The control of fracture healing and its therapeutic targeting: Improving upon nature

Fracture repair is a complex process involving timed cellular recruitment, gene expression, and synthesis of compounds that regenerate native tissue to restore the mechanical integrity, and thus function of injured bone. While the majority of fractures heal without complication, this takes time and a subset of patients (～10%) experience healing delays, extending their morbidity and treatment costs. Consequently, there is a need for efficacious therapeutics for the intervention of fracture healing. Recent studies into the molecular control of fracture repair and advances in the understanding of the skeleton as a whole have resulted in the identification of numerous novel targets and compounds for such intervention. These include traditional agents such bone morphogenetic proteins and other growth factors, but also relatively newer compounds such as parathyroid hormone and modulators of the Wnt signaling pathway. These agents, along with others, are discussed in the current article in terms of their investigative status and potential for clinical implementation. Hopefully, these agents, as well as others yet to be discovered, will demonstrate sufficient clinical utility for successful intervention of fracture healing. This may have significant implications for the duration of morbidity and costs associated with traumatic bone fractures. J. Cell. Biochem. 109: 302–311, 2010. © 2009 Wiley‐Liss, Inc.     

Angiostatin's molecular mechanism: aspects of specificity and regulation elucidated

Tumor growth requires the development of new vessels that sprout from pre-existing normal vessels in a process known as "angiogenesis" [Folkman (1971) N Engl J Med 285:1182-1186]. These new vessels arise from local capillaries, arteries, and veins in response to the release of soluble growth factors from the tumor mass, enabling these tumors to grow beyond the diffusion-limited size of approximately 2 mm diameter. Angiostatin, a naturally occurring inhibitor of angiogenesis, was discovered based on its ability to block tumor growth in vivo by inhibiting the formation of new tumor blood vessels [O'Reilly et al. (1994a) Cold Spring Harb Symp Quant Biol 59:471-482]. Angiostatin is a proteolytically derived internal fragment of plasminogen and may contain various members of the five plasminogen "kringle" domains, depending on the exact sites of proteolysis. Different forms of angiostatin have measurably different activities, suggesting that much remains to be elucidated about angiostatin biology. A number of groups have sought to identify the native cell surface binding site(s) for angiostatin, resulting in at least five different binding sites proposed for angiostatin on the surface of endothelial cells (EC). This review will consider the data supporting all of the various reported angiostatin binding sites and will focus particular attention on the angiostatin binding protein identified by our group: F(1)F(O) ATP synthase. There have been several developments in the quest to elucidate the mechanism of action of angiostatin and the regulation of its receptor. The purpose of this review is to describe the highlights of research on the mechanism of action of angiostatin, its' interaction with ATP synthase on the EC surface, modulators of its activity, and issues that should be explored in future research related to angiostatin and other anti-angiogenic agents.     

鹿茸角柄断面伤口无疤痕愈合过程中骨形态蛋白的表达及功能分析

为研究骨形态蛋白（bone morphogenetic proteins ,BMP）在鹿茸再生早期角柄断面伤口无疤痕愈合过程中的功能,本研究通过免疫组化技术对比分析了BMP 2 和BMP 4在正常皮肤及茸皮中的表达及分布差异,同时利用添加外源性蛋白分析了BMP 4对鹿真皮成纤维细胞和毛乳头细胞的影响。结果显示：(1)原代培养的真皮成纤维细胞表达波形蛋白阳性率几乎为100%;(2) BMP 2和BMP 4强烈表达于茸皮中新生毛囊的毛基质细胞中;(3) BMP 4可促进鹿真皮成纤维细胞向脂肪细胞转分化;(4) BMP 4可促进鹿真皮毛乳头细胞成团。以此推测BMP在鹿毛囊形成及伤口愈合过程中发挥重要作用。     

bFGF/BMP/ 胶原膜加速颌骨骨折愈合的大体及X 线观察

目的:了解胶原膜作为生长因子缓释材料治疗颌骨骨折的应用前景。方法:将100μg的rhBMP-2用1ml的bFGF溶液完全溶解;用移液器移出40μl的该溶液,滴加到面积为0.5cm×1cm的胶原膜组织块中,冻干后制成生长因子缓释系统;在12只新西兰大白兔两侧制成人工下颌骨骨折模型,左侧置放bFGF/BMP/胶原膜;右侧均为空白对照;术后2、4、12周行临床大体观察及X线片观察。结果:实验组骨折愈合速度明显快于对照组。术后2周,X线结果显示bFGF/BMP/胶原膜组骨折断端边缘模糊。对照组骨折线明显。术后4周,X线结果显示bFGF/BMP/胶原膜骨折线基本不可见,骨折对位良好,断端边缘基本消失,骨折无错位。对照组骨折下缘可见纤维性骨痂形成,骨折线模糊。术后12周,各组X线结果无差异,骨折部位接近正常骨组织。结论:bFGF/BMP/胶原膜能加速骨折愈合,提高骨折愈合效果。     

