Noradrenergic and opioidergic alterations in neuropathy in different rat strains

The Fischer 344 (F344) rat strain differs from the Lewis strain in the response to neuropathic pain. Recently, we found that F344 rats totally recover from mechanical allodynia induced by chronic constriction injury (CCI) of the sciatic nerve 28 days after surgery whereas Lewis rats are initiating their recovery at this time point. Thus, the use of this neuropathic pain model in these different rat strains constitutes a good strategy to identify possible target genes involved in the development of neuropathic pain. Since differences between Lewis and F344 rats in their response to pain stimuli in acute pain models have been related to differences in the endogenous opioid and noradrenergic systems, we aimed to determine the levels of expression of key genes of both systems in the spinal cord and dorsal root ganglia (DRG) of both strains 28 days after CCI surgery. Real time RT-PCR revealed minimal changes in gene expression in the spinal cord after CCI despite the strain considered, but marked changes in DRG were observed. A significant upregulation of prodynorphin gene expression occurred only in injured DRG of F344 rats, the most resistant strain to neuropathic pain. In addition, we found a significant downregulation of tyrosine hydroxylase and proenkephalin gene expression levels in both strains whereas δ-opioid receptor was found to be significantly downregulated only in injured DRG of Lewis rats although the same trend was observed in F344 rats. The data strongly suggest that dynorphins could be involved in strain differences concerning CCI resistance.     

Hospital Frailty Risk Score Outperforms Current Risk Stratification Models in Primary Total Hip and Knee Arthroplasty

BackgroundModels for risk stratification and prediction of outcome, such as the Charlson Comorbidity Index (CCI), the Elixhauser Comorbidity Method (ECM), the 5-factor modified Frailty Index (mFI-5), and the Hospital Frailty Risk Score (HFRS) have been validated in orthopedic surgery. The aim of this study is to compare the predictive power of these models in total hip and knee replacement.MethodsIn a retrospective analysis of 8250 patients who had undergone total joint replacement between 2011 and 2019, CCI, ECM, mFI-5, and HFRS were calculated for each patient. Receiver operating characteristic curve plots were generated and the area under the curve (AUC) was compared between each score with regard to adverse events such as transfusion, surgical, medical, and other complications. Multivariate logistic regression models were used to assess the relationship among risk stratification models, demographic factors, and postoperative adverse events.ResultsIn prediction of surgical complications, HFRS performed best (AUC: 0.719, P < .001), followed by ECM (AUC: 0.578, P < .001), mFI-5 (AUC: 0.564, P = .003), and CCI (AUC: 0.555, P = .012). With regard to medical complications, other complications, and transfusion, HFRS also was superior to ECM, mFI-5, and CCI. Multivariate logistic regression analyses revealed HFRS as an independent risk stratification model associated with all captured adverse events (P ≤ .001).ConclusionThe HFRS is superior to current risk stratification models in the context of total joint replacement. As the HRFS derives from routinely collected administrative data, healthcare providers can identify at-risk patients without additional effort or expense.     

Predictive Factors of Extended Length of Hospital Stay Following Total Joint Arthroplasty in a Veterans Affairs Hospital Population

BackgroundImproved perioperative care for total joint arthroplasty (TJA) procedures has resulted in decreased hospital length of stay (LOS), including effective discharge on postoperative day (POD) 1 in many patients. It remains unclear what contributes to discharge delay in patients that are not discharged on POD 1. This study investigated factors associated with delayed discharge in patients whose original planned discharge was on POD 1.MethodsA retrospective cohort of 451 patients who underwent a hip or knee TJA procedure from April 2015 to March 2018 with planned discharge on POD 1 was analyzed. Patient characteristics included demographics, lab values, course of treatment, procedure, Charlson Comorbidity Index (CCI), complications, and other factors. Statistical regression was used to identify factors associated with delayed discharge; odds ratios (OR) were calculated for significant factors (α = 0.05).ResultsOf those studied, 70/451 (15.5%) experienced a delay from the planned POD 1 discharge. An increased likelihood of delayed discharge was associated with a nonhome discharge (P < .001, OR = 8.72 [95% CI: 4.22-18.06]) and higher CCI (P = .034, OR = 1.16 [95% CI: 1.01-1.32]). Inpatient physical therapy on the day of surgery was found to significantly correlate with successful discharge on POD 1 (P = .004, OR = 0.44 [95% CI: 0.25-0.77]).ConclusionMost patients can be discharged on POD 1 after TJA. Physical therapy on the day of surgery increased the likelihood of patients being discharged on POD 1. Those with a higher CCI and a nonhome discharge were more likely to have a discharge delay. This information can help surgeons counsel patients and prepare for postoperative care.     

