔPR was significantly higher than ΔHR (12.1±8.6 vs 3.6±2.5bpm, P0.001). However, in the 0-15 subgroup, the correlation between mPR and mHR was high (R2=0.800), and the 95% limits were only from -11.3 to 14.2bpm with a difference of 1.4bpm. The coincidence (mPR-mHR10bpm) rate was 93.9% when PR≤80bpm, 96.3% when PR 81-100bpm, and 88.9% when PR over 100bpm.The average of three PR values reported by an oscillometric BP device could provide a clinically accepted estimation of mean HR of 3min in AF patients with ΔPR 0-15bpm and mean PR ≤100bpm.

Background To develop a machine learning model for predicting acute respiratory distress syndrome (ARDS) events through commonly available parameters, including baseline characteristics and clinical and laboratory parameters. Methods A secondary analysis of a multi-centre prospective observational cohort study from five hospitals in Beijing, China, was conducted from January 1, 2011, to August 31, 2014. A total of 296 patients at risk for developing ARDS admitted to medical intensive care units (ICUs) were included. We applied a random forest approach to identify the best set of predictors out of 42 variables measured on day 1 of admission. Results All patients were randomly divided into training (80%) and testing (20%) sets. Additionally, these patients were followed daily and assessed according to the Berlin definition. The model obtained an average area under the receiver operating characteristic (ROC) curve (AUC) of 0.82 and yielded a predictive accuracy of 83%. For the first time, four new biomarkers were included in the model: decreased minimum haematocrit, glucose, and sodium and increased minimum white blood cell (WBC) count. Conclusions This newly established machine learning-based model shows good predictive ability in Chinese patients with ARDS. External validation studies are necessary to confirm the generalisability of our approach across populations and treatment practices.

Trimethylamine N-oxide (TMAO) is closely related to cardiovascular diseases, particularly heart failure (HF). Recent studies shows that 3,3-dimethyl-1-butanol (DMB) can reduce plasma TMAO levels. However, the role of DMB in overload-induced HF is not well understood. In this research study, we explored the effects and the underlying mechanisms of DMB in overload-induced HF. Aortic banding (AB) surgery was performed in C57BL6/J mice to induce HF, and a subset group of mice underwent a sham operation. After surgery, the mice were fed with a normal diet and given water supplemented with or without 1% DMB for 6 weeks. Cardiac function, plasma TMAO level, cardiac hypertrophy and fibrosis, expression of inflammatory, electrophysiological studies and signaling pathway were analyzed at the sixth week after AB surgery. DMB reduced TMAO levels in overload-induced HF mice. Adverse cardiac structural remodeling, such as cardiac hypertrophy, fibrosis and inflammation, was elevated in overload-induced HF mice. Susceptibility to ventricular arrhythmia also significantly increased in overload-induced HF mice. However, these changes were prevented by DMB treatment. DMB attenuated all of these changes by reducing plasma TMAO levels, hence negatively inhibiting the p65 NF-κB signaling pathway and TGF-β1/Smad3 signaling pathway. DMB plays an important role in attenuating the development of cardiac structural remodeling and electrical remodeling in overload-induced HF mice. This may be attributed to the p65 NF-κB signaling pathway and TGF-β1/Smad3 signaling pathway inhibition.

Background and aim Obesity is an important risk factor for ventricular arrhythmia (VA), and myeloid differentiation protein 1 (MD1) has been reported to decrease in obese hearts. Nevertheless, underlying mechanisms linking MD1 and VA have not been fully studied. This study aims to investigate the regulatory role of MD1 in VA caused by diet-induced obesity. Methods and results MD1 knock-out (KO) and wild type (WT) mice from experimental groups were fed with a high-fat diet (HFD) since the age of six weeks for 20 weeks. The body weight gain, fast glucose and serum lipid levels were measured and recorded. In addition, pathological analysis, echocardiography, electrocardiography, langendorff-perfused heart and molecular analysis were performed to detect HFD-induced vulnerability to VA and its underlying mechanisms. After a 20-week HFD feeding, the mice showed an increase in body weight, glycemic, lipid levels, QTc interval, LVEDd, LVEDs and LVFS. HFD feeding also increased vulnerability to VA, as shown by the prolonged action potential duration (APD), enhanced APD alternans threshold and greater incidence of VA. Moreover, HFD feeding caused LV hypertrophy and fibrosis, and decreased the protein expressions of Kv4.2, Kv4.3, Kv1.5, Kv2.1 and Cav1.2 channels. At last, the above-mentioned HFD-induced adverse effects were further exacerbated in KO mice compared with WT mice. Mechanistically, MD1 deletion markedly enhanced the activation of TLR4/MyD88/CaMKII signaling pathway in HFD-fed mice. Conclusion MD1 deficiency increased HFD-induced vulnerability to VA. This is mainly caused by the aggravated maladaptive LV hypertrophy, fibrosis and decreased protein expressions of ion channels, which are induced by the enhanced activation of the TLR4/MyD88/CaMKII signaling pathway.

