Deletion of calcineurin from GFAP-expressing astrocytes impairs excitability of cerebellar and hippocampal neurons through astroglial Na+/K+ ATPase

Astrocytes perform important housekeeping functions in the nervous system including maintenance of adequate neuronal excitability, although the regulatory mechanisms are currently poorly understood. The astrocytic Ca²⁺/calmodulin-activated phosphatase calcineurin (CaN) is implicated in the development of reactive gliosis and neuroinflammation, but its roles, including the control of neuronal excitability, in healthy brain is unknown. We have generated a mouse line with conditional knockout (KO) of CaN B1 (CaNB1) in glial fibrillary acidic protein-expressing astrocytes (a stroglial c alcin eurin KO [ACN-KO]). Here, we report that postnatal and astrocyte-specific ablation of CaNB1 did not alter normal growth and development as well as adult neurogenesis. Yet, we found that specific deletion of astrocytic CaN selectively impairs intrinsic neuronal excitability in hippocampal CA1 pyramidal neurons and cerebellar granule cells (CGCs). This impairment was associated with a decrease in after hyperpolarization in CGC, while passive properties were unchanged, suggesting impairment of K⁺ homeostasis. Indeed, blockade of Na⁺/K⁺-ATPase (NKA) with ouabain phenocopied the electrophysiological alterations observed in ACN-KO CGCs. In addition, NKA activity was significantly lower in cerebellar and hippocampal lysates and in pure astrocytic cultures from ACN-KO mice. While no changes were found in protein levels, NKA activity was inhibited by the specific CaN inhibitor FK506 in both cerebellar lysates and primary astroglia from control mice, suggesting that CaN directly modulates NKA activity and in this manner controls neuronal excitability. In summary, our data provide formal evidence for the notion that astroglia is fundamental for controlling basic neuronal functions and place CaN center-stage as an astrocytic Ca²⁺-sensitive switch.     

集中带量,还是挂网议价采购——生物类似物采购模式研究

生物制品疗效显著、价格高昂,采购是价格调控的重要措施。我国目前已有4个生物类似物获批上市。生物类似物应如何开展采购,在确保临床用药安全与供应的同时,有效控制价格,成为各方关注的问题。本文重点探讨生物类似物采购模式,并就生物类似物的采购方案给出政策建议。     

Therapeutic effect of regulating autophagy in spinal cord injury: a network meta-analysis of direct and indirect comparisons

Objective:An increasing number of studies indicate that autophagy plays an important role in the pathogenesis of spinal cord injury,and that regulating autophagy can enhance recovery from spinal cord injury.However,the effect of regulating autophagy and whether autophagy is detrimental or beneficial after spinal cord injury remain unclear.Therefore,in this study we evaluated the effects of autophagy regulation on spinal cord injury in rats by direct and indirect comparison,in an effort to provide a basis for further research.Data source:Relevant literature published from inception to February 1,2018 were included by searching Wanfang,CNKI,Web of Science,MEDLINE(OvidSP),PubMed and Google Scholar in English and Chinese.The keywords included"autophagy","spinal cord injury",and"rat".Data selection:The literature included in vivo experimental studies on autophagy regulation in the treatment of spinal cord injury(including intervention pre-and post-spinal cord injury).Meta-analyses were conducted at different time points to compare the therapeutic effects of promoting or inhibiting autophagy,and subgroup analyses were also conducted.Outcome measure:Basso,Beattie,and Bresnahan scores.Results:Of the 622 studies,33 studies of median quality were included in the analyses.Basso,Beattie,and Bresnahan scores were higher at 1 day(MD=1.80,95%CI:0.81-2.79,P=0.0004),3 days(MD=0.92,95%CI:0.72-1.13,P<0.00001),1 week(MD=2.39,95%CI:1.85-2.92,P<0.00001),2 weeks(MD=3.26,95%CI:2.40-4.13,P<0.00001),3 weeks(MD=3.13,95%CI:2.51-3.75,P<0.00001)and 4 weeks(MD=3.18,95%CI:2.43-3.92,P<0.00001)after spinal cord injury with upregulation of autophagy compared with the control group(drug solvent control,such as saline group).Basso,Beattie,and Bresnahan scores were higher at 1 day(MD=6.48,95%CI:5.83-7.13,P<0.00001),2 weeks(MD=2.43,95%CI:0.79-4.07,P=0.004),3 weeks(MD=2.96,95%CI:0.09-5.84,P=0.04)and 4 weeks(MD=4.41,95%CI:1.08-7.75,P=0.01)after spinal cord injury with downregulation of autophagy compared with the control group.Indirect comparison of upregulation and downregulation of autophagy showed no differences in Basso,Beattie,and Bresnahan scores at 1 day(MD=-4.68,95%CI:-5.840 to-3.496,P=0.94644),3 days(MD=-0.28,95%CI:-2.231-1.671,P=0.99448),1 week(MD=1.83,95%CI:0.0076-3.584,P=0.94588),2 weeks(MD=0.81,95%CI:-0.850-2.470,P=0.93055),3 weeks(MD=0.17,95%Cl:-2.771-3.111,P=0.99546)or 4 weeks(MD=-1.23,95%Cl:-4.647-2.187,P=0.98264)compared with the control group.Conclusion:Regulation of autophagy improves neurological function,whether it is upregulated or downregulated.There was no difference between upregulation and downregulation of autophagy in the treatment of spinal cord injury.The variability in results among the studies may be associated with differences in research methods,the lack of clearly defined autophagy characteristics after spinal cord injury,and the limited autophagy monitoring techniques.Thus,methods should be standardized,and the dynamic regulation of autophagy should be examined in future studies.     

