Epigenetic combined with transcriptomic analysis of the m6A methylome after spared nerve injury-induced neuropathic pain in mice

Epigenetic changes in the spinal cord play a key role in the initiation and maintenance of nerve injury-induced neuro pathic pain.N6-methyladenosine(m6A)is one of the most abundant internal RNA modifications and plays an essential function in gene regulation in many diseases.However,the global m6A modification status of mRNA in the spinal cord at different stages after neuropathic pain is unknown.In this study,we established a neuropathic pain model in mice by preserving the complete sural nerve and only damaging the common peroneal nerve.High-throughput methylated RNA immunoprecipitation sequencing res ults showed that after spared nerve injury,there were 55 m6A methylated and diffe rentially expressed genes in the spinal cord.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway results showed that m6A modification triggered inflammatory responses and apoptotic processes in the early stages after spared nerve injury.Over time,the diffe rential gene function at postoperative day 7 was enriched in "positive regulation of neurogenesis" and "positive regulation of neural precursor cell prolife ration." These functions suggested that altered synaptic morphological plasticity was a turning point in neuropathic pain formation and maintenance.Results at postoperative day 14 suggested that the persistence of neuropathic pain might be from lipid metabolic processes,such as "very-low-density lipoprotein particle clearance," "negative regulation of choleste rol transport" and "membrane lipid catabolic process." We detected the expression of m6A enzymes and found elevated mRNA expression of Ythdf2 and Ythdf3 after spared nerve injury modeling.We speculate that m6A reader enzymes also have an important role in neuropathic pain.These results provide a global landscape of mRNA m6A modifications in the spinal cord in the spared nerve injury model at diffe rent stages after injury.

Long-term treatment with PP2 after spinal cord injury resulted in functional locomotor recovery and increased spared tissue

The spinal cord has the ability to regenerate but the microenvironment generated after trauma reduces that capacity. An increase in Src family kinase （SFK） activity has been implicated in neuropathological conditions associated with central nervous system trauma. Therefore, we hypothesized that a decrease in SFK activation by a long-term treatment with 4-amino-5-（4- chlorophenyl）-7-（t-butyl）pyrazolo[3,4-d]pyramidine （PP2）, a selective SFK inhibitor, after spinal cord contusion with the New York University （NYU） impactor device would generate a permissive environment that improves axonal sprouting and/or behavioral activity. Results demonstrated that long-term blockade of SFK activation with PP2 increases locomotor activity at 7, 14, 21 and 28 days post-iniury in the Basso, Beattie, and Bresnahan open field test, round and square beam crossing tests. In addition, an increase in white matter spared tissue and serotonin fiber density was observed in animals treated with PP2. However, blockade of SFK activity did not change the astrocytic response or infiltration of cells from the immune system at 28 days post-injury. Moreover, a reduced SFK activity with PP2 diminished Ephexin （a guanine nudeotide exchange factor） phosphorylation in the acute phase （4 days post-injury） after trauma. Together, these findings suggest a potential role of SFK in the regulation of spared tissue and/or axonal outgrowth that may result in functional locomotor recovery during the pathophysiology generated after spinal cord injury. Our study also points out that ephexinl phosphorylation （activation） by SFK action may be involved in the repulsive microenvironment generated after spinal cord injury.

Proteomic analysis of the dorsal spinal cord in the mouse model of spared nerve injury-induced neuropathic pain

