Neuropathic pain is a common chronic pain condition that severely impacts patients' quality of life. While Small proline-rich protein 1A (SPRR1A) is a well-known marker for axonal regeneration, its specific role and the underlying molecular mechanisms in neuropathic pain remain elusive. The present study demonstrates that SPRR1A is significantly increased in the spinal dorsal horn of spared nerve injury (SNI) mice, accompanied by ephrin-A5 downregulation, activation of the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) pathway, and enhanced neuronal excitability. SPRR1A overexpression induces allodynia in naïve mice, whereas knockdown of SPRR1A alleviates hyperalgesia and reduces neuronal hyperactivity. Silencing SPRR1A restores ephrin-A5 expression and suppresses BDNF/TrkB activation. Co-immunoprecipitation confirms that SPRR1A interacts with ephrin-A5, while ephrin-A5 competitively binds TrkB to block BDNF-mediated signaling. Conversely, SPRR1A overexpression decreases ephrin-A5 level and facilitates BDNF/TrkB activation. Ephrin-A5 siRNA reverses the inhibitory effects of SPRR1A knockdown on TrkB signaling. Furthermore, intrathecal administration of recombinant ephrin-A5 significantly attenuates hyperalgesia in SNI mice. Together, these findings identify SPRR1A as a key mediator of neuropathic pain that promotes central sensitization by suppressing ephrin-A5, thereby enhancing BDNF/TrkB signaling in the spinal dorsal horn. Targeting the SPRR1A-ephrin-A5-BDNF/TrkB axis may represent a promising therapeutic strategy for neuropathic pain management.

Background Postoperative hypotension is a common symptom in elderly patients undergoing total knee arthroplasty (TKA), which is associated with intraoperative blood pressure (BP) management. The study aimed to explore the causes of perioperative hypotension in TKA elderly patients and analyze the effects of BP management strategies based on non-invasive heart function monitoring on reducing postoperative hypotension. Methods A total of 176 elderly TKA patients were divided into four groups: the tourniquet group (Group T), the non-tourniquet group (Group N), the goal-oriented BP management tourniquet group (Group GT), and the goal-oriented BP management non-tourniquet group (Group GN). Patients in Groups T and GT received TKA with a tourniquet. The BP of patients in Groups GT and GN was maintained based on non-invasive heart function monitoring. The mean arterial pressure (MAP), index of cardiac contractility (ICON), stroke volume (SV), and other circulatory indicators were measured using the non-invasive cardiometer monitor at five time points, including before anesthesia (T1), after anesthesia (T2), after completion of the osteotomy (T3), after suturing (T4), and after leaving the post-anesthesia care unit (T5). The frequency of postoperative hypotension within 24 hours was recorded, and the incidence of hypotension was calculated. Results The ICON, SV, and MAP were lower in Groups N and GN than in Groups T and GT at T3 (P < 0.05). The ICON, SV, and MAP were lower in Group N than in Groups GN at T4 and T5 (P < 0.05), and no significant difference was observed between Groups T and GT (P > 0.05). The incidence of postoperative hypotension within 24 hours was higher in Group N (47.1%) (P = 0.007) than in Group GN (21.6%), Group T (19.4%), and Group GT (14.8%). Conclusions Postoperative hypotension in elderly patients undergoing TKA with a non-tourniquet was associated with decreased myocardial contractility. Enhancing myocardial contractility based on non-invasive cardiac function monitoring reduced the incidence of postoperative hypotension.

