Symposia Report Immunoglobulin G for the Treatment of Chronic Pain：Report of an Expert Workshop

背景:慢性疼痛的治疗效果仍不理想。尽管现在治疗慢性疼痛的药物种类较多,但许多患者对疗效仍不满意或诉药物的副作用太大。越来越多的证据表明,免疫系统参与了伤害性和神经病理性慢性疼痛的病理过程。设计:在英国利物浦的专题会议上,专家们出示了免疫系统参与慢性疼痛的证据。近来的研究表明,静脉(IVIg)或皮下(SCIg)注射免疫调节药物——多价免疫球蛋白(Ig G)可缓解外周神经病理性疼痛和其他疼痛性疾病。专题会议讨论了IVIg和SCIg治疗的适应证、效价比及其副作用。结果:Ig G可缓解某些伤害性和神经病理性慢性疼痛,如糖尿病、干燥综合征、纤维肌痛症、复杂性区域疼痛综合征、小儿麻痹后遗症和继发于病理性自身抗体的疼痛。结论:Ig G对某些慢性疼痛具有一定的治疗前景。Ig G是一种相对安全的治疗方法,副作用少而轻,但价格较贵。今后有必要对Ig G治疗顽固性疼痛进行随机对照研究和预测性临床试验。

Overexpression of Sirt6 ameliorates sleep deprivation induced-cognitive impairment by modulating glutamatergic neuron function

Sleep benefits the restoration of energy metabolism and thereby suppo rts neuronal plasticity and cognitive behaviors.Sirt6 is a NAD+-dependent protein deacetylase that has been recognized as an essential regulator of energy metabolism because it modulates various transcriptional regulators and metabolic enzymes.The aim of this study was to investigate the influence of Sirt6 on cerebral function after chronic sleep deprivation(CSD).We assigned C57BL/6J mice to control or two CSD groups and subjected them to AAV2/9-CMV-EGFP or AAV2/9-CMV-Sirt6-EGFP infection in the prelimbic cortex(PrL).We then assessed cerebral functional connectivity(FC) using resting-state functional MRI,neuron/astrocyte metabolism using a metabolic kinetics analysis;dendritic spine densities using sparse-labeling;and miniature excitato ry postsynaptic currents(mEPSCs) and action potential(AP) firing rates using whole-cell patchclamp recordings.In addition,we evaluated cognition via a comprehensive set of behavioral tests.Compared with controls,Sirt6 was significantly decreased(P<0.05) in the PrL after CSD,accompanied by cognitive deficits and decreased FC between the PrL and accumbens nucleus,piriform cortex,motor co rtex,somatosensory co rtex,olfactory tubercle,insular cortex,and cerebellum.Sirt6 ove rexpression reve rsed CSD-induced cognitive impairment and reduced FC.Our analysis of metabolic kinetics using [1-13C] glucose and [2-13C] acetate showed that CSD reduced neuronal Glu4and GABA2synthesis,which could be fully restored via forced Sirt6 expression.Furthermore,Sirt6 ove rexpression reversed CSD-induced decreases in AP firing rates as well as the frequency and amplitude of mEPSCs in PrL pyramidal neurons.These data indicate that Sirt6 can improve cognitive impairment after CSD by regulating the PrL-associated FC network,neuronal glucose metabolism,and glutamatergic neurotransmission.Thus,Sirt6 activation may have potential as a novel strategy for treating sleep disorder-related diseases.

