1.Quality evaluation of Xinjiang Rehmannia glutinosa and Rehmannia glutinosa based on fingerprint and multi-component quantification combined with chemical pattern recognition.
Pan-Ying REN ; Wei ZHANG ; Xue LIU ; Juan ZHANG ; Cheng-Fu SU ; Hai-Yan GONG ; Chun-Jing YANG ; Jing-Wei LEI ; Su-Qing ZHI ; Cai-Xia XIE
China Journal of Chinese Materia Medica 2025;50(16):4630-4640
The differences in chemical quality characteristics between Xinjiang Rehmannia glutinosa and R. glutinosa were analyzed to provide a theoretical basis for the introduction and quality control of R. glutinosa. In this study, the high performance liquid chromatography(HPLC) fingerprints of 6 batches of Xinjiang R. glutinosa and 10 batches of R. glutinosa samples were established. The content of iridoid glycosides, phenylethanoid glycosides, monosaccharides, oligosaccharides, and polysaccharides in Xinjiang R. glutinosa and R. glutinosa was determined by high performance liquid chromatography-diode array detection(HPLC-DAD), high performance liquid chromatography-evaporative light scattering detection(HPLC-ELSD), and ultraviolet-visible spectroscopy(UV-Vis). The determination results were analyzed with by chemical pattern recognition and entropy weight TOPSIS method. The results showed that there were 19 common peaks in the HPLC fingerprints of the 16 batches of R. glutinosa, and catalpol, aucubin, rehmannioside D, rehmannioside A, hydroxytyrosol, leonuride, salidroside, cistanoside A, and verbascoside were identified. Hierarchical cluster analysis(HCA) and principal component analysis(PCA) showed that Qinyang R. glutinosa, Mengzhou R. glutinosa, and Xinjiang R. glutinosa were grouped into three different categories, and eight common components causing the chemical quality difference between Xinjiang R. glutinosa and R. glutinosa in Mengzhou and Qinyang of Henan province were screened out by orthogonal partial least squares discriminant analysis(OPLS-DA). The results of content determination showed that there were glucose, sucrose, raffinose, stachyose, polysaccharides, and nine glycosides in Xinjiang R. glutinosa and R. glutinosa samples, and the content of catalpol, rehmannioside A, leonuride, cistanoside A, verbascoside, sucrose, and glucose was significantly different between Xinjiang R. glutinosa and R. glutinosa. The analysis with entropy weight TOPSIS method showed that the comprehensive quality of R. glutinosa in Mengzhou and Qinyang of Henan province was better than that of Xinjiang R. glutinosa. In conclusion, the types of main chemical components of R. glutinosa and Xinjiang R. glutinosa were the same, but their content was different. The chemical quality of R. glutinosa was better than Xinjiang R. glutinosa, and other components in R. glutinosa from two producing areas and their effects need further study.
Rehmannia/classification*
;
Drugs, Chinese Herbal/chemistry*
;
Chromatography, High Pressure Liquid/methods*
;
Quality Control
2.Relationship between maternal arsenic exposure during pregnancy and congenital heart disease in offspring: A meta-analysis
Lan LAN ; Huai HU ; Nan JING ; Qianlei YANG ; Hailin TIAN ; Yan AN
Chinese Journal of Endemiology 2024;43(3):247-252
Objective:To systematically evaluate the correlation between maternal arsenic exposure during pregnancy and congenital heart disease (CHD) in offspring.Methods:Literature search was performed through databases such as PubMed, Web of Science, Embase, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, and VIP.com to include epidemiological literature on association between maternal arsenic exposure during pregnancy and offspring CHD published domestically and internationally. The search was conducted from database establishment until November 2, 2022. Stata MP15 software was used for meta-analysis of binary variables, and I 2 statistics and Q test were used for heterogeneity test, fixed effect model or random effect model was selected based on the test results. Using OR value (95% CI) as the effect evaluation indicator, subgroup analysis was conducted based on CHD subtypes [conotruncal defects (CTD), atrioventricular septal defect (AVSD), total anomalous pulmonary venous return (TAPVR), left ventricular outflow tract obstruction (LVOTO), right ventricular outflow tract obstruction (RVOTO), atrial septal defect (ASD)/ventricular septal defect (VSD), and patent ductus arteriosus (PDA)]. Results:Nine articles were finally included, including two Chinese and seven English articles. Among them, 8 articles had CHD as the outcome, 5 articles had ASD/VSD as the outcome, 4 articles had CTD as the outcome, 3 articles had LVOTO as the outcome, 2 articles had PDA as the outcome, and 1 article had RVOTO as the outcome. An analysis was conducted on 8 articles with CHD as the outcome. After heterogeneity testing, I 2 = 88.5% and P < 0.001, indicating significant heterogeneity. A random effect model was used for meta-analysis, and the combined OR value (95% CI) was 1.51 (1.40 - 1.62). The results of CHD subgroup analysis showed that the combined OR values (95% CI) for ASD/VSD, CTD, LVOTO, PDA, and RVOTO were 1.68 (1.53 - 1.84), 1.64 (1.29 - 2.09), 2.89 (1.82 - 4.61), 1.78 (1.53 - 2.08), and 0.81 (0.64 - 1.03), respectively. Conclusion:Maternal arsenic exposure during pregnancy is associated with development of offspring CHD, including ASD/VSD, CTD, LVOTO, and PDA as the common lesions in offspring CHD.
