Changes of antithrombotic prescription in atrial fibrillation patients with acute coronary syndrome or percutaneous coronary intervention and the subsequent impact on long-term outcomes: a longitudinal cohort study.

OBJECTIVES: The choice of optimal antithrombotic therapy in atrial fibrillation (AF) patients with acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) remains controversial. The aim of this longitudinal cohort study is to investigate the prescribing pattern of antithrombotic regimen in different cohorts and its subsequent impact. SETTING AND DESIGN: Longitudinal data from the Tri-Service General Hospital-Coronary Heart Disease (TSGH-CHD) registry, between January 2016 and August 2018 was screened. PARTICIPANTS AND METHOD: Patients with prior history of nonvalvular AF, who had ACS presentation or underwent PCI were selected, and these patients were divided into cohort 1 and cohort 2, according to the index date of antithrombotic prescription before and after the PIONEER AF-PCI study. PRIMARY AND SECONDARY OUTCOMES: The primary safety endpoints were composites of major bleeding and/or clinically relevant non-major bleeding. The secondary efficacy endpoints included the occurrence of all-cause mortality, stroke/systemic embolization, nonfatal myocardial infarction (MI), and >30-days coronary revascularization. RESULTS: A total of 121 patients were included into analysis (cohort 1=35; cohort 2=86). Comparing with cohort 1, the prescription rate of triple antithrombotic therapy (TAT) increased from 17.1 to 38.4%, especially the regimen with dual antiplatelet therapy (DAPT) plus low-dose non-vitamin-K dependent oral anticoagulation (NOAC). However, the prescription rate of dual antithrombotic therapy (DAT) decreased (14.3-10.5%), as well as the prescription rate of DAPT (68.6-51.2%). These changes of antithrombotic prescription across different cohorts were not associated with risk of adverse safety (HR= 0.87; 95% CI, 0.42-1.80, p=0.710) and efficacy outcomes (HR=0.96; 95% CI, 0.40-2.32, p=0.930). CONCLUSIONS: Entering the NOAC era, the prescription of TAT increased alongside the decrease in DAT. As the prescription rate of DAPT without anticoagulation remained high, future efforts are mandatory to improve the implementation of guidelines and clinical practice.

Prognostic Effect of Restoring Sinus Rhythm in Patients with New-Onset Atrial Fibrillation during Acute Coronary Syndrome.

BACKGROUND: New-onset atrial fibrillation (NOAF) in acute coronary syndrome (ACS) may be associated with a poor prognosis. However, whether restoring sinus rhythm (SR) at discharge in patients with ACS improves outcomes remains unknown. METHODS: A total of 552 patients with ACS at an emergency department during 2011-2016 were enrolled. According to documented electrocardiography at admission and medical records, the patients were classified into without atrial fibrillation (WAF), NOAF, and prior atrial fibrillation (PAF) groups. Major adverse events (MAEs) were defined as cardiac death, recurrent myocardial infarction, heart failure requiring hospitalization, target lesion revascularization, and stroke. The mean follow-up period of MAEs was 25 ± 15 months. RESULTS: Compared with the NOAF and PAF groups, the WAF group was younger and had a significantly lower heart rate, prior stroke rate, CHA2DS2-VASc score, and lower Global Registry of Acute Coronary Events (GRACE) score in the emergency department (p < 0.001). The patients in the NOAF group had the highest incidence of MAEs (p < 0.001) during follow-up, and those whose SR was restored at discharge had a lower MAE rate than those with AF at discharge (p = 0.001). In multivariable analysis, prior myocardial infarction, GRACE score, use of beta-blockers, and restoring SR at discharge were independent predictors of MAEs in the NOAF group. CONCLUSIONS: The patients with ACS who presented with NOAF had worse outcomes than those with PAF or WAF. The patients with NOAF whose rhythm was restored to SR at discharge were associated with better outcomes than those with AF at discharge.

Profiles of Hospitalized Patients with Angiographic Coronary Heart Disease in Taiwan during 2014-2016: Report of a Tertiary Hospital.