Peripheral nerve injury often causes neuropathic pain and is associated with changes in the expression of numerous proteins in the dorsal horn of the spinal cord. To date, proteomic analysis method has been used to simultaneously analyze hundreds or thousands of proteins differentially expressed in the dorsal horn of the spinal cord in rats or dorsal root ganglion of rats with certain type of peripheral nerve injury. However, a proteomic study using a mouse model of neuropathic pain could be attempted because of abundant protein database and the availability of transgenic mice. In this study, whole proteins were extracted from the ipsilateral dorsal half of the 4th-6th lumbar spinal cord in a mouse model of spared nerve injury（SNI）-induced neuropathic pain. In-gel digests of the proteins size-separated on a polyacrylamide gel were subjected to reverse-phase liquid-chromatography coupled with electrospray ionization ion trap tandem mass spectrometry（MS/MS）. After identifying proteins, the data were analyzed with subtractive proteomics using ProtAn, an in-house analytic program. Consequently, 15 downregulated and 35 upregulated proteins were identified in SNI mice. The identified proteins may contribute to the maintenance of neuropathic pain,and may provide new or valuable information in the discovery of new therapeutic targets for neuropathic pain.

Contribution of spinal glia activation to mechanical hyperalgesia induced by spared nerve injury in rats

Objective: To investigate the role of spinal glial cells activation in neuropathic pain in a recently developed spared nerve injury (SNI) animal model by Decosterd and Woolf. Methods: A lesion was made to two of the three terminal branches of the sciatic nerve of rats (tibial and common peroneal nerves) leaving the sural nerve intact. Continuous intrathe-cal administration of propentofylline, a glial modulating agent, 1 d before and 5 d after operation, was performed to disrupt spinal cord glia function. The vehicle was intrathecally administrated as control. The paw withdrawal threshold to mechanical stimulation (paw withdrawal mechaical threshold PWMT), body mass and motor function were determined pre- and post-surgery. Results: It produced a prolonged mechanical allodynia in the medial and lateral part of the ipsilateral hind paw in SNL models. The treatment with propentofylline significantly prevented the development of mechanical allodynia located in either medial or lateral plantar surface. Rats in two groups showed normal motor function and body weight increase. Conclusion: SNI model can be applied as a useful method with little variance in searching the mechanism of neuropathic pain. These study suggest that spinal glia activation may contribute to mechanical allodynia induced by SNI.

Upregulation of Chemokine CXCL12 in the Dorsal Root Ganglia and Spinal Cord Contributes to the Development and Maintenance of Neuropathic Pain Following Spared Nerve Injury in Rats

Emerging evidence indicates that CXCL12/ CXCR4 signaling is involved in chronic pain. However, few studies have systemically assessed its role in direct nerve injury-induced neuropathic pain and the underlying mech- anism. Here, we determined that spared nerve injury （SNI） increased the expression of CXCL12 and its cognate receptor CXCR4 in lumbar 5 dorsal root ganglia （DRG） neurons and satellite glial cells. SNI also induced long- lasting upregulation of CXCL12 and CXCR4 in the ipsi- lateral L4-5 spinal cord dorsal horn, characterized by CXCL12 expression in neurons and microglia, and CXCR4 expression in neurons and astrocytes. Moreover, SNI- induced a sustained increase in TNF-α expression in the DRG and spinal cord. Intraperitoneal injection （i.p.） of the TNF-α synthesis inhibitor thalidomide reduced the SNI-in- duced mechanical hypersensitivity and inhibited the expression of CXCL12 in the DRG and spinal cord. Intrathecal injection （i.t.） of the CXCR4 antagonist AMD3100, both 30 rain before and 7 days after SNI, reduced the behavioral signs of allodynia. Rats given an i.t. or i.p. bolus of AMD3100 on day 8 of SNI exhibited attenuated abnormal pain behaviors. The neuropathic pain established following SNI was also impaired by i.t. admin- istration of a CXCL12-neutralizing antibody. Moreover, repetitive i.t. AMD3100 administration prevented the acti- vation of ERK in the spinal cord. The mechanical hyper- sensitivity induced in nai＇ve rats by i.t. CXCL12 was alleviated by pretreatment with the MEK inhibitor PD98059. Collectively, our results revealed that TNF-α might mediate the upregulation of CXCL12 in the DRG and spinal cord following SNI, and that CXCL 12/CXCR4 sig- naling via ERK activation contributes to the development and maintenance of neuropathic pain.

