BACKGROUND:Observational studies have shown that intervertebral disc degeneration affects sedentary and physical activity levels;however,the causal relationship between sedentary and physical activity levels in the Oswestry disability index score and intervertebral disc degeneration is unclear. OBJECTIVE:To explore the causal relationship between sedentary and physical activity levels in the Oswestry disability index score and intervertebral disc degeneration using the Mendelian randomization method. METHODS:Five features associated with behavioral correlations in the Oswestry disability index score,including time spent watching TV,time spent on the computer,and light/moderate/vigorous physical activity,were selected from large-scale population-based genome-wide association studies,and instrumental variables were extracted for each of these behaviorally related features.Mendelian randomization analyses were performed in conjunction with the extraction of intervertebral disc degeneration as an outcome from the Finn Gen latest version 9 database.The results were analyzed using the inverse variance weighted,MR-Egger regression,simple mode,weighted mode,weighted median estimator,and regression model odds ratios(OR)and 95%confidence interval(CI)to assess the causal relationship between sedentary and physical activity levels in the Oswestry disability index scoring and intervertebral disc degeneration.Cochran's Q was used to test for heterogeneity,MR-Egger intercept to test for multiplicity,and leave-one-out to test the sensitivity of single nucleotide polymorphisms to the causal relationship between exposure factors and disc degeneration. RESULTS AND CONCLUSION:The results of the Mendelian randomization analysis using inverse variance weighted method showed a positive causal association between time spent watching TV/on the computer and the risk of intervertebral disc degeneration(OR=1.775,95%CI:1.418-2.221,P<0.001)/(OR=1.384,95%CI:1.041-1.839,P<0.001),an inverse causal association between light physical activity and the risk of intervertebral disc degeneration(OR=1.000,95%CI:0.999-1.000,P=0.020).MR-Egger intercept analysis indicated there was potential horizontal polytropy between light physical activity and intervertebral disc degeneration(P=0.005),while there was no horizontal pleiotropy between time spent watching TV,time spent on the computer and intervertebral disc degeneration(P=0.521,P=0.851).Cochran's Q analysis showed that heterogeneity was observed between time spent watching TV,time spent on the computer and intervertebral disc degeneration(P=3.33×10-11,P=0.001),and no significant heterogeneity was observed between light physical activity and intervertebral disc degeneration(P=0.186).Overall,there is a bidirectional causal relationship between sedentary and physical activity levels in the Oswestry disability index score and intervertebral disc degeneration,i.e.,not only does intervertebral disc degeneration affect sedentary and physical activity levels in the Oswestry disability index score,but sedentary and physical activity levels in the Oswestry disability index score also affect intervertebral disc degeneration.These findings add to the genetic evidence for a positive effect of light physical activity on intervertebral disc degeneration,indicate that moderate/vigorous physical activity shows no significant causal relationship with intervertebral disc degeneration,and expand the evidence base for sedentary behaviors such as prolonged time spent watching TV/on the computer as a risk factor for intervertebral disc degeneration.

Objective To explore the clinical efficacy and safety of one-stage posterior lesion removal and internal spinal fixation in patients with lumbar Brucellosis spondylitis.Methods The clinical data of 24 patients admitted from October 2017 to October 2022 were retrospectively analyzed,2 patients were lost to follow-up at 10 months after surgery,at the final 22 cases were included in the study,including 13 males and 9 females with an average age of(52.00±6.89)years old,were treated with one-stage posterior lesion removal and internal spinal fixation.The operation time,intraoperative bleeding,follow-up time,ery-throcyte sedimentation rate(ESR)and C-reactive protein(CRP)before and after operation were recorded.The pain visual ana-logue scale(VAS),Oswestry disability index(ODI),the Japanese Orthopaedic Association(JOA)score for neurofunction,American Spinal Injury Association(ASIA)spinal cord injury grade and modified MacNab criteria were ussed to evaluate the efficacy.Results All patients were followed up from 12 to 30 months with an average of(17.41±4.45)months.The operation time was 70 to 155 min with an average of(1 16.59±24.32)min;the intraoperative bleeding volume was 120 to 520 ml with an average of(275.00±97.53)ml.CRP and ESR levels decreased more significantly at 1 week and at the final follow-up than pre-operative levels(P＜0.05).VAS,JOA score and ODI at 1 week and at the latest follow-up were more significantly improved than preoperative results(P＜0.05).There was no significant difference between ASIA preoperative and 1 week after operation(P＞0.05),and a significant difference between preoperative and last follow-up(P＜0.05).In the final follow-up,21 patients had ex-cellent efficacy,1 patient had fair,and there was no recurrence during the follow-up.Conclusion One-stage transpedicular le-sion removal and internal spinal fixation,with few incisions and short operation time,helps the recovery of neurological func-tion,and the prognosis meets the clinical requirements,which can effectively control Brucella spondylitis.

