bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Landing Biomechanics Between Male and Female Professional Dancers
Authors: Orishimo Karl F. , Kremenic Ian J. , Pappas Evangelos , Hagins Marshall , Liederbach Marijeanne
Published: June 2009

Background

The incidence of anterior cruciate ligament injuries among dancers is much lower than that among team sport athletes and no clear gender disparity has been reported in the dance population. Although numerous studies have observed differences in lower extremity landing biomechanics between male and female athletes, there is currently little research examining the landing biomechanics of male and female dancers. Comparing landing biomechanics within this population may help explain the lower overall anterior cruciate ligament injury rates and the lack of gender disparity.

Hypothesis

Due to the fact that dancers receive jump-specific and balance-specific training from a very young age, we hypothesized that there would be no gender differences in drop-landing biomechanics in professional dancers.

Study Design

Controlled laboratory study.

Methods

Kinematics and ground-reaction forces were recorded as 33 professional modern and ballet dancers (12 men and 21 women) performed single-legged drop landings from a 30-cm platform. Joint kinematics and kinetics were compared between genders.

Results

No gender differences in joint kinematics or kinetics were found during landings (multivariate analysis of variance: P = .490 and P = .175, respectively). A significant relationship was found between the age at which the dancers began training and the peak hip adduction angle during landing ( r = .358, P = .041).

Conclusion

In executing a 30-cm drop landing, male and female dancers exhibited similar landing strategies and avoided landing patterns previously associated with increased injury rates.

Clinical Relevance

Commonly reported biomechanical differences between men and women, as well as the gender disparity among athletes in the incidence of ACL injuries, may be the result of inadequate experience in proper balance and landing technique rather than intrinsic gender factors. Beginning jump-specific and balance-specific training at an early age may counteract the potentially harmful adaptations in landing biomechanics observed in female athletes after maturity.
Attenuation of Incident Heat Flux by Pyrolysis Volatiles when Heated Using Resistance Element Radiant Heater
Authors: Zhou Yupeng , Yang Lizhong , Dai Jiakun , Wang Yafei , Deng Zhihua
Published: July 2009

The attenuation of an incident radiant heat flux by pyrolysis volatiles when heated under a resistance element radiant heater, a phenomenon that is not well understood, is studied by simulated experiment and mathematical models. The radiation attenuation of an incident heat flux when pine or PMMA is heated (6—14%) obviously commences before ignition, although it is not as large as the result reported by Kashiwagi (50—80%) using a laser radiant heater. The calculated results clearly indicate that ignition models must consider radiation attenuation by pyrolysis volatiles.
Biocompatible PEG Grafting on DLC-coated Nitinol Alloy for Vascular Stents
Authors: Shin Hong-Sub , Park Kwideok , Ji Heung Kim  , Kim Jae-Jin , Dong Keun Han  , Moon Myoung-Woon , Lee Kwang-Ryeol , Ji Hoon Shin
Published: July 2009

The surfaces of Nitinol (TiNi), a popular metal alloy for arterial stents were thin-coated with diamond-like carbon (DLC) and then grafted with poly(ethylene glycol) (PEG) to increase biocompatibility. The TiNi control, DLC-coated TiNi (TiNi—DLC), and the PEG-grafted TiNi—DLC (TiNi—DLC—PEG) surface characteristics and biocompatibility were evaluated. The hydrophilicity of the TiNi—DLC—PEG significantly increased and the amount of both oxygen and nitrogen on the TiNi—DLC—PEG also increased compared to the TiNi control and TiNi—DLC due to the grafted PEG. The ratio between albumin and fibrinogen was higher on the PEG-grafted surface than the other surfaces when tested with human blood components; the platelet adhesion decreased the most on the TiNi—DLC—PEG surface, indicating improved blood compatibility. For in vivo tests using a rat model, the samples that were implanted for 6 weeks formed fibrous tissue; the tissue layer was much thinner on the PEG-grafted sample than the other two groups. The present results indicate that PEG-grafted TiNi—DLC surface may be effective in enhancing biocompatibility of blood-contacting biomaterials including vascular stents.
Electroresponsive Polyacrylamide-grafted-xanthan Hydrogels for Drug Delivery
Authors: Kulkarni Raghavendra V. , Sa Biswanath
Published: July 2009

