Disrupted redox status primarily contributes to myocardial ischemia/reperfusion injury (MIRI). NRF2, the endogenous antioxidant regulator, might provide therapeutic benefits. Dihydrotanshinone-I (DT) is an active component in Salvia miltiorrhiza with NRF2 induction potency. This study seeks to validate functional links between NRF2 and cardioprotection of DT and to investigate the molecular mechanism particularly emphasizing on NRF2 cytoplasmic/nuclear translocation. DT potently induced NRF2 nuclear accumulation, ameliorating post-reperfusion injuries via redox alterations. Abrogated cardioprotection in NRF2-deficient mice and cardiomyocytes strongly supports NRF2-dependent cardioprotection of DT. Mechanistically, DT phosphorylated NRF2 at Ser40, rendering its nuclear-import by dissociating from KEAP1 and inhibiting degradation. Importantly, we identified PKC-δ-(Thr505) phosphorylation as primary upstream event triggering NRF2-(Ser40) phosphorylation. Knockdown of PKC-δ dramatically retained NRF2 in cytoplasm, convincing its pivotal role in mediating NRF2 nuclear-import. NRF2 activity was further enhanced by activated PKB/GSK-3β signaling via nuclear-export signal blockage independent of PKC-δ activation. By demonstrating independent modulation of PKC-δ and PKB/GSK-3β/Fyn signaling, we highlight the ability of DT to exploit both nuclear import and export regulation of NRF2 in treating reperfusion injury harboring redox homeostasis alterations. Coactivation of PKC and PKB phenocopied cardioprotection of DT in vitro and in vivo, further supporting the potential applicability of this rationale. Graphical abstract

Objective:To evaluate the indications, surgical skills and clinic outcomes of abdominal minimal incision sacrocolpopexy (AMISC) for treatment of advanced pelvic organ prolapse (POP).Methods:The retrospective study analyzed 30 women with advanced POP who underwent AMISC between June 2016 and October 2019, including 9 cases of recurrent prolapse and 10 cases of vault prolapse. AMISC was especially applicable to: (1) patients with several medical complications who was unable to tolerate general anesthesia or laparoscopic surgery, but able to tolerate combined spinal-epidural anesthesia and open surgery; (2) other abdominal procedures were indicated to perform with AMISC simultaneously, such as myomectomy, subtotal hysterectomy etc, the specimens were easy to get out of the abdominal cavity and morcellation was avoided; (3) surgeons preferring open surgery to laparoscopic surgery or skilled in open surgery; (4) patients with prior pelvic operations, presenting severe abdominal and pelvic adhesions. Objective outcomes were assessed by pelvic organ prolapse quantification (POP-Q) system. Subjective outcome were assessed by pelvic floor distress inventory-short form 20 (PFDI-20), pelvic floor impact questionnaire-short form (PFIQ-7) and patient global impression of improvement (PGI-I).Results:All patients with 1-3 medical complications were successfully performed with AMISC without stopping procedure, enlarging the incision or changing to other procedure, the operation duration was (110±19) minutes. The mean time of follow-up was (33.5±12.4) months (range: 8-49 months). The postoperative points of Aa, Ba, C, Ap, Bp reduced significantly and point C improved from (2.33±2.50) cm to (-7.54±1.18) cm after AMISC ( P<0.01). The objective cure rates were both 100% (30/30) in apex and posterior compartment, while 97% (29/30) in anterior compartment. Postoperative scores of PFDI-20 and PFIQ-7 were all significant decreased (all P<0.01). About PGI-I, 29 patients chose “significant improvement”, subjective satisfaction was 97% (29/30). Anterior sacral plexus hemorrhage occurred in 2 cases (7%, 2/30). There was no intestinal obstruction or injury of bladder, bowel and ureter intra- and postoperation. Two cases (7%, 2/30) had mesh exposure. Conclusion:AMISC is a safety, convenient, minimal traumatic and durable procedure for apical prolapse with short learning curve in the most of cases.

