Mechanical pain is one of the most common causes of clinical pain, but there remains a lack of effective treatment for debilitating mechanical and chronic forms of neuropathic pain. Recently, neurotoxin GsMTx4, a selective mechanosensitive (MS) channel inhibitor, has been found to be effective, while the underlying mechanism remains elusive. Here, with multiple rodent pain models, we demonstrated that a GsMTx4-based 17-residue peptide, which we call P10581, was able to reduce mechanical hyperalgesia and neuropathic pain. The analgesic effects of P10581 can be as strong as morphine but is not toxic in animal models. The anti-hyperalgesic effect of the peptide was resistant to naloxone (an μ-opioid receptor antagonist) and showed no side effects of morphine, including tolerance, motor impairment, and conditioned place preference. Pharmacological inhibition of TRPV4 by P10581 in a heterogeneous expression system, combined with the use of Trpv4 knockout mice indicates that TRPV4 channels may act as the potential target for the analgesic effect of P10581. Our study identified a potential drug for curing mechanical pain and exposed its mechanism.

BACKGROUND:Currently,pedicle screw fixation technology is recognized as the gold standard for lumbar posterior fusion surgery.However,this technique is associated with several complications such as suboptimal screw placement,loosening,and fracture.Addressing these issues,it requires a thorough investigation into the mechanical properties of screw reinsertion to optimize surgical procedures and enhance success rates and safety.OBJECTIVE:By combining finite element analysis with biomechanical experiments,this study aims to compare and analyze the mechanical performance of traditional trajectory pedicle screws during multiple extraction processes.The goal is to reveal patterns in screw extraction strength over repeated withdrawals,providing scientific insights into the safety and effectiveness of pedicle screw reinsertion for clinicians.METHODS:Based on CT scan data,a three-dimensional reconstruction of the L4 vertebra model was performed.Three-dimensional printing technology was used to create biological experimental samples.A pull-out experiment was conducted according to a screw placement plan.Utilizing CT data and standard pedicle screw parameters,a finite element model of the L4 vertebra and a pedicle screw model(diameter 6.0 mm,length 45 mm)were established.The model was divided into five operating conditions based on screw placement angle and cycles.A finite element model was developed to simulate axial pull-out testing,analyzing stress distribution in the vertebral body and maximum axial pull-out strength of the screw.Mechanics experimental results of three-dimensional printing were compared and analyzed against simulation outcomes.RESULTS AND CONCLUSION:(1)A dedicated experimental setup for pedicle screw extraction from single vertebrae was designed and constructed.(2)In the three-dimensional printing experiment,our groups of models were compared between correctly placed screws and once improperly placed screws.The correctly placed screws group exhibited a maximum pull-out force of(1 422.63±23.80)N.Furthermore,with increasing deviation angles in screw placement,the maximum pull-out forces of each group gradually decreased.(3)Comparing the condition of a single improper nail placement with repositioning the nail correctly,when the offset angle of the improper placement exceeded that of Model 3,correctly repositioning the nail helps to increase the screw's pull-out resistance.(4)Comparing the scenario of two consecutive improper nail placements with repositioning correctly after two improper placements,correctly repositioning the nail reduced the screw's pull-out resistance.Without replacing the screw,it was not advisable to attempt a third nail placement.(5)Experimental pull-out strength of three-dimensional printing correlates significantly with finite element simulation results,with a correlation coefficient of 0.98.There is no significant difference in the outcomes between the two methods(P＞0.05).