Central IRAK-4 kinase inhibition for the treatment of pain following nerve injury in rats

There is ample evidence for the role of the immune system in developing chronic pain following peripheral nerve injury. Especially Toll-like receptors (TLRs) and their associated signaling components and pro-inflammatory cytokines such as IL-1β, induced after injury, are involved in nociceptive processes and believed to contribute to the manifestation of chronic neuropathic pain states. Whereas the inhibition of the kinase function of IRAK-4, a central kinase downstream of TLRs and IL-1 receptors (IL-1Rs), seems efficacious in various chronic inflammatory and autoimmune models, it’s role in regulating chronic neuropathic pain remained elusive to date. Here, we examined whether pharmacological inhibition of IRAK-4 kinase activity using PF-06650833 and BMS-986147, two clinical-stage kinase inhibitors, is effective for controlling persistent pain following nerve injury. Both inhibitors potently inhibited TLR-triggered cytokine release in human peripheral blood mononuclear cell (PBMC) as well as human and rat whole blood cultures. BMS-986147 showing favorable pharmacokinetic (PK) properties, significantly inhibited R848-triggered plasma TNF levels in a rat in vivo cytokine release model after single oral dosing. However, BMS-986147 dose dependently reversed cold allodynia in a rat chronic constriction injury (CCI) model following intrathecal administration only, supporting the notion that central neuro-immune modulation is beneficial for treating chronic neuropathic pain. Although both inhibitors were efficacious in inhibiting IL-1β- or TLR-triggered cytokine release in rat dorsal root ganglion cultures, only partial efficacy was reached in IL-1β-stimulated human glial cultures indicating that inhibiting IRAK-4́’s kinase function might be partially dispensable for human IL-1β driven neuroinflammation. Overall, our data demonstrate that IRAK-4 inhibitors could provide therapeutic benefit in chronic pain following nerve injury, and the central driver for efficacy in the neuropathic pain model as well as potential side effects of centrally available IRAK-4 inhibitors warrant further investigation to develop effective analgesia for patients in high unmet medical need.     

Real-world cost-effectiveness of drug-eluting stents vs. bare-metal stents for coronary heart disease—A five-year follow-up study

Objective

To evaluate the cost-effectiveness of using drugeluting stents (DES) compared to bare-metal stents (BMS) for coronary heart disease (CHD).

A Before and After Analysis of Health Care Utilization by Patients Enrolled in Opioid Controlled Substance Agreements for Chronic Noncancer Pain

Objective

To evaluate the impact of opioid controlled substance agreements (CSAs) enrollment on health care utilization.

Effect of oxymatrine on CaMKII expression in sciatic nerve ligation-induced neuropathic pain in mice北大核心CSCD

