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Aims: To characterise the clinicopathological and genetic characteristics of gastric neuroendocrine tumour G3 (gNET G3) and to compare them with those of gastric neuroendocrine carcinoma (gNEC) and gNET G2. Methods and results: A total of 115 gastric neuroendocrine neoplasms (NENs) were included, of which gNET G3 was different from gNET G1/G2 in terms of tumour location (P = 0.029), number (P = 0.003), size (P = 0.010), the Ki67 index (P < 0.001), lymph node metastasis (P < 0.001) and TNM stage (P = 0.011), and different from gNEC/gastric mixed neuroendocrine–non‐neuroendocrine neoplasm (gMiNEN) in terms of tumour size (P = 0.010) and the Ki67 index (P = 0.001). High‐resolution copy number (CN) profiling and validation experiments showed CN gains and high expression of DLL3 in gNET G3. Hierarchical clustering analysis based on CN characteristics showed that gNET G3 was separated from gNEC but mixed with gNET G2. In gene set enrichment analysis, eight pathways were significantly enriched in gNEC when comparing gNET G3 and gNEC (P < 0.05), while no pathways were enriched when comparing gNET G3 and gNET G2. Whole‐exome sequencing and validation experiments showed nonsense mutation of TP53 in one gNET G3, with wild‐type staining for p53. In gNEC, TP53 mutations were detected in four of eight cases, and abnormal expression of p53 was detected in all cases. Conclusion: Gastric NET G3 is a distinct entity with unique genetic characteristics, which are different from those of gNEC than gNET G2. Our results provide insight into some molecular alterations that may contribute to the development and progression of gNET G3 and serve as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Abstract Background The Friedewald formula (FF) is useful for calculating serum low-density lipoprotein cholesterol (LDL-C) values, but has a remarkable deviation and limitation especially in hypertriglyceridemia. We modify the formula which is now more suitable for LDL-C calculation. Methods 2180 cases were classified into three groups according to their TG concentrations (A: < 200 mg/dl, n = 1220; B: 200-400 mg/dl, n = 480; C: 400-1000 mg/dl, n = 480). The concentrations of LDL-C were measured or estimated by 1) a direct measurement (DM); 2) the FF; and 3) our modified Friedewald formula (MFF): LDL-C (mg/dl) = Non-HDL-C × 90% - TG × 10%. Results Linear regression showed a significant correlation (P < 0.001) between the measured and calculated LDL-C values. Bland-Altman plots indicated that the methods (DM/MFF) were in better agreement than those (DM/FF). The LDL-C/Non-HDL-C ratio in FF calculated values was significantly lower (P < 0.05) than that in MFF or DM values, while no significant difference between MFF and DM was found. In Group A and Group B, 4.26% and 14.79% of the MFF calculated values had more than 20% deviation from those measured by DM. These percentages were significantly lower than those calculated by FF, where 7.30% and 25.63% were observed, respectively (P < 0.01 and P < 0.001). The MFF calculated values were all positive even in Group C. Conclusions Compared with the FF calculation, serum LDL-C values estimated by our modified formula are closer to those measured by a direct assay. The modification significantly diminishes the interference caused by hypertriglyceridemia.

Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation and cardiac fibrosis. Emerging evidence indicated that endothelial-to-mesenchymal transition (Endo-MT) is a crucial event during organ fibrosis. This study was performed to clarify whether Endo-MT contributed to the progression of cardiac fibrosis in DCM. Cardiac samples from patients with DCM and control were obtained. The presence of endothelial markers, cluster of differentiation (CD)31 and vascular endothelial (VE)-cadherin, and mesenchymal markers, α smooth muscle actin (SMA) and fibroblast-specific protein 1 (FSP1) was performed using immunohistochemistry. Co-localization of endothelial markers and mesenchymal markers were identified using confocal immunofluorescence staining. Serum procollagen type I carboxy-terminal propeptide (PICP) and procollagen type III amino-terminal propeptide (PIIINP) were measured by ELISA. Protein levels of Wnt, ß-catenin and Snail were determined using western blot analysis. Immunohistochemistry and double-immunofluorescence staining demonstrated that the expression of CD31 and VE-cadherin were significantly decreased in DCM samples, whereas the FSP-1, and αSMA were significantly increased. CD31 and VE-cadherin labeling indexes were respectively negatively correlated with left ventricular end-diastolic diameter (LVEDD) (CD31 r=-0.82, P<0.01; VE-cadherin r=-0.73, P<0.01), while FSP-1 and αSMA were positively associated with LVEDD (αSMA r=0.65, P<0.01, FSP1 r=0.53, P<0.01) and left ventricular ejection fraction (αSMA r=-0.18, P<0.05; FSP1 r=-0.21, P<0.05). Furthermore, PICP and PIIINP levels were positively associated with the co-expression labeling indexes (CD31/SMA co-labeling index and PICP r=0.727, P<0.01; CD31/SMA co-labeling index and PIIINP r=0.741, P<0.01; VE-Cadherin/FSP-1 co-labeling index and PICP r=0.716, P<0.01; VE-cadherin/FSP-1 co-labeling index and PIIINP r=0.648, P<0.05). Western blot analysis indicated that proteins levels of Wnt signaling and snail were significantly increased in DCM samples. These results suggested that Endo-MT is potentially implicated in the pathogenesis of myocardial fibrosis and remodeling during the development of DCM, indicating a potential therapeutic target for DCM treatment. [ABSTRACT FROM AUTHOR]

The Th17/interleukin ( IL)-17 axis controls inflammation and might be important in the pathogenesis of experimental autoimmune myocarditis ( EAM) and other autoimmune diseases. However, the mechanism underlying the increased Th17 cell response in coxsackievirus-induced myocarditis remains unclear. This study aimed to elucidate the regulatory mechanisms affected by blocking IL-17 A responses in acute virus-induced myocarditis ( AVMC) mice. The results showed that IL-17 A and COX-2 proteins were significantly increased in the cardiac tissue of acute myocarditis, as were Th17 cells in the spleen. Using anti-mouse IL-17 Ab to block IL-17 A on day 7 of the viral myocarditis led to decreased expressions of cardiac tumor-necrosis factor alpha, IL-17 A and transforming growth factor beta in AVMC mice compared to isotype control mice. COX-2 and prostaglandin E2 proteins were dramatically elevated, followed by marked reductions in CVB3 replication and myocardial injury. These results hint that the Th17/ IL-17 axis is intimately associated with viral replication in acute myocarditis via induction of COX-2 and prostaglandin E2. [ABSTRACT FROM AUTHOR]

Determines the effects of HOE 694, a potent sodium-hydrogen exchange blocker, on transient inward current (Iti) and sodium-calcium exchange during hypoxia-reoxygenation in guinea pig cardiomyocytes. Effect of HOE 694 on Iti; Effect of HOE 694 on sodium-calcium exchange current; Proton production by anaerobic metabolism during ischema or hypoxia.

In the mass campaigns to exterminate the four pests and eliminate diseases in our country, serious ventricular arrhythmias are not infrequently encountered in rural areas because of the prevalent use of certain parasiticides such as trivalent antimony compound, bepheninum, and chloroquin. Most of these patients are seen at rural basic medical units and the medical personnel there, including the "barefoot" doctors, have accumulated experience in managing such complications. Electrical pacing is an important measure especially when the arrhythmia does not respond to routine drug therapy. The ventricles of these patients are often very irritable and there is usually some disturbance in blood electrolyte balance such as hypokalemia. etc. Once atrial or ventricular pacing has been established, one must adjust (he pacing rate frequently according to the level of ventricular irritability. Drugs that depress ventricular irritability such as lidocaine should be used and metabolic abnormalities corrected. Profound hypokalemia may induce ventricular tachyarrhythmia which is sometimes difficult to manage in a short period of time. Application of direct current countershock may make the condition worse. Electrical pacing plus replacement of potassium salt is the treatment of choice. Seven of our patients died at the time of hospitalization of which 4 deaths were due to causes other than tachyarrhythmias. Three patients died of recurrent ventricular tachyarrhythmia uncontrolled by electrical pacing. All were suffering from coronary heart disease and it is possible that these patients had acute myocardial infarction at the time of admission which was masked by the ventricular tachyarrhythmias and became the undiscovered cause of death. [ABSTRACT FROM AUTHOR]