Background: Cardiac remodeling predisposes the heart to failure (HF) if the burden not solved, and HF is a growing cause of morbidity and mortality worldwide. Cardiac extracellular matrix (ECM) not only by providing structural support, but also a core aspect of myocardial response to various biomechanical stress and HF. Microfibrillar-associated protein 4 (MFAP4) is an integrin ligand and located in the ECM, whose biological functions in heart remain poorly understood. In the current study we aimed to test the role of MFAP4 in cardiac remodeling. Methods: MFAP4-deficient (MFAP4-/-) and wild type (WT) mice were subjected to aortic banding (AB) surgery and isoproterenol (ISO) induced models of cardiac remodeling. And evaluate the functional effect of MFAP4 on cardiac hypertrophy, fibrosis, cardiac electrical remodeling. Findings: The expression level of MFAP4 was increased in animal cardiac remodeling models induced by pressure load and ISO. When challenged with 8 weeks AB or 2 weeks ISO intraperitoneal, MFAP4 -/- mice exhibited lower levels of cardiac fibrosis and fewer ventricular arrhythmias. However, it has no significant effect on cardiomyocyte hypertrophy. Interpretation: These findings are the first to demonstrate an inhibitory role of MFAP4 deficiency on cardiac fibrosis and ventricular arrhythmias, but has no significant effect on hypertrophy response. Funding Statement: This work was supported by grants from the Key Project of the National Natural Science Foundation (No. 81530012); National Key RD Development Center for Medical Science and Technology National Health and Family Planning Commission of the People's Republic of China (The prevention and control project of cardiovascular disease, 2016ZX-008-01); the Fundamental Research Funds for the Central Universities (2042018kf1032). Declaration of Interests: The authors have declared no conflicts of interest. Ethics Approval Statement: All animal studies adhered to the guidelines for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (NIH Publication, revised 2011) and the guidelines of the Animal Care and Use Committee of Renmin Hospital of Wuhan University.

Background At present, the estimation of rest heart rate (HR) in atrial fibrillation (AF) is obtained by apical auscultation for 1min or on the surface electrocardiogram (ECG) by multiplying the number of RR intervals on the 10second recording by six. But the reasonability of 10second ECG recording is controversial. Methods ECG was continuously recorded at rest for 60s to calculate the real rest HR (HR60s). Meanwhile, the first 10s and 30s ECG recordings were used for calculating HR10s (sixfold) and HR30s (twofold). The differences of HR10s or HR30s with the HR60s were compared. The patients were divided into three sub-groups on the HR60s 100bpm. Results No significant difference among the mean HR10s, HR30s and HR60s was found. A positive correlation existed between HR10s and HR60s or HR30s and HR60s. Bland–Altman plot showed that the 95% reference limits were high as −11.0 to 16.0bpm for HR10s, but for HR30s these values were only −4.5 to 5.2bpm. Among the three subgroups with HR60s 100bpm, the 95% reference limits with HR60s were −8.9 to 10.6, −10.5 to 14.0 and −11.3 to 21.7bpm for HR10s, but these values were −3.9 to 4.3, −4.1 to 4.6 and −5.3 to 6.7bpm for HR30s. Conclusion As 10s ECG recording could not provide clinically accepted estimation HR, ECG should be recorded at least for 30s in the patients with AF. It is better to record ECG for 60s when the HR is rapid.

