Global antiplatelet sales trend: A focus on P2Y12 inhibitors from 2008 to 2018

BACKGROUND: P2Y12 inhibitors are an important component of dual antiplatelet therapy. Yet, their accessibility and affordability across countries stratified by income levels have not been studied. METHODS: Sales data were retrieved from the IQVIA Multinational Integrated Data Analysis System for the description of P2Y12 inhibitors global sales. Countries were stratified into 38 high-income countries and 27 middle-income countries. RESULTS: Global sales of P2Y12 inhibitors increased from 0.80 SU per year per person in 2008 to 1.79 in 2018. Growth in sales of P2Y12 inhibitors was greater in middle-income countries compared to high-income countries. Clopidogrel had the highest sales volume in both high-income and middle-income countries from 2008 to 2018, while ticagrelor sales volume increased mainly in high-income countries. CONCLUSIONS: Despite current guideline recommendations favoring ticagrelor and prasugrel for the prevention of atherothrombotic complications in patients with an acute coronary syndrome, clopidogrel retained the highest sales volume among the P2Y12 inhibitors from 2008 to 2018

Association Between Non-vitamin K Antagonist Oral Anticoagulants or Warfarin and Liver Injury: A Cohort Study

INTRODUCTION: The risk of liver injury in patients with atrial fibrillation (AF) using nonvitamin K antagonist oral anticoagulants (NOACs) has not been previously examined using liver function tests as the primary outcome in the real-world setting. This study assessed the association between NOACs (dabigatran, rivaroxaban, and apixaban) and warfarin and the risk of liver injury, as defined by laboratory tests. METHODS: Patients newly diagnosed with AF and prescribed NOACs or warfarin between 2010 and 2016, identified using the Hong Kong Clinical Database and Reporting System, were matched on age, sex, health status scores, comorbidities, and medications by propensity score on a 1:1 ratio. Risk of liver injury, defined as laboratory test values >3 times the upper limit of normal of alanine aminotransferase or aspartate aminotransferase and >2 times the upper limit of normal of total bilirubin, was compared between NOAC and warfarin users using Cox proportional hazards regression. RESULTS: After propensity score matching, 13,698 patients were included, of which 141 (2.1%) NOAC users and 232 (3.4%) warfarin users developed liver injury. The hazard ratio (HR) for NOAC vs warfarin users was 0.71 (95% confidence interval: 0.58–0.89). When comparing individual NOACs, only dabigatran (hazard ratio: 0.63; 95% confidence interval: 0.48–0.82) was associated with a lower risk of liver injury. DISCUSSION: Among patients with AF, NOACs as a group, and dabigatran alone were associated with a significantly lower risk of laboratory-based liver injury when compared with warfarin. However, liver injury occurs more frequently in real-world practice than in NOAC randomized controlled trials

Health related quality of life measured by SF-36: a population-based study in Shanghai, China

<p>Abstract</p> <p>Background</p> <p>Health related quality of life (HRQL) is a research topic that has attracted increasing interests around the world over the past two decades. The 36-item Short Form (SF-36) is a commonly used instrument for measuring HRQL. However, the information on Chinese adults' quality of life is limited. This paper reports on the feasibility of using the Mandarin version of SF-36 to evaluate HRQL in the population of Shanghai, China.</p> <p>Methods</p> <p>A total of 1034 subjects were randomly sampled using a stratified multiple-stage sampling method in Shanghai. Demographic information was collected, and SF-36 was used to measure HRQL.</p> <p>Results</p> <p>Internal reliability coefficients were greater than 0.7 in six of the eight SF-36 dimensions, except social function and mental health. Intraclass correlation coefficients ranged from 0.689 to 0.972. Split-half reliability coefficients were higher than 0.9 in five SF-36 dimensions. Validity was assessed by factor analysis and correlation analysis. Our results were basically in accordance with the theoretical construction of SF-36. The average scores of most SF-36 dimensions were higher than 80. The primary influencing risk factors of HRQL included chronic diseases, age, frequency of activities, and geographical region, which were identified using multivariate stepwise regression.</p> <p>Conclusion</p> <p>Overall, HRQL in the population of Shanghai is quite good. The Mandarin version of SF-36 is a valid and reliable tool for assessing HRQL.</p