3.Prognostic factor and its predictive value of patients with Wilson's disease-related acute-on-chronic liver failure
Lu-Lu TANG ; Huai-Zhen CHEN ; Jing ZHANG ; Ting DONG ; Jun LI ; Hai-Lin JIANG ; Wen-Ming YANG
Medical Journal of Chinese People's Liberation Army 2024;49(2):131-136
Objective To explore the prognostic factor and its predictive value of patients with Wilson disease-related acute-on-chronic liver failure(WD-ACLF).Methods The clinical data of 70 patients diagnosed as WD-ACLF admitted to the Department of Encephalopathy of the First Affiliated Hospital of Anhui University of Chinese Medicine from January 1,2017 to January 1,2022 were retrospectively collected.According to the 12-week prognosis,patients were divided into survival group(n=36)and death group(n=34).The data of the two groups were analyzed by univariate and multivariate logistic analysis to screen the prognostic risk factors and evaluate their predictive value.The model coefficient is omnibus tested,and the model-fitting degree is evaluated by the Hosmer-Lemeshow test.ROC curve was used to analyze the prognostic value for WD-ACLF between the new model and chronic liver failure-sequential organ failure assessment(CLIF-SOFA)score,model for end-stage liver disease(MELD)score and Child-Turcotte-Pugh(CTP)score.Results A total of 70 WD-ACLF patients were enrolled in present study,including 36 cases in survival group[22 males and 14 females with median age of 30.0(17.3,40.0)]and 34 cases in death group[25 males and 9 females with median age of 34.0(28.8,41.0)].Univariate analysis showed that the course of disease,prothrombin time(PT),activated partial thromboplastin time(APTT)were shorter in survival group than that in death group,the white blood cells(WBC),international normalized ratio(INR),aspartate transaminase(AST),total bilirubin(TBIL),blood urea nitrogen(BUN),creatinine(Cre)and ceruloplasmin(CER)levels and the proportion of infection,ascites,and upper gastrointestinal bleeding were lower in survival group than those in death group,however,the proportion of infection,ascites and upper digestive bleeding in the survival group were lower than those in the death group.Meanwhile,the red blood cells(RBC),hemoglobin(Hb),Na+ and total cholesterol(TC)level in the survival group were higher than those in the death group(P<0.05 or P<0.01).The results of multivariate logistic regression analysis showed that disease course(OR=1.176,95%CI 1.043-1.325),INR(OR=7.635,95%CI 1.767-32.980),TBIL(OR=1.012,95%CI 1.003-1.021),and upper gastrointestinal bleeding(OR=11.654,95%CI 1.029-131.980)were independent risk factors affecting the prognosis of WD-ACLF(P<0.05).Based on the results of logistic regression analysis,a joint model for predicting the prognosis of WD-ACLF was established.The AUC of the model for evaluating the prognosis of WD-ACLF was 0.941,which was greater than the CLIF-SOFA score(AUC=0.802),MELD score(AUC=0.897),and CTP score(AUC=0.722).Conclusions The course of disease,TBIL,INR,and upper gastrointestinal bleeding are risk factors that affect the prognosis of WD-ACLF.The prognosis model established based on this can more accurately predict the prognosis of WD-ACLF patients,and its predictive value is superior to CLIF-SOFA score,MELD score,and CTP score.
