The electrocardiographic characteristics of an acute embolism in the pulmonary trunk and the main pulmonary arteries.

OBJECTIVE: Pulmonary embolism (PE) is a common cardiovascular disease that can be easily missed or misdiagnosed. Electrocardiogram (ECG) is valuable in making early diagnoses and performing risk stratification with regard to acute PE. METHODS: A total of 147 hospitalized patients diagnosed with acute PE were enrolled in this study and divided into the following 2 groups: main pulmonary artery trunk or main pulmonary artery (MPA) embolism and lobar artery or remote branch embolism. Electrocardiographic abnormalities associated with acute PE were subsequently identified. RESULTS: Electrocardiographic abnormalities were significantly different between the pulmonary trunk/MPA embolism group and the lobar artery/remote branch embolism group. The incidence of pulmonary trunk/MPA emboli was significantly related to the number of ECG abnormalities (t = -7.086, P = 5.556e-11). Furthermore, the number of ECG abnormalities noted among patients with pulmonary trunk/MPA emboli was 5.276 times greater than the number observed among the lobar artery/remote branch embolism group (P < .001, 95% confidence interval = -6.57 to 3.97). The risk of either moderate or severe right ventricular hypertrophy was increased by 16.18% among patients with either pulmonary trunk or MPA emboli compared with patients with either lobar artery or remote branch emboli (P < .001, 95% confidence interval = -2.76 to 0.876). The correct classification rate was as high as 92.3% when ECG was used to classify the prognosis of PE patients. CONCLUSIONS: The number of ECG abnormalities and the degree of right ventricular hypertrophy as determined via ECG can be used to assess the probability of developing a PE in the pulmonary trunk and MPA. Furthermore, ECGs can assist clinicians with risk stratification.

Fenofibrate treatment of rats with experimental autoimmune myocarditis by alleviating Treg/Th17 disorder.

OBJECTIVE: To investigate the curative effect of fenofibrate on rats with experimental autoimmune myocarditis (EAM) and its immunological mechanism. MATERIAL AND METHODS: Twenty-four rats were equally randomised into three groups: an EAM group, fenofibrate group, and control group, then a subcutaneous injection of purified pig cardiac myosin was given to the EAM group rats and the fenofibrate group, while equivalent normal saline (NS) was given to the control group. After that, the fenofibrate group received fenofibrate by gavage (100 mg/kg/d) and equivalent NS was given to the other groups, lasting for 17 days. Then the rats were sacrificed in order to take heart tissues; HE staining and qRT-PCR method was used to assess the severity of heart failure and mRNA level of cytokines; NK-κB protein content was analyzed by Western-blot. Healthy rat spleen tissue was prepared for splenocyte suspension. Subsequently, splenocytes were administrated similarly to the test in vivo for detecting cytokine mRNA levels. RESULTS: Compared with the control group, heart weight in EAM group was heavier than in the other groups (p < 0.05), and there was severe inflammatory cell infiltration in heart tissue of the EAM group. Th17 cell-related cytokines mRNA levels in the EAM group/induction group were evidently higher than in other groups (p < 0.05); FOX-p3 mRNA level in the EAM group/induction group was lower than other groups, mRNA levels of IL-10 and FOX-p3 in the fenofibrate group were higher than in the EAM group/induction group (p < 0.05). Fenofibrate could significantly inhibit the up-regulation of NF-κB protein in EAM rats (p < 0.05). CONCLUSIONS: By inhibiting the development of Th17 cells and promoting the differentiation of Tregs, fenofibrate alleviated Treg/Th17 disorder and inhibited inflammation in rats with EAM, thus improving the prognosis.

[Postpartum pelvic floor rehabilitation on prevention of female pelvic floor dysfunction: a multicenter prospective randomized controlled study].