Intervention effects of Ganoderma lucidum spores on epileptiform discharge hippocampal neurons and expression of Neurotrophin-4 and N-Cadherin

Epilepsy can cause cerebral transient dysfunctions. Ganoderma lucidum spores (GLS), a traditional Chinese medicinal herb, has shown some antiepileptic effects in our previous studies. This was the first study of the effects of GLS on cultured primary hippocampal neurons, treated with Mg2+ free medium. This in vitro model of epileptiform discharge hippocampal neurons allowed us to investigate the anti-epileptic effects and mechanism of GLS activity. Primary hippocampal neurons from <1 day old rats were cultured and their morphologies observed under fluorescence microscope. Neurons were confirmed by immunofluorescent staining of neuron specific enolase (NSE). Sterile method for GLS generation was investigated and serial dilutions of GLS were used to test the maximum non-toxic concentration of GLS on hippocampal neurons. The optimized concentration of GLS of 0.122 mg/ml was identified and used for subsequent analysis. Using the in vitro model, hippocampal neurons were divided into 4 groups for subsequent treatment i) control, ii) model (incubated with Mg2+ free medium for 3 hours), iii) GLS group I (incubated with Mg2+ free medium containing GLS for 3 hours and replaced with normal medium and incubated for 6 hours) and iv) GLS group II (neurons incubated with Mg2+ free medium for 3 hours then replaced with a normal medium containing GLS for 6 hours). Neurotrophin-4 and N-Cadherin protein expression were detected using Western blot. The results showed that the number of normal hippocampal neurons increased and the morphologies of hippocampal neurons were well preserved after GLS treatment. Furthermore, the expression of neurotrophin-4 was significantly increased while the expression of N-Cadherin was decreased in the GLS treated group compared with the model group. This data indicates that GLS may protect hippocampal neurons by promoting neurotrophin-4 expression and inhibiting N-Cadherin expression

Antioxidant Activities of Hydrolysates of Arca Subcrenata Prepared with Three Proteases

In order to get products with antioxidant activity from Arca subcrenata Lischke, the optimal hydrolase and hydrolysis conditions were investigated in the paper. Three proteases (neutrase, alcalase and papain) were applied to hydrolyze the homogenate of A. subcrenata. An orthogonal design was used to optimize hydrolysis conditions, and the pH-stat methods was used to determine the degree of hydrolysis. Viewed from the angle of reducing power, such as scavenging activities against α,α-diphenyl-β-picrylhydrazyl (DPPH) radical and hydrogen peroxide, the antioxidant activities of the alcalase hydrolysate (AH) were superior to neutrase hydrolysate (NH) and papain hydrolysate (PH), and its EC50 values in DPPH radical and hydrogen peroxide scavenging effect were 6.23 mg/ml and 19.09 mg/ml, respectively. Moreover, compared with products hydrolyzed by neutrase and papain, the molecular mass of AH was lower and its content of amino acid of peptides was higher. Therefore, alcalase was selected as the optimal enzyme to produce active ingredients since its hydrolysate exhibited the best antioxidant activity among them and possessed large amount of potential active peptides

Differential expression of members of the E2F family of transcription factors in rodent testes

