Acute exacerbation of postoperative idiopathic pulmonary fibrosis in a patient with lung cancer caused by invasive mechanical ventilation: A case report.

Study design and objection: Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disease characterized by damage to alveolar epithelial cells and abnormal deposition of the extracellular matrix. Although the disease course for most patients with IPF is progressive, in some cases the disease may appear as an acute exacerbation. Mechanical ventilation life support plays an important role in the treatment of patients with IPF but is associated with an increased risk of acute exacerbation of IPF (AE-IPF). Treatment is controversial and is not supported by sufficient clinical evidence. AE-IPF after lung cancer surgery is extremely rare, and the etiology and mechanism remain unclear, and its clinical manifestations are very similar to acute pulmonary edema and are easily misdiagnosed. Summaryof background data: We describe a 66-year-old male patient with IPF complicated with lung cancer who underwent thoracoscopic resection of the right upper lobe of the lung. Seventy-two hours after surgery, chest computed tomography indicated that AE-IPF in the mechanically ventilated lung was significantly greater than that in the operated lung. The patient's own lung was used as a control and proved that mechanical ventilation can lead to AE-IPF. Results and conclusions: By highlighting the clinical characteristics of patients with acute exacerbation of idiopathic pulmonary fibrosis, this article will enhance the vigilance of clinicians on AE-IPF caused by mechanical ventilation. Importantly, preoperative nintedanib therapy should be applied in advance to prevent AE-IPF on in patients with mild IPF. Precise pulmonary protective ventilation strategies need to be formulated for patients with IPF to reduce mortality.

Educational environments in Asian medical schools: A cross-national comparison between Malaysia, Singapore, and China.

INTRODUCTION: Perceptions of the educational environment (EE) represent an important source of information on medical students' learning experience. Understanding and addressing these perceptions can help inform initiatives designed to improve the learning experience and educational outcomes, while comparison of student perceptions across medical schools can provide an added perspective. The aim of the study was to compare the EEs of three Asian medical schools: Royal College of Surgeons in Ireland and University College Dublin Malaysia Campus, Yong Loo Lin School of Medicine, Singapore and Xiangya School of Medicine, China. METHODS: Medical students in the clinical years (N = 1063) participated in a cross-sectional study using the Dundee Ready Educational Environment Measure (DREEM). Data were analyzed using SPSS version 22. RESULTS: There were significant differences between the three medical schools in the total DREEM scores (F [2, 1059] = 38.29, p < .001), but all were in the category "more positive than negative" (mean score 135.42, range 128.97-142.44). Highest DREEM scores were noted in year 5 at RUMC (139.79 ± 79), year 3 at YLL (145.93 ± 14.52), and year 4 at XSM (138.56 ± 18.91). Variations in total and subscale DREEM scores were also found between clinical years in each medical school. DISCUSSION: Total DREEM scores at the three medical schools are similar to those reported from other undergraduate settings. However, significant variations occurred in perceptions of the EE, as students progressed through the clinical years. Greater attention to the learning environment and the curriculum may improve students' educational experience.

Reversible and Irreversible Inhibition of Cytochrome P450 Enzymes by Methylophiopogonanone A.

