“大、小、重、慢”疾病定义与全科医生“4善”定位的探讨

随着我国医药卫生体制的深度改革,特别是分级诊疗制度的推进,全科医生在基层医疗保健体系中的角色日益重要。全科医生不仅是居民健康的第一道防线,更是常见疾病预防、诊断、治疗及健康教育的关键执行者。国家对全科医生提出了“小病善治、大病善识、重病善转、慢病善管”的临床定位。本文通过问答形式,分析“小、大、重、慢”疾病的分类与全科医生的“4善”定位,探讨全科医生在新医改时代下的重要职能及挑战。访谈者认为虽然分级诊疗制度旨在优化医疗资源配置,但在实践中仍面临“大、小、重、慢”疾病分类的模糊性和基层医疗资源的不均衡分配等问题。全科医生在这个体系中扮演着至关重要的角色,其需要具备综合的临床诊疗能力,并与专科医生共同制定临床判断标准和诊疗标准。为了应对这些挑战并充分发挥全科医生在现代医疗体系中的作用,迫切需要对全科医学教育和实践进行进一步改革与优化,同时强化全科医生的角色定位,以确保在提升医疗服务质量和效率的同时,实现公平和可持续的健康保障体系。

以患者为中心的慢性阻塞性肺疾病患者参与医疗质量改进的实施现状:一项范围综述

背景以患者为中心的医疗质量改进中,将患者从医疗服务的接受者转变为合作者,将患者在医疗全流程中的体验和需求整合到医疗服务实践中,以提高医疗服务的有效性、效率和质量。然而,已被证明有效的以患者为中心的患者参与医疗质量改进策略在我国慢性阻塞性肺疾病(简称慢阻肺)领域中如何实施尚有待探索。目的对国内外慢阻肺患者参与医疗质量改进策略的实施现状进行范围综述,旨在为构建适合我国环境的慢阻肺患者参与实施策略提供参考。方法采用澳大利亚乔安娜布里格斯研究所的范围综述指南为方法学框架,计算机检索PubMed、Embase、Cochrane Library、中国知网、万方数据知识服务平台和中华医学期刊全文数据库,检索时限为建库至2022-11-29。采用主题分析法梳理慢阻肺患者参与的实施现状。结果共纳入37篇文献。根据参与类别分为患者参与直接的诊疗过程、患者参与组织层面的设计与管理及患者参与临床研究三类。根据参与程度分为咨询、参与和合作领导三层。参与程度与类别交叉为9类参与行为矩阵。慢阻肺患者参与实施主要体现在5类8项行为:包括患者参与直接的诊疗过程(患者对治疗计划提出意愿和偏好);患者参与组织管理层面的咨询(调查了解患者治疗体验、组织患者讨论其关注的问题)和参与(参与医疗质量改进工具开发);以及患者参与临床研究层面的咨询(倾听患者需求)和参与(对干预措施提出意愿和偏好、参与评估工具开发、参与研究设计与实施讨论)。调查了解患者治疗体验(10/37,27.03%)及收集患者对研究干预措施的意愿和偏好(10/37,27.03%)是实施较多的两类慢阻肺患者参与行为。结论患者参与医疗质量改进的行为措施较多,但在慢阻肺领域落地实践的尚较少,且极少见患者参与对临床结局及生活质量的改善评估,如何促进我国乃至全球慢阻肺患者参与医疗质量改进的实施仍有待进一步探索。

