NMDA Receptor Modulates Spinal Iron Accumulation Via Activating DMT1(-)IRE in Remifentanil-Induced Hyperalgesia

N-methyl-D-aspartate (NMDA) receptor activation is known to be critical in remifentanil-induced hyperalgesia. Evidence indicates that iron accumulation participates in NMDA neurotoxicity. This study aims to investigate the role of iron accumulation in remifentanil-induced hyperalgesia. Remifentanil was delivered intravenously in rats to induce hyperalgesia. The NMDA receptor antagonist MK-801 was intrathecally administrated. The levels of divalent metal transporter 1 without iron-responsive element [DMT1(-)IRE] and iron were detected. Behavior testing was performed in DMT1(-)IRE knockdown rats and rats treated with iron chelator DFO. Meanwhile, the spinal dorsal horn neurons were cultured and transfected with DMT1(-)IRE siRNA, and then respectively incubated with remifentanil and MK-801. The levels of intracellular Ca²⁺ and iron were assessed by fluorescence imaging. Our data revealed that spinal DMT1(-)IRE and iron content significantly increased in remifentanil-treated rats, and MK-801 inhibited the enhancements. DMT1(-)IRE knockdown and DFO prevented against remifentanil-induced hyperalgesia. Notably, the levels of Ca²⁺ and iron increased in remifentanil-incubated neurons, and these growths can be blocked by MK-801. DMT1(-)IRE knockdown attenuated iron accumulation but did not influence Ca²⁺ influx. This study suggests that DMT1(-)IRE-mediated iron accumulation is likely to be the downstream event following NMDA receptor activation and Ca²⁺ influx, contributing to remifentanil-induced hyperalgesia.PerspectiveRemifentanil-induced hyperalgesia is common even when used within clinical accepted doses. This study presents that aberrant iron accumulation is involved in the development of remifentanil-induced hyperalgesia in vivo and in vitro. Iron chelation may be a potential therapeutic strategy for the prevention of hyperalgesia in populations at high risk.     

A retrospective analysis of clinical efficacy of ribavirin in adults hospitalized with severe COVID-19

IntroductionCoronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) swept rapidly throughout the world. So far, no therapeutics have yet proven to be effective. Ribavirin was recommended for the treatment of COVID-19 in China because of its in vitro activity. However, evidence supporting its clinical use with good efficacy is still lacking.MethodsA total of 208 confirmed severe COVID-19 patients who were hospitalized in Wuhan Union West Campus between 1 February 2020 and 10 March 2020 were enrolled in the retrospective study. Patients were divided into two groups based on the use of ribavirin. The primary endpoint was the time to clinical improvement. The secondary endpoints included mortality, survival time, time to throat swab SARS-CoV-2 nucleic acid negative conversion, and the length of hospital stay.Results68 patients were treated with ribavirin while 140 not. There were no significant between-group differences in demographic characteristics, baseline laboratory test results, treatment, and distribution of ordinal scale scores at enrollment, except for coexisting diseases especially cancer (ribavirin group vs no ribavirin group, P = 0.01). Treatment with ribavirin was not associated with a difference in the time to clinical improvement (P = 0.48, HR = 0.88, 95% CI = 0.63–1.25). There were also no significant differences between-group in SARS-CoV-2 nucleic acid negative conversion, mortality, survival time, and the length of hospital stay.ConclusionsIn hospitalized adult patients with severe COVID-19, no significant benefit was observed with ribavirin treatment.     

ICU患者影响万古霉素血药浓度的相关因素分析

目的 通过分析影响重症监护病房(ICU)患者万古霉素血药浓度的相关因素,探讨优化ICU患者万古霉素给药方案。方法 采用回顾性研究方法,收集东莞市人民医院ICU2016年1月至2018年9月使用并监测万古霉素血药浓度的出院患者。统计ICU患者万古霉素血药浓度分布情况,根据肌酐清除率(CrCl)将患者分为CrCl>90mL/min、CrCl 50~90mL/min、CrCl 10~50mL/min及CrCl<10mL/min 4组,分析不同肌酐清除率组对万古霉素血药浓度水平和达标率的影响以及比较指南推荐剂量与实际剂量的差别,并利用多重线性回归分析进一步探讨影响万古霉素血药浓度的相关因素。结果 99例ICU患者监测万古霉素血药浓度共230例次,45例次(19.57%)达到目标浓度(15~20mg/L),72例次(31.30%)未达标(<15mg/L),113例次(49.13%)超标(>20mg/L)。 CrCl 50~90mL/min和CrCl 10~50mL/min组平均血药浓度[(20.16±7.51)mg/L, (23.12±9.37)mg/L]、血药浓度超标比例(45.45%,62.79%)显著高于CrCl>90mL/min组[(14.65±9.07)mg/L, 19.15%]。CrCl>90mL/min、CrCl 50~90mL/min组实际剂量显著低于推荐剂量,而CrCl 10~50mL/min、CrCl<10mL/min组实际剂量显著高于推荐剂量。多重线性回归分析显示,给药剂量(B=11.631,95%CI=7.030~16.232,P<0.001)、肌酐清除率(B=-0.064,95%CI=-0.097~-0.032,P<0.001)、白蛋白水平(B=-0.334,95%CI= -0.634~-0.035,P=0.029)是影响ICU患者万古霉素血药浓度的主要相关因素。结论 ICU患者万古霉素血药浓度达标率较低,在优化ICU患者万古霉素给药方案时应考虑给药剂量、肌酐清除率和白蛋白水平因素的影响。     

宫颈癌初始治疗后腹主动脉旁淋巴结转移调强放疗的临床观察

目的 对比单纯调强放疗(IMRT)与IMRT同步TP方案化疗治疗宫颈癌初始治疗后腹主动脉旁淋巴结(PALN)转移的疗效和不良反应.方法 选取2008年10月至2013年8月宫颈癌初始治疗后出现PALN转移的56例患者,PALN转移病灶给予放疗剂量GTV 55～60 Gy,CTV45 ～ 50 Gy,共25 ～ 30次,5～6周,接受同步放化疗(CRT组)者36例,单纯放疗(RT组)者20例.CRT组的同步化疗方案为TP方案,第1天紫杉醇135 mg/m2,顺铂60 mg/m2 2 d,21 d重复.单纯PALN转移(iPALN)患者33例,合并其他部位复发转移(niPALN)患者23例.结果 中位随访时间22.7个月(2.7 ～74.4个月).98.2％(55/56)的患者完成了放疗,CRT组中,38.9％的患者完成化疗2～3个周期,61.1％的患者完成化疗1个周期.CRT和RT组的有效率(CR +PR)分别为91.7％(33/36)和85％ (17/20)(x2=0.516,P＞0.05).两组患者的中位总生存(OS)时间为38和23个月,3年OS率分别为57.5％和32.7％ (x2 =4.059,P＜0.05),中位无进展生存时间(PFS)为68.3和16个月,3年PFS率分别为50.4％和29.2％(x2=4.184,P＜0.05).单纯PALN转移(iPALN)(33例)患者与合并其他部位复发转移(niPALN)患者(23例)的中位OS分别为71.2和21.4个月,3年OS率分别为53％和39.5％(x2=4.265,P＜ 0.05).CRT和RT组出现3或4级白细胞低下的患者分别为10例(27.8％)和6例(30％),3级消化道反应各有1例,差异均无统计学意义(x2=0.693、0.847,P＞ 0.05).结论 IMRT同步TP化疗对PALN转移的患者近期效果和远期生存均优于单纯放疗的患者,且不良反应可耐受.