Background:Laparoscopic renal cyst decompression (LRCD) is a common procedure in urology, but postoperative pain remains a significant challenge. While regional nerve blocks provide more targeted pain relief, there is no universally accepted pain management strategy for LRCD. The ultrasound-guided modified thoracoabdominal nerve block (M-TAPA) may offer effective analgesia by blocking the anterior and lateral branches of the intercostal nerves (T5-T12). However, its efficacy in LRCD has not been thoroughly evaluated. Objective:This study aimed to assess the efficacy and safety of unilateral M-TAPA in reducing postoperative pain and opioid consumption in patients undergoing LRCD, and to evaluate its potential benefits in enhancing recovery. Methods:In this randomized, double-blind, controlled trial, 61 patients undergoing LRCD were assigned to either the M-TAPA group (n = 31) or the Control group (n = 30). The M-TAPA group received ultrasound-guided nerve block, while the Control group received a placebo injection. Postoperative pain was assessed using the numerical rating scale (NRS) over a 48-h period. Additional outcomes included opioid consumption and opioid-related side effects, such as nausea and vomiting. Results:The M-TAPA group had significantly lower NRS scores at all time points compared to the Control group, with the largest difference observed at 6 h postoperatively (4.27 ± 0.83 in the Control group vs. 2.19 ± 0.54 in the M-TAPA group). Repeated measures ANOVA revealed a significant interaction between time and treatment (F = 20.813, p < 0.001). Opioid consumption was reduced by 22% in the M-TAPA group over 48 h (p < 0.001), and the need for antiemetic drugs was significantly lower (p = 0.020). No M-TAPA-related complications were observed. Conclusion:M-TAPA was found to be an effective method for reducing postoperative pain and opioid consumption in patients undergoing LRCD. Clinical Trial Registration:www.chictr.org.cn.

Immobilization-induced Neuromuscular Dysfunction (NMD) increases morbidity and mortality of patients in Intensive Care Units. However, the underlying mechanism of NMD remain poorly elucidated which limited the development of therapeutic method for NMD. Here we developed an immobilization rat model and tested the hypothesis that decreased expression of NRG-1, abnormal expression and distribution of nicotinic acetylcholine receptors (nAChRs) in skeletal muscle caused by immobilization can lead to NMD. To investigate the role of NRG-1/ErbB pathway on immobilization-induced NMD, exogenous recombinant human neuregulin-1 (rhNRG-1) was used to increase the expression of NRG-1 in skeletal muscle during immobilization. It was observed rhNRG-1 significantly alleviated the muscle loss and enhanced the expression of ε-nAChR, while diminished the expression of γ- and α7-nAChR and NMD. Interestingly, ErbB inhibitor PD158780 blocked the protective effects of rhNRG-1. Collectively, the results of present study suggested that rhNRG-1 attenuated immobilization-induced muscle loss and NMD, suppressed γ- and α7-nAChR production, enhanced ε-nAChR synthesis via activating NRG-1/ErbB pathway. Taken together, our findings provide novel insights into NMD contribution, suggesting that the rhNRG-1 is a promising therapy to protect against immobilization-induced myopathy.

ObjectiveCurrently, a multitude of studies are underway to investigate the factors affecting the degree of frailty, with a significant focus on the critical role of body mass index (BMI). This study aims to conduct a cross-sectional survey to investigate the multifaceted relationship between multiple body habitus and the factors that influence the degree of frailty.MethodsA questionnaire survey was conducted among 840 adult residents in Chongqing communities. A total of 723 participants were included in the data analysis, with an effective response rate of 92.0%. Fried’s frailty scale was used to classify individuals into fit, pre-frail, or frail. Non-parametric tests and chi-square tests were employed to evaluate the inter-group differences in frailty levels under different influencing factors. Multivariate logistic regression analysis was performed to select the independent variables associated with frailty statistics. According to the results of the parallel line test, ordered or disordered multivariate logistic regression was used to evaluate the impact of a single independent variable on frailty for different variables.ResultsAdult community residents in Chongqing accounted for 29.18 and 5.67% in pre-frailty and frailty, respectively. In multivariate logistic regression analysis, high BMI, and high waist-hip ratio (WHR) were identified as major risk factors for frailty. Furthermore, the process of aging, coupled with moderate to heavy alcohol consumption, active weight loss behavior in the past year, and the presence of comorbidities, emerged as significant contributors to frailty. Conversely, factors such as a positive inclination toward taste, consistent meal timing, habitual breakfast consumption, sound nutritional intake, and the cultivation of healthy dietary practices were recognized as pivotal elements that act as protective factors against frailty.ConclusionThe integration of both BMI and WHR provides a more comprehensive perspective, effectively capturing the intertwined influence of obesity and sarcopenia on the extent of frailty. To mitigate the risk of community-wide frailty, a multipronged approach is essential, involving the promotion of favorable dietary practices and achieving nutritional equilibrium, diligent management of coexisting medical conditions, moderation in alcohol consumption, and the enhancement of physical functionality.

