There is endothelial hyperpermeability in sepsis,trauma,ischaemia-reperfusion injury,acute respiratory distress syndrome and thrombosis,while an important mechanism underlying this process is increased paracellular leakage of plasma fluid and protein because of cytoskeleton contration under the role of histamine, thrombin,vascular endothelial growth factor and activated neutrophil. Structural changes initiate with agonist-re-ceptor binding,followed by activation of intracellular signalling molecules,then phosphorylate alter the hyperme-ability of cell-cell adhesion. Targeting key signalling molecules that mediate endothelial-junction-cytoskeleton dissociation demonstrates a therapeutic potential to improve vascular barrier function during inflammatory injury.

Objective To investigate the relationships between the levels of plasma soluble CD40 ligand (sCD40L),fetuin-A and pregnancy-associated plasma protein A (PAPP-A) and carotid plaque in patients with acute ischemic stroke.Methods The patients with acute ischemic stroke were enrolled in the study.Carotid arteries were assessed by using carotid artery ultrasound.The patients were divided into either a carotid artery plaque group or a non-carotid artery plaque group according to the assessment results.The former were further divided into a stable plaque sub-group and an unstable plaque sub-group according the nature of plaque.Enzyme-linked immunosorbent assay was used to detect the levels of plasma sCD40L,fetuin-A and PAPP-A.The demography,previous history,complications,laboratory tests and plasma inflammatory biomarkers between the carotid artery plaque group and the non-carotid artery plaque group and between the stable plaque subgroup and the unstable plaque subgroup were compared.Multivariate logistic regression analysis was used to investigate the relationship between plasma inflammatory biomarkers and carotid plaques.Results A total of 200 patients with acute ischemic stroke were included.Among them,78 were females and 122 were males (aged 33 to 87 years,mean 60.1 ± 10.3 years); 139 patients were in the carotid artery plaque group and 61 were in the non-plaque group; 43 were in the stable plaque subgroup and 96 were in the unstable plaque subgoup.The mean age of the carotid artery plaque subgroup was significantly greater than that in the non-plaque subgroup (63.2 ± 8.7 years vs.50.3 ± 9.5 years; t ＝ 10.179,P =0.000),the constituent ratios of men (68.3％ vs.44.3％;x2＝ 10.336,P＝ 0.001),hypertension (71.2 vs.54.1％;x2=5.540,P=0.019),diabetes (46.8％ vs.29.5％ ;x2 =5.199,P =0.023),and hyperlipidemia (78.4％ vs.37.7％ ;x2 =31.31,P =0.000)in patients of carotid plaque group were significantly higher than those of the non-carotid plaque group.The levels of total cholesterol (5.7 ± 1.1 mmol/L vs.5.3 ± 1.0 mmol/L; t =2.433,P =0.016),low-density lipoprotein cholesterol (4.5 ± 1.0 mmol/L vs.4.1 ±0.9 mmol/L; t =2.683,P =0.008),fasting glucose (7.5 ±2.5 mmol/Lvs.6.4±2.1 mmol/L; t=3.002,P＝0.003),sCD40L (151.4 ± 55.8 pg/mlvs.102.8 ±65.9 pg/ml; t =5.360,P=0.000),fctuin-A (390.1 ± 80.6 μg/ml v.s.352.9 ± 98.6 μg/ml; t =2.591,P =0.011),and PAPP-A (11.49 ±4.67 mIU/L vs.8.46 ± 3.99 mIU/L; t =4.409,P =0.000) were significantly higher than those of the non-carotid plaque group.Multivariate logistic regression analysis showed that hyperlipidemia (odds ratio [OR] 6.582,95％ confidence interval [CI] 2.321-18.662; P =0.000),sCD40L (OR6.372,95％ CI 2.174-18.670;P=0.010),and fetuin-A (OR 4.101,95％ CI 1.012-16.619; P=0.048) were the independent predictors for carotid artery plaques in patients with acute ischemic stroke.The mean age of the stable plaque subgroup was significantly lower than that of the unstable plaque subgroup (59.6 ± 9.3 years vs.64.1 ± 7.2 years; t =3.231,P =0.002).The constituent ratio in patients with hypertension was significantly lower than that of the unstable plaque subgroup (55.8％ vs.78.1％ ; x2 =7.213,P =0.007).The levels of total cholesterol (5.4 ±0.9 mmol/L vs.6.0 ± 1.1 mmol/L; t =3.136,P =0.002),low-density lipoprotein cholesterol (4.0 ± 1.2 mmol/L vs.5.7 ± 1.0 mmol/L; t =8.696,P =0.000),fasting glucose (7.1 ± 2.3 mmol/L vs,7.9 ± 1.9 mmol/L; t =2.147,P =0.034),sCD40L (135.3 ±74.3 pg/ml vs.176.5 ±64.5 pg/ml; t =3.319,P ＝0.001),and PAPP-A (10.96 ± 5.02 mIU/L vs.13.98 ±4.63 mIU/L; t =3.463,P =0.001) were significantly lower than those of the unstable plaque subgroup,while the level of high-density lipoprotein cholesterol was significantly higher than that of the unstable plaque subgroup (1.2 ± 0.2 mmol/L vs.1.1 ± 0.3 mmol/L; t =2.314,P=0.022).Multivariate logistic regression analysis showed that HDL-C (OR 0.234,95％ CI0.060-0.906; P =0.022) was an independent protective factor for unstable plaques,while sCD40L (OR 5.290,95％ CI 1.613-17.351; P =0.029) and PAPP-A (OR4.125,95％ CI 1.281-13.283; P =0.021) were the independent predictors for unstable plaques.Conclusions The levels of sCD40L,PAPP-A,and fetuin-A were associated with the existence and stability of carotid artery plaque.The increased plasma sCD40L and fetuin-A were the independent predictors for carotid artery plaques in patients with acute ischemic stroke,and the increased levels of plasma sCD40L and PAPP-A were the independent predictors for carotid artery plaque instability in patients with acute ischemic stroke.