Methylophiopogonanone A (MOA), an abundant homoisoflavonoid bearing a methylenedioxyphenyl moiety, is one of the major constituents in the Chinese herb Ophiopogon japonicas This work aims to assess the inhibitory potentials of MOA against cytochrome P450 enzymes and to decipher the molecular mechanisms for P450 inhibition by MOA. The results showed that MOA concentration-dependently inhibited CYP1A, 2C8, 2C9, 2C19, and 3A in human liver microsomes (HLMs) in a reversible way, with IC50 values varying from 1.06 to 3.43 µM. By contrast, MOA time-, concentration-, and NADPH-dependently inhibited CYP2D6 and CYP2E1, along with KI and kinact values of 207 µM and 0.07 minute-1 for CYP2D6, as well as 20.9 µM and 0.03 minutes-1 for CYP2E1. Further investigations demonstrated that a quinone metabolite of MOA could be trapped by glutathione in an HLM incubation system, and CYP2D6, 1A2, and 2E1 were the major contributors to catalyze the metabolic activation of MOA to the corresponding O-quinone intermediate. Additionally, the potential risks of herb-drug interactions triggered by MOA or MOA-related products were also predicted. Collectively, our findings verify that MOA is a reversible inhibitor of CYP1A, 2C8, 2C9, 2C19, and 3A but acts as an inactivator of CYP2D6 and CYP2E1. SIGNIFICANCE STATEMENT: Methylophiopogonanone A (MOA), an abundant homoisoflavonoid isolated from the Chinese herb Ophiopogon japonicas, is a reversible inhibitor of CYP1A, 2C8, 2C9, 2C19, and 3A but acts as an inactivator of CYP2D6 and CYP2E1. Further investigations demonstrated that a quinone metabolite of MOA could be trapped by glutathione in a human liver microsome incubation system, and CYP2D6, 1A2, and 2E1 were the major contributors to catalyze the metabolic activation of MOA to the corresponding O-quinone intermediate.

Development and validation of a UPLC-MS/MS method for quantification of doxofylline and its metabolites in human plasma.

A sensitive and specific ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for simultaneous determination of doxofylline and its two metabolites in human plasma. After protein precipitation with methanol, the chromatographic separation was carried out on an ACQUITY UPLC HSS T3 column, with acetonitrile and 0.1% formic acid in water as mobile phase at a flow rate of 0.30 mL·min-1. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source, with target quantitative ion pairs of m/z 267.0→181.1 for doxofylline, 239.0→181.1 for theophylline-7-acetic acid and 225.1→181.1 for etofylline. The calibration curve was linear over the range of 2-3000 ng·mL-1 (r > 0.99). The LLOQ was evaluated to be 2 ng·mL-1. The method described herein allowed simultaneous determination of the three analytes for the first time and was successfully applied to the pharmacokinetic study of doxofylline and its metabolites after intravenous administration in healthy volunteers.

[Inhibitory effect of flavonoids from Scutellariae Radix on human cytochrome P450 1A].

This study investigated the inhibitory effect of eight natural flavonoids in Chinese herb Scutellariae Radix on huamn cytochrome P450 1 A(CYP1 A), a key cancer chemo-preventive target. In this study, phenacetin was used as a probe substrate for CYP1 A, while human liver microsomes and recombinant human CYP1 A enzymes were used as enzyme sources. Liquid chromatography-tandem mass spectrometry was used to monitor the formation rates of acetaminophen, the O-deethylated metabolite of phenacetin. The dose-dependent inhibition curves were depicted based on the changes of the formation rates of acetaminophen, while the IC_(50) were determined. Inhibition kinetic analyses and docking simulations were used to investigate the inhibition modes and mechanism of wogonin(the most potent CYP1 A inhibitor in this herb), while the inhibition constants(K_i) of wogonin against both CYP1 A1 and CYP1 A2 were determined. Among all tested flavonoids, wogonin, 7-methoxyflavanone and oroxylin A displayed a strong inhibitory effect on CYP1 A(IC_(50)<1 µmol·L~(-1)), baicalein exhibited a moderate inhibitory effect on CYP1 A(IC_(50) between 1-10 µmol·L~(-1)), and baicalin, scutellarein and wogonoside displayed a very weak inhibitory effect on CYP1 A(IC_(50) between 10-25 µmol·L~(-1)), but scutellarin displayed a negligible inhibitory effect on CYP1 A(IC_(50)>100 µmol·L~(-1)). Further investigations demonstrated that wogonin had a weak inhibitory effect on other human CYP enzymes, suggesting that it could be used as a lead compound for the development of specific inhibitors of CYP1 A. Furthermore, the inhibition kinetic analyses clearly demonstrated that wogonin could strongly inhibit phenacetin O-deethylation in both CYP1 A1 and CYP1 A2 in a competitive manner, with K_i values at 0.118 and 0.262 µmol·L~(-1), respectively. Molecular docking demonstrated that wogonin could strongly interact with CYP1 A1 and CYP1 A2 via hydrophobic and π-π interactions, as well as Ser120 and Ser116 in CYP1 A1 via hydrogen-bonding. In conclusion, this study found that some flavonoids in Scutellariae Radix displayed a strong inhibitory effect on CYP1 A, while wogonin is the most potent CYP1 A inhibitor with a relatively high selectivity towards CYP1 A over other human CYPs.