Objectives: This study aimed to evaluate the level and factors affecting the perioperative exercise intention in China. Design: This study was a cross-sectional survey in Southwest China. Methods: Four hundred and ninety nine participants were randomly sampled in eight medical centers from November 23, 2020 to November 27, 2020. The survey included sociodemographic information and a 24-item modified questionnaire, which aimed to evaluate the attitude toward daily exercise, perception of perioperative exercise, social support and the perioperative exercise intention. A multivariable linear regression model was used to evaluate the effect of different items on the patients' intention for perioperative exercise. Results: A total of 523 responses (95.09%) were collected and 499 (95.41%) were analyzed. The level of exercise intention of the patients during the perioperative period was: 14.83% planned to exercise every day in the hospital, 21.04% planned to exercise every other day, and 35.87% planned to exercise every week. Intensity of daily exercise (P = 0.016), positive attitude of daily exercise (P < 0.001), positive attitude of perioperative exercise (P < 0.001) and social support (P < 0.001) were positively associated with the intention for perioperative exercise. Female (P = 0.012), non-tertiary center (P = 0.011), and preoperative anxiety (P = 0.023) was negatively associated with it. Conclusions: The intention for perioperative exercise was low in Southwest China. The authors aimed to relieve preoperative anxiety, promote the education of perioperative exercise, design perioperative exercise programs, and provide more social support from medical staff and family for inpatients undergoing elective surgery.

Background: The aim of this study was to determine the functional and biochemical changes at the neuromuscular junction (NMJ) induced by sepsis.Materials and methods: Male Sprague-Dawley rats were divided into three groups as follows: control, denervation, and sepsis. The rats were subjected to cecal ligation and puncture (CLP) or tibias nerve transection. NMJ function and the area of end plates were assessed, and the protein level of acetylcholine receptors and axonal neuregulin-1 was evaluated on postoperative days 1, 7, and 14.Results: In the control group, the amplitude of compound muscle action potential (CMAP) was 16.51 +/- 2.53 mV. In the sepsis group, the amplitude of CMAP decreased, and duration was prolonged on postoperative days 7 and 14 (P < 0.01). Meanwhile, motor conduction velocity decreased significantly (P < 0.01). CMAP was lost in the denervation group. The twitch tension magnitude gradually declined (P < 0.05) in the sepsis group, although it could not be recorded after lesion. Sepsis and denervation upregulated the expression of gamma-nicotinic acetylcholine receptor (nAChR) and alpha 7-nAChR in muscle membrane, compared with those in normal NMJ (261.4 +/- 26.5 mu m(2)). The NMJ area decreased from 254.6 +/- 23.8 mu m(2) (1 d after CLP) to 275.4 +/- 22.6 mu m(2) (7 d after CLP) to 322.7 +/- 34.4 mu m(2) (14 d after CLP). The postsynaptic NMJ had more discrete fragments (3.84 +/- 0.6) compared with the control group (2.13 +/- 0.4; P < 0.01). After denervation, NMJ underwent fragmentation and the number of discrete fragments increased (5.57 +/- 1.2; P < 0.01). NMJ area increased from 254.6 +/- 23.8 mu m(2) (1 d after CLP) to 275.4 +/- 22.6 mu m(2) (7 d after CLP) to 322.7 +/- 34.4 mm2 (14 d after CLP). Sepsis induced neuregulin-1 to decrease from 1 d up to 2 wk compared with the control group (P < 0.05).Conclusions: Chronic sepsis has a denervation-like effect on the NMJ, which was indicated by upregulation of heterogeneous nAChRs, the increased area of end plates, and demyelination of the motoneuron axon. (C) 2016 Elsevier Inc. All rights reserved.