孕妇铅镉锰暴露及金属硫蛋白基因多态性与新生儿出生缺陷的关系

目的 探讨铅镉锰暴露及金属硫蛋白基因多态性与新生儿出生缺陷的关系，为出生缺陷的防治以及制定干预措施提供参考依据。方法 本研究采用巢式病例对照研究方法，从广西壮族人群出生队列中选取广西壮族人群聚居的平果、田东、德保、靖西、隆安等县的人民医院及妇幼保健院2015年9月 - 2018年4月期间纳入队列的孕妇作为研究对象。随访收集一般人口学资料、孕期产检资料、出生结局资料等。采用原子吸收分光光度计（石墨炉法）测定孕妇血浆中铅、镉、锰的含量，采用PCR - RFLP法检测金属硫蛋白基因单核苷酸多态性位点。采用多因素logistic回归模型分析孕妇血浆中铅、镉、锰暴露与金属硫蛋白基因多态性与出生缺陷的关系。结果 多因素logistic回归分析显示:孕妇血镉值升高（OR = 1.93,95%CI:1.11～3.36，P＜0.05）、血锰值升高（OR = 1.22,95%CI:1.12～1.34，P＜0.01）、携带MT - 2A rs10636位点突变型基因型（OR = 3.96,95%CI:1.02～15.39，P＜0.05）是出生缺陷发生的危险因素。金属暴露 - 基因多态性交互作用分析结果显示，孕妇锰暴露与MT - 2A rs10636在出生缺陷发生中存在交互作用。结论 镉、锰高暴露、携带MT - 2A rs10636位点突变型基因型可能是出生缺陷发生的危险因素。     

Sex-specific sagittal and frontal plane gait mechanics in persons post-hip arthroscopy for femoroacetabular impingement syndrome

Postoperative gait mechanics in persons with femoroacetabular impingement syndrome (FAIS) remain understudied as a treatment outcome despite observed, yet inconclusive, preoperative gait abnormalities. Females with FAIS demonstrate worse preoperative patient-reported hip function and altered hip mechanics when compared with males; it is unknown whether these sex differences persist postarthroscopy. The purpose of this study was to compare sex-specific gait kinematics between persons at least 1 year postarthroscopy for FAIS and healthy comparisons. General linear models with estimating equations were used to evaluate the effect of (a) limb and sex within each group, and (b) limb and group within each sex for peak sagittal and frontal plane trunk, pelvis, and hip kinematics during stance phase of gait. Analyses were covaried by gait speed. Seventeen females and eight males an average 2.5 years postarthroscopy (1.1-7.2 year) for FAIS were compared with healthy females (n = 7) and males (n = 5). Females in the FAIS group presented with an average of 4.6° more anterior pelvic tilt, and 4.8° less hip extension compared with healthy females (P ≤ .03) and 8.6° less trunk flexion, 4.8° more anterior pelvic tilt, 3.1° more pelvic drop, and 7.5° more hip flexion than males with FAIS (P ≤ .03). Males in the FAIS group presented with 2.9° less pelvic drop, and 3.2° less hip adduction than healthy males. Preoperative gait mechanics were not collected and thus changes in mechanics could not be evaluated. This study is significant to clinicians who treat patients postarthroscopy to consider sex-specific gait impairments.     

The management of psychosocial risks at work: state of the art and future perspectives

Background:Psychosocial risk management represents a current challenge in Occupational Health and Safety (OSH) due to their impacts of such risks on work stress and the rapid changes of the world of work. An effective psychosocial risk management can be carried out on the basis of an integrated multidisciplinary model founded on the risk management paradigm. Over years, the occupational medicine has played an important role at national level in this area, contributing to the creation of an integrated and participatory approach.Objectives:This study explores the developmental process of psychosocial risk management over time in Europe and Italy, to offer an update on the state of the art at a national level and insights on future perspectives.Methods:Through a reflection on research developments, in Europe and in Italy, we outline how the knowledge obtained has been translated into policies, which have encouraged the implementation at international and national level of consolidated practices for the management of psychosocial risks.Results:An overview of some key steps of the inclusion of psychosocial aspects in OSH is presented, highlighting the positive impact of the multidisciplinary approach. Moreover, the driving role played by policies for implementation in organizational practice is also highlighted, with particular reference to the Italian example.Discussion:Starting from the existing knowledge, it is necessary to tackle emerging risks by continuing to translate the knowledge obtained from research into policies that have a driving role in the identification and implementation of actions and practical tools.Key words: Psychosocial risks, risk management, policy implementation, work-related stress     

Subacute posttraumatic ascending myelopathy (SPAM): A potential complication of subarachnoid shunt for syringomyelia?

Context: Treatment of primary spinal syringomyelia is still controversial. Among others, shunting syrinx fluid to the subarachnoid, peritoneal or pleural space has been utilized with varying success. Shunt obstruction, migration, and infection represent the most common complications of these procedures.

Findings: The authors present the case of an 81-year-old woman who developed an unusual neurological deterioration resembling a subacute posttraumatic ascending myelopathy (SPAM) after the insertion of a syringosubarachnoid shunt for the treatment of slow-growing D10 syringomyelia.

Conclusion/Clinical Relevance: To date, no cases of SPAM secondary to the insertion of a syringosubarachnoid shunt for the treatment of syringomyelia have been reported. The potential pathogenesis related to this phenomenon is discussed.