The Zuo Jin Wan Formula increases chemosensitivity of human primary gastric cancer cells by AKT mediated mitochondrial translocation of cofilin-1.

Resistance to cisplatin (DDP)-based chemotherapy is a major cause of treatment failure in human gastric cancer (GC). It is necessary to identify the drugs to re-sensitize GC cells to DDP. In our previous research, Zuo Jin Wan Formula (ZJW) has been proved could increase the mitochondrial apoptosis via cofilin-1 in a immortalized cell line, SGC-7901/DDP. Due to the immortalized cells may still difficult highly recapitulate the important molecular events in vivo, primary GC cells model derived from clinical patient was constructed in the present study to further evaluate the effect of ZJW and the underlying molecular mechanism. Immunofluorescent staining was used to indentify primary cultured human GC cells. Western blotting was carried out to detect the protein expression. Cell Counting Kit-8 (CCK-8) was used to evaluate cell proliferation. Flow cytometry analysis was performed to assess cell apoptosis. ZJW inhibited proliferation and induced apoptosis in primary DDP-resistant GC cells. Notably, the apoptosis in GC cells was mediated by inducing cofilin-1 mitochondrial translocation, down-regulating Bcl-2 and up-regulating Bax expression. Surprisingly, the level of p-AKT protein was higher in DDP-resistant GC cells than that of the DDP-sensitive GC cells, and the activation of AKT could attenuate ZJW-induced sensitivity to DDP. These data revealed that ZJW can increase the chemosensitivity in DDP-resistant primary GC cells by inducing mitochondrial apoptosis and AKT inactivation. The combining chemotherapy with ZJW may be an effective therapeutic strategy for GC chemoresistance patients.

Photodynamic therapy for middle-advanced stage upper gastrointestinal carcinomas: A systematic review and meta-analysis.

AIM: To determine the therapeutic effect of photodynamic therapy (PDT) for middle-advanced stage upper gastrointestinal carcinomas. METHODS: We searched PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure, China Science and Technology Journal Database, and Wanfang Database from inception to April 2018 for randomized controlled studies. These studies compared PDT with other palliative therapies (radiotherapy, chemotherapy, or Nd:YAG laser) and compared PDT, radiotherapy, or chemotherapy alone with PDT combined with chemotherapy/radiotherapy. In our meta-analysis, both fixed and random effects models were used to estimate the risk ratio (RR) for dichotomous outcomes (the response rate and one-year survival rate). RESULTS: Ten random controlled clinical studies with 953 patients were included in the analysis. The effective rate for PDT was better than that of radiotherapy or Nd:YAG laser for the treatment of middle-advanced upper gastrointestinal carcinomas [RR = 1.36; 95% confidence interval (CI): 1.13-1.65; P = 0.001]. In addition, PDT combined with chemotherapy had significantly better efficacy and a higher one-year survival rate than PDT or chemotherapy alone (significant remission rate, RR = 1.62; 95%CI: 1.34-1.97; P < 0.00001; one-year survival rate, RR = 1.81; 95%CI: 1.13-2.89; P = 0.01). CONCLUSION: PDT is a useful method for the treatment of middle-advanced stage upper gastrointestinal carcinomas. PDT combined with chemotherapy or radiotherapy can enhance its efficacy and prolong survival time.

