Phase-specific manipulation of neuronal activity: a promising stroke therapy approach

Introduction: Ischemic stroke accounts for ~87% of all stroke cases(Virani et al., 2020).It is a leading cause of death and long-term disability worldwide, and constitutes a major burden for families and healthcare systems alike.

Controversies in fluid therapy: Type, dose and toxicity

Fluid therapy is perhaps the most common intervention received by acutely ill hospitalized patients; however, a number of critical questions on the efficacy and safety of the type and dose remain. In this review, recent insights derived from randomized trials in terms of fluid type, dose and toxicity are discussed. We contend that the prescription of fluid therapy is context-specific and that any fluid can be harmful if administered inappropriately. When contrasting ‘‘crystalloid vs colloid'', differences in efficacy are modest but differences in safety are significant. Differences in chloride load and strong ion difference across solutions appear to be clinically important. Phases of fluid therapy in acutely ill patients are recognized, including acute resuscitation, maintaining homeostasis, and recovery phases. Quantitative toxicity(fluid overload) is associated with adverse outcomes and can be mitigated when fluid therapy basedon functional hemodynamic parameters that predict volume responsiveness and minimization of non-essential fluid. Qualitative toxicity(fluid type), in particular for iatrogenic acute kidney injury and metabolic acidosis, remain a concern for synthetic colloids and isotonic saline, respectively. Physiologically balanced crystalloids may be the ‘‘default'' fluid for acutely ill patients and the role for colloids, in particular hydroxyethyl starch, is increasingly unclear. We contend the prescription of fluid therapy is analogous to the prescription of any drug used in critically ill patients.

Targeting O-GlcNAcylation in ischemic stroke

Ischemic stroke is a common and often devastating disease that prima rily affects the elderly.Treatment currently consists predominantly of acute thrombolysis and/or thrombectomy to restore blood flow.This reperfusion therapy,however,is only accessible to a small fraction of stroke patients,and even among these patients,many still suffer lifelong neurologic deficits.Thus,new stroke therapeutics are urgently needed to improve the quality of life for stroke patients.

Regulation of Pain and Itch by TRP Channels

Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily （TRPV1, TRPV3, and TRPV4）, and finally members of the melastatin group （TRPM2, TRPM3, and TRPMS）. Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory com- pounds targeting specific pain/itch-TRPs so that physio- logical protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1- modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accom- plished via simple dosing strategies, and also by incorpo- rating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.

Sex-Dependent Glial Signaling in Pathological Pain:Distinct Roles of Spinal Microglia and Astrocytes

Increasing evidence suggests that spinal micro- glia regulate pathological pain in males. In this study, we investigated the effects of several microglial and astroglial modulators on inflammatory and neuropathic pain follow- ing intrathecal injection in male and female mice. These modulators were the microglial inhibitors minocycline and ZVEID （a caspase-6 inhibitor） and the astroglial inhibitors L-α-aminoadipate （L-AA, an astroglial toxin） and car- benoxolone （a connexin 43 inhibitor）, as well as U0126 （an ERK kinase inhibitor） and D-JNKI-1 （a c-Jun N-terminal kinase inhibitor）. We found that spinal administration of minocycline or ZVEID, or Caspase6 deletion, reduced formalin-induced inflammatory and nerve injury-induced neuropathic pain primarily in male mice. In contrast, intrathecal L-AA reduced neuropathic pain but not inflam- matory pain in both sexes. Intrathecal U0126 and D-JNKI- 1 reduced neuropathic pain in both sexes. Nerve injury caused spinal upregulation of the astroglial markers GFAP and Connexin 43 in both sexes. Collectively, our data confirmed male-dominant microglial signaling but also revealed sex-independent astroglial signaling in the spinal cord in inflammatory and neuropathic pain.

Emerging Role of PD-1 in the Central Nervous System and Brain Diseases

Programmed cell death protein 1(PD-1)is an immune checkpoint modulator and a major target of immunotherapy as anti-PD-1 monoclonal antibodies have demonstrated remarkable efficacy in cancer treatment.Accumulating evidence suggests an important role of PD-1 in the central nervous system(CNS).PD-1 has been implicated in CNS disorders such as brain tumors,Alzheimer’s disease,ischemic stroke,spinal cord injury,multiple sclerosis,cognitive function,and pain.PD-1 signaling suppresses the CNS immune response via resident microglia and infiltrating peripheral immune cells.Notably,PD-1 is also widely expressed in neurons and suppresses neuronal activity via downstream Src homology 2 domain-containing protein tyrosine phosphatase 1 and modulation of ion channel function.An improved understanding of PD-1 signaling in the cross-talk between glial cells,neurons,and peripheral immune cells in the CNS will shed light on immunomodulation,neuromodulation,and novel strategies for treating brain diseases.