Kir2.1 Channel Regulation of Glycinergic Transmission Selectively Contributes to Dynamic Mechanical Allodynia in a Mouse Model of Spared Nerve Injury

Neuropathic pain is a chronic debilitating symptom characterized by spontaneous pain and mechanical allodynia. It occurs in distinct forms, including brushevoked dynamic and filament-evoked punctate mechanical allodynia. Potassium channel 2.1(Kir2.1), which exhibits strong inward rectification, is and regulates the activity of lamina I projection neurons. However, the relationship between Kir2.1 channels and mechanical allodynia is still unclear. In this study, we first found that pretreatment with ML133, a selective Kir2.1 inhibitor, by intrathecal administration, preferentially inhibited dynamic, but not punctate, allodynia in mice with spared nerve injury(SNI).Intrathecal injection of low doses of strychnine, a glycine receptor inhibitor, selectively induced dynamic, but not punctate allodynia, not only in na¨?ve but also in ML133-pretreated mice. In contrast, bicuculline, a GABAAreceptor antagonist, induced only punctate, but not dynamic,allodynia. These results indicated the involvement of glycinergic transmission in the development of dynamic allodynia. We further found that SNI significantly suppressed the frequency, but not the amplitude, of the glycinergic spontaneous inhibitory postsynaptic currents(gly-sIPSCs) in neurons on the lamina II-III border of the spinal dorsal horn, and pretreatment with ML133 prevented the SNI-induced gly-sIPSC reduction. Furthermore, 5 days after SNI, ML133, either by intrathecal administration oracute bath perfusion, and strychnine sensitively reversed the SNI-induced dynamic, but not punctate, allodynia and the gly-sIPSC reduction in lamina IIi neurons, respectively.In conclusion, our results suggest that blockade of Kir2.1 channels in the spinal dorsal horn selectively inhibits dynamic, but not punctate, mechanical allodynia by enhancing glycinergic inhibitory transmission.

Fertility preservation in patients with gynecologic cancer

In this editorial we comment on the article by Gu et al.We focus and debate the necessity of fertility sparing surgery in young women’s with gynecologic cancers,specifically on those patients with the desire to conceive.This type of individu-alized treatment options is often very difficult,due to the risk of disease evolution and multiple disparities in fertility preservation services among women in di-fferent countries and societies.For this reason national policy interventions are mandatory in order to ensure equitable access this procedures,in women with cancer.

Organ sparing to cure stage IV rectal cancer: A case report and review of literature

BACKGROUND Rectal sparing is an option for some rectal cancers with complete or good response after chemoradiotherapy(CRT);however,it has never been evaluated in patients with metastases.We assessed long-term outcomes of a rectal-sparing approach in a liver-first strategy for patients with rectal cancer with resectable liver metastases.CASE SUMMARY We examined patients who underwent an organ-sparing approach for rectal cancer with synchronous liver metastases using a liver-first strategy during 2010-2015(n=8).Patients received primary chemotherapy and pelvic CRT.Liver surgery was performed during the interval between CRT completion and rectal tumor re-evaluation.Clinical and oncological characteristics and long-term outcomes were assessed.CASE SUMMARY All patients underwent liver metastatic resection with curative intent.The R0 rate was 100%.Six and two patients underwent local excision and a watch-and-wait(WW)approach,respectively.All patients had T3N1 tumors at diagnosis and had good clinical response after CRT.The median survival time was 60(range,14-127)mo.Three patients were disease free for 5,8,and 10 years after the procedure.Five patients developed metastatic recurrence in the liver(n=5)and/or lungs(n=2).Only one patient developed local recurrence concurrent with metastatic recurrence 24 mo after the WW approach.Two patients died during follow-up.CONCLUSION The results suggest good local control in patients undergoing organ-sparing strategies for rectal cancer with synchronous liver metastasis.Prospective trials are required to validate these data and identify good candidates for these strategies.