[Distribution laws of Chinese medical syndrome types and analyses of risk factors in senile hypertension patients: a clinical study].

OBJECTIVE: To explore the distribution laws of TCM syndrome types and to analyze the distribution of dynamic blood pressure curve, atherosclerosis, and age in senile hypertension patients. METHODS: Totally 1 131 senile hypertension patients were recruited from 7 provinces and municipal cities. Features of TCM syndromes, classification and distribution curves, and syndrome distribution laws were observed. The distribution curves of dynamic blood pressure, carotid atherosclerosis, and age were compared in each TCM syndrome types. RESULTS: There were four main syndrome types in 736 cases (56.15%), i.e., excessive accumulation of phlegm-dampness syndrome (210 cases, 16.02%), yin deficiency and hyperactivity of yang syndrome (177 cases, 13.50%), Gan-Shen yin deficiency syndrome (79 cases, 6.03%), and deficiency of qi and yin syndrome (252 cases, 19.22%). Besides, there were two more sub-types, i.e., collateral obstruction by blood stasis syndrome and collateral obstruction by phlegm and stasis. Circadian blood pressure monitor was completed in 211 cases. Of them, abnormal circadian blood pressure occurred in 152 cases (accounting for 72. 38%); yin deficiency and hyperactivity of yang syndrome, excessive accumulation of phlegm-dampness syndrome, deficiency of qi and yin syndrome plus collateral obstruction by blood stasis syndrome were most often seen. Color ultrasound of carotid artery was performed in 660 patients of main syndromes. The incidence was quite higher in those of excessive accumulation of phlegm-dampness syndrome (182 cases, 27. 58%), deficiency of qi and yin syndrome plus collateral obstruction by blood stasis syndrome or collateral obstruction by phlegm and stasis (322 cases, 48.79%). Yin deficiency and hyperactivity of yang syndrome was dominant in patients 60 -79 years old, while deficiency of qi and yin syndrome and Gan-Shen yin deficiency syndrome were dominant in patients older than 80 years. CONCLUSIONS: Excessive accumulation of phlegm-dampness syndrome, yin deficiency and hyperactivity of yang syndrome, Gan-Shen yin deficiency syndrome, and deficiency of qi and yin syndrome were main syndrome types in senile hypertension patients. There was statistical difference in the distribution curves of blood pressure, atherosclerosis, and age of various TCM syndrome types.

Xiao Yao San Improves Depressive-Like Behaviors in Rats with Chronic Immobilization Stress through Modulation of Locus Coeruleus-Norepinephrine System.

Most research focuses on the hypothalamic-pituitary-adrenal (HPA) axis, hypothalamus-pituitary-thyroid (HPT) axis, and hypothalamus-pituitary-gonadal (HPGA) axis systems of abnormalities of emotions and behaviors induced by stress, while no studies of Chinese herbal medicine such as Xiao Yao San (XYS) on the mechanisms of locus coeruleus-norepinephrine (LC-NE) system have been reported. Therefore, experiments were carried out to observe mechanism of LC-NE system in response to chronic immobilization stress (CIS) and explore the antidepressant effect of XYS. Rat model was established by CIS. LC morphology in rat was conducted. The serum norepinephrine (NE) concentrations and NE biosynthesis such as tyrosine hydroxylase (TH), dopamine-ß-hydroxylase (DBH), and corticotrophin-releasing-factor (CRF) in LC were determined. Results showed that there were no discernible alterations in LC in rats. The serum NE concentrations, positive neurons, mean optical density (MOD), and protein levels of TH, DBH, and CRF in model group were significantly increased compared to the control group. But XYS-treated group displayed a significantly decreased in NE levels and expressions of TH, DBH, and CRF compared to the model group. In conclusion, CIS can activate LC-NE system to release NE and then result in a significant decrease in rats. XYS treatment can effectively improve depressive-like behaviors in rats through inhibition of LC-NE neurons activity.

The effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of glipizide in Chinese subjects.

OBJECTIVE: To study the effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of glipizide. METHODS: Eighteen healthy male subjects were divided into three groups according to their genotypes: group I, CYP2C9*1/*1 and CYP2C19 extensive metabolizers (EMs); group II, CYP2C9*1/*1 and CYP2C19 poor metabolizers (PMs); and group III, CYP2C9*1/*3 and CYP2C19 EMs. After a single dose of a 5-mg glipizide tablet, plasma concentrations of glipizide for a 36-h period were determined. Meanwhile, plasma glucose levels and plasma insulin levels were determined from 0 to 4 h after dosing. RESULTS: The area under the plasma concentration-time curve (AUC(0-infinity)) was 2.0-fold higher and the oral clearance was 51.1% lower in group III than in group I. The change in fasting insulin level within 1 h (DeltaAUEC(insulin0-1h)) in group III was 3.8-fold higher than that in group I. The glipizide parameters in group II exhibited similar tendencies to those in group III. CONCLUSIONS: These results suggest that CYP2C9 polymorphism significantly influences the pharmacokinetics and pharmacodynamics of glipizide, which needs to be considered in clinical practice. CYP2C19 polymorphism exhibits a tendency to influence the effects of glipizide, to a certain extent similarly to CYP2C9 polymorphism.

[Simultaneous determination of metformin and glipizide in human plasma by liquid chromatography-tandem mass spectrometry].

To develop a sensitive and rapid liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method for simultaneous quantitation of metformin and glipizide in human plasma, metformin, glipizide and internal standard diphenhydramine were separated from plasma by protein precipitation with acetonitrile (containing 0.3% formic acid), then chromatographed by using a Zorbax Extend C18 column. The mobile phase consisted of acetonitrile-water-formic acid (70:30: 0.3, v/v/v), at a flow rate of 0.50 mL x min(-1). A tandem mass spectrometer equipped with atmospheric pressure chemical ionization source was used as detector and operated in the positive ion mode. Selected reaction monitoring (SRM) using the precursor/production combinations of m/z 130-->m/z 60, m/z 446-->m/z 321 and m/z 256-->m/z 167 were used to quantify metformin, glipizide and diphenhydramine, respectively. The linear concentration ranges of the calibration curves for metformin and glipizide were 2.00 - 2000 ng x mL(-1) and 1.00 - 1000 ng x mL(-1), respectively. The lower limits of quantitation of metformin and glipizide were 2.00 ng x mL(-1) and 1.00 ng x mL(-1), respectively. The method proved to be sensitive, simple and rapid, and suitable for clinical investigation of compound preparation containing metformin and glipizide.

[The clinical staging and tissue bacterial quantification in the diagnosis of burn wound sepsis].

OBJECTIVE: To investigate and re-evaluate the relationship between burn wound sepsis and tissue bacterial quantity. METHODS: Thirty-two patients admitted during past 5 years were enrolled in the study. Bacterial isolation and quantity in burn wound tissue were carried out. Meanwhile clinical signs were evaluated for the staging of burn wound sepsis. RESULTS: 1) Bacterial invasion could be identified in 123 pieces of tissue samples from 32 patients. Samples with tissue bacterial quantity > or = 10(5)/g were found in 82 subeschar tissue samples, and 41 samples with bacteria <10(5)/g. Subeschar tissue samples with bacterial quantity > or = 10(5)/g could be determined in 68 samples from 18 patients, and < 10(5)/g in 20 samples from 5 cases. In addition, samples of subeschar tissue with bacterial quantity > or = 10(5)/g could only be found in some of the samples form 9 cases. 2) Burn wound sepsis could be classified into I-IV stages according to tissue bacterial quantification and clinical signs. CONCLUSION: Burn wound sepsis could be established by identification of bacterial invasion into living tissue with clinical symptoms of toxemia.