ObjectiveTo examine the influences of Shenfu injection on the endogenous metabolic byproducts in the myocardium of the rat model exhibiting chronic heart failure， thus deciphering the therapeutic mechanism of the Qi-reinforcing and Yang-warming method. MethodsSD rats were randomly allocated into a control group and a modeling group. Chronic heart failure with heart-Yang deficiency syndrome in rats was modeled by multi-point subcutaneous injection of isoproterenol， and the rats were fed for 14 days after modeling. The successfully modeled rats were randomized into model， Shenfu injection （6.0 mL·kg^-1）， and trimetazidine （10 mg·kg^-1） groups and treated with corresponding agents for 15 days. The control group and the model group were injected with equal doses of normal saline， and the samples were collected after the intervention was completed. Cardiac color ultrasound was performed. Hematoxylin-eosin （HE） staining was used to observe histopathological morphology， and the serum level of N-terminal pro-brain natriuretic peptide （NT-proBNP） was assessed by enzyme-linked immunosorbent assay （ELISA）. The mitochondrial morphological and structural changes of cardiomyocytes were observed by transmission electron microscopy， and the metabolic profiling was carried out by ultra high performance liquid chromatography-quantitative exactive-mass spectrometry （UHPLC-QE-MS）. Differential metabolites were screened and identified by orthogonal partial least squares-discriminant analysis （OPLS-DA） and other methods， and then the MetaboAnalyst database was used for further screening. The relevant biological pathways were obtained through pathway enrichment analysis. The receiver operating characteristic （ROC） curve was established to evaluate the diagnostic value of each potential biomarker for myocardial injury and the evaluation value for drug efficacy. ResultsThe results of color ultrasound showed that Shenfu Injection improved the cardiac function indexes of model rats （P<0.05）. The results of HE staining showed that Shenfu injection effectively alleviated the pathological phenomena such as myocardial tissue structure disorder and inflammatory cell infiltration in model rats. The results of ELISA showed that Shenfu injection effectively regulated the serum NT-proBNP level in the model rats. Transmission electron microscopy （TEM） showed that Shenfu injection effectively restored the mitochondrial morphological structure. The results of metabolomics showed that the metabolic phenotypes of myocardial samples presented markedly differences between groups. Nine differential metabolites could be significantly reversed in the Shenfu injection group， involving three metabolic pathways： pyruvate metabolism， histidine metabolism， and citric acid cycle （TCA cycle）. The results of ROC analysis showed that the area under the curve （AUC） values of all metabolites were between 0.75 and 1.0， indicating that the differential metabolites had high diagnostic accuracy for myocardial injury， and the changes in their expression levels could be used as potential markers for efficacy evaluation. ConclusionShenfu injection significantly alleviated the damage of cardiac function， myocardium， and mitochondrial structure in the rat model of chronic heart failure with heart-Yang deficiency syndrome by ameliorating energy metabolism remodeling. Reinforcing Qi and warming Yang is a key method for treating chronic heart failure with heart-Yang deficiency syndrome.

Objective Rapid health technology assessment(HTA)was used to evaluate the efficacy,safety and economy of argatroban in the treatment of acute ischemic stroke,so as to provide evidence-based reference for clinical treatment decision making.Methods PubMed,Embase,Web of Science,Cochrane Library,CNKI,WanFang Data,VIP,SinoMed databases and HTA website were electronically searched to collect the HTA report,systematic review/Meta-analysis and pharmacoeconomic research of argatroban in the treatment of acute ischemic cerebral infarction from inception to February 6,2024.Two reviewers independently identified studies,extracted data,assessed the quality of included studies,and descriptively analyzed and summarised the results.Results A total of 21 articles were included,including 15 systematic reviews/Meta-analysis and 6 pharmacoeconomic studies.The analysis results of effectiveness showed that argatroban could improve the clinical effective rate,neurological deficit score compared with placebo,routine treatment,or other drugs(such as alteplase),but a few studies were inconsistent with the current results.The analysis results of safety showed that argatroban alone or in combination with other drugs did not increase the risk of systemic hemorrhage,intracranial hemorrhage,mortality and other adverse reactions compared with the control group,and had a favorable safety profile.The analysis results of pharmacoeconomic studies that argatroban combined with routine treatment or argatroban combined with urokinase had economic advantages.Conclusion Argatroban is generally effective and safe in the treatment of acute ischemic stroke,and it has economic advantages for patients to choose argatroban combined with routine treatment or urokinase treatment.

