BACKGROUND:Knee osteoarthritis is a common disease in middle-aged and elderly people.It is a kind of disease that seriously affects the quality of life of patients and even has the risk of disability.Therefore,the pathogenesis and treatment of knee osteoarthritis have become the focus of research.In Chinese medicine,knee osteoarthritis is often treated as"biness,"which is closely related to"biness"caused by blood stasis and blood vessels blocking collaterals in the theory of"blood stasis"in traditional Chinese medicine.Iron overload is a kind of pathological state caused by iron metabolism disorder,which highly coincides with the pathogenic characteristics and clinical manifestations of the"blood stasis"theory of traditional Chinese medicine,and is a risk factor that promotes the development of knee osteoarthritis. OBJECTIVE:Based on the"blood stasis"theory,to summarize the effects of iron overload on cartilage metabolism and subchondral bone reconstruction,to lay a new theoretical foundation for the treatment of knee osteoarthritis with traditional Chinese medicine,and to explore the therapeutic effect of traditional Chinese medicine for promoting blood circulation after interfering with bone tissue. METHODS:CNKI,WanFang database,PubMed and Web of Science databases were searched for relevant literature.The Chinese search terms were"ferroptosis,iron,iron overload,osteoarthritis,blood stasis"and the English search terms were"ferroptosis,iron,iron overload,osteoarthritis,TCM."In the end,76 articles were included for further review. RESULTS AND CONCLUSION:First of all,we explored the potential of the"blood stasis"theory in treating knee osteoarthritis,and found that"blood stasis"is a crucial part in the progress of knee osteoarthritis,indicating that the"blood stasis"theory is the key to the treatment of knee osteoarthritis in traditional Chinese medicine.Secondly,"blood stasis"and iron overload have a high degree of similarity in pathogenic factors,clinical manifestations,and pathogenic characteristics,suggesting the possibility of"blood stasis"theory in treating iron overload.This finding reminds us that iron overload may be an important mechanistic basis for the"blood stasis"theory in the treatment of knee osteoarthritis.The extracts of blood-activating drugs can relieve iron overload and treat knee osteoarthritis,but the specific mechanism is still unclear.Therefore,we believe that the relationship between"blood stasis"theory and iron overload and related mechanisms are important research directions for knee osteoarthritis in the future.The related mechanism of"blood stasis"theory to alleviate iron overload and then treat knee osteoarthritis also provides a theoretical basis for the modernization of traditional Chinese medicine,such as the development of new drugs and innovative usage,and has certain guiding significance for clinical practice.

Bacteria have posed a threat to human health,and the emergence of super bacteria has made it more difficult to cure bacterial infections in clinical practice.Currently,vaccines are one of the effective means of preventing bacterial infections.With the rapid development of cutting-edge technologies in recent years in such disciplines as biology,medicine,and materials science,various innovative strategies have been provided for vaccine research and preparation.This article summarizes the status quo and prospects of innovative vaccines for treating bacterial infections in recent years,including subunit vaccines,mRNA vaccines and attenuated live vaccine in the hopes of providing data for subsequent development and research of bacterial vaccines.

