ObjectiveTo investigate the effects of modified Buyang Huanwu Tang on cerebral ischemia-reperfusion injury （CI/RI） in mice via the PTEN-induced putative kinase 1/E3 ubiquitin ligase （PINK1/Parkin） signaling pathway-mediated mitophagy， and to explore the underlying mechanism by which modified Buyang Huanwu Tang improves CI/RI. MethodsSeventy-two male C57BL/6J mice were randomly divided into six groups （n = 12 per group）： Sham-operated group， middle cerebral artery occlusion/reperfusion （MCAO/R） model group， low-， medium-， and high-dose modified Buyang Huanwu Tang groups （8.84， 17.68， 35.36 g·kg^-1·d^-1）， and an aspirin group （13.00 mg·kg^-1·d^-1）. Neurological deficit scores were assessed using the Zea-Longa method. Cerebral infarct volume ratio was measured by 2，3，5-triphenyltetrazolium chloride （TTC） staining. Histopathological changes and neuronal injury in brain tissues were observed using hematoxylin-eosin （HE） staining and Nissl staining. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling （TUNEL） assay. Mitochondrial ultrastructure in brain tissue was observed by transmission electron microscopy （TEM）. Serum levels of superoxide dismutase （SOD） and malondialdehyde （MDA） were determined by enzyme-linked immunosorbent assay （ELISA）. The mRNA and protein expression levels of PINK1， Parkin， microtubule-associated protein 1 light chain 3B （LC3B， LC3Ⅱ/Ⅰ）， and p62 in brain tissues were detected by real-time quantitative reverse transcription PCR （Real-time PCR） and Western blot， respectively. ResultsCompared with the sham-operated group， the MCAO/R model group showed significantly increased neurological deficit scores and cerebral infarct volume ratios （P<0.01）. Severe cortical injury on the infarct side was observed， characterized by decreased neuronal density， cytoplasmic vacuolation， nuclear pyknosis， a marked reduction in Nissl bodies， dissolution of Nissl bodies in the cytoplasm of some pyramidal neurons， and blurred cellular boundaries. The number of TUNEL-positive cells increased significantly （P<0.01）. Mitochondria exhibited cristae membrane rupture and matrix vacuolation， with rupture of the outer mitochondrial membrane and formation of autophagosomes， the number of which increased significantly. Serum SOD activity decreased significantly （P<0.01）， while MDA content increased significantly （P<0.01）. In infarcted brain tissues of model mice， the relative mRNA expression and protein levels of PINK1， Parkin and LC3B were significantly increased （P<0.05， P<0.01）， whereas p62 mRNA and protein expression were significantly decreased （P<0.05， P<0.01）， showing statistical significance. Compared with the model group， all treatment groups showed significantly decreased neurological deficit scores and cerebral infarct volume ratios （P<0.01）. Neuronal density increased significantly， cytoplasmic vacuolation was alleviated， nuclear morphology tended to be more regular and clearer， Nissl body density increased significantly with reduced dissolution and improved contour clarity. The mitochondrial cristae structure was partially restored， with some mitochondria showing autophagosome encapsulation， and the degree of mitochondrial damage was alleviated. Serum SOD activity increased significantly （P<0.01）， while MDA content decreased significantly. The mRNA and protein expression levels of PINK1， Parkin， and LC3Ⅱ/Ⅰ were significantly increased （P<0.05， P<0.01）， while p62 mRNA and protein expression in the low- and medium-dose modified Buyang Huanwu Tang groups were significantly decreased （P<0.05， P<0.01）， showing statistical significance. ConclusionModified Buyang Huanwu Tang can upregulate the protein expression levels of PINK1， Parkin， and LC3Ⅱ/Ⅰ and downregulate p62 protein expression， suggesting that it may improve CI/RI by regulating the expression of proteins related to the PINK1/Parkin signaling pathway. Regulation of the mitophagy pathway may be one of the mechanisms by which modified Buyang Huanwu Tang alleviates CI/RI in mice.