TNF-αTNFR1 Signaling is Required for the Full Expression of Acute and Chronic Itch in Mice via Peripheral and Central Mechanisms

Increasing evidence suggests that cytokines and chemokines play crucial roles in chronic itch. In the present study, we evaluated the roles of tumor necrosis factor-alpha （TNF-c0 and its receptors TNF receptor subtype-I （TNFR1） and TNFR2 in acute and chronic itch in mice. Compared to wild-type （WT） mice, TNFRl-knockout （TNFR1-KO） and TNFR1/R2 double-KO （DKO）, but not TNFR2-KO mice, exhibited reduced acute itch induced by compound 48/80 and chloroquine （CQ）. Application of the TNF-synthesis inhibitor thalidomide and the TNF-at antagonist etanercept dose-dependently suppressed acute itch. Intradermal injection of TNF-α was not sufficient to evoke scratching, but potentiated itch induced by compound 48/80, but not CQ. In addition, compound 48/80 induced TNF-α mRNA expression in the skin, while CQ induced its expression in the dorsal root ganglia （DRG） and spinal cord. Furthermore, chronic itch induced by dry skin was reduced by administration of thalidomide and etaner- cept and in TNFR1/R2 DKO mice. Dry skin induced TNF- expression in the skin, DRG, and spinal cord and TNFR1 expression only in the spinal cord. Thus, our findings suggest that TNF-c^-fNFR1 signaling is required for the full expression of acute and chronic itch via peripheral and central mechanisms, and targeting TNFR1 may be benefi- cial for chronic itch treatment.

Expression and Role of Voltage-Gated Sodium Channels in Human Dorsal Root Ganglion Neurons with Special Focus on Nav1.7,Species Differences, and Regulation by Paclitaxel

Voltage-gated sodium channels （Navs） play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained human dorsal root ganglion （hDRG） tissues from healthy donors. PCR analysis of seven DRG-expressed Nav subtypes revealed that the hDRG has higher expression of Navl.7 （,-~ 50% of total Nav expression） and lower expres- sion of Navl.8 （~ 12%）, whereas the mouse DRG has higher expression of Nav 1.8 （- 45%） and lower expression of Navl.7 （- 18%）. To mimic Nav regulation in chronic pain, we treated hDRG neurons in primary cultures with paclitaxel （0.1-1 μmol/L） for 24 h. Paclitaxel increased the Navl.7 but not Navl.8 expression and also increased the transient Na＋ currents and action potential firing frequency in small-diameter （〈50 ~tm） hDRG neurons. Thus, the hDRG provides a translational model in which to study ＂human pain in a dish＂ and test new pain therapeutics.

Differential Inhibition of Nav1.7 and Neuropathic Pain by Hybridoma-Produced and Recombinant Monoclonal Antibodies that Target Nav1.7

Abstract The voltage-gated Na＋ channel subtype Nav1.7 is important for pain and itch in rodents and humans. We previously showed that a Nav1.7-targeting monoclonal antibody （SVmab） reduces Na＋ currents and pain and itch responses in mice. Here, we investigated whether recom- binant SVmab （rSVmab） binds to and blocks Nav1.7 similar to SVmab. ELISA tests revealed that SVmab was capable of binding to Nav1.7-expressing HEK293 cells, mouse DRG neurons, human nerve tissue, and the voltagesensor domain II of Nav1.7. In contrast, rSVmab showed no or weak binding to Nav1.7 in these tests. Patch-clamp recordings showed that SVmab, but not rSVmab, markedly inhibited Na＋ currents in Nav1.7-expressing HEK293 cells. Notably, electrical field stimulation increased the blocking activity of SVmab and rSVmab in Nav1.7- expressing HEK293 cells. SVmab was more effective than rSVmab in inhibiting paclitaxel-induced mechanical allodynia. SVmab also bound to human DRG neurons and inhibited their Na＋ currents. Finally, potential reasons for the differential efficacy of SVmab and rSVmab and future directions are discussed.

Spinal CCL2 Promotes Central Sensitization, Long-Term Potentiation, and Inflammatory Pain via CCR2： Further Insights into Molecular, Synaptic, and Cellular Mechanisms

Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 （C-C motif chemokine ligand 2） has been shown to enhance N-methyl-D-aspartate （NMDA）-induced currents in spinal outer lamina II （Iio） neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expres- sion in excitatory vesicular glutamate transporter subtype 2-positive （VGLUT2＋） neurons. CCL2 increased NMDA- induced currents in CCR2＋/VGLUT2＋ neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin- expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2- expressing excitatory neurons in spinal lamina Iio, and this underlies the generation of central sensitization in patho- logical pain.

