The physiologically based pharmacokinetic (PBPK) modeling strategy was adopted to predict the pharmacokinetic behavior of crystal forms I and II of rifampicin in humans, which was used to determine whether the two were bioequivalent.After conducting studies in vitro of the two crystal forms, a rat PBPK model was established based on the pharmacokinetic data of intravenous administration in rats.The model was optimized by the pharmacokinetic data of oral administration in rats.Species were extrapolated to healthy humans, and the extrapolation model was used to predict such pharmacokinetic behaviors as the drug-time curve, absorption site, and absorption amount of the two crystal forms of rifampicin in healthy humans.The prediction results of the healthy human model showed that the cmax of form I and form II rifampicin were 8.42 and 10.35 μg/mL, tmax were 0.40 and 0.32 h,and AUC0-t were both 62.90 μg·h/mL.According to the prediction results of absorption, neither crystal form I nor crystal form II rifampicin was absorbed in the stomach, yet both were completely absorbed in the intestinal tract, with both the absorption site and the absorption amount were basically the same.The pharmacokinetic parameters of both crystal forms I and II of rifampicin were very close, which could indicate bioequivalence.

Traumatic brain injury (TBI)-induced coagulopathy has increasingly been recognized as a significant risk factor for poor outcomes, but the pathogenesis remains poorly understood. In this study, we aimed to investigate the causal role of acrolein, a typical lipid peroxidation product, in TBI-induced coagulopathy, and further explore the underlying molecular mechanisms. We found that the level of plasma acrolein in TBI patients suffering from coagulopathy was higher than that in those without coagulopathy. Using a controlled cortical impact mouse model, we demonstrated that the acrolein scavenger phenelzine prevented TBI-induced coagulopathy and recombinant ADAMTS-13 prevented acrolein-induced coagulopathy by cleaving von Willebrand factor (VWF). Our results showed that acrolein may contribute to an early hypercoagulable state after TBI by regulating VWF secretion. mRNA sequencing (mRNA-seq) and transcriptome analysis indicated that acrolein over-activated autophagy, and subsequent experiments revealed that acrolein activated autophagy partly by regulating the Akt/mTOR pathway. In addition, we demonstrated that acrolein was produced in the perilesional cortex, affected endothelial cell integrity, and disrupted the blood-brain barrier. In conclusion, in this study we uncovered a novel pro-coagulant effect of acrolein that may contribute to TBI-induced coagulopathy and vascular leakage, providing an alternative therapeutic target.

Traumatic brain injury (TBI) triggers the activation of the endogenous coagulation mechanism, and a large amount of thrombin is released to curb uncontrollable bleeding through thrombin receptors, also known as protease-activated receptors (PARs). However, thrombin is one of the most critical factors in secondary brain injury. Thus, the PARs may be effective targets against hemorrhagic brain injury. Since the PAR1 antagonist has an increased bleeding risk in clinical practice, PAR4 blockade has been suggested as a more promising treatment. Here, we explored the expression pattern of PAR4 in the brain of mice after TBI, and explored the effect and possible mechanism of BMS-986120 (BMS), a novel selective and reversible PAR4 antagonist on secondary brain injury. Treatment with BMS protected against TBI in mice. mRNA-seq analysis, Western blot, and qRT-PCR verification in vitro showed that BMS significantly inhibited thrombin-induced inflammation in astrocytes, and suggested that the Tab2/ERK/NF-κB signaling pathway plays a key role in this process. Our findings provide reliable evidence that blocking PAR4 is a safe and effective intervention for TBI, and suggest that BMS has a potential clinical application in the management of TBI.

Clinical advances in the treatment of intracranial hemorrhage (ICH) are restricted by the incomplete understanding of the molecular mechanisms contributing to secondary brain injury. Acrolein is a highly active unsaturated aldehyde which has been implicated in many nervous system diseases. Our results indicated a significant increase in the level of acrolein after ICH in mouse brain. In primary neurons, acrolein induced an increase in mitochondrial fragmentation, loss of mitochondrial membrane potential, generation of reactive oxidative species, and release of mitochondrial cytochrome c. Mechanistically, acrolein facilitated the translocation of dynamin-related protein1 (Drp1) from the cytoplasm onto the mitochondrial membrane and led to excessive mitochondrial fission. Further studies found that treatment with hydralazine (an acrolein scavenger) significantly reversed Drp1 translocation and the morphological damage of mitochondria after ICH. In parallel, the neural apoptosis, brain edema, and neurological functional deficits induced by ICH were also remarkably alleviated. In conclusion, our results identify acrolein as an important contributor to the secondary brain injury following ICH. Meanwhile, we uncovered a novel mechanism by which Drp1-mediated mitochondrial oxidative damage is involved in acrolein-induced brain injury.

