Mossy fiber-evoked subthreshold responses induce timing-dependent plasticity at hippocampal CA3 recurrent synapses

Dentate granule cells exhibit exceptionally low levels of activity and rarely elicit action potentials in targeted CA3 pyramidal cells. It is thus unclear how such weak input from the granule cells sustains adequate levels of synaptic plasticity in the targeted CA3 network. We report that subthreshold potentials evoked by mossy fibers are sufficient to induce synaptic plasticity between CA3 pyramidal cells, thereby complementing the sparse action potential discharge. Repetitive pairing of a CA3–CA3 recurrent synaptic response with a subsequent subthreshold mossy fiber response induced long-term potentiation at CA3 recurrent synapses in rat hippocampus in vitro. Reversing the timing of the inputs induced long-term depression. The underlying mechanism depends on a passively conducted giant excitatory postsynaptic potential evoked by a mossy fiber that enhances NMDA receptor-mediated current at active CA3 recurrent synapses by relieving magnesium block. The resulting NMDA spike generates a supralinear depolarization that contributes to synaptic plasticity in hippocampal neuronal ensembles implicated in memory.The CA3 area of the hippocampus exhibits a distinctive, highly recurrent circuitry proposed to support autoassociative memory representation (1, 2). This prediction has been confirmed by experimental work demonstrating the pattern completion capabilities of CA3 networks (3), as well as their roles in the spatial tuning of CA1 pyramidal cells, in one-trial contextual learning (4) and in certain forms of memory consolidation (5). CA3 pyramidal cells receive, via the mossy fibers, information processed by granule cells important for both pattern separation (6, 7) and pattern completion functions (7). The faithful transmission of mossy fiber input appears to be ensured by giant synapses composed of presynaptic boutons with up to 45 release sites (8) that target massive spines, the thorny excrescences, on the apical dendrite of CA3 pyramidal cells. Thus, the mossy fiber synapse is often referred to as a detonator synapse (9). In fact, mossy fiber signaling is more compatible with a gatekeeper function than a high-throughput data relay. Although high-frequency bursts of action potentials in a hippocampal granule cell can discharge a targeted CA3 pyramidal cell, the majority of responses evoked by granule cells in CA3 pyramidal cells do not attain the firing threshold (10). Nevertheless, mossy fibers generate powerful signals evoking subthreshold responses that are much larger than typical synaptic events in the brain, with excitatory postsynaptic potentials (EPSPs) and excitatory postsynaptic currents (EPSCs) reaching amplitudes of 10 mV and 1 nA, respectively (11). Here we examined in rat slice cultures how EPSPs generated at mossy fiber synapses are processed in CA3 pyramidal cell dendrites, and evaluated whether subthreshold synaptic responses evoked by mossy fiber stimulation can act as instructive signals to induce plasticity at the pyramidal cell synapses forming the CA3 recurrent network.     

The Factors Affecting Pain Pattern after Arthroscopic Rotator Cuff Repair

Background

We evaluated the factors that affect pain pattern after arthroscopic rotator cuff repair.

Methods

From June 2009 to October 2010, 210 patients underwent arthroscopic rotator cuff repair operations. Of them, 84 patients were enrolled as subjects of the present study. The evaluation of postoperative pain was conducted by visual analog scale (VAS) scores during postoperative outpatient interviews at 6 weeks, 3 months, 6 months, and 12 months. The factors that were thought to affect postoperative pain were evaluated by dividing into three categories: preoperative, operative, and postoperative.

Results

Pain after arthroscopic rotator cuff repair surgery showed a strictly decreasing pain pattern. In single analysis and multiple regression tests for factors influencing the strictly decreasing pain pattern, initial VAS and pain onset were shown to be statistically significant factors (p = 0.012, 0.012, 0.044 and 0.028, respectively). With regard to the factors influencing lower than average intensity pain pattern for each period, the stiffness of internal rotation at 3 months postoperatively was shown to be a statistically significant factor in single and multiple regression tests (p = 0.017 and p = 0.004, respectively).

Conclusions

High initial VAS scores and the acute onset of pain affected the strictly decreasing postoperative pain pattern. Additionally, stiffness of internal rotation at postoperative 3 months affected the higher than average intensity pain pattern for each period after arthroscopic rotator cuff repair.     

上颌牙列及牙槽骨三维有限元模型的建立

目的：探讨利用螺旋CT原始数据建立上颌牙列及牙槽骨三维有限元模型的数字化方法,建立一个具有生物力学特性的,包含牙髓腔的上颌牙列及牙槽骨的动态三维有限元模型。方法：利用自主建立的颅面复合体三维几何模型,选取上颌牙列和牙槽骨所在的局部层面,利用ANSYS10.0软件对所建体的模型自动划分有限元网格。结果：建立了包括完整牙列的上颌牙槽骨三维有限元模型,由805086个单元和150753个节点组成。模型具有良好的几何相似形及其生物力学特性。结论：应用螺旋CT薄层扫描、自编程序和有限元分析工具ANSYS10.0相结合的方法,建立了包含牙髓腔的上颌牙列及牙槽骨的动态三维有限元模型是一种精确度较高的方法。     

胰岛素类似物的研究和临床应用

两种速效胰岛素类似物(赖脯胰岛素、天冬胰岛素),由于改变了胰岛素分子间相互作用的重要区域,其起效、达到峰值、作用持续时间均较常规人胰岛素短,对迅速降低餐后血糖、减少下一餐前低血糖优于常规人胰岛素.而两种长效胰岛素类似物(甘精胰岛素、地特胰岛素)通过改变胰岛素的等电点或增加类似物分子量的方法,使其分解、吸收及作用时间延长,吸收变异度小,而且无峰值,能更好地模拟生理基础胰岛素分泌.     

