Mechanism studies underlying the alleviatory effects of isoliquiritigenin on abnormal glucolipid metabolism triggered by type 2 diabetes / 药学学报

Isoliquiritigenin (ISL) is an active chalcone compound isolated from licorice. It possesses anti-inflammatory and anti-oxidative activities. In our previous study, we uncovered a great potential of ISL in treatment of type 2 diabetes mellitus (T2DM). Therefore, this study aims to reveal the mechanism underlying the alleviatory effects of ISL on T2DM-induced glycolipid metabolism disorder. High-fat-high-sugar diet (HFD) combined with intraperitoneal injection of streptozotocin (STZ) were used to establish T2DM mice model. All animal experiments were carried out with approval of the Committee of Ethics at Beijing University of Chinese Medicine. HepG2 cells were used in in vitro experiments, and sodium palmitate (SP) was applied to establish insulin resistance (IR) model cells. The effects of ISL on body weight, fasting blood glucose levels, and pathological changes in the livers of mice were examined. Enzyme-linked immune sorbent assay (ELISA) and real-time quantitative PCR (RT-qPCR) were applied to detect the regulatory effects of ISL on key targets involved in glucolipid metabolism. Additionally, molecular docking and analytical dynamics simulation methods were used to analyze the interaction between ISL and key target protein. The results indicate that ISL significantly downregulates the transcriptional levels and inhibits the activities of key enzymes involved in gluconeogenesis, including pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK), and fructose-1, 6-bisphosphatase (FBP). It also downregulates the transcriptional and protein levels of hepatocyte nuclear factor 4α (HNF4α) and cAMP response element binding protein (CREB), the two transcriptional factors involved in gluconeogenesis. Thus, ISL inhibits hepatic gluconeogenesis in T2DM mice. In addition, ISL reduces total cholesterol (TC) and triglyceride (TG) levels in the livers of T2DM mice. Moreover, ISL downregulates the mRNA levels of lipogenesis genes and upregulates those of genes involved in fatty acid oxidation, lipid uptake, and lipid export. In conclusion, ISL suppresses hepatic gluconeogenesis, promotes lipolysis, and restrains lipogenesis in T2DM mice, thereby improving the abnormal glycolipid metabolism caused by T2DM.

Myricetin attenuates renal fibrosis by activating Nrf2/HO-1 pathway to inhibit oxidative stress / 药学学报

This paper investigates the effect of myricetin (MYR) on renal fibrosis induced by unilateral ureteral obstruction (UUO) and common bile duct ligation (CBDL) in mice and its mechanism. The animal experiment has been approved by the Ethics Committee of China Pharmaceutical University (NO: 2022-10-020). Thirty-five ICR mice were divided into control, UUO, UUO+MYR, CBDL and CBDL+MYR groups. H&E and Masson staining were used to detect pathological changes in kidney tissues. Western blot (WB) was used to detect the expression of fibrosis-related proteins in renal tissue, and total superoxide dismutase (SOD) activity detection kit (WST-8) was used to detect the changes of total SOD in renal tissue of CBDL mice. In vitro, HK-2 cells and transforming growth factor beta 1 (TGF-β1, 10 ng·mL-1) were used to induce fibrotic model, and high glucose (30 mmol·L-1) was used to induce oxidative stress model, and then treated with different concentrations of MYR, WB was used to detect the expression of fibrosis and oxidative stress-related proteins, while NIH/3T3 cells were treated with different concentrations of MYR, and their effects on cell proliferation were detected by 5-bromo-2′-deoxyuridine (Brdu). The results showed that the renal lesions in UUO group and CBDL group were severe, collagen deposition was obvious, the expression of collagen-Ⅰ (COL-Ⅰ), α-smooth muscle actin (α-SMA), fibronectin (FN), vimentin and plasminogen activator inhibitor-1 (PAI-1) protein was up-regulated, and the activity of SOD enzyme in CBDL group was significantly decreased. MYR partly reversed the above changes after treatment. MYR inhibited the proliferation of NIH/3T3 cells but had no effect on the proliferation of HK-2 cells, and decreased the upregulation of PAI-1, FN and vimentin in HK-2 cells stimulated by TGF-β1. MYR can also up-regulate the down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in HK-2 cells stimulated by high glucose. To sum up, MYR can improve renal fibrosis in vivo and in vitro, probably by inhibiting the proliferation of fibroblasts and activating Nrf2/HO-1 signal pathway to inhibit oxidative stress.

Mechanism of action of traditional Chinese medicine in treatment of nonalcoholic fatty liver disease based on intestinal microecology / 临床肝胆病杂志

Nonalcoholic fatty liver disease （NAFLD） is a multisystem disease associated with obesity， insulin resistance， and dyslipidemia and has a complex pathogenesis. Studies have shown that gut microbiota dysbiosis is closely associated with the onset of NAFLD， and traditional Chinese medicine treatment can improve the laboratory markers and clinical symptoms of NAFLD patients by regulating intestinal microbiota and its metabolites. This article elaborates on the association between NAFLD and gut microbiota， the involvement of gut microbiota dysbiosis in the pathogenesis of NAFLD， and the possible mechanism of traditional Chinese medicine treatment in improving NAFLD from the perspective of gut microbiota， in order to provide new ideas for the treatment of NAFLD.

Basic psychological needs satisfaction and smartphone addiction among high school students： the mediating role of loneliness and social anxiety / 四川精神卫生

