Objective To investigate the pharmacokinetic characteristics of asparaginase-loaded sulfobutyl ether-β-cyclodextrin supramolecule lipidic nanoparticles (ASLN) in rats and its inhibitory effect on the proliferation of small cell lung cancer cells. Methods ASLN were prepared by a reverse phase evaporation method,and their physicochemical properties,including morphology,particle size,zeta potential,and drug entrapment efficiency,were characterized. Twelve male Sprague-Dawley rats were randomly divided into 2 groups,with 6 rats in each group. After intravenous injection of ASLN and free asparaginase (Aase) 2 kU/kg,the activity of Aase in plasma samples was measured at different time points in 48 h,and the activity-time curve was drawn. The pharmacokinetic parameters were calculated by software DAS 2.1.1. The cytotoxicity of ASLN on H446 cells was explored by the MTT method. Results ASLN showed a spherical shape with a mean particle size of (321.27±1.42) nm,zeta potential of (-9.31±0.42) mV,and entrapment efficiency of (66.46±1.57)％. Pharmacokinetic parameters of ASLN and Aase were as follows:the area under curve (AUC(0-48 h)) (199.48±2.18) U·mL-1·h,(57.63±3.89) U·mL-1·h;the mean residence time (MRT(0-48 h)) (4.40±0.05) h,(2.09±0.07) h;and the peak concentration (Cmax) (35.49±1.11) U/mL,(27.58±1.28) U/mL. The relative bioavailability of ASLN to Aase was 325.96％. The cytotoxicity results indicated that ASLN had a proliferation inhibitory effect on H446 cells,and there was a positive correlation between the inhibition rate and the dose. Conclusion ASLN can improve the pharmacokinetics of Aase,enhance the bioavailability of Aase,and inhibit the proliferation of small cell lung cancer cells.

The intestine is the largest immune and metabolic site in the body and is thus important for animal health.The integrity of the mucosal barrier and function are fundamental factors protecting the health of the intestine.Stress has been reported to have profound effects on the gastrointestinal tract,including altering gut permeability,the intestinal barrier,and homeostasis.Tryptophan is a functional essential amino acid that alters the gut microbiota and regulates intestine structural and functional change,thus contributing to host physiology and metabolism.Changes in tryptophan metabolism and its metabolites in brain and intestinal tissues during stress suggest that tryptophan may play an important role in the stress response.We therefore review the literature on the mechanisms underlying stress-related diseases and the role of tryptophan metabolism in the regulation of gut homeostasis,with particular focus on functional bowel disorders and their relationship to stress,to provide a theoretical foundation for targeting tryptophan in stress-related intestine diseases.

To solve the problems in the course teaching of Pharmacokinetics and change the current situation of the course, a pharmacokinetic solution program based on Excel has been developed. The program, based on Excel, is the most widely used data processing software. The data processing and drawing functions of Excel are used and encapsulated as a program by Excel-VBA. The program is specially used in pharmacokinetic teaching, which includes 25 solution templates arranged according to the 5th edition of Biopharmaceutics and Pharmacokinetics, a textbook published by the People's Medical Publishing House Co., LTD. Each solution template includes six functional areas: operation setting area, data input area, data relationship display area, return parameter output area, pharmacokinetic parameter output area and chart area. In this course, the teaching content is reorganized. Starting from a case, the concept and knowledge of pharmacokinetics are taught by explaining how to apply the program to solve case problems. After years of practice, the teaching effect has been significantly improved.