Background Bilirubin has been involved in the process of ageing and the pathology of ageing-related diseases. Circulating bilirubin is mainly derived from the clearance of disintegrated erythrocytes in the blood. However, the change of serum bilirubin level and its regulation during ageing and in ageing-related diseases remain to be elucidated. Methods A retrospective study was conducted by analyzing the blood cell test results and liver function results of 14,049 healthy research subjects at the Physical Examination Center and 2052 patients with various types of cardiovascular diseases (CVD) at the Department of Cardiology in Renmin Hospital of Wuhan University. Spearman correlation analysis and linear-regression analysis were used for correlation studies. Differences between male and female were investigated. Results Whereas the erythrocyte counts continuously decreased along with age, the proportion of aged erythrocytes was significantly increased in both male and female. The level of total circulating bilirubin was positively correlated with age and erythrocyte counts. The increase of bilirubin was associated with the increased morphological deviation of erythrocytes during ageing. Compared with health controls, the level of circulating bilirubin in CVD patients was significantly decreased consistent with the decline of erythrocyte counts and hemoglobin. Conclusions Ageing may be accompanied by an increased ageing rate of erythrocytes, which contributes to the ageing-related decline of erythrocyte counts. Both erythrocyte counts and the proportion of aged erythrocytes coordinately might determine the circulating level of bilirubin during ageing. In CVD, the decline of circulating bilirubin may be largely attributed to concurrent anemia.

Background Myeloid differentiation protein 1 (MD1) is expressed in various tissues, including the heart. However, the role of MD1 in obesity-related atrial remodelling remains incompletely understood. Here, this study intends to determine the regulatory role and underlying mechanisms of MD1 in obesity-related atrial remodelling. Methods A high-fat diet (HFD) feeding was performed in 6-week-old MD1-knockout (MD1-KO) mice and wild-type (WT) littermates for 20 weeks. Morphological, biochemical, functional, histological, and electrophysiological studies were conducted at the age of 26 weeks. Results Our results revealed that the MD1 expression levels were downregulated in the atrium of the HFD-fed induced obesity mice. An increase in body weight, glucose intolerance, hyperlipidemia, and adverse atrial remodelling, such as atrial inflammation and fibrosis, were induced by HFD feeding in WT mice. Vulnerability to atrial fibrillation (AF) was also significantly increased by HFD feeding in WT mice. In addition, these adverse effects caused by HFD-fed induced obesity were further exaggerated in MD1-KO mice compared with WT mice. Mechanistically, MD1-KO activated TLR4/NF-κB signaling pathways, which led to atrial remodelling in mice fed by HFD by increasing the phosphorylation of p65 and IκBα. Conclusions Our data suggested that MD1 deficiency played an important role in accelerating the development of inflammatory atrial fibrosis and increasing vulnerability to AF in mice with HFD-fed induced obesity, providing an essential target for improving HFD-induced atrial remodelling.

Myeloid differentiation protein 1(MD1), also known as lymphocyte antigen 86 (LY86), plays an important role in the toll-like receptor 4 (TLR4) signaling pathway. Recent studies show that MD1 is involved in regulating pressure overload-induced cardiac structural and electrical remodeling. However, the effect of MD1 on myocardial ischemia-reperfusion (I/R) injury and I/R related arrhythmia remains unknown. To further investigate that, the present study used MD1-knockout (MD1-KO) mice to study the role of MD1 in regulating myocardial I/R injury and its electrophysiology. The results demonstrate that the loss of MD1 led to a larger infarct size, increased activity of cardiac injury markers, aggravated histological damage, worsened cardiac function and decreased survival rate after myocardial I/R. Meanwhile, MD1 deficiency also aggravated inflammatory responses, promoted cardiomyocyte apoptosis and increased susceptibility to ventricular arrhythmia in mice subjected to myocardial I/R. Furthermore, loss of MD1 enhanced the activation of toll-like receptor 4 (TLR4) / nuclear factor kappa B (NF-κB) signaling pathway after myocardial I/R. Therefore, loss of MD1 exacerbated myocardial I/R injury and increased the susceptibility to ventricular arrhythmia, both of which are possibly related to the up-regulation of TLR4/NF-κB signaling pathway.