Objective:To evaluate the immunogenicity and immune persistence of purified Vero cells rabies vaccine (PVRV) with Zagreb and Essen regimen.Methods:Prospective study: Patients with first Class II exposure to rabies were recruited from the Dog Injury Cinic of Guangxi Center for Disease Control and Prevention (Guangxi CDC) and randomly divided into the Zagreb (2-1-1) and Essen (1-1-1-1-1) regimen group. All patients were inoculated with the vaccines from the same manufacturer and batch, and 3 ml serum was collected at the 45th day and in 1-year, 2-year and 3-year after immunization. Rapid fluorescent inhibition test (RFFIT) was used to detect rabies virus neutralizing antibody (RVNA). The attenuation of RVNA positive rate and geometric mean titer (GMT) with time was analyzed. Retrospective study: The informed consents for rabies vaccine in the Dog Injury Clinic of Guangxi CDC were checked out. The patients who were injected with PVRV (same manufacturer but unlimited batch) but without passive immune agents for the first time within 3 years were selected and divided into 1-year, 2-year and 3-year group. Each group was further divided into Zagreb and Essen regimen group. The serum (3 ml) was collected at 1 year, 2 years and 3 years after immunization and detected the RVNA by RFFIT.Results:Prospective study: The RVNA positive rates on the 45th day and in 1-year, 2-year and 3-year after immunizationin in the Zagreb and Essen regimen group were 100%, 95%, 85%, 80% and 98.25%, 89.47%, 89.47%, 85.96%, respectively. There was no statistically significant difference in the RVNA positive rates at the same time point between the two regimen groups ( P>0.05). The RVNA GMT on the 45th day and in 1-year, 2-year, and 3-year in the Zagreb and Essen regimen group were 11.32 IU/ml, 1.69 IU/ml, 1.30 IU/ml, 1.30 IU/m and 13.18 IU/ml, 2.13 IU/ml, 1.87 IU/ml, 1.84 IU/m, respectively. There was no significant difference in the RVNA GMT levels at the same time point between the two regimen groups ( F=1.971, P=0.164). The RVNA GMT levels in the two regimen groups had the same trend of attenuation over time (time*group F=0.702, P=0.435). Retrospective study: The RVNA positive rates in 1-year, 2-year and 3-year after immunization in the Zagreb and Essen regimen group were 100%, 95%, 91.43%和94.73%, 86.21%, 87.5%, respectively. There was no statistically significant difference in the RVNA positive rates at the same time point between the two regimen groups ( P>0.05). The RVNA GMT in 1-year, 2-year, and 3-year groups after immunization in the Zagreb and Essen regimen group were 2.65 IU/ml, 2.03 IU/ml, 1.57 IU/ml和3.2 IU/ml, 2.58 IU/ml, 2.45 IU/ml, respectively. There was no significant difference in the RVNA GMT levels at the same time point between the two regimen groups ( P>0.05). Conclusions:The PVRV showed the same excellent immunogenicity and immune persistence after the vaccination with the Zagreb and Essen regimens.

Objective To evaluate the indications and clinic outcomes of vaginal high uterosacral ligament suspension (HUS) for treatment of recurrent advanced pelvic organ prolapse (POP). Methods This retrospective study analyzed 42 women with recurrent advanced POP who were referred to Fourth Medical Center of PLA General Hospital and underwent transvaginal HUS between November 2005 and January 2018. Primary surgeries included 30 vaginal colporrhaphy, 5 Manchester operation, 5 transvaginal mesh repair,2 sacrospinous ligament fixation.The median time for recurrence from primary pelvic floor repair surgery was 9 months, including 14 cases (33%, 14/42)≤3 months (median time was 2 months) and 25 cases (67%, 28/42) longer than 3 months (median time was 18 months).The rate of recurrent prolapse in stageⅢorⅣ was 79% (33 cases), 45% (19 cases) and 17%(7 cases) in anterior, apical and posterior compartment respectively. Results Transvaginal high bilateral uterosacral ligaments were identified and used for successful vaginal vault suspension after vaginal hysterectomy and residual cervical resection in all 42 consecutive patients. The cases of transvaginal mesh used in anterior wall and posterior wall were 25 (60%, 25/42) and 3 (7%, 3/42) respectively. There was no major intra-and postoperative complications,such as ureter and other pelvic organ injury. The median time of follow-up was 5.3 years after transvaginal HUS. The points of pelvic organ prolapse quantification system reduced significantly and point C improved from+0.3 cm to-8.2 cm after reoperation (P<0.01). The objective cure rate were 100% (42/42) both in apex and posterior compartment,while 93% (39/42) in anterior compartment. None had reoperation or pessary usage for recurrence of prolapse. Conclusion Transvaginal HUS with vaginal wall repair could be as a safety, cost-effective, minimal traumatic and durable procedure for recurrent POP in the most of cases.