OBJECTIVE: To study the postpartum pelvic floor rehabilitation on the improvement of pelvic floor electrical physiological indexes and the prevention of female pelvic floor dysfunction in China. METHODS: A multicenter prospective randomized controlled study was carried out. From October 2011, postpartum women in five provinces were randomly assigned into treatment group and control group. The women in treatment group received electrical stimulation and biofeedback treatment. The women in control group performed pelvic floor muscle exercise at home. When 6 months and 12 months after delivery, comparing two groups of patients with pelvic floor electrical physiological indexes and pelvic organ prolapse quantitation measurements (POP-Q), to evaluate the effect of postpartum pelvic floor rehabilitation on the prevention of pelvic floor dysfunction. Pelvic floor impact questionnaire short form (PFIQ-7) and pelvic organ prolapse/incontinence sexual questionnaire-12 (PISQ-12) were used to evaluate the influence on quality of life and sexual life. RESULTS: Until June 2013, 324 women were participated, 124 in control group, 200 in treatment group. According to the baseline results, there was statistical significance in the results of pelvic floor electrical physiological indexes between the treatment and control groups in postpartum 6 months and 12 months; the proportion above level III of type I and type II muscle fibers strength in the treatment group, it was from 41.5% (83/200) and 40.5% (81/200) to 76.3% (145/190) and 79.5% (151/190) in postpartum 6 weeks and postpartum 6 months, increased to 80.6% (58/72) and 80.6% (58/72) in postpartum 12 months, improved significantly comparing with the control group (P < 0.01). According to Point Aa, treatment group and control group in the postpartum 6 weeks was (-2.2 ± 0.7) versus (-2.4 ± 0.6) cm, in postpartum 12 months (- 2.5 ± 1.1) versus (- 2.7 ± 0.6) cm, the improvement in treatment group was statistically significant (P < 0.01). And the other points were not significantly different (P > 0.05). There was no significant difference in the questionnaires in quality of life and quality of sexual life (P > 0.05). CONCLUSION: Neuromuscular electrical stimulation and biofeedback therapy in the early postpartum period could obviously improve pelvic floor electrical physiological indexes, and is beneficial to prevent the pelvic floor dysfunction.

miR828a-CsMYB114 Module Negatively Regulates the Biosynthesis of Theobromine in Camellia sinensis.

Theobromine is an important quality component in tea plants (Camellia sinensis), which is produced from 7-methylxanthine by theobromine synthase (CsTbS), the key rate-limiting enzyme in theobromine biosynthetic pathway. Our transcriptomics and widely targeted metabolomics analyses suggested that CsMYB114 acted as a potential hub gene involved in the regulation of theobromine biosynthesis. The inhibition of CsMYB114 expression using antisense oligonucleotides (ASO) led to a 70.21% reduction of theobromine level in leaves of the tea plant, which verified the involvement of CsMYB114 in theobromine biosynthesis. Furthermore, we found that CsMYB114 was located in the nucleus of the cells and showed the characteristic of a transcription factor. The dual luciferase analysis, a yeast one-hybrid assay, and an electrophoretic mobility shift assay (EMSA) showed that CsMYB114 activated the transcription of CsTbS, through binding to CsTbS promoter. In addition, a microRNA, miR828a, was identified that directly cleaved the mRNA of CsMYB114. Therefore, we conclude that CsMYB114, as a transcription factor of CsTbS, promotes the production of theobromine, which is inhibited by miR828a through cleaving the mRNA of CsMYB114.

[Incidence of metabolic syndrome in systemic lupus erythematosus and its influence by glucocorticoids].

OBJECTIVE: To investigate the incidence and correlative factors of metabolic syndrome (MS) in patients with systemic lupus erythematosus (SLE). METHODS: A total of 116 SLE patients and 115 controls were enrolled into the study. The incidence of MS, SLE disease activity index (SLEDAI) of patients with SLE combined with MS (MS-SLE) and patients without MS (n-MS-SLE), lupus characteristics, cumulative glucocorticoids, administration dose of glucocorticoids and hydroxychloroquine were compared between SLE group and the control group. RESULTS: The incidence of MS of SLE group was obviously higher than that of the control (34.48% vs 14.78%, P < 0.05). The ratios of patients with lower HDL-C, higher TG and higher blood pressure in SLE group (50.86%, 56.03%, 46.55%) were higher than those in the controls (34.78%, 16.52%, 20.00%, all P < 0.05). MS-SLE group had significantly higher mean waist circumference, BMI, systolic blood pressure and diastolic blood pressure and lower HDL-C than n-MS-SLE group (all P < 0.05). No significant difference was found regarding duration of disease, renal involvement, ESR, C-reactive protein,high-sensitivity C-reactive protein, SLEDAI, cumulative and current glucocorticoids use in MS-SLE group and n-MS-SLE group. The ratio of patients taking hydroxychloroquine in n-MS-SLE group was higher than that of MS-SLE group (46.05% vs 15.00%, P < 0.05). CONCLUSIONS: Patients with SLE has a higher incidence rate of MS. Hydroxychloroquine may reduce their MS incidence.