bFGF/BMP/胶原膜加速颌骨骨折愈合的大体及X线观察

目的：了解胶原膜作为生长因子缓释材料治疗颌骨骨折的应用前景。方法：将100μg的rhBMP-2用1ml的bFGF溶液完全溶解;用移液器移出40μl的该溶液,滴加到面积为0.5cm×1cm的胶原膜组织块中,冻干后制成生长因子缓释系统;在12只新西兰大白兔两侧制成人工下颌骨骨折模型,左侧置放bFGF/BMP/胶原膜;右侧均为空白对照;术后2、4、12周行临床大体观察及X线片观察。结果：实验组骨折愈合速度明显快于对照组。术后2周,X线结果显示bFGF/BMP/胶原膜组骨折断端边缘模糊。对照组骨折线明显。术后4周,X线结果显示bFGF/BMP/胶原膜骨折线基本不可见,骨折对位良好,断端边缘基本消失,骨折无错位。对照组骨折下缘可见纤维性骨痂形成,骨折线模糊。术后12周,各组X线结果无差异,骨折部位接近正常骨组织。结论：bFGF/BMP/胶原膜能加速骨折愈合,提高骨折愈合效果。     

The importance of a pleasant process of treatment: lessons on healing from South India

This paper considers the significance of the positive and negative aesthetic qualities of different therapies—in other words, how pleasant (a term that is elaborated in the paper) it is to undergo various treatments. Interviews were conducted with patients undergoing three forms of healing for mental illness and related problems in the state of Kerala in southern India—ayurvedic (indigenous) psychiatry, allopathic (biomedical) psychiatry, and religious healing. Informants revealed concerns about the aesthetic process of therapy, reporting adverse reactions to allopathic treatments and in some cases asserting that they enjoyed ayurvedic procedures. Some informants with long-term illnesses had chosen to live in the process of therapy and reside indefinitely in the aesthetically engaging environment of a mosque, temple, or church after pursuing medical therapies for years. Thus considerations of the quality of the process of therapy also call for an examination of the limitations of the concept of cure for describing what is accomplished in healing in some therapeutic settings.     

Factors influencing initial larval settlement: temporal, spatial and surface molecular components

The impact of initial surface chemistry on settlement of barnacle, bryozoan, and hydroid larvae was assessed. Temporal (on a scale of weeks to months) and fine scale spatial (centimeter to meter) variation in settlement were quantified. Four arrays of silanized glass surfaces, deployed at ≈2-wk intervals, were monitored after 1 and 3 days of immersion. Settlement of all larval types exhibited strong temporal variation. There was a 25, 22- and 18-fold difference between the highest and lowest Day 1 settlement for barnacles, bryozoans and hydroids, respectively. Bryozoan and hydroid settlement was spatially variable, barnacle settlement was not. Barnacle and bryozoan settlement was influenced by inttial surface chemistry, hydroid settlement was not. For barnacles, there was a 2-fold difference between total settlement over the four arrays on untreated glass and diphenyl-silanized surfaces; for bryozoans, there was a 51-fold difference, and in the opposite direction. There was a negative correlation between barnacle and bryozoan settlement with respect to surface. This result was independent of the presence of the other species. Bryozoan settlement was also spatially and temporally quantified in a separate, single surface 56-h array, and total bryozoan settlement ·h⁻¹ was found to be correlated with light intensity. Patterns of initial colonization were strongly influenced by surface chemistry and spatial temporal variation in larval supply. These effects on initial colonization may influence subsequent community development.     