OBJECTIVE To study the neural circuits involved in regulating the strong drug-taking motivation in susceptible mice,and provide novel insights into the intervention and treatment of drug addiction.METHODS A heroin intermittent-access(Int A)self-administration model was established.Mice were divided into susceptible,unsusceptible,and non-learnt subgroups based on parameters,such as the number of times of drug infusions,effective lever presses,and breakpoints(BP)in the progres-sive ratio schedule during the drug acquisition phase.Using chemogenetic techniques,the neural projection from the orbitofrontal cortex(OFC)to the dorsomedial striatum(DMS)was selectively manipulated in the progressive ratio schedule,and its impact on drug motivation was assessed across the three subgroups.RESUITS Selectively inhibiting the OFC-DMS circuit significantly reduced the BP in susceptible mice,with no significant effect on the other two subgroups.Conversely,selective activation of this pathway significantly increased BP in susceptible mice,but had no impact on the other subgroups.CONCLU-SION The OFC-DMS circuit specifically modulates drug motivation behavior in susceptible mice,but not in the unsusceptible,and non-learnt subgroups.

OBJECTIVE To study the neural circuits involved in regulating the strong drug-taking motivation in susceptible mice,and provide novel insights into the intervention and treatment of drug addiction.METHODS A heroin intermittent-access(Int A)self-administration model was established.Mice were divided into susceptible,unsusceptible,and non-learnt subgroups based on parameters,such as the number of times of drug infusions,effective lever presses,and breakpoints(BP)in the progres-sive ratio schedule during the drug acquisition phase.Using chemogenetic techniques,the neural projection from the orbitofrontal cortex(OFC)to the dorsomedial striatum(DMS)was selectively manipulated in the progressive ratio schedule,and its impact on drug motivation was assessed across the three subgroups.RESUITS Selectively inhibiting the OFC-DMS circuit significantly reduced the BP in susceptible mice,with no significant effect on the other two subgroups.Conversely,selective activation of this pathway significantly increased BP in susceptible mice,but had no impact on the other subgroups.CONCLU-SION The OFC-DMS circuit specifically modulates drug motivation behavior in susceptible mice,but not in the unsusceptible,and non-learnt subgroups.

OBJECTIVE: To explore the diagnostic value of ¹⁸F-FDG PET/CT in bone marrow infiltration (BMI) of newly diagnosed diffuse large B-cell lymphoma (DLBCL), compared with the results of bone marrow biopsy (BMB) and investigate whether the BMI diagnosed by ¹⁸F-FDG PET/CT and other factors have independent prognostic values. METHODS: Ninety-four newly diagnosed DLBCL patients who underwent PET/CT in Clinical Medical College of Shanghai General Hospital of Nanjing Medical University were included. BMB was performed within 2 weeks before or after PET/CT, and standardized treatment was performed after PET/CT. The manifestations of bone marrow (BM) FDG uptake were recorded. The diagnostic criteria of BMI were BMB positive or focal BM FDG uptake confirmed by imaging follow-up. The relationship between clinical features and BM FDG uptake and the values of PET/CT and BMB in the diagnosis of BMI was analyzed. The progression-free survival (PFS) was analyzed by Kaplan-Meier survival curves, log-rank test was used to compare PFS rate, and Cox regression model was used to analyze the independent risk factors affecting PFS. RESULTS: Among 94 DLBCL patients, 34 patients showed focal BM uptake (fPET), 7 patients showed super BM uptake (sBMU), 11 patients showed diffuse homogenous uptake higher than liver (dPET), and the other 42 patients had normal BM uptake (nPET) (lower than liver). BMB positive was found in all sBMU patients, in 20.6%(7/34) of fPET patients, and in 27.3% (3/11) of dPET patients. All nPET patients had negative BMB results. dPET patients were associated with lower hemoglobin level and leukocyte count compared with nPET group (P < 0.001, P =0.026). Compared with fPET patients, sBMU patients were more likely to have B symptoms and elevated lactate dehydrogenase (LDH). A total of 44 patients were diagnosed BMI, including 17 cases with BMB⁺. The sensitivity and specificity of BMB in the diagnosis of BMI was 38.6% (17/44) and 100% (50/50), respectively. Using fPET and sBMU as criteria of PET BMI, the diagnostic sensitivity and specificity of PET/CT was 93.2% (41/44) and 