BACKGROUND: The Taiwan Society of Cardiology (TSOC) has established multicenter registries for coronary artery disease (CAD) to investigate clinical characteristics, management and risks for mortality. However, the impacts of newly-emerged evidence-based therapies, including the use of drug-eluting stents (DESs), on patients with CAD in Taiwan remain unclear. METHODS: The Tri-Service General Hospital-Coronary Heart Disease (TSGH-CHD) registry is a single-center, prospective, longitudinal registry in Taiwan containing data from 2014-2016. Individuals who were admitted for coronary angiography were enrolled. Patient profiles, management and in-hospital outcome data were collected. RESULTS: We included 3352 patients: 2349 with stable angina and 1003 with acute coronary syndrome (ACS). In the stable angina group, both patients receiving stenting and those receiving medical treatment had a 0.7% mortality rate; DESs were used in 70.4% of the patients receiving stenting. In the ACS group, the patients receiving stenting and those receiving medical treatment had a 4.9% and 10.7% mortality rate, respectively; DESs were used in 63.1% of the patients receiving stenting. In the 2008-2010 Taiwan ACS registry, DESs were used in only 28% of all stenting procedures, and the estimated hospital mortality rate was 1.8%. Multivariate analysis indicated that older age, prior stroke, and cardiogenic shock on admission were associated with an increased risk of in-hospital mortality in the ACS group. CONCLUSIONS: Compared with the Taiwan ACS cohort, the TSGH-CHD registry revealed increased DES use and increased disease complexity and severity after 2010. Although unlikely to significantly improve survival, interventionists seemed to perform high-risk procedures for complex CAD more often in the new DES era.

JNK/AP-1 activation contributes to tetrandrine resistance in T-cell acute lymphoblastic leukaemia.

T-cell acute lymphoblastic leukaemia (T-ALL) is a challenging malignancy with a high relapse rate attributed to drug resistance. Tetrandrine (TET), a bisbenzylisoquinoline alkaloid extracted from a Chinese herb, is a potential anti-cancer and anti-leukaemic drug. In this study we investigated the mechanisms of TET resistance in T-ALL cells in vitro. Among the four T-ALL cell lines tested, Jurkat and CEM cells exhibited the lowest and highest resistance to TET with IC50 values at 24 h of 4.31±0.12 and 16.53±3.32 µmol/L, respectively. When treated with TET, the activity of transcription factor activator protein 1 (AP-1) was significantly decreased in Jurkat cells but nearly constant in CEM cells. To avoid cell-specific variation in drug resistance and transcription factor activities, we established a TET-R Jurkat subclone with the estimated IC50 value of 10.90±.92 µmol/L by exposing the cells to increasing concentrations of TET. Interestingly, when treated with TET, TET-R Jurkat cells exhibited enhanced AP-1 and NF-κB activity, along with upregulation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling pathways, whereas the expression of P-gp was not altered. Selective inhibition of JNK but not ERK suppressed AP-1 activity and TET resistance in TET-R Jurkat cells and in CEM cells. These results demonstrate that Jurkat cells acquire TET resistance through activation of the JNK/AP-1 pathway but not through P-gp expression. The JNK/AP-1 pathway may be a potential therapeutic target in relapsed T-ALL.

Clinical Characteristics of Patients Less than Forty Years Old with Coronary Artery Disease in Taiwan: A Cross-Sectional Study.

BACKGROUND: Coronary artery disease (CAD) rarely occurs in young adults. Our objective was to investigate the baseline characteristics and outcomes of young patients with CAD. METHODS: We retrospectively enrolled patients aged < 40 years of age who underwent coronary angiography in a tertiary hospital in Taiwan between 2002 and 2015. The baseline characteristics and in-hospital outcomes of patients with acute coronary syndrome (ACS) and occlusive CAD (stenotic lesions > 50%) were compared with those of patients without ACS and non-occlusive CAD, respectively. RESULTS: We enrolled 245 young patients including 131 (53.5%) with ACS and 178 with occlusive CAD. The median age of the patients was 36.08 years and the mean follow-up period was 4.84 years. Of all study subjects, 220 (89.8%) were men and 140 (57.1%) were current smokers; there was an overall in-hospital mortality rate of 3.3%. Furthermore, age, body mass index, smoking, total leukocyte count, neutrophil-to-lymphocyte ratio, total cholesterol, and low-density lipoprotein were higher in patients with ACS and significant CAD than in those without ACS and nonstenotic CAD. Interestingly, triglyceride (TG) levels and the TG to high-density lipoprotein ratio were significantly higher in patients with ACS and occlusive CAD than in those without ACS and non-occlusive CAD. Logistic regression analysis revealed that smoking is an independent predictor of ACS and occlusive CAD. CONCLUSIONS: Our findings suggest that classical risk factors, obesity, and inflammation remain potent contributors to occlusive CAD and ACS in young adults in Taiwan. Efforts to prevent or minimize these risk factors, such as smoking cessation and aggressive lipid control, are necessary in young adults.

