Population pharmacokinetics of daptomycin in critically ill patients receiving extracorporeal membrane oxygenation.

BACKGROUND: Daptomycin is widely used in critically ill patients for Gram-positive bacterial infections. Extracorporeal membrane oxygenation (ECMO) is increasingly used in this population and can potentially alter the pharmacokinetic (PK) behaviour of antibiotics. However, the effect of ECMO has not been evaluated in daptomycin. Our study aims to explore the effect of ECMO on daptomycin in critically ill patients through population pharmacokinetic (PopPK) analysis and to determine optimal dosage regimens based on both efficacy and safety considerations. METHODS: A prospective, open-label PK study was carried out in critically ill patients with or without ECMO. The total concentration of daptomycin was determined by UPLC-MS/MS. NONMEM was used for PopPK analysis and Monte Carlo simulations. RESULTS: Two hundred and ninety-three plasma samples were collected from 36 critically ill patients, 24 of whom received ECMO support. A two-compartment model with first-order elimination can best describe the PK of daptomycin. Creatinine clearance (CLCR) significantly affects the clearance of daptomycin while ECMO has no significant effect on the PK parameters. Monte Carlo simulations showed that, when the MICs for bacteria are  ≥1 mg/L, the currently recommended dosage regimen is insufficient for critically ill patients with CLCR > 30 mL/min. Our simulations suggest 10 mg/kg for patients with CLCR between 30 and 90 mL/min, and 12 mg/kg for patients with CLCR higher than 90 mL/min. CONCLUSIONS: This is the first PopPK model of daptomycin in ECMO patients. Optimal dosage regimens considering efficacy, safety, and pathogens were provided for critical patients based on pharmacokinetic-pharmacodynamic analysis.

A comparison of carotid atherosclerosis in symptomatic patients between 2002-2005 and 2012-2015 cohorts using multi-contrast magnetic resonance vessel wall imaging.

OBJECTIVE: To compare the morphological and compositional characteristics of carotid plaques in two cohorts (2002-2005 and 2012-2015) of Chinese patients using magnetic resonance vessel wall imaging. METHODS: Symptomatic patients with carotid atherosclerotic plaques who underwent carotid vessel wall magnetic resonance imaging between 2002-2005 and 2012-2015 were retrospectively recruited. Plaque morphology [including mean wall area, wall thickness, and maximum normalized wall index (NWI)] and composition [including calcification, intraplaque hemorrhage, and lipid-rich necrotic core (LRNC)] in symptomatic carotid arteries were evaluated and compared between patients in these two time periods. RESULTS: A total of 258 patients, including 129 patients in the 2002-2005 cohort and 129 patients in the 2012-2015 cohort, were recruited. Statin use (49.6%vs. 32.6%, P = 0.004) and hypertension (76.0% vs. 62.8%, P = 0.015) were significantly more common in the 2012-2015 cohort than in the 2002-2005 cohort. Patients in the 2012-2015 cohort also exhibited significantly low plaque burden parameters (allP < 0.05), as well as a lower prevalence (68.2% vs. 89.9%, P < 0.001) and volume percentages of LRNC (11.2% ± 14.2% vs. 25.7% ± 17.7%, P < 0.001). These differences remained significant after adjustment for clinical factors. The differences in the volume percentages of LRNC also remained significant after an additional adjustment for maximum NWI ( P < 0.001). CONCLUSIONS: Patients in the 2012-2015 cohort had a lower plaque burden and volume percentages of LRNC in symptomatic carotid arteries than those in the 2002-2005 cohort. These findings indicate that carotid plaques in the recent cohort had a lower severity and vulnerability.

Meta-analysis for the Efficacy and Safety of Ticagrelor and Clopidogrel in Acute Coronary Syndrome Patients After Percutaneous Coronary Intervention in China / 中国循环杂志

Objective: To systematically evaluate the efficacy and safety of ticagrelor and clopidogrel in acute coronary syndrome (ACS) patients after percutaneous coronary intervention (PCI) in China. Methods: We searched the databases of CNKI, Wanfang, VIP, CBM, PubMed and Web of Science to collect RCTs for the efficacy and safety of ticagrelor and clopidogrel in ACS patients after PCI; R software was used to perform Meta-analysis. Results: A total of 31 RCTs with 4342 patients were enrolled. Meta-analysis presented that compared with clopidogrel, during follow-up period, ticagrelor had the reduced incidences of major adverse cardiac events (MACE) (RR=0.37, 95％ CI 0.31-0.45, P<0.05), myocardial infarction (MI) (RR=0.37, 95％ CI 0.23-0.57, P<0.05), stent thrombosis (RR=0.28; 95％ CI 0.16-0.49, P<0.05) and stroke (RR=0.44, 95％ CI 0.23-0.81, P<0.05); while elevated incidences of hemorrhagic events (RR=1.47; 95％ CI 1.19-1.81, P<0.05) and dyspnea (RR=2.05; 95％ CI 1.47-2.84, P<0.05) . Conclusion: Ticagrelor treatment may decrease the risk of MACE, MI, stent thrombosis and stroke in Chinese ACS patients after PCI; while the incidences of hemorrhagic events and dyspnea should be alert.