鱼类干扰素反应及分子调控

干扰素反应在脊椎动物抵抗病毒感染过程中发挥重要作用。近年来,鱼类干扰素抗病毒免疫反应的研究取得了重要进展,不仅克隆鉴定了一系列鱼类干扰素系统基因,而且通过功能研究揭示了鱼类具有类似于高等哺乳类的干扰素反应。但是,鱼类干扰素反应及分子调控具有自身特点。以下综述了最近这方面的研究结果。     

Myostatin regulation of muscle development: molecular basis, natural mutations, physiopathological aspects

Since its identification in 1997, myostatin has been considered as a novel and unique negative regulator of muscle growth, as mstn-/- mice display a dramatic and widespread increase in skeletal muscle mass. Myostatin also appears to be involved in muscle homeostasis in adults as its expression is regulated during muscle atrophy. Moreover, deletion of the myostatin gene seems to affect adipose tissue mass in addition to skeletal muscle mass. Natural myostatin gene mutations occur in cattle breeds such as Belgian Blue, exhibiting an obviously increased muscle mass, but also in humans, as has recently been demonstrated. Here we review these natural mutations and their associated phenotypes as well as the physiological influence of the alterations in myostatin expression and the physiopathological consequences of changes in myostatin expression, especially with regard to satellite cells. Interestingly, studies have demonstrated some rescue effects of myostatin in muscular pathologies such as myopathies, providing a novel pharmacological strategy for treatment. Furthermore, the myostatin pathway is now better understood thanks to in vitro studies and it consists of inhibition of myoblast progression in the cell cycle, inhibition of myoblast terminal differentiation, in both cases associated to protection from apoptosis. The molecular pathway driving the myogenic myostatin influence is currently under extensive study and many molecular partners of myostatin have been identified, suggesting novel potent muscle growth enhancers for both human and agricultural applications.     

Effect of bovine fetal growth plate as a new xenograft in experimental bone defect healing: radiological,histopathological and biomechanical evaluation

Bone grafting is used to enhance healing in osteotomies, arthrodesis, and multifragmentary fractures and to replace bony loss resulting from neoplasia or cysts. They are source of osteoprogenitor cells and induce bone formation and provide mechanical support for vascular and bone ingrowth. Autografts are used commonly but quantity of retrieved bone is limit. This study was designed to evaluate autograft and new xenograft (Bovine fetal growth plate) effects on bone healing process. Twenty male White New Zealand rabbits were used in this study. In autograft group the defect was filled by fresh autogenous cortical graft, in xenograft group the defect was filled by a segment of bovine fetal growth plate and was fixed by cercelage wire. Radiological, histopathological and biomechanical evaluations were performed blindly and results scored and analyzed statistically. Statistical tests did not support significant differences between two groups at the 14th and 28th postoperative day radiographically (P > 0.05). There was a significant difference for remodeling at the 42nd postoperative radiologically (P < 0.05). Xenograft was superior to autograft at the 56th postoperative day for radiological bone formation (P < 0.03). Histopathological and biomechanical evaluation revealed no significant differences between two groups. The results of this study indicate that satisfactory healing occurred in rabbit radius defect filled with calf fetal growth plate. Complications were not identified and healing was faster than cortical autogenous grafting. It was concluded that the use of calf fetal growth plate as a new xenograft is an acceptable alternative to cortical autogenous graft and could reduce the morbidity associated with harvesting autogenous graft during surgery.     

Olfactory coding in the insect brain: molecular receptive ranges, spatial and temporal coding

Odor information is coded in the insect brain in a sequence of steps, ranging from the receptor cells, via the neural network in the antennal lobe, to higher order brain centers, among which the mushroom bodies and the lateral horn are the most prominent. Across all of these processing steps, coding logic is combinatorial, in the sense that information is represented as patterns of activity across a population of neurons, rather than in individual neurons. Because different neurons are located in different places, such a coding logic is often termed spatial, and can be visualized with optical imaging techniques. We employ in vivo calcium imaging in order to record odor‐evoked activity patterns in olfactory receptor neurons, different populations of local neurons in the antennal lobes, projection neurons linking antennal lobes to the mushroom bodies, and the intrinsic cells of the mushroom bodies themselves, the Kenyon cells. These studies confirm the combinatorial nature of coding at all of these stages. However, the transmission of odor‐evoked activity patterns from projection neuron dendrites via their axon terminals onto Kenyon cells is accompanied by a progressive sparsening of the population code. Activity patterns also show characteristic temporal properties. While a part of the temporal response properties reflect the physical sequence of odor filaments, another part is generated by local neuron networks. In honeybees, γ‐aminobutyric acid (GABA)‐ergic and histaminergic neurons both contribute inhibitory networks to the antennal lobe. Interestingly, temporal properties differ markedly in different brain areas. In particular, in the antennal lobe odor‐evoked activity develops over slow time courses, while responses in Kenyon cells are phasic and transient. The termination of an odor stimulus is reflected by a decrease in activity within most glomeruli of the antennal lobe and an off‐response in some glomeruli, while in the mushroom bodies about half of the odor‐activated Kenyon cells also exhibit off‐responses.     