100% (50/50), respectively. Kaplan-Meier analysis showed that there was no significant difference in 2-year PFS rate between nPET and dPET patients (P >0.05), while sBMU patients had lower 2-year PFS rate compared with fPET patients (P < 0.001). Multivariate analysis showed that higher Ann Arbor stage (HR=9.010, P =0.04) and sBMU (HR=3.964, P =0.002) were independent risk factors affecting PFS. CONCLUSIONS Increased BM FDG uptake of DLBCL can be manifested as dPET, fPET and sBMU. fPET and sBMU can replace BMB to diagnose BMI. Although dPET cannot completely exclude the possibility of BMI, it does not affect the prognosis, so it can be diagnosed as PET BMI negative. sBMU is an independent prognostic risk factor.
Humans ; Positron Emission Tomography Computed Tomography/methods* ; Fluorodeoxyglucose F18 ; Prognosis ; Bone Marrow/pathology* ; Retrospective Studies ; China ; Positron-Emission Tomography/methods* ; Lymphoma, Large B-Cell, Diffuse/pathology* ; Biopsy

Objective: To evaluate the effect of Li's catheter in cardiac resynchronization therapy (CRT) implantation. Methods: This study was a retrospective cohort study. Patients with indications for CRT implantation who visited the Department of Cardiology, Peking University People's Hospital from January 1, 2016 to January 1, 2022 were enrolled. Patients were divided into Li's catheter group (CRT implantation with Li's catheter) and control group (CRT implantation with the traditional method). The general clinical data of the patients were obtained through the electronic medical record system. Li's catheter is a new type of coronary sinus angiography balloon catheter independently developed by Dr. Li Xuebin (patent number: 201320413174.1). The primary outcome was the success rate of CRT device implantation, and the secondary outcomes included efficacy and safety parameters. Efficacy indicators included operation time, coronary sinus angiography time, left ventricular lead implantation time, X-ray exposure time, left ventricular lead threshold, and diaphragm stimulation. Safety outcomes included incidence of coronary sinus dissection, cardiac tamponade, and pericardial effusion. Results: A total of 170 patients were enrolled in this study, including 90 in Li's catheter group and 80 in control group. Age, male proportion of patients, proportion of patients with ischemic cardiomyopathy, hypertension, diabetes mellitus, chronic renal insufficiency, New York Heart Association (NYHA) functional classification, left ventricular ejection fraction, left ventricular end-diastolic diameter, proportion of left bundle branch block, and preoperative QRS wave width were similar between the two groups (all P>0.05). In Li's catheter group, 34 cases (37.8%) implanted with CRT defibrillators, and 28 cases (35.0%) implanted with CRT defibrillators in control group, the difference was not statistically significant (P=0.710). The success rate of CRT device implantation in Li's catheter group was 100% (90/90), which was significantly higher than that in control group (93.8%, 75/80, P=0.023).The operation time was 57.0 (52.0, 62.3) minutes, the time to complete coronary sinus angiography was 8.0 (6.0, 9.0) minutes, and the time of left ventricular electrode implantation was 8.0 (7.0, 9.0) minutes in Li's catheter group, and was 91.3 (86.3, 97.0), 18.0 (16.0, 20.0), 25.0 (22.0, 27.7) minutes respectively in control group, all significantly shorter in Li's catheter group (all P<0.05). The exposure time of X-ray was 15.0 (14.0, 17.0) minutes in Li's catheter group, which was also significantly shorter than that in control group (32.5 (29.0, 36.0) minutes, P<0.001). There was no coronary sinus dissection and cardiac tamponade in Li's catheter group, and 1 patient (1.1%) had diaphragmatic stimulation in Li's catheter group. In control group, 6 patients (6.7%) had coronary sinus dissection, and 1 patient (1.1%) developed pericardial effusion, and 3 patients (3.3%) had diaphragmatic stimulation. The incidence of coronary sinus dissection in Li's catheter group was significantly lower than that in control group (P=0.011). The postoperative left ventricular thresholds in Li's catheter group and control group were similar (1.80 (1.60, 2.38) V/0.5 ms vs. 1.80 (1.60, 2.40) V/0.5 ms, P=0.120). Conclusions: Use of Li's catheter is associated with higher success rate of CRT implantation, short time of coronary sinus angiography and left ventricular electrode implantation, reduction of intraoperative X-ray exposure, and lower incidence of coronary vein dissection in this patient cohort.
