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Backgrounds: Influenza vaccination could decrease the risk of major cardiac events in patients with hypertension. However, the vaccine’s effects on decreasing the risk of chronic kidney disease (CKD) development in such patients remain unclear. Methods: We retrospectively analysed the data of 37,117 patients with hypertension (≥55 years old) from the National Health Insurance Research Database during 1 January 2001 to 31 December 2012. After a 1:1 propensity score matching by the year of diagnosis, we divided the patients into vaccinated (n = 15,961) and unvaccinated groups (n = 21,156). Results: In vaccinated group, significantly higher prevalence of comorbidities such as diabetes, cerebrovascular disease, dyslipidemia, heart and liver disease were observed compared with unvaccinated group. After adjusting age, sex, comorbidities, medications (anti-hypertensive agents, metformin, aspirin and statin), level of urbanization and monthly incomes, significantly lower risk of CKD occurrence was observed among vaccinated patients in influenza season, non-influenza season and all season (Adjusted hazard ratio [aHR]: 0.39, 95% confidence level [C.I.]: 0.33–0.46; 0.38, 95% C.I.: 0.31–0.45; 0.38, 95% C.I.: 0.34–0.44, respectively). The risk of hemodialysis significantly decreased after vaccination (aHR: 0.40, 95% C.I.: 0.30–0.53; 0.42, 95% C.I.: 0.31–0.57; 0.41, 95% C.I.: 0.33–0.51, during influenza season, non-influenza season and all season). In sensitivity analysis, patients with different sex, elder and non-elder age, with or without comorbidities and with or without medications had significant decreased risk of CKD occurrence and underwent hemodialysis after vaccination. Moreover, the potential protective effect appeared to be dose-dependent. Conclusions: Influenza vaccination decreases the risk of CKD among patients with hypertension and also decrease the risk of receiving renal replacement therapy. Its potential protective effects are dose-dependent and persist during both influenza and noninfluenza seasons.

Sleep disorder (SD), especially sleep apnea, and its effect on atrial fibrillation (AF) are gathering attention. However, other SDs may also play an essential role in AF. The aim of the study is to investigate the effects of other SDs on the risk of atrial fibrillation development.This study investigated the risk of AF in people diagnosed with SD compared with that in age and sex-matched unaffected individuals. This longitudinal, nationwide, population-based cohort study was conducted using data from the Taiwan National Health Insurance Research Database (NHIRD) of individuals diagnosed with SD from January 1, 2001, to December 31, 2012.The sample consisted of 193,288 people with the SD, which include of 4406 people with sleep apnea, 73,704 people with insomnia, 107,395 people with sleep disturbance, 7,783 people with other SD, and 193,288 matched controls. A Cox proportional hazard regression was used to compute the risk of AF in people with SD and subgroup of SD, relative to that in people without SD. The AF incidences were 1.21-fold higher (95% CI 1.15-1.27) in the SD cohort, 1.19-fold higher (95% CI 0.91-1.56) in the sleep apnea cohort, 1.26-fold higher (95% CI 1.19-1.34) in the insomnia cohort, 1.15-fold higher (95% CI 1.08-1.22) in the sleep disturbance cohort, and 1.30-fold higher (95% CI 1.11-1.53) in other SDs, than in the control cohort, after age, sex, and comorbidities were adjusted.This nationwide population-based cohort study indicates a strong relationship between SD and incident AF, and insomnia has a higher impact on AF compared with other SD.

Heart failure (HF) and cancer have similar risk factors. HMG-CoA reductase inhibitors, also known as statins, are chemoprotective agents against carcinogenesis. We aimed to evaluate the chemoprotective effects of statins against liver cancer in patients with HF. This cohort study enrolled patients with HF aged ≥20 years between 1 January 2001 and 31 December 2012 from the National Health Insurance Research Database in Taiwan. Each patient was followed to assess liver cancer risk. A total of 25,853 patients with HF were followed for a 12-year period; 7364 patients used statins and 18,489 did not. The liver cancer risk decreased in statin users versus non-users (adjusted hazard ratio (aHR) = 0.26, 95% confidence interval (CI): 0.20–0.33) in the entire cohort in the multivariate regression analysis. In addition, both lipophilic and hydrophilic statins reduced the liver cancer risk in patients with HF (aHR 0.34, 95% CI: 0.26–0.44 and aHR 0.42, 95% CI: 0.28–0.54, respectively). In the sensitivity analysis, statin users in all dose-stratified subgroups had a reduced liver cancer risk regardless of age, sex, comorbidity, or other concomitant drug use. In conclusion, statins may decrease liver cancer risk in patients with HF.

Chronic kidney disease (CKD) is associated with malignancy, including colorectal cancer, via the potential mechanism of chronic inflammation status. This study aimed to determine whether influenza vaccines can reduce the risk of colorectal cancer in patients with CKD. Our cohort study enrolled 12,985 patients older than 55 years with a diagnosis of CKD in Taiwan from the National Health Insurance Research Database at any time from 1 January 2001 to 31 December 2012. Patients enrolled in the study were divided into a vaccinated and an unvaccinated group. In this study, 7490 and 5495 patients were unvaccinated and vaccinated, respectively. A propensity score was utilized to reduce bias and adjust the results. Cox proportional hazards regression was used to estimate the correlation between the influenza vaccine and colorectal cancer in patients with CKD. The results showed that the influenza vaccine exerted a protective effect against colorectal cancer in populations with CKD. The incidence rate of colon cancer in the vaccinated group was significantly lower than in the unvaccinated group, with an adjusted hazard rate (HR) of 0.38 (95% CI: 0.30–0.48, p < 0.05). After the propensity score was adjusted for Charlson comorbidity index, age, sex, dyslipidemia, hypertension, diabetes, monthly income, and level of urbanization, the dose-dependent effect was found, and it revealed adjusted HRs of 0.74 (95% CI: 0.54–1.00, p < 0.05), 0.41 (95% CI: 0.30–0.57, p < 0.001), 0.16 (95% CI: 0.11–0.25, p < 0.001) for one, two to three, and four or more vaccinations, respectively. In summary, the influenza vaccine was found to be associated with a reduced risk of colorectal cancer in CKD patients. This study highlights the potential chemopreventive effect of influenza vaccination among patients with CKD. Future studies are required to determine whether the aforementioned relationship is a causal one.