Objective To explore root cause of poor prognosis after successful endovascular treatment(EVT)in patients with acute ischemic stroke with large vascular occlusion(AIS-LVO)of anterior circulation.Methods Patients with AIS-LOV of anterior circulation who received successful EVT(postoperative modified thrombolysis incerebral infarction[mTICI]grade≥2b)were retrospectively and continuously collected in the Department of Neurology of Bozhou People's Hospital from January 2022 to March 2024.The baseline and clinical data of the patients were collected,including gender,age,vascular risk factors(hypertension,diabetes,coronary heart disease,hyperlipidemia,valvular heart disease,atrial fibrillation,smoking,and alcohol consumption),prior stroke or transient ischemic attack,baseline blood pressure,baseline National Institutes of Health Stroke scale(NIHSS)score,laboratory test indicators(pre-operative C-reactive protein and D-dimer,post-operative fasting blood glucose,lipid levels,homocysteine,etc).Meanwhile,the data of perioperative indicators was collected,including the time from onset to admission,the time from admission to puncture,the time from puncture to revascularization,the time from onset to puncture,the time from onset to revascularization,remedial measures(balloon dilation,stent placement,arterial thrombolysis)during the surgery or not,using tirofiban or not,postoperative complications(stroke-related pneumonia,stress ulcers,deep vein thrombosis,acute heart failure or renal failure,etc)or not.The patient's medical history and imaging data were collected,and these indicators were defined and collected,including Alberta stroke program early CT score(ASPECTS),location of occlusion(C1 segment of the internal carotid artery,C2 segment to C7 segment of the internal carotid artery,M1 segment of the middle cerebral artery),and the trial of org 10172 in acute stroke treatment(TOAST)classification and a postoperative transformation of cerebral infarction after ischemic stroke and symptomatic intracranial hemorrhage or not.According to the modified Rankin scale(mRS)score at 90 d after surgery,all patients were divided into poor prognosis group(mRS score≥ 3)and good prognosis group(mRS score≤2).The baseline and clinical data of two groups were compared using univariate analysis.Variables with P＜0.1 in the univariate analysis were selected as independent variables,and the poor prognosis was used as the dependent variable.Further,multivariate Logistic regression analysis was performed to identify the influencing factors of poor prognosis after EVT.Results Finally,a total of 192 patients with AIS-LVO of anterior circulation who received successful revascularization were included in this study.There were 101 male patients and 91 female patients.The poor prognosis group had 102 cases and the good prognosis group had 90 cases.Univariate analysis showed that the poor prognosis group had statistically significant differences with the good prognosis group in terms of age(Z=-3.088,P=0.002)and age distribution(x2=13.457,P=0.001),fasting blood glucose(Z=-3.347,P=0.001),baseline NIHSS score(Z=-4.469,P＜0.01),location of occlusion(x2=10.488,P=0.005),transformation of hemorrhage after ischemic stroke(x2=16.943,P＜0.01),and symptomatic intracranial hemorrhage(X2=25.449,P＜0.01),and the baseline ASPECTS of the poor prognosis group was significantly lower than that of the good prognosis group(Z=-4.547,P＜0.01).There were no significant differences in other baseline and clinical data(all P＞0.05).Further multivariate Logistic regression analysis showed that age＞80 years(OR,3.224,95％CI 1.033-10.058,P=0.044),baseline NIHSS score(OR,1.102,95％CI 1.013-1.199,P=0.023),baseline ASPECTS(OR,0.375,95％CI 0.212-0.665,P=0.001),and symptomatic intracranial hemorrhage(OR,7.127,95％CI 1.296-39.203,P=0.024)were independent influencing factors of poor prognosis.Conclusion The independent factors of 90 d poor prognosis after successful EVT in patients with AIS-LVO of anterior circulation are age＞80 years,baseline NIHSS score,baseline ASPECTS,and symptomatic intracranial hemorrhage.

