Effects of G-CSF on cardiac remodeling after acute myocardial infarction in swine

We examined whether granulocyte colony-stimulating factor (G-CSF) prevents cardiac dysfunction and remodeling after myocardial infarction (MI) in large animals. MI was produced by ligation of left anterior descending coronary artery in swine. G-CSF (10 microg/kg/day, once a day) was injected subcutaneously from 24h after ligation for 7 days. Echocardiographic examination revealed that the G-CSF treatment induced improvement of cardiac function and attenuation of cardiac remodeling at 4 weeks after MI. In the ischemic region, the number of apoptotic endothelial cells was smaller and the number of vessels was larger in the G-CSF treatment group than in control group. Moreover, vascular endothelial growth factor was more abundantly expressed and Akt was more strongly activated in the ischemic region of the G-CSF treatment group than of control group. These findings suggest that G-CSF prevents cardiac dysfunction and remodeling after MI in large animals.     

Postcranial robusticity in Homo. II: Humeral bilateral asymmetry and bone plasticity

The analysis of humeral asymmetry in Recent human skeletal samples and an extant tennis-player sample documents minimal asymmetry in bone length, little asymmetry in distal humeral articular breadth, but pronounced and variable asymmetry in mid- and distal diaphyseal crosssectional geometric parameters. More specifically, skeletal samples of normal modern Euroamericans, prehistoric and early historic Amerindians, and prehistoric Japanese show moderate (ca. 5–14%) median asymmetry in diaphyseal cross-sectional areas and polar second moments of area, whereas the tennis-player sample, with pronounced unilateral physical activity, exhibits median asymmetries of 28–57% in the same parameters. A sample of Neandertals with nonpathological upper limbs exhibits similarly low articular asymmetry but pronounced diaphyseal asymmetries, averaging 24–57%. In addition, three Neandertals with actual or possible post-traumatic upper limb alterations have the same low articular asymmetry but extremely high diaphyseal asymmetries, averaging 112–215%. These data support those from experimental work on animals, exercise programs of humans, and human clinical contexts in establishing the high degree of diaphyseal plasticity possible for humans, past and present, under changing biomechanical loading conditions. This lends support to activity-related functional interpretations of changing human diaphyseal morphology and robusticity during the Pleistocene. © 1994 Wiley-Liss, Inc.     

Expression of the multifunctional Y-box protein, YB-1, in myofibroblasts of the infarcted rat heart

Intracellular signaling mechanisms regulating the turnover of alpha-SMA-positive myofibroblasts (myoFbs) at the site of myocardial infarction (MI) are poorly understood. Y-Box (YB)-1, a multifunctional protein, may be involved in regulation of proliferation, migration and apoptosis of myoFbs. Our objective was to study the expression of YB-1 in the infarcted rat heart and its localization in myoFbs. On days 3-28 following MI, we monitored YB-1 expression and its colocalization with alpha-SMA, and proliferation markers PCNA and Ki-67 in infarcted tissue by Western blot, immunohistochemistry, and immunofluorescent double-labeling. YB-1 is barely detectable in normal myocardium. At the infarct site, however, YB-1 is markedly elevated from day 3 post-MI concomitant with the induction of cell proliferation. MyoFbs are the major source of YB-1 and retain it up to day 28 post-MI. We suggest early expression of YB-1 promotes proliferation and migration of myoFbs, whereas prolonged expression may be responsible for scar formation.     

Effects of the basic multicellular unit and lamellar thickness on osteonal fatigue life

A remodeling cycle sets the size of the osteon and associated lamellae in the basic multicellular unit. Treatments and aging affect these micro-structural features. We previously demonstrated decreased fatigue life with an unexplained mechanism and decreased osteon size in cortical bone treated with high-dose bisphosphonate. Here, three finite element models were examined: type-1: a single osteon, as a homogeneous unit and with heterogeneous lamellae and interlamellae, type-2: a control, interstitial-only tissue and type-3: the osteon with cement line, set within the interstitial tissue. Models were loaded in simulated, sinusoidal bending fatigue. As osteon size was decreased, lamellar number and lamellar thickness were incrementally adjusted for each model. As hypothesized, lamellae within the larger type-1 models attained greater cycles to failure and the addition of an osteon to type-2 models (generating a type-3 model set) yielded increased fatigue life. However, as the osteon size was decreased, the potential for compressive damage nucleation was increased within the lamellae of the osteons versus the interstitium. Also, osteons with fewer, thicker lamellae displayed increased fatigue life. Osteonal microstructure plays a role in damage initiation location, especially when BMU size is smaller. Previous findings by us and others could partially be explained by this further understanding of increased probability for damage nucleation in smaller osteons.     

Peri-implant Bone Remodeling after Total Hip Replacement Combined with Systemic Alendronate Treatment: A Finite Element Analysis

In order to decrease the peri-implant bone loss during the life-time of the implant, oral use of anti-osteoporosis drugs (like bisphosphonates) has been suggested.

In this study, bone remodeling parameters identified from clinical trials of alendronate were used to simulate the effect of those drugs used after total hip arthroplasty on the peri-implant bone density. Results of the simulation show that the oral administrated drugs increase bone density around the implant and decreases, at the same time, the micromovements between the implant and the surrounding bone tissue.

Incorporation of drug effect in numerical studies of bone remodeling is a promising tool especially to predetermine safe bisphosphonate doses that could be used with orthopedic implants.     