An electroresponsive drug delivery system was developed using poly(acrylamide-grafted-xanthan gum) (PAAm-g-XG) hydrogel for transdermal delivery of ketoprofen. The electrically sensitive PAAm-g-XG copolymer was synthesized by free radical polymerization under nitrogen atmosphere followed by alkaline hydrolysis. When a swollen PAAm-g-XG hydrogel was placed in between a pair of electrodes, deswelling of the hydrogel was observed in the vicinity of electrodes carrying the electric stimulus. The membrane-controlled drug delivery systems were prepared using drug-loaded PAAm-g-XG hydrogel as the reservoir and crosslinked with poly(vinyl alcohol) to form films as rate controlling membranes (RCM). The in vitro drug permeation study from the formulations was performed through excised rat abdominal skin. Drug permeation across the skin was greatly enhanced in the presence of electric stimulus as compared to passive diffusion and was found to be dependent upon the applied electric current strength and crosslink density of RCM. A pulsated pattern of drug release was observed as the electric stimulus was switched `on' and `off.' The skin histopathology study demonstrated that, after the application of an electrical stimulus, there were changes in the structure of stratum corneum and cell structure. These PAAm-g-XG hydrogel could be useful as transdermal drug delivery systems actuated by an electric signal to provide on-demand release of drugs.
Matrix Gene Expression in Dermal Fibroblasts Cultured on Hyaluronan-coated Polysulfone Membranes
Authors: Attia J. , Boumédiène K. , Pujol J.P. , Valleton J.M. , Huet E. , Nguyen Q.T.
Published: July 2009

Polysulfone (PSU) membranes, coated and uncoated hyaluronan (HA), were compared for their ability to allow dermal fibroblast express genes related to extracellular matrix synthesis and remodeling. Fibroblasts type I and type III collagens were studied on both types of membranes; only type I collagen was synthesized on control cultures in plastic Petri dishes, whereas type III collagen was also expressed on PSU membranes. Expression of metalloproteinase (MMP)1, MMP3, and MMP2 was enhanced on PSU and HA-coated PSU membranes, with a lower level of MMP2 on HA-covered membranes. These membranes promote fetal-like matrices that provide good support for skin wound healing as well as favor nonscarring tissue repair.
Chitosan/Alginate Multilayer Scaffold Encapsulating Bone Marrow Stromal Cells In Situ on Titanium
Authors: Wu Ming-Yue , Ning Chen  , Liu Lai-Kui , Hua Yuan  , Li Quan-Li , Chen Shou-Hui
Published: July 2009

A biofilm-like scaffold with bone marrow stromal cells (BMSC) encapsulated in situ was constructed on a titanium surface using a layer-by-layer self-assembly technique for the potential application for dental or joint implant. The scaffold was formed by depositing a single layer of positively charged poly(L-lysine) on a negatively charged NaOH-treated titanium substrate, followed by alternate immersion into a negatively charged alginate—BMSC suspension and positively charged chitosan solution, respectively, and terminated a layer of chitosan. The cell-encapsulated scaffolds were evaluated by scanning electron microscopy and confocal laser scanning microscopy. The BMSC remained viable and grew well in the scaffold. This approach provides a method for the preparation of tissue engineering scaffold on titanium surfaces.
Rechargeable Antibacterial and Antifungal Polymeric Silver Sulfadiazines
Authors: Zhengbing Cao  , Xinbo Sun  , Yuyu Sun  , Hao Fong
Published: July 2009

Poly(methyl methacrylate) (PMMA)-based rechargeable antibacterial and antifungal polymeric silver sulfadiazines were prepared by copolymerizing acryloyl sulfadiazine with methyl methacrylate and sequentially treating the copolymers with dilute silver nitrate aqueous solutions. The chemical structures of the samples were characterized by FT-IR, 1H-NMR, XPS, and TGA analyses. On contact, the PMMA-based polymeric silver sulfadiazines provided 100% inactivation of 108—109 CFU/mL of Escherichia coli (Gram-negative bacteria) and Staphylococcus aureus (Gram-positive bacteria) in 10 min, and Candida tropicalis (yeast) in 30 min. Kirby—Bauer test data indicated that the antibacterial and antifungal effects were achieved through contact kill; no silver ions leached out of the new copolymers. The antibacterial and antifungal functions were stable for at least 12 months under normal storage conditions. Silver nitrate treatments regenerated any lost of antibacterial and antifungal activity; this recharging can be repeated as needed to achieve long-term protection. These properties make the new PMMA-based polymeric silver sulfadiazines attractive candidates for a broad range of medical (orthopedic), dental, and other related applications to reduce the risks of bacterial and fungal contamination on high-touch/high-risk surfaces and foreign body-related infections.
Polypropylene Nanocomposites with Thermally Stable Imidazolium Modified Clay: Mechanical Modeling and Effect of Compatibilizer
Authors: Mittal V.
Published: July 2009