Robot-Assisted Nephrotomy as a Nephron-Sparing Approach for Completely Intraparenchymal Renal Tumors

Introduction: The diagnosis of small renal masses and the endophytic tumor approach have become challenging. This study aims to describe exclusively robot-assisted surgery as an alternative nephron-sparing approach for renal intraparenchymal tumors. Patients and Methods: We retrospectively analyzed all patients with completely endophytic tumors undergoing robot-assisted partial nephrectomy, treated under the Da Vinci System®, aided by intraoperative ultrasound. The patients’ demographic characteristics, perioperative and oncological outcomes were assessed. Results: From a total of 13 partial nephrectomies performed between 06/2010 and 10/2021, all patients underwent nephrotomy. The patients’ mean age was 52 years and the tumor measured mean 2.6 cm. Warm ischemia time was 24 minutes and histopathological analysis revealed that 12 patients had renal cell carcinoma. In a mean 36-month follow-up, no significant renal function alterations were found and no local or systemic recurrences occurred. Conclusion: Robot-assisted access is a safe and effective option for the nephron-sparing technique in completely intraparenchymal renal tumors.

Dynamic Prediction Method for Valuable Spare Parts Demand in Weaponry Equipment Based on Data Perception

Missile is an important weapon system of the army.The spare parts of missile equipment are significant effect on military operations.In order to improve the mission completion rate of missile equipment in wartime,this paper introduces data sensing method to forecast the demand of valuable spare parts of missile equipment dynamically.Firstly,the information related to valuable spare parts of missile equipment was obtained by data sensing,and the sample size was determined by Bernoulli uniform sampling probability.Secondly,according to the data quality of multi-source and multi-modal,the data requirement for dynamic demand prediction of valuable spare parts of missile equipment was obtained.Finally,according to the characteristics of the spare parts,the life of the spare parts was predicted,realizing the dynamic prediction of the demand for valuable spare parts of missile equipment.The results show that the demand of valuable spare parts of missile equipment can be predicted dynamically by using this method,the accuracy is higher than 95%,and the real-time performance is more excellent.

Muscle-sparing切口在胸部手术中的应用

目的探讨胸部Muscle-sparing切口在临床中的应用价值。方法采用Muscle-sparing切口开胸手术56例,其中周围型肺癌行肺叶切除术39例,随机抽取同期39例肺癌患者及其他病变行后外侧切口开胸手术病例共计56例作为对照组;对两组病例术后切口疼痛、术侧肩关节功能等指标进行分析。术后肩关节功能的评估采用Constant评分法;术后切口疼痛的评估采用Prince-Henry评分法。结果治疗组术后3天、1周、4周切口疼痛程度明显低于对照组;术侧肩关节功能明显优于对照组。治疗组无围术期死亡,术后无皮下积液、切口血肿发生。结论有选择地应用Muscle-sparing切口,可以在保证手术质量和的安全性的前提下,减轻术后切口疼痛,减少术后肩关节功能障碍。

普通高校田径队课余洲练的研究与实践

普通高校学生课余田径训练是一个完整、复杂、多层次的教学过程。大学生在校以文化课学习为主。课余时间训练，其训练特点既不同于专业队，也有别于少年体校。因此，探索课余田径训练的规律性，构建符合高校实际的最佳模式，是迅速提高运动成绩的有力举措。本文在高等院校课余田径训练的运动员选材、训练时间安排、运动负荷、训练周期安排等方面，进行了归纳和阐述。

Radionuclide Colloid ^(32)P Used for the Treatment of Stage II Lung Cancer by Video Enhanced Minimal Access Muscle Sparing Thoracotomy