Meta-analysis for the Efficacy and Safety of Ticagrelor and Clopidogrel in Acute Coronary Syndrome Patients After Percutaneous Coronary Intervention in China / 中国循环杂志

Objective: To systematically evaluate the efficacy and safety of ticagrelor and clopidogrel in acute coronary syndrome (ACS) patients after percutaneous coronary intervention (PCI) in China. Methods: We searched the databases of CNKI, Wanfang, VIP, CBM, PubMed and Web of Science to collect RCTs for the efficacy and safety of ticagrelor and clopidogrel in ACS patients after PCI; R software was used to perform Meta-analysis. Results: A total of 31 RCTs with 4342 patients were enrolled. Meta-analysis presented that compared with clopidogrel, during follow-up period, ticagrelor had the reduced incidences of major adverse cardiac events (MACE) (RR=0.37, 95％ CI 0.31-0.45, P<0.05), myocardial infarction (MI) (RR=0.37, 95％ CI 0.23-0.57, P<0.05), stent thrombosis (RR=0.28; 95％ CI 0.16-0.49, P<0.05) and stroke (RR=0.44, 95％ CI 0.23-0.81, P<0.05); while elevated incidences of hemorrhagic events (RR=1.47; 95％ CI 1.19-1.81, P<0.05) and dyspnea (RR=2.05; 95％ CI 1.47-2.84, P<0.05) . Conclusion: Ticagrelor treatment may decrease the risk of MACE, MI, stent thrombosis and stroke in Chinese ACS patients after PCI; while the incidences of hemorrhagic events and dyspnea should be alert.

Exploring the size limit of protein diffusion through the periplasm in cyanobacterium Anabaena sp. PCC 7120 using the 13 kDa iLOV fluorescent protein.

In the filamentous heterocyst-forming cyanobacterium Anabaena PCC 7120, vegetative cells and heterocysts are interdependent on each other and engaged in exchanges of metabolites for survival when grown under diazotrophic conditions. In this organism, the periplasm appears to be continuous along each filament, with a shared outer membrane; however, barriers exist preventing free diffusion of the fluorescent protein GFP (27 kDa) targeted into the periplasmic space. Here we expressed a smaller fluorescent protein iLOV (≈ 13 kDa) fused to the All3333 (a putative homologue of NrtA) signal sequence corresponding to those recognized by the TAT protein translocation system, which exports iLOV to the periplasm of either heterocysts or vegetative cells. Fluorescence microscopy and immunoblot analysis indicated that the iLOV protein is translocated into the periplasm of the producing cell and properly processed, but does not diffuse to neighboring cells via the periplasm. Thus, periplasmic barriers appear to block diffusion of molecules with a size of 13 kDa, the minimum size tested thus far. Assuming that the physical barrier is the peptidoglycan sacculus, its pores might allow diffusion of molecules within the size range between the PatS pentapeptide and iLOV, thus between 0.53 kDa and 13 kDa.

Existence of periplasmic barriers preventing green fluorescent protein diffusion from cell to cell in the cyanobacterium Anabaena sp. strain PCC 7120.

When deprived of combined nitrogen, the filamentous cyanobacterium Anabaena PCC 7120 relies on intercellular cooperation involving two cell types: nitrogen-fixing heterocysts and photosynthetic vegetative cells. Heterocysts send fixed nitrogen to vegetative cells over long distances along the filament, receiving a reduced carbon source from them. These intercellular exchanges might involve a continuous periplasm along the filament or cytoplasm-to-cytoplasm conduits or both. In the present study, the green fluorescent protein (GFP) was fused to a twin-arginine translocation signal sequence, which exported GFP to the periplasm of either a heterocyst using the heterocyst-specific promoters PhepA and PpatB or to the periplasm of vegetative cells using the vegetative cell-specific promoter PrbcL. Using the techniques of FRAP (fluorescence recovery after photobleaching) and FLIP (fluorescence loss in photobleaching), we found no evidence for intercellular diffusion of GFP through the periplasm, either from a heterocyst to vegetative cells or vice versa, or among vegetative cells. GFP could diffuse within the periplasm of the producing cell, but the diffusion stopped at the cell border. GFP diffusion could occur between two dividing cells before septum closure. This study indicates that barriers exist at the periplasmic space to prevent free GFP diffusion across cell border along the filament.

BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes.

During lymphocyte development, the assembly of genes coding for antigen receptors occurs by the combinatorial linking of gene segments. The stochastic nature of this process gives rise to lymphocytes that can recognize self-antigens, thereby having the potential to induce autoimmune disease. Such autoreactive lymphocytes can be silenced by developmental arrest or unresponsiveness (anergy), or can be deleted from the repertoire by cell death. In the thymus, developing T lymphocytes (thymocytes) bearing a T-cell receptor (TCR)-CD3 complex that engages self-antigens are induced to undergo programmed cell death (apoptosis), but the mechanisms ensuring this 'negative selection' are unclear. We now report that thymocytes lacking the pro-apoptotic Bcl-2 family member Bim (also known as Bcl2l11) are refractory to apoptosis induced by TCR-CD3 stimulation. Moreover, in transgenic mice expressing autoreactive TCRs that provoke widespread deletion, Bim deficiency severely impaired thymocyte killing. TCR ligation upregulated Bim expression and promoted interaction of Bim with Bcl-XL, inhibiting its survival function. These findings identify Bim as an essential initiator of apoptosis in thymocyte-negative selection.