Objective:To study the pupillary centroid shift of myopia and characteristics of pupil diameter change from scotopic to photopic condition.Methods:A case series study was carried out, 140 eyes of 70 myopia patients from September to November 2016 in Tianjin Eye Hospital were enrolled.The pupillary centroid shift and pupil diameter parameters were measured by visual quality analyzer from scotopic (0.017 lx) to photopic (10.400 lx) condition.This study followed the Declaration of Helsinki.Results:Under the scotopic and photopic conditions, the pupil diameter was positively correlated between the bilateral eyes (scotopic: rs=0.85, P<0.001; photopic: r=0.85, P<0.001), and the pupil diameter variation from scotopic to photopic condition was positively correlated between the bilateral eyes ( r=0.75, P<0.001). The pupil diameter in scotopic and photopic conditions, and the change of pupil diameter in the right eyes were significantly higher than those in the left eyes (all at P<0.05). The pupillary centroid shift was within 0.2 mm in the left eyes of 94.2% (66/70) subjects and in the right eyes of 97.1%(68/70) subjects.The pupillary centroid shift of all subjects was within 0.3 mm.From scotopic to photopic condition, the pupil centroid was mainly shift to the nasal superior direction.There was no significant correlation between pupil diameter and age or gender.There was no significant correlation between pupillary centroid shift and age, diopter or pupil diameter. Conclusions:The binocular pupillary centroid shift are symmetrical from scotopic to photopic condition in myopic eyes, and the pupil centroid mainly shift to nasal superior direction.

With the innovation of radiotherapy equipment and the promotion of targeted therapy and immunotherapy,the therapeutic mode and status of radiotherapy in non-small cell lung cancer(NSCLC)are constantly changing. For early NSCLC,stereotactic radiotherapy may be an alternative to surgery,but the optimal segmentation model still needs to be explored. As for locally advanced NSCLC,postoperative radio-therapy is still controversial for operable patients,the results of consolidated immunotherapy after concurrent chemoradiotherapy in inoperable patients are encouraging,prophylactic cranial irradiation does not improve sur-vival. Local radiotherapy for patients with oligometastasis is expected to prolong survival.

Objective To improve the preparation method of rat model of acute myocardial ischemia reperfusion injury(MI/RI), to make a comprehensive evaluation and to lay a good model foundation for following MI/RI research. Methods Thirty-six clean grade Wistar rats were randomly divided into 3 groups: normal group without intervention of the left anterior descending coronary artery (LAD), sham operation group with only wearing thread but no ligation of the coronary artery, and ischemia reperfusion group, with ligation of the LAD for 30 min and reperfusion for 120 min. Rats after anesthesia had continuous ECG recording, and tracheostomy for mechanical auxiliary ventilation. Thoracotomy and LAD intervention were carried out on the rats, and then the rat models were comprehensively evaluated by electrocardiography, detection of myocardial enzyme content, determination of the infarct size, and pathological examination of the myocardium. Results The electrocardiogram of the MI/RI group showed obvious ST-T dynamic changes. The level of CK-MB in the MI/RI group was significantly increased at 2 h after surgery. Compared with the sham group, the infarct size of the MI/RI group was significantly increased, with evident degeneration and necrosis of cardiomyocytes and extensive inflammatory cell infiltration in the myocardium. Conclusions The improved modeling method not only reduced the difficulties of operation, but has also successfully established the rat model of MI/RI, providing a good foundation for further MI/RI research.