Objective: To study the feasibility of radionuclide colloid 32P used for the treatment of stage II lung cancer by video enhanced minimal access muscle sparing thoracotomy (VEMAST). Methods: Video assisted thoracoscopic surgery (VATS) was carried out under general anesthesia. A double lumen endobronchial tube was intubated into trachea. One lung ventilation of the healthy side was done during operation. An incision of 8–10 cm long was made along the 4th or 5th intercostals. The lobectomy could be performed under VATS. Radionuclide colloid 32P was injected locally into the area where surgical cleaning of lymph node around was considered to be unsatisfactory or desection of the tumor was not completed. Results: The operation with VEMAST was successful in 29 patients. A conventional lobectomy by thoracotomy had to be done due to unusual bleeding from the pulmonary artery involved during VEMAST in one case and the procedure was interrupted because the pulmonary artery cloud not be separated from the tumor in another patient. There was no dead case or the patient who had any severe complication or adverse response to the radiant. Conclusion: Radionuclide therapy was performed to the treatment of stage II lung cancer with VEMAST in case that surgical resection was considered not to be satisfactory. Minithoractomy assisted with VATS lobectomy and radionuclide colloid 32P therapy is a safe and e?ective technique for some selected stage II lung cancer.

保留胸部肌肉的侧方开胸切口36例临床分析

目的评价腋下Muscle—sparing切口，即保留胸部肌肉的侧方开胸切口的优点。方法主要是通过对背阔肌及前锯肌的移动和拉开后显露骨性胸廓后进胸。结果全组切口长度（13．5±1．5）cm，进胸时间平均13min，关胸时间平均15min。全组切口均达甲等愈合。入胸失血量均〈50ml，患者术后1—3d肩关节活动度恢复到术前状态，胸部疼痛轻微，切口愈合平整，外形美观，术后平均住院日比常规开胸少1．5d。结论腋下Muscle—sparing切口具有创伤小、出血少、术后恢复快以及外形美观的特点，值得推广。

突触前NMDA受体,还是突触束泡连接蛋白?

突触前ＮＭＤＡ受体，还是突触束泡连接蛋白？Ｓｍｉｒｎｏｖｎ等用抗谷氨酸结合蛋白抗体突触束泡连接蛋白ｓｙｎｔｕｘｉｎ相同。然而，ＧＲ３３－ｍＲＮＡ在爪蟾卵母细胞表达时却产生一种谷氨酸受体，其药理学特征类似与突触后ＮＭＤＡ受体，电生理学特性则明显不同。作...

Muscle spare开胸术在胸部手术中特殊情况下的应用

目的:探讨Muscle spare切口在胸部手术中特殊情况下的应用。方法:对2011-01～2011-12收治必须或最适宜进行muscle spare开胸术患者的临床资料进行回顾总结。结果:6例术中顺利,出院后随访2月无并发症发生。结论:Muscle spare切口对术后引流量减少,平均住院日缩短,对肺功能较差的患者和老年患者具有更为重要的临床价值。

Joint optimization of LORA and spares stocks considering corrective maintenance time

Level of repair analysis（LORA） is an important method of maintenance decision for establishing systems of operation and maintenance in the equipment development period. Currently, the research on equipment of repair level focuses on economic analysis models which are used to optimize costs and rarely considers the maintenance time required by the implementation of the maintenance program. In fact, as to the system requiring high mission complete success, the maintenance time is an important factor which has a great influence on the availability of equipment systems. Considering the relationship between the maintenance time and the spares stocks level, it is obvious that there are contradictions between the maintenance time and the cost. In order to balance these two factors, it is necessary to build an optimization LORA model. To this end, the maintenance time representing performance characteristic is introduced, and on the basis of spares stocks which is traditionally regarded as a decision variable, a decision variable of repair level is added, and a multi-echelon multiindenture（MEMI） optimization LORA model is built which takes the best cost-effectiveness ratio as the criterion, the expected number of backorder（EBO） as the objective function and the cost as the constraint. Besides, the paper designs a convex programming algorithm of multi-variable for the optimization model, provides solutions to the non-convex objective function and methods for improving the efficiency of the algorithm. The method provided in this paper is proved to be credible and effective according to the numerical example and the simulation result.

