Expression and effect of sodium-potassium-chloride cotransporter on dorsal root ganglion neurons in a rat model of chronic constriction injury

Sodium-potassium-chloride cotransporter 1 (NKCC1) and potassium-chloride cotransporter 2 (KCC2) are associated with the transmission of peripheral pain.We investigated whether the increase of NKCC1 and KCC2 is associated with peripheral pain transmission in dorsal root ganglion neurons.To this aim,rats with persistent hyperalgesia were randomly divided into four groups.Rats in the control group received no treatment,and the rat sciatic nerve was only exposed in the sham group.Rats in the chronic constriction injury group were established into chronic constriction injury models by ligating sciatic nerve and rats were given bumetanide,an inhibitor of NKCC1,based on chronic constriction injury modeling in the chronic constriction injury + bumetanide group.In the experiment measuring thermal withdrawal latency,bumetanide (15 mg/kg) was intravenously administered.In the patch clamp experiment,bumetanide (10 μg/μL) and acutely isolated dorsal root ganglion neurons (on day 14) were incubated for 1 hour,or bumetanide (5 μg/μL) was intrathecally injected.The Hargreaves test was conducted to detect changes in thermal hyperalgesia in rats.We found that the thermal withdrawal latency of rats was significantly decreased on days 7,14,and 21 after model establishment.After intravenous injection of bumetanide,the reduction in thermal retraction latency caused by model establishment was significantly inhibited.Immunohistochemistry and western blot assay results revealed that the immune response and protein expression of NKCC1 in dorsal root ganglion neurons of the chronic constriction injury group increased significantly on days 7,14,and 21 after model establishment.No immune response or protein expression of KCC2 was observed in dorsal root ganglion neurons before and after model establishment.The Cl^– (chloride ion) fluorescent probe technique was used to evaluate the change of Cl^– concentration in dorsal root ganglion neurons of chronic constriction injury model rats.We found that the relative optical density of N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (a Cl^– fluorescent probe whose fluorescence Cenintensity decreases as Cl– concentration increases) in the dorsal root ganglion neurons of the chronic constriction injury group was significantly decreased on days 7 and 14 after model establishment.The whole-cell patch clamp technique revealed that the resting potential and action potential frequency of dorsal root ganglion neurons increased,and the threshold and rheobase of action potentials decreased in the chronic constriction injury group on day 14 after model establishment.After bumetanide administration,the above indicators were significantly suppressed.These results confirm that CCI can induce abnormal overexpression of NKCC1,thereby increasing the Cl^– concentration in dorsal root ganglion neurons;this then enhances the excitability of dorsal root ganglion neurons and ultimately promotes hyperalgesia and allodynia.In addition,bumetanide can achieve analgesic effects.All experiments were approved by the Institutional Ethics Review Board at the First Affiliated Hospital,College of Medicine,Shihezi University,China on February 22,2017 (approval No.A2017-169-01).     

Risk of Infection Associated With Ibrutinib in Patients With B-Cell Malignancies: A Systematic Review and Meta-analysis of Randomized Controlled Trials

IntroductionB-cell malignancies confer an increased risk of infection due to associated immune defects. Conflicting evidence exists on the risk of infection in patients receiving ibrutinib. We conducted a systematic review and meta-analysis to estimate relative risk of infection with ibrutinib in B-cell malignancies.MethodsA systematic search of Embase, Medline, Web of Science, Scopus, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, European Union Clinical Trials Register, and ClinicalTrials.gov was performed through January 15, 2019, to identify randomized controlled trials comparing ibrutinib with other agents or placebo in B-cell malignancies. We pooled point estimates using the Der Simonian and Laird random-effects model. Statistical analyses were performed by Stata/SE 15.1.ResultsSeven studies randomizing 2167 patients were included in the final analysis. Treatment duration in studies ranged from 9.4 to 38.7 months. Ibrutinib was associated with a significantly increased risk of infection (any grade and grade 3-5) in patients with B-cell malignancies [pooled risk ratio (RR) = 1.34, 95% confidence interval [CI], 1.06-1.69, P = .015; and RR = 1.35, 95% CI, 1.05-1.74, P = .018, respectively]. In patients with chronic lymphocytic leukemia, a significantly increased risk of grade 3-5 infection was noted in the ibrutinib group [pooled RR = 1.24, 95% CI, 1.02-1.50, P = .028]. Incidences of pneumonia and upper respiratory tract infection were not significantly different between groups.ConclusionOur meta-analysis found that ibrutinib was associated with significantly higher risk of infections in patients with B-cell malignancies. Occurrence of major individual subtypes was not different between groups, possibly as a result of inconsistent reporting across studies.     