Cardiac Resynchronization Therapy/methods* ; Cardiac Tamponade/therapy* ; Catheters ; Heart Failure/therapy* ; Humans ; Male ; Pericardial Effusion ; Retrospective Studies ; Stroke Volume ; Treatment Outcome ; Ventricular Function, Left

Objective: For patients with paroxysmal atrial fibrillation, superior vena cava isolation on the basis of pulmonary vein isolation may further improve the long-term success rate of radiofrequency ablation. We aimed to explore the efficacy and safety of superior vena cava isolation by high-power and short-duration (HPSD) ablation plus conventional radiofrequency ablation (RA) in patients with paroxysmal atrial fibrillation. Methods: It was a prospective randomized controlled study. From January 1, 2019 to June 1, 2020, 180 patients who underwent radiofrequency ablation for paroxysmal atrial fibrillation in our center were consecutively screened. Patients were eligible if there was a trigger potential and the muscle sleeve length was greater than 3 cm. A total of 60 eligible patients were finally included and randomly divided into HPSD group (HPSD plus RA) and common power and duration (CPD) group (CPD plus RA) by random number table method (n=30 in each group). Efficacy was evaluated by ablation points, isolation time and ablation time. Safety was evaluated by the incidence of POP, cardiac tamponade, phrenic nerve injury, sinoatrial node injury and all-cause. Results: Superior vena cava isolation was achieved by 14 (13, 15) points in the HPSD group, which was significantly less than that in the CPD group (20(18, 22), P<0.001). The superior vena cava isolation time was 8 (7, 9) minutes in the HPSD group, which was significantly shorter than in the CPD group (17(14, 20) minutes, P<0.001). The average ablation time significantly shorter in HPSD group than in CPD group (78.0(71.1, 80.0) s vs. 200(167.5, 212.5)s, P<0.001). The average impedance drop was more significant in the HPSD group than in the CPD group (20.00(18.75, 21.00)Ω (and the percentage of impedance drop was 15%) vs. 12.00(11.75, 13.25)Ω (the percentage of impedance decrease was 12%), P<0.001). There was 1 POP (3.3%) in the HPSD group, and 3 POPs (10.0%) in the CPD group (P>0.05). There was no cardiac tamponade, phrenic nerve injury, sinoatrial node injury and death in both groups. Conclusions: HPSD technique for the isolation of superior vena cava is safe and effective in patients with paroxysmal atrial fibrillation undergoing conventional radiofrequency ablation.