Coronary artery disease (CAD) is the leading cause of death in developed countries. Studies have indicated that ischemic tissues may release exosome-carried microRNAs (miRNAs) into circulation. miRNAs are a class of small, endogenous, noncoding RNAs that regulate the expression of multiple target genes at the posttranscriptional level on the basis of sequences that are complementary to target mRNA molecules. However, the prognostic role of exosomal miRNAs in CAD remains unclear. In this study, we compared the profiles of circulating exosomal miRNA expression in patients with angiographically assessed absent and well-developed collateral vessels. A total of 109 patients who underwent coronary angiography were recruited, including 31 patients with CAD and well-developed collateral circulation, 44 patients with no collateral flow (as indicated by their Rentrop scores), and 34 patients with patent coronary arteries (control group). miRNAs were then extracted from exosomes collected from peripheral blood and amplified, and a miRNA microarray system was used to profile the expression of these miRNAs in the exosomes. Subsequently, the effects of specific miRNAs on angiogenesis were identified in vitro. On the basis of the array data, miRNAs with high differential expression ratios along with Grade 0–2 collateral flow were selected. Among patients with adequate collateral perfusion, the top five overexpressed candidate miRNA markers were miR-29a, miR-592, miR-518e, miR-32, and miR-766. Similarly, among patients with no collateral flow, the top five overexpressed miRNAs were miR-300, miR-576-3p, miR-642, miR-620, and miR-1255a. As a next step, the angiogenic ability and proangiogenic signaling pathway of two specific angiogenesis-related miRNAs (i.e., miR-300 and miR-29a) with high differential expression ratios were determined. According to the microarray data and study results, miRNAs with high expression levels can be used as biomarkers to distinguish between types of collateral circulation in patients with CAD and can be used in diagnostic or prognostic applications for high-risk patients with CAD. These findings may serve as a reference for the development of noninvasive and cost-effective approaches aimed at identifying the high risk of CAD and for the development of novel therapeutic targets for vascular diseases, including CAD with impaired collateral angiogenesis.

Various adverse events and complications have been attributed to COVID-19 (coronavirus disease 2019) vaccinations, which can affect the cardiovascular system, with conditions such as myocarditis, thrombosis, and ischemia. The aim of this study was to combine noninvasive pulse measurements and frequency domain analysis to determine if the Pfizer-BioNTech COVID-19 vaccine (BNT162b2) vaccination and its accompanying cardiovascular side effects will induce changes in arterial pulse transmission and waveform. Radial blood pressure waveform and photoplethysmography signals were measured noninvasively for 1 min in 112 subjects who visited Shuang-Ho Hospital for a BNT162b2 vaccination. Based on side effects, each subject was assigned to Group N (no side effects), Group CV (cardiac or vascular side effects), Group C (cardiac side effects only), or Group V (vascular side effects only). Two classification methods were used: (1) machine-learning (ML) analysis using 40 harmonic pulse indices (amplitude proportions, phase angles, and their variability indices) as features, and (2) a pulse-variability score analysis developed in the present study. Significant effects on the pulse harmonic indices were noted in Group V following vaccination. ML and pulse-variability score analyses provided acceptable AUCs (0.67 and 0.80, respectively) and hence can aid discriminations among subjects with cardiovascular side effects. When excluding ambiguous data points, the AUC of the score analysis further improved to 0.94 (with an adopted proportion of around 64.1%) for vascular side effects. The present findings may help to facilitate a time-saving and easy-to-use method for detecting changes in the vascular properties associated with the cardiovascular side effects following BNT162b2 vaccination.

Type 2 diabetes mellitus (DM) patients are at a higher risk for developing lung cancer due to immune dysfunction and chronic inflammation. They also have increased morbidity and mortality related to influenza, and it is recommended that they receive an annual influenza vaccination. In this study, we evaluate whether influenza vaccination could reduce the incidence of lung cancer in DM patients. This cohort study included DM patients (≥55 years old) between 1 January 2002 and 31 December 2012 by using the Taiwan Health Insurance Database. Cox proportional hazard regression method was used to compare the relation between the influenza vaccination and lung cancer incidence after adjusting for potential confounders. Sub-group analyses were done according to vaccination status (unvaccinated, total number of vaccinations: 1, 2–3, ≥4) and evaluated the dose-dependent effects on lung cancer events. Among 22,252 eligible DM patients, 7860 (35.32%) received an influenza vaccination and 67.68% (14392) did not receive an influenza vaccination. Lung cancer incidence was significantly lower in the vaccinated group versus the unvaccinated group (adjusted HR 0.77, 95% CI 0.62–0.95, p &lt, 0.05). Significant protective effects were observed among male sex (adjusted HR 0.72, 95% CI 0.55–0.94, p &lt, 0.05) and 55–64 year (adjusted HR 0.61, 95% CI 0.40–0.94, p &lt, 0.05) and ≥75 year (adjusted HR 0.63, 95% CI 0.42–0.92, p &lt, 0.05) age groups, respectively. A dose-dependent protective effect was noted with a significant protective effect in those that received ≥4 vaccinations (adjusted HR 0.42, 95% CI 0.29–0.61, p &lt, 0.001). In sub-group analysis, elder patients with ≥65 years of age were significantly protected from ≥4 vaccinations (adjusted HR 0.37, 95% CI 0.23–0.62, p &lt, 0.001 in 65–74 years and adjusted HR 0.31, 95% CI 0.15–0.66, p = 0.002 in ≥75 years group, respectively). Male sex with ≥4 vaccinations had a significantly lower risk of lung cancer (adjusted HR 0.35, 95% CI 0.21–0.57, p &lt, 0.001). Patients with comorbid conditions that received ≥4 vaccinations were also protected, and was especially significant among those with CCI ≥ 3 (adjusted HR 0.38, 95% CI 0.18–0.80, p = 0.009) as compared to 1 and 2–3 vaccination groups, including those with hypertension (adjusted HR 0.35, 95% CI 0.22–0.57, p &lt, 0.001). This population-based cohort study demonstrated that annual influenza vaccination significantly reduced the lung cancer risk in DM patients and specifically demonstrates that a higher number of vaccinations is related with a more protective effect. Whether this is due to vaccine booster effects on anti-tumor immune regulation among DM patients still needs to be explored.