渗透树脂联合美白技术修复微裂氟斑牙

背景:微研磨、家庭美白联合渗透树脂治疗氟斑牙具有良好的效果,但该方法对氟斑牙微裂纹的影响尚不清楚。目的:探究微研磨、家庭美白联合渗透树脂修复微裂氟斑牙的效果。方法:①临床研究:选择2020年7月至2021年3月就诊于天津医科大学口腔医院修复科的23例微裂氟斑牙患者,包括255颗微裂氟斑牙,均接受牙齿微研磨术、家庭美白与渗透树脂联合治疗,对比治疗前及治疗结束后1周、1个月的牙齿颜色、牙齿敏感程度和牙齿疼痛阈值。②体外实验:收集牙齿表面至少存在一条裂纹的氟斑牙60颗,随机分3组处理:对照组不进行任何处理,美白组进行微研磨与家庭美白处理,联合组进行微研磨、家庭美白和渗透树脂联合处理,每组20颗,测量处理后3组牙齿样本的显微硬度。结果与结论:①临床研究:治疗结束后6个月,255颗微裂氟斑牙中牙齿美白治疗显效207颗、有效48颗,总体治疗有效率为100%。随着治疗时间的延长,中、重度牙齿度敏感程度占比呈下降趋势,治疗结束后6个月,255颗氟斑牙中无重度敏感、15颗为中度敏感、125颗为轻度敏感、115颗无敏感,与治疗前的氟斑牙敏感程度相比差异有显著性意义(P<0.05)。治疗前与治疗结束后1周、6个月的牙齿疼痛阈值比较差异无显著性意义(P>0.05)。②体外实验:美白组牙齿显微硬度值低于对照组、联合组(P<0.05),对照组与联合组牙齿显微硬度值比较差异无显著性意义(P>0.05)。③结果表明,微研磨、家庭美白联合渗透树脂治疗微裂氟斑牙具有较好的疗效。

智能机器人在基层慢性病管理中的应用与挑战

全球慢性病患病率不断上升,给社会的发展和个人健康带来重大挑战。管理慢性病需要长期治疗和监测,对患者的生活方式提出了一定要求。随着人口老龄化和人们生活方式的改变,慢性病防控正变得越发重要。近年来,随着医疗卫生领域科技创新向纵深发展,借助人工智能的智能机器人在医疗领域的应用也逐渐成为国家重要战略方向之一,传统的慢性病管理方法过于依赖医生和患者之间的线下交流,导致医生无法与患者保持长期且有效的沟通和随访,患者病情出现变化时医生可能无法及时发现和监测。此外,传统的慢性病管理方法通常是一种通用化的方法,无法充分考量到每位患者的个体差异。鉴于传统慢性病管理方法的局限性,本文提倡利用智能机器人提供更便捷高效的基层服务。本文认为,通过个性化健康管理方案、辅助医疗诊断、定时提醒服药等功能,使智能机器人能够致力于改善患者生活质量、减轻医疗资源压力,从而推动全球智能化医疗管理的发展。

干细胞治疗肌萎缩侧索硬化症:细胞来源、数量、修饰手段及给药途径

背景:随着医疗技术的不断进步,干细胞疗法已经被用于包括肌萎缩侧索硬化症在内的多种疾病的治疗。目的:综述干细胞治疗肌萎缩侧索硬化症的研究进展,展望该领域的发展趋势。方法:以“肌萎缩侧索硬化症,间充质干细胞,神经干/祖细胞,多能诱导干细胞;amyotrophic lateral sclerosis,mesenchymal stem cells,neural stem/progenitor cells,pluripotent stem cells”为关键词,在PubMed、中国知网、万方数据库进行检索,检索时限为1995-2024年。共检索到1700余篇文献,最终纳入58篇文献用于综述。结果与结论:肌萎缩侧索硬化症是一种影响脑干和脊髓的下部运动神经元以及运动皮质的上部运动神经元的神经退行性疾病。干细胞治疗肌萎缩侧索硬化症的相关研究已成为一大研究热点。在这篇综述中,总结了不同种类干细胞在肌萎缩侧索硬化症研究领域中的应用情况,包括间充质干细胞、神经干祖细胞、多能诱导干细胞,评估了干细胞来源、细胞量、干细胞修饰手段及给药途径等临床前研究关键,为未来干细胞治疗的应用奠定了基础。