BACKGROUND:Currently,pedicle screw fixation technology is recognized as the gold standard for lumbar posterior fusion surgery.However,this technique is associated with several complications such as suboptimal screw placement,loosening,and fracture.Addressing these issues,it requires a thorough investigation into the mechanical properties of screw reinsertion to optimize surgical procedures and enhance success rates and safety.OBJECTIVE:By combining finite element analysis with biomechanical experiments,this study aims to compare and analyze the mechanical performance of traditional trajectory pedicle screws during multiple extraction processes.The goal is to reveal patterns in screw extraction strength over repeated withdrawals,providing scientific insights into the safety and effectiveness of pedicle screw reinsertion for clinicians.METHODS:Based on CT scan data,a three-dimensional reconstruction of the L4 vertebra model was performed.Three-dimensional printing technology was used to create biological experimental samples.A pull-out experiment was conducted according to a screw placement plan.Utilizing CT data and standard pedicle screw parameters,a finite element model of the L4 vertebra and a pedicle screw model(diameter 6.0 mm,length 45 mm)were established.The model was divided into five operating conditions based on screw placement angle and cycles.A finite element model was developed to simulate axial pull-out testing,analyzing stress distribution in the vertebral body and maximum axial pull-out strength of the screw.Mechanics experimental results of three-dimensional printing were compared and analyzed against simulation outcomes.RESULTS AND CONCLUSION:(1)A dedicated experimental setup for pedicle screw extraction from single vertebrae was designed and constructed.(2)In the three-dimensional printing experiment,our groups of models were compared between correctly placed screws and once improperly placed screws.The correctly placed screws group exhibited a maximum pull-out force of(1 422.63±23.80)N.Furthermore,with increasing deviation angles in screw placement,the maximum pull-out forces of each group gradually decreased.(3)Comparing the condition of a single improper nail placement with repositioning the nail correctly,when the offset angle of the improper placement exceeded that of Model 3,correctly repositioning the nail helps to increase the screw's pull-out resistance.(4)Comparing the scenario of two consecutive improper nail placements with repositioning correctly after two improper placements,correctly repositioning the nail reduced the screw's pull-out resistance.Without replacing the screw,it was not advisable to attempt a third nail placement.(5)Experimental pull-out strength of three-dimensional printing correlates significantly with finite element simulation results,with a correlation coefficient of 0.98.There is no significant difference in the outcomes between the two methods(P＞0.05).

Objective To investigate the effect of colquhounia root tablet(CRT)on hyperglucose-in-duced epithelial-mesenchymal transition(EMT)in renal tubular epithelial cells(HK-2),and to explore its possible action mechanism.Methods HK-2 was cultured in vitro,and HK-2 was divided into the following five groups:control group(CON group),hyperosmolar group(MA group),high glucose group(HG group),high sugar+CRT group(HG+CRT group),high sugar+phosphatidylinositol 3 kinase inhibitor group(HG+LY29400 group),high sugar+CRT+phosphatidylinositol 3 kinase inhibitor group(HG+CRT+LY29400).The real time immunofluorescence quantitative PCR(qPCR)was used to detect the mRNA ex-pression levels of E-cadherin,α-smooth muscle actin(α-SMA)and phosphatase and tensin homolog(PTEN)in each group.Western-blot was used to detect the protein expression levels of PTEN,phosphatidylinositol 3 kinase(PI3K),protein kinase B(Akt),phosphorylated protein kinase B(p-Akt),E-cadherin and α-SMA in each group.Results Compared with the CON group,the protein and mRNA expression levels of α-SMA,p-Akt protein expression level and p-Akt/Akt ratio in the HG group were increased,the protein and mRNA ex-pression levels of E-cadherin and PTEN were decreased,and the differences were statistically significant(P＜0.05).Compared with the HG group,the α-SMA protein and mRNA expression levels in the HG+CRT group were decreased,while the E-cadherin protein and mRNA expression levels were increased,and the differences were statistically significant(P＜0.05).Compared with the HG+CRT group,there was no significant differ-ence in the E cadherin,α SMA,PTEN,P13K and Akt protein expression levels and p-Akt/Akt ratio in the HG+CRT+LY29400 group had no significant differences(P＞0.05).while the expression level of p-Akt protein was increased,and the difference was statistically significant(P＜0.05).Conclusion In vitro,CRT could re-verse hyperglucose-induced renal tubular epithelial cell EMT via the PTEN/PI3K/Akt signaling pathway.