Aim To observe the analgesic effect of oxymatrine (OMT) and its mechanism. Methods A peripheral mononeuropathy was produced in adult mice by placing loosely constrictive ligatures around the common sciatic nerve. The antinociceptive effects of the OMT were assessed in mechanical allodynia and cold allodynia tests. The CAMKII inhibitor KN-93 and AIP were adopted to investigate the influence of OMT on the analgesic effect and analyze its analgesic mechanisms. Western blot was used to evaluate the expressions of tCaMKII and pCaMKII protein. Results The intraperitoneal administration of OMT (160, 80 mg · kg-1) increased the paw withdrawal threshold in the mechanical allodynia test (P < 0. 05), OMT (160, 80, 40 mg · kg-1 , ip) remarkably decreased the paw lifts in the cold allodynia test (P < 0. 05). Ith KN-93 (1. 25 (μg/site), AIP (0. 02 μg/site) significantly enhanced the analgesic effect of OMT (35 mg · kg-1) (P<0. 01). Protein expression of pCaMKII was decreased by OMT(160 mg · kg-1). Conclusion OMT has significant protective effects on chronic constriction injury(CCI) in mice, and the effective mechanism of OMT inhibits the expression of CaMKII receptor.     

Does time of CCI measurement affect the evaluation of platelet transfusion effectiveness?

The measurement of corrected count increment at 1-h post-transfusion (CCI-1 h) of platelet concentrate (PC) transfusion is recommended, but in the revised Japanese Guideline (2017) it was changed to “after 10-min to 1-h”, following the revision of the guidelines from Western countries. Here, we aimed to investigate on the feasibility to apply the CCI measured at 10-min or 30-min post-transfusion as the surrogate of CCI-1 h. Peripheral blood was collected at 10-min, 30-min and 1-h post-transfusion of PC and the effectiveness of the transfusion was analyzed based on the CCI. In the period from December 2017 to February 2020, 8 patients, who received multiple PC transfusion (total 208) at our institution, were analyzed. We performed the univariate analyses to examine the relationship between CCI value and the categorical variables, p-value <0.1 was obtained for gender (p = 2.91 × 10^?19), fever after transfusion (p = 0.0163). The qualitative variables, namely measurement time (p = 0.0553), also showed p-value <0.1. Using these factors as covariates in the mixed effect model, we found that the measurement time (p = 0.0007) had a significant effect on the CCI value when looking at fixed effects. Although there is a tendency for decreased CCI values with time progression, the slope of the change in the mixed model was -0.00307, indicating that the CCI difference among the 3 measurements was small. Here we provide evidence that CCI measured at 10-min and 30-min post-transfusion give results comparable to those measured at 1-h post-transfusion, under the Japanese practice of platelet transfusion, which relies on 100 % single-donor apheresis PC, and ABO-identical whenever possible.     

阿霉素减轻坐骨神经慢性缩窄性损伤大鼠的神经病理性疼痛及其机制

目的观察阿霉素(DOX)对坐骨神经慢性缩窄性损伤(CCI)模型大鼠的镇痛作用,并从形态学及组织凋亡蛋白的角度对其机制进行分析。方法将SD大鼠随机分为4组:假手术组(Sham)、CCI模型组(Model)、假手术+阿霉素5 mg·kg^-1组(Sham+DOX)、CCI模型+阿霉素5 mg·kg^-1组(Model+DOX)。造模成功后,各组采用尾静脉注射的方式给药,Sham组和Model组给予等量生理盐水,检测各组大鼠机械痛阈值和热痛阈值。在行为学检测结束后,即手术后d 15取大鼠右侧L4-5DRG,观察DRG细胞形态、超微结构及DOX的分布情况,采用Western blot法测定DRG组织中Bax、Bcl-2、PKCɑ、PKCδ及PKCε的蛋白表达。结果静脉注射DOX可在DRG组织检测到其自发荧光表达。与Sham组相比,Sham+DOX组痛阈值在整个观察期未见差别,而Model组在术后d 7痛阈值明显降低。与Model组相比,Model+DOX组的痛阈值在给药后明显回升,并表现出DRG细胞明显损伤,Bax/Bcl-2升高以及PKCδ、PKCε的蛋白表达量降低等现象。结论 DOX静脉注射可以到达并蓄积于DRG组织,明显减轻CCI大鼠的疼痛反应,这一作用与其降低PKCδ和PKCε的蛋白表达,诱导DRG的凋亡有关。