[Application of fuzzy reasoning to myocardial ischemia judgment based on electrocardiogram ST-T complex].

Electrocardiogram (ECG) is a convenient, economic, and non-invasive detecting tool in myocardial ischemia (MI). Its clinical appearance is mainly exhibited by ST-T complex change. MI events are usually instantaneous and asymptomatic in some cases, which cannot be forecasted to have a precautionary measure in time by doctors. The automatic detection of MI by computer and a cued warning of danger in real time play an important role in diagnosing heart disease. With the help of the medical staff, some quantitative approbatory indicators, such as ST-segment deviation, the amplitude of T-wave peak and the rate of ST and heart rate (HR), were combined to judge MI using fuzzy reasoning. After MIT-BIH database and the long-term ST database (LTST) verification, sensitivity and positive predictive values reached 75% and 78% respectively, and specificity and negative predictive values were 85% and 87% respectively. In addition, the proposed method was close to human way of thinking and understanding, and easy to apply in clinical detection and engineering fields.

[Study of the correlation between polycyclic aromatic hydrocarbons exposure during pregnancy and neonatal neurobehavioral development in Taiyuan and Changzhi cities].

OBJECTIVE: To compare the difference of polycyclic aromatic hydrocarbons (PAHs) levels in the urban air and the scores of Neonatal Behavioral Neurological Assessment (NBNA) between Taiyuan and Changzhi cities and to explore the effects of PAHs in the urban air during pregnancy on neonatal behavioral neurological development. METHODS: High-performance liquid chromatography (HPLC) with subsequent fluorescence detection was used to determine the PAHs levels in the cooperational hospitals in Changzhi and Taiyuan cities and the urinary 1-hydroxypyrene levels of the 297 pregnant women living Changzhi and Taiyuan cities during Nov. 2009 to May 2010. NBNA was used to determine the development of neonatal neural behavior. The differences of PAHs levels in the urban air, the pregnant women urinary 1-hydroxypyrene levels and NBNA scores between Taiyuan and Changzhi were compared. RESULTS: There are significant differences of levels of pyrene, benz [a] anthracene, Chrysene, benz [a] pyrene, dibenz [a, h] anthracene in the urban air between Taiyuan and Changzhi (P < 0.10). The median of urinary 1-hydroxypyrene levels in pregnant women of Taiyuan was 1.140 microg/mmolCr, (P25 was 0.457 microg/mmolCr, P75 was 2.678 microg/mmolCr), the median of urinary 1-hydroxypyrene levels in pregnant women of Changzhi was 0.761 microg/mmolCr, (P25 was 0.133 microg/mmolCr, P75 was 2.095 microg/mmolCr). There are significant differences of urinary 1-hydroxypyrene levels in pregnant women between Taiyuan and Changzhi (t = -3.140, P = 0.002). There are significant differences of the NBNA scores, capacity scores, passive muscle tension scores, active muscle tension scores and general assessment scores between Taiyuan and Changzhi (P < 0.10). There was correlation between NBNA scores and urinary 1-hydroxypyrene level in pregnant women. CONCLUSION: The PAHs in the urban air during pregnancy may adversely affect the neonatal neurobehavioral development.

Identification of LHFPL3-AS2 as a prognostic biomarker in lung adenocarcinoma.