Comparative studies on the binding site of anesthetics to GABA a receptors using in silico docking methods

Although the GABAA receptor(GABAAR)has been proposed as the main action site for sevoflurane,isoflurane,halothane,enflurane,propofol,and benzodiazepines(BZDs),binding of these anesthetics with high-resolution structures of the GABAAR have been rarely examined by comparative docking analyses.Moreover,various combinations of ligands on more GABAARs with various subtypes need to be analyzed to understand the elaborate action mechanism of GABAARs better because some GABAA ligands showed specificity toward the distinct subtypes of the GABAAR.Methods:We performed in silico docking analysis to compare the binding modes of sevoflurane,isoflurane,halothane,enflurane,propofol,and BZDs to the GABAAR based on one of the most recently provided 3D structures.We performed the docking analysis and the affinity-based ranking of the binding sites.Results:Our docking studies revealed that isoflurane,halothane,and enflurane docked in an extracellular domain(ECD)on GABAARs,in contrast to sevoflurane.Conclusion:Our results supported a multi-site mechanism for the allosteric modulation of propofol.Propofol was bound to the pore or favored various subsites in the transmembrane domain(TMD).Our result confirmed that different chemically related BZD ligands interact via distinct binding modes rather than by using a common binding mode,as previously suggested.

Bioinspired MXene-Based User-Interactive Electronic Skin for Digital and Visual Dual-Channel Sensing

User-interactive electronic skin(e-skin) that could convert mechanical stimuli into distinguishable outputs displays tremendous potential for wearable devices and health care applications. However, the existing devices have the disadvantages such as complex integration procedure and lack of the intuitive signal display function. Here, we present a bioinspired user-interactive e-skin, which is simple in structure and can synchronously achieve digital electrical response and optical visualization upon external mechanical stimulus. The e-skin comprises a conductive layer with a carbon nanotubes/cellulose nanofibers/MXene nanohybrid network featuring remarkable electromechanical behaviors, and a stretchable elastomer layer, which is composed of silicone rubber and thermochromic pigments. Furthermore, the conductive nanohybrid network with outstanding Joule heating performance can generate controllable thermal energy under voltage input and then achieve the dynamic coloration of silicone-based elastomer. Especially, such an innovative fusion strategy of digital data and visual images enables the e-skin to monitor human activities with evermore intuition and accuracy. The simple design philosophy and reliable operation of the demonstrated e-skin are expected to provide an ideal platform for next-generation flexible electronics.

Neurovascular ageing:transcriptomic readout and implications on therapeutic targeting in Alzheimer’s disease

Ageing is one of the greatest risk factors for neurodegenerative diseases.How the complex biological changes in ageing increase the brain’s susceptibility to neurodegeneration remains incompletely understood.Research into neurodegenerative disorders has shifted from a neuron-centric approach,to the contributing roles of age-related neurovascular and glial cell dysfunction.

Glycerol solutions of highly concentrated biomineral counter-ions towards water-responsive mineralization: Demonstration on bacterial cellulose and its application in hard tissue repair

Mineralization has found widespread use in the fabrication of composite biomaterials for hard tissue regeneration.The current mineralization processes are mainly carried out in neutral aqueous solutions of biomineral counter-ions(a pair of cation and anion that form the corresponding minerals at certain conditions),which are stable only at very low concentrations.This typically results in inefficient mineralization and weak control over biomineral formation.Here,we find that,in the organic solvent glycerol,a variety of biomineral counter-ions(e.g.,Ca/PO_(4),Ca/CO_(3),Ca/SO_(4),Mg/PO_(4),or Fe/OH)corresponding to distinct biominerals at significantly high concentrations(up to hundreds-fold greater than those of simulated body fluid(SBF))are able to form translucent and stable solutions(mineralizing solution of highly concentrated counter-ions(MSCIs)),and mineralization can be triggered upon them with external solvents(e.g.,water or ethanol).Furthermore,with pristine bacterial cellulose(BC)membrane as a model,we demonstrate an effective and controllable mineralization performance of MSCIs on organic substrates.This approach not only forms the homogeneous biominerals on the BC fibers and in the interspaces,but also provides regulations over mineralization rate,mineral content,phase,and dopants.The resulting mineralized BC membranes(MBCs)exhibit high cytocompatibility and favor the proliferation of rat bone marrow mesenchymal stem cells(rBMSC).Following this,we prepare a mineralized bone suture(MBS)from MBC for non-weight bearing bone fixation,which then is tested on a rabbit median sternotomy model.It shows firm fixation of the rabbit sternum without causing discernible toxicity or inflammatory response.This study,by extending the mineralization to the organic solution system of highly concentrated counter-ions,develops a promising strategy to design and build targeted mineral-based composites.