Objective To explore the clinical manifestations, electroencephalographic characteristics and therapeutic effect of drugs in children with Jeavons syndrome. Methods The clinical and electroencephalographic characteristics and thera-peutic effect of drugs were analyzed in 4 children with Jeavons syndrome. Results Among the four children there were 3 female and 1 male. The age at the onset of the disease was from 1 to 6 years. The typical clinical manifestations of this disease were brief, fast and repeated eyelid myoclonia (EM) with or without absence seizure. The typical electroencephalography (EEG) in two patients showed 3-6 Hz generalized spike and waves and polyspikes burst, and the eye closure and intermittent photic stimu-lation helped to induce discharges and clinical events. The typictal EEG in the other two patients showed 3.0-3.5 Hz generalizedδslow wave rhythm burst. The drugs of choice for treatment was sodium valproate monotherapy in two cases, levetiracetam in one case, sodium valproate combined with levetiracetam in one case. During the follow-up, seizures were controlled in one case, decreased in frequency in two cases and were still frequent in one case. Conclusions Jeavons syndrome is one of the idiopathic and generalized epileptic syndromes and characterized by EM with or without absence seizure. Video EEG monitoring plays an important role in the diagnosis of this disease. Sodium valproate and levetiracetam were effective for this disease.

Endometrial cancer has been identified by The Cancer Genome Atlas program with four molecular subtypes by genome sequence analysis. Clinical trials to select suitable immunotherapeutic agents based on the different immune characteristics of each subtype have been conducted in several countries and have made important progress. The main clinical applications of immune checkpoint inhibitors include anti-programmed cell death protein-1/programmed death-ligand 1 antibodies and poly ADP-ribose polymerase inhibitors. Optimizing drug selection and drug combination based on the target characteristics of different immune checkpoint inhibitors may provide new opportunities for immunotherapy of endometrial cancer and bring new light to improve survival rates.