Activity of Galidesivir in a Hamster Model of SARS-CoV-2

Coronavirus disease 2019 (COVID-19) has claimed the lives of millions of people worldwide since it first emerged. The impact of the COVID-19 pandemic on public health and the global economy has highlighted the medical need for the development of broadly acting interventions against emerging viral threats. Galidesivir is a broad-spectrum antiviral compound with demonstrated in vitro and in vivo efficacy against several RNA viruses of public health concern, including those causing yellow fever, Ebola, Marburg, and Rift Valley fever. In vitro studies have shown that the antiviral activity of galidesivir also extends to coronaviruses. Herein, we describe the efficacy of galidesivir in the Syrian golden hamster model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Treatment with galidesivir reduced lung pathology in infected animals compared with untreated controls when treatment was initiated 24 h prior to infection. These results add to the evidence of the applicability of galidesivir as a potential medical intervention for a range of acute viral illnesses, including coronaviruses.     

Analgesic effects and hemodynamic mechanisms of perpendicular and transverse needling at Sanyinjiao (SP 6) in patients with primary dysmenorrhea: A randomized controlled trial

ObjectiveTo explore the analgesic effects and uterine hemodynamics of perpendicular needling (PN) and transverse needling (TN) at SP 6 in patients with primary dysmenorrhea (PD).MethodsIn this randomized controlled trial, patients with PD diagnosed with cold-dampness congealing pattern were randomly assigned in a ratio of 1:1 to receive PN or TN at bilateral SP 6 for 10 min. Acupuncture was performed when the menstrual pain score was over 40 mm on the first day of menstruation, as measured using the visual analog scale for pain (VAS-P). The primary outcome was average menstrual pain (VAS-P). Secondary outcomes included the pulsatility index (PI), resistance index (RI), and systolic-diastolic peaks ratio (S/D) in uterine arteries as measured using color Doppler ultrasonography; anxiety as assessed using the Hamilton Anxiety Rating Scale (HAMA), blood pressure (BP), and heart rate (HR).ResultsForty-eight patients completed the study. The TN group exhibited a significant reduction in VAS-P scores (–5.71 mm, 95% confidence interval (CI): –8.78, –2.63, P = .001), RI values (–0.05, 95% CI: –0.09, –0.01, P = .015), and HAMA values (–2.50, 95% CI: –4.78, –0.22, P = .032) when compared with the PN group. No significant differences in PI, S/D, BP, or HR values were observed between the two groups (P > .05).ConclusionTN at SP 6 was superior to PN in alleviating menstrual pain and anxiety in patients with PD. This analgesic effect of TN may be due to its better ability to improve uterine arterial blood flow via decreases in RI values.     

Cardiovascular effects of microinjections of adenosine analogs into the fourth ventricle of rats

Rats were implanted with chronic indwelling cannulae into the posterior region of the fourth ventricle. After recovery from surgery, acute experiments on blood pressure were conducted under urethane anesthesia. The blood pressure and heart rate responses following administration of two adenosine analogs, NECA and L-PIA were examined. Microinjections of both analogs produced dose-dependent reductions in blood pressure and heart rate. NECA was approximately 20-fold more potent than L-PIA in reducing blood pressure and depressing heart rate. The cardiovascular effects of both analogs were antagonized by parenteral injections of caffeine. These findings show that microinjections of analogs of adenosine into the fourth ventricle can influence areas of the central nervous system involved in cardiovascular control.     

肝细胞癌根治性治疗后口服维生素K2类似物的Meta分析

目的:评价肝细胞癌(hepatocellular carcinoma,HCC)根治性治疗后口服维生素K2(vitamin K2,VK2)类似物预防肿瘤复发及提高总生存率的疗效.方法:计算机检索中国知网、Medline、Embase和Cochrane图书馆数据库中的相关文献.检索所有关于HCC根治性术后VK2类似物治疗的研究.对纳入文献进行资料提取及质量评价.采用相对危险度(risk ratio,RR)及其95%可信区间(confidence interval,CI)表示统计效应量.结果:共纳入6个随机对照试验和1个队列研究,合计930例患者.Meta分析结果显示:(1)HCC根治性术后口服VK2类似物不能降低术后1年复发率(RR=0.67,95%CI:0.39-1.13,P=0.13),但术后2年及3年复发率显著降低(RR=0.65,95%CI:0.51-0.83,P<0.001;RR=0.70,95%CI:0.58-0.85,P<0.001);(2)1、2、3年总生存率:口服VK2类似物治疗组与单纯手术治疗组比较,2组差异有统计学意义(RR=1.03,95%CI:1.01-1.05,P=0.02;RR=1.11,95%CI:1.03-1.19,P=0.005;RR=1.14,95%CI:1.02-1.28,P=0.02);(3)口服VK2类似物安全,无不良反应报道.结论:目前证据显示辅助VK2类似物治疗对降低HCC患者根治性术后复发率及提高总生存率有一定的疗效.由于纳入研究的随访时间较短和存在的局限性,有必要开展多中心大样本的随机对照试验长期随访观察进一步证实其疗效.