Orthopaedic Implant as Drug Delivery System: a Numerical Approach

Abstract

There is a current trend to propose cementless total joint arthroplasty (TJA) to younger patients. These patients have more demanding physical activity resulting in an increased failure rate of the implants. In particular for these type of patients, the desired service life of the implant should be extended. The actual implant used do not fulfil this requirement.

In this study, a new concept of orthopaedic implant is presented where the implant is not only a structural support but also a local drug delivery system. The delivered drug is meant to influence the bone remodeling in a way so as to compensate the effects of peri-implant osteolysis. To test this concept, we extended an existing bone remodeling model to include the effect of a drug. The results show that a more homogeneous bone density distribution can be obtained around the implant. Implants used as drug delivery systems could then be an alternative way to increase implant service life.     

Stem cell therapy for heart failure:Medical breakthrough,or dead end?

Heart failure continues to be one of the leading causes of morbidity and mortality worldwide.Myocardial infarction is the primary causative agent of chronic heart failure resulting in cardiomyocyte necrosis and the subsequent formation of fibrotic scar tissue.Current pharmacological and non-pharmacological therapies focus on managing symptoms of heart failure yet remain unable to reverse the underlying pathology.Heart transplantation usually cannot be relied on,as there is a major discrepancy between the availability of donors and recipients.As a result,heart failure carries a poor prognosis and high mortality rate.As the heart lacks significant endogenous regeneration potential,novel therapeutic approaches have incorporated the use of stem cells as a vehicle to treat heart failure as they possess the ability to self-renew and differentiate into multiple cell lineages and tissues.This review will discuss past,present,and future clinical trials,factors that influence stem cell therapy outcomes as well as ethical and safety considerations.Preclinical and clinical studies have shown a wide spectrum of outcomes when applying stem cells to improve cardiac function.This may reflect the infancy of clinical trials and the limited knowledge on the optimal cell type,dosing,route of administration,patient parameters and other important variables that contribute to successful stem cell therapy.Nonetheless,the field of stem cell therapeutics continues to advance at an unprecedented pace.We remain cautiously optimistic that stem cells will play a role in heart failure management in years to come.     

早期吸入不同浓度布地奈德对哮喘大鼠气道炎症和重构的干预

目的：研究早期吸入不同浓度布地奈德对哮喘大鼠气道炎症和气道重构的干预情况。方法i32只Wistar大鼠随机分为4组：A对照组8只,B卵蛋白（OVA）致哮喘组8只,C卵蛋白致哮喘后吸入低浓度布地奈德治疗组8只,D卵蛋白致哮喘后吸入高浓度布地奈德治疗组8只。分别测定各组大鼠血中肿瘤坏死因子-α（TNF-α）及肺泡灌洗液（BALF）中内皮素．1（ET-1）的水平,计数BALF中细胞总数及分类。各组大鼠行肺组织切片HE染色,再行胶原染色、免疫组化NGF、TGF-β1染色,借助计算机图象分析软件测量单位气道面积炎性细胞数目,基底膜周径（Pbm）、平滑肌面积（WArn）、气道内壁面积（WAi）、胶原面积（Wcol）,NGF及TGF-β1阳性信号积分吸光度。结果：B组BALF中细胞总数、嗜酸细胞分类及TNF—α、ET-1水平与A组比较均明显增加,差异有统计学意义（P〈0．01）,C组及D组较B组均明显降低,差异有统计学意义（P〈0．01）。B组NGF及TGF-β1的表达、气道壁炎性细胞计数、气道内壁面积、平滑肌面积、胶原面积与A组比较均明显增加,差异有统计学意义（P〈0．01）,C组及D组与B组比较均明显降低,差异有统计学意义（P〈0．01）,C组及D组与A组比较差异有统计学意义（P〈0．05,P〈0．01）,C组与D组差异均有统计学意义（P〈0．05,P〈0．01）。结论：早期吸入不同浓度的布地奈德均可明显抑制气道炎症和气道重构,高浓度较低浓度对气道炎症和气道重构的影响更明显。     

Subunit Rtt102 Controls the Conformation of the Arp7/9 Heterodimer and Its Interactions with Nucleotide and the Catalytic Subunit of SWI/SNF Remodelers

Chromatin-remodeling complexes are assembled around a catalytic subunit that contains a central ATPase domain and flanking sequences that recruit auxiliary subunits. The catalytic subunits of SWI/SNF remodelers recruit Arp7/9 through a helicase/SANT-associated (HSA) domain N-terminal to the ATPase domain. Arp7/9-containing remodelers also carry the auxiliary subunit Rtt102, but the role of this subunit is poorly understood. Here, we show that Rtt102 binds with nanomolar affinity to the Arp7/9 heterodimer and modulates its conformation and interactions with the ATPase subunit and nucleotide. When bound to Rtt102, Arp7/9 interacts with a shorter segment of the HSA domain. Structural analysis by small-angle x-ray scattering further shows that when bound to Rtt102, the complex of Arp7/9 with the catalytic subunit assumes a more stable compact conformation. We also found that Arp7, Arp9, and Arp7/9 interact very weakly with ATP, but Rtt102 promotes high-affinity ATP binding to a single site in the heterodimer. Collectively, the results establish a function for subunit Rtt102 as a stabilizing factor for the Arp7/9 heterodimer, enhancing its interaction with nucleotide and controlling the conformation of SWI/SNF remodelers in an Arp7/9-dependent manner.