5.Distribution and Drug Resistance of Pathogens Causing Bloodstream Infection in Patients with Hematological Malignancies
Ming YANG ; Huai-Xin GENG ; Jin-Ge TAI ; Hai-Lian SHAO ; Jing-Wen CHEN ; Ke DONG
Journal of Experimental Hematology 2024;32(2):583-587
Objective:To investigate distribution and drug resistance of pathogens of bloodstream infection in patients with hematological malignancies,in order to provide reference for clinical infection control and treatment.Methods:The clinical information of blood culture patients in the hematology department of our hospital from January 2016 to December 2021 was reviewed.They were divided into transplantation group and non-transplantation group according to whether they had undergone hematopoietic stem cell transplantation.The types of pathogens and their drug resistance were analyzed.Results:Two hundred and ninety-nine positive strains of pathogenic bacteria were detected.In the transplantation group,Gram-negative bacteria accounted for 68.5%(50/73),Gram-positive bacteria accounted for 6.8%(5/73),and fungi accounted for 24.7%(18/73).The resistance rate of Escherichia coli to the third-generation cephalosporins was 77.8%,and 11.5%to carbapenems.The resistance rate of Klebsiella pneumoniae to the third-generation cephalosporins was 50.0%,and 56.2%to carbapenems.In the non-transplantation group,Gram-negative bacteria accounted for 64.1%(145/226),Gram-positive bacteria accounted for 31.0%(70/226),and fungi accounted for 4.9%(11/226).Gram-positive bacteria were mainly Enterococcus faecium(6.6%,15/226)and Coagulase-negative Staphylococci(6.2%,14/226).The fungi were all Candida tropicalis.The resistance rate of Escherichia coli to the third-generation cephalosporins was 63.8%,and 10.3%to carbapenems.The resistance rate of Klebsiella pneumoniae to the third-generation cephalosporins was 46.3%,and 26.8%to carbapenems.Conclusion:The types of pathogenic bacteria in bloodstream infection in patients with hematological malignancies are varied.Gram-negative bacteria is the main pathogenic bacteria.The resistance of pathogenic bacteria to antibiotics is severe.Antibiotics should be used scientifically and reasonably according to the detection and resistance of pathogenic bacteria.
6.METTL3 regulates glucose transporter expression in placenta exposed to hyperglycemia through the mTOR signaling pathway
Jie NING ; Jing HUAI ; Shuxian WANG ; Jie YAN ; Rina SU ; Muqiu ZHANG ; Mengtong LIU ; Huixia YANG
Chinese Medical Journal 2024;137(13):1563-1575
Background::Alterations in the placental expression of glucose transporters (GLUTs), the crucial maternal-fetal nutrient transporters, have been found in women with hyperglycemia in pregnancy (HIP). However, there is still uncertainty about the underlying effect of the high-glucose environment on placental GLUTs expression in HIP.Methods::We quantitatively evaluated the activity of mammalian target of rapamycin (mTOR) and expression of GLUTs (GLUT1, GLUT3, and GLUT4) in the placenta of women with normal pregnancies (CTRL, n = 12) and pregnant women complicated with poorly controlled type 2 diabetes mellitus (T2DM, n = 12) by immunohistochemistry. In addition, BeWo cells were treated with different glucose concentrations to verify the regulation of hyperglycemia. Then, changes in the expression of GLUTs following the activation or suppression of the mTOR pathway were also assessed using MHY1485/rapamycin (RAPA) treatment or small interfering RNA (siRNA)-mediated silencing approaches. Moreover, we further explored the alteration and potential upstream regulatory role of methyltransferase-like 3 (METTL3) when exposed to hyperglycemia. Results::mTOR, phosphorylated mTOR (p-mTOR), and GLUT1 protein levels were upregulated in the placenta of women with T2DM compared with those CTRL. In BeWo cells, mTOR activity increased with increasing glucose concentration, and the expression of GLUT1, GLUT3, and GLUT4 as well as GLUT1 cell membrane translocation were upregulated by hyperglycemia to varying degrees. Both the drug-mediated and genetic depletion of mTOR signaling in BeWo cells suppressed GLUTs expression, whereas MHY1485-induced mTOR activation upregulated GLUTs expression. Additionally, high glucose levels upregulated METTL3 expression and nuclear translocation, and decreasing METTL3 levels suppressed GLUTs expression and mTOR activity and vice versa. Furthermore, in METTL3 knockdown BeWo cells, the inhibitory effect on GLUTs expression was eliminated by activating the mTOR signaling pathway using MHY1485. Conclusion::High-glucose environment-induced upregulation of METTL3 in trophoblasts regulates the expression of GLUTs through mTOR signaling, contributing to disordered nutrient transport in women with HIP.