Objective:To evaluate the effect of pre-injection of young rat plasma on cognitive dysfunction after cerebral ischemia-reperfusion (I/R) in aged rats and the role of phosphatidylinositol 3-kinase/serine threonine protein kinase (PI3K/Akt) signaling pathway.Methods:Seventy-two SPF-grade healthy male Sprague-Dawley rats, aged 18 months, weighing 600-650 g, were divided into 4 groups ( n=18 each) by the random number table method: control group (group C), cerebral I/R group (group IR), pre-injection of young rat plasma group (group P) and PI3K inhibitor LY294002 group (group LY). In group P and group LY, young rat plasma 100 μl/time was injected via the tail vein. In group C and group IR, the equal volume of normal saline was injected via the the tail vein, 2 times a week for 4 weeks. Then the model of cerebral I/R injury was developed under sevoflurane anesthesia in IR, P and LY groups. LY294002 0.3 mg/kg was injected through the tail vein at 1 h before anesthesia in LY group. The neurological deficit score (Longa score) was performed at 24 h after reperfusion, and then 6 rats were randomly sacrificed, and brain tissues were obtained to determine the cerebral infarct volume. Spontaneous mobility and anxiety-like behavior were assessed by the open field test at day 29 of reperfusion, and cognitive function was assessed by the novel object recognition test at day 30 of reperfusion. At the end of the behavioral test, rats were sacrificed, hippocampal tissues were isolated for determination of the expression of phosphorylated PI3K (p-PI3K), phosphorylated Akt (p-Akt), postsynaptic dense protein-95 (PSD-95) and synaptic vesicle protein (SYN) (by Western blot), and the dendritic length and dendritic spine density of neurons in the hippocampal CA1 region. Results:There was no significant difference in motor speed, distance traveled, and time of staying at the center of the open field among the four groups ( P>0.05). Compared with group C, the Longa score and cerebral infarct volume were significantly increased, the percentage of novel object exploration and discrimination index were decreased, the expression of p-PI3K, p-Akt, PSD-95 and SYN in hippocampal tissues was down-regulated, and the dendritic length and dendritic spine density of hippocampal neurons were decreased in IR, P and LY groups ( P<0.05). Compared with group IR, Longa score and cerebral infarct volume were significantly decreased, the percentage of novel object exploration and discrimination index were increased, the expression of p-PI3K, p-Akt, PSD-95 and SYN in hippocampal tissues was up-regulated, and the dendritic length and dendritic spine density of hippocampal neurons were increased in group P ( P<0.05), and no significant change was found in the parameters mentioned above in group LY ( P>0.05). Compared with group P, Longa score and cerebral infarct volume were significantly increased, the percentage of novel object exploration and discrimination index were decreased, the expression of p-PI3K, p-Akt, PSD-95 and SYN in hippocampal tissues was down-regulated, and the dendritic length and dendritic spine density of hippocampal neurons were decreased in group LY ( P<0.05). Conclusions:Pre-injection of young rat plasma can attenuate cognitive dysfunction after cerebral I/R in aged rats, and the mechanism is related to activation of hippocampal PI3K/Akt signaling pathway and improvement in synaptic plasticity.

Objective:To evaluate the effects of hemoclips on preventing delayed bleeding for early gastric cancer (EGC) after endoscopic submucosal dissection (ESD).Methods:Clinical data of 459 patients who underwent ESD for EGC in Beijing Friendship Hospital from June 2013 to August 2020 were collected retrospectively. Patients were divided into group A (hemoclip group, n=162) and group B (non-hemoclip group, n=297) according to whether preventive hemostatic clip treatment was performed after resection. Delayed bleeding within 2 weeks after ESD was observed. Univariate analysis and subgroup analysis were conducted for the delayed bleeding incidence and clinicopathological features. Results:Delayed bleeding incidences of group A and group B were 3.1% (5/162) and 8.1% (24/297) with significant difference between the two groups ( χ2=4.418, P=0.036). Subgroup analysis showed that there were significant differences in the delayed bleeding incidence between the two groups when the diameter of the tumor >20 mm [3.5% (2/57) VS 15.3% (13/85), χ2=5.016, P=0.025], the tumor located in the lower part of the stomach [1.0% (1/97) VS 10.4% (20/192), χ2=8.425, P=0.004], and the depth of tumor invasion was M/SM1 [3.2% (5/157) VS 8.1% (23/285), χ2=4.072, P=0.044]. There were no significant differences in the delayed bleeding incidence between group A and group B when the diameter of the tumor ≤20 mm, the tumor located in the upper/medial part of the stomach and the depth of tumor invasion was SM2 ( P>0.05). Conclusion:Hemoclips can prevent delayed bleeding after ESD for EGC, which is mainly observed in a tumor of diameter >20 mm, located in the lower part of the stomach and M/SM1 tumor invasion. It has little effect on the prevention when the tumor diameter ≤20 mm and located in the upper/medial part of the stomach.

Objective To establish a preliminary evaluation system for gastrointestinal qi stagnation syndrome.Methods On the basis of the systematic evaluation of medical literature in the early stage of the research group,24 high-frequency items were subjected to Delphi method,the item indexes were determined through three rounds of expert consultation,and the proportion value of the indexes was determined by AHP,and the evaluation system of gastrointestinal qi stagnation syndrome was initially constructed.Results A total of 84 valid questionnaires were collected by three rounds of Delphi method,including 15 in the first round,32 in the second round and 37 in the third round.According to the statistics,16 items including distention(stuffy)or distending pain or moving pain(epigastric,abdominal,etc.),belching,borborygmus,flatus,etc.were selected.The order of the proportion of the first level indexes obtained by the analytic hierarchy process from high to low is:clinical symptoms,pulse,tongue;The proportion of secondary indicators from high to low is as follows:distention(stuffy)or distending pain or moving pain(epigastric,abdominal,etc.),pulse string,greasy fur,thin white fur,slippery pulse string,pulse sinking string,light red tongue,flatus,borborygmus,belching,induced or aggravated in case of emotional distress,hiccup,abdominal mass,anorexia,vomiting,belching and swallowing acid.Conclusion Delphi method and analytic hierarchy process have been used to study gastrointestinal qi stagnation syndrome,and an evaluation system has been preliminarily formed.The index structure is reasonable,targeted and has strong clinical practicability.

