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31.
Background:
Patients prescribed antiplatelet treatment to prevent recurrent acute myocardial infarction are often also given a selective serotonin reuptake inhibitor (SSRI) to treat coexisting depression. Use of either treatment may increase the risk of bleeding. We assessed the risk of bleeding among patients taking both medications following acute myocardial infarction.Methods:
We conducted a retrospective cohort study using hospital discharge abstracts, physician billing information, medication reimbursement claims and demographic data from provincial health services administrative databases. We included patients 50 years of age or older who were discharged from hospital with antiplatelet therapy following acute myocardial infarction between January 1998 and March 2007. Patients were followed until admission to hospital due to a bleeding episode, admission to hospital due to recurrent acute myocardial infarction, death or the end of the study period.Results:
The 27 058 patients in the cohort received the following medications at discharge: acetylsalicylic acid (ASA) (n = 14 426); clopidogrel (n = 2467), ASA and clopidogrel (n = 9475); ASA and an SSRI (n = 406); ASA, clopidogrel and an SSRI (n = 239); or clopidogrel and an SSRI (n = 45). Compared with ASA use alone, the combined use of an SSRI with antiplatelet therapy was associated with an increased risk of bleeding (ASA and SSRI: hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.08–1.87; ASA, clopidogrel and SSRI: HR 2.35, 95% CI 1.61–3.42). Compared with dual antiplatelet therapy alone (ASA and clopidogrel), combined use of an SSRI and dual antiplatelet therapy was associated with an increased risk of bleeding (HR 1.57, 95% CI 1.07–2.32).Interpretation:
Patients taking an SSRI together with ASA or dual antiplatelet therapy following acute myocardial infarction were at increased risk of bleeding.Antiplatelet agents such as acetylsalicylic acid (ASA) and clopidogrel are a mainstay of therapy following acute myocardial infarction. These agents are effective in reducing the risk of recurrent acute myocardial infarction and other cardiovascular events, with the potential for additive benefit when used in combination.1–3 The risk of bleeding associated with their use, however, is of concern.4–6 This risk may be increased further by the frequent concomitant use of other medications associated with an increased risk of bleeding, such as anticoagulant therapy7 and selective serotonin reuptake inhibitors (SSRIs).Up to 20% of patients with cardiovascular disease experience depression and are most often prescribed an SSRI.8–13 The vast majority of these patients also use antiplatelet therapy. The risk of bleeding associated with combining SSRI therapy with single or dual antiplatelet therapy is uncertain. Two large clinical trials that examined SSRI use following acute myocardial infarction did not specifically report on the risk of bleeding,14,15 and earlier studies suggested no increase in risk associated with SSRI therapy combined with single-agent antiplatelet therapy.16,17SSRI use itself has been associated with an increased risk of bleeding, particularly during the first month of use.18 The inhibition of serotonin transporters by SSRIs is thought to be responsible for the risk of bleeding.19 Platelets release serotonin at sites of bleeding and vascular damage; however, they do not synthesize serotonin and instead acquire it from the blood and store it.19,20 By this mechanism, SSRIs may also worsen the bleeding caused by ASA and clopidogrel.19,20 Inhibition of cytochrome P450 by certain SSRIs has also been associated with increased risk of drug interaction causing bleeding;21 however, data on this issue are scarce.We examined the risk of bleeding associated with the use of SSRIs when combined with single and dual antiplatelet therapy among patients following acute myocardial infarction. 相似文献32.
INF2 is a unique formin that can both polymerize and depolymerize actin filaments. Mutations in INF2 cause the kidney disease focal and segmental glomerulosclerosis. INF2 can be expressed as two C-terminal splice variants: CAAX and non-CAAX. The CAAX isoform contains a C-terminal prenyl group and is tightly bound to endoplasmic reticulum (ER). The localization pattern and cellular function of the non-CAAX isoform have not been studied. Here we find that the two isoforms are expressed in a cell type-dependent manner, with CAAX predominant in 3T3 fibroblasts and non-CAAX predominant in U2OS, HeLa, and Jurkat cells. Although INF2-CAAX is ER localized in an actin-independent manner, INF2-non-CAAX localizes in an actin-dependent meshwork pattern distinct from ER. INF2-non-CAAX is loosely attached to this meshwork, being extracted by brief digitonin treatment. Suppression of INF2-non-CAAX causes fragmentation of the Golgi apparatus. This effect is counteracted by treatment with the actin monomer-sequestering drug latrunculin B. We also find discrete patches of actin filaments in the peri-Golgi region, and these patches are reduced upon INF2 suppression. Our results suggest that the non-CAAX isoform of INF2 serves a distinct cellular function from that of the CAAX isoform. 相似文献
33.