7.Effect of balance training relying on tilted table on diaphragmatic function in patients with prolonged disorder of consciousness
Li LIN ; Ranran XING ; Jing GU ; Ruilong HUANG ; Yanyan ZENG ; Huai HUANG
Chinese Journal of Neuromedicine 2024;23(9):918-924
Objective:To observe the rehabilitation effect of balance training relying on tilted table on diaphragmatic function of patients with prolonged disorder of consciousness (pDoC).Methods:A prospective study was performed. Thirty patients with pDoC were enrolled from Department of Hyperbaric Oxygen Medicine and Rehabilitation, General Hospital of Southern Theater Command of PLA from May to December 2023. The pateints were divided into study group ( n=15) and control group ( n=15) according to different rehabilitation. Patients from the control group received conventional rehabilitation, while those in the study group received passive balance training relying on tilted table in addition to conventional rehabilitation. Diaphragmatic ultrasound examination was performed before treatment, and 4 and 8 weeks after treatment to measure diaphragm excursion (DE), diaphragm thickening inspiration (DTei), diaphragm thickening expiration (DTee) and diaphragm thickening fraction (DTF) so as to assess the diaphragmatic functions of patients with pDoC. Results:During treatment, 2 patients dropped out from the study group resulting from the willing of the family members, ultimately including 13 and 15 patients in the study and control groups, respectively. (1) Between-group comparison: no significant difference in DE, DTei, DTee or DTF was noted between the study group and control group 4 weeks after treatment ( P>0.05). However, 8 weeks after treatment, the study group had statistically increased DE, DTei and DTF compared with the control group ([1.65±0.32] cm vs. [1.21±0.22] cm; [2.07±0.26] cm vs. [1.83±0.26] cm; and [24.39±3.19]% vs. [18.93±2.50]%). (2) Within-group comparison: both group had significantly increased DE 4 and 8 weeks after treatment compared with those before treatment ( P<0.05); in the study group, DE 8 weeks after treatment was significantly increased compared with that 4 weeks after treatment ( P<0.05). No significant difference in DTei, DTee or DTF was noted in both groups between 4 weeks after treatment and before treatment ( P>0.05). In the study group, DTei, DTee and DTF 8 weeks after treatment were significantly higher than those before treatment and 4 weeks after treatment ( P<0.05). Conclusion:Balance training relying on tilted table is feasible and effective in improving diaphragmatic function in patients with pDoC, and the effect is positively correlated with treatment time within a certain time.