ObjectiveTo investigate the mediating role of loneliness and social anxiety in the relationship between basic psychological needs satisfaction and smartphone addiction among high school students， and to provide references for the intervention to smartphone addiction for high school students. MethodsIn April 2022， a total of 14 666 high school students from 5 middle schools in a county of Sichuan Province were included by random sampling method. Basic Psychological Needs Scales （BPNS）， the UCLA Loneliness Scale-3 edition （UCLA-3）， Interaction Anxiousness Scale （IAS） and the Mobile Phone Addiction Index （MPAI） were used for cross-sectional investigation. Bootstrap method was used to analyze the mediating role of loneliness and social anxiety in the relationship between the basic psychological needs satisfaction and smartphone addiction. Results① In this study， 14 036 valid questionnaires were returned， and 1 752 （12.48%， 95% CI： 0.114~0.136） high school students were found to be addicted to smartphone phone. The BPNS score was negatively correlated with UCLA-3， IAS and MPAI scores （r=-0.771， -0.486， -0.417， P<0.01）. And MPAI score was positively correlated with IAS and UCLA-3 scores （r=0.403， 0.424， P<0.01）. IAS score was positively correlated with UCLA-3 score （r=0.458， P<0.01）. ②The degree of basic psychological needs satisfaction in high school students can directly negatively predict smartphone addiction （β=-0.383， P<0.05）， and can also indirectly affect smartphone addiction through loneliness and social anxiety （β=-0.130， P<0.05）. ③Loneliness （indirect effect value was -0.145） and social anxiety （indirect effect value was -0.074） partially mediate between the basic psychological needs satisfaction and smartphone addiction. Loneliness-social anxiety also has significant chain mediating effect （indirect effect value was -0.034）， which accounted for 8.88%. ConclusionThe basic psychological needs satisfaction can not only directly affect the occurrence of smartphone addiction， but also indirectly affect the occurrence of smartphone addiction through the chain mediation of loneliness and social anxiety.

Visual analysis of adolescent psychological resilience studies based on the CNKI database / 四川精神卫生

ObjectiveTo sort out and analyze the research progress of adolescent psychological resilience， and to grasp the research hotspots and frontiers in this field. MethodsCiteSpace was used to make a visual analysis of the number of publications， authors and institution， and co-occurrence， clustering and burst terms of keywords in literatures related to adolescent psychological resilience collected in CNKI database from January 1， 2012 to December 31， 2021. Results① For almost a decade， the research on adolescent psychological resilience was divided into a slow growth stage （2012-2018） and a rapid growth stage （2018-2021）. ② The cooperation between authors were relatively close， and most of them were small and medium-sized cooperative organizations. There was less cooperation in scientific research institutions and most of them were normal universities. ③ In terms of co-occurrence analysis， hot keywords could be roughly divided into three categories： mental health status， influencing factors， and prevention and intervention research. ④ The related high-frequency keywords generate ten clusters， including academic emotions， learning burnout， adolescents， migrant children， mental health， internalized problems， social support， coping style， self-esteem and happiness. ⑤ The keywords with high burst intensity were coping style， mental health， mediation， regression analysis， social work， mental health and anxiety. ConclusionIn the future， cooperation between research institutions can be strengthened to improve the quality of the research on psychological resilience of adolescents. In addition， intervention research related to psychological resilience may become a hotspot in this field in the future.

Effects of in vivo targeted carboxylesterase 1f gene knockdown on the Kupffer cells polarization activity in mice with acute liver failure / 中华肝脏病杂志

Objective: To investigate the effect of targeted carboxylesterase 1f (Ces1f) gene knockdown on the polarization activity of Kupffer cells (KC) induced by lipopolysaccharide/D-galactosamine (LPS/D-GalN) in mice with acute liver failure. Methods: The complex siRNA-EndoPorter formed by combining the small RNA (siRNA) carrying the Ces1f-targeting interference sequence and the polypeptide transport carrier (Endoporter) was wrapped in β-1, 3-D glucan shell to form complex particles (GeRPs). Thirty male C57BL/6 mice were randomly divided into a normal control group, a model group (LPS/D-GalN), a pretreatment group (GeRPs), a pretreatment model group (GeRPs+LPS/D-GalN), and an empty vector group (EndoPorter). Real-time fluorescent quantitative PCR and western blot were used to detect Ces1f mRNA and protein expression levels in the liver tissues of each mouse group. Real-time PCR was used to detect the expression levels of KC M1 polarization phenotypic differentiation cluster 86(CD86) mRNA and KC M2 polarization phenotypic differentiation cluster 163 (CD163) mRNA in each group. Immunofluorescence double staining technique was used to detect the expression of Ces1f protein and M1/M2 polarization phenotype CD86/CD163 protein in KC. Hematoxylin-eosin staining was used to observe the pathological damage to liver tissue. A one-way analysis of variance was used to compare the means among multiple groups, or an independent sample nonparametric rank sum test was used when the variances were uneven. Results: The relative expression levels of Ces1f mRNA/protein in liver tissue of the normal control group, model group, pretreatment group, and pretreatment model group were 1.00 ± 0.00, 0.80 ± 0.03/0.80 ± 0.14, 0.56 ± 0.08/0.52 ± 0.13, and 0.26 ± 0.05/0.29 ± 0.13, respectively, and the differences among the groups were statistically significant (F = 9.171/3.957, 20.740/9.315, 34.530/13.830, P < 0.01). The percentages of Ces1f-positive Kupffer cells in the normal control group, model group, pretreatment group, and pretreatment model group were 91.42%, ± 3.79%, 73.85% ± 7.03%, 48.70% ± 5.30%, and 25.68% ± 4.55%, respectively, and the differences between the groups were statistically significant (F = 6.333, 15.400, 23.700, P < 0.01). The relative expression levels of CD86 mRNA in the normal control group, model group, and pretreatment model group were 1.00 ± 0.00, 2.01 ± 0.04, and 4.17 ± 0.14, respectively, and the differences between the groups were statistically significant (F = 33.800, 106.500, P < 0.01). The relative expression levels of CD163 mRNA in the normal control group, the model group, and the pretreatment model group were 1.00 ± 0.00, 0.85 ± 0.01, and 0.65 ± 0.01, respectively, and the differences between the groups were statistically significant (F = 23.360, 55.350, P < 0.01). The percentages of (F4/80(+)CD86(+)) and (F4/80(+)CD163(+)) in the normal control group and model group and pretreatment model group were 10.67% ± 0.91% and 12.60% ± 1.67%, 20.02% ± 1.29% and 8.04% ± 0.76%, and 43.67% ± 2.71% and 5.43% ± 0.47%, respectively, and the differences among the groups were statistically significant (F = 11.130/8.379, 39.250/13.190, P < 0.01). The liver injury scores of the normal control group, the model group, and the pretreatment model group were 0.22 ± 0.08, 1.32 ± 0.36, and 2.17 ± 0.26, respectively, and the differences among the groups were statistically significant (F = 12.520 and 22.190, P < 0.01). Conclusion: Ces1f may be a hepatic inflammatory inhibitory molecule, and its inhibitory effect production may come from the molecule's maintenance of KC polarization phenotypic homeostasis.