Objective:To investigate the status quo of psychological contracts and influencing factors among members of the "1+N" family doctor teams in Shenzhen and to explore the impact of psychological contracts on job burnout.Methods:This cross-sectional study was conducted from September 30 to October 31, 2022 among 361 members of 92 family doctor teams from 92 community health service centers which provided family doctor team service in Shenzhen city. A self-designed general information questionnaire, an employee psychological contract questionnaire (including organizational responsibility and personal responsibility dimensions), and a job burnout scale (including emotional exhaustion, depersonalization, and personal accomplishment dimensions) were used in the study. T-tests, one-way ANOVA, Pearson correlation analysis, and multiple linear regression analysis were used to analyze the influencing factors of psychological contracts and job burnout.Results:Among 361 respondents, there were 299 females (82.8%) and 62 males (17.2%), and a higher proportion of general practitioners (37.5%, 129/361) and nurses (41.8%, 151/361). The total score of psychological contracts among the 361 respondents was (141.6±19.5), with organizational responsibility scoring (70.6±11.2) and personal responsibility scoring (71.0±9.3). On the job burnout scale, emotional exhaustion scored (17.89±6.82), depersonalization scored (6.51±2.54), and personal accomplishment scored (30.95±5.70). General practitioners scored lower in organizational responsibility and personal responsibility compared to other members ( F=7.341,3.119, all P<0.05), and higher in emotional exhaustion and depersonalization ( F=7.637, 2.415, all P<0.05). Members with≤5 years of work experience scored lower in personal responsibility and personal accomplishment ( F=3.656, 4.205, all P<0.05). Correlation analysis showed that scores of organizational responsibility and personal responsibility were negatively correlated with levels of emotional exhaustion and depersonalization ( r=-0.618, -0.526, all P<0.01), ( r=-0.404, -0.393, all P<0.01), and positively correlated with personal accomplishment ( r=0.500, 0.558, all P<0.01). Multiple linear regression analysis indicated that organizational responsibility negatively affected emotional exhaustion and depersonalization ( β=-0.554, -0.274, all P<0.01), and positively affected personal accomplishment ( β=0.172, P<0.05). Personal responsibility positively affected personal accomplishment ( β=0.404, P<0.01). Conclusions:The study demonstrates that general practitioners in family doctor teams in Shenzhen city have lower psychological contract levels and are more prone to emotional exhaustion and depersonalization; members with≤5 years of work experience have lower personal responsibility and accomplishment. The results indicate that enhancing organizational responsibility can reduce job burnout of members in family doctor teams.

Objective To explore the impact of Suzi Jiangqi decoction(SJD)on the inflammatory state of patients with chronic obstructive pulmonary disease(COPD)through the regulation of the mitogen-activated protein kinase(MAPK)signaling pathway.Methods A total of 70 patients with stable COPD,treated from April 2023 to April 2024 at the Department of Traditional Chinese Medicine and Department of Respiratory outpatient clinic of Affiliated Jinhua Hospital,School of Medicine Zhejiang University were selected and randomly divided into observation group and control group,with 35 cases in each group.The control group received tiotropium bromide powder inhalation combined with budesonide/formoterol powder inhalation treatment,while the observation group was given SJD in addition to treatment of control group.After 12 weeks of treatment,the therapeutic effects were evaluated by assessing lung function,airway mucus hypersecretion,levels of interleukin(IL)-17,IL-6,and tumor necrosis factor(TNF)-α,CT quantitative parameters of the lung,as well as the expression levels of IL-17,p38MAPK,nuclear factor kappa-B(NF-κB)and C-X-C motif chemokine ligand 8(CXCL8)mRNA in sputum.Results Following treatment,there was a significant improvement in lung function indicators such as first second expiratory volume/forced vital capacity％,cough score,sputum difficulty score,sputum quality score,and sputum volume score for patients in both groups,with more pronounced improvements observed in observation group(P＜0.05).The levels of serum cytokines IL-17,IL-6 and TNF-αdecreased in both groups after treatment,with observation group showing a more significant reduction(P＜0.05).Additionally,the percentage ratio of low attenuation area to lung area(LAA％),emphysema index of lung CT in observation group significantly decreased after treatment(P＜0.05).Similarly,the expression levels of IL-17,p38MAPK,NF-κB and CXCL8 mRNA in sputum were also significantly reduced after treatment in observation group(P＜0.05).Conclusion SJD may improve lung function and inflammatory status in COPD patients by regulating the MAPK signaling pathway mediated by IL-17,demonstrating a positive therapeutic effect on the treatment of COPD.