Aging contributes to the progression of vascular dysfunction and is a major nonreversible risk factor for cardiovascular disease. The aim of this study was to determine the effectiveness of using arterial pulse-wave measurements, frequency-domain pulse analysis, and machine-learning analysis in distinguishing vascular aging. Radial pulse signals were measured noninvasively for 3 min in 280 subjects aged 40–80 years. The cardio-ankle vascular index (CAVI) was used to evaluate the arterial stiffness of the subjects. Forty frequency-domain pulse indices were used as features, comprising amplitude proportion (Cn), coefficient of variation of Cn, phase angle (Pn), and standard deviation of Pn (n = 1–10). Multilayer perceptron and random forest with supervised learning were used to classify the data. The detected differences were more prominent in the subjects aged 40–50 years. Several indices differed significantly between the non-vascular-aging group (aged 40–50 years; CAVI 80%, and the AUC was >0.8). For subjects aged 50–60 and 60–70 years, the detection accuracies of the two trained algorithms were around 80%, with AUCs of >0.73 for both, which indicated acceptable discrimination. The present method of frequency-domain analysis may improve the index reliability for further machine-learning analyses of the pulse waveform. The present noninvasive and objective methodology may be meaningful for developing a wearable-device system to reduce the threat of vascular dysfunction induced by vascular aging.

This study performed beat-to-beat and spectral analyses of 20-minute skin-surface laser-Doppler-flowmetry (LDF) and radial blood-pressure-waveform (BPW) signals in order to compare the blood-flow perfusion condition and regulatory mechanisms between essential-hypertension (EHT) patients and aged-matched control subjects. Beat-to-beat LDF analyses yielded the pulse width (PW), AC-to-DC ratio (AD), and their corresponding variability indices (coefficients of variation [CVs]). The relative energy contributions (RECs) of five characteristic frequency peaks (defined as FR1–FR5) were also calculated. Spectral BPW analysis obtained the amplitude proportion (Cn) and phase angle (Pn) of each harmonic component n. PW, AD, AD_CV, and REC of FR2 were significantly smaller in the EHT group than in the control group. Regarding BPW indices, C1, C2, C4, and C5 were significantly larger and P2–P8 were significantly smaller in EHT patients than in controls. The present results indicate that BPW and LDF indices can be used to evaluate the blood-flow perfusion efficiency and microcirculatory regulatory activities in EHT. Sex differences were found, with the effects being more prominent in female patients. These findings may be partly attributable to impairment of endothelial and neural regulatory functions. The present findings might aid the development of new noninvasive methods for reducing the risk of EHT-induced damage.

Through population-based studies, associations have been found between coffee drinking and numerous health benefits, including a reduced risk of cardiovascular disease. Active ingredients in coffee have therefore received considerable attention from researchers. A wide variety of effects have been attributed to cafestol, one of the major compounds in coffee beans. Because cardiac hypertrophy is an independent risk factor for cardiovascular events, this study examined whether cafestol inhibits urotensin II (U-II)-induced cardiomyocyte hypertrophy. Neonatal rat cardiomyocytes were exposed only to U-II (1[Formula: see text]nM) or to U-II (1[Formula: see text]nM) following 12-h pretreatment with cafestol (1–10[Formula: see text][Formula: see text]M). Cafestol (3–10[Formula: see text][Formula: see text]M) pretreatment significantly inhibited U-II-induced cardiomyocyte hypertrophy with an accompanying decrease in U-II-induced reactive oxygen species (ROS) production. Cafestol also inhibited U-II-induced phosphorylation of redox-sensitive extracellular signal-regulated kinase (ERK) and epidermal growth factor receptor transactivation. In addition, cafestol pretreatment increased Src homology region 2 domains-containing phosphatase-2 (SHP-2) activity, suggesting that cafestol prevents ROS-induced SHP-2 inactivation. Moreover, nuclear factor erythroid-2-related factor 2 (Nrf2) translocation and heme oxygenase-1 (HO-1) expression were enhanced by cafestol. Addition of brusatol (a specific inhibitor of Nrf2) or Nrf2 siRNA significantly attenuated cafestol-mediated inhibitory effects on U-II-stimulated ROS production and cardiomyocyte hypertrophy. In summary, our data indicate that cafestol prevented U-II-induced cardiomycyte hypertrophy through Nrf2/HO-1 activation and inhibition of redox signaling, resulting in cardioprotective effects. These novel findings suggest that cafestol could be applied in pharmacological therapy for cardiac diseases.