斜外侧椎间融合联合侧方钢板固定治疗单节段腰椎退变性疾病的短期疗效

背景:单纯斜外侧椎间融合术融合器沉降并发症率高,辅助后方的固定可以提供稳定的支撑,但术中体位变化、双切口都弱化了该技术的微创优势。斜外侧椎间融合术联合侧方钢板固定可以实现一期同切口完成减压,同时侧方内固定提供了稳定支撑。目的:分析斜外侧椎间融合联合侧方钢板固定治疗单节段腰椎退变性疾病的短期临床疗效。方法:收集2020年5月至2022年10月应用斜外侧椎间融合联合侧方钢板固定治疗单节段腰椎退变性疾病34例患者的临床资料,其中男14例,女20例;年龄41-72岁,平均(58.6±9.9)岁;腰椎滑脱症(Ⅰ度)11例,腰椎间盘突出症并节段不稳7例,腰椎管狭窄症16例。记录患者手术时间、出血量及并发症。评估术前、术后3个月及末次随访腰痛及双下肢放射痛疼痛目测类比评分和Oswestry功能障碍指数评分;测量并观察手术前后硬膜囊面积、椎间隙高度及椎间融合情况。结果与结论:(1)34例患者随访14-36个月,平均(21.3±5.2)个月;(2)手术时间50-92 min,平均(68.5±11.1)min;术中出血量50-170 mL,平均(71.6±25.3)mL;(3)与术前相比,术后3个月及末次随访目测类比评分和Oswestry功能障碍指数评分均显著降低,差异均有显著性意义(P<0.001),最大Oswestry功能障碍指数评分改善近50%;(4)术后半年随访所有患者均达到骨性融合,总体并发症发生率为21%(7/34),其中钢板移位1例、融合器下沉3例、术侧腰大肌无力1例、术侧大腿前侧疼痛2例;(5)提示斜外侧椎间融合联合侧方钢板固定治疗单节段腰椎退变性疾病,具有出血量少、手术时间短、术后恢复快的特点,短期临床疗效显著且可提供一定稳定支撑,长期疗效有待进一步随访观察。

人类白细胞抗原相合同胞新鲜脐血移植治疗儿童β重型地中海贫血

背景:异基因造血干细胞移植是目前根治重型地中海贫血最有效的方法,然而仅有不到一半的患者能找到相合的骨髓或外周血干细胞。同胞来源脐血干细胞与骨髓和外周血干细胞具有不同的特征,是重型地中海贫血患者移植治疗的一种潜在造血干细胞替代来源。目的:探讨应用人类白细胞抗原相合同胞新鲜脐血移植治疗儿童β重型地中海贫血的疗效。方法:选择2010年6月至2020年6月南方医科大学南方医院收治的β重型地中海贫血患儿48例,男28例,女20例,中位年龄4岁,均接受人类白细胞抗原相合同胞新鲜脐血移植治疗,脐血移植前均采用清髓性不含抗胸腺细胞球蛋白的预处理方案,脐血移植后均采用环孢素A+吗替麦考酚酯+/-短程甲氨蝶呤预防移植物抗宿主病。结果与结论:(1)48例患儿输注的总有核细胞中位数为8.17×10^(7)/kg,输注的CD34^(+)细胞中位数为2.40×10^(5)/kg,脐血移植后中位随访时间98个月,44例植入成功,粒细胞和血小板植入中位时间分别为28 d和31 d,其中37例移植后植入证据检测为供者型完全嵌合,7例移植后早期检测为供受者稳定混合嵌合;(2)44例植入成功患儿中,4例发生急性移植物抗宿主病,分别为Ⅰ级(n=2)和Ⅱ级(n=2),受累器官均为皮肤,均未发生慢性移植物抗宿主病;(3)脐血移植后,48例患儿中5例发生巨细胞病毒感染及激活,12例发生败血症,3例发生侵袭性真菌病,21例发生口腔炎,8例发生出血性膀胱炎,1例发生肝静脉闭塞;(4)48例患儿中,47例存活,1例在移植后28 d因重症肺炎合并急性心力衰竭死亡,43例无病存活,3例发生原发性植入失败,1例发生移植后全血细胞减少,5年总生存率和无病生存率分别为98%和89%,1年时移植相关死亡的累计发病率为2.1%;(5)结果显示,人类白细胞抗原相合同胞新鲜脐血移植治疗儿童β重型地中海贫血的效果良好,移植物抗宿主病的发生风险低。