Objective To assess the five?year effect of the transvaginal high uterosacral ligament suspension (HUS) with or without additional concomitant native?tissue anterior and (or) posterior repair in women suffering from middle compartment defect. Methods A retrospective review of records identified 79 women who underwent transvaginal HUS with or without additional concomitant native?tissue anterior and (or) posterior repair from January 2007 to January 2018 in Fourth Medical Center, General Hospital of People′s Liberation Army. The middle compartment defects were predominant in these patients with point C no less than point Ba or Bp if accompanied with anterior or posterior vaginal wall prolapse. Follow?up visits were performed 2,6 and 12 months after surgery and then annually. Anatomic results of pelvic organ prolapse (POP) was established by pelvic examination using pelvic organ prolapse quantitation system (POP?Q) staging. Funtional results were obtained by patient global impression of improvement (PGI?I) scale in POP, pelvic floor distress inventory?short form 20 (PFDI?20) and pelvic floor impact questionnaire short form (PFIQ?7). Surgical success required the fulfillment of all 3 criteria: (1) anterior or posterior vaginal wall prolapsed leading edge of 0 cm or less and apex of 1/2 total vaginal length or less; (2) the absence of POP symptoms as reported on the PFDI?20 question No.3 ("Do you usually have a bulge or something falling out that you can see or feel in your vaginal area?"); and (3) no prolapse reoperations or pessary use during the study period. Results Of 79 women, 51(65%, 51/79) women completed the five?year follow?up during the study period. The median follow?up time was 5.2 years (2.8-8.3 years). The overall surgery success rate was 86% (44/51) according to above all 3 criteria. Prolapse recurrence rates were isolated anterior 8% (4/51), isolated apical 0, isolated posterior 2% (1/51) and multiple compartments 4% (2/51). Seven women (14%,7/51) developed anterior or posterior prolapse beyond the hymen with the leading edge≤1 cm. No apical prolapsed occurred. None of recurrent women underwent retreatment,including either surgery or pessary usage at last follow?up. The subjective satisfaction rate was 90% (46/51). There was a 1% (1/79) rate of intraoperative ureteral kinking and 3% (2/79) rate of postoperative morbidity. Conclusions The transvaginal HUS for middle compartment defect offers good long?term anatomical results with excellent vault suspension. With additional concomitant native?tissue anterior and (or) posterior repair, it will be a reconstructive surgery for the majority of moderate?to?severe POP. It is minimal traumatic and worthy of being popularized for clinical application.