Critical care medicine-related treatment is an interdisciplinary and multi-professional process,often leading to secondary or concomitant mental disorders in clinical practice.Currently,there is no consensus on the pharmacological treatment of related mental illnesses in China.The Chinese Society of Psychosomatic Medicine collaborated with the Critical Care Medicine expert group to form a consensus writing expert group.After a systematic review of relevant literature,summarizing published domestic and foreign literature,and extensive discussions,the consensus was developed.The consensus elaborates on the principles and processes of the standardized use of psychotropic drugs in critical care medicine,as well as the clinical indications,precautions,and specific drug selection of various psychiatric medications,providing feasible suggestions and guidance for the clinical application of psychiatric medications in the intensive care unit.

BACKGROUND:Yougui Pill is a famous formula of the Chinese traditional medicine,which has good efficacy for lumbar disc herniation due to kidney yang insufficiency. OBJECTIVE:To investigate the potential targets and mechanism of action of Yougui Pill in the treatment of lumbar disc herniation by using network pharmacology and molecular docking technology,and verified by animal experiments. METHODS:(1)Network pharmacological analysis:We obtained the active ingredients and targets of Yougui Pill from TCMSP and other databases,collected genes related to lumbar disc herniation from GeneCards database,and took the intersection of the two for the topological analysis to derive the main active ingredients and core therapeutic targets.Gene ontology function analysis and Kyoto encyclopedia of genes and genomes pathway enrichment analysis were performed using R software.(2)Molecular docking:Autodock and Pymol software were utilized for the prediction of molecular binding energy of TCM active ingredients to core therapeutic targets.(3)Animal experiments:Eighteen Sprague-Dawley rats were randomly divided into a control group,a degeneration group and a Yougui Pill group,with 6 rats in each group.A rat model of intervertebral disc degeneration was prepared by fiber puncture method in the degeneration and Yougui Pill groups.At 2 weeks after modeling,Yougui Pill was given by gavage in the Yougui Pill group,once a day for 2 consecutive weeks.The level of tumor necrosis factor-α in serum was detected by the ELISA method,and morphological changes of the annulus fibrosus and nucleus pulposus cells were observed using hematoxylin-eosin staining. RESULTS AND CONCLUSION:There were 90 active ingredients and 64 targets,and the main active ingredients were found to be quercetin,kaempferol,β-carotene,soybean flavonoid,and 4'-O-methylnyasol.The core targets of Yougui Pill for the treatment of lumbar disc herniation were interleukin 6,tumor necrosis factor-α,AKT1,interleukin 1B,and vascular endothelial growth factor A.Enrichment analysis revealed that the intersecting genes might be expressed through the interleukin-17 signaling pathway,tumor necrosis factor signaling pathway,MAPK signaling pathway,PI3K-AKT signaling pathway,and other signaling pathways to improve intervertebral disc degeneration.The molecular docking test verified that quercetin,kaempferol,and β-carotene had strong binding ability to the core targets.Animal experiments showed that the level of serum tumor necrosis factor α in the degeneration group was higher than that in the control group(P<0.05),and the level of serum tumor necrosis factor α in the Yougui Pill group was lower than that in the degeneration group(P<0.05).Hematoxylin-eosin staining showed that the fibrous annulus of the intervertebral discs and the structure of the nucleus pulposus in the degeneration group were destroyed,and the number of nucleus pulposus cells was reduced;there was a tendency to reconstructing the fibrous annulus of the intervertebral discs in the Yougui Pill group,and the number of nucleus pulposus cells increased compared with the degeneration group.To conclude,Yougui Pill may treat lumbar disc herniation by improving disc degeneration through the effects of quercetin,kaempferol,beta-carotene and other key active ingredients on core targets such as tumor necrosis factor.