Objective:To evaluate the effect of esketamine on hippocampal neuronal necroptosis in aged rats with postoperative cognitive dysfunction.Methods:One hundred and twenty SPF-grade healthy male Sprague-Dawley rats, aged 22 months, weighing 550-600 g, were divided into 4 groups ( n=30 each) using a random number table method: control group (group C), postoperative cognitive dysfunction group (group P), postoperative cognitive dysfunction+ esketamine group (group PE), and esketamine group (group CE). Rats received exploratory laparotomy under sevoflurane anesthesia, and esketamine 10 mg/kg and the equal volume of 0.9% sodium chloride were intraperitoneally injected at the end of surgery once a day for 6 consecutive days in group P and group PE, respectively. Rats received no anesthesia and surgery, and esketamine 10 mg/kg and the equal volume of 0.9% sodium chloride were intraperitoneally injected at the end of surgery once a day for 6 consecutive days in group CE and group C, respectively. Morris water maze test was performed at 7th day after surgery. The escape latency, times of crossing the original platform and time spent in the original platform quadrant were recorded. The rats were sacrificed at the end of Morris water maze test, and the hippocampal tissues were collected for determination of the rate of necroptosis and cytosolic Ca 2+ concentrations (by flow cytometry) and expression of mixed lineage kinase domain-like protein (MLKL), phosphorylated MLKL (p-MLKL), receptor-interacting protein kinase-3 (RIPK3), phosphorylated RIPK3 (p-RIPK3), receptor-interacting protein kinase-1 (RIPK1) and phosphorylated RIPK1 (p-RIPK1) (by Western blot). Results:Compared with group C, the escape latency was significantly prolonged, the times of crossing the original platform were decreased, the time spent in the original platform quadrant was shortened, the necroptosis rate of hippocampal neurons and cytosolic Ca 2+ concentrations were increased, and the expression of MLKL, p-MLKL, RIPK3, p-RIPK3, RIPK1 and p-RIPK1 was up-regulated in group P and group PE ( P<0.05). Compared with group P, the escape latency was significantly shortened, the times of crossing the original platform were increased, the time spent in the original platform quadrant was prolonged, the necroptosis rate of hippocampal neurons and cytosolic Ca 2+ concentrations were decreased, and the expression of MLKL, p-MLKL, RIPK3, p-RIPK3, RIPK1 and p-RIPK1 was down-regulated in group PE ( P<0.05). Conclusions:The mechanism by which esketamine attenuates postoperative cognitive dysfunction may be related to inhibition of necroptosis in hippocampal neurons of aged rats.

Objective:To evaluate the role of N-methyl-D-aspartate receptors (NMDA receptors) in sevoflurane anesthesia-caused necroptosis in hippocampal neurons of aged mice.Methods:Ninety clean-grade healthy male C57BL/6 mice, aged 18 months, weighing 27-30 g, were divided into 3 groups ( n=30 each) using a random number table method: control group (group C), sevoflurane anesthesia group (group S) and sevoflurane anesthesia plus NMDA receptor antagonist memantine hydrochloride group (group S+ M). Mice inhaled 3% sevoflurane for 2 h for 3 consecutive days in S group and S+ M group, and memantine hydrochloride 20 mg/kg was intraperitoneally injected at 1 h before each inhalation of sevoflurane in S+ M group.Mice only inhaled pure oxygen for 2 h in group C. Ten mice of each group were selected on 1 day before anesthesia and 3 and 7 days after anesthesia to perform Morris water maze test.The mice were sacrificed immediately after Morris water maze test, and hippocampus was removed for microscopic examination of pathological changes (with a light microscope) and for determination of the necroptosis rate of neurons and cytoplasmic free calcium concentration([Ca 2+ ] i)(by flow cytometry), and expression of NMDA receptor subtypes GluN2A, GluN2B and receptor-interacting protein kinase 1 (RIP1) (by Western blot). Results:Compared with group C, the escape latency was significantly prolonged, and the frequency of crossing the original platform was decreased, and the [Ca 2+ ] i and neuronal necroptosis rate in the hippocampus were increased at each time point after anesthesia, and the expression of GluN2A, GluN2B and RIP1 was up-regulated( P<0.05), and the pathologic changes were accentuated in S group and S+ M group.Compared with group S, the escape latency was significantly shortened, and the frequency of crossing the original platform was increased, and the [Ca 2+ ] i and neuronal necroptosis rate in the hippocampus were decreased at each time point after anesthesia, and the expression of GluN2A, GluN2B and RIP1 was down-regulated ( P<0.05), and the pathologic changes were attenuated in group S+ M. Conclusions:NMDA receptors are involved in the process of cognitive dysfunction induced by sevoflurane anesthesia in aged mice, and the mechanism may be related to the promotion of necrptosis in hippocampal neurons.