8.Antimicrobial resistance of bacteria from blood specimens:surveillance re-port from Hunan Province Antimicrobial Resistance Surveillance System,2012-2021
Hong-Xia YUAN ; Jing JIANG ; Li-Hua CHEN ; Chen-Chao FU ; Chen LI ; Yan-Ming LI ; Xing-Wang NING ; Jun LIU ; Guo-Min SHI ; Man-Juan TANG ; Jing-Min WU ; Huai-De YANG ; Ming ZHENG ; Jie-Ying ZHOU ; Nan REN ; An-Hua WU ; Xun HUANG
Chinese Journal of Infection Control 2024;23(8):921-931
Objective To understand the change in distribution and antimicrobial resistance of bacteria isolated from blood specimens of Hunan Province,and provide for the initial diagnosis and treatment of clinical bloodstream infection(BSI).Methods Data reported from member units of Hunan Province Antimicrobial Resistance Survei-llance System from 2012 to 2021 were collected.Bacterial antimicrobial resistance surveillance method was imple-mented according to the technical scheme of China Antimicrobial Resistance Surveillance System(CARSS).Bacteria from blood specimens and bacterial antimicrobial susceptibility testing results were analyzed by WHONET 5.6 soft-ware and SPSS 27.0 software.Results A total of 207 054 bacterial strains were isolated from blood specimens from member units in Hunan Province Antimicrobial Resistance Surveillance System from 2012 to 2021,including 107 135(51.7%)Gram-positive bacteria and 99 919(48.3%)Gram-negative bacteria.There was no change in the top 6 pathogenic bacteria from 2012 to 2021,with Escherichia coli(n=51 537,24.9%)ranking first,followed by Staphylococcus epidermidis(n=29 115,14.1%),Staphylococcus aureus(n=17 402,8.4%),Klebsiella pneu-moniae(17 325,8.4%),Pseudomonas aeruginosa(n=4 010,1.9%)and Acinetobacter baumannii(n=3 598,1.7%).The detection rate of methicillin-resistant Staphylococcus aureus(MRSA)decreased from 30.3%in 2015 to 20.7%in 2021,while the detection rate of methicillin-resistant coagulase-negative Staphylococcus(MRCNS)showed an upward trend year by year(57.9%-66.8%).No Staphylococcus was found to be resistant to vancomy-cin,linezolid,and teicoplanin.Among Gram-negative bacteria,constituent ratios of Escherichia coli and Klebsiella pneumoniae were 43.9%-53.9%and 14.2%-19.5%,respectively,both showing an upward trend(both P<0.001).Constituent ratios of Pseudomonas aeruginosa and Acinetobacter baumannii were 3.6%-5.1%and 3.0%-4.5%,respectively,both showing a downward trend year by year(both P<0.001).From 2012 to 2021,resistance rates of Escherichia coli to imipenem and ertapenem were 1.0%-2.0%and 0.6%-1.1%,respectively;presenting a downward trend(P<0.001).The resistant rates of Klebsiella pneumoniae to meropenem and ertapenem were 7.4%-13.7%and 4.8%-6.4%,respectively,presenting a downward trend(both P<0.001).The resistance rates of Pseudomonas aeruginosa and Acinetobacter baumannii to carbapenem antibiotics were 7.1%-15.6%and 34.7%-45.7%,respectively.The trend of resistance to carbapenem antibiotics was relatively stable,but has de-creased compared with 2012-2016.The resistance rates of Escherichia coli to the third-generation cephalosporins from 2012 to 2021 were 41.0%-65.4%,showing a downward trend year by year.Conclusion The constituent ra-tio of Gram-negative bacillus from blood specimens in Hunan Province has been increasing year by year,while the detection rate of carbapenem-resistant Gram-negative bacillus remained relatively stable in the past 5 years,and the detection rate of coagulase-negative Staphylococcus has shown a downward trend.
9.Antimicrobial resistance of bacteria from cerebrospinal fluid specimens:surveillance report from Hunan Province Antimicrobial Resistance Survei-llance System,2012-2021
Jun LIU ; Li-Hua CHEN ; Chen-Chao FU ; Chen LI ; Yan-Ming LI ; Xing-Wang NING ; Guo-Min SHI ; Jing-Min WU ; Huai-De YANG ; Hong-Xia YUAN ; Ming ZHENG ; Nan REN ; An-Hua WU ; Xun HUANG ; Man-Juan TANG
Chinese Journal of Infection Control 2024;23(8):932-941
