ObjectiveTo investigate the effect and potential mechanism of Dihuangyin on 2， 4-dinitrochlorobenzene （DNCB） -induced model mice with atopic dermatitis （AD）. MethodA mouse model with AD was established by repeatedly stimulating the back skin of mice with DNCB. After successful modeling， the mice were randomly divided into model group， Runzao group （0.78 g·kg^-1）， and high， medium， and low dose （40.30， 20.15， and 10.08 g·kg^-1） groups of Dihuangyin， with 12 mice in each group， and the blank group consisted of 12 mice， 72 in total. The administration groups were given the corresponding liquid by dose， and the blank group and model group were given the same dose of pure water by intragastric administration， once a day. The skin lesions and scratching times of mice were observed after continuous administration for two weeks. The back skin lesions of mice were stained with hematoxylin-eosin （HE） and toluidine blue to observe the pathology. The contents of serum immunoglobulin E （IgE）， interleukin-4 （IL-4）， interleukin-6 （IL-6）， and interferon-γ （IFN-γ） were detected by enzyme-linked immunosorbent assay （ELISA）. The mRNA expression levels of IFN-γ， IL-4， IL-6， Janus kinase 1 （JAK1）， and transcriptional activator 3 （STAT3） in skin lesion tissue were detected by Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. The expressions of JAK1， phosphorylation（p）-JAK1， STAT3， and p-STAT3 proteins in skin lesion tissue were detected by Western blot. ResultCompared with the blank group， the back skin of the model group showed large-scale scab， dryness， erosion， hypertrophy with scratching， epidermal hyperplasia with hyperkeratosis and parakeratosis， hyperacanthosis with edema， and a large number of mast cell infiltration in the dermis， some of which were degranulated. The contents of IgE， IL-4， IL-6， and IFN-γ in the serum of mice were significantly increased （P<0.01）， and the protein expression levels of p-JAK1， STAT3， and p-STAT3 and mRNA expressions of IL-4， IL-6， IFN-γ， JAK1， and STAT3 in skin lesion tissue were significantly increased （P<0.01）. Compared with the model group， only a small amount of dryness and desquamation were observed in the back skin of mice in each administration group， and cell edema was reduced. The inflammatory infiltration was significantly reduced， and the number of mast cell infiltration was significantly decreased. The serum IgE， IL-4， IL-6， and IFN-γ of mice were decreased to varying degrees （P<0.05， P<0.01）. The protein expression levels of p-JAK1， STAT3， and p-STAT3 and mRNA expressions of IL-4， IL-6， IFN-γ， JAK1， and STAT3 in skin lesion tissue were significantly decreased， and the effect of high dose group of Dihuangyin was the best （P<0.01）. ConclusionDihuangyin can improve skin lesions and pruritus in mice with AD， and its mechanism may be related to the effective regulation of cytokines on the helper T cells （Th1）/Th2 axis by interfering with the JAK1/STAT3 signaling pathway and affecting skin barrier function.