Objective:To evaluate the role of RhoA/ROCK2 signaling pathway in multiple exposures to sevoflurane-induced long-term cognitive impairment in neonatal rats.Methods:Sixty SPF healthy neonatal Sprague-Dawley rats of either sex, aged 6 days, weighing 12-20 g, were divided into 3 groups ( n=20 each) using a random number table method: control group (group C), multiple exposures to sevoflurane group (group S) and RhoA/ROCK2 signaling pathway inhibitor Y-27632 group (group Y). Group S and group Y inhaled 3% sevoflurane for 2 h at days 6, 7 and 8 after birth.In group Y, Y-27632 5 mg/kg was intraperitoneally injected before sevoflurane anesthesia.The spontaneous activity was evaluated by open field test on day 35 after birth.The cognitive function was detected by Morris water maze test at day 36 after birth.The rats were sacrificed after Morris water maze test, and the hippocampal tissues were isolated for determination of the apoptosis rate of hippocampal neurons and cytoplasmic calcium concentration ([Ca 2+ ] i) (by flow cytometry) and expression of phosphorylated RhoA (p-RhoA), ROCK2 and cleaved-caspase-3 (by Western blot) and for microscopic examination of the ultrastructure of hippocampal neurons (with a transmission electron microscope). Results:There was no significant difference in movement speed, distance and time of stay in the open field center in the open field test among the three groups ( P>0.05). Compared with group C, the escape latency was significantly prolonged, the number of crossing the original platform was reduced, the apoptosis rate of hippocampal neurons and [Ca 2+ ] i were increased, the expression of p-RhoA, ROCK2 and cleaved-caspase-3 was up-regulated ( P<0.05), and the pathological injury to hippocampal neurons was found in group S. Compared with group S, the escape latency was significantly shortened, the number of crossing the original platform was increased, the apoptosis rate of hippocampal neurons and [Ca 2+ ] i were decreased, the expression of p-RhoA, ROCK2 and cleaved-caspase-3 was down-regulated ( P<0.05), and the pathological injury to hippocampal neurons was attenuated in group Y. Conclusions:The mechanism by which multiple exposures to sevoflurane induces long-term cognitive impairment is related to activation of RhoA/Rock2 signaling pathway and induction of apoptosis rate of hippocampal neurons in neonatal rats.