Thermally stable imidazolium modification as compared to the conventional ammonium modification is chosen to prepare polypropylene nanocomposites. Different volume fractions of organo-montmorillonite are used to generate polymer nanocomposites and the effect of the modified clay on mechanical properties is studied. The mechanical properties are also compared with Halpin—Tsai models and its modified versions to achieve better insight into the system. Addition of small amount of compatibilizer enhanced the extent of delamination of the filler. Compatibilizers are selected on the basis of their chemical nature, molecular weight, amount of grafting, and location of the polar groups. Incompatibility of the surface modification with the compatibilizer is suspected to counterbalance the delamination effect thus resulting in no change or deterioration of the oxygen permeation through the composite films. However, the tensile modulus is enhanced on addition of comaptibilizer owing to increased exfoliation, which exceeded the amount of matrix plasticization caused by the addition of the low-molecular weight compatibilizer. The compatibilizers neither affected the crystallization behavior of polymer nor the thermal behavior of the resulting composite.
Helping Them Live Until They Die: Volunteer Practices in Palliative Home Care
Authors: Sévigny Andrée , Dumont Serge , Cohen S. Robin , Frappier Annie
Published: June 2009

Volunteers traditionally play an essential role in palliative care. Without them, many community and institutional programs would not survive. Despite the significant number of volunteers involved in palliative care, the nature and scope of their actions remain ambiguous. The blurred boundaries of their contribution create tensions between professionals, families, and volunteers with regards to patient care and sharing of responsibilities. This article reports on a comprehensive and descriptive qualitative study aimed at understanding volunteer practices in home palliative care in Canada through analysis of volunteers’ discourse. The conceptual framework not only allows for a description of volunteer practices but also for an understanding of those practices in terms of the meaning volunteers ascribe to their actions and interactions. The information gathered provides a better understanding of the place of volunteers within the palliative care system, thereby allowing communities to optimize their contribution to the palliative care mission.
Participation and competence as joint components in a cross-national analysis of scientific citizenship
Authors: Mejlgaard Niels , Stares Sally
Published: June 2009

Recent years have witnessed a ‘democratic turn’ towards active citizen participation in science and technology. The emerging participatory approach has been framed as a critique of a reductionist, outdated ‘deficit model’ of citizen competence, literacy or understanding. Participatory modes of citizen involvement with science are presented as competing rather than complementary in offering a strategy for making science and technology accountable and open to society. We use latent class models to develop cross-national measures of competence and participation, and explore the relation between the two. We argue that the question of how to analyze and assess the role of citizens in knowledge societies should not be an either/or — participation or competence — but a matter of understanding the balance and interconnected-ness of both. We suggest that the idea of a ‘scientific citizenship’ could be a useful integrative notion to bridge the divide between concerns about public participation and public competence.
The Royal Chapel in Iberia
Authors: Costa-Gomes Rita
Published: July 2009

This article analyses the main aspects of the activities of the late medieval royal chapel, comparing several Iberian Christian monarchies. Three definitions of the chapel were proposed since medieval times: the chapel as a collection of liturgical objects, as the human group devoted to the king's service by performing the Christian cult, and as a specific space inside royal residences. All three were put to use for the reproduction of the specific position of kings in Christian societies, as it was expressed in liturgical activities and in devotional practices. Common patterns and mutual influences are analysed, and the example of two ceremonial practices shows that these were more current than it has been argued by historians of the early modern period.
MST With Conduct Disordered Youth in Sweden: Costs and Benefits After 2 Years
Authors: Olsson Tina M.
Published: June 2009

Objectives: The purpose of this study was to investigate the costs and benefits associated with multisystemic therapy (MST) for conduct disordered youth, 2 years following intake. Methods: The study employed a secondary analysis of 156 youth enrolled in a randomized trial assessing the psychosocial and behavioral outcomes of MST. Results: MST cost on average 105,400 SEK per youth. MST was associated with a direct benefit to participants of 1,000 SEK per youth and positively impacted the use of nonplacement downstream interventions for a benefit of 62,100 SEK per youth. These benefits did not offset the cost of MST. Conclusions: MST was associated with a net loss to society after 2 years of 44,500 SEK per youth.
A Study on the Effect of the Stress State on Ductile Fracture
Authors: Xiaosheng Gao  , Guihua Zhang  , Roe Charles
Published: June 2009

The main purpose of this paper is to demonstrate that besides the stress triaxiality parameter, the Lode angle, which can be related to the third invariant of the deviatoric stress tensor, also has an important effect on ductile fracture. This is achieved by conducting a series of micromechanics analyses of void-containing unit cells and experimental-numerical studies of carefully designed specimens experiencing a wide range of stress states. As a result, a fracture criterion is expressed in terms of the equivalent failure strain as a function of the stress triaxiality and the Lode angle (or the third invariant of the stress deviator) and this function is calibrated for a DH36 steel plate.
Pharmacogenetic Impact of VKORC1 and CYP2C9 Allelic Variants on Warfarin Dose Requirements in a Hispanic Population Isolate
Authors: Palacio Lina , Falla Diana , Tobon Ignacio , Mejia Fernando , Lewis John E. , Martinez Ariel F. , Arcos-Burgos Mauricio , Camargo Mauricio
Published: July 2009

