Objective Based on U.S.Food and Drug Administration Adverse Event Reporting System(FAERS)database,the signal mining of tizanidine adverse drug events(ADEs)was conducted to explore the occurrence characteristics of ADE,hoping to provide references for the safe clinical application of tizanidine.Methods The reporting odds ratio(ROR)and medicines and healthcare products regulatory agency methods(MHRA)were used to analyse the ADE of tizanidine using FAERS registration data from the first quarter of 2004 to the second quarter of 2022.After valid signals were obtained,the MedDRA was used for translation and system organ classification.Results A total of 7 135 reports of tizanidine ADE were obtained,including 1 732 patients,1 304 ADE types were involved.According to the results of 2 ADE signal mining methods,at the preferred term(PT)level,177 signals were detected.There were 32 PT signals not included in the drug instructions,including potassium wasting nephropathy,cardio-respiratory arrest,and foetal growth restriction etc.In 1 732 patients,the number of ADE cases of female was 2.37 times that in male(1 057 vs.446),and the age group between 40 and 64 accounted for a large proportion(36.03％).The highest proportion(32.79％)reported by consumers.The system organ class involved mainly included various neurological diseases and psychosis.The median time to onset of tizanidine-related ADEs was 75 d(interquartile range:28-223 d),but it was necessary to be vigilant that ADE may still occur 1 year after starting the drug(13.38％).Conclusion This study aims to suggest that clinical application of tizanidin-related ADE should be paid full attention to the occurrence of ADE such as potassium-wasting nephropathy and suicidally completed,as well as key populations such as women and patients of 40-64 years old.

Benign prostatic hyperplasia(BPH)is one of the major chronic complications of type 2 diabetes mellitus(T2DM),and sex steroid hormones are common risk factors for the occurrence of T2DM and BPH.The profiles of sex steroid hormones are simultaneously quantified by LC-MS/MS in the clinical serum of patients,including simple BPH patients,newly diagnosed T2DM patients,T2DM complicated with BPH patients and matched healthy individuals.The G protein-coupled estrogen receptor(GPER)inhibitor G15,GPER knockdown lentivirus,the YAP1 inhibitor verteporfin,YAP1 knockdown/overexpression lentivirus,targeted metabolomics analysis,and Co-IP assays are used to investigate the molecular mechanisms of the disrupted sex steroid hormones homeostasis in the pathological process of T2DM complicated with BPH.The homeostasis of sex steroid hormone is disrupted in the serum of patients,accompanying with the proliferated prostatic epithelial cells(PECs).The sex steroid hormone metabolic profiles of T2DM patients complicated with BPH have the greatest degrees of separation from those of healthy individuals.Elevated 17β-estradiol(E2)is the key contributor to the disrupted sex steroid hormone homeostasis,and is significantly positively related to the clinical characteristics of T2DM patients complicated with BPH.Activating GPER by E2 via Hippo-YAP1 signaling exacerbates high glucose(HG)-induced PECs prolifer-ation through the formation of the YAP1-TEAD4 heterodimer.Knockdown or inhibition of GPER-mediated Hippo-YAP1 signaling suppresses PECs proliferation in HG and E2 co-treated BPH-1 cells.The anti-proliferative effects of verteporfin,an inhibitor of YAP1,are blocked by YAP1 overexpression in HG and E2 co-treated BPH-1 cells.Inactivating E2/GPER/Hippo/YAP1 signaling may be effective at delaying the progression of T2DM complicated with BPH by inhibiting PECs proliferation.