Prognostic impact of restored sinus rhythm in patients with sepsis and new-onset atrial fibrillation.

BACKGROUND: New-onset atrial fibrillation (NeOAF) is a common type of tachyarrhythmia in critically ill patients and is associated with increased mortality in patients with sepsis. However, the prognostic impact of restored sinus rhythm (SR) in septic patients with NeOAF remains unclear. METHODS: A total of 791 patients with sepsis, who were admitted to a medical intensive care unit from January 2011 to January 2014, were screened. NeOAF was detected by continuous electrocardiographic monitoring. Patients were categorized into three groups: no NeOAF, NeOAF with restored SR (NeOAF to SR), and NeOAF with failure to restore SR (NeOAF to atrial fibrillation (AF)). The endpoint of this study was in-hospital mortality. Patients with pre-existing AF were excluded. RESULTS: We reviewed the data of 503 eligible patients, including 263 patients with no NeOAF and 240 patients with NeOAF. Of these 240 patients, SR was restored in 165 patients, and SR could not be restored in 75 patients. The NeOAF to AF group had the highest in-hospital mortality rate of 61.3% compared with the NeOAF to SR and no NeOAF groups (26.1% and 17.5%, respectively). Moreover, multivariate logistic regression analysis revealed that failure of restored SR was independently associated with increased in-hospital mortality in patients with sepsis and NeOAF. CONCLUSIONS: Failure to restore a sinus rhythm in patients with new-onset atrial fibrillation may be associated with increased in-hospital mortality in patients with sepsis. Further prospective studies are needed to clarify the effects of restoration of sinus rhythm on survival in patients with sepsis and new-onset atrial fibrillation.

Chest Pain with Normal Thallium-201 Myocardial Perfusion Image - Is It Really Normal?

BACKGROUND: Thallium-201 myocardial perfusion image (MPI) is commonly used to detect coronary artery disease in patients with chest pain. Although a normal thallium-201 MPI result is generally considered to be a good prognosis and further coronary angiogram is not recommended, there are still a few patients who suffer from unexpected acute coronary events. The aim of this study was to investigate the clinical prognosis in patients with normal thallium-201 MPI. METHODS: From January 2006 to August 2012, a total 22,003 patients undergoing thallium-201 MPI in one tertiary center were screened. Of these, 8092 patients had normal results and were investigated retrospectively. During follow-up, 54 patients underwent coronary angiogram because of refractory typical angina pectoris or unexpected acute coronary events. These 54 patients were divided into 2 groups: group I consisted of 26 (48.1%) patients with angiography-proven significant coronary artery stenosis, and group II consisted of 28 (51.9%) patients without significant stenosis. RESULTS: Patients in group I had a higher prevalence of prior coronary stenting and electrocardiographic features of ST depression compared with patients in group II. The multivariate analysis demonstrated that both prior coronary stenting and ST depression were risk predictors of unexpected acute coronary events in the patients with normal thallium-201 MPI [odds ratio (OR), 5.93; 95% confidence interval (CI): 1.03-34.06, p = 0.05 and OR, 7.10; 95% CI: 1.28-39.51, p = 0.03,respectively]. CONCLUSIONS: Although there is a low incidence of unexpected acute coronary events in patients with chest pain and normal thallium-201 MPI, physicians should be aware of the potentials risk in certain patients in this specific population.

The Prognostic Role of QTc Interval in Acute Myocarditis.