Background: Deregulation of long noncoding RNAs (lncRNAs) was considered one of the main characteristics of several human cancers. However, detailed genome-wide expression and functional significance studies of lnc RNAs in lung adenocarcinoma are still limited. This study aims to discover a new lncRNA that may play an important role in regulating the pathogenesis of lung adenocarcinoma (ADC). Methods: We conducted a comprehensive analysis of three Gene Expression Omnibus (GEO) microarray datasets and TCGA datasets. Differentially expressed lncRNAs between ADC and normal tissues were screened and verified using Gene Expression Profiling Interactive Analysis (GEPIA). Moreover, Kaplan-Meier plotter was used to construct the gene prognosis profile. The downstream targets of miRNA and related functional pathways were predicted and validated. Results: With microarray gene expression analysis, we found that only lncRNAs-PCAT6 was commonly upregulated among four datasets, and four lncRNAs (LINC00968, PGM5-AS1, LHFPL3-AS2 and SFTA1P) were significantly downregulated in the ADC samples as compared to the normal tissues. Meanwhile, for LHFPL3-AS2, high-risk patients showed better overall survival (HR=0.6 or 0.62; P < .0001 or P = 0.0014), overall survival from TCGA datasets (HR=0.72; P = 0.015) and recurrence-free survival (HR=0.72; P = 0.015). Then, LHFPL3-AS2 was predicted to bind to two miRNAs, miR-127-5p and miR-424-5p. Finally, validation and functional enrichment analysis of the downstream key mRNAs showed significant enrichment in some cancer-related pathways, such as cell adhesion in cancer and small cell lung cancer. Conclusions: Taken together, our study indicated that LHFPL3-AS2 was associated with tumorigenesis, and it could be used as a useful biomarker in the diagnosis, prognosis and treatment of ADC.

Early Initiation of Evolocumab Treatment in Chinese Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

PURPOSE: Evolocumab has been shown to improve cardiovascular outcomes in patients with stable atherosclerotic disease. Whether this benefit persists in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) remains undetermined. This study aimed to evaluate the efficacy and safety of the early initiation of evolocumab in Chinese patients with ACS undergoing PCI. METHODS: This retrospective cohort study involved 1564 consecutive patients who had been hospitalized with ACS and underwent PCI, and who had elevated LDL-C levels (≥1.8 mmol/L after receiving high-intensity statin therapy for ≥4 weeks; ≥2.3 mmol/L after receiving low- or moderate-intensity statin; or ≥3.2 mmol/L without statin therapy). Patients who received evolocumab (initiated in-hospital and after 18 months) were included in the evolocumab group (n = 414), and all other patients were included in the control group (n = 1150). The primary outcome at 18 months was a composite of ischemic stroke, cardiovascular death, myocardial infarction, hospitalization for unstable angina, or coronary revascularization. The evolocumab treatment effect on the primary outcome was assessed in all prespecified subgroups. FINDINGS: At 18 months, evolocumab combined with statins reduced LDL-C levels from baseline levels by 42.48% compared with statins alone. After multivariable adjustment, evolocumab combined with statins significantly reduced the primary outcome (8.2% vs 12.4%; adjusted hazard ratio, 0.65; 95% CI, 0.45-0.95; P = 0.025). In addition, evolocumab consistently reduced the primary outcome across the major subgroups. For the safety outcomes, no significant differences between the groups were observed in any adverse events. IMPLICATIONS: Among Chinese patients who underwent PCI for ACS, the early initiation of evolocumab combined with statin treatment effectively reduced LDL-C levels and lowered the incidence of recurrent ischemic cardiovascular events, with satisfactory tolerability and safety. Chinese Clinical Trial Registry identifier: ChiCTR2100049364.

Comparative Transcriptome Analysis of Agrobacterium tumefaciens Reveals the Molecular Basis for the Recalcitrant Genetic Transformation of Camellia sinensis L.

