密质骨弥散性微损伤非骨重建自修复

弥散性微损伤是骨疲劳引发的主要骨微损伤之一。骨损伤修复普遍认为完全通过骨重建过程完成。研究发现与线性裂痕不同,弥散性微损伤的骨细胞未凋亡,损伤区在"无骨重建过程"下进行了直接修复。基于此新发现,本文对弥散性基质微损伤的特殊自修复相关机制研究进行综述,旨在为骨微损伤修复研究提供一个新视角,并为临床治疗骨组织疾病提供新思路。     

骨吸收抑制剂对老年短尾猴椎体松质骨微损伤和骨重建的影响

目的 评估骨吸收抑制剂对骨微损伤和骨重建的影响.方法将20只雌性短尾猴（18～22岁）按体重随机分为5组：对照组（CNT,n=4）,低剂量依降钙素组[0.5 U/（kg·d）,ELL,n=4],高剂量依降钙素组[5 U/（kg·d）,ELH,n=4],低剂量阿仑膦酸盐组[10 μg/（kg·d）,ALL,n=4]和高剂量阿仑膦酸盐组[100 μg（kg·d）,ALH,n=4].所有动物均皮下注射给药,每周2次,持续给药29周.处死前给予钙黄绿素双标,处死后取胸椎第2椎体进行松质骨微损伤测量及骨重建指标检测.结果 微损伤测量结果表明2个阿仑膦酸盐组椎体的微损伤总裂缝长度（crack length）、裂缝总数量（crack number）、骨表面密度（surface density）及裂缝密度（crack density）均较对照组和依降钙素组明显增加（P＜0.01）,但微损伤平均长度（mean crack length）较对照组和依降钙素组明显降低（P＜0.05）.高剂量降钙素组骨表面密度较对照组明显增高（P＜0.01）,其余各指标间差异均无统计学意义.骨重建检测结果表明阿仑膦酸盐组椎骨单标表面（sLS）、类骨质表面/骨表面（OS/BS）、类骨质厚度（O.Th）及单标表面/骨表面（sLS/BS）均较对照组明显降低（P＜0.05）;高剂量阿仑膦酸盐组矿化表面/类骨质表面（MS/OS）和标记表面/类骨质表面（LS/OS）较对照组明显减低（P＜0.05）.高剂量依降钙素组矿化表面/类骨质表面（OS/BS）和类骨质厚度（O.Th）较对照组明显降低（P＜0.05）,依降钙素组其余指标差异均无统计学意义.结论 依降钙素可轻微抑制老年短尾猴椎体松质骨的骨重建,但未引起骨微损伤的聚积;阿仑膦酸盐可显著抑制该猴椎体松质骨的骨重建,以及引起微损伤的聚积,但微损伤的平均长度明显降低.     

活体大鼠尺骨四点弯曲疲劳试验夹具的研制与应用

目的研制专用于活体大鼠尺骨四点弯曲疲劳试验的夹具装置,制作活体微损伤动物模型,探讨活体大鼠疲劳试验方法并分析其骨生物力学性能。方法根据四点弯曲原理研制与PLD-5010型电子疲劳损伤试验机配套的夹具装置,该夹具由装载大鼠的载物盘和活体大鼠左（右）前肢加载装置2部分组成,后者包括上连接杆、弹簧上连接轴、线弹性弹簧、四点弯曲试验装置主体和下连接杆等零部件。选择4只12周龄雌性sD大鼠,随机分成对照组和负载组,每组各2只。2％戊巴比妥钠腹腔注射麻醉后,负载组大鼠用该夹具进行活体双侧尺骨四点弯曲疲劳损伤试验。负载频率：2Hz,负载：10000次,负载力0．0555N／g（体重）,隔天1次,共2次;对照组不行疲劳损伤试验。试验结束后处死2组大鼠,取双侧尺骨,用碱性品红染色,塑料包埋,磨片至50—80仙m,Leica显微镜下发现骨微损伤后,用CCD头摄取图像并输入计算机储存。结果成功制作了疲劳夹具,可与骨电子疲劳损伤试验机配套应用。在负载组大鼠活体损伤的左右尺骨4个标本共20张磨片中均发现有微破裂,对照组未发现前述变化。结论该夹具适合于PLD-5010型电子疲劳损伤试验机,经过四点弯曲疲劳试验可初步建立活体大鼠尺骨微损伤模型,该活体大鼠疲劳试验方法可用于进一步的微损伤研究。     

AlkB蛋白介导的DNA氧化脱甲基化作用的研究进展

环境和细胞内各种因素所引起的DNA碱基甲基化改变可导致DNA损伤.DNA损伤修复对维持基因组功能的完整性非常蘑要,如未及时修复可能导致遗传信息功能的改变,并引起相关疾病,如癌症、发育缺陷等.最近发现AlkB蛋白家族利用单核非血红素Fe2＋以及α-酮戊二酸作为辅助因子和协同底物可直接祛除部分DNA碱基甲基化损伤.因此,对AlkB功能的深入研究有助于了解DNA损伤修复机制以及研发新型抗肿瘤药物.     