BACKGROUND: Acute myocarditis is an inflammatory disease of the myocardium. Although a fulminant course of the disease is difficult to predict, it may lead to acute heart failure and death. Previous studies have demonstrated that reduced left ventricular systolic function and prolonged QRS duration can predict the fulminant course of acute myocarditis. This study aimed to identify whether prolonged QTc interval could also be predictive of fulminant disease in this population. METHODS: We retrospectively included 40 patients diagnosed with acute myocarditis who were admitted to our hospital between 2002 and 2013. They were divided into the fulminant group (n = 9) and the non-fulminant group (n = 31). Clinical symptoms, laboratory findings, electrocardiographic, and echocardiographic parameters were analyzed. Multivariate logistic regression analysis was used to identify the independent factors predictive of fulminant disease. RESULTS: Patients with fulminant myocarditis had a higher mortality rate than those with non-fulminant disease (55.6% vs. 0%, p < 0.001). Multivariate analysis revealed that wider QRS durations (133.22 ± 45.85 ms vs. 92.81 ± 15.56 ms, p = 0.030) and longer QTc intervals (482.78 ± 69.76 ms vs. 412.00 ± 33.31 ms, p = 0.016) were significant predictors associated with a fulminant course of myocarditis. CONCLUSIONS: Prolonged QRS duration and QTc interval, upon patient admission, may be associated with an increased risk of fulminant disease and increased in-hospital mortality. Therefore, early recognition of fulminant myocarditis and early mechanical support could provide improved patient outcomes. KEY WORDS: Fulminant myocarditis • Predictors • QRS complex • QTc interval.

Gentiana scabra Reduces SR-A Expression and Oxidized-LDL Uptake in Human Macrophages.

BACKGROUND: Macrophages can imbibe low-density lipoprotein (LDL) through scavenger receptors to become foam cells, which is critical in the initiation and progression of atherosclerosis. Mounting evidence suggests that the anti-inflammatory nature of Chinese herbs have the capacity to halt the complex mechanisms underlying atherosclerosis. This study examined the effects of Chinese herbs on foam cell formation. METHODS: Chinese herbs were obtained from the Sun Ten pharmaceutic company. Using oxidized LDL (OxLDL) uptake and a cell toxicity assay, we screened more than 30 types of Chinese herbs. Western blotting was used to determine expressions of scavenger receptors (SRs) and extracellular-signal-regulated kinase (ERK) activities. RESULTS: We found that Gentiana scabra reduced oxidized LDL uptake effectively in THP-1 macrophages (p < 0.05 vs. OxLDL treated control). Moreover, treatment with Gentiana scabra in THP-1 macrophages resulted in decreased expression of scavenger receptor- A (SR-A) (p < 0.05 vs. control). Molecular investigation revealed that Gentiana scabra inhibited SR-A protein expression, possibly by regulating ERK signaling pathways (p < 0.05 vs. control). CONCLUSIONS: By regulating SR-A expression, Gentiana scabra reduced oxidized LDL uptake in human macrophages. These results support the potential use of Gentiana scabra in treating atherosclerosis.

Activation of Krüppel-Like Factor 2 with Ginkgo Biloba Extract Induces eNOS Expression and Increases NO Production in Cultured Human Umbilical Endothelial Cells.

BACKGROUND: The mechanisms responsible for the effects of Ginkgo biloba extract (GbE) are not fully understood. Krüppel-like factor 2 (KLF2), a zinc transcription factor, has vasculoprotective effects if activated. The present study attempted to explore whether GbE may activate KLF2 and its consequences. METHODS: To determine the effects of GbE on endothelial cells, human umbilical vein endothelial cells (HUVECs) were incubated with various concentrations of GbE. KLF2 expression levels were determined by quantitative reverse transcription polymerase chain reaction. Cytoskeleton staining and cell migration assays were performed to determine the effects of KLF2 activation. Moreover, endothelial NO synthase (eNOS) expression levels were detected by PCR and Western blot testing. Nitric oxide (NO) production was also measured with 4,5-diaminofluorescein. A knockdown of KLF2 was performed to identify the role of KLF2 in GbE-induced eNOS expression and NO production. RESULTS: HUVECs that were incubated with GbE increased KLF2 expression. These cells demonstrated an altered cell morphology, cytoskeleton rearrangement, and inhibited migration activity. Moreover, eNOS expression and NO production increased in a dose-dependent manner when cells were treated with GbE. Correspondingly, silencing of KLF2 in HUVECs decreased eNOS expression and NO production in GbE-treated cells. CONCLUSIONS: GbE significantly activated KLF2 expression and KLF2-related endothelial function, including cytoskeleton rearrangement, inhibition of migration, eNOS activation, and NO production. These findings suggest that GbE may induce a vasculoprotective effect in endothelial cells. KEY WORDS: Endothelial cells; eNOS; Ginkgo biloba extract; KLF2; NO.