延续性护理对提高老年慢性支气管炎患者生活质量的影响

目的:探讨延续性护理对提高老年慢性支气管炎患者生活质量及降低并发症的影响。方法:2017年5月至2018年2月收治的45例患者为对照组,应用常规护理方法;2018年3-12月收治的46例为干预组,在对照组的基础上采取出院后延续性护理。比较干预前、干预3个月后2组患者生活质量及并发症发生的情况。结果:SF-36生活质量量表中除日常活动功能(RP)维度外(62.61±9.79VS63.76±8.53,P>0.05),干预组患者在躯体功能(60.88±7.86)、社会活动功能(58.32±6.74)、身体疼痛(53.37±8.67)、活力(59.67±11.41)、总体健康(58.94±7.62)5个维度评分均高于对照组(66.18±8.81、63.27±7.19、56.47±7.34、65.38±9.47、62.71±10.08)P<0.05;干预组并发症发生率低于对照组(10.87%VS26.67%,P<0.05)。结论:延续性护理能提高老年慢性支气管炎患者的生活质量,降低并发症的发生率。     

Exendin-4 attenuates pain-induced cognitive impairment by alleviating hippocampal neuroinflammation in a rat model of spinal nerve ligation

Glucagon-like peptide-1 receptor has anti-apoptotic,anti-inflammatory,and neuroprotective effects.It is now recognized that the occurrence and development of chronic pain are strongly associated with anti-inflammatory responses;however,it is not clear whether glucagon-like peptide-1 receptor regulates chronic pain via anti-inflammatory mechanisms.We explored the effects of glucagon-like peptide-1 receptor on nociception,cognition,and neuroinflammation in chronic pain.A rat model of chronic pain was established using left L5 spinal nerve ligation.The glucagon-like peptide-1 receptor agonist exendin-4 was intrathecally injected into rats from 10 to 21 days after spinal nerve ligation.Electrophysiological examinations showed that,after treatment with exendin-4,paw withdrawal frequency of the left limb was significantly reduced,and pain was relieved.In addition,in the Morris water maze test,escape latency increased and the time to reach the platform decreased following exendin-4 treatment.Immunohistochemical staining and western blot assays revealed an increase in the numbers of activated microglia and astrocytes in the dentate gyrus of rat hippocampus,as well as an increase in the expression of tumor necrosis factor alpha,interleukin 1 beta,and interleukin 6.All of these effects could be reversed by exendin-4 treatment.These findings suggest that exendin-4 can alleviate pain-induced neuroinflammatory responses and promote the recovery of cognitive function via the glucagon-like peptide-1 receptor pathway.All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Renmin Hospital of Wuhan University of China(approval No.WDRM 20171214)on September 22,2017.     

蜘蛛香环烯醚萜部位干预CUMS致抑郁小鼠脑组织的1H-NMR代谢组学分析

目的:利用代谢组学技术分析慢性温和不可预知应激(CUMS)抑郁模型小鼠脑组织样本,寻找与抑郁相关的差异代谢物,探讨蜘蛛香环烯醚萜部位(IEFV)可能的抗抑郁作用机制。方法:42只昆明小鼠随机分为6组,包括正常组,模型组,氟西汀组(2.5 mg·kg-1),IEFV低、中、高剂量组(给药剂量分别为5.73,11.47,22.94 mg·kg-1)。采用CUMS对小鼠造模,以IEFV及阳性药(氟西汀)为干预药物,用行为指标和生化指标进行药效学评价。采用核磁共振氢谱(1H-NMR)代谢组学技术分析IEFV对CUMS抑郁模型小鼠脑组织中内源性物质的影响,结合多变量统计分析方法来确认差异代谢物,并对差异代谢物参与的代谢通路进行富集。结果:造模后,小鼠的不动时间大幅度提高、蔗糖偏好率明显下降,兴奋性神经递质5-羟色胺和去甲肾上腺素显著下降,表明造模成功。给予IEFV和氟西汀后,小鼠不动时间、蔗糖偏好率和兴奋性神经递质向正常水平回调,提示给药后抑郁状态得到了一定程度的缓解。脑组织中内源性代谢物主成分分析(PCA)结果显示,模型组可与正常组明显分开,同时IEFV低、中、高剂量组和氟西汀组均显示有偏离模型组向正常组靠拢的趋势,与行为学结果一致。模型组与正常组进行正交偏最小二乘法-判别分析(OPLS-DA)得到了16个变化显著的差异代谢物,包括12个水溶性差异代谢物和4个脂溶性差异代谢物。通过MetPA数据库分析得到7条潜在靶标代谢通路,包括三羧酸循环(TCA),牛磺酸和亚牛磺酸的代谢,丙氨酸、天冬氨酸和谷氨酸代谢等。IEFV高剂量组可显著回调11种差异代谢物。结论:IEFV可能主要通过影响能量代谢,氨基酸代谢和神经递质水平发挥抗抑郁作用,可为IEFV抗抑郁作用机制的深入研究提供参考依据。     