Tea (Camellia sinensis L.), an important economic crop, is recalcitrant to Agrobacterium-mediated transformation (AMT), which has seriously hindered the progress of molecular research on this species. The mechanisms leading to low efficiency of AMT in tea plants, related to the morphology, growth, and gene expression of Agrobacterium tumefaciens during tea-leaf explant infection, were compared to AMT of Nicotiana benthamiana leaves in the present work. Scanning electron microscopy (SEM) images showed that tea leaves induced significant morphological aberrations on bacterial cells and affected pathogen-plant attachment, the initial step of a successful AMT. RNA sequencing and transcriptomic analysis on Agrobacterium at 0, 3 and 4 days after leaf post-inoculation resulted in 762, 1923 and 1656 differentially expressed genes (DEGs) between the tea group and the tobacco group, respectively. The expressions of genes involved in bacterial fundamental metabolic processes, ATP-binding cassette (ABC) transporters, two-component systems (TCSs), secretion systems, and quorum sensing (QS) systems were severely affected in response to the tea-leaf phylloplane. Collectively, these results suggest that compounds in tea leaves, especially gamma-aminobutyrate (GABA) and catechins, interfered with plant-pathogen attachment, essential minerals (iron and potassium) acquisition, and quorum quenching (QQ) induction, which may have been major contributing factors to hinder AMT efficiency of the tea plant.

Comparative transcriptome analysis reveals key pathways and genes involved in trichome development in tea plant (Camellia sinensis).

Trichomes, which develop from epidermal cells, are considered one of the important characteristics of the tea plant [Camellia sinensis (L.) O. Kuntze]. Many nutritional and metabolomic studies have indicated the important contributions of trichomes to tea products quality. However, understanding the regulation of trichome formation at the molecular level remains elusive in tea plants. Herein, we present a genome-wide comparative transcriptome analysis between the hairless Chuyeqi (CYQ) with fewer trichomes and the hairy Budiaomao (BDM) with more trichomes tea plant genotypes, toward the identification of biological processes and functional gene activities that occur during trichome development. In the present study, trichomes in both cultivars CYQ and BDM were unicellular, unbranched, straight, and soft-structured. The density of trichomes was the highest in the bud and tender leaf periods. Further, using the high-throughput sequencing method, we identified 48,856 unigenes, of which 31,574 were differentially expressed. In an analysis of 208 differentially expressed genes (DEGs) encoding transcription factors (TFs), five may involve in trichome development. In addition, on the basis of the Gene Ontology (GO) annotation and the weighted gene co-expression network analysis (WGCNA) results, we screened several DEGs that may contribute to trichome growth, including 66 DEGs related to plant resistance genes (PRGs), 172 DEGs related to cell wall biosynthesis pathway, 29 DEGs related to cell cycle pathway, and 45 DEGs related to cytoskeleton biosynthesis. Collectively, this study provided high-quality RNA-seq information to improve our understanding of the molecular regulatory mechanism of trichome development and lay a foundation for additional trichome studies in tea plants.

E3 ubiquitin ligase RNF5 attenuates pathological cardiac hypertrophy through STING.

Ring-finger protein 5 (RNF5) is an E3 ubiquitin ligase which is expressed in a variety of human tissues. RNF5 is involved in the regulation of endoplasmic reticulum stress, inflammation, and innate immunity and plays an important role in the occurrence and development of various tumors. However, the role of RNF5 in cardiac hypertrophy has not been reported. In this study, we found the expression of RNF5 was increased in the hearts of mice with pathological cardiac hypertrophy. The loss-of-function research demonstrated that RNF5 deficiency exacerbated cardiac hypertrophy, whereas gain-of-function studies revealed that overexpression of RNF5 had opposite effects. The stimulator of interferon genes (STING) is a signaling molecule that can activate type I interferon immunity, which can meditate inflammation and immune response in many diseases. The protein-protein interaction experiments confirmed that STING interacted with RNF5. Further studies showed that RNF5 inhibited cardiac hypertrophy by promoting STING degradation through K48-linked polyubiquitination. Therefore, we defined RNF5 as importantly regulated signaling for cardiac hypertrophy.

Effects of mixing temperature on the extrusion rheological behaviors of rubber-based compounds.