Epidural Spinal Cord Stimulation Promotes Motor Functional Recovery by Enhancing Oligodendrocyte Survival and Differentiation and by Protecting Myelin after Spinal Cord Injury in Rats

Epidural spinal cord stimulation (ESCS) markedly improves motor and sensory function after spinal cord injury (SCI), but the underlying mechanisms are unclear.Here, we investigated whether ESCS affects oligodendrocyte differentiation and its cellular and molecular mechanisms in rats with SCI. ESCS improved hindlimb motor function at 7 days, 14 days, 21 days, and 28 days after SCI.ESCS also significantly increased the myelinated area at 28days, and reduced the number of apoptotic cells in the spinal white matter at 7 days. SCI decreased the expression of 20,30-cyclic-nucleotide 30-phosphodiesterase (CNPase,an oligodendrocyte marker) at 7 days and that of myelin basic protein at 28 days. ESCS significantly upregulated these markers and increased the percentage of Sox2/CNPase/DAPI-positive cells (newly differentiated oligodendrocytes) at 7 days. Recombinant human bone morphogenetic protein 4 (rh BMP4) markedly downregulated these factors after ESCS. Furthermore, ESCS significantly decreased BMP4 and p-Smad1/5/9 expression after SCI,and rh BMP4 reduced this effect of ESCS. These findings indicate that ESCS enhances the survival and differentiation of oligodendrocytes, protects myelin, and promotes motor functional recovery by inhibiting the BMP4-Smad1/5/9 signaling pathway after SCI.

Amorphous calcium magnesium phosphate nanocomposites with superior osteogenic activity for bone regeneration

The seek of bioactive materials for promoting bone regeneration is a challenging and longterm task.Functionalization with inorganic metal ions or drug molecules is considered effective strategies to improve the bioactivity of various existing biomaterials.Herein,amorphous calcium magnesium phosphate(ACMP)nanoparticles and simvastatin(SIM)-loaded ACMP(ACMP/SIM)nanocomposites were developed via a simple co-precipitation strategy.The physiochemical property of ACMP/SIM was explored using transmission electron microscope(TEM),Fourier transform infrared spectroscopy(FTIR),powder X-ray diffraction(XRD)and highperformance liquid chromatograph(HPLC),and the role of Mg^(2+) in the formation of ACMP/SIM was revealed using X-ray absorption near-edge structure(XANES).After that,the transformation process of ACMP/SIM in simulated body fluid(SBF)was also tracked to simulate and explore the in vivo mineralization performance of materials.We find that ACMP/SIM releases ions of Ca^(2+),Mg^(2+)and PO_(4)^(3),when it is immersed in SBF at 37℃,and a phase transformation occurred during which the initially amorphous ACMP turns into self-assembled hydroxyapatite(HAP).Furthermore,ACMP/SIM displays high cytocompatibility and promotes the proliferation and osteogenic differentiation of MC3T3-E1 cells.For the in vivo studies,lamellar ACMP/SIM/Collagen scaffolds with aligned pore structures were prepared and used to repair a rat defect model in calvaria.ACMP/SIM/Collagen scaffolds show a positive effect in promoting the regeneration of calvaria defect after 12weeks.The bioactive ACMP/SIM nanocomposites are promising as bone repair materials.Considering the facile preparation process and superior in vitro/vivo bioactivity,the as-prepared ACMP/SIM would be a potential candidate for bone related biomedical applications.