BACKGROUND: Previous research demonstrated that a homozygous mutation of g.136372044G>A (S12N) in caspase recruitment domain family member 9 ( CARD9 ) is critical for producing Aspergillus fumigatus -induced ( Af -induced) T helper 2 (T H 2)-mediated responses in allergic bronchopulmonary aspergillosis (ABPA). However, it remains unclear whether the CARD9S12N mutation, especially the heterozygous occurrence, predisposes the host to ABPA. METHODS: A total of 61 ABPA patients and 264 controls (including 156 healthy controls and 108 asthma patients) were recruited for sequencing the CARD9 locus to clarify whether patients with this heterozygous single-nucleotide polymorphisms are predisposed to the development of ABPA. A series of in vivo and in vitro experiments, such as quantitative real-time polymerase chain reaction, flow cytometry, and RNA isolation and quantification, were used to illuminate the involved mechanism of the disease. RESULTS: The presence of the p.S12N mutation was associated with a significant risk of ABPA in ABPA patients when compared with healthy controls and asthma patients, regardless of Aspergillus sensitivity. Relative to healthy controls without relevant allergies, the mutation of p.S12N was associated with a significant risk of ABPA (OR: 2.69 and 4.17 for GA and AA genotypes, P = 0.003 and 0.029, respectively). Compared with patients with asthma, ABPA patients had a significantly higher heterozygous mutation (GA genotype), indicating that p.S12N might be a significant ABPA-susceptibility locus ( aspergillus sensitized asthma: OR: 3.02, P = 0.009; aspergillus unsensitized asthma: OR: 2.94, P = 0.005). The mutant allele was preferentially expressed in ABPA patients with heterozygous CARD9S12N , which contributes to its functional alterations to facilitate Af -induced T H 2-mediated ABPA development. In terms of mechanism, Card9 wild-type ( Card9WT ) expression levels decreased significantly due to Af -induced decay of its messenger RNA compared to the heterozygous Card9S12N . In addition, ABPA patients with heterozygous CARD9S12N had increased Af -induced interleukin-5 production. CONCLUSION Our study provides the genetic evidence showing that the heterozygous mutation of CARD9S12N , followed by allele expression imbalance of CARD9S12N , facilitates the development of ABPA.
Humans ; Aspergillosis, Allergic Bronchopulmonary/complications* ; Aspergillus fumigatus/genetics* ; Asthma/genetics* ; Aspergillus ; Mutation/genetics* ; CARD Signaling Adaptor Proteins/genetics*

Nanotechnology has emerged as an ideal approach for achieving the efficient chemo agent delivery. However, the potential toxicity and unclear internal metabolism of most nano-carriers was still a major obstacle for the clinical application. Herein, a novel "core‒shell" co-assembly carrier-free nanosystem was constructed based on natural sources of ursolic acid (UA) and polyphenol (EGCG) with the EpCAM-aptamer modification for hepatocellular carcinoma (HCC) synergistic treatment. As the nature products derived from food-plant, UA and EGCG had good anticancer activities and low toxicity. With the simple and "green" method, the nanodrugs had the advantages of good stability, pH-responsive and strong penetration of tumor tissues, which was expected to increase tumor cellular uptake, long circulation and effectively avoid the potential defects of traditional carriers. The nanocomplex exhibited the low cytotoxicity in the normal cells

To investigate the in situ intestinal absorption characteristics and pharmacokinetic behavior of metformin-resveratrol compound water-in-oil nanoemulsion (MRCE) in rats, the in situ intestinal perfusion model was constructed in rats to study the intestinal absorption characteristics of MRCE in different intestinal segments. Male Sprague-Dawley rats were randomly divided into two groups. After intragastric administration of metformin and MRCE, blood was taken at a preset time point. The content of metformin in intestinal perfusion samples and blood samples at various time points was determined by HPLC. Plasma concentration-time profiles of free metformin and MRCE were calculated, and the main pharmacokinetic data were processed and analyzed by DAS 2.1.1 software. The absorption rate constant (Ka), the effective permeability (Peff) and the percentage of absorption (PA) of MRCE in each intestinal segment were significantly higher than those of metformin (P < 0.05). The area under the drug-time curve (AUC0-72 h), the half-life (t1/2) and mean residence time (MRT0-72 h) of MRCE were 1.68, 11.25 and 6.97 times of metformin, respectively (P < 0.01).The relative bioavailability of MRCE was 167.6%. The 90% confidence interval of AUC0-72 h was 156.9%-187.4%, which was not within the standard interval of bioequivalence. The intestinal absorption of MRCE was significantly better than that of free metformin; MRCE improved the oral bioavailability of metformin and was not bioequivalent to metformin.