In this study, rim strip (R) and sidewall (S) compounds were prepared at varying initial mixing temperatures. The effects of the mixing temperature on the extrusion rheological behaviors of the compounds were investigated, and the relationships between the compound structure and the extrusion rheological behaviors were studied. The results showed that the tensile stress relaxation rates of both R and S were more sensitive to the mixing temperature than the shear stress relaxation rate, and the former was affected by both the dispersion of carbon black (CB) and the actual molecular weight of the rubbers. Strain sweep results showed that R, which had a higher CB content, had a more obvious Payne effect than S. When the initial mixing temperature increased from 80 °C to 90 °C, both storage modulus (G') at a low shear strain and the ΔG' of R obviously decreased, indicating CB dispersion improvement. The S extrudates showed higher die swell ratios (B) than the R extrudates, and the former was more sensitive to mixing temperature. The main factors influencing the B of the R and S were the CB dispersity and the molecular weight, respectively. In addition, at high extrusion rates, a sharkskin phenomenon could be observed for the R extrudate surfaces, whereas the S extrudates were more likely to be integrally distorted.

Efficacy and Safety of Bivalirudin During Percutaneous Coronary Intervention in Chronic Total Occlusion: A Retrospective Study.

PURPOSE: Bivalirudin as a thrombin inhibitor is proven to have a low risk of bleeding during percutaneous coronary intervention (PCI). Some evidence indicates comparable effectiveness and safety between bivalirudin and unfractionated heparin (UFH). Although bivalirudin during PCI offers more clinical and safety benefits to patients with chronic total occlusion (CTO), mostly via radial access, this has not been confirmed. The objective of this study was to examine the efficacy and safety of bivalirudin during percutaneous coronary intervention (PCI) in patients with CTO. METHODS: This trial used a retrospective cohort study design. Medical information from 736 patients with CTO who underwent PCI with bivalirudin or UFH at the First Affiliated Hospital of Zhengzhou University from July 2019 to September 2020 was extracted and analyzed. The primary end point was the 30-day incidence of net adverse clinical events (NACEs), and the secondary end point was the major adverse cardiovascular events (MACEs), which were related to safety and efficacy, respectively. Other end points incorporated each component of the primary outcome, target vessel revascularization, and stent thrombosis. Clinical and procedural characteristics at baseline were adjusted by using a logistic regression model. FINDINGS: Overall, 71.5% of patients with CTO used the radial approach. Both groups exhibited nonsignificant differences in the majority of baseline characteristics. The bivalirudin group was associated with a significant reduction in NACEs (12.9% vs 21.5%; P = 0.002) and major bleeding (2.5% vs 8.0%; P = 0.001) versus the UFH group at the end of the 30-day follow-up. The incidence of MACEs, myocardial infarction, death, stroke, stent thrombosis, and target vessel revascularization did not differ significantly between the 2 groups. Moreover, the bivalirudin group also reported a lower incidence of NACEs in the prespecified subgroups. IMPLICATIONS: Bivalirudin exhibited comparative efficacy but superior safety compared with UFH among patients with CTO undergoing PCI. Chinese Clinical Trial Registry: ChiCTR2000034771.

A donor-DNA-free CRISPR/Cas-based approach to gene knock-up in rice.

Structural variations (SVs), such as inversion and duplication, contribute to important agronomic traits in crops1. Pan-genome studies revealed that SVs were a crucial and ubiquitous force driving genetic diversification2-4. Although genome editing can effectively create SVs in plants and animals5-8, the potential of designed SVs in breeding has been overlooked. Here, we show that new genes and traits can be created in rice by designed large-scale genomic inversion or duplication using CRISPR/Cas9. A 911 kb inversion on chromosome 1 resulted in a designed promoter swap between CP12 and PPO1, and a 338 kb duplication between HPPD and Ubiquitin2 on chromosome 2 created a novel gene cassette at the joint, promoterUbiquitin2::HPPD. Since the original CP12 and Ubiquitin2 genes were highly expressed in leaves, the expression of PPO1 and HPPD in edited plants with homozygous SV alleles was increased by tens of folds and conferred sufficient herbicide resistance in field trials without adverse effects on other important agronomic traits. CRISPR/Cas-based genome editing for gene knock-ups has been generally considered very difficult without inserting donor DNA as regulatory elements. Our study challenges this notion by providing a donor-DNA-free strategy, thus greatly expanding the utility of CRISPR/Cas in plant and animal improvements.

Bivalirudin versus unfractionated heparin during percutaneous coronary intervention in high-bleeding-risk patients with acute coronary syndrome in contemporary practice.