Objective: To prospectively compare single-shot (SS) echo-planar imaging (EPI) and field-of-view optimized and constrained undistorted single-shot multiplexed sensitivity-encoding (FOCUS MUSE) for diffusion-weighted imaging (DWI) in evaluating thyroid-associated ophthalmopathy (TAO). Materials and Methods: SS EPI and FOCUS MUSE DWIs were obtained from 39 patients with TAO (18 male; mean ± standard deviation: 48.3 ± 13.3 years) and 26 healthy controls (9 male; mean ± standard deviation: 43.0 ± 18.5 years). Two radiologists scored the visual image quality using a 4-point Likert scale. The image quality score, signal-to-noise ratio (SNR), contrast-tonoise ratio (CNR), and apparent diffusion coefficient (ADC) of extraocular muscles (EOMs) were compared between the two DWIs. Differences in the ADC of EOMs were also evaluated. The performance of discriminating active from inactive TAO was assessed using receiver operating characteristic curves. The correlation between ADC and clinical activity score (CAS) was analyzed using Spearman correlation. Results: Compared with SS EPI DWI, FOCUS MUSE DWI demonstrated significantly higher image quality scores (P < 0.001), a higher SNR and CNR on the lateral rectus muscle (LRM) and medial rectus muscle (MRM) (P < 0.05), and a non-significant difference in the ADC of the LRM and MRM. Active TAO showed higher ADC than inactive TAO and healthy controls with both SS EPI and FOCUS MUSE DWIs (P < 0.001). Inactive TAO and healthy controls did not show a significant ADC difference with both DWIs. Compared with SS EPI DWI, FOCUS MUSE DWI demonstrated better discrimination of active from inactive TAO (AUC:0.925 vs. 0.779; P = 0.007). The ADC was significantly correlated with CAS in SS EPI DWI (r = 0.391, P < 0.001) and FOCUS MUSE DWI (r = 0.645, P < 0.001). Conclusion FOCUS MUSE DWI provides better images for evaluating EOMs and better performance in diagnosing active TAO than SS EPI DWI. The application of FOCUS MUSE will facilitate the DWI evaluation of TAO.

Neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision (TME) and adjuvant chemotherapy serves as a traditional standard treatment for locally advanced rectal cancer (LARC). However, such treatment suffers low pathological complete response (pCR) rates, which are merely less than 15%, and low anal-preservation rates, failing to meet the demand of patients for high quality of life. Recently, total neoadjuvant therapy (TNT) whereby postoperative adjuvant chemotherapy is performed preoperatively has further increased the pCR rate, gradually becoming a novel therapeutic approach. Nevertheless, the pCR rate of TNT remains below 30%. Presently, immune checkpoint inhibitors (ICIs) have been proved to be highly successful in treating various solid tumors, yet they are scarcely employed to treat LARC. In recent years, many clinical trials have been conducted to explore the application of nCRT combined with ICIs in the treatment of LARC. This paper reviews the advances in research on this therapy.

OBJECTIVE: To investigate whether the acetaldehyde dehydrogenase 2 specific activator, Alda-1, can alleviate brain injury after cardiopulmonary resuscitation (CPR) by inhibiting cell ferroptosis mediated by acyl-CoA synthetase long-chain family member 4/glutathione peroxidase 4 (ACSL4/GPx4) pathway in swine. METHODS: Twenty-two conventional healthy male white swine were divided into Sham group (n = 6), CPR model group (n = 8), and Alda-1 intervention group (CPR+Alda-1 group, n = 8) using a random number table. The swine model of CPR was reproduced by 8 minutes of cardiac arrest induced by ventricular fibrillation through electrical stimulation in the right ventricle followed by 8 minutes of CPR. The Sham group only experienced general preparation. A dose of 0.88 mg/kg of Alda-1 was intravenously injected at 5 minutes after resuscitation in the CPR+Alda-1 group. The same volume of saline was infused in the Sham and CPR model groups. Blood samples were collected from the femoral vein before modeling and 1, 2, 4, 24 hours after resuscitation, and the serum levels of neuron specific enolase (NSE) and S100 β protein were determined by enzyme-linked immunosorbent assay (ELISA). At 24 hours after resuscitation, the status of neurologic function was evaluated by neurological deficit score (NDS). Thereafter, the animals were sacrificed, and brain cortex was harvested to measure iron deposition by Prussian blue staining, malondialdehyde (MDA) and glutathione (GSH) contents by colorimetry, and ACSL4 and GPx4 protein expressions by Western blotting. RESULTS: Compared with the Sham group, the serum levels of NSE and S100β after resuscitation were gradually increased over time, and the NDS score was significantly increased, brain cortical iron deposition and MDA content were significantly increased, GSH content and GPx4 protein expression in brain cortical were significantly decreased, and ACSL4 protein expression was significantly increased at 24 hours after resuscitation in the CPR model and CPR+Alda-1 groups, which indicated that cell ferroptosis occurred in the brain cortex, and the ACSL4/GPx4 pathway participated in this process of cell ferroptosis. Compared with the CPR model group, the serum levels of NSE and S100 β starting 2 hours after resuscitation were significantly decreased in the CPR+Alda-1 group [NSE (μg/L): 24.1±2.4 vs. 28.2±2.1, S100 β (ng/L): 2 279±169 vs. 2 620±241, both P < 0.05]; at 24 hours after resuscitation, the NDS score and brain cortical iron deposition and MDA content were significantly decreased [NDS score: 120±44 vs. 207±68, iron deposition: (2.61±0.36)% vs. (6.31±1.66)%, MDA (μmol/g): 2.93±0.30 vs. 3.68±0.29, all P < 0.05], brain cortical GSH content and GPx4 expression in brain cortical was significantly increased [GSH (mg/g): 4.59±0.63 vs. 3.51±0.56, GPx4 protein (GPx4/GAPDH): 0.54±0.14 vs. 0.21±0.08, both P < 0.05], and ACSL4 protein expression was significantly decreased (ACSL4/GAPDH: 0.46±0.08 vs. 0.85±0.13, P < 0.05), which indicated that Alda-1 might alleviate brain cortical cell ferroptosis through regulating ACSL4/GPx4 pathway. CONCLUSIONS Alda-1 can reduce brain injury after CPR in swine, which may be related to the inhibition of ACSL4/GPx4 pathway mediated ferroptosis.
Male ; Animals ; Swine ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Ferroptosis ; Brain Injuries ; Glutathione ; Cardiopulmonary Resuscitation ; Ligases ; Iron