端粒长度与10种常见肌肉骨骼疾病的关系孟德尔随机化分析

背景:多项观察性研究表明,端粒长度与肌肉骨骼疾病之间存在潜在的关联,然而它们之间的潜在机制仍不清楚。目的:利用两样本孟德尔随机化分析来探索端粒长度与肌肉骨骼疾病之间的遗传因果关系。方法:从英国生物银行中获得端粒长度的全基因组关联研究汇总数据。从FinnGen财团中获得了关于10种常见肌肉骨骼疾病(骨坏死、骨髓炎、骨质疏松、类风湿关节炎、腰痛、椎管狭窄、痛风、肩周炎、强直性脊柱炎和下肢深静脉血栓)的全基因组关联研究汇总数据。使用逆方差加权、孟德尔随机化-Egger和加权中位数方法评估端粒长度与10种肌肉骨骼疾病的因果关系,逆方差加权作为主要的孟德尔随机化分析方法,并进行敏感性分析探讨结果稳健性。结果与结论:①逆方差加权法结果表明,遗传预测的端粒长度与类风湿关节炎(OR=0.78,95%CI:0.64-0.95,P=0.015)和骨坏死(OR=0.56,95%CI:0.36-0.90,P=0.016)风险之间存在负向因果关系,但未发现端粒长度与其他8种肌肉骨骼疾病之间存在因果关系(P均>0.05)。②敏感性分析结果表明因果关系稳健,孟德尔随机化-Egger截距分析未检测到潜在的水平多效性(P均>0.05)。③此项孟德尔随机化研究支持端粒长度对类风湿关节炎和骨坏死的保护作用的结论,然而,未来将需要更多的基础和临床研究来验证。

残余胆固醇与进展为主要不良心血管事件的非罪犯病变易损斑块的相关性研究

背景 残余胆固醇(RC)被认为是动脉粥样硬化性心血管疾病的重要危险因素,而冠状动脉非罪犯病变(NCCLs)进展也是影响冠心病患者预后的重要因素,但是残余胆固醇与进展为主要不良心血管事件(MACE)的NCCLs易损斑块的关系尚不明确。目的 探讨RC对发生MACE的NCCLs易损斑块的预测价值及长期预后的相关性。方法 选取2015年2月—2022年2月于新疆医科大学第一附属医院心脏中心住院的488例冠心病患者为研究对象,通过电子病历系统收集患者基线资料,行冠状动脉造影及光学相干断层扫描OCT。入组患者在出院1、3、6和12个月接受预定随访。采用Spearman秩相关检验探究RC与NCCLs中薄纤维帽粥样硬化斑块(TCFA)斑块特征的相关性。采用多因素Logistic回归分析探究NCCLs中TCFA发生MACE的影响因素。绘制受试者工作特征曲线(ROC曲线)并计算ROC曲线下面积(AUC),探究RC对NCCLs中TCFA发生MACE的预测价值。结果 共纳入488例冠心病患者,根据NCCLs是否发生MACE将患者分为发生MACE组(n=38)和未发生MACE组(n=450)。通过OCT识别NCCLs的斑块特征,共分析了749个NCCLs斑块,304个NCCLs斑块最小管腔面积(MLA)<3.5 mm^(2)。随访期间38例(7.8%)患者共发生了41例次NCCLs斑块引起的MACE事件,18例(3.7%)患者发生了支架内再狭窄,15例(3.1%)发生了不确定因素的死亡。发生MACE组患者高血压、糖尿病、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、RC、糖化血红蛋白(Hb A1c)、TCFA、MLA<3.5 mm^(2)比例高于未发生MACE组(P<0.05)。105例患者检查出TCFA,其中22例发生MACE(发生MACE的TCFA组),83例未发生MACE(未发生MACE的TCFA组)。发生MACE的TCFA组糖尿病比例与RC高于未发生MACE的TCFA组(P<0.05)。Spearman秩相关分析结果示,RC与最薄纤维帽厚度、MLA呈负相关(r_(s)=-0.665、-0.771,P<0.05),与最大脂质弧度、巨噬细胞浸润呈正相关(r_(s)=0.806、0.481,P<0.05)。多因素Logistic回归分析结果显示糖尿病(OR=3.410,95%CI=1.165~9.988,P=0.025)、高RC水平(OR=5.879,95%CI=1.436~24.073,P=0.014)是NCCLs中TCFA发生MACE的危险因素。绘制RC预测NCCLs中TCFA发生MACE的ROC曲线,结果显示AUC为0.695(95%CI=0.571~0.819,P=0.005),最佳截断值为0.606 mmol/L,灵敏度、特异度分别为0.818、0.518。结论 RC水平升高可能是冠心病患者中NCCLs易损斑块发生MACE的危险因素,对NCCLs中TCFA发生MACE有一定的预测价值。