BACKGROUND: Bivalirudin, as compared with unfractionated heparin (UFH), has been shown to reduce bleeding complications and supply a better safety profile among low/medium-bleeding-risk patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) in some previous studies. Whether this advantage persists in patients at high risk of bleeding according to contemporary practice characterized by frequent use of radial-artery access and novel P2Y12 inhibitors, and low use of glycoprotein IIb/IIIa inhibitors (GPIs) is unclear. AIM OF THE STUDY: This study aimed to assess the efficacy and safety of bivalirudin compared with UFH in high bleeding risk patients with ACS undergoing PCI in current practice. MATERIALS AND METHODS: All consecutive high-bleeding-risk patients who underwent PCI for ACS at the First Affiliated Hospital of Zhengzhou University from January to September 2019 were retrospectively analyzed. The 30-day primary outcome was a composite of major bleeding, myocardial infarction, all-cause death, or stroke (net adverse clinical events [NACEs]), and the secondary outcomes at 30 days included a composite of myocardial infarction, stoke, or all-cause death (major adverse cardiovascular events [MACEs]), each component of the primary outcome, target vessel revascularization (TVR) and stent thrombosis (ST). Besides, we assessed angina-related health status at 30 days, the length of hospital stay, and hospitalization costs. A logistic regression model was used to adjust for baseline differences. Consistency of the treatment effect of bivalirudin for NACEs and MACEs compared with UFH was evaluated in 15 prespecified subgroups. RESULTS: From January to September 2019, 823 patients (361 treated with bivalirudin and 462 treated with UFH) were enrolled in the study. GPIs, novel P2Y12 inhibitors, and radial approach was used in 5.6 %, 66.1 %, and 89.7 % of the patients, respectively. After adjusting for baseline differences, bivalirudin was associated with significant reduction in NACEs, MACEs, major bleeding, and myocardial infarction at 30 days compared with UFH. The individual endpoints of death, stroke, ST and TVR did not differ significantly between the 2 groups after adjusting for covariates. Furthermore, bivalirudin consistently reduced the rates of NACEs and MACEs in the 15 prespecified subgroups compared with UFH. These benefits of bivalirudin can translate into improved angina-related health status, shorter hospital stays, and lower hospitalization costs. CONCLUSIONS: The treatment of bivalirudin showed better efficacy and safety as compared to UFH among patients with ACS undergoing PCI at high risk of bleeding in contemporary practice.

Synergistic Effect of Dofetilide and Mexiletine on Prevention of Atrial Fibrillation.

BACKGROUND: Although atrial fibrillation (AF) is the most common abnormal heart rhythm and its prevalence continues to rise, there is a marked paucity of effective and safe antiarrhythmic drugs for AF. This study was done to test whether combined use of dofetilide and mexiletine exhibits not only a synergistic effect on AF suppression but also a safer profile in drug-induced ventricular proarrhythmias. METHODS AND RESULTS: The effects of dofetilide plus mexiletine on atrial effective refractory period (ERP), AF inducibility, QT, and QT-related ventricular arrhythmias were studied using the isolated arterially perfused rabbit atrial and ventricular wedge preparations. Dofetilide or mexiletine alone mildly to moderately prolonged atrial ERP, but their combined use produced a markedly rate-dependent increase in atrial ERP. Dofetilide (3 nmol/L) plus mexiletine (10 µmol/L) increased the ERP by 28.2% from 72.2±5.7 to 92.8±5.9 ms (n=9, P<0.01) at a pacing rate of 0.5 Hz and by 94.5% from 91.7±5.2 to 178.3±12.0 ms (n=9, P<0.01) at 3.3 Hz. Dofetilide plus mexiletine strongly suppressed AF inducibility. On the other hand, dofetilide at 10 nmol/L produced marked QT and Tp-e prolongation, steeper QT-BCL and Tp-e-BCL slopes, and induced early afterdepolarizations and torsade de pointes in the ventricular wedges. Mexiletine at 10 µmol/L reduced dofetilide-induced QT and Tp-e prolongation, QT-BCL and Tp-e-BCL slopes, and abolished early afterdepolarizations and torsade de pointes. CONCLUSIONS: In rabbits, combined use of dofetilide and mexiletine not only synergistically increases atrial ERP and effectively suppresses AF inducibility, but also markedly reduces QT liability and torsade de pointes risk posed by dofetilide alone.