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*

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is the endoscopic modality of choice for the treatment of biliary and pancreatic diseases. However, patients with cirrhosis, particularly those with decompensated cirrhosis, are believed to be at increased risk for complications associated with ERCP. There is a paucity of literature describing the outcomes of ERCP for patients with cirrhosis. This study aimed to investigate the outcomes of ERCP for cirrhosis patients, especially adverse events, and evaluated its safety and efficacy. METHODS: We performed a multicenter, retrospective study of all patients at Beijing Friendship Hospital affiliated to Capital Medical University, Xijing Hospital affiliated to Air Force Military Medical University, Beijing Youan Hospital affiliated to Capital Medical University, and the Fifth Medical Center of the People's Liberation Army General Hospital from June 2003 to August 2019. The adverse events of inpatient ERCP for patients with ( n  = 182) and without liver cirrhosis (controls; n  = 385) were compared. RESULTS: A total of 567 patients underwent ERCP between January 2003 and December 2019 were enrolled in this study. Compared to patients without cirrhosis, patients with cirrhosis were at higher risk for postoperative complications (odds ratio [OR], 4.172; 95% confidence interval [CI], 1.232-7.031; P  < 0.001) such as postoperative pancreatitis (OR, 2.026; 95% CI, 1.002-4.378; P  = 0.001) and cholangitis (OR, 3.903; 95% CI, 1.001-10.038; P  = 0.036). The main indications for ERCP for patients with cirrhosis in this study included choledocholithiasis (101 cases; 55.5%), benign bile duct strictures (46 cases; 25.3%), and malignant bile duct strictures (28 cases; 15.4%). Among them, 23 patients (12.6%) underwent balloon dilation and 79 patients (43.4%) underwent sphincterotomy. Of the patients with cirrhosis, delayed bleeding occurred in ten patients (5.5%), postoperative pancreatitis occurred in 80 patients (44.0%), and postoperative cholangitis occurred in 25 patients (13.7%). An additional multivariate analysis showed that the total bilirubin (TBIL) level (OR, 4.58; 95% CI, 2.37-6.70) and Child-Pugh score of C (OR, 3.11; 95% CI, 1.04-5.37) were risk factors for postoperative complications in patients with cirrhosis. CONCLUSIONS Compared with the general population of patients undergoing ERCP, patients with cirrhosis were more prone to postoperative pancreatitis and cholangitis. TBIL levels and Child-Pugh scores were risk factors for postoperative complications in patients with cirrhosis.
Humans ; Cholangiopancreatography, Endoscopic Retrograde/adverse effects* ; Retrospective Studies ; Constriction, Pathologic ; Risk Factors ; Liver Cirrhosis/complications* ; Pancreatitis/etiology* ; Postoperative Complications/epidemiology* ; Cholangitis

The major reason for the resistance of Gram-negative bacteria to β-lactam antibiotics is the expression of β-lactamases.Metallo-β-lactamases (MBL) hydrolyze almost all types of β-lactam antibiotics including carbapenems, posing a challenge to global public health. Developing MBL inhibitors is an important method to treat the infections caused by resistant bacteria. As an important type of MBL inhibitors, chelating agents can inhibit MBL by chelating, stripping, and binding Zn2+ in the active center of MBL.This review summarizes recent publications on chelators as MBL inhibitors, discussing their chemical structures, inhibitory potency, synergistic effects with antibiotics, selectivity and mechanism of action, including EDTA and related compounds, aspergillomarasmine A (AMA) and its derivatives, NOTA and related compounds, pyridine carboxylic acid and pyridine methylamine compounds, aiming to provide reference for future development of potent, selective and safe clinical MBL inhibitors.