The Angiotensin II Receptor Neprilysin Inhibitor LCZ696 Inhibits the NLRP3 Inflammasome By Reducing Mitochondrial Dysfunction in Macrophages and Alleviates Dextran Sulfate Sodium-induced Colitis in a Mouse Model.

The intracellular sensor protein complex known as the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome plays a crucial role in regulating inflammatory diseases by overseeing the production of interleukin (IL)-1ß and IL-18. Targeting its abnormal activation with drugs holds significant promise for inflammation treatment. This study highlights LCZ696, an angiotensin receptor-neprilysin inhibitor, as an effective suppressor of NLRP3 inflammasome activation in macrophages stimulated by ATP, nigericin, and monosodium urate. LCZ696 also reduces caspase-11 and GSDMD activation, lactate dehydrogenase release, propidium iodide uptake, and the extracellular release of NLRP3 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) in ATP-activated macrophages, suggesting a potential mitigation of pyroptosis. Mechanistically, LCZ696 lowers mitochondrial reactive oxygen species and preserves mitochondrial integrity. Importantly, it does not significantly impact NLRP3, proIL-1ß, inducible nitric oxide synthase, cyclooxygenase-2 expression, or NF-κB activation in lipopolysaccharide-activated macrophages. LCZ696 partially inhibits the NLRP3 inflammasome through the induction of autophagy. In an in vivo context, LCZ696 alleviates NLRP3-associated colitis in a mouse model by reducing colonic expression of IL-1ß and tumor necrosis factor-α. Collectively, these findings suggest that LCZ696 holds significant promise as a therapeutic agent for ameliorating NLRP3 inflammasome activation in various inflammatory diseases, extending beyond its established use in hypertension and heart failure treatment.

Repositioning of the Angiotensin II Receptor Antagonist Candesartan as an Anti-Inflammatory Agent With NLRP3 Inflammasome Inhibitory Activity.

Aberrant activation of the NLRP3 inflammasome promotes the pathogenesis of many inflammatory diseases. The development of the NLRP3 inflammasome inhibitors from existing drugs for new therapeutic purposes is becoming more important. Candesartan is an angiotensin II receptor antagonist widely used as a blood pressure-lowering drug; however, the inhibitory potential of candesartan on the NLRP3 inflammasome has not yet been investigated. We demonstrated that candesartan significantly inhibited the NLRP3 inflammasome and pyroptosis in macrophages. Mechanistic analysis revealed that candesartan inhibited the expression of NLRP3 and proIL-1ß by suppressing NF-κB activation and reducing the phosphorylation of ERK1/2 and JNK1/2. Candesartan reduced mitochondrial damage and inhibited the NLRP3 inflammasome assembly by suppressing NLRP3 binding to PKR, NEK7 and ASC. In addition, candesartan inhibited IL-1ß secretion partially through autophagy induction. Furthermore, oral administration of candesartan reduced peritoneal neutrophil influx, NLRP3 and ASC expression in peritoneal cells, and lavage fluid concentrations of active caspase-1, IL-1ß, IL-6 and MCP-1 in uric acid crystal-injected mice. These results indicated that candesartan has board anti-inflammatory effects and has the potential to be repositioned to ameliorate inflammatory diseases or NLRP3-associated complications.

The leaves of the seasoning plant Litsea cubeba inhibit the NLRP3 inflammasome and ameliorate dextran sulfate sodium-induced colitis in mice.

The intracellular sensor NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome controls caspase-1 activity and the maturation and release of the cytokines interleukin (IL)-1ß and IL-18. The NLRP3 inflammasome has attracted the attention of the pharmaceutical industry because it promotes the pathogenesis of many diseases, making it a promising target for drug development. Litsea cubeba (Lour.) is a plant traditionally used as a seasoning in Taiwan and in other Asian countries. In this study, we investigated the inhibitory activity of the leaves of L. cubeba against the NLRP3 inflammasome. We found that the ethanol extract of L. cubeba leaves (MLE) inhibited the NLRP3 inflammasome in macrophages by reducing caspase-1 activation and IL-1ß secretion. MLE reduced pyroptosis in macrophages and inhibited the release of NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC). In a mechanistic study, MLE reduced mitochondrial reactive oxygen species (ROS) production and preserved mitochondrial integrity, which led to reduced mitochondrial DNA release into the cytosol. MLE did not reduce the expression levels of NLRP3, IL-1ß precursor or TNF-α in lipopolysaccharide (LPS)-activated macrophages. These results indicated that MLE inhibited the NLRP3 inflammasome by suppressing the activation signals of the NLRP3 inflammasome but not by reducing the priming signal induced by LPS. In addition, oral administration of MLE (20-80 mg/kg) ameliorated dextran sulfate sodium (DSS)-induced colitis in a mouse model. Notably, mice that received MLE (1 and 2 g/kg) daily for 7 days did not exhibit visible side effects. Gas chromatography-mass spectrometry (GC-MS) analysis found that α-Terpinyl acetate (27.2%) and 1,8-Cineole (17.7%) were the major compounds in MLE. These results indicated that L. cubeba leaves have the potential to be a nutraceutical for preventing and improving NLRP3 inflammasome-related diseases.