Patients with type 2 diabetes mellitus (T2DM) have a higher risk of chronic kidney disease (CKD) due to vascular complications and chronic inflammation. T2DM contributes to a higher risk of mortality and morbidity related to influenza. In Taiwan, influenza vaccination is recommended for patients with T2DM. A previous meta-analysis reported the efficacy of influenza vaccination in reducing hospitalization and mortality in patients with diabetes; however, the renal protective effect of the vaccine remains unclear. This study evaluated whether influenza vaccination could reduce the incidence of CKD and dialysis in patients with T2DM. The study cohort included all patients aged ≥55 years who were diagnosed as having T2DM between 1 January 2000 and 31 December 2012, by using data from Taiwan’s National Health Insurance Research Database. Each patient was followed up with to assess factors associated with CKD. A time-dependent Cox proportional hazard regression model after adjustment for potential confounders was used to calculate the hazard ratio (HR) of CKD in the vaccinated and unvaccinated patients. The study population comprised 48,017 eligible patients with DM; 23,839 (49.7%) received influenza vaccination and the remaining 24,178 (50.3%) did not. The adjusted HRs (aHRs) for CKD/dialysis decreased in the vaccinated patients compared with the unvaccinated patients (influenza season, noninfluenza season, and all seasons: aHRs: 0.47/0.47, 0.48/0.49, and 0.48/0.48, respectively, all p < 0.0001). We observed similar protective effects against CKD during the influenza and noninfluenza seasons. Regardless of comorbidities or drug use, influenza vaccination was an independent protective factor. Furthermore, aHRs for CKD/dialysis were 0.71 (0.65–0.77)/0.77 (0.68–0.87), 0.57 (0.52–0.61)/0.69 (0.56–0.70), and 0.30 (0.28–0.33)/0.28 (0.24–0.31) in the patients who received 1, 2–3, and ≥4 vaccinations during the follow-up period, respectively. This population-based cohort study demonstrated that influenza vaccination exerts a dose-dependent and synergistic protective effect against CKD in the patients with T2DM with associated risk factors.

Chronic kidney disease (CKD) is significantly associated with lung cancer incidence. The aim of this study was to elucidate whether influenza vaccination reduces the incidence of lung cancer in patients with CKD. This cohort study enrolled patients with a record of CKD diagnosis from 2000 to 2012 in Taiwan’s National Health Insurance Research Database. Included patients were divided into vaccinated and unvaccinated groups. In total 12,985 patients with CKD were enrolled. Among these patients, 5495 were vaccinated and 7490 were unvaccinated. The risk of lung cancer was significantly lower in the influenza vaccination group after adjusting for age, sex, dialysis status, lung diseases, comorbidities, level of urbanization, and monthly income (adjusted hazard ratio (HR): 0.50, 95% confidence interval (CI; 0.38–0.65), p < 0.05). Lower risk of lung cancer was observed in both sexes, all age groups, dialysis status and co-existed lung diseases. The association between the risk of lung cancer and vaccination appeared to be dose-dependent (adjusted HRs: 0.91 (0.66–1.25), 0.49 (0.34–0.71), and 0.25 (0.17–0.38) for patients who received 1, 2 or 3, and ≥4 vaccinations during the follow-up period, respectively). In conclusion, Influenza vaccination decreased the risk of lung cancer in patients diagnosed with CKD. This potentially protective effect against lung cancer appeared to be dose dependent.

The ventricular arrhythmia (VA)–chronic obstructive pulmonary disease (COPD) association and related risk factors remain unclear. Using 2001–2012 data from National Health Insurance Research Database, we retrospectively reviewed 71,838 patients diagnosed as having COPD and 71,838 age- and sex-matched controls. After adjustments for comorbidities, medication, urbanization level, and monthly income, patients with COPD had higher incidence rates of VA than did the controls (adjusted hazard ratio [aHR] [95% confidence interval (CI)]: 1.45 [1.25–1.68]). More hospitalization or emergency visits because of acute COPD exacerbation (aHRs [95% CIs] for first, second, and third visits: 1.28 [1.08–1.50], 1.75 [1.32–2.32], and 1.88 [1.46–2.41], respectively) and asthma–COPD overlap (aHR [95% CI]: 1.49 [1.25–1.79]) were associated with high VA risk in patients with COPD. In the multivariate analysis, heart failure (aHR [95% CI]: 2.37 [1.79–3.14]), diabetes (aHR [95% CI]:1.64 [1.29–2.08]), age ≥75 (aHR [95% CI]: 2.48 [1.68–3.67]), male (aHR [95% CI]: 1.69[1.34–2.12]), and class III antiarrhythmic drug use (aHR [95% CI]: 2.49 [1.88–3.28]) are the most significant risk factors of new onset of VA in patients with COPD.

Diabetes is associated with the development of myocardial fibrosis, which is related to various cardiac diseases. Cafestol, one of the active ingredients in coffee, has been reported to exert biological effects. However, whether cafestol can ameliorate diabetes-induced cardiac fibrosis remains unknown. The aim of this study was to evaluate the effects of cafestol on cardiac fibrosis in high-glucose-treated cardiac fibroblasts and streptozocin- (STZ-) induced diabetic rats. Rat cardiac fibroblasts were cultured in high-glucose (25 mM) media in the absence or presence of cafestol, and the changes in collagen synthesis, transforming growth factor-β1 (TGF-β1) production, and related signaling molecules were assessed on the basis of 3H-proline incorporation, enzyme-linked immunosorbent assay, and western blotting. Cardiac fibroblasts exposed to high-glucose conditions exhibited increased collagen synthesis, TGF-β1 production, and Smad2/3 phosphorylation, and these effects were mitigated by cafestol treatment. Furthermore, cafestol increased the translocation of nuclear factor erythroid 2-related factor 2 and increased the expression of heme oxygenase-1. The results of molecular docking analysis suggested a selective interaction of cafestol with Kelch-like ECH-associated protein 1. The rats with untreated STZ-induced diabetes exhibited considerable collagen accumulation, which was ameliorated by cafestol. Moreover, activities of catalase, superoxide dismutase, general matrix metalloproteinase, and reduced glutathione concentration were upregulated, whereas malondialdehyde level was downregulated by treatment with cafestol in rats with cardiac fibrosis. These findings highlight the effects of cafestol, which may be useful in treating diabetes-related cardiac fibrosis.