AIkkB蛋白介导的DNA氧化脱甲基化作用的研究进展

环境和细胞内各种因素所引起的DNA碱基甲基化改变可导致DNA损伤。DNA损伤修复对维持基因组功能的完整性非常重要,如未及时修复可能导致遗传信息功能的改变,并引起相关疾病,如癌症、发育缺陷等。最近发现AlkB蛋白家族利用单核非血红素Fe~(2+)以及α-酮戊二酸作为辅助因子和协同底物可直接祛除部分DNA碱基甲基化损伤。因此,对AlkB功能的深入研究有助于了解DNA损伤修复机制以及研发新型抗肿瘤药物。     

原位成孔骨水泥的体外降解与强度变化的关系

目的 探讨复合聚乳酸羟基乙酸共聚物(PLGA)微球对自制可注射磷酸钙骨水泥(CPC)理化性质的影响及其相互关系.方法 将PLGA微球与CPC复合,检测其固化时间、可注射性能、重量丢失、体外降解、抗压强度及微结构改变,并构建重量丢失和抗压强度之间的关系.结果 载入药物和微球后,骨水泥的固化时间延长,可注射性能提高,抗压强度下降.电镜示药物复合后CPC大体结构无明显改变,而载入微球后空隙明显增多、增大.CPC/PLGA强度的降低与质量丢失呈负相关.结论 CPC与微球复合时会导致其强度的减弱,这一点或许可以通过控制微球的降解来解决.     

细胞微核的研究进展

微核是细胞在有丝分裂时因各种有害因素损伤，使细胞核成份残留在核外的微小核染色质块。其作为评价药物、放射线及细胞毒性物质对人、动物及体外细胞损伤已有较长的历史。为了解最新相关的研究情况，我们就最近国外有关细胞微核的形成机理、特性及临床实用价值等综述如下。１　微核形成的机理１．１　微核形成的机理　①化学毒性物质损伤所致的微核：纺锤丝毒性类药物如秋水仙碱、ＨＯ－２２１等能直接抑制动物细胞纺锤丝的形成，阻止细胞分裂中期纺锤丝将染色体拉至细胞的两端。Ａｎｄｏ等〔１〕应用抗肿瘤药（ＨＯ－２２１）抑制纺锤丝微…     

目的性骨重建与非目的性骨重建

骨重建作为骨组织新陈代谢的手段,在维持机体内环境的稳定和防止骨骼衰老,修复损伤等方面起着重要的作用。其作用形式可分为目的性骨重建和非目的性骨重建。本文综述了骨重建的形成过程以及两种性质骨重建的调控方式和相互关系,探讨了药物对两种骨重建的影响。     

微透析技术在重症脓毒症抗菌药物治疗方面的应用进展

作为一种新型生物取样技术,微透析技术具有活体、微创、实时、高效等特点。近年来微透析技术已经广泛地应用于临床各个学科,在实验研究、临床诊断和治疗方面都具有积极意义。重症脓毒症和脓毒症休克的患者病理生理学的改变、液体复苏和体内液体的再分布等使药物表观分布容积发生改变,同时经常合并肾功能或肝功能不全引起药代学、药效学特征的变化,以往的评价指标多依赖于血清药物浓度及静态的体外药效学参数,很难真实反映药物的实际情况。研究微透析在重症脓毒血症中的应用,探讨药物在血液和组织中的浓度变化,对重症脓毒血症的治疗具有现实意义。为此本文综合近年文献,对微透析技术在脓毒痒杭菌药物治疗方面的府用讲展作一综沭．     