Objective:To investigate the different types of renal artery involvement in Stanford type B aortic dissection (TBAD) and the comparison of clinical effecacy after thoracic endovascular aortic repair (TEVAR).Methods:This is a retrospective cohort study included 330 patients with TBAD and renal artery involvement treated with TEVAR from June 2002 to September 2021 in General Hospital of Northern Theater Command of the PLA. According to aortic CTA image, unilateral renal artery involvement conditions were divided into 5 types: the true lumen type (renal artery opening completely from the true lumen), false lumen type (renal artery opening completely from the false lumen), double lumen type (renal artery opening from the true and false double lumen), compression type (renal artery opening connected with the true lumen, but the renal artery opening was extremely squeezed by the inner membrane), open type (renal artery opening with intimal tear). There were seven types of bilateral renal artery involvement: true-true type (true lumen-true lumen type), true and false type (true lumen-false lumen type), true-double type (true lumen-double lumen type), true-opening type (true lumen-opening type), false-false type (false lumen-false lumen type), false-compression type (false lumen-compression type), double-double type (double lumen-double lumen type). The primary observation index of this study was the comparison of postoperative renal function and the incidence of clinical adverse events of different types of renal artery involvement. One-way ANOVA test, Kruskal-Wallis H test and paired sample rank sum test were used to compare postoperative renal function between different types of bilateral renal artery involvement. The Chi-square test or Fisher′s exact probability test were used to compare the near and long term adverse events between different types of bilateral renal artery involvement. Kaplan-Meier method was used to compare the all-cause mortality of patients with severe renal functional injury and non-severe renal functional injury before surgery. Results:The average age of the patients included in this study was (53±11) years, including 276 males (83.6%) and 54 females (16.4%). There were statistical difference in the level of serum creatinine (preoperative: H=18.686, P=0.005, postoperative: H=18.101, P=0.006) and cystatin C (preoperative: H=17.566, P=0.007, postoperative: H=10.433, P=0.016), pre-and post-operative, between the seven groups of TBAD patients with different renal artery involvement types ( P<0.05), and the false-false type group shown the worst kidney function. However, no statistically significant differences were shown when comparing their pre- and post-operative change values ( P>0.05). The 30-day follow-up result showed that there were statistically significant differences in the incidence of postoperative acute kidney injury ( χ2=15.623, P=0.007), aorta-related adverse events ( χ2=15.523, P=0.010), and intraoperative endoleak ( χ2=17.935, P=0.004) among the seven groups, and the false-false group was the highest (2/9, 5/9 and 5/9, respectively). In terms of long-term follow-up results, there were statistically significant differences in all-cause death ( χ2=14.772, P=0.011) and non-aortic death ( χ2=15.589, P=0.008) among the seven groups. Kaplan-Meier survival analysis showed that patients with worse pre-operative renal function showed higher long-term all cause death (17.7% vs. 4.8%, P=0.009). Conclusions:For TBAD patients with renal artery involvement, there were differences in renal function among different types, and TEVAR showed no significant effect on renal function in TBAD patients. The long-term all cause death was higher in patients with worse renal function pre-operative.