// Pai-Feng Kao 1, 6, * , Ju-Chi Liu 1, 6, * , Yi-Ping Hsu 1 , Li-Chin Sung 1, 6 , Tsung-Yeh Yang 1 , Wen-Rui Hao 1 , Ying-Chin Lin 2, 3 and Szu-Yuan Wu 4, 5, 6, 7 1 Division of Cardiovascular Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan 2 Department of Family Medicine, Shung Ho Hospital, Taipei Medical University, New Taipei, Taiwan 3 Department of Family Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 4 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan 5 Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 6 Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 7 Department of Biotechnology, Hungkuang University, Taichung, Taiwan * These authors have contributed equally to this work Correspondence to: Szu-Yuan Wu, email: szuyuanwu5399@gmail.com Keywords: influenza vaccination; atrial fibrillation; ischemic stroke Received: June 11, 2017 Accepted: July 26, 2017 Published: November 09, 2017 ABSTRACT Purpose: Atrial fibrillation (AF) is associated with the risk of ischemic stroke, regardless of the administration of appropriate antithrombotic prophylaxis. This study investigated whether influenza vaccination is associated with the risk of ischemic stroke, to determine a solution to reduce this risk in patients with AF. Methods: We used data from the Taiwan National Health Insurance Research Database. The study cohort comprised all patients diagnosed as having AF (n = 14 454) before January 1, 2005; these patients were followed until December 31, 2012. The index date was January 1, 2005. A propensity score was derived using a logistic regression model to estimate the effect of vaccination by accounting for covariates that predict receiving the intervention (vaccine). A Cox proportional hazard model was used to calculate the hazard ratios (HRs) of ischemic stroke in vaccinated and unvaccinated patients with AF. Results: We included 6570 patients (2547 [38.77%] with and 4023 [61.23%] without influenza vaccination). The adjusted HRs (aHRs) of ischemic stroke were lower in the vaccinated patients than in the unvaccinated patients (influenza season, noninfluenza season, and all seasons: aHRs = 0.59, 0.50, and 0.55; P < 0.001, P < 0.001, and P < 0.001, respectively). Conclusions: Influenza vaccination might exert a dose-response effect against ischemic stroke in patients with AF who have risk factors for ischemic stroke by reducing the incidence of ischemic stroke, particularly in those aged 65–74 and ≥75 y.

Background This study investigated whether lipopolysaccharide (LPS) increase protease-activated receptor-2 (PAR-2) expression and enhance the association between PAR-2 expression and chemokine production in human vascular endothelial cells (ECs). Methods The morphology of ECs was observed through microphotography in cultured human umbilical vein ECs (EA. hy926 cells) treated with various LPS concentrations (0, 0.25, 0.5, 1, and 2 μg/mL) for 24 h, and cell viability was assessed using the MTT assay. Intracellular calcium imaging was performed to assess agonist (trypsin)-induced PAR-2 activity. Western blotting was used to explore the LPS-mediated signal transduction pathway and the expression of PAR-2 and adhesion molecule monocyte chemoattractant protein-1 (MCP-1) in ECs. Results Trypsin stimulation increased intracellular calcium release in ECs. The calcium influx was augmented in cells pretreated with a high LPS concentration (1 μg/mL). After 24 h treatment of LPS, no changes in ECs viability or morphology were observed. Western blotting revealed that LPS increased PAR-2 expression and enhanced trypsin-induced extracellular signal-regulated kinase (ERK)/p38 phosphorylation and MCP-1 secretion. However, pretreatment with selective ERK (PD98059), p38 mitogen-activated protein kinase (MAPK) (SB203580) inhibitors, and the selective PAR-2 antagonist (FSLLRY-NH2) blocked the effects of LPS-activated PAR-2 on MCP-1 secretion. Conclusions Our findings provide the first evidence that the bacterial endotoxin LPS potentiates calcium mobilization and ERK/p38 MAPK pathway activation and leads to the secretion of the pro-inflammatory chemokine MCP-1 by inducing PAR-2 expression and its associated activity in vascular ECs. Therefore, PAR-2 exerts vascular inflammatory effects and plays an important role in bacterial infection-induced pathological responses. Electronic supplementary material The online version of this article (10.1186/s12929-017-0393-1) contains supplementary material, which is available to authorized users.

The sensitivities of solid-phase immunoassays are limited by the quantity of detection antibodies bound to their antigens on the solid phase. Here, we developed a poly-protein G-expressing bacterium as an antibody-trapping microparticle to enhance the signals of immunoassays by increasing the accumulation of detection antibodies on the given antigen. Eight tandemly repeated fragment crystallisable (Fc) binding domains of protein G were stably expressed on the surface of Escherichia coli BL21 cells (termed BL21/8G). BL21/8G cells showed a higher avidity for trapping antibodies on their surface than monomeric protein G-expressing BL21 (BL21/1G) cells did. In the sandwich enzyme-linked immunosorbent assay (ELISA), simply mixing the detection antibody with BL21/8G provided a detection limit of 6 pg/mL for human interferon-α (IFN-α) and a limit of 30 pg/mL for polyethylene glycol (PEG)-conjugated IFN-α (Pegasys), which are better than that of the traditional ELISA (30 pg/mL for IFN-α and 100 pg/mL for Pegasys). Moreover, the sensitivity of the Western blot for low-abundance Pegasys (0.4 ng/well) was increased by 25 folds upon mixing of an anti-PEG antibody with BL21/8G cells. By simply being mixed with a detection antibody, the poly-protein G-expressing bacteria can provide a new method to sensitively detect low-abundance target molecules in solid-phase immunoassays.