Objective:To explore the role of cathepsin S(CTSS) in diabetic vascular injury-induced restenosis.Methods:(1) Dendritic cells(DCs) were stimulated with different concentrations of glucose, and CTSS was either knocked down or upregulated in dendritic cells using adenovirus transfection. The mRNA and protein expression levels of CTSS were detected by RT-qPCR and Western blot, and the changes of interleukin(IL)-6 levels were assessed using RT-qPCR and ELISA in response to CTSS. (2) The extent of Th17 cell differentiation was evaluated with Flow cytometry when CTSS was downregulated or overexpressed. Levels of ROR-γt, IL-17A, IL-17F, IL-22, and IL-23 were measured. (3) Streptozomycin(STZ, 60 mg/kg) was injected into the intraperitoneal cavity of rats fasted for 12 h to obtain a diabetic rat model, and the restenosis model was obtained by balloon catheter and carotid guidewire injury, and the differentiation degree of Th17 cells in different groups of rats was compared when CTSS was up-regulated and down-regulated.Results:(1) DC viability decreased when stimulated with 35 mmol/L glucose for 48 hours. Compared to the control group, glucose treatment led to a concentration-dependent increase in CTSS and IL-6 levels in DCs( P<0.05). Inhibition of CTSS reduced IL-6 protein levels, while its overexpression increased IL-6 protein levels( P<0.05). (2) Compared with the control group, CTSS inhibition in DC decreased the percentage of Th17 cells in T cells, with decreased protein levels of ROR-γt, IL-17A, IL-17F, IL-22, and IL-23, and vice versa ( P<0.050). (3) After carotid artery injury, CTSS expression was increased in perivascular adipose tissue(PVAT) of rats, and levels of ROR-γt, IL-17A, IL-17F, IL-22, and IL-23 in PVAT were significantly elevated. Down-regulation of CTSS eliminated the glucose-induced enhancement. Conclusion:Inhibition of CTSS in DC reduces Th17 cell differentiation and thereby suppresses restenosis following diabetic vascular injury.

In unicompartmental replacement surgery, there are a wide variety of commercially available unicompartmental prostheses, and the consistency of the contact surface between the common liner and the femoral prosthesis could impact the stress distribution in the knee after replacement in different ways. Medial tibial plateau fracture and liner dislocation are two common forms of failure after unicompartmental replacement. One of the reasons is the mismatch in the mounting position of the unicompartmental prosthesis in the knee joint, which may lead to failure. Therefore, this paper focuses on the influence of the shape of the contact surface between the liner and the femoral prosthesis and the mounting position of the unicompartmental prosthesis on the stress distribution in the knee joint after replacement. Firstly, a finite element model of the normal human knee joint was established, and the validity of the model was verified by both stress and displacement. Secondly, two different shapes of padded knee prosthesis models (type A and type B) were developed to simulate and analyze the stress distribution in the knee joint under single-leg stance with five internal or external rotation mounting positions of the two pads. The results showed that under a 1 kN axial load, the peak contact pressure of the liner, the peak ACL equivalent force, and the peak contact pressure of the lateral meniscus were smaller for type A than for type B. The liner displacement, peak contact pressure of the liner, peak tibial equivalent force, and peak ACL equivalent force were the smallest for type A at 3° of internal rotation in all five internal or external rotation mounting positions. For unicompartmental replacement, it is recommended that the choice of type A or type B liner for prosthetic internal rotation up to 6° should be combined with other factors of the patient for comprehensive analysis. In conclusion, the results of this paper may reduce the risk of liner dislocation and medial tibial plateau fracture after unicompartmental replacement, providing a biomechanical reference for unicompartmental prosthesis design.
Arthroplasty, Replacement, Knee/methods* ; Biomechanical Phenomena ; Finite Element Analysis ; Humans ; Knee Joint/surgery* ; Knee Prosthesis ; Tibia/surgery*

Since December 2019, novel coronavirus pneumonia (NCP) has been reported in Wuhan, Hubei Province, and spreads rapidly to all through Hubei Province and even to the whole country. The virus is 2019 novel coronavirus (2019-nCoV), never been seen previously in human, but all the population is generally susceptible. The virus spreads through many ways and is highly infectious, which brings great difficulties to the prevention and control of NCP. Based on the needs of orthopedic trauma patients for emergency surgery and review of the latest NCP diagnosis and treatment strategy and the latest principles and principles of evidence-based medicine in traumatic orthopedics, the authors put forward this expert consensus to systematically standardize the clinical pathway and protective measures of emergency surgery for orthopedic trauma patients during prevention and control of NCP and provide reference for the emergency surgical treatment of orthopedic trauma patients in hospitals at all levels.