Objective:To evaluate the effect of esketamine on the efficacy of postoperative patient-controlled intravenous analgesia (PCIA) in the patients with moderate central sensitization undergoing high tibial osteotomy.Methods:Fifty-four patients of both sexes with moderate central sensitization, aged 45-64 yr, with body mass index of 18.0-32.5 kg/m 2, of American Society of Anesthesiologists Physical Status classification Ⅰ or Ⅱ, undergoing elective high tibial osteotomy, were divided into 2 groups ( n=27 each) using a random number table method: control group (group C) and esketamine group (group ES). Ultrasound-guided femoral nerve block was performed with 0.5% ropivacaine 30 ml on the operated side at 30 min before induction of anesthesia.In C and ES groups, midazolam 0.1 mg/kg, sufentanil 0.2 μg/kg, propofol 1.5 mg/kg, and cisatracurium besilate 0.15 mg/kg were intravenously injected in turn during induction of anesthesia, and in addition esketamine hydrochloride 0.5 mg/kg was injected in ES group, and the equal volume of 0.9% sodium chloride was injected in C group, and then a laryngeal mask airway was placed.Anesthesia was maintained with intravenous infusion of remifentanil 0.1-0.3 μg·kg -1·min -1 and propofol 4-6 mg·kg -1·h -1.Esketamine hydrochloride 0.2 mg/kg was intravenously injected once every 20 min until 30 min before the end of operation in ES group, the equal volume of 0.9% sodium chloride was injected according to the amount of esketamine hydrochloride injected for the same body weight at the same time point in C group, and additional cisatracurium besilate was administered intermittently according to the degree of muscle relaxation.Intraoperative BIS values were maintained at 40-60.Postoperative PCIA was performed, and the patient was admitted to the post-anesthesia care unit.When the efficacy of PCIA was not good, ketorolac tromethamine 30 mg was intravenously injected for rescue analgesia.The intraoperative consumption of remifentanil and propofol and emergence time in the anesthesia recovery room were recorded.The pressing times of PCA and the number of rescue analgesia in each group were recorded within 2 days after operation.The Chinese Richards-Campbell Sleep Questionnaire was used to assess the nighttime sleep quality on the night of surgery and 1 and 2 days after surgery.The Chinese Quality of Recovery was used to assess the early recovery quality at 1 and 2 days after surgery.The first postoperative off-bed time and first walked distance were recorded.The adverse reactions were recorded. Results:Compared with group C, the consumption of remifentanil and propofol was significantly reduced, the emergence time in the anesthesia recovery room was prolonged, the pressing times of PCA and the number of rescue analgesia were decreased within 2 days after operation, the quality of nighttime sleep was improved on the night of surgery and 1 and 2 days after operation, the quality of early recovery on 1 and 2 days after operation was increased, the first postoperative off-bed time was shortened, the first walked distance was prolonged, and the incidence of postoperative adverse effects was decreased in group ES ( P<0.05). Conclusions:Esketamine can enhance the efficacy of postoperative PCIA in the patients with moderate central sensitization undergoing high tibial osteotomy.

Objective:To evaluate the role of 1, 4, 5-inositol triphosphate receptor (IP3R) in necroptosis of hippocampal neurons induced by sevoflurane anesthesia in aged rats.Methods:Sixty healthy male Sprague-Dawley rats, aged 18 months, weighing 500-600 g, were divided into 3 groups ( n=20 each) using a random number table method: control group (group C), sevoflurane anesthesia group (group S) and sevoflurane anesthesia + IP3R antagonist group (group S+ I). S and S+ I groups inhaled 2% sevoflurane for 5 h. In group S+ I, IP3 receptor antagonist 2-APB 3 mg/kg was intraperitoneally injected at 10 min before sevoflurane inhalation, and the equal volume of dimethyl sulfoxide was intraperitoneally injected in group C and group S. Morris water maze test was used to test the cognitive function on the day after the end of sevoflurane anesthesia.Then the animals were sacrificed and the brain tissues were obtained for microscopic examination of the pathological changes after HE staining and Nissl staining (with a light microscope) and for determination of the free calcium concentration ([Ca 2+ ] i) and rate of necroptosis of hippocampal neurons (by flow cytometry) and expression of IP3R, receptor-interacting protein kinase-1 (RIPK1), receptor-interacting protein kinase-3 (RIPK3) and phosphorylated mixed lineage kinase domain-like protein (p-MLKL) (by Western blot). Results:Compared with group C, the escape latency was significantly prolonged, the times of crossing the platform were reduced, the time of staying at the target quadrant was shortened, the [Ca 2+ ] i and necroptosis rate of hippocampal neurons were increased, and the expression of IP3R, RIPK1, RIPK3 and p-MLKL in hippocampal neurons was up-regulated in group S and group S+ I ( P<0.05). Compared with group S, the escape latency was significantly shortened, the times of crossing the platform were increased, the time of staying at the target quadrant was prolonged, the [Ca 2+ ] i and necroptosis rate of hippocampal neurons were decreased, and the expression of IP3R, RIPK1, RIPK3 and p-MLKL in hippocampal neurons was down-regulated in group S+ I ( P<0.05). Conclusions:The mechanism by which sevoflurane induces cognitive dysfunction may be related to the imbalance of calcium homeostasis caused by activation of IP3R and thus inducing programmed necrosis in aged rats.