Targeting the SUMO pathway for neuroprotection in brain ischaemia

Small ubiquitin-like modifier(SUMO)conjugation(SUMOylation)is a post-translational protein modification that modulates almost all major cellular processes,and has been implicated in many human diseases.A growing body of evidence from in vitro and in vivo studies demonstrates that increasing global levels of SUMO conjugated proteins(global SUMOylation)protects cells against ischaemia-induced damage,while suppressing global SUMOylation promotes cell injury after ischaemia.Indeed,SUMOylation has emerged as a potential therapeutic target for neuroprotection in brain ischaemia,including global brain ischaemia and focal brain ischaemia(ischaemic stroke).Here,we summarise findings on the role of SUMOylation in human diseases,brain ischaemia in particular,and review recent developments in drug discovery targeting SUMOylation with a major focus on its neuroprotective applications.

正方观点：食品药品监督管理局对氟哌利多的黑盒子警告是不合理的

氟哌利多（droperidol）是一种广泛应用在麻醉领域中的物美价廉的止吐剂。0．625～1．25mg的静脉剂量被推荐为手术后恶心、呕吐（PONV）的一线预防用药方案。然而，美国食品药品监督管理局（FDA）于2001年12月发布黑盒子警告，认为注射氟哌利多后有可能导致严重的心律失常甚至死亡。FDA指出，甚至当剂量小于2．5mg的常规剂量时，

去氧肾上腺素对蛛网膜下隙麻醉剖宫产产妇血流动力学和母婴预后的影响

去氧肾上腺素针对于剖宫产产妇因蛛网膜下隙麻醉引起的低血压具有良好效果。过去麻黄素被认为是产科患者首选的升压药，但现在去氧肾上腺素得到越来越广泛的应用，主要是因为研究表明注射去氧肾上腺素能改善胎儿的酸碱状态，预防性使用去氧肾上腺素能减少低血压的发生率及相关副作用。本篇综述针对麻黄素与去氧肾上腺素对产妇血流动力学（动脉血压、心率和心排血量）及术中恶心和呕吐的影响加以较，同时比较了去氧肾上腺素治疗性单剂给药与预防性输注对低血压的疗效，还评价了与麻黄素相比，去氧肾上腺素对子宫胎盘血流灌注以及胎儿预后（如新生儿酸碱状态和Apgar评分）的影响，还对去氧肾上腺素的最佳给药方案进行了讨论。

血管手术的区域麻醉

背景建立初级动静脉瘘（arteriovenous fistula，AVF）的失败率约为25％，其原因在于血栓形成或管径与血流不足。患者的特征和手术技术影响瘘管的成熟，但是增加血管直径和提高瘘管血流速度是AVFs成功的两个最重要的预后因素。应用于血管手术的麻醉技术（监测下的麻醉、区域阻滞和全身麻醉）可能影响这些特征和瘘管的建立。方法通过关键字在PubMed／MEDLINE数据库进行文献检索。有7篇文章涉及麻醉对AVF形成的影响，包括交感阻滞、静脉扩张、血流、不良后果或者开放率，本综述的数据来源于这7篇文章。结果区域麻醉处理后血管显著扩张，见于头静脉和贵要静脉，这些血管扩张的特性可能有助于AVF部位的选择。在术中和术后，区域麻醉的应用相比于其他的麻醉技术，可明显增加瘘管血流。交感阻滞有利于血管扩张和减少血管痉挛。应用区域阻滞来建立AVF可缩短瘘管成熟时间，降低失败率，提高开放率。结论区域阻滞可有效的扩张血管，增加瘘管血流，交感截断样效应和缩短成熟时间，从而提高血管手术的成功率。然而仍需要大规模的前瞻性的临床试验来比较不同麻醉技术从而证实本文的观点。