Humans ; Atrial Fibrillation/surgery* ; Vena Cava, Superior/surgery* ; Prospective Studies ; Treatment Outcome ; Radiofrequency Ablation

Objective: To analyze the feasibility and safety of bridge therapy with active fixed electrodes connected to external permanent pacemakers (AFLEP) for patients with infective endocarditis after lead removal and before permanent pacemaker implantation. Methods: A total of 44 pacemaker-dependent patients, who underwent lead removal due to infective endocarditis in our center from January 2015 to January 2020, were included. According to AFLEP or temporary pacemaker option during the transition period, patients were divided into AFLEP group or temporary pacemaker group. Information including age, sex, comorbidities, indications and types of cardial implantable electionic device (CIED) implantation, lead age, duration of temporary pacemaker or AFLEP use, and perioperative complications were collected through Haitai Medical Record System. The incidence of pacemaker perception, abnormal pacing function, lead perforation, lead dislocation, lead vegetation, cardiac tamponade, pulmonary embolism, death and newly infection of implanted pacemaker were compared between the two groups. Pneumothorax, hematoma and the incidence of deep vein thrombosis were also analyzed. Results: Among the 44 patients, 24 were in the AFLEP group and 20 in the temporary pacemaker group. Age was younger in the AFLEP group than in the temporary pacemaker group (57.5(45.5, 66.0) years vs. 67.0(57.3, 71.8) years, P=0.023). Male, prevalence of hypertension, diabetes mellitus, chronic renal dysfunction and old myocardial infarction were similar between the two groups (all P>0.05). Lead duration was 11.0(8.0,13.0) years in the AFLEP group and 8.5(7.0,13.0) years in the temporary pacemaker group(P=0.292). Lead vegetation diameter was (8.2±2.4)mm in the AFLEP group and (9.1±3.0)mm in the temporary pacemaker group. Lead removal was successful in all patients. The follow-up time in the AFLEP group was 23.0(20.5, 25.5) months, and the temporary pacemaker group was 17.0(14.5, 18.5) months. In the temporary pacemaker group, there were 2 cases (10.0%) of lead dislocation, 2 cases (10.0%) of sensory dysfunction, 2 cases (10.0%) of pacing dysfunction, and 2 cases (10.0%) of death. In the AFLEP group, there were 2 cases of abnormal pacing function, which improved after adjusting the output voltage of the pacemaker, there was no lead dislocation, abnormal perception and death. Femoral vein access was used in 8 patients (40.0%) in the temporary pacemaker group, and 4 patients developed lower extremity deep venous thrombosis. There was no deep venous thrombosis in the AFLEP group. The transition treatment time was significantly longer in the AFLEP group than in the temporary pacemaker group (19.5(16.0, 25.8) days vs. 14.0(12.0, 16.8) days, P=0.001). During the follow-up period, there were no reinfections with newly implanted pacemakers in the AFLEP group, and reinfection occurred in 2 patients (10.0%) in the temporary pacemaker group. Conclusions: Bridge therapy with AFLEP for patients with infective endocarditis after lead removal and before permanent pacemaker implantation is feasible and safe. Compared with temporary pacemaker, AFLEP is safer in the implantation process and more stable with lower lead dislocation rate, less sensory and pacing dysfunction.
Humans ; Male ; Bridge Therapy ; Feasibility Studies ; Pacemaker, Artificial ; Endocarditis, Bacterial/etiology* ; Electrodes ; Device Removal

BACKGROUND: Generic drugs are bioequivalent to their brand-name counterparts; however, concerns still exist regarding the effectiveness and safety of generic drugs because of small sample sizes and short follow-up time in most studies. The purpose of this study was to evaluate the long-term antihypertensive efficacy, cost-effectiveness and cardiovascular outcomes of generic drugs compared with brand-name drugs. METHODS: In a multicenter, community-based study including 7955 hypertensive patients who were prospectively followed up for an average of 2.5 years, we used the propensity-score-matching method to match the patients using brand-name drugs to those using generic drugs in a ratio of 1:2, 2176 patients using brand-name drugs and 4352 patients using generic drugs. RESULTS: There were no significant differences between generic drugs and brand-name drugs in blood pressure (BP)-lowering efficacy, BP control rate, and cardiovascular outcomes including coronary heart disease and stroke. The adjusted mean (95% confidence interval [CI]) of systolic BP (SBP)-lowering was -7.9 mmHg (95% CI, -9.9 to -5.9) in the brand-name drug group and -7.1 mmHg (95% CI, -9.1 to -5.1) in the generic drug group after adjusting for age, sex, body mass index, number of antihypertensive drugs and traditionally cardiovascular risk factors. Among patients aged <60 years, brand-name drugs had a higher BP control rate (47% vs. 41%; P = 0.02) and a greater effect in lowering SBP compared with generic drugs, with the between-group difference of 1.5 mmHg (95% CI, 0.2-2.8; P = 0.03). BP control rate was higher in male patients using brand-name drugs compared with those using generic drugs (46% vs. 40%; P = 0.01). Generic drugs treatment yielded an average annual incremental cost-effectiveness ratio of $315.4 per patient per mmHg decrease in SBP compared with brand-name drugs treatment. CONCLUSIONS Our data suggested that generic drugs are suitable and cost-effective in improving hypertension management and facilitating public health benefits, especially in low- and middle-income areas.