Regulatory T cells (Tregs) suppress excessive immune responses and are potential therapeutic targets in autoimmune disease and organ transplantation rejection. However, their role in renal ischemia-reperfusion injury (IRI) is unclear. Levels of Tregs and expression of CXCR3 in Tregs were analyzed to investigate their function in the early phase of renal IRI. Mice were randomly divided into Sham, IRI, and anti-CD25 (PC61) + IRI groups. The PC61 + IRI group was established by i.p. injection of PC61 monoclonal antibody (mAb) to deplete Tregs before renal ischemia. CD4(+)CD25(+)Foxp3(+) Tregs and CXCR3 on Tregs were analyzed by flow cytometry. Blood urea nitrogen (BUN), serum creatinine (Scr) levels, and tubular necrosis scores, all measures of kidney injury, were greater in the IRI group than in the Sham group. Numbers of Tregs were increased at 72 h after reperfusion in kidney. PC61mAb preconditioning decreased the numbers of Tregs and aggravated kidney injury. There was no expression of CXCR3 on Tregs in normal kidney, while it expanded at 72 h after reperfusion and inversely correlated with BUN, Scr, and kidney histology score. This indicated that recruitment of Tregs into the kidney was related to the recovery of renal function after IRI and CXCR3 might be involved in the migration of Tregs.

Ischemia reperfusion injury (IRI) is critical in the pathogenesis of acute renal failure and graft rejection. Regulatory T cells (Tregs) suppress excessive immune responses in IRI. We investigated the role of CD4(+)CD25(high)CD127(low) Tregs in the early phase of renal IRI pathogenesis in a mouse model. CD4(+)CD25(high)CD127(low) Tregs in the kidney, tubular necrosis scores, and renal function were measured 24 or 72 h after reperfusion. PC61, an anti-CD25 monoclonal antibody, was used to deplete Tregs before renal ischemia to confirm the effect of these Tregs. CD4(+)CD25(high)CD127(low) Tregs were expanded 24 and 72 h after reperfusion. Depletion of CD4(+)CD25(high)CD127(low) Tregs was associated with worsening of renal function and histology, particularly at 72 h after reperfusion. These results indicated that expansion of CD4(+)CD25(high)CD127(low) Tregs in the early phase of renal IRI may participate in tissue repair. These data reveal new insights into the pathogenesis of ischemic acute renal failure and a novel therapeutic approach.

OBJECTIVES:Programmed death (PD)-1 is a cell death receptor that, upon stimulation, leads to apoptosis. Previous studies have shown alteration of PD-1 expression on T cells and PD-1 genes in patients with systemic lupus erythematosus (SLE). The aim of this study was to assess the expression of this receptor on effector T cells in patients with SLE.METHOD:In this study we enrolled 32 SLE patients and 31 healthy controls. T cells from peripheral blood were analysed by flow cytometry for the expression of PD-1. Interferon (IFN)-γ and interleukin (IL)-17-producing cells were investigated for the expression of this co-stimulatory marker.RESULTS:Percentages of CD4(+) T cells expressing PD-1 were significantly increased in patients with SLE compared to healthy controls. The percentage of PD-1 expression was correlated with the production of INF-γ (r = 0.83, p < 0.0001). We also investigated the production of IL-17 by PD-1(+) CD3(+) T cells. Inactive patients (3.2 ± 1.2% vs. 5.9 ± 3.5%, p = 0.002) and patients without lupus nephritis (LN) (3.2 ± 1.5% vs. 5.9 ± 3.5%, p = 0.005) showed lower levels of IL-17 compared to healthy controls.CONCLUSION:We have demonstrated increased expression of PD-1 on CD4(+) T cells in SLE patients and an association between PD-1 expression on CD4(+) T cells and IFN-γ expression on CD3(+) T cells. We have also shown that there is an altered subset of PD-1(+) T cells in inactive patients and patients without LN producing lower amounts of IL-17.