// Ju-Chi Liu 1, 4, * , Tsung-Yeh Yang 1, * , Yi-Ping Hsu 1 , Wen-Rui Hao 1 , Pai-Feng Kao 1, 4 , Li-Chin Sung 1, 4 , Chun-Chao Chen 1 , Szu-Yuan Wu 2, 3, 4, 5 1 Division of Cardiovascular Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan 2 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan 3 Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 4 Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 5 Department of Biotechnology, Hungkuang University, Taichung, Taiwan * Co-first authors, These authors contributed equally to this work Correspondence to: Szu-Yuan Wu, email: szuyuanwu5399@gmail.com Keywords: statins, COPD, lung cancer Received: March 09, 2016 Accepted: July 09, 2016 Published: August 09, 2016 ABSTRACT Purpose: Chronic obstructive pulmonary disease (COPD) is associated with increased lung cancer risk. We evaluated the association of statin use with lung cancer risk in COPD patients and identified which statins possess the highest chemopreventive potential. Results: After adjustment for age, sex, CCI, diabetes, hypertension, dyslipidemia, urbanization level, and monthly income according to propensity scores, lung cancer risk in the statin users was lower than that in the statin nonusers (adjusted hazard ratio [aHR] = 0.37). Of the individual statins, lovastatin and fluvastatin did not reduce lung cancer risk significantly. By contrast, lung cancer risk in patients using rosuvastatin, simvastatin, atorvastatin, and pravastatin was significantly lower than that in statin nonusers (aHRs = 0.41, 0.44, 0.52, and 0.58, respectively). Statins dose-dependently reduced lung cancer risk in all subgroups and the main model with additional covariates (nonstatin drug use). Materials and Methods: The study cohort comprised all patients diagnosed with COPD at health care facilities in Taiwan ( n = 116,017) between January 1, 2001 and December 31, 2012. Our final study cohort comprised 43,802 COPD patients: 10,086 used statins, whereas 33,716 did not. Patients were followed up to assess lung cancer risk or protective factors. In addition, we also considered demographic characteristics, namely age, sex, comorbidities (diabetes, hypertension, dyslipidemia, and Charlson comorbidity index [CCI]), urbanization level, monthly income, and nonstatin drug use. The index date of statin use was the COPD confirmation date. To examine the dose–response relationship, we categorized statin use into four groups in each cohort: 365 cumulative defined daily doses (cDDDs). Patients receiving < 28 cDDDs were defined as nonstatin users. Conclusions: Statins dose-dependently exert a significant chemopreventive effect against lung cancer in COPD patients. Rosuvastatin, simvastatin, and atorvastatin exhibited the highest chemopreventive potential.

// Ju-Chi Liu 1, 4, * , Wen-Rui Hao 1, * , Yi-Ping Hsu 1 , Li-Chin Sung 1, 4 , Pai-Feng Kao 1, 4 , Chao-Feng Lin 1 , Alexander T.H. Wu 6 , Kevin Sheng-Po Yuan 7 , Szu-Yuan Wu 2, 3, 4, 5 1 Division of Cardiovascular Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan 2 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan 3 Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 4 Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 5 Department of Biotechnology, Hungkuang University, Taichung, Taiwan 6 Ph.D. Program for Translational Medicine, Taipei Medical University, Taipei, Taiwan 7 Department of Otorhinolaryngology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan * These authors have contributed equally to this work Correspondence to: Szu-Yuan Wu, email: szuyuanwu5399@gmail.com Keywords: statins, chronic obstructive pulmonary disease, colon cancer Received: March 22, 2016 Accepted: June 27, 2016 Published: August 12, 2016 ABSTRACT Purpose: We evaluated the chemopreventive effect of statins on colon cancer in patients with chronic obstructive pulmonary disease (COPD) and identified the statin exerting the strongest chemopreventive effect. Methods: Using the National Health Insurance Research Database, we identified patients who received a COPD diagnosis in Taiwan between January 1, 2001, and December 31, 2012, and included them in the study cohort. Each patient was followed to assess the colon cancer risk and protective factors. A propensity score was derived using a logistic regression model to estimate the effect of statins by accounting for covariates predicted during the intervention (statins). To examine the dose–response relationship, we categorized statin doses into four groups in each cohort [ 365 cumulative defined daily dose]. Results: Compared with the statin nonusers, the adjusted hazard ratio (aHR) for colon cancer decreased in the statin users (aHR = 0.52, 95% confidence interval = 0.44, 0.62). Hydrophilic statins exerted a stronger preventive effect against colon cancer. Regarding the statin type, lovastatin, pravastatin, and fluvastatin nonsignificantly reduced the colon cancer risk in the patients with COPD. Compared with the statin nonusers, the aHRs for colon cancer decreased in the individual statin users (rosuvastatin, simvastatin, and atorvastatin: aHRs = 0.28, 0.64, and 0.65, respectively). In the sensitivity analysis, statins dose-dependently reduced the colon cancer risk. Conclusions: Statins dose-dependently exert significant chemopreventive effects on colon cancer in patients with COPD, with rosuvastatin exerting the largest chemopreventive effect.