Effects of small GTP-binding protein GDP dissociation stimulator on adipocyte hypertrophy and glucose metabolism disorder in mice / 中华内科杂志

Objective: To explore the effect and mechanism of small GTP-binding protein GDP dissociation stimulator (SmgGDS) on the development of obesity. Methods: (1) 8-week-old C57BL/6J mice were randomly assigned to normal diet and high fat diet group, with 6 mice in each group. They were fed regular feed and a high fat diet containing 60% fat for 4 months, respectively. The expression of SmgGDS in epididymal adipose tissue (eWAT), liver, and skeletal muscle were measured using Western-blot. (2) 6-week-old wild-type (WT) and SmgGDS knockdown (KD) mice were divided into four groups, each receiving high fat diet for 4 months (7 in each group) and 7 months (9 in each group). Glucose tolerance test (GTT) and insulin tolerance test (ITT) were conducted; The weight, adipose tissue, and liver weight of mice were recorded; HE staining examined adipose tissue structural changes; Western-blot determined extracellular signal-regulated kinase (ERK) 1/2 phosphorylation levels in eWAT; Real time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to detect mRNA levels of CCAAT/enhancer binding protein α (C/EBPα), C/EBPβ and peroxisome proliferator activated receptor γ (PPARγ) in eWAT. (3) Mouse embryonic fibroblasts (MEFs) extracted from WT and KD mice were induced for differentiation. Oil red O staining and Western-blot were used to detect lipid droplet and expression of SmgGDS and phospho-ERK; C/EBPα, C/EBPβ and PPARγ mRNA levels were measured using RT-qPCR. (4) 10-week-old C57BL/6J mice were randomly assigned into two groups, with 7 mice in each group. Mice were infected with SmgGDS overexpressing adeno-associated virus (AAV-SmgGDS) or empty vector intraperitoneally, then fed with high fat diet. After 4 weeks, performed GTT and ITT; Recorded the weight and adipose tissue weight of mice; HE staining was used to analyze structural changes of eWAT; Western-blot was used to detect the phosphorylation level of ERK in eWAT. Results: (1) The expression of SmgGDS was significantly upregulated in eWAT of high fat diet fed mice (normal diet group: 0.218±0.037, high fat diet group:0.439±0.072, t=2.74, P=0.034). (2) At 4 months of high fat diet intervention, the glucose tolerance (60 minutes after glucose injection, WT group: 528 mg/dl±21 mg/dl, KD group: 435 mg/dl±17 mg/dl, t=3.47, P=0.030; 90 minutes, WT group: 463 mg/dl±24 mg/dl, KD group: 366 mg/dl±18 mg/dl, t=3.23, P=0.047;120 minutes, WT group: 416 mg/dl±21 mg/dl, KD group: 297 mg/dl±16 mg/dl, t=4.49, P=0.005) and insulin sensitivity (15 minutes after insulin injection, WT group: 77.79%±3.45%, KD group: 54.30%±2.92%, t=3.49, P=0.005; 30 minutes, WT group: 62.27%±5.31%, KD group: 42.25%±1.85%, t=2.978, P=0.024; 90 minutes, WT group: 85.69%±6.63%, KD group: 64.71%±5.41%, t=3.120, P=0.016) of KD mice were significantly improved compared to the WT group, with an increase in eWAT weight ratio (WT: 4.19%±0.18%, KD: 5.12%±0.37%, t=2.28, P=0.042), but a decrease in average adipocyte area (WT group: 5221 μm²±241 μm², KD group: 4410 μm²±196 μm², t=2.61, P=0.026). After 7 months of high fat diet, the eWAT weight ratio of KD mice decreased (WT: 5.02%±0.20%, KD: 3.88%±0.21%, t=3.92, P=0.001) and adipocyte size decreased (WT group: 6 783 μm²±390 μm², KD group: 4785 μm²±303 μm², t=4.05, P=0.002). The phospho-ERK1 in eWAT increased (WT group: 0.174±0.056, KD group: 0.588±0.147, t=2.64, P=0.025), and mRNA level of PPARγ significantly decreased (WT group: 1.018±0.128, KD group: 0.029±0.015, t=7.70, P=0.015). (3) The expression of SmgGDS was significantly increased in differentiated MEF (undifferentiated: 6.789±0.511, differentiated: 10.170±0.523, t=4.63, P=0.010); SmgGDS knock-down inhibited lipid droplet formation in MEF (WT group: 1.00±0.02, KD group: 0.88±0.02, t=5.05, P=0.007) and increased ERK1 (WT group: 0.600±0.179, KD group: 1.325±0.102, t=3.52, P=0.025) and ERK2 (WT group: 2.179±0.687, KD group: 5.200±0.814, t=2.84, P=0.047) activity, which can be reversed by ERK1/2 inhibitor. (4) SmgGDS over expression resulted in weight gain, increased eWAT weight (control group: 3.29%±0.36%, AAV-SmgGDS group: 4.27%±0.26%, t=2.20, P=0.048) and adipocyte size (control group: 3525 μm²±454 μm², AAV-SmgGDS group: 5326 μm²±655 μm², t=2.26, P=0.047), impaired insulin sensitivity(30 minutes after insulin injection, control group: 44.03%±4.29%, AAV-SmgGDS group: 62.70%±2.81%, t=3.06, P=0.019), and decreased ERK1 (control group: 0.829±0.077, AAV-SmgGDS group: 0.326±0.036, t=5.96, P=0.001)and ERK2 (control group: 5.748±0.287, AAV-SmgGDS group: 2.999±0.845, t=3.08, P=0.022) activity in eWAT. Conclusion: SmgGDS knockdown improves obesity related glucose metabolism disorder by inhibiting adipogenesis and adipose tissue hypertrophy, which is associated with ERK activation.