Challenge of Drosophila melanogaster with Cryptococcus neoformans and role of the innate immune response 下载免费PDF全文
Apidianakis Y Rahme LG Heitman J Ausubel FM Calderwood SB Mylonakis E 《Eukaryotic cell》2004,3(2):413-419
We found that the ingestion of Cryptococcus neoformans by Drosophila melanogaster resulted in the death of the fly but that the ingestion of Saccharomyces cerevisiae or the nonpathogenic Cryptococcus kuetzingii or Cryptococcus laurentii did not. The C. neoformans protein kinase A and RAS signal transduction pathways, previously shown to be involved in virulence in mammals, also played a role in killing DROSOPHILA: Mutation of the Toll immune response pathway, the predominant antifungal pathway of the fly, did not play a role in Drosophila defense following ingestion of the yeast. However, the Toll pathway was necessary for the clearance of C. neoformans introduced directly into the hemolymph of D. melanogaster and for the survival of systemically infected flies. 相似文献
34.
A novel genetic pathway for sudden cardiac death via defects in the transition between ventricular and conduction system cell lineages 总被引:9,自引:0,他引:9
35.
Lesic B Lépine F Déziel E Zhang J Zhang Q Padfield K Castonguay MH Milot S Stachel S Tzika AA Tompkins RG Rahme LG 《PLoS pathogens》2007,3(9):1229-1239
Long-term antibiotic use generates pan-resistant super pathogens. Anti-infective compounds that selectively disrupt virulence pathways without affecting cell viability may be used to efficiently combat infections caused by these pathogens. A candidate target pathway is quorum sensing (QS), which many bacterial pathogens use to coordinately regulate virulence determinants. The Pseudomonas aeruginosa MvfR-dependent QS regulatory pathway controls the expression of key virulence genes; and is activated via the extracellular signals 4-hydroxy-2-heptylquinoline (HHQ) and 3,4-dihydroxy-2-heptylquinoline (PQS), whose syntheses depend on anthranilic acid (AA), the primary precursor of 4-hydroxy-2-alkylquinolines (HAQs). Here, we identified halogenated AA analogs that specifically inhibited HAQ biosynthesis and disrupted MvfR-dependent gene expression. These compounds restricted P. aeruginosa systemic dissemination and mortality in mice, without perturbing bacterial viability, and inhibited osmoprotection, a widespread bacterial function. These compounds provide a starting point for the design and development of selective anti-infectives that restrict human P. aeruginosa pathogenesis, and possibly other clinically significant pathogens. 相似文献
36.
Robustness of prevalence estimates derived from misclassified data from administrative databases 总被引:2,自引:0,他引:2
Because primary data collection can be expensive, researchers are increasingly using information collected in medical administrative databases for scientific purposes. This information, however, is typically collected for reasons other than research, and many such databases have been shown to contain substantial proportions of misclassification errors. For example, many administrative databases contain fields for patient diagnostic codes, but these are often missing or inaccurate, in part because physician reimbursement schemes depend on medical acts performed rather than any diagnosis. Errors in ascertaining which individuals have a given disease bias not only prevalence estimates, but also estimates of associations between the disease and other variables, such as medication use. We attempt to estimate the prevalence of osteoarthritis (OA) among elderly Quebeckers using a government administrative database. We compare a naive estimate relying solely on the physician diagnoses of OA listed in the database to estimates from several different Bayesian latent class models which adjust for misclassified physician diagnostic codes via use of other available diagnostic clues. We find that the prevalence estimates vary widely, depending on the model used and assumptions made. We conclude that any inferences from these databases need to be interpreted with great caution, until further work estimating the reliability of database items is carried out. 相似文献
37.