Aged ; Antihypertensive Agents/therapeutic use* ; Blood Pressure ; China ; Drugs, Generic/therapeutic use* ; Humans ; Male ; Prospective Studies

OBJECTIVE: To evaluate the efficacy of autologous peripheral blood hematopoietic stem cell transplantation (auto-PBHSCT) on patients with multiple myeloma( MM) after Sequential different chemotherapy. METHODS: Seven cases of patients with MM were included in the A group, and 14 cases of patients received 4-6 courses of chemotherapy with VAD and MP before transplantation were included in the B group and received 4-6 courses of chemotherapy with VTD and VD before transplantation. Auto-peripheral blood hematopoietic stem cell were mobilized by G-CSF. Condition regimen were melphalan(A group) or bortezomib combined melphalan(B group). IFN-α(A group) or Thalidomide(B group) was used as maintenance treatment after auto-PBHSCT. RESULTS: Two cases of patients reached to complete remission (CR)(2/7,28.6%),1 case got very good partial remission (VGPR) (1/7,14.3%), 4 cases got partial remission(PR) (4/7,57.1%) in A group, and 9 cases got CR (9/14,64.3%), 3 cases got VGPR(3/14,21.4%), and 2 cases got PR(2/14,14.3%) in the B group before auto-PBHSCT. The CR and VGPR were significant difference between 2 groups (P<0.05). All the patients got hematopoietic recovery. In 2 groups, the median time of ANC recovery≥0.5×10/L was 13 (11-16) and 14（11-18）days, that of WBC recovery ≥4.0×10/L were 16(15-19) and 18(16-20)days, Plt recovery ≥ 50 ×10/L was 21 (18-25) and 21(17-25) days. Bone marrow showed CR in 21 to 28 days after transplantation. All of 7 cases of patients remised in 6 to 47 months after transplantation, and 4 cases died lastly and 3 cases failed to be followed up in A group. The median time of progression-free survival(PFS) was 36(6-47) months, and that of overall survival(OS) was 37(7-50) months. In B group, 2 cases of patients remissed in 5 and 17 months after transplantation, and did lastly, 1 case relieved in 12 months after transplantation and failed to be followed up. 1 case of patient relived in 46 months after transplantation, and then received the second auto-PBHSCT, and got CR for 105 months. Other 10 cases got CR, their median time of PFS was 45.5(4-105) months, the median time of overall survival(OS) was 45.5(4-105) months. The PFS and OS were very significant different between 2 groups (P<0.01). CONCLUSION Bortezomib-based chemotherapy, Auto-PBHSCT and maintenance treatment with thalidomide were favorable to the patients of MM for survival prolongation.
Antineoplastic Combined Chemotherapy Protocols ; Disease-Free Survival ; Hematopoietic Stem Cell Transplantation ; Humans ; Multiple Myeloma ; therapy ; Peripheral Blood Stem Cell Transplantation ; Transplantation, Autologous ; Treatment Outcome