Copper homeostasis and neurodegenerative diseases

Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins,including copper transporters(CTR1 and CTR2),the two copper ion transporters the Cu-transporting ATPase 1(ATP7A)and Cu-transporting beta(ATP7B),and the three copper chaperones ATOX1,CCS,and COX17.Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue.Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins,including ceruloplasmin and metallothionein,is involved in the pathogenesis of neurodegenerative disorders.However,the exact mechanisms underlying these processes are not known.Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress.Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction.Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation,with elevated levels activating several critical inflammatory pathways.Additionally,copper can bind aberrantly to several neuronal proteins,including alphasynuclein,tau,superoxide dismutase 1,and huntingtin,thereby inducing neurotoxicity and ultimately cell death.This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases,with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis.By synthesizing the current findings on the functions of copper in oxidative stress,neuroinflammation,mitochondrial dysfunction,and protein misfolding,we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders,such as Wilson's disease,Menkes'disease,Alzheimer's disease,Parkinson's disease,amyotrophic lateral sclerosis,Huntington's disease,and multiple sclerosis.Potential clinically significant therapeutic targets,including superoxide dismutase 1,D-penicillamine,and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline,along with their associated therapeutic agents,are further discussed.Ultimately,we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.

Toward understanding the role of genomic repeat elements in neurodegenerative diseases

Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage sequencing technology, researchers have started to notice that genomic repeat regions, previously neglected in search of disease culprits, are active contributors to multiple neurodegenerative diseases. In this review, we describe the association between repeat element variants and multiple degenerative diseases through genome-wide association studies and targeted sequencing. We discuss the identification of disease-relevant repeat element variants, further powered by the advancement of long-read sequencing technologies and their related tools, and summarize recent findings in the molecular mechanisms of repeat element variants in brain degeneration, such as those causing transcriptional silencing or RNA-mediated gain of toxic function. Furthermore, we describe how in silico predictions using innovative computational models, such as deep learning language models, could enhance and accelerate our understanding of the functional impact of repeat element variants. Finally, we discuss future directions to advance current findings for a better understanding of neurodegenerative diseases and the clinical applications of genomic repeat elements.

Unraveling brain aging through the lens of oral microbiota

The oral cavity is a complex physiological community encompassing a wide range of microorganisms.Dysbiosis of oral microbiota can lead to various oral infectious diseases,such as periodontitis and tooth decay,and even affect systemic health,including brain aging and neurodegenerative diseases.Recent studies have highlighted how oral microbes might be involved in brain aging and neurodegeneration,indicating potential avenues for intervention strategies.In this review,we summarize clinical evidence demonstrating a link between oral microbes/oral infectious diseases and brain aging/neurodegenerative diseases,and dissect potential mechanisms by which oral microbes contribute to brain aging and neurodegeneration.We also highlight advances in therapeutic development grounded in the realm of oral microbes,with the goal of advancing brain health and promoting healthy aging.