Cloud-based BP system integrated with CPOE at the point of care achieved better BP control compared to traditional care.Cloud BP records positively reinforced both BP measuring and medication adherence behaviors.Cloud-based BP system does not require any technical skills and is therefore suitable for every age group. BackgroundLess than 50% of patients with hypertensive disease manage to maintain their blood pressure (BP) within normal levels. ObjectiveThe aim of this study is to evaluate whether cloud BP system integrated with computerized physician order entry (CPOE) can improve BP management as compared with traditional care. MethodsA randomized controlled trial done on a random sample of 382 adults recruited from 786 patients who had been diagnosed with hypertension and receiving treatment for hypertension in two district hospitals in the north of Taiwan. Physicians had access to cloud BP data from CPOE. Neither patients nor physicians were blinded to group assignment. The study was conducted over a period of seven months. ResultsAt baseline, the enrollees were 50% male with a mean (SD) age of 58.18 (10.83) years. The mean sitting BP of both arms was no different. The proportion of patients with BP control at two, four and six months was significantly greater in the intervention group than in the control group. The average capture rates of blood pressure in the intervention group were also significantly higher than the control group in all three check-points. ConclusionsCloud-based BP system integrated with CPOE at the point of care achieved better BP control compared to traditional care. This system does not require any technical skills and is therefore suitable for every age group. The praise and assurance to the patients from the physicians after reviewing the Cloud BP records positively reinforced both BP measuring and medication adherence behaviors.

PURPOSE: Chronic obstructive pulmonary disease (COPD) is associated with an increased cancer risk. We evaluated the chemopreventive effect of statins against all cancers in COPD patients and identified the statin with the strongest chemopreventive effect. PATIENTS AND METHODS: All patients diagnosed with COPD at health care facilities in Taiwan (n = 116,017) from January 1, 2001, to December 31, 2012, were recruited. Each patient was followed to assess the following protective and risk factors for all cancers: age; sex; comorbidities (diabetes, hypertension, dyslipidemia) and the Charlson comorbidity index [CCI]); urbanization level; monthly income; and nonstatin drug use. The index date of statins use was the date of COPD confirmation. Propensity scores (PSs) were derived using a logistic regression model to estimate the effect of statins by considering the covariates predicting intervention (statins) receipt. To examine the dose-response relationship, we categorized statin use into four groups in each cohort (365 cumulative defined daily dose). RESULTS: After PS adjustment for age, sex, CCI, diabetes, hypertension, dyslipidemia, urbanization level, and monthly income, we analyzed the all-cancer risk. The adjusted hazard ratios (aHRs) for the all-cancer risk were lower among statin users than among statin nonusers (aHR = 0.46, 95% confidence interval: 0.43 to 0.50). The aHRs for the all-cancer risk were lower among patients using rosuvastatin, simvastatin, atorvastatin, pravastatin, and fluvastatin than among statin nonusers (aHRs = 0.42, 0.55, 0.59, 0.66, and 0.78, respectively). Sensitivity analysis indicated that statins dose-dependently reduced the all-cancer risk. CONCLUSION: Statins dose-dependently exert a significant chemopreventive effect against various cancers in COPD patients. In particular, rosuvastatin has the strongest chemopreventive effect.

Diabetes-associated cardiac fibrosis is a severe cardiovascular complication. Momordicine I, a bioactive triterpenoid isolated from bitter melon, has been demonstrated to have antidiabetic properties. This study investigated the effects of momordicine I on high-glucose-induced cardiac fibroblast activation. Rat cardiac fibroblasts were cultured in a high-glucose (25 mM) medium in the absence or presence of momordicine I, and the changes in collagen synthesis, transforming growth factor-β1 (TGF-β1) production, and related signaling molecules were assessed. Increased oxidative stress plays a critical role in the development of high-glucose-induced cardiac fibrosis; we further explored momordicine I’s antioxidant activity and its effect on fibroblasts. Our data revealed that a high-glucose condition promoted fibroblast proliferation and collagen synthesis and these effects were abolished by momordicine I (0.3 and 1 μM) pretreatment. Furthermore, the inhibitory effect of momordicine I on high-glucose-induced fibroblast activation may be associated with its activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the inhibition of reactive oxygen species formation, TGF-β1 production, and Smad2/3 phosphorylation. The addition of brusatol (a selective inhibitor of Nrf2) or Nrf2 siRNA significantly abolished the inhibitory effect of momordicine I on fibroblast activation. Our findings revealed that the antifibrotic effect of momordicine I was mediated, at least partially, by the inhibition of the TGF-β1/Smad pathway, fibroblast proliferation, and collagen synthesis through Nrf2 activation. Thus, this work provides crucial insights into the molecular pathways for the clinical application of momordicine I for treating diabetes-associated cardiac fibrosis.

Moderate coffee consumption is inversely associated with cardiovascular disease mortality; however, mechanisms underlying this causal effect remain unclear. Cafestol, a diterpene found in coffee, has various properties, including an anti-inflammatory property. This study investigated the effect of cafestol on cyclic-strain-induced inflammatory molecule secretion in vascular endothelial cells. Cells were cultured under static or cyclic strain conditions, and the secretion of inflammatory molecules was determined using enzyme-linked immunosorbent assay. The effects of cafestol on mitogen-activated protein kinases (MAPK), heme oxygenase-1 (HO-1), and sirtuin 1 (Sirt1) signaling pathways were examined using Western blotting and specific inhibitors. Cafestol attenuated cyclic-strain-stimulated intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein- (MCP-) 1, and interleukin- (IL-) 8 secretion. Cafestol inhibited the cyclic-strain-induced phosphorylation of extracellular signal-regulated kinase and p38 MAPK. By contrast, cafestol upregulated cyclic-strain-induced HO-1 and Sirt1 expression. The addition of zinc protoporphyrin IX, sirtinol, or Sirt1 silencing (transfected with Sirt1 siRNA) significantly attenuated cafestol-mediated modulatory effects on cyclic-strain-stimulated ICAM-1, MCP-1, and IL-8 secretion. This is the first study to report that cafestol inhibited cyclic-strain-induced inflammatory molecule secretion, possibly through the activation of HO-1 and Sirt1 in endothelial cells. The results provide valuable insights into molecular pathways that may contribute to the effects of cafestol.