Effect of pancreatic extracorporeal shock wave lithotripsy on chronic pancreatitis stones / 中华外科杂志

Objective: To analyze the therapeutic effect and safety of pancreatic extracorporeal shock wave lithotripsy(P-ESWL) for patients with chronic pancreatitis complicated by stones of the pancreatic duct and to investigate the influencing factors. Methods: A retrospective analysis was performed on clinical data from 81 patients with chronic pancreatitis complicated by pancreatic duct calculus treated with P-ESWL in the Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi 'an Jiaotong University from July 2019 to May 2022. There were 55 males(67.9%) and 26 females(32.1%). The age was (47±15)years (range: 17 to 77 years). The maximum diameter(M(IQR)) of the stone was 11.64(7.60) mm, and the CT value of the stone was 869 (571) HU. There were 32 patients (39.5%) with a single pancreatic duct stone and 49 patients(60.5%) with multiple pancreatic duct stones. The effectiveness, remission rate of abdominal pain, and complications of P-ESWL were evaluated. Student's t test, Mann Whitney U test, χ2 test, or Fisher's exact test was used to compare the characteristics between the effective and ineffective groups of lithotripsy. The factors influencing the effect of lithotripsy were analyzed by univariate and multivariate logistic regression analysis. Results: Eighty-one patients with chronic pancreatitis were treated with P-ESWL 144 times, with an average of 1.78 (95%CI:1.60 to 1.96) times per person. Among them, 38 patients(46.9%) were treated with endoscopy. There were 64 cases(79.0%) with effective removal of pancreatic duct calculi and 17 cases(21.0%) with ineffective removal. Of the 61 patients with chronic pancreatitis accompanied by abdominal pain, 52 cases(85.2%) had pain relief after lithotripsy. After lithotripsy treatment, 45 patients(55.6%) developed skin ecchymosis, 23 patients(28.4%) had sinus bradycardia, 3 patients(3.7%) had acute pancreatitis, 1 patient(1.2%) had a stone lesion, and 1 patient(1.2%) had a hepatic hematoma. Univariate and multivariate logistic regression analysis showed that the factors affecting the efficacy of lithotripsy included the age of patient(OR=0.92, 95%CI: 0.86 to 0.97), the maximum diameter of the stone(OR=1.12,95%CI:1.02 to 1.24) and the CT value of the stone(OR=1.44, 95%CI: 1.17 to 1.86). Conclusions: P-ESWL is effective in the treatment of patients with chronic pancreatitis complicated by calculi of the main pancreatic duct.Factors affecting the efficacy of lithotripsy include patient's age, maximum stone diameter, and CT value of calculi.

A risk prediction model of cervical cancer developed based on nested case-control design / 中华流行病学杂志

Objective: To construct a cervical cancer risk prediction model based on nested case-control study design and Yinzhou Health Information Platform in Ningbo, and provide reliable reference for self-risk assessment of cervical cancer in local women. Methods: In local women aged 25-75 years old who had no history of cervical cancer registered in Yinzhou before October 31, 2018, a follow up was conducted for at least three years, the patients who developed cervical cancer during the follow up period were selected as the case group and matched with a control group at a ratio of 1∶10. The prediction indicators before the onset was used in model construction. Variables were selected by Lasso-logistic regression, the variables with non-zero β were selected to fit the logistic regression model and Bootstrap was used for internal validation. The discrimination of the model was evaluated by area under the receiver operating characteristic curve(AUROC), and the calibration was evaluated by calibration curve and Hosmer-Lemeshow test. Results: The prediction indicators included in the final model were age, smoking status, history of cervicitis, history of adenomyosis, HPV testing, and thinprep cytologic test. The AUROC calculated in the internal validation was 0.740 (95%CI:0.739-0.740), and the calibration curve was almost identical with the ideal curve, P=0.991 in Hosmer-Lemeshow test, indicating that the model discrimination and calibration were good. Conclusions: In this study, a simple and practical cervical cancer risk prediction model was developed. The model can be used in general population with strong interpretability, good discrimination and calibration in internal validation, which can provide a reference for women to assess their risk of cervical cancer.

Analysis of on-demand adherence and related factors in men who have sex with men who access HIV pre-exposure prophylaxis services via the internet / 中华流行病学杂志

Objective: To understand the compliancy to on-demand HIV pre-exposure prophylaxis (PrEP) and related factors in men who have sex with men (MSM) accessing to PrEP service through an Internet platform. Methods: A cross-sectional study method was used to recruit survey respondents through the Heer Health platform from July 6 to August 30, 2022, and a questionnaire survey on the current status of medication use was conducted in MSM who use PrEP through the platform and take medication on demand. The MSM's information collected in the survey mainly included socio-demographic characteristics, behavioral characteristics, risk perception characteristics, PrEP awareness and the status of dose taking. Univariate and multivariate logistic regression analyses were used to evaluate factors related with compliancy to PrEP. Results: A total of 330 MSM who met the recruitment criteria were included during the survey period, with a valid response rate of 96.7% (319/330) to the questionnaire survey. The age of the 319 MSM was (32.5±7.3) years. Most of them had education level of junior college or college and above (94.7%, 302/319), most of them were unmarried (90.3%, 288/319), most of them had full-time works (95.9%, 306/319), and 40.8% of them had average monthly income ≥10 000 yuan (130/319). The proportion of the MSM with good compliancy to PrEP was 86.5% (276/319). The results of univariate and multivariate logistic analyses showed that the MSM with good awareness of PrEP had relatively better compliancy to PrEP compared with those with poor awareness of PrEP (aOR=2.43, 95%CI:1.11-5.32). Conclusions: The compliancy to on-demand PrEP was good in MSM who accessed to the services through Internet platform, but there is still a need to strengthen PrEP promotion in MSM for the further improvement of PrEP compliancy and reduction of the risk for HIV infection in this population.