The effect of substrate topography on hFOB cell behavior and initial cell adhesion evaluated by a cytodetacher.

This study examined human fetal osteoblast (hFOB) cell morphology, adhesion force, and proliferation on a titanium-coated grooved surface. V-shaped grooves with a depth of 2.4 µm (T1) or 4.8 µm (T2) were produced in silicon wafers using photolithography and wet etching techniques. The grooved substrates were coated with a 200-nm-thick layer of titanium using a sputtering system. Smooth Ti-coated Si wafers were used as control surfaces. Analysis of the scanning electron microscopy observations shows that the cells responded to the micropattern by spreading out and becoming elongated. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay indicated that the grooved specimens had a significantly larger number of cells than did the control group after 5- and 15-day cultures. The cytocompatibility of specimens was quantitatively evaluated by a cytodetacher, which directly measures the detachment shear force of an individual cell to the substrate. After 30-min culture, the cell adhesion forces were 48.4, 136.6, and 103.3 nN for the smooth specimen, the T1 specimen, and the T2 specimen, respectively. The cell adhesion strengths were 294, 501, and 590 Pa for the smooth specimen, the T1 specimen, and the T2 specimen, respectively. The cell adhesion force and cell adhesion strength indicate the quality of cell adhesion, explaining the largest number of cells on grooved specimens. The experimental results suggest that the grooved patterns affect the cell shape and cytoskeletal structure, and thus influence the cell proliferation and cell adhesion force. The cytodetachment test with nanonewton resolution is a sensitive method for studying cell-biomaterial interaction.

Corrigendum: A Synthetic Small Molecule F240B Decreases NLRP3 Inflammasome Activation by Autophagy Induction.

[This corrects the article DOI: 10.3389/fimmu.2020.607564.].

A Synthetic Small Molecule F240B Decreases NLRP3 Inflammasome Activation by Autophagy Induction.

Conjugated polyenes are a class of widely occurring natural products with various biological functions. We previously identified 4-hydroxy auxarconjugatin B (4-HAB) as anti-inflammatory agent with an IC50 of ~20 µM. In this study, we synthesized a new anti-inflammatory 4-HAB analogue, F240B, which has an IC50 of less than 1 µM. F240B dose-dependently induced autophagy by increasing autophagic flux, LC3 speck formation and acidic vesicular organelle formation. F240B inhibited NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome activation through autophagy induction. In a mechanistic study, F240B inhibited interleukin (IL)-1ß (IL-1ß) precursor expression, promoted degradation of NLRP3 and IL-1ß, and reduced mitochondrial membrane integrity loss in an autophagy-dependent manner. Additionally, F240B inhibited apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and speck formation without affecting the interaction between NLRP3 and ASC or NIMA-related kinase 7 (NEK7) and double-stranded RNA-dependent kinase (PKR). Furthermore, F240B exerted in vivo anti-inflammatory activity by reducing the intraperitoneal influx of neutrophils and the levels of IL-1ß, active caspase-1, IL-6 and monocyte chemoattractant protein-1 (MCP-1) in lavage fluids in a mouse model of uric acid crystal-induced peritonitis. In conclusion, F240B attenuated the NLRP3 inflammasome through autophagy induction and can be developed as an anti-inflammatory agent in the future.

ECG changes with elevated troponin I in a patient with tension pneumothorax.

An 86-year-old man presented with sudden onset of dyspnea during hospitalization. Initial electrocardiography (ECG) showed poor R-wave progression of precordial leads with elevation of troponin I. Tension pneumothorax was subsequently diagnosed and the ECG returned to normal after resolution of clinical compromise.