Objective:To compare the clinical results and costs of treatment between internal fixation and total hip replacement in patients aged 60 to 75 years with femoral neck fractures, in order to provide a reference basis for choosing the appropriate surgical procedure for patients in this age group.Methods:According to the inclusion and exclusion criteria, we selected 69 patients treated with internal fixation and 88 patients treated with total hip replacement for femoral neck fractures, and collected relevant data to analyze the differences in clinical characteristics and prognosis between the two groups.Results:The total hip replacement group was older than the internal fixation group[68(64, 72) vs.63(61, 68), Z=-4.536, P<0.001]. There were 20 men(29.0%)and 49 women(71.0%)in the internal fixation group, and 13 men(14.8%)and 75 women(85.2%)in the total hip replacement group.Both groups had more women than men( χ2=4.706, P=0.030). The ratio of the displaced type to the non-displaced type was higher in the total hip replacement group than in the internal fixation group(90.9% vs.46.4%, χ2=37.510, P<0.001). Postoperative serum albumin levels were lower than preoperative levels in both groups, with greater decreases in the total hip replacement group than in the internal fixation group[(9.06±3.45)g/L vs.(7.07±3.37)g/L, t=-3.393, P=0.001]. The total hip replacement group had a higher intraoperative bleeding volume and blood transfusion volume than the internal fixation group( P<0.05), and the days of hospitalization[12(9, 14)d]and hospitalization costs[￥89222.1(84826.8, 93040.0)]were higher than those in the internal fixation group[9(8, 10)d; ￥51158.9(47816.5, 54098.4), Z=-5.138, -10.737, P<0.001 for both]. Weight-bearing after total hip replacement occurred earlier than the internal fixation group[32.0(28.0, 36.5)d vs.92.0(89.3, 95.5)d, Z=-10.228, P<0.001]. There were no significant differences between the two types of surgery for non-displaced femoral neck fractures at 1 year after surgery in the Harris hip score and the quality of life score EQ-5D.For patients with displacement, the rates of excellent and good outcomes based on the Harris score for the total hip replacement group were significantly higher than those for the internal fixation group at 1 year after surgery(97.5% vs.81.3%, χ2=6.697, P=0.010); the postoperative quality of life score EQ-5D was also better than that of the internal fixation group[0.9(0.7, 1.0) vs.1.0(1.0, 1.0), Z=-4.785, P<0.001], and the incidence of postoperative pain and anxiety was lower than that in the internal fixation group(6.3% vs.28.1%, 1.3%, vs.50.0%, χ2=7.928, 38.032, all P<0.01). Conclusions:The mortality and short-term postoperative complications between internal fixation and total hip replacement have no significant differences.There is no significant difference in postoperative function between the two surgical methods for patients with non-displaced femoral neck fractures.For patients with displacement, total hip arthroplasty is superior to internal fixation.The cost of initial hospitalization for internal fixation is significantly lower than for total hip replacement.