Objective:To investigate the effect of nano lead oxide (nano-PbO) exposure on learning and memory as well as spatial exploration ability in the mice, and the role of leukocyte infiltration of brain tissue in neurobehavioral damage caused by nano-PbO exposure.Methods:A total of 60 male SPF grade Kunming mice were divided into control group, low-dose nano-PbO group, medium-dose nano-PbO group and high-dose nano-PbO group according to body mass matching method, with 15 mice in each group.Mice in low, medium and high dose groups of nano-PbO were intraperitoneally injected with 5 mg·kg -1, 10 mg·kg -1, 20 mg·kg -1 nano-PbO, respectively. And mice in the control group were intraperitoneally injected with the same volume of 0.9% normal saline.The frequency of intervention was once a day for 28 days.Morris water maze test and open field test were used to detect the ability of learning and memory and spatial exploration of mice. Western blot was used to detect the protein expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) in hippocampus of mice, intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) in mouse microvessels and lymphocyte function-associated antigen-1 (LAF-1) in mouse blood leukocyte. The proportion of leukocytes in mouse brain was detected by flow cytometry. All statistical analyses were performed by SPSS 20.0. Morris water maze data were analyzed by repeated measures ANOVA, the other data among multiple groups were compared by one-way ANOVA, and Tukey's test was used for further pairwise comparison.Pearson correlation analysis was performed to evaluate the correlation between neurobehavioral indexes and the proportion of white blood cells, TNF-α and IL-1β in brain tissue. Results:Morris water maze results showed that the escape latency of the four groups of mice had a significant interaction between group and time( F=3.21, P<0.05). The escape latencies of mice in middle and high dose groups of nano-PbO were higher than that in the control group (both P<0.05), and the numbers of crossing the platform of the two groups were lower than that in the control group (both P<0.05). The results of open field test showed that there was a statistically significant difference in the residence time of the mice in the four groups ( F=119.10, P<0.01). The total standing times of mice in the middle group and high dose group of nano-PbO were lower than that in the control group (both P<0.01). The results of Western blot showed that the levels of TNF-α and IL-1β in hippocampus tissue of mice were significant differences among the four groups ( F=7.21, 9.89, both P<0.05). The levels of TNF-α and IL-1β in the hippocampus of mice in the high-dose nano-PbO group were higher than those in the control group (TNF-α: (0.35±0.10), (1.03±0.30), P<0.05; IL-1β: (0.32±0.10), (0.50±0.15), P<0.05). The results of flow cytometry analysis showed that the proportions of leukocytes in the brain tissue of mice in the low, medium and high dose groups of nano-PbO were (9.99±1.09)%, (13.03±0.94)% and (16.51±3.89)%, respectively. Among them, the proportions of leukocytes in the middle and high dose groups of nano-PbO were significantly higher than that in the control group((8.13±1.29)%) (both P<0.05). The results of correlation analysis showed that the proportion of leukocytes, levels of TNF-α, IL-1β protein of hippocampus in the medium, high dose groups of nano-PbO were negatively correlated with the behavioral indexes ( r=-0.815, -0.744, -0.578, all P<0.01; r=-0.771, -0.836, -0.704, all P<0.05; r=-0.823, -0.876, -0.695, all P<0.05). The results of Western blot showed that the levels of ICAM-1 and VCAM-1 in cerebral microvessels of mice in the four groups were significantly different ( F=5.51, 16.19, both P<0.05). The levels of ICAM-1 and VCAM-1 in the middle and high dose groups of nano-PbO were higher than those in the control group(ICAM-1: (1.07±0.16), (1.21±0.35), (0.59±0.19), all P<0.05; VCAM-1: (0.68±0.12), (1.92±0.23), (0.23±0.05), both P<0.05). In addition, there was a significant difference in the level of LFA-1 protein in blood leukocytes of mice in the four groups ( F=41.80, P<0.05). The levels of LFA-1 in the middle and high dose groups of nano-PbO were higher than that in the control group((0.33±0.06), (0.89±0.23), (0.05±0.01), both P<0.05). Conclusion:The nano-PbO exposure can lead to cognitive impairment and increased inflammatory factors in the hippocampus of mice, which may be related to the increase of ICAM-1 and VCAM-1 in vascular endothelial cells, which promotes leukocyte infiltration into brain tissue.