Objective To understand the changing resistance proifle ofProteus,Serratia,Citrobacter,Morganella andProvidencia in hospitals across China according to the data from CHINET Antimicrobial Resistance Surveillance Program 2005-2014.Methods Antimicrobial susceptibility was tested by using Kirby-Bauer method or automatic minimum inhibitory concentration determination according to a uniifed protocol.Results A total of 21 663 clinical isolates were collected from January 2005 to December 2014. The proportion ofProteus andSerratia isolates increased with time from 1.41% in 2005 to 2.09% in 2014, and from 0.99% in 2005 to 1.28% in 2014 among all the isolates. No change was found for the proportion ofCitrobacter,Morganella, orProvidencia. Less than 10% of theProteus isolates were resistant to cefoperazone-sulbactam, piperacillin-tazobactam, ceftazidime, cefoxitin, amikacin and tigecycline. Less than 10% of theSerratia isolates were resistant to cefoperazone-sulbactam, piperacillin-tazobactam, amikacin and tigecycline. Less than 20% of theCitrobacter isolates were resistant to cefoperazone-sulbactam, piperacillin-tazobactam, cefepime, amikacin and tigecycline. Less than 10% of theMorganella isolates were resistant to cefoperazone-sulbactam, piperacillin-tazobactam, cefepime, amikacin and tigecycline. Less than 20% of theProvidencia isolates were resistant to cefoperazone-sulbactam, piperacillin-tazobactam, cefepime, cefoxitin and tigecycline.Conclusions The antibiotic resistance ofProteus,Serratia, Citrobacter,Morganella andProvidencia isolates in hospitals across China is growing during the period from 2005 to 2014. Strengthening infection control and rational antibiotic use are effective to slow the growth of drug resistance.

ObjectiveTo investigate the role of CD4+ CD25+ regulatory T cells(Treg) in peripheral blood and intestinal endotoxin (ET) in liver injury of rat severe acute pancreatitis (SAP).MethodsSixty male Wistar rats were randomly allocated into sham operation group(SO group) and severe acute pancreatitis group(SAP group).The rats in SAP group recevied the injection of Sodium Taurocholate(NaTc) into their far-end of bile-pancreatic duct and were sacrificed in 3-,6-and 12-hour,serum amylase(AMY) and alanine aminotransferase(ALT) determined by full-automatic biochemistry instrument,limulus reagent method is used to determine ET content in plasma,the proportion of Treg among peripheral lymphocytes was determined by Flow Cytometry(FCM),HE stain is used to observe pathological changes in liver and pancreas,the protein of Foxp3 activity was evaluated by immunohistochemistry staining,and the relationships between these indicators were analyzed using Pearson correlation analysis test.ResultsHistopathologic examination and the level of ALT revealed the occurrence of pancreatic inflammation and pathological changes of liver in SAP group.The percentage of Treg in SAP groups significantly increased at 3 h(2.26％ ±0.32％),6 h(2.36 ％ ±0.48％)and 12 h(2.80％ ±0.35％) comparing to the SO groups(P＜0.01) ; plasma ET levels compared with the SO group was statistically significant (P＜ 0,01 ),and 12 h (0.85 ± 0.11) compared to,3 h (0.74±0.11) and 6 h (0.78-±-0.07) was no significant difference (P＞0.05).The expression of Foxp3 protein on the livers were upregulated markedly.Pearson correlation analysis teat showed that quantities of Treg were positively proportional to the levels of ET(r=0.89,P＜0.01) after liver injury of SAP.ConclusionsSAP may lead to liver injury and the high plasma levels of ET and Treg in peripheral blood may play an important role in liver injury of SAP.

In order to deliver power to the capsule endoscope, whose position and orientation are always changing when traveling along the alimentary tract, a wireless power transmission system based on electromagnetic coupling was proposed. The system is composed of Helmholtz transmitting coil and three-dimensional receiving coil. Helmholtz coil outside the body generates a uniform magnetic field covering the whole alimentary tract; three-dimensional coil inside retrieves stable power regardless of its position and orientation. The transmitter and receiver were designed and implemented, and the experiments validated the feasibility of the system. The results show that at least 320 mW of usable power can be transmitted to capsule endoscope when its position and orientation are changing at random and the transmitting power is 25W.
Capsule Endoscopes ; Capsule Endoscopy ; instrumentation ; Electric Conductivity ; Electric Power Supplies ; Electromagnetic Fields ; Equipment Design ; Gastrointestinal Diseases ; diagnosis ; Humans