小金胶囊联合左甲状腺素钠片治疗桥本氏甲状腺炎的临床研究

目的:探讨小金胶囊联合左甲状腺素钠片治疗桥本氏甲状腺炎的临床研究。方法:选取2017年8月—2019年1月收治的桥本氏甲状腺炎患者106例,按照数字表法将其随机分为两组,对照组应用左甲状腺素钠片治疗,研究组应用小金胶囊联合左甲状腺素钠片治疗,对两组患者临床疗效、甲状腺功能及炎症反应等指标进行分析。结果:研究组的临床治愈比例高于对照组(50.9%vs 18.7%);研究组的T3(2.2±0.5) nmol/L、T4(124.2±17.8) nmol/L、FT3(4.3±0.7) pmol/L及FT4(14.4±2.9) pmol/L与对照组无明显差异(P 0.05),研究组的TSH(1.8±0.2)μIU/L低于对照组(P 0.05);研究组甲状腺抗体水平TG-Ab(253.4±12.8) IU/mL、TPO-Ab(241.3±12.8) IU/mL均低于对照组(P 0.05);研究组IL-8(0.4±0.2) ng/mL、IL-17(7.4±2.1) pg/mL及APN(5.9±1.1)μg/mL低于对照组(P 0.05),研究组的IL-10(91.8±12.6) pg/mL高于对照组(P 0.05);研究组不良反应(22.64%)与对照组(24.53%)无明显差异(P 0.05)。结论:采用小金胶囊联合左甲状腺素钠片治疗桥本氏甲状腺炎患者,能有效改善患者甲状腺抗体水平,调节自身炎症因子平衡,具有较高的安全性,可以在临床中进行进一步推广。     

COPD患者相关炎性因子水平与其病情严重程度的相关性研究

探讨慢性阻塞性肺病(COPD)患者的可溶性髓系细胞触发受体-1(sTREM-1)、结缔组织生长因子(CTGF)、亲环素-A(CyPA)水平与其病情严重程度的相关性。ELISA检测COPD患者与健康人血清sTREM-1、CTGF、CyPA水平。结果显示,COPD患者sTREM-1、CTGF、CyPA水平高于健康人。随着肺功能分级的增加,COPD患者血清中sTREM-1、CTGF、CyPA水平也随之增加。sTREM-1、CTGF、CyPA水平与FEV1/FVC呈现显著负相关性(P＜0.05)。Logistic回归分析显示,sTREM-1、CTGF、CyPA水平是严重COPD的影响因素。结果说明,COPD患者血清sTREM-1、CTGF、CyPA水平显著升高,并且与患者肺功能指标显著相关,可用于判断COPD患者的病情严重程度。     

Therapeutic effect of mesenchymal stem cell on Hashimoto’s thyroiditis in a rat model by modulating Th17/Treg cell balance

Abstract

The autoimmune condition Hashimoto’s thyroiditis (HT) is a disease wherein lymphocytes mediate the autoimmune damage and destruction of the thyroid gland. There are currently no effective means of treating HT, with the primary strategies of thyroid hormone therapy, surgery, or immunomodulatory therapy being associated with serious risks and side effects. There is thus a clear and urgent need to identify novel treatments for HT. In this study, we utilize female SD rats induced HT to evaluated the ability of transplanted MSCs to regulate Th17/Treg interactions in a rat Hashimoto’s thyroiditis (HT) model system. The results showed that Rats in the HT model group exhibited increased thyroid autoantibody levels consistent with successful model development, whereas these levels were lower in rats treated with MSCs. There were also fewer thyroid lesions and less lymphoid infiltration of the thyroid in MSC-treated rats relative to HT model rats, as well as fewer Th17 cells and more Treg cells – an observation consistent with the cytokine analyses. All of these showed that MSCs can regulate Th17/Treg interactions in a rat Hashimoto’s thyroiditis (HT) model system. It suggested that transplanted MSCs could be a potential immunotherapy strategy for the treatment of Hashimoto’s thyroiditis.     

益肾化湿颗粒辅助治疗慢性肾小球肾炎的效果研究

目的 探究慢性肾小球肾炎患者应用益肾化湿颗粒辅助治疗的临床疗效。方法 选择2017年3月1日—2019年3月1日在河南科技大学第一附属医院接受治疗的慢性肾小球肾炎患者120例作为临床研究对象,随机投掷硬币法分组。对照组60例患者应用氯沙坦钾片治疗,观察组60例患者应用氯沙坦钾片与益肾化湿颗粒联合治疗,比较所有患者治疗后的临床疗效以及对血清中白细胞诱素-1(LKN－1)、肿瘤坏死因子α(TNF－α)和白细胞介素13(IL－13)水平的影响情况。结果 经治疗后,观察组患者的治疗总有效率为96.67%,高于对照组患者的73.33%(P<0.05);观察组患者的尿红细胞为(4.09±1.01)个/HP、24 h尿蛋白定量为(0.79±0.35)g/L、血尿素氮(BUN)为(9.11±2.65)mmol/L以及血肌酐(Scr)为(119.44±48.99)umol/L,均低于对照组患者水平(P<0.05):尿红细胞(6.20±1.98)个/HP、24 h尿蛋白定量(1.25±0.39)g/L、血尿素氮(BUN)(10.60±3.18)mmol/L以及血肌酐(Scr)(137.01±55.43)umol/L;观察组患者血清中IL-13水平为(12.08±2.24)ng/L、TNF-α为(13.57±4.34)ng/L、LKN－1为(70.43±33.88)pmol/L,均低于对照组患者水平,差异均具有统计学意义(P<0.05)。结论 应用益肾化湿颗粒治疗慢性肾小球肾炎患者,可有效消除炎症,改善肾功能,提高临床治疗效果,值得推广应用。