Background Lead exposure induces microglial cell death, of which the mechanism is unclear. Ferroptosis is a new death form and its role in microglia death has not been reported. Objective To investigate the role of ferroptosis in microglia following lead exposure in order to provide a theoretical basis for the mechanism of lead neurotoxicity. Methods Microglial cell line BV-2 cells were co-cultured with 0, 10, 20 and 40 μmol·L⁻¹ lead acetate for 24 h. The 40 μmol·L⁻¹ lead acetate group with iron chelator (DFO) was named the 40+DFO group. Changes in BV-2 cell morphology after lead exposure were observed under an inverted microscope; tissue iron kit and glutathione kit were used to detect intracellular iron and glutathione (GSH) respectively; flow cytometry was applied to detect lipid reactive oxygen species (lipid ROS) immunofluorescence intensity. Western blotting and qPCR were adopted to detect the expressions of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), transferrin receptor 1 (TFR-1), divalent metal transporter 1 (DMT1), ferroportin 1 (FPN1) protein and mRNA. Results Compared with the control group, the number of BV-2 cells decreased with increasing doses of lead and the cells showed a large, round amoeboid shape. The intracellular levels of iron of BV-2 cells were (1.08±0.04), (1.29±0.03), and (1.72±0.10) mg·g⁻¹ (calculated by protein, thereafter) in the 10, 20, and 40 μmol·L⁻¹ lead acetate groups, respectively, significantly higher than that in the control group (P<0.05), and the intracellular level of iron in the 40+DFO group, (1.34±0.10) mg·g⁻¹, was lower than that in the 40 μmol·L⁻¹ lead acetate group, (1.72±0.03) mg·g⁻¹ (P<0.05). Compared with the control group, the TFR-1 and DMT1 protein and mRNA expressions were increased in BV-2 cells in the 10, 20, 40 μmol·L⁻¹ lead acetate groups (P<0.05), especially in the 40 μmol·L⁻¹ lead acetate group; the FPN1 protein expression did not change significantly, but the FPN1 mRNA expressions in BV-2 cells in the 10, 20, 40 μmol·L⁻¹ lead acetate groups were significantly decreased (P<0.05). Compared with the control group, the intracellular GSH level decreased and the lipid ROS content increased in all three lead acetate groups; compared with the 40 μmol·L⁻¹ lead acetate group, the GSH level increased by 12.30% and the lipid ROS content decreased by 13.00% in the 40+DFO group (P<0.05). The expressions of GPX4 protein were reduced to 50.00%, 35.00%, and 17.00% of that of the control group in the 10, 20, and 40 μmol·L⁻¹ lead acetate groups respectively, while the expressions of GPX4 mRNA were also significantly reduced; the expressions of SLC7A11 protein and mRNA in the 20 and 40 μmol·L⁻¹ lead acetate groups were lower than that in the control group, with the most significant decrease in the 40 μmol·L⁻¹ lead acetate group (P<0.05). Conclusion Lead exposure could induce ferroptosis in BV-2 cells, in which iron transport imbalance and oxidative damage might be involved.

BACKGROUND: Few studies have assessed the relationship between multimorbidity patterns and mortality risk in the Chinese population. We aimed to identify multimorbidity patterns and examined the associations of multimorbidity patterns and the number of chronic diseases with the risk of mortality among Chinese middle-aged and older adults. METHODS: We used data from the China Kadoorie Biobank and included 512,723 participants aged 30 to 79 years. Multimorbidity was defined as the presence of two or more of the 15 chronic diseases collected by self-report or physical examination at baseline. Multimorbidity patterns were identified using hierarchical cluster analysis. Cox regression was used to estimate the associations of multimorbidity patterns and the number of chronic diseases with all-cause and cause-specific mortality. RESULTS: Overall, 15.8% of participants had multimorbidity. The prevalence of multimorbidity increased with age and was higher in urban than rural participants. Four multimorbidity patterns were identified, including cardiometabolic multimorbidity (diabetes, coronary heart disease, stroke, and hypertension), respiratory multimorbidity (tuberculosis, asthma, and chronic obstructive pulmonary disease), gastrointestinal and hepatorenal multimorbidity (gallstone disease, chronic kidney disease, cirrhosis, peptic ulcer, and cancer), and mental and arthritis multimorbidity (neurasthenia, psychiatric disorder, and rheumatoid arthritis). During a median of 10.8 years of follow-up, 49,371 deaths occurred. Compared with participants without multimorbidity, cardiometabolic multimorbidity (hazard ratios [HR] = 2.20, 95% confidence intervals [CI]: 2.14 - 2.26) and respiratory multimorbidity (HR = 2.13, 95% CI:1.97 - 2.31) demonstrated relatively higher risks of mortality, followed by gastrointestinal and hepatorenal multimorbidity (HR = 1.33, 95% CI:1.22 - 1.46). The mortality risk increased by 36% (HR = 1.36, 95% CI: 1.35 - 1.37) with every additional disease. CONCLUSION Cardiometabolic multimorbidity and respiratory multimorbidity posed the highest threat on mortality risk and deserved particular attention in Chinese adults.