OBJECTIVE： To explore potential mechanism of “Astragalus membranaceus-Draba nemorosa” couplet medicine for heart failure. METHODS： By network pharmacology， based on drug-like and oral bioavailability， the active components of “A. membranaceus-D. nemorosa” for chronic heart failure were screened and the targets of treating chronic heart failure were predicted by using TCMSP，GeneCards database， OMIM database and DRAR-CPI. The active component-chronic heart failure target network was established by Cytoscape 3.6.0 software. The protein-protein interaction network was constructed by utilizing STRING database. Then top 5 targets in the list of connectivity were screened and performed a molecular docking in molecular docking server. Finally， GO bioprocess analysis and KEGG pathway enrichment analysis were performed in DAVID database. RESULTS： The study predicted 28 active components in total， including 20 A. membranaceus and 12 D. nemorosa， such as kaempferol and quercetin， there were four components in common. Totally 92 target gene of active components were obtained， including heat shock protein 90α （HSP90AA1）， tyrosine protein kinase SRC gene， etc. Results of GO bioprocess analysis showed an association with mitochondrial electron transport， mitochondrial intima， cytoplasmic sol， extracellular body， mitochondrial matrix and drug response. KEGG pathway enrichment analysis showed a link with MAPK signal pathway， TGF signal pathway， PI3K signal pathway， cAMP signal pathway， protein kinase B signal pathway， EPK1 signal pathway and NF-κB signal pathway. CONCLUSIONS： “A. membranaceus-D. nemorosa” couplet medicine exerts therapeutic effects on heart failure from multiple targets as HSP90AA1， SRC and mitochondrial electron transport and MAPK signaling pathway. The study can provide reference for further researches on its material basis and mechanism.

Objective To analyze the clinical features and validation of Brighton criteria in Guillain-Barré syndrome (GBS) patients from southern China.Methods The clinical data of hospitalized GBS patients from 69 hospitals of 14 provinces/cities in southern China,the area south of the Huaihe River,between 1 January 2013 and 30 September 2016,were collected and analyzed retrospectively,and patients were classified according to the Brighton criteria of case definition,ranging from a highest (defined as level one) to a lowest (level four) level of diagnostic certainty.Results A total of 1 358 GBS patients were collected,including 51 cases with cranial nerve variants,157 with Miler-Fisher syndrome and 1 150 with classic GBS characterized by flaccid weakness of limbs.Among 1 150 cases of classic GBS,49.57％ (570/1 150) patients had antecedent events,with respiratory infection predominated (71.23％,406/570);83.74％ (963/1 150) presented limb weakness at onset,99.21％ (1 124/1 133) reached the peak within four weeks,with a score of 3.15 ± 1.16 for Hughes Disability Scale;99.56％ (1 128/1 133)developed bilateral weakness and 95.39％ (1 097/1 150) manifested flexia or hyporeflexia;the cerebrospinal fluid showed albuminocytologic dissociation in 80.58％ (772/958) patients whose lumbar puncture was performed;demyelinating GBS accounted for 48.14％ (401/833) and axonal subtype 18.01％ (150/833) respectively in patients with findings of nerve conduction studies available.According to Brighton criteria,the patients were stratified as level one in 44.09％ (507/1 150),level two in 45.74％ (526/1 150),level three in 7.57％ (87/1 150) and level four in 2.61％ (30/1 150) of all the patients,and 69.55％ (507/729),28.67％ (209/729),0％ (0/729) and 1.78％ (13/729),respectively in the patients with complete data (n =729).Conclusions In southern China,demyelinating subtype of GBS is predominant,whereas the proportion of axonal subtype is remarkably lower than that in northern China.The Brighton criteria have a high sensitivity for the diagnosis of GBS in southern China,and examination of cerebrospinal fluid and electrodiagnostic studies are necessary for stratified diagnosis.