System optimization-oriented spare parts dynamic configuration model for multi-echelon multi-indenture system

In order to optimize the spares configuration project at different stages during the life cycle, the factor of time is considered to relax the assumption of the spares steady demand in multi-echelon technique for recoverable item control (METRIC) theory. According to the method of systems analysis, the dynamic palm theorem is introduced to establish the prediction model of the spares demand rate, and its main influence factors are analyzed, based on which, the spares support effectiveness evaluation index system is studied, and the system optimization-oriented spares dynamic configuration method for multi-echelon multi-indenture system is proposed. Through the analysis of the optimization algorithm, the layered marginal algorithm is designed to improve the model calculation efficiency. In a given example, the multi-stage spares configuration project during its life cycle is gotten, the research result conforms to the actual status, and it can provide a new way for the spares dynamic optimization.

Evolution of transanal total mesorectal excision for rectal cancer:From top to bottom

The gold standard for curative treatment of locally advanced rectal cancer involves radical resection with a total mesorectal excision(TME). TME is the most effective treatment strategy to reduce local recurrence and improve survival outcomes regardless of the surgical platform used. However, there are associated morbidities, functional consequences, and quality of life(QoL) issues associated with TME; these risks must be considered during the modern-day multidisciplinary treatment for rectal cancer. This has led to the development of new surgical techniques to improve patient, oncologic, and QoL outcomes. In this work, we review the evolution of TME to the transanal total mesorectal excision(TaTME) through more traditional minimally invasive platforms. The review the development, safety and feasibility, proposed benefits and risks of the procedure, implementation and education models, and future direction for research and implementation of the TaTME in colorectal surgery. While satisfactory short-term results have been reported, the procedure is in its infancy, and long term outcomes and definitive results from controlled trials are pending.As evidence for safety and feasibility accumulates,structured training programs to standardize teaching,training, and safe expansion will aid the safe spread of the TaTME.

Treating inflammatory bowel disease by adsorptive leucocytapheresis:A desire to treat without drugs

Ulcerative colitis and Crohn’s disease are the major phenotypes of the idiopathic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms, impairing function and quality of life. Current medications are aimed at reducing the symptoms or suppressing exacerbations. However, patients require life-long medications, and this can lead to drug dependency, loss of response together with adverse side effects. Indeed, drug side effects become additional morbidity factor in many patients on long-term medications. Nonetheless, the efficacy of anti-tumour necrosis factors (TNF)-α biologics has validated the role of inflammatory cytokines notably TNF-α in the exacerbation of IBD. However, inflammatory cytokines are released by patients’ own cellular elements including myeloid lineage leucocytes, which in patients with IBD are elevated with activation behaviour and prolonged survival. Accordingly, these leucocytes appear logical targets of therapy and can be depleted by adsorptive granulocyte/monocyte apheresis (GMA) with an Adacolumn. Based on this background, recently GMA has been applied to treat patients with IBD in Japan and in the European Union countries. Efficacy rates have been impressive as well as disappointing. In fact the clinical response to GMA seems to define the patients’ disease course, response to medications, duration of active disease, and severity at entry. The best responders have been first episode cases (up to 100%) followed by steroid naïve and patients with a short duration of active disease prior to GMA. Patients with deep ulcers together with extensive loss of the mucosal tissue and cases with a long duration of IBD refractory to existing medications are not likely to benefit from GMA. It is clinically interesting that patients who respond to GMA have a good long-term disease course by avoiding drugs including corticosteroids in the early stage of their IBD. Additionally, GMA is very much favoured by patients for its good safety profile. GMA in 21st century reminds us of phlebotomy as a major medical practice at the time of Hippocrates. However, in patients with IBD, there is a scope for removing from the body the sources of pro-inflammatory cytokines and achieve disease remission. The bottom line is that by introducing GMA at an early stage following the onset of IBD or before patients develop extensive mucosal damage and become refractory to medications, many patients should respond to GMA and avoid pharmacologics. This should fulfill the desire to treat without drugs.