How to determine cardiac ion channels targeted by drugs using the isolated rabbit ventricular wedge model.

INTRODUCTION: The rabbit left ventricular wedge (RLVW) has been demonstrated as a highly sensitive and specific preclinical model in assessing drug-induced QT prolongation and proarrhythmias. However, there is a need to determine drugs' cardiac ion channel profiles beyond QT measurement. In this study, we present an approach to determine cardiac ion channels targeted by drugs with analyzing a few key ECG parameters plus a contractility parameter obtained from the RLVW. METHODS: The RLVW assay was used for testing 18 drugs with well-known ion channel profiles. A transmural ECG and isometric contractility were recorded. Five parameters including QRS, QT, Tp-e/QT ratio, QT-BCL slope and the positive staircase response of contractility were analyzed. RESULTS: There were distinguished drug-induced ECG and contractility changes from which targeted cardiac ion channels by drugs could be determined. Inhibition of sodium channel resulted in rate-dependent QRS widening, QT and Tp-e shortening and a reduced QT-BCL slope. Although both IKr and IKs blockers prolonged QT interval, IKr blockers but not IKs increased Tp-e/QT ratio. Both potassium channel openers and calcium channel blockers markedly shortened QT and Tp-e intervals, but only calcium channel blockers could reverse the positive staircase response of contractility. DISCUSSION: The results in the present study are correlated closely to the drugs' well-known clinical profiles. This indicates that the RLVW assay with an adequate experimental protocol plus analysis of 5 key parameters is highly valuable in preclinical assessment of drug candidates for their detailed ion channel activities, proarrhythmic risks and other adverse effects. The limitations of the RLVW assay are also addressed.

Bacterial Cell Growth Inhibitors Targeting Undecaprenyl Diphosphate Synthase and Undecaprenyl Diphosphate Phosphatase.

We synthesized a series of benzoic acids and phenylphosphonic acids and investigated their effects on the growth of Staphylococcus aureus and Bacillus subtilis. One of the most active compounds, 5-fluoro-2-(3-(octyloxy)benzamido)benzoic acid (7, ED50 ∼0.15 µg mL-1 ) acted synergistically with seven antibiotics known to target bacterial cell-wall biosynthesis (a fractional inhibitory concentration index (FICI) of ∼0.35, on average) but had indifferent effects in combinations with six non-cell-wall biosynthesis inhibitors (average FICI∼1.45). The most active compounds were found to inhibit two enzymes involved in isoprenoid/bacterial cell-wall biosynthesis: undecaprenyl diphosphate synthase (UPPS) and undecaprenyl diphosphate phosphatase (UPPP), but not farnesyl diphosphate synthase, and there were good correlations between bacterial cell growth inhibition, UPPS inhibition, and UPPP inhibition.

Functional and structural analyses of a 1,4-ß-endoglucanase from Ganoderma lucidum.

Ganoderma lucidum is a saprotrophic white-rot fungus which contains a rich set of cellulolytic enzymes. Here, we screened an array of potential 1,4-ß-endoglucanases from G. lucidum based on the gene annotation library and found that one candidate gene, GlCel5A, exhibits CMC-hydrolyzing activity. The recombinant GlCel5A protein expressed in Pichia pastoris is able to hydrolyze CMC and ß-glucan but not xylan and mannan. The enzyme exhibits optimal activity at 60°C and pH 3-4, and retained 50% activity at 80 and 90°C for at least 15 and 10min. The crystal structure of GlCel5A and its complex with cellobiose, solved at 2.7 and 2.86Å resolution, shows a classical (ß/α)8 TIM-barrel fold as seen in other members of glycoside hydrolase family 5. The complex structure contains a cellobiose molecule in the +1 and +2 subsites, and reveals the interactions with the positive sites of the enzyme. Collectively, the present work provides the first comprehensive characterization of an endoglucanase from G. lucidum that possesses properties for industrial applications, and strongly encourages further studying in the cellulolytic enzyme system of G. lucidum.