BACKGROUND: The aryl hydrocarbon receptor (AhR) is commonly known as an environmental sensor. Polymorphisms in AhR gene have been implicated in susceptibility to cancer. However, the results were controversial. This study was conducted to quantitatively summarize the association between AhR polymorphisms and cancer risk by meta-analysis. METHODS: Relevant reports were searched in four databases (Embase, PubMed, Wanfang, and China National Knowledge Infrastructure). We used pooled odds ratio (OR) and 95% confidence interval (95% CI) to evaluate the strength of the association in both standard and cumulative meta-analysis. Subgroup and sensitivity analysis was also performed, and between-study heterogeneity and publication bias were checked. RESULTS: A total of seventeen studies referring to three AhR polymorphisms (rs2066853, rs7796976, and rs2074113) were identified, and 9557 cases and 10038 controls were included. There was no statistically significant association of AhR rs2066853 polymorphism with cancer risk in the overall population, and the negative results were repeated in subgroup analysis by the ethnicity and cancer type. Concerning AhR rs7796976 or rs2074113 polymorphism, no significant correlation was detected. Moreover, these non-significant findings were stable in sensitivity analysis, and the cumulative meta-analysis indicated a trend of no significant link between this three AhR polymorphisms and cancer risk as more data accumulated over time. CONCLUSION This meta-analysis provides evidence that the rs2066853, rs7796976, or rs2074113 polymorphism in AhR gene is not a susceptible predictor of cancer. Further clinical and functional investigation between AhR polymorphisms and cancer susceptibility are needed.
Basic Helix-Loop-Helix Transcription Factors/genetics* ; Confidence Intervals ; Genetic Predisposition to Disease/epidemiology* ; Humans ; Neoplasms/genetics* ; Odds Ratio ; Polymorphism, Genetic ; Receptors, Aryl Hydrocarbon/genetics*

Vision formation is classically based on projections from retinal ganglion cells (RGC) to the lateral geniculate nucleus (LGN) and the primary visual cortex (V1). Neurons in the mouse V1 are tuned to light stimuli. Although the cellular information of the retina and the LGN has been widely studied, the transcriptome profiles of single light-stimulated neuron in V1 remain unknown. In our study, in vivo calcium imaging and whole-cell electrophysiological patch-clamp recording were utilized to identify 53 individual cells from layer 2/3 of V1 as light-sensitive (LS) or non-light-sensitive (NS) by single-cell light-evoked calcium evaluation and action potential spiking. The contents of each cell after functional tests were aspirated in vivo through a patch-clamp pipette for mRNA sequencing. Moreover, the three-dimensional (3-D) morphological characterizations of the neurons were reconstructed in a live mouse after the whole-cell recordings. Our sequencing results indicated that V1 neurons with a high expression of genes related to transmission regulation, such as Rtn4r and Rgs7, and genes involved in membrane transport, such as Na/K ATPase and NMDA-type glutamatergic receptors, preferentially responded to light stimulation. Furthermore, an antagonist that blocks Rtn4r signals could inactivate the neuronal responses to light stimulation in live mice. In conclusion, our findings of the vivo-seq analysis indicate the key role of the strength of synaptic transmission possesses neurons in V1 of light sensory.

Objective To investigate the effect and mechanism of miR-885-3p on the radiosensitivity of colorectal cancer cell HT-29. Methods The expression of miR-885-3p in HT-29 cells irradiated with different doses (0, 2, 4, 6, 8 Gy) of X-rays was detected by qPCR. The effect of miR-885-3p in modulating cell radiosensitivity was assessed in HT-29 cells with miR-885-3p overexpression. Bioinformatics prediction and dual luciferase reporter gene assay were employed to identify the direct target gene of miR-885-3p. Relationship between miR-885-3p and target gene tyrosine kinase 1 (AKT1) was investigated via regulation of miR-885-3p expression. The effect of AKT1 on radiosensitivity in HT-29 cells was evaluated through knockdown AKT1. The effect of AKT1 on miR-885-3p-induced radiosensitivity was detected by co-transferring miR-885-3p and AKT1 gene into HT-29 cells. Results miR-885-3p expression was up-regulated in radiation-induced HT-29 cells (F=46. 64, P<0. 05). Over-expression of miR-885-3p and knockdown of AKT1 enhanced cell radiosensitization by inhibiting survival and promoting apoptosis (t=12. 33, 12. 95, P <0. 05) with SER of 1. 602 and 1. 946, respectively. Inhibition of miR-885-3p promoted radioresistance by increasing cell survival and inhibiting apoptosis (t=11. 94, P<0. 05) with a SER of 0. 839. AKT1 is a target gene downstream of miR-885-3p, overexpression of AKT1 reversed the effect of miR-885-3p on cell radiosensitivity with a SER of 0. 680. Conclusions miR-885-3p can enhance the radiosensitivity of colorectal cancer HT-29 cells by directly targeting AKT1, which provides a target for improving the radiosensitivity of clinical colorectal cancer.