Comparison of intracoronary adenosine and isosorbide dinitrate on no-reflow/slow flow during rotational atherectomy.

OBJECTIVE: To compare the effect of intracoronary adenosine and isosorbide dinitrate (ISDN) on no-reflow/slow flow during high-speed rotational atherectomy (HSRA) in patients with complex coronary artery disease (CAD). METHODS AND RESULTS: Medical records from consecutive patients diagnosed with complex CAD between November 2002 and March 2006 who underwent HSRA at the Tri-Service General Hospital, National Defence Medical Centre in Taipei, Taiwan, were included in this study. Patients in the adenosine group (n=32) received a 50 microg intracoronary adenosine bolus prior to the initiation of burr rotation and during each ablation. Patients in the ISDN group (n=58) received a 0.5 mg intracoronary ISDN bolus at comparable time points. Angiographic success was achieved in 100% of patients in the adenosine group and 98.3% (57/58) in the ISDN group.The procedural success rates were 96.9% (31/32) in the adenosine group and 89.7% (52/58) in the ISDN group. One patient (3.1%) from the adenosine group and six patients (10.3%) from the ISDN group experienced no-reflow/slow flow (P = 0.414). No in-hospital mortality occurred and target vessel revascularization was unnecessary. CONCLUSIONS: Intracoronary administration of either adenosine or ISDN during HSRA appears safe and administration of either agent may be effective in decreasing the incidence of no-reflow/slow flow during HSRA. Further large, prospective, randomized, placebo-controlled trials are required.

Differential effects of triptolide and tetrandrine on activation of COX-2, NF-kappaB, and AP-1 and virus production in dengue virus-infected human lung cells.

Most virus infections induce cycloxygenase-2 (COX-2) expression and subsequent prostaglandin E(2) (PGE(2)) production in cells, an inflammatory response that might be detrimental to virus replication and pathogenesis. This response in dengue virus infection remains to be elucidated. Triptolide and tetrandrine, compounds derived from two commonly used Chinese herbs, both demonstrate anti-inflammatory and immunosuppressive effects partly through modulation of COX-2 expression and, hence, may have antiviral effects. In this study, we examined, firstly, the immune response to dengue virus infection with respect to COX-2 expression and PGE(2) production in human lung cells (A549), liver cells (HepG2) and dendritic cells. Secondly, we assessed the potential antiviral effects of triptolide and tetrandrine on dengue virus infection vis-à-vis expression of COX-2, PGE(2), transcription factors, as well as virus production. We found that dengue virus infection enhanced COX-2 expression and PGE(2) production in A549 cells, similarly to the response in dendritic cells, but not in HepG2 cells. In dengue virus-infected A549 cells, nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1) were also activated, and both were dose-dependently inhibited by triptolide (0.5-4 ng/ml). Tetrandrine (1-10 microM) had no similar immunosuppressive effects and, moreover, at higher concentrations, enhanced NF-kappaB and AP-1 activity, COX-2 expression and PGE(2) production. However, unexpectedly, tetrandrine, but not triptolide, dose-dependently suppressed dengue virus production in A549 cells, independent of PGE(2) level. Our findings imply that triptolide and tetrandrine may attenuate dengue virus infection in human lung cells, but through distinct pathways.

A life-threatening double gap metabolic acidosis.

Double gap metabolic acidosis represents the high anion gap metabolic acidosis combined with raised serum osmolal gap due to retention of unmeasured osmole with accompanied metabolite. We describe a 62-year-old man diagnosed with community-acquired pneumonia undergoing continuous sedation in the context of asynchronous mechanical ventilation. High anion gap metabolic acidosis coupled with high plasma osmolal gap was noted with resultant severe bradyarrhythmia. D-Lactic acidosis and high serum concentration of propylene glycol (PG) eventually established the diagnosis of lorazepam-induced PG intoxication. Discontinuation of lorazepam followed by emergent long-extended hemodialysis effectively resolved the metabolic derangement without further recurrence. Serum osmolal gap is a sensitive and convenient surrogate for both early bedside detection and monitoring the therapeutic efficacy. Therefore, PG intoxication must be considered in the differential diagnosis of double gap metabolic acidosis. Early recognition with prompt hemodialysis intervention can avoid a life-threatening catastrophe.