Pyrroloquinoline quinone:a potential neuroprotective compound for neurodegenerative diseases targeting metabolism

Pyrroloquinoline quinone is a quinone described as a cofactor for many bacterial dehydrogenases and is reported to exert an effect on metabolism in mammalian cells/tissues.Pyrroloquinoline quinone is present in the diet being available in foodstuffs,conferring the potential of this compound to be supplemented by dietary administration.Pyrroloquinoline quinone’s nutritional role in mammalian health is supported by the extensive deficits in reproduction,growth,and immunity resulting from the dietary absence of pyrroloquinoline quinone,and as such,pyrroloquinoline quinone has been considered as a“new vitamin.”Although the classification of pyrroloquinoline quinone as a vitamin needs to be properly established,the wide range of benefits for health provided has been reported in many studies.In this respect,pyrroloquinoline quinone seems to be particularly involved in regulating cell signaling pathways that promote metabolic and mitochondrial processes in many experimental contexts,thus dictating the rationale to consider pyrroloquinoline quinone as a vital compound for mammalian life.Through the regulation of different metabolic mechanisms,pyrroloquinoline quinone may improve clinical deficits where dysfunctional metabolism and mitochondrial activity contribute to induce cell damage and death.Pyrroloquinoline quinone has been demonstrated to have neuroprotective properties in different experimental models of neurodegeneration,although the link between pyrroloquinoline quinone-promoted metabolism and improved neuronal viability in some of such contexts is still to be fully elucidated.Here,we review the general properties of pyrroloquinoline quinone and its capacity to modulate metabolic and mitochondrial mechanisms in physiological contexts.In addition,we analyze the neuroprotective properties of pyrroloquinoline quinone in different neurodegenerative conditions and consider future perspectives for pyrroloquinoline quinone’s potential in health and disease.

Potential role of tanycyte-derived neurogenesis in Alzheimer's disease

Tanycytes, specialized ependymal cells located in the hypothalamus, play a crucial role in the generation of new neurons that contribute to the neural circuits responsible for regulating the systemic energy balance. The precise coordination of the gene networks controlling neurogenesis in naive and mature tanycytes is essential for maintaining homeostasis in adulthood. However, our understanding of the molecular mechanisms and signaling pathways that govern the proliferation and differentiation of tanycytes into neurons remains limited. This article aims to review the recent advancements in research into the mechanisms and functions of tanycyte-derived neurogenesis. Studies employing lineage-tracing techniques have revealed that the neurogenesis specifically originating from tanycytes in the hypothalamus has a compensatory role in neuronal loss and helps maintain energy homeostasis during metabolic diseases. Intriguingly,metabolic disorders are considered early biomarkers of Alzheimer's disease. Furthermore,the neurogenic potential of tanycytes and the state of newborn neurons derived from tanycytes heavily depend on the maintenance of mild microenvironments, which may be disrupted in Alzheimer's disease due to the impaired blood–brain barrier function.However, the specific alterations and regulatory mechanisms governing tanycyte-derived neurogenesis in Alzheimer's disease remain unclear. Accumulating evidence suggests that tanycyte-derived neurogenesis might be impaired in Alzheimer's disease, exacerbating neurodegeneration. Confirming this hypothesis, however, poses a challenge because of the lack of long-term tracing and nucleus-specific analyses of newborn neurons in the hypothalamus of patients with Alzheimer's disease. Further research into the molecular mechanisms underlying tanycyte-derived neurogenesis holds promise for identifying small molecules capable of restoring tanycyte proliferation in neurodegenerative diseases. This line of investigation could provide valuable insights into potential therapeutic strategies for Alzheimer's disease and related conditions.