Background Tricresyl phosphate (TCP) is mainly used as a flame retardant. Studies have confirmed that it has cytotoxicity and neurotoxicity, but its reproductive toxicity is not clear. Objective To investigate the reproductive toxicity and potential mechanism of TCP subacute exposure on Caenorhabditis elegans. Methods Caenorhabditis elegans were exposed to solvent control and 0.1, 1, 10, 100, and 1000 μg·L⁻¹ TCP respectively for 72 h. Brood size and number of fertilized eggs in the uterus were detected to evaluate reproductive ability. The number of total germline cells and the relative area of gonad arm were measured to evaluate the development of gonads. The body length and body width of Caenorhabditis elegans were detected to evaluate growth and development. The activities of reactive oxygen species (ROS) and superoxide dismutase (SOD) in Caenorhabditis elegans, and the mitochondrial active oxygen metabolism genes (mev-1 and gas-1) of N2 nematodes were detected by real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) to evaluate oxidative stress. WS1433 transgenic nematodes and wild-type nematodes N2 were exposed to solvent control or TCP (0.1, 1, 10, 100, and 1000 μg·L⁻¹) respectively. DNA damage in germ cells of WS1433 transgenic nematodes was detected, the relative expressions of DNA damage-related genes (hus-1, clk-2, cep-1, and egl-1) in N2 nematodes were detected by qRT-PCR to evaluate the effect of TCP exposure on genetic damage. Results Compared with the solvent control group (217.00 ± 12.20), the brood size of N2 nematodes in the 100 μg·L⁻¹ and 1000 μg·L⁻¹ TCP groups decreased (170.80 ± 11.51, 169.60 ± 10.52, P < 0.05). Compared with the solvent control group (18.43 ± 1.69), the number of fertilized eggs of N2 nematodes in the 100 μg·L⁻¹ and 1000 μg·L⁻¹ TCP groups decreased (13.47 ± 0.81, 11.95 ± 0.90, P < 0.05). Compared with the solvent control group (312.46 ± 77.4), the number of total germline cells of N2 nematodes in the 100 μg·L⁻¹ and 1000 μg·L⁻¹ TCP groups decreased (281.80 ± 12.98, 273.50 ± 8.53, P < 0.05). Compared with the solvent control group, the relative area of gonads of N2 nematodes in the 100 μg·L⁻¹ and 1000 μg·L⁻¹ TCP groups decreased by 13.83% and 17.25% respectively (P<0.05). Compared with the solvent control group [(1058.10±80.12) μm, (78.21±14.69) μm], the body length and body width of N2 nematodes in the 100 μg·L⁻¹ and 1000 μg·L⁻¹ TCP groups decreased (P<0.05). Compared with the solvent control group, the relative fluorescence intensity of ROS in nematodes in the 10, 100, and 1000 μg·L⁻¹ TCP groups increased significantly (107.60%±1.02%, 105.90%±1.40%, and 106.40%±1.85%, respectively, P<0.05), and the activities of SOD were reduced (by 20.66%, 15.88%, and 16.44%, respectively, P<0.05). Compared with the solvent control group (1.3±1.3), the number of DNA-damaged germ cells of WS1433 nematodes in the 100 and 1000 μg·L⁻¹ TCP groups increased significantly (2.4±0.3, 2.7±0.3, P<0.05); the expressions of mev-1 and gas-1 genes in N2 nematodes in the 10, 100 and 1000 μg·L⁻¹ TCP groups decreased significantly (P<0.05); the expressions of hus-1 in the 0.1-1000 μg·L⁻¹ TCP groups significantly increased (P<0.05); the expressions of clk-2 and egl-1 in the 100 and 1000 μg·L⁻¹ TCP groups increased significantly (P<0.05); the expressions of cep-1 in the 1, 10, and 100 μg·L⁻¹ TCP groups increased significantly (P<0.05). Conclusion TCP may cause reproductive damage to nematodes through oxidative stress and germ cell DNA damage.