Objective To explore the occurrence and related factors of diarrhea in the early stage of enternal nutrition in critically ill patients, therefore providing guidance for the optimization of enteral nutrition. Methods A prospective cross-sectional study was conducted in 29 ICUs of 28 general hospitals of Zhejiang Province between June 1 and October 1, 2016. Patients who were admitted to ICU required for enteral nutrition were included and continuously observed for over 7 days or till discharged from ICU. The patient's general characteristics, severity of disease, enteral nutrition, diarrhea-related and prognostic indicators were recorded. Multivariable logistic regression was performed to analysis risk factors associated with diarrhea and in-hospital mortality. Results A total of 533 critically ill patientswere enrolled in this study. The overall incidence of diarrhea was 30.8％ (n = 164). Diarrhea occurred most frequently on the three days after EN, with a median duration of 2 (1, 3) days. The daily incidence of diarrhea were significantly different between groups (all P< 0.05), which were gradually reduced on day 7. Multivariable logistic regression analysis showed that prokinetic drugs (OR=1.82; 95％ CI: 1.24-2.65), APACHE II score (OR=1.04; 95％ CI: 1.02-1.07), post-pylorus enteral feeding (OR=1.90; 95％ CI:1.11-3.36) were independent risk factors for diarrhea, while interruption of EN (OR=3.74; 95％ CI: 1.85-7.54), APACHE II score (OR=1.07; 95％ CI: 1.04-1.11), vasoactive agent (OR=2.31; 95％ CI: 1.42-3.77), and timing (>48 h) (OR=2.00; 95％ CI: 1.08-3.70) were independent risk factors for in-hospital mortality. Conclusions Our study showed that APACHE II score, the use of prokinetic drugs, and post-pylorus enteral feeding were risk factors for diarrhea. Patients suffering diarrhea experienced increased ICU length of stay, increased the time of mechanical ventilation and in-hospital mortality compared with patients without diarrhea. Interruption of EN induced by diarrhea significantly increased the risk of in-hospital mortality.

OBJECTIVE To investigate the regulatory effects of couplet medicinals of Atractylodes macrocephala-Aucklandia lappa on gut microbiota and short-chain fatty acids （SCFAs） in the diarrhea-type irritable bowel syndrome （IBS-D） rats with spleen deficiency. METHODS The IBS-D rat model with spleen deficiency was induced by intragastric administration of Senna alexandrina combined with restraint stimulation. The model rats were divided into model group， positive control group （pinaverium bromide 1.5 mg/kg）， A. macrocephala-A. lappa low-dose， medium-dose and high-dose groups （0.7， 1.4， 2.8 g/kg）， with 6 rats in each group. Another 6 healthy rats were taken as the blank control group. The blank control group and the model group were given normal saline intragastrically， and other groups were given relevant drug liquid intragastrically， once a day， for consecutive 14 days. The general characteristics of rats and fecal water content were observed， and intestinal sensitivity [evaluating by abdominal wall withdrawal reflex （AWR） threshold] and the intestinal propulsion rate were determined. The serum levels of 5- hydroxytryptamine（5-HT）and SP were detected， and the pathological changes of colon tissue were observed； the protein expressions of 5-HT-3 receptor（5-HT3R）， 5-HT4R and 5-HT transporter（SERT） in colon tissue of rats were detected. 16S rRNA sequencing was performed for the feces of rats in blank control group， model group and A. macrocephala-A. lappa high-dose group； the contents of acetic acid， propionic acid and butyric acid in the feces of the rats were determined. RESULTS Compared with the model group， the body weight after 7 and 14 days of medication， fecal water content， AWR threshold， and the protein expressions of 5-HT4R and SERT in colon tissue were increased significantly in the A. macrocephala-A. lappa medium-dose and high-dose groups （P＜0.05 or P＜0.01）； serum contents of 5-HT and SP， intestinal propulsion rate （except for A. macrocephala-A. lappa medium-dose group）， the protein expression of 5-HT3R in colon tissue were decreased significantly （P＜0.01）； diarrhea relief， mental state recovery， and partially recovery of the structure of colon tissue were all found； moreover， the diversity and species number of gut microbiota were reduced in A. macrocephala-A. lappa high-dose group and the content of butyric acid in fecal samples was significantly reduced （P＜0.05）. CONCLUSIONS The compatibility of A. macrocephala and A. lappa can improve intestinal motility and sensitivity of IBS-D model rats with spleen deficiency， and alleviate diarrhea. This may be related to improving changes in intestinal microbiota structure， reducing 5-HT expression and butyric acid content， and increasing 5-HT4R and SERT expression.