The aim of this study was to investigate the in vivo pharmacokinetic behavior characteristics and in situ intestinal absorption characteristics of the evodiamine lipidic nanoparticle in rats. Evodiamine lipidic nanoparticle was prepared by the solvent evaporation methods. The particle size and zeta potential of evodiamine lipidic nanoparticle were measured by dynamic light scattering analysis. Male SD rats were divided into two groups randomly. Each group was given single dose of evodiamine and evodiamine lipidic nanoparticle by gavage at evodiamine dose of 250 mg/kg,respectively. The blood samples were collected at scheduled time points. The content of evodiamine in plasma samples was determined by high performance liquid chromatography (HPLC) method. The main pharmacokinetic parameters of evodiamine and evodiamine lipidic nanoparticle were calculated using DAS 2.1.1 software. Moreover,the single-pass intestinal perfusion model was also established in rats to investigate the in situ intestinal absorption characteristics of evodiamine lipidic nanoparticle. The mean particle size and mean zeta potential of evodiamine lipidic nanoparticle were 180.10 nm and -17.90 mV,respectively. The area under the curve of evodiamine and evodiamine lipidic nanoparticle were (862.60±14.03) and (4084.31±17.21) μg/L·h,respectively,and the peak concentration were (163.40±13.27) and (616.90±21.04) μg/L,respectively. Moreover,the absorption of evodiamine lipidic nanoparticle was significantly higher than that of evodiamine in each segment of intestinal tract in rats (P<0.05). The absorption of evodiamine lipidic nanoparticle in colon was better than those of evodiamine lipidic nanoparticle in stomach,duodenum,jejunum and ileum. The absorption rate constant of evodiamine lipidic nanoparticle in stomach,duodenum,jejunum,ileum and colon were (45.10±6.08)×10-5,(48.20±1.21)×10-5,(22.10±3.18)×10-5,(59.10±1.21)×10-5 and (90.00±3.85)×10-5 s-1,respectively,and the effective permeability coefficient in duodenum,jejunum,ileum and colon was (44.10±0.51)×10-5,(17.21±0.77)×10-5,(35.36±0.31)×10-5 and (40.33±0.34)×10-5 cm/s,respectively.All in all, evodiamine lipidic nanoparticle remarkably improved the in situ intestinal absorption of evodiamine in different segments of the intestinal tract in rats and its oral bioavailability in rats.

Objective:To explore the significance of multimodal monitoring in the monitoring and treatment of neurocritical care patients.Methods:104 neurocritical care patients admitted to the department of Critical Care Medicine of Fujian Provincial Hospital from March 2019 to January 2020 were enrolled. Patients were randomly assigned into two groups, with 52 in each group. In the routine monitoring treatment group, heart rate, blood pressure, respiratory rate and the changes in consciousness and pupils were monitored after operation. The patients were treated with routine medicine to reduce intracranial pressure (ICP), maintain proper cerebral perfusion pressure (CPP), balance fluid intake and output, and maintain the airway clear. Patients in the multimodal monitoring treatment group were treated with invasive ICP monitoring, ultrasound to assess brain structure, ultrasound to measure optic nerve sheath diameter (ONSD), transcranial color doppler (TCCD), internal jugular venous blood oxygen saturation monitoring, near-infrared spectroscopy (NIRS), non-invasive cerebral blood oxygen saturation monitoring and quantitative electroencephalogram monitoring. According to the monitoring results, the patients were given targeted treatment with the goal of controlling ICP and improving brain metabolism. The length of intensive care unit (ICU) stay, the incidences of neurological complications (secondary cerebral infarction, cerebral hemorrhage, high intracranial pressure, etc.), and the incidences of poor prognosis [6 months after the onset of Glasgow outcome score (GOS) 1 to 3] were compared between the two groups. Spearman rank correlation analysis of the correlation between invasive ICP and the ICP value which was calculated by TCCD. The receiver operating characteristic (ROC) curve of invasive ICP and pulsatility index of middle cerebral artery (PI MCA) were used to predict poor prognosis. Results:The length of ICU stay in the multimodal monitoring treatment group was significantly shorter than that of the routine monitoring treatment group (days: 6.27±3.81 vs. 9.61±5.09, P < 0.01), and the incidence of neurological complications was significantly lower than that in the routine monitoring treatment group (9.62% vs. 25.00%, P < 0.05). In the multimodal monitoring treatment group, 37 cases had a good prognosis and 15 cases had a poor prognosis, while the routine monitoring treatment group had a good prognosis in 27 cases and a poor prognosis in 25 cases. The incidence of poor prognosis in the multimodal monitoring treatment group was lower than that of the routine monitoring treatment group (28.85% vs. 48.08%, P < 0.05). In the multimodal monitoring treatment group, the invasive ICP and PI MCA of patients with good prognosis were significantly lower than those of patients with poor prognosis [invasive ICP (mmHg, 1 mmHg = 0.133 kPa): 16 (12, 17) vs. 22 (20, 24), PI MCA: 0.90±0.33 vs. 1.39±0.58, both P < 0.01]. There was no significant difference in resistance index of the middle cerebral artery (RI MCA) between the good prognosis group and the poor prognosis group (0.63±0.12 vs. 0.66±0.15, P > 0.05). There was a positive correlation between the invasive ICP and the ICP value which was calculated by TCCD ( r = 0.767, P < 0.001). ROC curve analysis showed that the area under ROC curve (AUC) of invasive ICP for poor prognosis prediction was 0.906, the best cut-off value was ≥ 18 mmHg, the sensitivity was 86.49%, and the specificity was 86.67%. The AUC of PI MCA for poor prognosis prediction was 0.759, the best cut-off value was ≥ 1.12, the sensitivity was 81.08%, and the specificity was 60.00%. The AUC of invasive ICP was greater than PI MCA ( Z = 2.279, P = 0.023). Conclusion:Comprehensive analysis of multimodal monitoring indicators for neurocritical care patients to guide clinical treatment can reduce the length of hospital stay, and reduce the risk of neurosurgery complications and disability; invasive ICP can predict poor prognosis of neurocritical care patients.