LILIAN JÄRVEKÜLG JÜRI SõBER RIIVO SINIJÄRV INDREK TOOTS MART SAARMA 《The Annals of applied biology》1989,114(2):279-291
Mouse monoclonal antibodies (MAbs) specific for potato virus M (PVM) were prepared and the properties of three of them were studied. MAb M4C1 is IgG2b, it binds with high affinity to PVM coat protein, to purified virus preparations and recognises PVM in infected potato leaves and tubers. MAb M6D5 is IgG2a and also reacts with PVM coat protein, purified PVM and with PVM in potato leaf and tuber extracts. In double-antibody sandwich ELISA (DAS ELISA) MAbs M4C1 and M6D5 reacted with all 17 PVM isolates tested. MAb M7 is IgG2b and recognises PVM only in indirect dot ELISA on nitrocellulose filters and viral coat protein on Western blots. MAbs against PVM were used as capture antibodies and europium-labelled MAbs as conjugates in time-resolved fluoroimmunoassay (EuTRFIA). The standard EuTRFIA curve of PVM detection is approximately linear over a range of PVM concentrations from 0.5 ng/ml to 1000 ng/ml. The lowest PVM concentration detectable in EuTRFIA was 0.5 ng/ml and correspondingly 6 ng/ml in DAS ELISA. The use of the europium chelate label allows PVM detection in potato leaf and tuber sap at dilutions greater than 10--4 with very low background fluorescence. EuTRFIA with MAbs, with either one or two incubations is about 10–20 times more sensitive for PVM detection than is DAS ELISA. PVM and PVX, mixed with healthy potato tuber sap, were simultaneously tested in a single sample at concentrations lower than 10 ng/ml by double-label TRFIA using europium-labelled MAbs to PVM and samarium-labelled MAbs to PVX. 相似文献
38.
Pingping Mao Mary P. Hever-Jardine Gilbert J. Rahme Eric Yang Janice Tam Anita Kodali Bijesh Biswal Camilo E. Fadul Arti Gaur Mark A. Israel Michael J. Spinella 《PloS one》2013,8(11)
STK17A is a relatively uncharacterized member of the death-associated protein family of serine/threonine kinases which have previously been associated with cell death and apoptosis. Our prior work established that STK17A is a novel p53 target gene that is induced by a variety of DNA damaging agents in a p53-dependent manner. In this study we have uncovered an additional, unanticipated role for STK17A as a candidate promoter of cell proliferation and survival in glioblastoma (GBM). Unexpectedly, it was found that STK17A is highly overexpressed in a grade-dependent manner in gliomas compared to normal brain and other cancer cell types with the highest level of expression in GBM. Knockdown of STK17A in GBM cells results in a dramatic alteration in cell shape that is associated with decreased proliferation, clonogenicity, migration, invasion and anchorage independent colony formation. STK17A knockdown also sensitizes GBM cells to genotoxic stress. STK17A overexpression is associated with a significant survival disadvantage among patients with glioma which is independent of age, molecular phenotype, IDH1 mutation, PTEN loss, and alterations in the p53 pathway and partially independent of grade. In summary, we demonstrate that STK17A provides a proliferative and survival advantage to GBM cells and is a potential target to be exploited therapeutically in patients with glioma. 相似文献
39.
Valeria Righi Yiorgos Apidianakis Laurence G. Rahme A. Aria Tzika 《Journal of visualized experiments : JoVE》2010,(38)
High-Resolution Magic Angle Spinning (HRMAS) proton magnetic resonance spectroscopy (1H-MRS) is a novel non-destructive technique that improves spectral line-widths and allows high-resolution spectra to be obtained from extracts, intact cells, cell cultures, and more importantly intact tissue to investigate relationships between metabolites and cellular processes. In vivo HRMAS 1H-MRS studies have yet to be reported in the live fruit fly Drosophila melanogaster.Drosophila, as a simpler genetic organism, allows the multiple biological functions and various evolutionarily conserved signaling pathways to be examined at the whole organism level and it is a useful model for investigating genetics and physiology. To this end, we developed and implemented an in vivo HRMAS 1H-MRS method to investigate live Drosophila at 14.1 T. Here, we outline an HRMAS 1H-MRS protocol for the molecular characterization of Drosophila with a conventional MR spectrometer equipped with an HRMAS probe. This technique is a novel, in vivo, non-destructive Drosophila metabolite measurement approach, which enables the identification of disease biomarkers and thus may contribute to novel therapeutic development.Download video file.(85M, mp4) 相似文献
40.
Lee DG Urbach JM Wu G Liberati NT Feinbaum RL Miyata S Diggins LT He J Saucier M Déziel E Friedman L Li L Grills G Montgomery K Kucherlapati R Rahme LG Ausubel FM 《Genome biology》2006,7(10):R90-14