Nodular gastritis is directly related to Helicobacter pylori (Hp) infection. Refractory Hp infection has significant impact on the treatment efficacy and prognosis of nodular gastritis. Aims: To analyze the spheroidization and antibiotic resistance of refractory Hp and PPI drug metabolic enzyme CYP2C19 gene polymorphism in patients with nodular gastritis, so as to promote the eradication rate of refractory Hp infection in patients with nodular gastritis. Methods: Refractory Hp infection patients with nodular gastritis from Oct. 2019 to Nov. 2020 at the Second Affiliated Hospital of Baotou Medical College were enrolled. Hp strains were cultured in microaerophilic environment. Immunohistochemistry was used to detect Hp spheroidization. Mutation sites of antibiotic resistance genes and host CYP2C19 gene polymorphism were detected by PCR. According to the results of genetic testing, individualized therapy was given and follow up was performed, the eradication rate of intention-to-treat was calculated. Results: A total of 42 patients with refractory Hp nodular gastritis were enrolled. Among them, lymphocyte accumulation was found in 33.3% patients. Hp spheroidization was found in 2 patients, and the spheroidization rates were 20% and 10%, respectively. There were 25 intensive metabolizer, 15 intermediate metabolizer and 2 poor metabolizer of CYP2C19. Antibiotic resistance gene detection showed that the drug resistance rate of amoxicillin, clarithromycin, levofloxacin, furazolidone, tetracycline, metronidazole were 4.8%, 38.1%, 35.7%, 47.6%, 42.9% and 61.9%, respectively. Twenty-two (52.4%) of the patients developed resistance to 3 or more antibiotics. The total eradication rate of intention-to-treat was 83.3%, of which high-dose dual therapy was 88.9%. Conclusions: Multi-antibiotic resistance and CYP2C19 may be the main reason for the failure of eradication of refractory Hp in nodular gastritis. Hp spheroidization has little effect on the efficacy of eradication therapy. The amoxicillin resistance rate is still significantly lower than that of other antibiotics, and high-dose dual therapy is a better option.

Background: There is still controversy whether the existence of esophageal heterotopic gastric mucosa (EHGM) and its histological type are related to the laryngopharyngeal symptoms. Aims: To analyze the clinical and histological characteristics of EHGM and its correlation with gastroesophageal reflux. Methods: A retrospective study was conducted in consecutive gastroscopy-proved EHGM cases from September 2018 to January 2020 at the Second Affiliated Hospital of Baotou Medical College. Besides clinical data review and questionnaire survey on reflux symptoms, histological typing of EHGM and immunohistochemistry were also performed in some cases. Results: A total of 1 229 cases of EHGM were recruited. The male-to-female ratio was 1.67:1, and middle-aged people were predominant. Most of the heterotopic mucosa were located 15-18 cm away from the incisors, and were mainly single. Two hundred and ninety-four cases (23.9%) were complicated with reflux esophagitis (RE), of which Los Angeles grade A and B accounted for 96.6%. Regurgitation/acid reflux (15.5 %) and heartburn (12.3%) were the most common esophageal symptoms, while extraesophageal symptoms were rare. Histological typing was obtained in 57 cases, of which, 37 (64.9%) were cardia-type, 18 (31.6%) were fundic-type, and 2 (3.5%) were mixed type. There were no significant differences in gender, age, location and number of EHGM, expression levels of H

The many-banded krait, Bungarus multicinctus, has been recorded as the animal resource of JinQianBaiHuaShe in the Chinese Pharmacopoeia. Characterization of its venoms classified chief phyla of modern animal neurotoxins. However, the evolutionary origin and diversification of its neurotoxins as well as biosynthesis of its active compounds remain largely unknown due to the lack of its high-quality genome. Here, we present the 1.58 Gbp genome of B. multicinctus assembled into 18 chromosomes with contig/scaffold N50 of 7.53 Mbp/149.8 Mbp. Major bungarotoxin-coding genes were clustered within genome by family and found to be associated with ancient local duplications. The truncation of glycosylphosphatidylinositol anchor in the 3'-terminal of a LY6E paralog released modern three-finger toxins (3FTxs) from membrane tethering before the Colubroidea divergence. Subsequent expansion and mutations diversified and recruited these 3FTxs. After the cobra/krait divergence, the modern unit-B of β-bungarotoxin emerged with an extra cysteine residue. A subsequent point substitution in unit-A enabled the β-bungarotoxin covalent linkage. The B. multicinctus gene expression, chromatin topological organization, and histone modification characteristics were featured by transcriptome, proteome, chromatin conformation capture sequencing, and ChIP-seq. The results highlighted that venom production was under a sophisticated regulation. Our findings provide new insights into snake neurotoxin research, meanwhile will facilitate antivenom development, toxin-driven drug discovery and the quality control of JinQianBaiHuaShe.