Objective To evaluate the role of regulatory T cells (Tregs) in the renal ischemia-reperfusion injury (IRI) in mice.Methods Forty-eight male C57BL/6J mice,weighing 20-25 g,were randomly divided into 3 groups (n =16 each):sham operation group (group S),group IRI and anti-CD25 monoclonal antibody PC61 group (group P).Bilateral kidneys were exposed and their pedicles were occluded for 45 min with atraumatic miniclamp followed by 72 h reperfusion.PC61 250 μg was injected intraperitoneally at 24 h before the model was established.Blood samples were collected from the inferior vena cava at 24 and 72 h of reperfusion (T1,2) for determination of serum blood urea nitrogen (BUN) and creatinine (Cr) concentrations.Bilateral kidneys were obtained for determination of the number of Tregs in renal tissues and the pathological changes of the kidney were scored.Results Compared with group S,the serum BUN and Cr concentrations and pathological scores were significantly increased at T1,2 in IRI and P groups,the number of Tregs was increased at T1,2 in IRI group,and the number of Tregs was decreased at T1,2 in P group (P ＜ 0.05).Compared with group IRI,the serum BUN and Cr concentrations and pathological scores were significantly increased at T2,and the number of Tregs was decreased at T1,2 in P group (P ＜ 0.05).The serum BUN and Cr concentrations and pathological scores were significantly lower,and the number of Tregs was larger at T2 than at T1 in group IRI (P ＜ 0.05).There was no significant difference in the parameters mentioned above between T1 and T2 in group P (P ＞ 0.05).Conclusion Tregs are endogenous regulatory factors during renal ischemia-reperfusion,are helpful in inhibiting the inflammatory response and reduce IRI in mice.

Peripheral immunoregulation depends on T regulatory cell trafficking into the allograft to modulate the local alloresponse. Little is known about the relevance of trafficking receptors for Tregs after solid organ transplantation in humans. In this study, expression of the peripheral chemokine receptors CXCR3 and CCR5 on CD4+ FOXP3+ Treg cells was analysed and correlated with allograft function in renal transplant recipients. Flow cytometry analysis of peripheral blood mononuclear cells of 54 renal transplant recipients receiving a calcineurin inhibitor‐based immunosuppression was performed for CD4, CD25, FOXP3, CXCR3 and CCR5 within the first 18 months post‐transplantation. Correlation analysis of chemokine receptor expression and glomerular filtration rate as calculated by MDRD (eGFR) was performed. Expression of the peripheral homing receptors CXCR3 (r = 0.44, P < 0.05) and CCR5 (r = 0.45, P < 0.05) on FOXP3+ Tregs correlated with renal allograft function (eGFR) in patients receiving tacrolimus (n = 28), but not cyclosporine A (CsA) (n = 26). CsA but not tacrolimus reduced surface expression of CXCR3 on FOXP3+ Tregs in renal transplant recipients as correlated to trough levels (r = −0.42, P < 0.05). In contrast to CD4+ CXCR3+ CD25lo T cells, flow‐sorted CD4+ CXCR3+ CD25hi Tregs isolated from healthy individuals did not produce IFNγ or IL‐17 ex vivo and expressed high levels of GARP mRNA both at baseline as well as after TCR activation indicating functional regulatory activity. Expression of the peripheral trafficking receptors CXCR3 and CCR5 on FOXP3+ Tregs is associated with renal allograft function. These results suggest that Treg trafficking may also depend on the interaction of CXCR3 or CCR5 and their respective ligands.

Objective. Persistent T-cell activation is frequently observed in granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis). T-cell activation is usually balanced by negative costimulatory molecules. The negative costimulator programmed death receptor-1 (PD-1) and its relevance to T-cell immunity have not been studied so far in GPA. Thus it is the aim of the study to characterize the role of PD-1 in GPA.Methods. Thirty-two patients suffering from GPA and 19 age-matched healthy controls (HCs) were enrolled. T-lymphocyte subsets from peripheral blood were analysed by flow cytometry for the expression of PD-1. The frequency of memory T cells and T cells producing pro-inflammatory cytokines was determined. Renal biopsies from GPA patients were stained for CD3 and PD-1.Results. PD-1 expression was increased on T-helper cells (Th cells) from GPA patients as compared with HCs. In addition, parameters of persistent T-cell activation and production of pro-inflammatory cytokines were positively associated with numbers of PD-1(+) Th cells in patients but not in HCs. Latent infection with CMV seemed to enhance PD-1 expression on CD4(+) and CD4(+)CD25(-) T cells. Interestingly, expression of PD-1 on CD4(+)CD25(+)T cells was inversely correlated with relapse rate. Importantly, lesional T cells were mostly lacking PD-1.Conclusions. The expression of the negative costimulator PD-1 is altered in GPA and might counterbalance persistent T-cell activation.