Establishment of leukemia cell model with inducible AML1-ETO expression and its effect on fatty acid metabolism in leukemia cells / 中华血液学杂志

Objective: To investigate the effect of the AML1-ETO (AE) fusion gene on the biological function of U937 leukemia cells by establishing a leukemia cell model that induces AE fusion gene expression. Methods: The doxycycline (Dox) -dependent expression of the AE fusion gene in the U937 cell line (U937-AE) were established using a lentivirus vector system. The Cell Counting Kit 8 methods, including the PI and sidanilide induction, were used to detect cell proliferation, cell cycle-induced differentiation assays, respectively. The effect of the AE fusion gene on the biological function of U937-AE cells was preliminarily explored using transcriptome sequencing and metabonomic sequencing. Results: ①The Dox-dependent Tet-on regulatory system was successfully constructed to regulate the stable AE fusion gene expression in U937-AE cells. ②Cell proliferation slowed down and the cell proliferation rate with AE expression (3.47±0.07) was lower than AE non-expression (3.86 ± 0.05) after inducing the AE fusion gene expression for 24 h (P<0.05). The proportion of cells in the G(0)/G(1) phase in the cell cycle increased, with AE expression [ (63.45±3.10) %) ] was higher than AE non-expression [ (41.36± 9.56) %] (P<0.05). The proportion of cells expressing CD13 and CD14 decreased with the expression of AE. The AE negative group is significantly higher than the AE positive group (P<0.05). ③The enrichment analysis of the transcriptome sequencing gene set revealed significantly enriched quiescence, nuclear factor kappa-light-chain-enhancer of activated B cells, interferon-α/γ, and other inflammatory response and immune regulation signals after AE expression. ④Disorder of fatty acid metabolism of U937-AE cells occurred under the influence of AE. The concentration of the medium and short-chain fatty acid acylcarnitine metabolites decreased in cells with AE expressing, propionyl L-carnitine, wherein those with AE expression (0.46±0.13) were lower than those with AE non-expression (1.00±0.27) (P<0.05). The metabolite concentration of some long-chain fatty acid acylcarnitine increased in cells with AE expressing tetradecanoyl carnitine, wherein those with AE expression (1.26±0.01) were higher than those with AE non-expression (1.00±0.05) (P<0.05) . Conclusion: This study successfully established a leukemia cell model that can induce AE expression. The AE expression blocked the cell cycle and inhibited cell differentiation. The gene sets related to the inflammatory reactions was significantly enriched in U937-AE cells that express AE, and fatty acid metabolism was disordered.

Isoliquiritigenin alleviates energy metabolism imbalance in type 2 diabetic mice / 药学学报

Isoliquiritigenin (ISL) is a flavonoid compound isolated from licorice. It possesses excellent antioxidant and anti-diabetic activities. This study aims to investigate the molecular mechanism underlying the alleviatory effect of ISL on energy metabolism imbalance caused by type 2 diabetes mellitus (T2DM). 8-week-old male C57BL/6J mice were used in in vivo experiments. The high-fat-high-glucose diet combined with intraperitoneal injection of streptozotocin was applied to establish T2DM animal model. All animal experiments were performed in accordance with the Institutional Guidelines of Laboratory Animal Administration issued by the Committee of Ethics at Beijing University of Chinese Medicine. HepG2 cells were used in in vitro experiments. Enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (RT-qPCR) were used to examine the protein and mRNA levels of mitochondrial function-related targets. The levels of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) in HepG2 cells were measured by the flow cytometry. Additionally, the molecular docking of ISL and key target proteins was analyzed. It was found that ISL significantly inhibited the activity of mitochondrial respiratory chain complex I and increased the protein levels of uncoupling protein 2 (UCP2) in the livers of mice and HepG2 cells. It also obviously decreased the ROS levels and increased the MMP levels in cultured HepG2 cells. In addition, ISL promoted mitochondrial biogenesis by activating proliferator-activated receptor gamma co-activator 1α (PGC-1α) and enhanced mitophagy by upregulating Parkin. It also improved mitochondrial fusion by increasing the mRNA and protein levels of mitofusin 2 (MFN2). In conclusion, ISL alleviates energy metabolism imbalance caused by T2DM through suppression of excessive mitochondrial oxidative phosphorylation and promotion of mitochondrial biogenesis, mitophagy, and fusion.

Research advances in natural drug and food monomers in prevention and treatment of alcoholic liver injury / 临床肝胆病杂志

A large number of data show that the prevalence rate of alcoholic liver injury （ALI） is increasing year by year， and it has become one of the main causes of death due to chronic liver diseases such as liver cancer and liver cirrhosis. Quitting drinking is the main method for the prevention of ALI in modern medicine， and the main treatment methods include Western medicine with antioxidant and anti－fibrotic effects and nutritional support. However， Western medicine tends to have an unsatisfactory treatment effect and can only alleviate initial symptoms， and severe ALI still requires surgical treatment. Studies have shown that the monomers extracted from natural drugs and foods have obvious preventive and therapeutic effects on ALI， with high safety and easy access. Therefore， this article systematically summarizes the main natural drug and food monomers used for the prevention and treatment of ALI and proposes the idea of the combination of drug and food for the prevention and treatment of ALI from the perspective of paying attention to the whole process of health， in order to explore more effective prevention， health care， and treatment methods and provide ideas for research on the prevention and control of ALI.

Clinical analysis of patients with oral and maxillofacial infections in oral emergency / 北京大学学报(医学版)

OBJECTIVE@#To analyze the composition, incidence and clinical characteristics of oral and maxillofacial infections in oral emergency.@*METHODS@#A retrospective study on patients with oral and maxillofacial infections who visited the Department of Oral Emergency in Peking University School and Hospital of Stomatology from January 2017 to December 2019 was conducted. General characteristics, such as disease composition, gender, age distribution and position of involved teeth were analyzed.@*RESULTS@#A total of 8 277 patients with oral and maxillofacial infections were finally collected, including 4 378 male patients (52.9%) and 3 899 female patients (47.1%), with gender ratio of 1.12:1. The common diseases were periodontal abscess (3 826 cases, 46.2%), alveolar abscess (3 537 cases, 42.7%), maxillofacial space infection (740 cases, 9.0%), sialadenitis (108 cases, 1.3%), furuncle & carbuncle (56 cases, 0.7%) and osteomyelitis (10 cases, 0.1%). Male patients were more easily affected by periodontal abscess, space infection and furuncle & carbuncle than female patients with the gender ratios 1.24:1, 1.26:1, 2.50:1 individually, while the incidence of alveolar abscess, sialadenitis, furuncle & carbuncle had no significant gender difference. Different diseases were prone to occur at different ages. The peak ages of alveolar abscess were 5-9 and 27-67 years, while the peak age of periodontal abscess was 30-64 years. Space infection tended to occur between 21-67 years. There were 7 363 patients with oral abscess (3 826 patients with periodontal abscess and 3 537 patients with alveolar abscess), accounting for 88.9% of all the patients with oral and maxillofacial infections, involving 7 999 teeth, including 717 deciduous teeth and 7 282 permanent teeth. Periodontal abscess usually occurred in permanent teeth, especially the molar teeth. Alveolar abscess may occur in both primary teeth and permanent teeth. In primary teeth, the most vulnerable sites were primary molar teeth and maxillary central incisors while in permanent teeth the most vulnerable sites were first molar teeth.@*CONCLUSION@#Understanding the incidence of oral and maxillofacial infection was conducive to the correct diagnosis and effective treatment of clinical diseases, as well as targeted education for patients of different ages and genders to prevent the occurrence of diseases.