Aged ; Arthritis, Rheumatoid ; Asians ; China/epidemiology* ; Humans ; Hypertension ; Middle Aged ; Multimorbidity

Objective To evaluate the effects of ketamine anesthesia on proteome in hippocampus in aged rats.Methods Thirty healthy male Wistar rats,aged 20 months,weighing 560-610 g,were di-vided into 2 groups(n＝15 each)using a random number table method: control group(group C)and ket-amine group(group K).In group K,ketamine 80 mg/kg was intraperitoneally injected,additional 1/2 ini-tial dose was given when the righting reflex was recovered,and anesthesia was maintained for 3 h.Morris water maze test was performed starting from 1st day after the end of anesthesia.Five rats were selected at days 1 and 7 after the end of anesthesia and sacrificed,and hippocampal tissues were obtained to extract proteins.Proteins extracted from rat hippocampi were identified by 2-dimensional electrophoresis(2-DE).The differentially expressed proteins were analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry(MALDI-TOF-MS)and biological information system.Results Compared with group C,the escape latency and total swimming distance to find the submerged platform in Morris water maze at the 1st day after anesthesia were significantly prolonged in group K(P＜0.05 or 0.01).The MAL-DI-TOF-MS analysis showed that there were 21 differentially expressed proteins at 1st day after ketamine an-esthesia,of which 6 proteins(involving maintenance of intracellular protein homeostasis,energy metabo-lism,etc.)presented with up-regulated expression and 15 proteins(involving synaptic vesicle transport ef-ficiency,synaptic structural and functional plasticity,maintenance of intracellular protein homeostasis,NMDA-mediated Ca2+signal transport,energy metabolism,etc.)presented with down-regulated expres-sion.There were 8 differentially expressed proteins at 7th day,including 3 proteins with up-regulated ex-pression and 5 proteins with down-regulated expression(P＜0.05).Conclusion Ketamine anesthesia can induce 21 differentially expressed proteins in hippocampi of aged rats,involving synaptic vesicle transport efficiency,synaptic structural and functional plasticity,intracellular protein homeostasis,NMDA-mediated Ca2+signal transport,energy metabolism,and etc.which may be involved in the mechanism of ketamine-induced temporary cognitive dysfunction.

Objective: To evaluate the effects of ketamine anesthesia on proteome in hippocampus in aged rats. Methods: Thirty healthy male Wistar rats, aged 20 months, weighing 560-610 g, were divided into 2 groups (n=15 each) using a random number table method: control group (group C) and ketamine group (group K). In group K, ketamine 80 mg/kg was intraperitoneally injected, additional 1/2 initial dose was given when the righting reflex was recovered, and anesthesia was maintained for 3 h. Morris water maze test was performed starting from 1st day after the end of anesthesia.Five rats were selected at days 1 and 7 after the end of anesthesia and sacrificed, and hippocampal tissues were obtained to extract proteins.Proteins extracted from rat hippocampi were identified by 2-dimensional electrophoresis (2-DE). The differentially expressed proteins were analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and biological information system. Results: Compared with group C, the escape latency and total swimming distance to find the submerged platform in Morris water maze at the 1st day after anesthesia were significantly prolonged in group K (P<0.05 or 0.01). The MALDI-TOF-MS analysis showed that there were 21 differentially expressed proteins at 1st day after ketamine anesthesia, of which 6 proteins (involving maintenance of intracellular protein homeostasis, energy metabolism, etc.) presented with up-regulated expression and 15 proteins (involving synaptic vesicle transport efficiency, synaptic structural and functional plasticity, maintenance of intracellular protein homeostasis, NMDA-mediated Ca²⁺ signal transport, energy metabolism, etc.) presented with down-regulated expression.There were 8 differentially expressed proteins at 7th day, including 3 proteins with up-regulated expression and 5 proteins with down-regulated expression (P<0.05). Conclusion Ketamine anesthesia can induce 21 differentially expressed proteins in hippocampi of aged rats, involving synaptic vesicle transport efficiency, synaptic structural and functional plasticity, intracellular protein homeostasis, NMDA-mediated Ca²⁺ signal transport, energy metabolism, and etc.which may be involved in the mechanism of ketamine-induced temporary cognitive dysfunction.

One patient with chronic refractory wound in right lower leg was admitted to our department in June 2017, which experienced repeated ulceration for 4 years. On 4 days post admission, two bamboo sticks were taken out from the deep muscle of the right lower leg. The wound was repaired by perforator flap of posterior tibial artery in the right lower leg. The donor site was covered with split-thickness skin in the upper leg of the same side. On 7 days post operation, the flap and skin graft survived. During follow-up of 12 months, the flap had good appearance. This case suggests that the first thing for the treatment of chronic refractory wound is to find out the cause of wound.