体外循环对大鼠体内白介素．6的释放、大脑NF-κB的表达及神经认知功能的影响

背景心外科手术中，体外循环（cardiopulmonary bypass，CPB）术后发生的神经认知功能障碍一直影响着患者的生活质量。炎症反应可能是其中的因素之一。本实验中我们检测了年轻大鼠围术期体内IL-6的浓度，海马NF-κB的表达含量和神经认知功能，同时评估了氧合器的大小对上述指标的影响。方法将大鼠随机分为4组：空白对照组（n=7），假手术组（n=10，麻醉、置管、不连接体外循环）和两组体外循环实验组，CPB组大鼠在麻醉、置管后行90分钟的体外循环，分别使用小容量的大鼠氧合器（n=10）和新生儿氧合器（n=10）。在术前、CPB结束时和CPB结束后2小时采集血样检测IL-6的含量。在术后第21天采用免疫组化的方法检测海马NF—κB的表达含量。在术前和术后的21天内对神经功能采用改良孔板实验进行评估。结果CPB组与假手术组相比，IL-6的水平明显升高，新生儿氧合器组在CPB结束后2小时与大鼠氧合器组相比IL-6的水平更高[CPB／大鼠氧合器组：220pg／ml（16～415）；CPB／新生儿氧合器组：1400pg／ml（592～5812）]（P〈0．05）。3组实验组中海马NF—KB的表达含量与对照组（10±4）相比明显升高。CPB组与假手术组（173±24）相比NF．KB表达含量更高（CPB／新生儿氧合器组：271±57；CPB／大鼠氧合器组：269±72）。神经认知功能和行为学的评估结果显示组间没有差异。结论CPB引发显著的全身性炎症反应并伴随着海马中NF-κB蛋白表达的增多并没有导致神经认知功能的损伤。由此可推断，排除体外循环和炎症反应这两个因素，可能有其他因素最终导致了患者CPB术后神经认知功能的障碍。

Rolapitant预防术后恶心呕吐：一项前瞻性、双盲、安慰剂对照的随机试验

背景术后恶心呕吐（postoperativenauseaandvomiting，PONV）是一种常见的术后并发症。研究证实神经激肽．1（neurokinin一1，NK，）受体拮抗剂可以安全有效地用于预防和治疗人类PONV。Rolapitant（罗纳吡坦）为一种吸收迅速、半衰期相当长（达180小时）的强效选择性NK、受体拮抗剂，潜在的药物相互作用低。我们对Rolapitant用于预防PONV高危人群的量效关系以及术后5天的预防迟发性IK）NV的效果进行了研究。方法这项关于Rolapitant的随机、多中心、双盲、有效剂量范围的研究设有安慰剂组和阳性对照组。纳入619例行开腹手术的成年妇女，基于PONV或晕动病史进行分层，分为6个研究组：Rolapitant口服剂量5mg组、20mg组、70nag组或200mg组；静注昂丹司琼4mg组或安慰剂组。主要研究终点：不考虑补救用药，拔管后24小时的无呕吐发生率。结果Rolapitant20mg、70mg或200mg组患者的术后24小时无呕吐发生率高于安慰剂组。Rolapitant剂量与主要转归呈线性相关。与安慰剂组相比，Rolapitant70mg和200mg组的呕吐次数明显更低（P≤0．001，对数秩和检验）。尽管术后24小时无呕吐次数在Rolapitant组和昂丹司琼对照组没有明显差异，但Rolapitant200mg组和70mg组的术后72小时和120小时无呕吐发生率更高（不考虑补救用药）。结论Rolapitant降低术后呕吐的疗效优于安慰剂，呈剂量依赖性地降低呕吐发生率。而且Rolapitant与安慰剂在不良反应方面没有差异。

围术期收缩压变异性是否可预测心脏手术后死亡率：ECLIPSE研究的探索性分析

背景目前，有关围术期血压稳定性-9手术预后关系的研究很少，本研究旨在验证心脏手术患者中收缩压（systolic blood pressure，SBP）变异性与术后30天死亡率具有相关性这一假设。方法本研究从ECLIPSE试验中随机选取1512例围术期高血压患者，分析其SBP变异性。通过超出既定SBP可变范围的偏差×持续时间（曲线下面积）衡量SBP变异性。手术中既定的SBP可变范围为65—135mmHg，手术前和手术后为75—145mmHg，按10mmHg递增提高SBP低限，将既定的SBP可变汜44-围逐步缩窄到手术中105-135mmHg及手术前手术后115—145mmHg。应用多元逻辑回归分析评价收缩压变异性与从ECLIPSE试验结果中得到手术后30天死亡率的关系。结果超过既定范围的SBP变异性（手术中75—135mmHg及手术前手术后85。145mmHg）与手术后30天的死亡率显著相关。每增加60mmHg·min^-1·h^-1的收缩压偏差，手术后30天死亡风险的比值比为1．16（95％可信区间1．04—1．30）。当曲线下的面积从0增加到300mmHg·min^-1·h^-1对于低危组患者，30天死亡率的预测概率从0．2％增加到0．5％，而高危患者从42．4％增加到60．7％。结论心脏手术患者围术期血压变异性与30天死亡率相关，并与超出既定的SBP可变范围（手术中75—135mlnng及手术前手术后85—145mmHg）的偏差程度成正比。与低危组患者相比，高危组患者死亡率的预测值更高。