BACKGROUND: The E2F family of transcription factors is required for the activation or repression of differentially expressed gene programs during the cell cycle in normal and abnormal development of tissues. We previously determined that members of the retinoblastoma protein family that interacts with the E2F family are differentially expressed and localized in almost all the different cell types and tissues of the testis and in response to known endocrine disruptors. In this study, the cell-specific and stage-specific expression of members of the E2F proteins has been elucidated. METHODS: We used immunohistochemical (IHC) analysis of tissue sections and Western blot analysis of proteins, from whole testis and microdissected stages of seminiferous tubules to study the differential expression of the E2F proteins. RESULTS: For most of the five E2F family members studied, the localizations appear conserved in the two most commonly studied rodent models, mice and rats, with some notable differences. Comparisons between wild type and E2F-1 knockout mice revealed that the level of E2F-1 protein is stage-specific and most abundant in leptotene to early pachytene spermatocytes of stages IX to XI of mouse while strong staining of E2F-1 in some cells close to the basal lamina of rat tubules suggest that it may also be expressed in undifferentiated spermatogonia. The age-dependent development of a Sertoli-cell-only phenotype in seminiferous tubules of E2F-1 knockout males corroborates this, and indicates that E2F-1 is required for spermatogonial stem cell renewal. Interestingly, E2F-3 appears in both terminally differentiated Sertoli cells, as well as spermatogonial cells in the differentiative pathway, while the remaining member of the activating E2Fs, E2F-2 is most concentrated in spermatocytes of mid to late prophase of meiosis. Comparisons between wildtype and E2F-4 knockout mice demonstrated that the level of E2F-4 protein displays a distinct profile of stage-specificity compared to E2F-1, which is probably related to its prevalence and role in Sertoli cells. IHC of rat testis indicates that localization of E2F-5 is distinct from that of E2F-4 and overlaps those of E2F-1 and E2F-2. CONCLUSION: The E2F-1 represents the subfamily of transcription factors required during stages of DNA replication and gene expression for development of germ cells and the E2F-4 represents the subfamily of transcription factors that help maintain gene expression for a terminally differentiated state within the testis

Systematic investigation of gastrointestinal diseases in China (SILC): validation of survey methodology

Background: Symptom-based surveys suggest that the prevalence of gastrointestinal diseases is lower in China than in Western countries. The aim of this study was to validate a methodology for the epidemiological investigation of gastrointestinal symptoms and endoscopic findings in China. Methods: A randomized, stratified, multi-stage sampling methodology was used to select 18 000 adults aged 18-80 years from Shanghai, Beijing, Xi'an, Wuhan and Guangzhou. Participants from Shanghai were invited to provide blood samples and undergo upper gastrointestinal endoscopy. All participants completed Chinese versions of the Reflux Disease Questionnaire (RDQ) and the modified Rome II questionnaire; 20% were also invited to complete the 36-item Short Form Health Survey (SF-36) and Epworth Sleepiness Scale (ESS). The psychometric properties of the questionnaires were evaluated statistically. Results: The study was completed by 16 091 individuals (response rate: 89.4%), with 3219 (89.4% of those invited) completing the SF-36 and ESS. All 3153 participants in Shanghai provided blood samples and 1030 (32.7%) underwent endoscopy. Cronbach's alpha coefficients were 0.89, 0.89, 0.80 and 0.91, respectively, for the RDQ, modified Rome II questionnaire, ESS and SF-36, supporting internal consistency. Factor analysis supported construct validity of all questionnaire dimensions except SF-36 psychosocial dimensions. Conclusion: This population-based study has great potential to characterize the relationship between gastrointestinal symptoms and endoscopic findings in China.Xiaoyan Yan, Rui Wang, Yanfang Zhao, Xiuqiang Ma, Jiqian Fang, Hong Yan, Xiaoping Kang, Ping Yin, Yuantao Hao, Qiang Li, John Dent, Joseph Sung, Duowu Zou, Saga Johansson, Katarina Halling, Wenbin Liu and Jia H

Tumor-Initiating Cells Are Enriched in CD44hi Population in Murine Salivary Gland Tumor