Correlation between aerobic training and physical endurance in basketball players / Correlação entre treinamento aeróbico e resistência física em jogadores de basquete / Correlación entre entrenamiento aeróbico y resistencia física en jugadores de baloncesto

ABSTRACT Introduction: Endurance is a quality that has been lacking in Chinese athletes. In most endurance sports training in China, there is a problem with attaching importance to high-intensity anaerobic training and ignoring aerobic training. The close combination of aerobic, strength and technical training is endurance training. A significant development trend in training. Objective: This study analyzes the relationship between aerobic training and physical endurance in basketball players. Methods: Basketball players were selected and randomly divided into groups through the analysis method with a questionnaire, observation method, and experimental method to analyze the relationship between aerobic exercise and physical endurance in basketball players. In this paper, the changes in physiological indicators of basketball players were recorded after aerobic exercise. Results: The physical endurance of basketball players were positively correlated with aerobic training time. The physiological indicators of basketball players and basketball skills after aerobic training were significantly improved (P<0.05). Conclusion: Aerobic exercise can improve basketball players' physical endurance and overall physical fitness, helping them achieve good results in competitions. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução: Resistência é uma qualidade que tem faltado aos atletas chineses. Na maioria dos treinos esportivos de resistência na China, há um problema para atribuir importância ao treino anaeróbico de alta intensidade e ignorar o treinamento aeróbico. A combinação próxima de treinamento aeróbico e força e treinamento técnico é o treinamento de resistência. Uma tendência de desenvolvimento significativa na formação. Objetivo: Este estudo tem como objetivo analisar a relação entre treinamento aeróbico e resistência física em praticantes do basquete. Métodos: Jogadores de basquete foram selecionados e aleatoriamente divididos entre grupos passando pelo método de análise com questionário, método de observação e método experimental para analisar a relação entre exercício aeróbico e resistência física dos jogadores de basquete. Neste artigo, as alterações dos indicadores fisiológicos dos jogadores de basquete foram registradas após exercício aeróbico. Resultados: A resistência física dos jogadores de basquete foi positivamente correlacionada com o tempo de treinamento aeróbico. Os indicadores fisiológicos dos jogadores de basquete e as habilidades de basquete após o treinamento aeróbico foram significativamente melhorados (P<0,05). Conclusão: O exercício aeróbico não só pode melhorar a resistência física dos jogadores de basquete como também sua aptidão física geral, ajudando-os a alcançarem bons resultados nas competições. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción: La resistencia es una cualidad de la que carecen los atletas chinos. En la mayoría de los entrenamientos de deportes de resistencia en China, existe el problema de dar importancia al entrenamiento anaeróbico de alta intensidad e ignorar el entrenamiento aeróbico. La estrecha combinación del entrenamiento aeróbico y el entrenamiento de fuerza y técnico es el entrenamiento de resistencia. Una tendencia de desarrollo importante en la formación. Objetivo: Este estudio pretende analizar la relación entre el entrenamiento aeróbico y la resistencia física en jugadores de baloncesto. Métodos: Se seleccionaron jugadores de baloncesto y se dividieron aleatoriamente entre grupos pasando por el método de análisis con cuestionario, método de observación y método experimental para analizar la relación entre el ejercicio aeróbico y la resistencia física en jugadores de baloncesto. En este trabajo se registraron los cambios de los indicadores fisiológicos de los jugadores de baloncesto después del ejercicio aeróbico. Resultados: La resistencia física de los jugadores de baloncesto se correlacionó positivamente con el tiempo de entrenamiento aeróbico. Los indicadores fisiológicos de los jugadores de baloncesto y las habilidades de baloncesto después del entrenamiento aeróbico mejoraron significativamente (P<0,05). Conclusión: El ejercicio aeróbico no sólo puede mejorar la resistencia física de los jugadores de baloncesto, sino también su estado físico general, ayudándoles a conseguir buenos resultados en las competiciones. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

Power supply characteristics of basketball players at different training intensities / Características do consumo de energia dos jogadores de basquete com diferentes intensidades de treinamento / Características del consumo de energía de los jugadores de baloncesto con diferentes intensidades de entrenamiento

ABSTRACT Introduction: In competitive basketball sports, athletes must repeatedly perform movements of maximum intensity quickly, followed by rest. A training mode called high-intensity interval training (HIIT) has the same characteristics. Objective: Explore basketball players' energy supply characteristics and training changes under different exercise intensities. Methods: The effects of different recovery methods in the intermittent period on exercise capacity and aerobic metabolic energy supply of young male basketball players during high-intensity intermittent interval training (HIIT) were presented. Results: Increased aerobic energy production during HIIT was closely related to the acceleration of kinetics. However, although the time to exhaustion, a parameter characterizing exercise capacity, increased by 3.5% and 4.6%, respectively, in the HIITa group compared to HIITs and HIITp, there was no significant difference. After analyzing each group for the 30s, a gradual increase in strength was noticed. Conclusion: The use of HIIT as training is an important way to improve the physical performance of athletes. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução: Na competição esportiva do basquete, os atletas precisam realizar repetidamente movimentos de intensidade máxima rapidamente, seguidos de repouso. Há um modo de treinamento chamado de treinamento de intervalo de alta intensidade (HIIT) que possui as mesmas características. Objetivo: Explorar as características de consumo de energia e as mudanças de treinamento dos jogadores de basquetebol sob diferentes intensidades de exercício. Métodos: Foram apresentados os efeitos de diferentes métodos de recuperação em período intermitente sobre a capacidade de exercício e fornecimento de energia metabólica aeróbica de jovens jogadores masculinos de basquetebol durante o treinamento intermitente de alta intensidade (HIIT). Resultados: O aumento da produção de energia aeróbica durante o HIIT foi estreitamente relacionado com a aceleração da cinética. Entretanto, embora o tempo de exaustão, parâmetro que caracteriza a capacidade de exercício, tenha aumentado em 3,5% e 4,6% respectivamente no grupo de HIITa em comparação com HIITs e HIITp, não houve diferença significativa. Depois de analisar cada grupo durante 30s, percebeu-se um aumento gradual da força. Conclusão: O uso do HIIT como treinamento demonstrou-se um meio importante para melhorar o desempenho físico dos atletas. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