Objective:To explore the incidence and relevant risk factors of acute kidney injury (AKI)after lung transplantation(LT).Methods:Retrospective analysis was performed for clinical data of 70 recipients of LT at China-Japan Friendship Hospital.Results:Among them, 61.4 % developed AKI within 3 days post-LT. As compared with non-AKI and AKI 1 groups, AKI 2~3 group had more plasma transfusion(median 0, 0, 200 ml, P=0.027) and more cardiovascular events during operation(0, 0, 14.3 %, P=0.023). As compared with non-AKI group, AKI 1 and 2~3 groups had lower postoperative hemoglobin in the first day(median 119, 106, 104 g/L, P=0.032). The duration of invasive mechanical ventilation was longer in AKI 2~3 group(median 56 h)than non-AKI group (median 49 h, P=0.034). The 3-month all-cause mortality post-LT was higher in AKI 2~3 (24.1 %)and AKI 1 recipients(21.4 %)than that in non-AKI counterparts(0)( P=0.034, P=0.007). Conclusions:Recipients with more blood transfusion and cardiovascular events during operation and those with more severe anemia in the first day post-LT might be at higher risks for postoperative AKI. Postoperative AKI prolongs the duration of invasive mechanical ventilation and increases 3-month all-cause mortality post-LT.

Objective:To investigate the awareness and knowledge of influenza and vaccine among primary care providers in Shanghai.Methods:An online questionnaires survey was conducted by Shanghai Alliance for Respiratory Diseases in Primary Care from December 2017 to August 2018, healthcare providers in district central hospitals and community health care centers of Shanghai were invited to participate in the survey. The questionnaire contained the following items: the basic information of respondents; knowledge of influenza and its vaccine; current status of influenza vaccination; factors affecting promoting vaccination; the intention, attitude, perception of promoting vaccination and the influencing factors, and suggestions on promoting influenza vaccination.Results:A total of 1 542 valid questionnaires were collected, 88.3% (1 361/1 542) responders correctly recognized main symptoms of influenza; 58.2% (898/1 542) ignored the contact transmission of influenza; 41.6% (641/1 542) didn′t know the frequency of influenza vaccination; 82.7% (1 276/1 542) failed to recognize that pregnant women should also receive influenza vaccination. The survey showed that 31.2% (481/1 542) of responders had been vaccinated against influenza. The vaccination rate in community health care institutions was significantly higher than that in district central hospitals [39.1% (304/778) vs. 23.2% (177/764), χ 2=45.44, P<0.05]. Factors affecting vaccination for healthcare providers were: influenza antigen was variable, and vaccination had no effects [49.5% (404/816)]; the efficacy of the flu vaccine was doubt [48.8% (634/1 298)]; the vaccine wasn′t free [46.5%(604/1 298)]. The respondents believed that the main ways to improve the influenza vaccination were to formulate relevant national vaccination policies [79.7%(1 229/1 542)], to regularly publicize knowledge of influenza and influenza vaccine to residents through communities [65.8% (1 015/1 542)], and to recommend the patients by primary care medical staff [64.4% (993/1 542)]. Conclusion:Many healthcare providers have insufficient knowledge about influenza and vaccine. The vaccination rate of community health institutions is higher than that in district central hospitals in Shanghai. The willingness to promote influenza vaccination can be influenced by some factors. Increasing the willingness of healthcare providers might be helpful to improve the vaccination coverage among residents in the community.