BACKGROUND:It has been found in recent observational studies that assessing localized fat mass is crucial in the evaluation of disc degeneration.Although obesity has been recognized as a risk factor for disc degeneration,the causal relationship between fat mass,which is a key factor in obesity,and intervertebral disc degeneration has been unclear in previous studies. OBJECTIVE:To investigate the causal risk factors of intervertebral disc degeneration associated with different distributions of fat mass,thereby enhancing the understanding of the pathogenesis of intervertebral disc degeneration and contributing to the development of preventive,therapeutic,and prognostic strategies. METHODS:Genetic markers associated with trunk and lower limb fat mass were extracted as instrumental variables from the publicly available IEU Open GWAS under the conditions of strong correlation and fulfillment of linkage disequilibrium.These markers were combined with the Mendelian randomization analysis to investigate the relationship between body fat and intervertebral disc degeneration.We used the latest version 9 database of FinnGen and assessed the results using several regression models,including inverse variance weighting,MR-Egger regression,simple mode,weighted mode,and weighted median estimator.We also assessed the heterogeneity of the genetic markers using Cochran's Q test,and multiplicity was assessed using the MR-Egger intercept test.Additionally,we used the leave-one-out method to determine the sensitivity of individual genetic markers to the causal effect of the exposure and outcome.The results were presented as odds ratios(OR)and 95%confidence intervals(CI). RESULTS AND CONCLUSION:The results from the inverse variance weighting method revealed that there was a positive causal relationship between trunk fat mass and the risk of developing intervertebral disc degeneration(OR=1.25,95%CI:1.15-1.35,P＜0.001).Additionally,there was an inverse causal relationship between bilateral lower limb fat mass and the risk of developing intervertebral disc degeneration(OR=0.7,95%CI:0.63-0.78,P＜0.001;OR=0.69,95%CI:0.62-0.76,P＜0.001).Furthermore,the MR-Egger intercept analysis did not detect any potential horizontal pleiotropy.No bias single nucleotide polymorphisms were detected,while heterogeneity tests were present,and the leave-one-out sensitivity analysis suggested reliable results.The results above demonstrate a positive causal relationship between trunk fat mass and intervertebral disc degeneration.As trunk fat mass increases,the risk of intervertebral disc degeneration rises.With an increase in both lower limb fat mass,the risk of intervertebral disc degeneration decreases.Fat content and distribution affects the risk of developing intervertebral disc degeneration and should be given more attention.

Cyclin-dependent kinase 5 (CDK5), a serine/threonine kinase, is one of the non-typical members of the CDKs family. CDK5 is mainly activated by non-cyclin activators p35 or p39 (as well as their respective fragments p25 and p29) to phosphorylate downstream substrates and regulate numerous neural and non-neural functions. Increasing evidence has confirmed that the overactivation of CDK5/p25 complex is closely related to neurodegenerative diseases, cancers, diabetes and inflammation. Consequently, CDK5 has become an important target in multiple diseases treatment. Nevertheless, to date, no selective CDK5 inhibitors are currently in the clinical stage. On the other hand, pan-CDK inhibitors are limited in clinical trials, due to their poor clinical efficacy and toxic side effects caused by the extensive inhibition of other kinases. In view of this, selective CDK5 inhibitors are of great significance not only for elucidating its exact biological functions, but also exploring the possibility of CDK5 inhibitors as a safe and effective therapy. This paper provides a brief overview of the structure and function of CDK5 protein as well as its relationship with diseases. In addition, the structural types and binding modes of CDK5 inhibitors targeting ATP active sites are also highlighted. Finally, we summarize and prospect the strategies to improve the selectivity of CDK5 inhibitors.

Bacterial biofilm widely exists in all kinds of bacteria, and is related to about 80 percent of bacterial infections. It is one of the main reasons for bacterial tolerance and resistance to existing antibiotics. Therefore, there is unmet clinical need for new anti-biofilm drugs. At present, there are three kinds of anti-biofilm agents under research, including biofilm inhibitors, biofilm dispersal agents and biofilm eradication agents. Among them, the biofilm eradication agent is unique, which can not only kill bacteria in biofilm but also eliminate biofilm as a monotherapy. Based on modifications of natural products with antibacterial activity, a variety of compounds with biofilm eradicating activities have been obtained, such as, acyldepsipeptides, pyrrolomycins, halogenated phenazines and halogenated 8-hydroxyquinolines. In this review, we summarize several major biofilm eradication agents above according to their structures and mechanisms.