This study was to evaluate whether a special lecture on the Chinese Guideline for Blood Pressure Measurement (CGBPM) improves end-digit preference (EDP) of blood pressure (BP) recordings in primary care clinics.In 2012, the doctors working in a clinic received a lecture, which emphasizes that when mercurial sphygmomanometer was used, only 0, and even numbers could be recorded as BP end-digit. In 2016, we collected the BP recordings (2011-2015) of 462 hypertensive patients followed in the educated clinic or in another no-educated clinic. The percentages of 0, 2, 4, 6, 8 in BP end-digit were calculated for evaluating zero EDP, and the percent decline in each year was calculated on the formula: (baseline percentage - actual percentage in a year)/baseline percentage.In 2011, the percentage of zero end-digit was over 75% for SBP or DBP in both clinics. Against the no-educated clinic, the educated clinic had significant higher percent decline of zero EDP on SBP (31.5% vs -2.6%) and DBP (36.9% vs -14.3%) in 2013, and in 2014 (SBP 38.0% vs 11.6%; DBP 42.8% vs -4.0%). In 2015, the educated clinic still had higher percent decline of zero EDP on DBP (43.3% vs 29.3%). Furthermore, the percentages of zero end-digit for SBP (43.6% vs 49.2%) or for DBP (43.5% vs 59.0%) were lower in the educated clinic in 2015.Education on BP measurement and recording could improve the quality of BP recordings, and this effect may last for three years.

Objectives: To identify prevalence and severity of nonpain symptoms and to clarify possible influences on each nonpain symptom. Methods: The study used a descriptive survey design. Chinese version of the Edmonton Symptom Assessment System was used. Patients’ demographic and pain characteristics were collected. Results: The most common symptoms reported were loss of appetite (94.3%) followed by insomnia (93.3%), and tiredness (91.6%). Prevalence rates of nonpain symptom were all above 70% except “thinking clearly.” Prevalence and severity of nonpain symptoms varied by gender, age, primary cancer, and pain characteristics, especially intensity, number of breakthrough pain episodes per day, and number of pain sites. Conclusions: Most inpatients with cancer pain experienced concurrent nonpain symptoms. Comprehensive symptom assessment and intervention managing multiple symptoms are essential for these inpatients.

Neutrophil elastase (HNE) is a destructive enzyme and plays crucial roles in the pathophysiology of acute respiratory distress syndrome (ARDS). Endogenous proteinase inhibitors elafin (PI3) is important to protect against lung tissue destruction. We proposed to examine whether HNE and PI3 serve as prognostic biomarkers for ARDS.This study is a survival and longitudinal analysis of plasma profiles of HNE and PI3 in ARDS patients from a multicenter prospective observational cohort in Beijing, China. Plasma samples were collected on day-1, day-3, and day-7 of study enrollment.HNE levels were higher in ARDS non-survivors than survivors, whereas PI3 showed opposite direction for all three measurements (P 0.01 for all). Patients with HNE level above median and PI3 level below median values had the lowest survival probability and died the fastest. There was a significant longitudinal effect of HNE levels and PI3 level on mortality. Receiver-operating characteristic analysis demonstrated combination of HNE and PI3 had the discrimination ability for 28-day mortality (area under the receiver-operating characteristic curve [AUC]: 0.76), better than the combination of Berlin categories and APACHE II (AUC: 0.63). The addition of HNE and PI3 to Berlin categories and APACHE II has significantly improved the prognostic discrimination ability (AUC: 0.81, P 0.0001).Imbalance between HNE and PI3 levels in ARDS patients was associated with ARDS mortality. By combining these biomarkers with Berlin categories and APACHE II, prognostic power of ARDS was greatly improved. Circulation levels of HNE and PI3 may have the potential to predict ARDS mortality and better inform clinicians about ARDS mortality risk.