Objective To analyze the characteristics of preoperative CTO lesions by coronary CT angiography (CCTA) and to compare the lesion characteristics and clinical data of patients with subsequent vs failed PCI.Methods A total of 113 patients were randomly selected and 116 vessels were analyzed by CCTA before PCI.The patients were further investigated as PCI success group vs PCI failure group according to their PCI result.Multivariate logistic regression analysis was used to determine the factors that affected the success of CTO intervention.The ROC curve was used to determine and evaluate the CT-CTO score and J-CTO score for diagnostic efficacy.Results The success rate of PCI was 55.2％.64 lesions were successfully opened,with the success rate of 72.4％.The prevalence of smoking in patients in the PCI failure group was significantly higher than that in PCI success group (65.4％ vs.42.2％,P ＜ 0.05).There were no significant differences between the two groups in age,gender,history of hypertension,diabetes mellitus,and myocardial infarction(P ＞ 0.05).Statistical differences were observed between the PCI success group and the PCI failure group in the presence of occlusion segment head-end bifurcation,occlusion severe incision,severe calcification (calcification ≥ 180°),occlusion segment length ≥ 20 mm,occlusion of calcification lesions,occlusion segment distal shape of the unambiguous of fiber cap shape of the distal occlusion segment under CCTA(P ＜ 0.05).In the PCI failure group,approximately 17.3％ of the patients had previous attempt to open the CTO lesions,which were higher than the PCI success group (9.4％).However,The difference was not statistically significant (P ＞ 0.05).Multivariate logistic regression analysis showed that the unambiguous distal fibrous cap of the occlusion segment and the occlusion of the proximal branch and the occlusion length ≥20 mm were the main factors affecting the failure of CTO intervention.In terms of prediction,the predictive value 30 CT-CTO score yielded a higher area under the ROC curve than that of the J-CTO score (0.8776 vs 0.7387,P ≤ 0.05).Conclusion CT angiography can predict the success rate of intervention for CTO lesions.Compared with J-CTO score,CT-CTO score has a higher predictive value.Unambiguous fiber cap shape,occlusion segment head end bifurcation,occlusion segment length ≥20 mm were the independent risk factors that affecting the success of CTO operation.

Objective To explore the related factors and diagnostic criteria of perioperative myocardial infarction (PMI) after on-pump coronary artery bypass grafting(CABG).Methods 258 CABG patients were selected.The cardiac troponin-I in immediately,6,12,24,and 48 hours after surgery were measured.95 percentile (P95) was used as the boundary,any measured value greater than P95 was identified PMI,as group I(13 cases),the rest as group II(245 cases).The age,sex,cardiopulmonary bypass time,aortic corss-clamp time,LV ejection fraction,left ventricular end diastolic diameter,grafted vessels,left anterior descending coronary artery occlusion,recent myocardial infarction (<3 months),severe complex coronary artery disease and other risk factors that may lead to PMI were analyzed.The data were analyzed using Student's test for continuous variables and the χ2 test for discontinuous variables.Results P95 value was 3.47,the cardiopulmonary bypass time(t=3.268,P<0.05),aortic corss-clamp time(t=2.047,P<0.05),severe complex coronary artery disease between the two groups had statistically significant difference (χ2=19.846,P<0.05).Conclusion cTnI>P95 (3.47) indicates that the myocardium injury is serious,cardiopulmonary bypass time,aortic corss-clamp time and severe complex coronary artery disease are associated with PMI in patients undergoing CABG.