OBJECTIVE: To observe the effect of needle-knife on the chondrocyte apoptosis of knee joint in rabbits with knee osteoarthritis (KOA) based on the CircSERPINE2-miR-1271-5P-E26 specific transformation-related gene (ERG) axis, and to explore the mechanism of needle-knife for KOA. METHODS: Thirty-six New Zealand white rabbits were randomly divided into a normal group, a model group, a needle-knife group and a sham needle-knife group, 9 rabbits in each group. The rabbits in the model group, the needle-knife group and the sham needle-knife group were treated with modified Videman method to prepare KOA model. After successful modeling, the rabbits in the needle-knife group were treated with needle-knife at cord adhesion and nodules near quadriceps femoris tendon and internal and external collateral ligament on the affected knee joint; the rabbits in the sham needle-knife group were treated with sham needle-knife baside the needle insertion point of the needle-knife group (needle-knife was only inserted, without any operation). The treatment was given once a week, 3 times in total. The Lequesne MG behavioral score was used to evaluate the knee joint damage in each group before and after intervention. After intervention, HE staining and transmission electron microscopy were used to observe the cartilage tissue morphology and ultrastructure of chondrocytes in the knee joint in each group; TUNEL method was used to detect the level of chondrocyte apoptosis in the knee joint; real-time fluorescence quantitative PCR was used to detect the expression of CircSERPINE2, miR-1271-5P and ERG mRNA in knee cartilage tissue in each group. RESULTS: After intervention, compared with the normal group, the Lequesne MG behavioral score in the model group was increased (P<0.01). Compared with the model group and the sham needle-knife group, the Lequesne MG behavioral score in the needle-knife group was decreased (P<0.01). In the model group and the sham needle-knife group, the number of chondrocytes and organelles was decreased, the cell nucleus was shrunk, mitochondria was swelling or disappeared; in the needle-knife group, the number of chondrocytes and organelles was increased, the cell nucleus was not obviously shrunk and the mitochondria was not obviously swelling. Compared with the normal group, the level of chondrocyte apoptosis in the model group was increased (P<0.01); compared with the model group and the sham needle-knife group, the level of chondrocyte apoptosis in the needle-knife group was decreased (P<0.01, P<0.05). Compared with the normal group, the expression of CircSERPINE2 and ERG mRNA in the model group was decreased (P<0.01), and the expression of miR-1271-5P mRNA was increased (P<0.01); compared with the model group and the sham needle-knife group, the expression of CircSERPINE2 and ERG mRNA in the needle-knife group was increased (P<0.01), and the expression of miR-1271-5P mRNA was decreased (P<0.01). CONCLUSION Needle-knife could reduce the knee joint damage and chondrocyte apoptosis in KOA rabbits, which may be related to up-regulating the expression of CircSERPINE2 and ERG mRNA, and inhibiting the expression of miR-1271-5P mRNA.
Rabbits ; Animals ; Osteoarthritis, Knee/metabolism* ; Chondrocytes/metabolism* ; Knee Joint/surgery* ; Apoptosis ; MicroRNAs/genetics*

Qualitative and quantitative analysis of 2-(2-phenylethyl) chromones in sodium chloride(NaCl)-treated suspension cells of Aquilaria sinensis was conducted by UPLC-Q-Exactive-MS and UPLC-QQQ-MS/MS. Both analyses were performed on a Waters T3 column(2.1 mm×50 mm, 1.8 μm) with 0.1% formic acid aqueous solution(A)-acetonitrile(B) as mobile phases at gradient elution. MS data were collected by electrospray ionization in positive ion mode. Forty-seven phenylethylchromones was identified from NaCl-treated suspension cell samples of A. sinensis using UPLC-Q-Exactive-MS, including 22 flindersia-type 2-(2-phenylethyl) chromones and their glycosides, 10 5,6,7,8-tetrahydro-2-(2-phenylethyl) chromones and 15 mono-epoxy or diepoxy-5,6,7,8-tetrahydro-2-(2-phenylethyl) chromones. Additionally, 25 phenylethylchromones were quantitated by UPLC-QQQ-MS/MS. Overall, the rapid and efficient qualitative and quantitative analysis of phenylethylchromones in NaCl-treated suspension cells of A. sinensis by two LC-MS techniques, provides an important reference for the yield of phenylethylchromones in Aquilariae Lignum Resinatum using in vitro culture and other biotechnologies.
Chromones ; Sodium Chloride ; Chromatography, Liquid ; Flavonoids ; Tandem Mass Spectrometry ; Thymelaeaceae