胃微生态与胃癌的研究进展

胃微生态平衡是人体健康的重要前提,幽门螺杆菌(Helicobacter pylori,Hp)是目前已发现的与胃癌相关的关键病原体之一,普遍存在于人胃黏膜上皮。Hp感染可引起胃内其他菌群的改变,还可引起长期慢性的胃黏膜损伤,导致一系列胃黏膜上皮恶性进展和胃癌的发生。本文就胃微生态与Hp感染的关系、Hp感染在胃癌发生中的作用、胃内其他菌群在胃癌发生中的作用及微生态制剂在胃癌治疗的作用进行综述。进一步揭示Hp感染对胃微生态平衡的影响,胃微生态平衡和Hp感染在胃癌发生发展中的作用及微生态制剂在胃癌治疗中的意义。     

Microdamage and bone quality

Fatigue occurs in every material under repetitive loading. Because bone is also being loaded under physiological condition, fatigue also occurs in bone and it is observed as microdamages under light microscope. However, in vivo bone is different from that ex-vivo. It is strongly suggests that in vivo microdamage is repaired by bone remodeling. Once generation and repair of microdamage is imbalanced, microdamage accumulates in bone and causes fatigue fracture.     

Biomechanics

Therapeutic agents used to treat osteoporosis reduce the incidence of vertebral and nonvertebral fractures in osteoporotic women. The antiremodeling agents, such as the bisphosphonates, prevent bone loss by suppressing the remodeling rate, perhaps increasing bone volume slightly, and increasing mineralization of the tissue. The anabolic agents, of which rhPTH(1–34) is the only one approved, accomplish this in a manner that is almost completely the opposite in terms of biological process. rhPTH(1–34) causes net bone gain by stimulating both modeling and remodeling, by increasing bone volume significantly through direct bone apposition to trabecular and endocortical surfaces, and by reducing the mean degree of tissue mineralization (a natural consequence of enhanced remodeling). Each of these treatments maintains or increases bone strength and is similarly effective at preventing fractures. However, because of their different mode of action, each has different consequences for bone matrix quality (defined here by microdamage accumulation and by the properties of mineral and collagen) and the mechanical properties of the tissue. Although bone's composite nature makes it a relatively tough material—more like fiberglass than glass—the accumulation of damage will nevertheless reduce its residual mechanical properties until the damage is repaired through remodeling. Agents that suppress remodeling are associated with both microdamage accumulation and increased mineralization. The biological importance of damage and mineralization to bone's mechanical properties is still a source of debate.     

Bone Biomechanics and Bone Quality: Effects of Pharmaceutical Agents Used to Treat Osteoporosis

The biomechanical properties of bone define skeletal fragility. Surrogates such as bone density or biochemical markers are used to estimate the mechanical properties of bone because mechanical properties cannot be measured in a clinical environment. Within the set of bone’s mechanical properties, the material properties of the tissue itself are the defining feature of bone quality. Because they are the summation of all bone quality characteristics, bone’s material properties can define whether bone is fragile or healthy, even though other studies are required to determine the exact characteristics of microarchitecture, microdamage, and tissue physical properties that make the bone more or less fragile. For these reasons, measurement of the mechanical properties of bone is critical to assess bone health following drug treatments meant to ameliorate low bone mass, and are a common outcome measure in preclinical studies that assess the potential of these medications. This review describes the effects of existing anti-catabolic (bisphosphonates, SERMS, RANKL inhibitors) and anabolic (rhPTH (1-34) agents used to treat osteoporosis, and also several emerging potential therapies (cathepsin K inhibitors, anti-sclerostin antibody), on bone’s structural and material mechanical properties.     

Skeletal Microdamage: Less About Biomechanics and More About Remodeling

The mechanical consequences of skeletal microdamage have been clearly documented using various experimental methods, yet recent experiments suggest that physiological levels of microdamage accumulation are not sufficient to compromise the bones’ biomechanical properties. While great advances have been made in our understanding of the biomechanical implications of microdamage, less is known concerning the physiological role of microdamage in bone remodeling. Microdamage has been shown to act as a signal for bone remodeling, likely through a disruption of the osteocyte-canalicular network. Interestingly, age-related increases in microdamage are not accompanied by increases in bone remodeling suggesting that the physiological mechanisms which link microdamage and remodeling are compromised with aging.     

Accumulation of microdamage and bone quality

Quantification of accumulated microdamage in bone is one of evaluation methods of bone quality. Microdamage accumulation in bone reduces some tissue material property of bone. However, microdamage is also closely associated with bone metabolism and mechanical environment of bone, and functions as accelerator of bone turnover through the detection and repair of damage.     

The structural and biomechanical basis of the gain and loss of bone strength in women and men.