Tumor-initiating cells (T-ICs) discovered in various tumors have been widely reported. However, T-IC populations in salivary gland tumors have yet to be elucidated. Using the established Pleomorphic Adenoma Gene-1 (Plag1) transgenic mouse model of a salivary gland tumor, we identified CD44high (CD44hi) tumor cells, characterized by high levels of CD44 cell surface expression, as the T-ICs for pleomorphic adenomas. These CD44hi tumor cells incorporated 5-bromo-2-deoxyuridine (BrdU), at a lower rate than their CD44negative (CD44neg) counterparts, and also retained BrdU for a long period of time. Cell surface maker analysis revealed that 25% of the CD44hi tumor cells co-express other cancer stem cell markers such as CD133 and CD117. As few as 500 CD44hi tumor cells were sufficient to initiate pleomorphic adenomas in one third of the wildtype mice, whereas more than 1×104 CD44neg cells were needed for the same purpose. In NIH 3T3 cells, Plag1 was capable of activating the gene transcription of Egr1, a known upregulator for CD44. Furthermore, deletion of sequence 81–96 in the Egr1 promoter region abolished the effect of Plag1 on Egr1 upregulation. Our results establish the existence of T-ICs in murine salivary gland tumors, and suggest a potential molecular mechanism for CD44 upregulation

Thrombocytopenia in the experimental leptospirosis of guinea pig is not related to disseminated intravascular coagulation

BACKGROUND: Thrombocytopenia is commonly observed in severe leptospirosis. However, previous studies on coagulation alterations during leptospirosis resulted in inconsistent conclusions. Some findings showed that the prominent levels of thrombocytopenia observed in severe leptospirosis did not reflect the occurrence of disseminated intravascular coagulation (DIC) syndrome, while the others reached the conclusion that the hemorrhages observed in leptospirosis were due to DIC. The aim of this study is to elucidate whether DIC is an important feature of leptospirosis. METHODS: The leptospirosis model of guinea pig was established by intraperitoneal inoculation of Leptospira interrogans strain Lai. Hematoxylin and eosin (HE) staining, electron microscopy and immunohistochemistry staining were used to detect the pathologic changes. Platelet thrombus or fibrin thrombus was detected by HE, Martius Scarlet Blue (MSB) staining and electron microscopy. Hemostatic molecular markers such as 11-dehydrogenate thromboxane B2 (11-DH-TXB2), thrombomodulin (TM), thrombin-antithrombin III complex (TAT), D-Dimer and fibrin (ogen) degradation products (FDPs) in the plasma were examined by quantitative enzyme-linked immunosorbent assay (ELISA) to evaluate the hematological coagulative alterations in leptospirosis models. RESULTS: Pulmonary hemorrhage appeared in the model guinea pig 24 hours after leptospires intraperitoneal inoculation, progressing to a peak at 96 hours after the infection. Leptospires were detected 24 hours post-inoculation in the liver, 48 hours in the lung and 72 hours in the kidney by immunohistochemistry staining. Spiral form of the bacteria was initially observed in the liver, lung and kidney suggestive of intact leptospires, granular form of leptospires was seen as the severity increased. Platelet aggregation in hepatic sinusoid as well as phagocytosis of erythrocytes and platelets by Kupffer cells were both observed. Neither platelet thrombus nor fibrin thrombus was found in the liver, lung or kidney via morphological observation. Thrombocytopenia was observed in all infected guinea pigs of our experimental leptospirosis study. Analysis of hematologic molecular markers showed that 11-DH-TXB2 and TM in the plasma were elevated significantly. TAT that reflects the thrombin activation had a trend of decline after infection. Although D-dimer and FDPs increased statistically, the increasing may not bear clinical significance. CONCLUSION: Pathologic and hematological studies for experimental leptospirosis of guinea pig indicated that the thrombocytopenia found in guinea pigs did not correlate with the occurrence of DIC. The platelet aggregation and Kupffer cells phagocytosis might be the potential causes of thrombocytopenia in severe leptospirosis