Objective: To examine the existing Framingham Risk Score (FRS) and Chinese Risk Score (CRS) in predicting the development of ischemic cardiovascular diseases (ICVD), and determine potential added value of novel risk factors., Methods: The China Multi-Provincial Cohort Study (CMCS) was a population-based prospective cohort study in 11 provinces of China. An annual follow up was conducted in 840 men aged 35 to 64 years in Shanghai cohort, who were without coronary heart disease and stroke at baseline examination in 1992, to collect the incidence data of ICVD events (coronary death, myocardial infarction, and ischemic stroke). The detection of novel risk factors were conducted for the cohort in 2007. The basic Framingham and Chinese prediction scores power were assessed by using C-statistic of ICVD events associated with risk scores, then the novel risk factors were evaluated by adding them independently to the basic Chinese models. The area under the curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement(IDI) were calculated to determine if each of the novel risk factors improved risk prediction., Results: By the end of December 2014, 24 cases of coronary heart disease (myocardial infarction or/and coronary death), 45 cases of ischemic stroke had occurred in 840 subjects in Shanghai cohort with a follow-up of 22.3 years averagely. Both the FRS and CRS had predicting power for ICVD, the AUCs were 0.6576 (95%CI: 0.5942-0.7240) and 0.7265 (95%CI: 0.6643-0.7887), respectively. The incremental AUC was 0.0689 (95%CI: 0.0196-0.1171) (P=0.006). None of the novel risk factors significantly improved the AUC. High-sensitive-CRP (hs-CRP) was the only novel risk factor resulting in a significant increase of NRI. CRS in 2007 significantly improved the IDI, but net changes were small., Conclusions: CRS had high power in the 20-year risk prediction for ICVD in middle-aged men in Shanghai. The inclusion of hs-CRP could make some improvement in risk prediction, but is unlikely to be meaningful when reclassification or new discrimination strategy are made which can change the clinical risk.

Recent studies in septic models have shown that myocardial calpain activity and TNF-α expression increase during sepsis and that inhibition of calpain activation downregulates myocardial TNF-α expression and improves cardiac dysfunction. However, the mechanism underlying this pathological process is unclear. Thus, in the present study, we aimed to explore whether IκBα/NF-κB signaling linked myocardial calpain activity and TNF-α expression in septic mice. Adult male mice were injected with LPS (4 mg/kg ip) to induce sepsis. Myocardial calpain activity, IκBα/NF-κB signaling activity, and TNF-α expression were assessed, and myocardial function was evaluated using the Langendorff system. In septic mice, myocardial calpain activity and TNF-α expression were increased and IκBα protein was degraded. Furthermore, NF-κB was activated, as indicated by increased NF-κB p65 phosphorylation, cleavage of p105 into p50, and its nuclear translocation. Administration of the calpain inhibitors calpain inhibitor Ш and PD-150606 prevented the LPS-induced degradation of myocardial IκBα, NF-κB activation, and TNF-α expression and ultimately improved myocardial function. In calpastatin transgenic mice, an endogenous calpain inhibitor and cultured neonatal mouse cardiomyocytes overexpressing calpastatin also inhibited calpain activity, IκBα protein degradation, and NF-κB activation after LPS treatment. In conclusion, myocardial calpain activity was increased in septic mice. Calpain induced myocardial NF-κB activation, TNF-α expression, and myocardial dysfunction in septic mice through IκBα protein cleavage.