Objective:To analyze the clinical characteristics of adult Chinese patients with syncope.Methods:This is a cross-sectional survey study. Patients with preliminary diagnosis of syncope in the Emergency Department, Geriatrics and Cardiology Outpatient Department, or Syncope Unit of 37 hospitals in 19 provinces, autonomous regions and the Hong Kong Special Administrative Region from June 2018 to March 2021 were included in this study. The clinical features of these patients with syncope were analyzed.Results:A total of 4 950 consecutive patients with syncope were included in this study. The age was (56.3±16.8)years, and 2 604 cases (52.6%) were male. The most common type of syncope was neurally mediated syncope (2 345 (47.4%)), followed by cardiac syncope (1 085 (21.9%)), orthostatic hypotensive syncope (311 (6.3%)), and unexplained syncope accounted for nearly one third (1 155 (23.3%)). Predisposing syncope was more common in patients under 65 years of age(2 066(72.4%) vs. 786(27.6%),χ 2=136.5, P<0.001). Presyncope was more common in patients with neurally mediated syncope (1 972(79.0%) vs.1 908(73.9%), χ 2=17.756, P<0.001). Premonitory symptoms were more common in women(1 837(80.0%) vs. 1 863(73.0%),χ 2=33.432, P<0.001). Presyncope syndrome was more common in patients under 65 years of age (2 482(77.8%) vs. 1 218(73.4%),χ 2=17.523, P=0.001). Cyanosis was more common in ≥65 years old patients (271(18.2%) vs. 369(12.7%), χ 2=23.235, P<0.001). Urinary incontinence was more common in old patients aged ≥65 years(252(15.2%) vs. 345(10.8%), χ 2=19.313, P<0.001). Family history was more common in patients with cardiogenic syncope compared with other types of syncope (264(24.3%) vs. 754(19.5%), χ 2=11.899, P=0.001). Hypertention(1 480(30.5%)), coronary heart disease(1 057(21.4%)), atrial flutter and atrial fibrillation(359(7.2%)), second degree atrioventricular block(236(4.8%)) were common complications of syncope. The proportion of patients with coronary heart disease was significantly higher in cardiac syncope than that of other types of syncope(417(38.4%) vs. 640(16.6%), χ 2=241.376, P<0.001). Other common complications included cerebrovascular diseases (551 (11.1%)) and diabetes mellitus (632(12.8%)). Conclusions:Neurally mediated syncope is the most common syncope in adult Chinese population. Patients with predisposing conditions and premonitory conditions are younger. Presyncope is more common in women. The proportion of family history and coronary heart disease is higher in patients with cardiogenic syncope.

Objective To evaluate the diagnostic value of related contrast material(Rel.CM)of the dual-energy CT (DECT) virtual noncalcium (VNCa) for detecting acute traumatic bone marrow edema in knee joint.Methods A total of 17 patients(18 knees)with definite trauma history and knee joint disorders were prospectively enrolled. Conventional CT, VNCa and MRI images were obtained by MRI and DECT scan. Each knee was divided into 12 regions, respectively, to observe the performance of MRI and VNCa images. The diagnostic efficacy of different Rel. CM values (1.25, 1.45, 1.75) was analyzed for the knee traumatic bone marrow edema,select the best Rel.CM value.And the CT values of bone marrow and bone marrow damage were measured on VNCa of the optimal Rel. CM parameters. Using ROC to evaluate the efficacy of VNCa in different Rel.CM values for diagnosing traumatic bone marrow edema,the difference of CT value between bone marrow lesion and bone marrow in normal region of bone marrow was obtained by using rank sum test. Results DECT and MRI were performed in 17 patients (18 knees). Eighteen knees were divided into 216 areas.MRI showed 94 areas of bone marrow edema,including 35 in distal portion of femur, 59 in proximal tibia. Rel.CM values of 1.25, 1.45, 1.75 of the VNCa map were used to diagnose traumatic bone marrow edema in the knee with the area under the ROC curve of 0.643, 0.871, 0.656, respectively. Rel.CM with 1.45 VNCa diagram was the most accurate. The CT values of the bone marrow edema region and the normal region were -64.3(-20.6 to-90.8)HU,-93.4(-70.5 to-120.7)HU, respectively, on the VNCa graph with the optimal Rel.CM parameters (1.45) (Z=-8.270, P<0.05). Conclusions The VNCa image with a Rel.CM value of 1.45 has a better diagnostic performance for traumatic bone marrow edema in knee joint. CT value measurement in VNCa image can be used for quantitative analysis of traumatic bone marrow edema.