Inhaled anesthetics increase the incidence of postoperative residual neuromuscular blockade, and the mechanism is still unclear. We have investigated the synergistic effect of low-concentration inhaled anesthetics and rocuronium on inhibition of the inward current of the adult-type muscle nicotinic acetylcholine receptor (ε-nAChR).

Summary The peripheral chemokine receptors chemokine receptor 3 (CXCR3) and CC chemokine receptor 5 (CCR5) have been reported to be associated with allograft rejection. The impact of the expression of immunosuppressive drugs on peripherally circulating CD4+ T cell subsets after renal transplantion is unknown. Expression of CXCR3 and CCR5 was investigated by flow cytometry in 20 renal allograft recipients participating in a prospective, randomized trial (NCT00514514). Initial immunosuppression consisted of basiliximab, cyclosporin A (CsA), mycophenolate sodium and corticosteroids. After 3 months, patients were treated either with CsA, mycophenolate sodium (MPA) plus corticosteroids (n = 6), CsA and everolimus plus corticosteroids (n = 8) or CsA-free (CsAfree) receiving everolimus, MPA and corticosteroids (n = 6). After initial reduction of CD4+forkhead box protein 3 (FoxP3)+ and CD4+CD25hiFoxP3+ regulatory T cells (Tregs) (P < 0·05; P < 0·01), 3-month post-transplant percentages of Tregs were reconstituted in CsAfree and CsAlo arms compared to CsAreg 12 months post transplant. Expression of CCR5 and CXCR3 on CD4+FoxP3+ and CD4+FoxP3- T cells 12 months post transplant was increased in CsAfreeversus CsAreg. Increase in CCR5+CXCR3+ co-expressing CD4+FoxP3- cells between 3 and 12 months correlated negatively with the glomerular filtration rate (GFR) slope/year [modification of diet in renal disease (MDRD); r = −0·59, P < 0·01]. CsA, but not everolimus, inhibits both Treg development and expression of CXCR3 and CCR5 on CD4+ T cell subsets. Increase in CCR5+CXCR3+ co-expressing CD4+FoxP3- T cells is associated with early loss in allograft function.

Aim of the study: Ion channel mechanism of cardiac electrophysiological effects of Shenfu Decoction (SFD, Ginseng and Aconiti Praeparatae Decoction), a traditional Chinese medicine (TCM) prescription, and its ingredient bases were investigated in guinea pigs.Materials and methods: After administration of an injection made from SFD (Shenfu Injection, SFI), the indexes of transmembrane action potential (TAP) in vivo and sodium channels in isolated ventricular myocyte were assayed by suspended microelectrodes and patch clamp techniques respectively, and ingredients of SFD were compared with.Results: After administration of SFI, the action potential amplitude (APA) and maximum velocity (V-max) of TAP decreased. In the presence of either SFI or Fuzi active ingredient (FZAI)(5, 10, and 15%), not any other ingredient, the density of voltage-dependent sodium current UNO decreased significantly, while the inhibition ratio of SFI was larger. EC50 of SFI was less than the one of FZAI, and SFI displayed effects on I-Na in wider voltage scope than FZAI in current-voltage curve. Both SFI and FZAI shifted the steady-state inactivation curve of sodium channels to the left, and the recovery curve to the right.Conclusions: The results indicated that the cardiac electrophysiological effects of SFI were exerted by blocking sodium channels, and FZAI contributed to such effects most but inferior to SFI, which justified its use in anti-arrhythmia, myocardial protection, etc. (C) 2008 Elsevier Ireland Ltd. All rights reserved.