This study was to evaluate the role of hospital environment or physician presence for white coat effect (WCE) in hypertensive patients. At first, 54 hypertensive outpatients diagnosed on office blood pressure (OBP) were included for 2-week placebo run in. During the second week of the run in period, home BP was measured using electronic BP monitors for 5-7 days. Finally, 26 sustained hypertensive patients with home systolic BP/diastolic BP over 135/85 (but180/110) mm Hg were enrolled for 8-week treatment of nifedipine controlled-release tablet. In the visit day, BP was measured by patient-self (OBP-p) or by doctor (OBP-d) according to order determined with randomization method. The self-BP measurement was performed in a reception room of hospital. The differences between home BP and OBP-d or OBP-p were calculated as WCE calculated on doctor-measurement (WCE-d) or WCE calculated on patient-measurement (WCE-p), respectively. The home and OBP were measured with the same BP device for each patient during the study period. In the total 54 outpatients received placebo, the WCE-d was similar to the WCE-p (for systolic BP 6.6 ± 14.4 vs. 6.8 ± 15.8 mm Hg, NS; for diastolic BP 3.3 ± 8.8 vs. 2.9 ± 9.2 mm Hg, NS). Meanwhile, the 26 sustained hypertensive patients had similar systolic WCE-d and WCE-p (4.8 ± 10.3 vs. 5.0 ± 12.2 mm Hg, NS) at placebo stage. Similarly, these values were comparable (3.0 ± 14.0 vs. 2.2 ± 14.4 mm Hg, NS) in treatment stage. Hospital environment plays a main role for the WCE in hypertensive patients.

Literature is limited on the relationship between opiate analgesics and the development of infections in cancer patients. This study aimed to determine whether opiate analgesics contribute to the advancement of infections and how infection rates differ among the various opiates used for cancer management.From January 2013 to October 2014, we analyzed retrospectively 642 consecutive advanced cancer patients who received single types of opiates, including morphine, oxycodone, or fentanyl, or a combination of these drugs, continuously for14 days. Binominal logistic regression analysis was used to analyze the factors that may promote the development of infections.A total of 303 patients were included in the final analysis. Of these patients, 85, 41, and 68 patients received only morphine, oxycodone, and fentanyl, respectively. Altogether, 87 (28.7%) patients developed infections; 20 (23.5%), 10 (24.4%), and 14 (20.6%) patients developed infections in the groups that received only morphine, oxycodone, and fentanyl, respectively (P0.05). Logistic regression analysis found that the daily oral morphine equivalent (OME) is the an independent factor that influences the development of infection in the single-opiate group (odds ratio=1.002, P0.01). The risk for developing infection increased by 2% per 10 mg increase in the daily OME.Our clinical results did not display any difference among the single-opiate groups in the development of infections. However, the increase in daily OME may serve as a risk factor for the development of infections in advanced cancer patients using one opiate type for pain management.

An oscillometric device is recommended for blood pressure (BP) measurement in atrial fibrillation (AF), but there is still controversy concerning its accuracy. Therefore, evaluation of BP values in AF patients remains a challenge. This study included 251 patients with AF and 154 participants with sinus rhythm (SR). Pulse rate (PR) and BP were measured using an oscillometric device three times. The differences between the highest and lowest PR and the systolic and diastolic BP (SBP and DBP) were calculated as ΔPR, ΔSBP and ΔDBP, respectively. AF patients were stratified with respect to ΔPR in 0-5, 6-10, 11-15 and15 subgroups. The AF group had a greater ΔPR (12.1±8.6 vs. 4.10±3.21 b.p.m., P0.001), ΔSBP and ΔDBP than the SR group at similar SBP and DBP. A positive correlation existed between ΔPR and ΔSBP (r=0.255, P0.001) in AF patients, but no correlation was found in SR subjects. Meanwhile, the ΔSBP in the 0-5 and 6-10 subgroups (9.58±5.61 and 10.67±6.77 vs. 8.45±5.25 mm Hg, nonsignificant) was similar to the SR group, whereas ΔSBP in the 11-15 and15 subgroups was significantly greater than the SR group. Regardless of ΔPR, the ΔDBP in the AF group was significantly greater than that of the SR group. The AF patients who exhibited greater variability in their PR also had a greater variability in their SBP readings. The SBP measurement for AF patients is accurate as the measurement for patients with SR if the ΔPR is of 0-10 b.p.m. in AF.