Objective To assess the application of MRI in diagnosis of oblique vaginal septum syndrome (OVSS).Methods Clinical and imaging data of 41 patients with OVSS confirmed by surgery from March 2011 to November 2016 were retrospectively analyzed.Results The average age of patients was 20.5 year (10-46 years).The primary clinical symptoms were menorrhalgia (16 cases) and menorrhagia (13 cases).There were 12 cases of type Ⅰ,23 cases of type Ⅱ,5 cases of type Ⅲ and 1 case of type Ⅳamong 41 cases of OVSS.The resections for OVSS were performed in 35 cases.Forty two cases were diagnosed as OVSS by MRI scan,and 41 were confirmed by surgery,the accuracy of MRI diagnosis was 97.6％ (41/42).MRI showed uterus didelphys,hydrocolpos or hematocolpos with varying degrees,and revealed ipsilateral renal agenesis in all 41 cases.Conclusion MRI scan can accurately diagnose oblique vaginal septum syndrome and provide comprehensive information for clinical treatment.

AIM:Chronic heart failure (CHF), caused by ischemic cardiomyopathy (ICM) and nonischemic cardiomyopathy (NICM), is among the leading causes of mortality and morbidity worldwide .Low-density lipoprotein receptor-related protein 6 (LRP6) plays a criti-cal role in regulating Wnt signaling .Dysregulated Wnt signaling contributes to high incidence of arrhythmias .Thus, there might be an association between genetic variations of LRP6 and sudden cardiac death ( SCD) .The objective of the study was to examine the associ-ation between common variants of LRP6 and prognosis of CHF patients .METHODS:From July 2005 to December 2009, patients with CHF referred from 10 hospitals and participants without structural heart disease in China were undergone a prospective study .The sin-gle-nucleotide polymorphism rs 2302684 was selected to evaluate the effect of LRP6 polymorphisms on the survival of the patients .RE-SULTS:A total of 1 887 patients (1 437 with CHF and 450 in the control group)were finally enrolled for the analysis.During a medi-an follow-up of 61 months, a total of 546 (38.00%) patients died, including 201(36.81%) cases with SCD and 345 (63.19%) ca-ses with NSCD.No end point event occurred in the control group .Patients carrying A allele of rs2302684 had increased risks of all-cause death (P<0.01) and SCD (P<0.01).After adjusted for the other risk factors , the associations remained significant in all-cause death (P<0.01) and SCD (P<0.01).In patients with CHF caused by ICM , those carrying A allele of rs2302684 also had in-creased risks of all-cause death (P<0.01) and SCD (P<0.01).After adjusted for the other risk factors , the associations remained significant in all-cause death (P<0.01) and SCD (P<0.01).However, there was no association between A allele of rs 2302684 and prognosis in patients with CHF caused by NICM .CONCLUSION:The SNP rs2302684 T>A in LRP6 is associated with an increased risk of all-cause death and SCD in patients with CHF in Chinese Han population , and the association is more prevalent in patients with CHF caused by ICM.Thus, LRP6 might be added as a novel predictor of SCD and could provide an attractive and direct therapeutic target in SCD prevention .

Objective:To observe the dynamic change of cystathionine β-synthase during cerebral ischemia-reperfusion and its effect in rats.Methods:The ischemic model was established with line embolism to block the middle cerebral artery .The reverse tran-scription-polymerase chain reaction ( RT-PCR) and Western blot assay were used to assess the expression of cystathionine β-synthase (CBS) in SHAM group,I group,and IR group.ELISA assay was performed to detected the homocysteine (HCY) level in plasma.After treating with the inhibitor of cystathionine β-synthase called hydroxyla mine(HA),the expression of hemeoxygenase 1(HO-1) and the pathologic change of the brain was evaluated .Results:As compared to sham group ,the expression of CBS was significantly up-regulated in ischemia-reperfusion group at 12 h post-reperfusion.Meanwhile,it existed the lowest level of HCY at 12 h post-reperfusion,comparing to sham grouzp ( 5.73 ±1.17 vs 2.88 ±0.93 , F=25.56 , P=0.001 ) .When inhibited the activity of CBS via using HA , the down-regulation of HO-1 protein and further damage in neuron were observed .Conclusion:Cystathionine β-synthase serves as an protective factor during cerebral ischemia-reperfusion.