基坑开挖对管桩竖向承载性状影响研究

针对基坑开挖引起管桩挤土效应的弱化,以及挤土效应弱化对管桩承载性质影响问题,开展了室内模型试验,并通过对模型试验进行数值建模,验证了数值模型的可靠性。在此基础上,从桩长、桩间距、桩侧摩阻力系数对开挖卸荷影响下管桩基础承载性状的影响展开研究。结果表明:开挖卸荷对管桩承载特性造成较大影响,极限承载力对应桩顶沉降量提高54.5%;数值计算发现,卸载前后极限荷载所对应最大沉降差率为9.52%,满足工程精度要求,验证了所提数值模型的可靠性;数值计算结果表明,随桩长提高,最大桩身轴力位置不断上升,而中性点位置却不断下降;桩间距越小,开挖卸荷对桩身轴力影响越大,而对负摩阻力影响越小;摩阻力系数为0.3时,摩阻力系数对桩身轴力及桩侧摩阻力发挥敏感度最高。

Targeting capabilities of engineered extracellular vesicles for the treatment of neurological diseases

Recent advances in research on extracellular vesicles have significantly enhanced their potential as therapeutic agents for neurological diseases.Owing to their therapeutic properties and ability to cross the blood–brain barrier,extracellular vesicles are recognized as promising drug delivery vehicles for various neurological conditions,including ischemic stroke,traumatic brain injury,neurodegenerative diseases,glioma,and psychosis.However,the clinical application of natural extracellular vesicles is hindered by their limited targeting ability and short clearance from the body.To address these limitations,multiple engineering strategies have been developed to enhance the targeting capabilities of extracellular vesicles,thereby enabling the delivery of therapeutic contents to specific tissues or cells.Therefore,this review aims to highlight the latest advancements in natural and targeting-engineered extracellular vesicles,exploring their applications in treating traumatic brain injury,ischemic stroke,Parkinson's disease,Alzheimer's disease,amyotrophic lateral sclerosis,glioma,and psychosis.Additionally,we summarized recent clinical trials involving extracellular vesicles and discussed the challenges and future prospects of using targeting-engineered extracellular vesicles for drug delivery in treating neurological diseases.This review offers new insights for developing highly targeted therapies in this field.

Neuronal regulated cell death in aging-related neurodegenerative diseases:key pathways and therapeutic potentials

Regulated cell death(such as apoptosis,necroptosis,pyroptosis,autophagy,cuproptosis,ferroptosis,disulfidptosis)involves complex signaling pathways and molecular effectors,and has been proven to be an important regulatory mechanism for regulating neuronal aging and death.However,excessive activation of regulated cell death may lead to the progression of aging-related diseases.This review summarizes recent advances in the understanding of seven forms of regulated cell death in age-related diseases.Notably,the newly identified ferroptosis and cuproptosis have been implicated in the risk of cognitive impairment and neurodegenerative diseases.These forms of cell death exacerbate disease progression by promoting inflammation,oxidative stress,and pathological protein aggregation.The review also provides an overview of key signaling pathways and crosstalk mechanisms among these regulated cell death forms,with a focus on ferroptosis,cuproptosis,and disulfidptosis.For instance,FDX1 directly induces cuproptosis by regulating copper ion valency and dihydrolipoamide S-acetyltransferase aggregation,while copper mediates glutathione peroxidase 4 degradation,enhancing ferroptosis sensitivity.Additionally,inhibiting the Xc-transport system to prevent ferroptosis can increase disulfide formation and shift the NADP^(+)/NADPH ratio,transitioning ferroptosis to disulfidptosis.These insights help to uncover the potential connections among these novel regulated cell death forms and differentiate them from traditional regulated cell death mechanisms.In conclusion,identifying key targets and their crosstalk points among various regulated cell death pathways may aid in developing specific biomarkers to reverse the aging clock and treat age-related neurodegenerative conditions.