ECLIPSE研究：氯维地平与硝酸甘油、硝普钠、尼卡地平治疗心外手术患者急性高血压的对比研究

背景心外手术过程中的高血压常难以控制，并进而影响手术疗效。氯维地平是一种新型的2-氢吡啶L型钙通道阻滞剂，可有效降低动脉压，起效迅速，且半衰期极短。氯维地平治疗围手术期高血压的安全性事件评估研究（evaluation of clevidipine in the perioperative treatment of hypertension assessing safety events trial, ECLIPSE）旨在比较氯维地平（CLV）与硝酸甘油（NTG）、硝普钠（SNP）、尼卡地平（NIC）治疗心外手术患者急性高血压的疗效与安全性。方法我们分析了3项前瞻性、随机、开放性平行对照研究的资料，这些研究由61家医疗中心参与完成，比较了氯维地平与硝酸甘油、硝普钠、尼卡地平在心外手术患者的围手术期应用情况。共选择1964例患者，1512例按临床标准需紧急治疗高血压，符合随机化纳入标准。这些患者按1：1比例随机编入3个平行的对比治疗组。主要结局为30天内的死亡事件、心肌梗死、中风和肾功能不全，次要结局为血压控制的充分性与精确度的评估报告。结果氯维地平组与其他治疗组相比，心肌梗死、中风和肾功能不全的发生率均无显著差异。硝普钠治疗组与氯维地平组相比，死亡例数显著增加（P=0．04）。与硝酸甘油（P=0．0006）和硝普钠（P=0．003）相比，氯维地平能更有效地把血压控制在预定范围内。在控制血压于一个预定范围方面氯维地平与尼卡地平等效，但当预定血压控制范围较窄时，氯维地平较尼卡地平超出范围的幅度更小。结论氯维地平用于治疗心外手术患者的急性高血压安全有效。

门诊手术麻醉协会关于手术后恶心呕吐的处理指南

本指南是在门诊手术麻醉协会发起下，由国际专家组编撰而成。该专家组成员涉及与手术后恶心、呕吐（PONV）相关的多个学科，他们审慎的评估了当前关于PONV的医学文献，为PONV高风险的成年及儿童外科手术患者提供了循证医学的参考工具。指南的重点是识别成人及儿童患者中发生PONV的危险因素；推荐降低PONV基础风险的方法；甄别出对PONV进行预防性治疗最为有效的单一药物及联合用药方案；推荐对已发生的PONV的治疗方法；并为具有较高PONV风险的患者提供了处理流程。

透皮东莨菪碱贴剂联合昂丹司琼对比单独应用昂丹司琼用于预防门诊手术后恶心呕吐的一项随机双盲多中心研究

背景手术后恶心、呕吐（PONV）是门诊手术常见的并发症。本试验目的是观察透皮东莨菪碱贴剂（TDS）联合静脉注射昂丹司琼（OND）对门诊患者PONV的疗效是否优于单独应用昂丹司琼。方法此项随机双盲多中心的临床试验纳入了620例接受门诊腹腔镜或隆胸手术的PONV高危女性患者，进入手术室前2小时分别给患者贴上TDS贴剂或外观相同的空白贴剂。在全麻诱导前2—5分钟给所有患者静脉注射OND4mg。手术后24~48小时评估止吐是否完善（彻底止吐标准为无呕吐或干呕，且没有追加止吐药）。同时记录发生呕吐、干呕、恶心以及追加止吐药的患者比例，记录手术后首次发生PONV的时间及离院时间，记录呕吐、干呕、恶心的发作次数与严重程度及患者对于止吐治疗的满意度。结果TDS＋OND组与OND组相比，手术后24小时恶心、呕吐的发生率显著降低，但手术后48小时两者差异无显著性。TDS＋OND组没有呕吐、干呕且未追加过止吐药的患者占48％，而OND组占39％（P〈0．02）。TDS＋OND组的彻底止吐（无恶心、呕吐或干呕，且未追加止吐药）率显著高于OND组（分别为35％和25％，P〈0．01）。TDS＋OND组手术后首次发生恶心、呕吐、干呕及追加止吐药的时间明显晚于OND组（P〈0．05）。前者不良反应的总发生率也低于后者（分别为36．7％和49％，P〈0．01）。结论与单独应用OND相比。TDS＋OND能更大程度地减少PONV，主要是通过减少不良反应而获得。