The purpose of this study was to evaluate the association between epidermal growth factor receptor (EGFR) mutations and prognosis in patients with completely resected lung adenocarcinoma. A total of 131 patients were included in this study. EGFR mutation status in exons 18–21 of the tyrosine kinase-binding domain was detected using nested PCR amplification of individual exon. The χ 2 test was used to analyze the associations between EGFR mutations and the different variables. The log-rank test and Cox regression model were used to evaluate the factors influencing disease-free survival (DFS) and overall survival (OS). EGFR mutations in 18–21 exons were detected in 58 of the 131 patients (44.3 %). Smoking status (P = 0.029), N stage (P = 0.021), and pathologic stage (P = 0.048) were significantly associated with EGFR mutations. The median DFS in mutant EGFR and wild-type EGFR groups was 36.6 and 25.7 months, respectively (P = 0.533). No significant correlation was observed between EGFR mutations and OS (P = 0.564). However, patients with exon 19 mutation tended to have longer DFS than those with exon 21 mutation (46.2 vs. 21.9 months, P = 0.056), and the 1-, 2-, and 3-year OS rates were significantly higher in patients with exon 19 mutation compared to patients with exon 21 mutation (100, 96.7, 93.3 vs. 91.3, 82.6, 60.9 %, respectively, P = 0.01). Our data demonstrated that EGFR mutations do not have significant prognostic value in primary resected lung adenocarcinomas, but patients with exon 19 mutation tended to have better prognostic value compared to patients with exon 21 mutation.

To investigate the effects of electroacupuncture (EA) at neiguan (PC6) on gastric distention-induced transient lower esophageal sphincter relaxations (TLESRs) and discuss the mechanisms of this treatment.Protocol I: Twelve healthy cats underwent gastric distention for 60 min on the first day. Electrical acupoint stimulation was applied at the neiguan or a sham point on the hip in randomized order before gastric distention, on the third day and fifth day. Those cats that underwent EA at neiguan on the fifth day were named "Neiguan Group" and the cats that underwent EA at a sham acupoint on the fifth day were named "Sham Group" (control group). During the experiment the frequency of TLESRs and lower esophageal sphincter (LES) pressure were observed by a perfused sleeve assembly. Plasma levels of gastrin (GAS) and motilin (MTL) were determined by radioimmunoassay. Nitrite/nitrate concentration in plasma and tissues were measured by Griess reagent. The nuclei in the brain stem were observed by immunohistochemistry method of c-Fos and NADPH-d dyeing. Protocol II: Thirty six healthy cats were divided into 6 groups randomly. We gave saline (2 mL iv. control group), phaclofen (5 mg/kg iv. GABA-B antagonist), cholecystokinin octapeptide (CCK-8) (1 microg/kg per hour iv.), L-Arginine (200 mg/kg iv.), naloxone (2.5 micromol/kg iv.) and tacrine (5.6 mg/kg ip. cholinesterase inhibitor) respectively before EA at Neiguan and gastric distention. And the frequencies of TLESRs in experimental groups were compared with the control group.Protocol I: Not only the frequency of gastric distention-induced TLESR in 60 min but also the rate of common cavity during TLESRs were significantly decreased by EA at neiguan compared to that of sham acupoint stimulation. C-Fos immunoreactivity and NOS reactivity in the solitarius (NTS) and dorsal motor nucleus of the vagus (DMV) were significantly decreased by EA at neiguan compared to that of the sham group. However, the positive nuclei of C-Fos and NOS in reticular formation of the medulla (RFM) were increased by EA at neiguan. Protocol II: The inhibited effect of EA at neiguan on TLESR's frequency was completely restored by pretreatment with CCK (23.5/h vs 4.5/h, P0.05), L-arginine (17.5/h vs 4.5/h, P0.05) and naloxone(12/h vs 4.5/h, P0.05). On the contrary, phaclofen (6/h vs 4.5/h, P0.05) and tacrine (9.5/h vs 4.5/h, P0.05) did not influence it.Electric acupoint stimulation at Neiguan significantly inhibits the frequency of TLESR and the rate of common cavity during TLESR in cats. This effect appears to act on the brain stem, and may be mediated through nitric oxide (NO), CCK-A receptor and mu-opioid receptors. But the GABAB receptor and acetylcholine may not be involved in it.