Nanomaterials-mediated lysosomal regulation:a robust protein-clearance approach for the treatment of Alzheimer’s disease

Alzheimer’s disease is a debilitating,progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins,including amyloid plaques and intracellular tau tangles,primarily within the brain.Lysosomes,crucial intracellular organelles responsible for protein degradation,play a key role in maintaining cellular homeostasis.Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases,including Alzheimer’s disease.Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer’s disease.Currently,the efficacy of drugs in treating Alzheimer’s disease is limited,with major challenges in drug delivery efficiency and targeting.Recently,nanomaterials have gained widespread use in Alzheimer’s disease drug research owing to their favorable physical and chemical properties.This review aims to provide a comprehensive overview of recent advances in using nanomaterials(polymeric nanomaterials,nanoemulsions,and carbon-based nanomaterials)to enhance lysosomal function in treating Alzheimer’s disease.This review also explores new concepts and potential therapeutic strategies for Alzheimer’s disease through the integration of nanomaterials and modulation of lysosomal function.In conclusion,this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer’s disease.The application of nanotechnology to the development of Alzheimer’s disease drugs brings new ideas and approaches for future treatment of this disease.

Liposomes as versatile agents for the management of traumatic and nontraumatic central nervous system disorders:drug stability,targeting efficiency,and safety

Various nanoparticle-based drug delivery systems for the treatment of neurological disorders have been widely studied.However,their inability to cross the blood–brain barrier hampers the clinical translation of these therapeutic strategies.Liposomes are nanoparticles composed of lipid bilayers,which can effectively encapsulate drugs and improve drug delivery across the blood–brain barrier and into brain tissue through their targeting and permeability.Therefore,they can potentially treat traumatic and nontraumatic central nervous system diseases.In this review,we outlined the common properties and preparation methods of liposomes,including thin-film hydration,reverse-phase evaporation,solvent injection techniques,detergent removal methods,and microfluidics techniques.Afterwards,we comprehensively discussed the current applications of liposomes in central nervous system diseases,such as Alzheimer's disease,Parkinson's disease,Huntington's disease,amyotrophic lateral sclerosis,traumatic brain injury,spinal cord injury,and brain tumors.Most studies related to liposomes are still in the laboratory stage and have not yet entered clinical trials.Additionally,their application as drug delivery systems in clinical practice faces challenges such as drug stability,targeting efficiency,and safety.Therefore,we proposed development strategies related to liposomes to further promote their development in neurological disease research.

The complex roles of m^(6)A modifications in neural stem cell proliferation, differentiation, and self-renewal and implications for memory and neurodegenerative diseases

N6-methyladenosine(m^(6)A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis and neural regeneration, where it is highly concentrated and actively involved in these processes. Changes in m^(6)A modification levels and the expression levels of related enzymatic proteins can lead to neurological dysfunction and contribute to the development of neurological diseases. Furthermore, the proliferation and differentiation of neural stem cells, as well as nerve regeneration, are intimately linked to memory function and neurodegenerative diseases. This paper presents a comprehensive review of the roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, as well as its implications in memory and neurodegenerative diseases. m^(6)A has demonstrated divergent effects on the proliferation and differentiation of neural stem cells. These observed contradictions may arise from the time-specific nature of m^(6)A and its differential impact on neural stem cells across various stages of development. Similarly, the diverse effects of m^(6)A on distinct types of memory could be attributed to the involvement of specific brain regions in memory formation and recall. Inconsistencies in m^(6)A levels across different models of neurodegenerative disease, particularly Alzheimer's disease and Parkinson's disease, suggest that these disparities are linked to variations in the affected brain regions. Notably, the opposing changes in m^(6)A levels observed in Parkinson's disease models exposed to manganese compared to normal Parkinson's disease models further underscore the complexity of m^(6)A's role in neurodegenerative processes. The roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, and its implications in memory and neurodegenerative diseases, appear contradictory. These inconsistencies may be attributed to the timespecific nature of m^(6)A and its varying effects on distinct brain regions and in different environments.