Objective To explore the clinical management and outcomes of polypropylene mesh and sling exposure after reconstructive pelvic surgery(RPS). Methods A total of 110 cases of mesh and sling exposure after RPS were analyzed, who admitted between Jan. 2002 and Oct. 2017 in First Affiliated Hospital of PLA General Hospital, in which 3 cases were referred from other hospitals. Mesh and sling exposures were identified in the outpatient clinic and categorized and managed according to International Continence Society and International Urogynecology Association(ICS-IUGA)classification about category, time and site(CTS)of mesh complication. Outpatient management included observation, topical estrogen use and mesh removal. Management in hospital included surgical removal of exposed mesh and repair of the resulting defects under the anesthesia. Seventy-four cases were managed in the outpatient setting, and 36 cases required inpatient management. Follow-up was consecutively performed from 1 month to 10 years. Objective outcome included the surgeon′s assessment of the healing state of the vaginal mucosa. Subjective outcome was evaluated with patient global impression of improvement questionnaire(PGI-I). Results One hundred and ten patients with mesh exposure were classified according to the different RPS underwent. There were 95 cases from transvaginal mesh surgery, 5 cases from anti-stress urinary incontinence sling surgery, and 10 cases from sacrocolpopxy. The outpatient group healed at an average of(3.0 ± 1.8)months. Of the 36 patients who required inpatient management, 21 cases healed completely at an average of 7 days after one surgery. The remaining 8 cases required either two or three times surgeries or conservative management. In the outpatient group, the PGI-I scale very much better was found in 65 cases(87.8％)and much better in 9 cases(12.2％). In the inpatient surgery group, the scale was very much better in 30 cases (83.3％), and much better in 6 cases(16.7％). Conclusions Among patients with mesh exposure after mesh-augmented RPS, 2/3 of patients with a CTS classification 1-3 could be managed in the office,and remaining 1/3 with CTS classification 4-6 need operation under anesthesia in hospital. If the mesh and sling exposure could be scientifically classified, according to the size, site and accompany symptoms, as well as pain, most of the mesh complications after explosure could be resolved. Using the pelvic floor repair and polypropylene mesh sling, the majority of the patients could get a better outcome, without affecting the effect of the original operation.

Epithelial-mesenchymal transition (EMT) is a process by which epithelial cells lose their own features and become mesenchymal cells, and more and more studies have shown that EMT plays an important role in the invasion and metastasis of hepatocellular carcinoma (HCC). This article reviews the signaling pathways involved in the progression of HCC and molecules involved in the regulation of EMT, in order to provide a new direction for the treatment of HCC.

Objective To assess the long-term effectiveness of the transvaginal high uterosacral ligament suspension (HUS) in women suffering from advanced pelvic organ prolapse (POP).Methods A retrospective review of records identified 118 women who underwent transvaginal HUS with or without additional concomitant anterior and (or) posterior repairs from June 2003 to August 2009 in the First Affiliated Hospital,General Hospital of People's Liberation Army.Of 118 women,104 women completed the follow-up during study period;these 104 women were analysed.Follow-up visits were performed 2,6 and 12 months after surgery and then annually.Anatomic results of POP was established by pelvic examination using pelvic organ prolapse quantitation system (POP-Q) staging.Funtional results were obtained by patient global impression of improvement (PGI-I),pelvic floor distress inventory-short form 20 (PFDI-20) and pelvic floor impact questionnaire short form (PFIQ-7).Surgical success required the fulfillment of all 3 criteria:(1) prolapse leading edge of 0 cm or less and apex of 1/2 total vaginal length or less;(2) the absence of pelvic organ prolapse symptoms as reported on the PFDI-20 question No.3 (Do you usually have a bulge or something falling out that you can see or feel in your vaginal area?);and (3) no prolapse reoperations or pessary use during the study period.Results The mean follow-up time was (9.1 ± 1.5) years.The overall surgery success rate was 91.3％ (95/104) according to above all 3 criteria.Prolapse recurrence rates were isolated anterior 6.7％ (7/104),isolated apical 0,isolated posterior 2.9％ (3/104) and multiple compartments 1.0％ (1/104).Five women (4.8％,5/104) developed bothersome vaginal bulge symptoms.None of recurrent women underwent retreatment,including either surgery or use of a pessary at last follow-up.The subjective satisfaction rate was 90.4％ (94/104).PFDI-20 and PFIQ-7 scores showed a statistically significant improvement from preoperative 72 and 65 points to postoperative 17 and 9 points respectively (all P＜0.01).There was a 2.9％ (3/104) rate of intraoperative ureteral kinking and 3.8％ (4/104) rate of postoperative morbidity.Conclusions The transvaginal HUS for vault prolapse offers good long-term anatomical results with excellent vault suspension.With additional concomitant anterior and (or) posterior repairs,it will be a reconstructive surgery for the majority of advanced POP.It is minimal traumatic and appropriate for different type of POP,especially for the eldly patients.It is worthy of being popularized for clinical application.