Objective To investigate changes in the distribution and antimicrobial resistance of bacteria isolated from cerebrospinal fluid(CSF)specimens in Hunan Province,and provide reference for correct clinical diagnosis and rational antimicrobial use.Methods Data reported by member units of Hunan Province Antimicrobial Resistance Surveillance System from 2012 to 2021 were collected according to China Antimicrobial Resistance Surveillance Sys-tem(CARSS)technical scheme.Data of bacteria isolated from CSF specimens and antimicrobial susceptibility tes-ting results were analyzed with WHONET 5.6 and SPSS 20.0 software.Results A total of 11 837 bacterial strains were isolated from CSF specimens from member units of Hunan Province Antimicrobial Resistance Surveillance Sys-tem from 2012 to 2021.The top 5 strains were coagulase-negative Staphylococcus(n=6 397,54.0%),Acineto-bacter baumannii(n=764,6.5%),Staphylococcus aureus(n=606,5.1%),Enterococcus faecium(n=465,3.9%),and Escherichia coli(n=447,3.8%).The detection rates of methicillin-resistant coagulase-negative Staphyloco-ccus(MRCNS)and methicillin-resistant Staphylococcus aureus(MRSA)were 58.9%-66.3%and 34.4%-62.1%,respectively.No Staphylococcus spp.were found to be resistant to vancomycin,linezolid,and teicoplanin.The de-tection rate of Enterococcus faecium was higher than that of Enterococcus faecalis,and the resistance rates of En-terococcus f aecium to penicillin,ampicillin,high concentration streptomycin and levofloxacin were all higher than those of Enterococcus faecalis(all P=0.001).Resistance rate of Streptococcus pneumoniae to penicillin was 85.0%,at a high level.Resistance rate of Escherichia coli to ceftriaxone was>60%,while resistance rates to enzyme inhibitors and carbapenem antibiotics were low.Resistance rate of Klebsiella pneumoniae to ceftriaxone was>60%,to en-zyme inhibitors piperacillin/tazobactam and cefoperazone/sulbactam was>30%,to carbapenem imipenem and me-ropenem was about 30%.Resistance rates of Acinetobacter baumannii to most tested antimicrobial agents were>60%,to imipenem and meropenem were 59.0%-79.4%,to polymyxin B was low.Conclusion Among the bac-teria isolated from CSF specimens,coagulase-negative Staphylococcus accounts for the largest proportion,and the overall resistance of pathogenic bacteria is relatively serious.Bacterial antimicrobial resistance surveillance is very important for the effective treatment of central nerve system infection.
10.Antimicrobial resistance of bacteria from intensive care units:surveillance report from Hunan Province Antimicrobial Resistance Surveillance Sys-tem,2012-2021
Li-Hua CHEN ; Chen-Chao FU ; Chen LI ; Yan-Ming LI ; Jun LIU ; Xing-Wang NING ; Guo-Min SHI ; Jing-Min WU ; Huai-De YANG ; Hong-Xia YUAN ; Ming ZHENG ; Nan REN ; Xun HUANG ; An-Hua WU ; Jian-Dang ZHOU
Chinese Journal of Infection Control 2024;23(8):942-953
Objective To investigate the distribution and antimicrobial susceptibility of clinically isolated bacteria from intensive care units(ICUs)in hospitals of Hunan Province Antimicrobial Resistance Surveillance System from 2012 to 2021.Methods According to China Antimicrobial Resistance Surveillance System,data of clinically isolated bacterial strains and antimicrobial susceptibility testing results of bacteria from ICUs reported by all member units of Hunan Province Antimicrobial Resistance Surveillance System were analyzed with WHONET 2022 software.Results From 2012 to 2021,the total number of bacteria isolated from ICUs of member units of the Hunan Province Antimi-crobial Resistance Surveillance System was 5 777-22 369,with Gram-negative bacteria accounting for 76.1%-78.0%annually.Staphylococcus aureus ranked first among isolated Gram-positive bacteria each year.The top 5 bacteria among Gram-negative bacteria were Acinetobacter baumannii,Klebsiella pneumoniae,Escherichia coli,Pseudo-monas aeruginosa,and Stenotrophomonas maltophilia.Detection rate of methicillin-resistant Staphylococcus aureus showed a downward trend year by year.No Staphylococcus spp.were found to be resistant to vancomycin,teico-planin and linezolid.Detection rates of vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Entero-coccus faecium were 0.6-1.1%and 0.6%-2.2%,respectively.Resistance rates of Escherichia coli and Kleb-siella pneumoniae to imipenem were 3.1%-5.7%and 7.7%-20.9%,respectively.Resistance rates of Pseudo-monasaeruginosa and Acinetobacter baumannii to imipenem were 24.6%-40.1%and 76.1%-80.9%,respective-ly.Detection rates of carbapenem-resistant Pseudomonas aeruginosa declined year by year.Acinetobacter baumannii maintained high susceptibility to polymyxin B,with resistance rate<10%.Conclusion Antimicrobial resistance of bacteria from ICUs is serious.Carbapenem-resistant Enterobacteriales has an upward trend after 2019.It is nece-ssary to strengthen the surveillance of bacterial resistance and carry out multidisciplinary collaboration.

Result Analysis
Print
Save
E-mail