复合应用利多卡因对鞘内注射布比卡因时效的影响

背景由于阻滞持续时间较长，布比卡因蛛网膜下腔阻滞技术在门诊手术中使用受限。近期动物研究结果证实复合利多卡因后能缩短布比卡因蛛网膜下腔阻滞的持续时间。我们的研究旨在证实人类蛛网膜下腔阻滞时布比卡因复合利多卡因是否如同动物实验结果一样能够缩短其阻滞时间。方法采用随机双盲的方法将90例纳入本项研究的经尿道行膀胱肿瘤切除或前列腺切除的患者分为3组。每组均鞘内注射0．5％布比卡因重比重液1．5ml及下述溶液0．6ml：组Ⅰ（30例，对照组）生理盐水，组Ⅱ（30例）1％利多卡因，组Ⅲ（30侧）2％利多卡因。记录感觉阻滞最高平面、达到感觉阻滞最高平面的时间、从感觉阻滞最高平面到消退两个节段以及消退至L1和S2平面的时间、在感觉阻滞最高平面时和平面消退至L1和S2时的运动阻滞评分及在麻醉恢复室（PACU）的留观时间。结果3组患者达到感觉阻滞最高平面的时间相似。组Ⅱ患者的感觉阻滞最高平面消退两个节段和消退至L1和S2水平的时间，以及PACU内留观时间均较组Ⅰ患者显著缩短。组Ⅲ患者的感觉阻滞最高平面消退至L1和S2水平的时间，以及PACU内留观时间均显著延长。结论复合使用利多卡因（6mg）能够缩短布比卡因（7．5mg）的蛛网膜下腔阻滞时间，阻滞后患者恢复程度较单独使用相同剂量布比卡因（7．5mg）的脊髓麻醉更加迅速。

大容量／低浓度与小容量／高浓度罗哌卡因用于小儿睾丸固定术骶管麻醉镇痛的比较研究

背景当药物总量固定时，局麻药的容积或浓度改变是否会对骶管麻醉的扩散平面及镇痛效果产生影响尚不清楚。方法本研究采用前瞻、随机、观测者盲法实施。年龄为1—5岁的小儿给予预先配置、剂量为2．25mg＆g的罗哌卡因。其中一组给予1．0ml／kg浓度为0．225％（小容量／高浓度[10wvolume／highconcentration，LVHC]，n=37）的药物，男一组给予1．5ml／kg浓度为0．15％（大容量“氐浓度[highvolume／lowconcentration，HVLC]，n=36）的药物。两种溶液中均舍有不透放射线的染料.结果HVLC组扩散平面的中位数及范围（T6，T3-II）明显高于LVHC组（T11，T8—12）（经X线透视证实）。、两组在恢复时间、术后疼痛评分和副作用方面没有显著性差异。停药舌，HVLC组与LVHC组相比，需要给予对乙酰氡基酚来缓解疼楠的儿重更少（50．0％vs75．7％）。HVLC组患儿首次需要口眼对乙酰氧基酚的时间明显晚干LVHC组（363．0分钟VS554．5分钟）．结论我们证实（经X线透视检查）以1ml／kg罗哌卡因施行骶管麻醉时扩散平面可达T11，而采用1．5ml／kg时则可扩散至T6水平。日间小儿睾丸固定术麻醉中，如果药物总量固定，大容量稀释的罗哌卡因（0．15％）相对小容量高浓度罗哐卡因（0．225％）具有更好的镇痛效果和更长的作用时间。罗哌卡因的麻醉扩散平面与首次口服对乙酰氯基酚的时间显著相关。

一例难治性脊髓损伤痛患者的处理：病例报道及文献综述

慢性疼痛是脊髓损伤众多后遗症之一，它会妨碍患者的基本活动、功能恢复及生活质量。脊髓损伤患者的疼痛常常难以治疗。有限的治疗选择，包括药物治疗和非药物治疗使疼痛的治疗更加困难。我们用检索词“脊髓损伤”或“脊髓损伤和疼痛”或“僵直”或“肌僵直”从Medline数据库查阅1975～2005年的关于脊髓损伤后疼痛的相关文章。我们也手工查阅了国际疼痛研究协会最近出版的关于脊髓损伤痛的书籍以及综述，同时检出参考文献中的相关文章。文中我们报道了一例难治性脊髓损伤痛患者，该患者通过采用综合性治疗措施成功治愈。同时对治疗方式的循证医学证据也进行了回顾。