The effects of acupuncture and electroacupuncture on Parkinson's disease: Current status and future perspectives for molecular mechanisms

Among the progressive neurodegenerative disorders, Parkinson's disease (PD) is the second most common. Different factors have critical role in pathophysiology of PD such as apoptosis pathways, inflammatory cytokines, oxidative stress, and neurotransmitters and its receptors abnormalities. Acupuncture and electroacupuncture were considered as nondrug therapies for PD. Although numerous studies has been conducted for assessing the mechanism underlying electroacupuncture and acupuncture, various principal aspects of these treatment procedures remain not well-known. There have also been few investigations on the molecular mechanism of acupuncture and electroacupuncture therapy effects in PD. This review evaluates the effects of electroacupuncture and acupuncture on the molecular mechanism in PD.     

Spanish National Hip Fracture Registry (SNHFR): a description of its objectives,methodology and implementation

Objective

To ascertain the current situation and clinical variability of the provision of care for Hip Fracture (HF) in Spain and the factors related to it by using a National Registry (NHFR) with high patient numbers and territorial representation NHFR, and to compare results on a national and international level and propose standards and criteria to improve healthcare quality.

Placebo studies and ritual theory: a comparative analysis of Navajo, acupuncture and biomedical healing

Using a comparative analysis of Navajo healing ceremonials, acupuncture and biomedical treatment, this essay examines placebo studies and ritual theory as mutually interpenetrating disciplines. Healing rituals create a receptive person susceptible to the influences of authoritative culturally sanctioned 'powers'. The healer provides the sufferer with imaginative, emotional, sensory, moral and aesthetic input derived from the palpable symbols and procedures of the ritual process-in the process fusing the sufferer's idiosyncratic narrative unto a universal cultural mythos. Healing rituals involve a drama of evocation, enactment, embodiment and evaluation in a charged atmosphere of hope and uncertainty. Experimental research into placebo effects demonstrates that routine biomedical pharmacological and procedural interventions contain significant ritual dimensions. This research also suggests that ritual healing not only represents changes in affect, self-awareness and self-appraisal of behavioural capacities, but involves modulations of symptoms through neurobiological mechanisms. Recent scientific investigations into placebo acupuncture suggest several ways that observations from ritual studies can be verified experimentally. Placebo effects are often described as 'non-specific'; the analysis presented here suggests that placebo effects are the 'specific' effects of healing rituals.     

Gene structure,cDNA sequence,and developmental regulation of a low molecular weight hemolymph protein from Locusta migratoria

From a Locusta migratoria genomic DNA library, a gene has been isolated that codes for a previously unrecognized hemolymph protein of M_r = 19,000, designated 19k protein. The gene has at least five exons, extending over about 9 kb of DNA. Its polypeptide product, obtained by cell-free translation of mRNA selected from adult fat body RNA by hybridization with the cloned DNA, is precipitated by antiserum against a low molecular weight hemolymph protein fraction. The mature protein product has been purified from locust hemolymph, and an N-terminal sequence of 20 amino acids has been determined. In polyacrylamide gel electrophoresis, this protein comigrates with apolipophorin III, from which it was previously not distinguished, but it is clearly distinct by amino acid composition and sequence. The genomic clone was used as a probe to isolate a fat body cDNA clone of the 19k protein mRNA. The 938-base pair cDNA clone contains a 516-base pair open reading frame. The deduced 172-amino acid polypeptide includes an apparent signal peptide, a sequence of four amino acids that may represent a prosegment, and a sequence identical (with a single exception, which may reflect polymorphism) with the N-terminal sequence of the hemolymph protein. Its mRNA occurs at a low level in late larval fat body, is abundant in the newly eclosed adult, then declines to a low level, and rises again at days 8–10; it is greatly reduced after destruction of the corpora allata with precocene and then is elevated after treatment with methoprene, suggesting stimulation by juvenile hormone. The biological role of 19k protein is unknown.