Nicorandil is an adenosine triphosphate-sensitive potassium channel opener with additional antioxidant properties. Doxorubicin (DOX) is an anticancer drug that exerts oxidation-mediated adverse cardiovascular effects. This study examined the effects of nicorandil on DOX-induced cytotoxicity in human umbilical vein endothelial cells (HUVECs) and underlying intracellular signaling mechanisms. Cultured HUVECs were pretreated with nicorandil (0.1, 0.3, 1, 3, and 10 μM) for 12 h and then treated with DOX (1 μM) for 24 h. Cell viability and cytotoxicity were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays, respectively. Cell apoptosis was examined using a caspase-3 activity assay, and DNA fragmentation was detected through TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) staining. Western blot analysis was conducted to determine the related protein expression. DOX markedly increased reactive oxygen species production, p53 expression, caspase-3 activity, cleaved caspase-3 levels, and TUNEL-positive cell numbers but reduced Bcl-2 expression and intracellular antioxidant enzyme levels; these effects were effectively antagonized through nicorandil (3 μM, 12 h) pretreatment, which resulted in HUVECs being protected from DOX-induced apoptosis. Activating transcription factor 3 (ATF3), a stress-induced transcription factor, was induced by nicorandil (3 μM). Furthermore, nicorandil (3 μM) enhanced nuclear factor erythroid 2–related factor 2 (Nrf2) translocation and heme oxygenase-1 (HO-1) expression. ATF3 short interfering RNA significantly attenuated nicorandil-mediated Nrf2 translocation, HO-1 expression, and inhibitory effects on DOX-stimulated reactive oxygen species production and cell apoptosis. In summary, nicorandil may protect HUVECs from DOX-induced apoptosis, in part through ATF3-mediated Nrf2/HO-1 signaling pathways, which potentially protect the vessels from severe DOX toxicity.

Research has indicated that inflammation promote all phases of atherosclerosis. The current study tested the hypothesis that rhinosinusitis is a risk marker for myocardial infarction (MI). Data on the general population were obtained from the Taiwan Longitudinal Health Insurance Database 2005 (LHID2005). The study cohort comprised patients who had received a recorded diagnosis of rhinosinusitis ( N = 52,930) between January 1, 2004 and December 31, 2004. The comparison group consisted of patients who had not received a rhinosinusitis diagnosis, and who were matched for age and sex with the study group at a ratio of 4 controls to 1 study patient (1:4) ( N = 211,720). Each patient's condition was followed using database entries until the end of 2006. Cox proportional hazard regressions were used to evaluate the 3-year MI-free survival rates, after adjusting for known confounding factors. We found that patients with rhinosinusitis were more likely than the control group to have MI, after adjusting for potential confounders [adjusted hazard ratio (HR), 1.84; 95% confidence interval (CI), 1.44 ∼ 2.40]. Of the total 264 650 patients, 290 experienced MI during the 3-year follow-up period, including 8 acute sinusitis patients, 77 chronic sinusitis patients, and 205 control patients. The incidence rate of MI was 6.19 (95% CI 5.01–7.65) per 10,000 person-years for rhinosinusitis patients, compared to 3.51 (95% CI, 3.06–4.02) for the control patients. From this study, rhinosinusitis may be associated with MI. Further research in this important area of public health is warranted.

Purpose The risk of hemorrhagic stroke in patients with atrial fibrillation (AF) is low but the consequences of its occurrence are extremely severe. In this study, we investigated the association of influenza vaccination with the risk of hemorrhagic stroke to develop an efficient strategy for reducing this risk in patients with AF. Methods In this study, data were retrieved from the Taiwan National Health Insurance Research Database. The study cohort comprised all patients who received a diagnosis of AF ( n =14,454) before January 1, 2005 (index date) and were followed until December 31, 2012. Propensity scores were calculated using a logistic regression model to determine the effects of vaccination by accounting for covariates that predict receiving the intervention (vaccine). A time-dependent Cox proportional hazard model was used to calculate the hazard ratios (HRs) for hemorrhagic stroke in vaccinated and unvaccinated patients with AF. Results The study population comprised 6570 patients who did (2547 [38.77%]) and did not receive (4023 [61.23%]) influenza vaccination. The adjusted HRs (aHRs) for hemorrhagic stroke were lower in the vaccinated patients than in the unvaccinated patients (influenza season, noninfluenza season, and all seasons: aHRs=0.97 [0.59–1.60], 0.51 [0.30–0.87], and 0.72 [0.50–1.03], respectively). Conclusions Influenza vaccination exerts dose–response and synergistic protective effects against hemorrhagic stroke in patients with AF who have a high risk of hemorrhagic stroke (i.e., male sex, age≥75years, Charlson comorbidity index ≥3, and hypertension) and reduces the incidence of hemorrhagic stroke.

Propofol-related infusion syndrome (PRIS) has a high mortality with myocardial failure and dysrhythmias. However, there is no detailed description of the serial cardiac conditions presenting during the critical and recovery periods during PRIS. We report the case of a 24-year-old man with a traumatic head injury who developed PRIS after propofol infusion. Cyanosis, hypotension, neck vein distension, cardiac arrest and ventricular tachycardia occurred. The patient survived PRIS by prompt cessation of propofol, the use of inotropic agents, and short-term hemofiltration. A timely Holter electrocardiogram (ECG) recording, serial echocardiograms and 12-lead ECGs revealed isolated right heart failure, sequential bradycardia, arrest, left bundle branch block-like ventricular tachycardia, and varied coved-type ST elevation in the right precordial leads. All these clinical abnormalities (symptoms, echocardiograms, and ECGs) subsided within a few hours after treatment. The patient was eventually discharged with clear consciousness and without any cardiopulmonary sequelae. Our cardiac survey implied that in PRIS, the right heart is severely injured, both mechanically and electrophysiologically. Injured right hearts can completely and rapidly recover if recognition and treatment are timely.