RESUMEN Introducción: En los deportes de baloncesto de competición, los atletas necesitan realizar repetidamente movimientos de máxima intensidad de forma rápida, seguidos de descanso. Existe una modalidad de entrenamiento llamada entrenamiento por intervalos de alta intensidad (HIIT) que tiene las mismas características. Objetivo: Explorar las características del suministro de energía y los cambios en el entrenamiento de los jugadores de baloncesto bajo diferentes intensidades de ejercicio. Métodos: Se presentaron los efectos de diferentes métodos de recuperación en período intermitente sobre la capacidad de ejercicio y el suministro de energía metabólica aeróbica de jóvenes jugadores de baloncesto durante el entrenamiento de intervalos intermitentes de alta intensidad (HIIT). Resultados: El aumento de la producción de energía aeróbica durante el HIIT estaba estrechamente relacionado con la aceleración de la cinética. Sin embargo, aunque el tiempo hasta el agotamiento, un parámetro que caracteriza la capacidad de ejercicio, aumentó un 3,5% y un 4,6% respectivamente en el grupo HIITa en comparación con los HIIT y HIITp, no hubo diferencias significativas. Tras analizar cada grupo durante 30 segundos, se percibió un aumento gradual de la fuerza. Conclusión: El uso del HIIT como entrenamiento ha demostrado ser una forma importante de mejorar el rendimiento físico de los atletas. Nivel de evidencia II;Estudios terapéuticos - investigación de los resultados del tratamiento.

Jiedu Huoxue Prescription Regulates NF-κB/NLRP3/Caspase-1 to Promote Vascular Reendothelialization in Rat Model of Injured Thoracic Aorta / 中国实验方剂学杂志

ObjectiveTo investigate the mechanism of Jiedu Huoxue prescription in promoting the reendothelialization of injured vessels by regulating the nuclear factor （NF）-κB/NOD-like receptor protein 3 （NLRP3）/cysteine-aspartic acid protease （Caspase）-1-mediated pyroptosis. MethodA rat model of injured thoracic aorta was established by balloon injury， and 36 rats were assigned into shame surgery， model， low-， medium-， and high-dose Jiedu Huoxue prescription， and atorvastatin calcium tablet groups. The injured aortic segment was collected 28 days after surgery. Hematoxylin-eosin （HE） staining and Evans blue staining were conducted to reveal the changes of vascular structural morphology and the reendothelialization of blood vessels， respectively. The enzyme-linked immunosorbent assay （ELISA） was employed to determine the levels of tumor necrosis factor-α （TNF-α）， intercellular adhesion molecule-1 （ICAM-1）， interleukin （IL）-1β， and nitric oxide （NO） in the serum. Western blotting was employed to determine the expression of endothelial nitric oxide synthase （eNOS）， NF-κB p65， phospho-NF-κB p65 （p-NF-κB p65）， NLRP3， and Caspase-1 in the vascular tissue. ResultThe model group showed thickened endovascular membrane， proliferation and disarrangement of smooth muscle cells of the artery wall， obvious inflammatory cell infiltration， and narrowed luminal area. Jiedu Huoxue prescription and atorvastatin calcium tablets mitigated the pathological changes of the thoracic aorta in different degrees. After balloon injury， the endothelial coverage rate of the model group decreased significantly， while Jiedu Huoxue prescription and atorvastatin calcium tablets increased the reendothelialization rate （P<0.05）. Compared with the shame surgery group， the model group showed elevated levels of TNF-α， ICAM-1， and IL-1β （P<0.01） and lowered NO level （P<0.01） in the serum. In addition， the model group presented down-regulated protein level of eNOS （P<0.01） and up-regulated phosphorylation of pyroptosis-associated proteins NLPR3， Caspase-1， and NF-κB p65 in the vascular tissue （P<0.05， P<0.01）. Compared with the model group， Jiedu Huoxue prescription and atorvastatin calcium tablets lowered TNF-α， ICAM-1， and IL-1β levels （P<0.05， P<0.01） and elevated the NO level in the serum （P<0.05， P<0.01）. Moreover， the drugs up-regulated the expression of eNOS （P<0.01） and down-regulated the expression of NLRP3， Caspase-1， and NF-κB p65 （P<0.05， P<0.01） in the vascular tissue. ConclusionJiedu Huoxue prescription can promote the reendothelialization and inhibit the intimal hyperplasia of vessels after balloon injury by regulating the NF-κB/NLRP3/Caspase-1 pathway to inhibit pyroptosis and reduce endothelial inflammatory injury.

Clinical application of non-invasive myocardial work imaging in ST-segment elevation myocardial infarction patients with left ventricular remodeling after percutaneous coronary intervention / 中华超声影像学杂志