Structural failure (fracture) is a problem in biomechanics. Its solution resides, in part, in identifying the material and structural properties of bone that determine its mechanical resistance to structural failure. Bones must be stiff so that they do not bend when loaded, otherwise movement against gravity would not be possible. However, bones must also be flexible, otherwise their ability to absorb energy by elastic and plastic deformation will decrease and the energy imparted will be dissipated only by microdamage or complete fracture. Thus, failure may occur if bones deform too much (exceeding their peak strain) or too little (exceeding their peak stress). Phylogeny and ontogeny make bone "just right" for the functions it is predicted to perform, but the genetic material was not warned about the increased longevity the female enjoys after ovarian failure. Age-related and menopause-related abnormalities in bone remodeling produce loss of the material and structural properties that no longer keep bone "just right". High remodeling reduces the mineral content of bone tissue resulting in loss of stiffness (resistance to shortening in compression and lengthening in tension when loaded). Sex hormone deficiency increases the volume of bone resorbed and reduces the volume of bone formed in each BMU. Solutions to the biomechanic problem will emerge provided that the material and structural properties of bone that determine its strength are measured and studied. Drugs are available to reduce remodeling rate so that there is more time for completion of secondary mineralization to restore bone stiffness. If remodeling is suppressed too much the production of microdamage may increase as homogeneous and highly mineralized bone is less resistant to microdamage progression while reduced remodeling targeted to microdamage may result in microdamage accumulation. Drugs are available to reduce osteoclastic bone resorption and increase osteoblastic bone formation, which together will restore bone balance in the BMU and so prevent further loss of bone mass, prevent thinning and loss of trabeculae, thinning of cortices, and progression of porosity. These approaches prevent the progression of fragility but will not restore bone architecture. Even if a positive BMU balance is achieved, drugs that reduce remodeling are unlikely to reverse the structure damage. Slow remodeling means there are too few remodeling foci depositing their small net positive bone volume to progressively thicken cortices or trabeculae. Agents that are anabolic, that increase bone formation on the periosteal and endosteal surfaces are needed to restore the structure of bone. Other articles in this volume address this challenge. We do not understand the proportional contributions made by differences in bone size, cortical thickness, trabecular number, thickness, connectivity, tissue mineral content, microdamage burden, osteocyte density, porosity, to differences in spine and hip fracture rates within a sex, between sexes, between races, or between treatment, and control arms in clinical trials. The challenge for the future is to measure these specific materials and structural determinants of bone strength. Whether a combination of these material and structural properties will more accurately identify women likely to sustain fractures, or improve approaches to drug therapy is unknown. The quest to eliminate fragility fractures is a distant horizon seen through a glass darkly at this time.     

骨纳米微结构与机械强度

骨强度主要由骨密度和骨质量两方面决定。骨质量属于骨生物力学范畴，用以描述骨的材料学特征和结构强度，骨质量下降则骨脆性增加。与骨质量密切相关的骨显微结构、代谢转化率、积累性损伤以及骨矿化和骨重建等因素都会影响骨强度。正常骨组织内各个纳米级组分的结构形态、生理特征和机械强度决定整体骨质量。了解骨基质内独立胶原纤维和矿化晶体的纳米级结构特征对理解骨质量具有重要意义。本文试从骨基质内部胶原纤维排列和导向、矿物晶体几何学形貌和构筑以及两者聚合方式等方面，讨论骨纳米级结构与骨强度的关系。     

Effects of Drugs on Bone Quality

The term bone quality refers to factors that define bone mechanical strength and hence its fracture risk, either inclusive or exclusive of the quantity of mineralized tissue present. These factors include: bone size, density, shape (microarchitecture, geometry, remodeling cavity number size and distribution), porosity, mineral and collagen distribution and alignment, amount and distribution of microdamage, mineral composition, collagen cross-linking and other material properties. In this review, we will consider how pharmaceuticals used to treat osteoporosis (anabolic and catabolic agents) and those used for other conditions that affect bone quality and induce “secondary osteoporosis” alter these parameters. Observed effects vary with different methods of drug delivery, length and periodicity of use, other drugs used concomitantly or consecutively, user gender, methods of analysis and, most importantly, the genetic background of the species tested. We suggest that while increases in quantity of mineralized tissue present account for much of the reported reduction in fracture risk, drugs that correct the composition and microarchitecture of the bone, returning it to its preosteoporotic status, may provide additional benefits.