Objective:To explore the application value of non-invasive myocardial work imaging in evaluating the cardiac function of ST-segment elevation myocardial infarction (STEMI) patients with left ventricular remodeling (LVR) after percutaneous coronary intervention (PCI).Methods:One hundred and twenty-six patients with STEMI undergoing PCI in General Hospital of Ningxia Medical University from December 2021 to September 2022 were prospectively collected and divided into left ventricular remodeling group (LVR group, 34 cases) and non left ventricular remodeling group (NLVR group, 92 cases) according to whether there was left ventricular remodeling 3 months after surgery. General data were collected. Routine echocardiography and noninvasive myocardial work imaging were performed before, 1 week, 1 month, and 3 months after surgery, the differences in the above parameters between the two groups were compared. Pearson correlation analysis was used to analyze the correlation between the indicators.Logistic regression analysis was used to determine the independent risk factors of left ventricular remodeling after STEMI, and a predictive model was obtained. The diagnostic value of the model was judged by ROC curve.Results:①General information comparison: There were statistically significant differences between the two groups in BMI, systolic blood pressure, diastolic blood pressure, average number of stents implanted, and history of hyperlipidemia (all P<0.05), but there was no significant difference in other data (all P>0.05). There was no statistically significant difference in two-dimensional transthoracic echocardiography (2D-TTE) parameters and non-invasive myocardial work (MW) parameters between the two groups before and 1 week after operation (both P>0.05). ②2D-TTE parameter comparison: LVESV and LVEDV at 3 months after PCI in the LVR group were significantly higher than those in the NLVR group, and LVEF and E/A were significantly lower than those in the NLVR group (all P<0.05); There were no significant differences in other indexes between the two groups by conventional echocardiography at 3 months after PCI(all P>0.05). ③Comparisons of noninvasive myocardial work parameters: GLS, GWE, GWI, GCW at 1 month and 3 months after PCI in the LVR group were significantly lower than those in the NLVR group, and GWW were significantly higher than those in the NLVR group ( P<0.001). ④Correlation analysis: GLS, GWE, GCW, GWI and LVEDV were negatively correlated at 1 month after operation ( r=-0.42, -0.38, -0.50, -0.53, all P<0.001), GWW was positively correlated with LVEDV ( r=0.45, P<0.001). ⑤Logistic regression analysis: GLS<17%, GCW<1 900 mmHg%, GWW>105 mmHg%, and GWE<90 mmHg% at 1 month after PCI were independent predictors for LVR in STEMI patients after PCI (all P<0.05). The predictive model was Logit (P)=0.692GLS+ 0.804GCW+ 0.972GWW+ 0.880GWE. The AUC of this model was 0.886, 95% CI=0.845-0.926, which was significantly higher than single index, the sensitivity was 0.86, and the specificity was 0.79. Conclusions:GLS, GWE, GWI, GCW are positively correlated with LVR, while GWW is negatively correlated with left ventricular remodeling. Noninvasive myocardial work parameters are independent risk factors for left ventricular remodeling in patients with STEMI after PCI surgery. This technique can be used to evaluate LVR and has great clinical application value.

Analysis of the status and risk factors of in stent restenosis in patients with acute myocardial infarction and diabetes mellitus one year after percutaneous coronary intervention / 中国医师杂志

Objective:To analyze the status of in stent restenosis (ISR) in patients with acute myocardial infarction (AMI) and diabetes mellitus (DM) one year after percutaneous coronary intervention (PCI), and explore the risk factors.Methods:From December 2019 to December 2020, 158 patients with AMI and DM who were treated by PCI in Qionghai Hospital of Traditional Chinese Medicine and the First Affiliated Hospital of Hainan Medical College were selected. They were followed up for one year after surgery to calculate the incidence of ISR. The patients were divided into ISR group and non ISR group according to whether ISR occurred. The difference of clinical data between the two groups was compared. Logistic regression was used to analyze the risk factors for the occurrence of ISR in AMI patients with DM 1 year after PCI.Results:55 patients were followed up for 1 year, and the incidence of ISR was 34.81% (55/158). There were significant difference between ISR group and non ISR group in hypertension history, old myocardial infarction history, smoking, exercise ratio, preoperative low density lipoprotein cholesterol (LDL-C), total bilirubin (TBIL), blood uric acid (UA), plasma fibrinogen (FIB), glycosylated hemoglobin (HbA 1c) levels, coronary artery lesion number, stenosis degree, stent length, stent diameter (all P<0.05). Multivariate logistic regression analysis showed that hypertension history, smoking, LDL-C, FIB, HbA 1c and stent length were independent risk factors for ISR in AMI patients with DM after PCI, and exercise and appropriate increase of stent diameter were protective factors (all P<0.05). Conclusions:The incidence of ISR in AMI patients with DM at 1 year after PCI is relatively high, and its occurrence is related to many factors. In order to reduce the risk of ISR after PCI, we should encourage smoking cessation, exercise, strengthen the monitoring of biochemical indicators, and appropriately increase the diameter of stent during PCI.

China Hospital Pharmacovigilance System-based study of trimetazidine-associated Parkinson's syndrome / 中国基层医药

Objective:To evaluate the active monitoring methods and population characteristics of trimetazidine-associated Parkinson's syndrome.Methods:The clinical data of patients with trimetazidine-associated Parkinson's syndrome who received treatment in Liaocheng People's Hospital from January 2019 to December 2020 were retrospectively analyzed using the China Hospital Pharmacovigilance System (CHPS).Results:In 4 883 patients included in the study,167 patients were alarmed by CHPS, of which 26 patients were confirmed positive by manual rechecks. The rate of positive pre-alarming by CHPS was 15.57%. The actual incidence of trimetazidine-associated Parkinson's syndrome was 0.53%. The average age of the 26 patients with Parkinson's syndrome was (75.08 ± 10.79) years. None of the 26 patients had a past history/family history of idiopathic Parkinson's disease. There were 21 patients (80.77%) aged over 65 years, 19 patients (73.08%) with a history of ischemic encephalopathy, 17 patients (65.38%) with positive symptoms in both limbs, 20 patients (76.92%) with abnormal brain CT or MRI findings, and 21 patients (80.77%) with medication doses of 60-70 mg/d. Among the 26 patients, 18 were female patients (69.23%) and 18 were patients with normal renal function (69.23%). The follow-up results showed that trimetazidine administration was not terminated in 14 patients (53.85%), symptoms were not alleviated or worsened in 8 patients (30.77%), and symptoms were alleviated or disappeared in 18 patients (69.23%).Conclusion:The use of CHPS can timely detect trimetazidine-associated Parkinson's syndrome. CHPS has significant advantages over traditional monitoring modes. Age > 65 years and a previous history of ischemic encephalopathy are risk factors for developing trimetazidine-associated Parkinson's syndrome. No history/family history of idiopathic Parkinson's disease, positive Alzheimer's disease symptoms in both limbs and abnormal brain CT and MRI findings contribute to early diagnosis and differentiation of trimetazidine- associated Parkinson's syndrome. Trimetazidine-associated Parkinson's syndrome is more common in women than in men. Trimetazidine-associated Parkinson's syndrome can also occur in a population with normal renal function or under a normal trimetazidine dose condition. Trimetazidine-associated Parkinson's syndrome is relatively rare. Patients with trimetazidine- associated Parkinson's syndrome have low awareness. Because of the difficult diagnosis and serious consequences, there is a need to strengthen research on trimetazidine-associated Parkinson's syndrome.