Warfarin is the most prescribed oral anticoagulant worldwide. Because of the complexity of warfarin therapy, we attempted to dissect genetic from bioenvironmental factors influencing warfarin dose responses in individuals of a genetic isolate of Hispanic ancestry. A total of 191 patients with standard values of international normalized ratio were recruited. Three groups with a significantly different warfarin dose response were identified, that is, sensitive (2.28 ± 0.50 mg/d), intermediate (4.2 ± 0.76 mg/d), and resistant (7.40 ± 1.54 mg/d; Tukey test, P < .001). Age had a significant inverse correlation with warfarin dose (P < .001; effective dose diminished 0.56 mg/d/decade). Required doses were higher for individuals with CYP2C9 variants containing the allele *1 compared to those individuals with variants composed of other alleles (P = .006). Similarly, individuals with VKORC1-1639GG and VKORC1-1639GA genotypes also required higher doses compared to the AA genotype (P < .001). Evaluation of potential gene-gene interactions between CYP2C9 and VKORC1 polymorphisms showed significant differences in dosing for CYP2C9 genotypes within the VKORC1-1639G/A subgroup (P = .013). A stepwise multivariate linear regression analysis showed that 38.2% of the warfarin dose response variance was accounted for by a model involving age (20.9%), VKORC1-1639G/A (11.3%), and CYP2C9*1, *2, and *3 variants (7.1%). These results corroborate previous findings on warfarin pharmacogenetics and define a contrastable gene-bioenvironment interaction model suited to be used in Hispanic populations.
Optimal Control of a Flexible Beam with Multiple Time Delays
Authors: Long-Xiang Chen , Guo-Ping Cai
Published: June 2009

In this paper, active control of a flexible cantilever beam with multiple time delays is studied, where a controller is designed using a discrete optimal control method and piezoelectric patches are used as actuators. Firstly, the state equation of controlled modes of the system with multiple time delays is obtained using modal orthogonality. Then, the state equation is discretized and transformed into a standard form without any explicit time delay by a particular augmenting for state variables. A continuous performance index is also discretized into a standard discrete form that is a function of the augmented states. So, the discrete controller may be designed based on the augmented system. In every step of computation for the controller, it contains not only the current step of state feedback but also a linear combination of some former steps of controls. Simulation results indicate that the system may suffer from instability at a small time delay if the time delay is not treated. It may be well compensated by the proposed controller and good control effectiveness may be obtained simultaneously. In addition, the proposed controller may possibly obtain better control effectiveness than the controller with no time delay.
Analytical Evaluation of Dynamic Responses of Time-varying Systems
Authors: Li Q.S.
Published: June 2009

An analytical approach for forced vibration of single-degree-of-freedom (SDOF) systems with arbitrary time-dependent parameters is presented. Unlike most of the previous studies on this topic, the function for describing the variation of mass of a SDOF system with time is an arbitrary continuous or piecewise real-valued function, and the variation of stiffness with time is expressed as a functional relation with the variation of mass and vice versa. Using appropriate functional transformation, the closed-form homogeneous solutions of the governing differential equations for forced vibrations of such a SDOF system with continuous time variable parameters (mass and stiffness) are derived for 10 important cases. The particular solutions of the non-homogeneous differential equations are determined based on the Lagrange method. Furthermore, the proposed exact method and solutions are developed to analyze the forced vibration of SDOF systems with multi-step (piecewise) non-periodical variable parameters. A numerical example illustrating the application of the proposed method shows that the proposed exact procedure is an efficient method.
Vibration Suppression Control of Beam-cart System with Piezoelectric Transducers by Decomposed Parallel Adaptive Neuro-fuzzy Control
Authors: Lin J. , Chao W.-S.
Published: June 2009

The main goal of this research is to develop a novel approach for achieving a high performance piezoelectric vibration absorber. Motion and control of a Bernoulli-Euler beam fixed on a moving cart will be analyzed in this study. The moving cart is mounted on the ball-screw mechanism system. Dynamic formulation for control purposes is first investigated for such a beam-cart system in this research. The controller has two separate feedback loops for positioning and damping, and the vibration suppression controller is independent of linear motion stage positioning control. The decomposed parallel fuzzy control with adaptive neuro-fuzzy concept has also been proposed for this research. An experimental device was constructed, constituted of a flexible cantilever aluminum beam type structure with piezoelectric patches symmetrically bonded on both sides to provide structural bending. Strip-bender type piezoelectric patches were attached to the surface of the beam to serve as actuators and sensor, respectively. Experimental validation for such a structure demonstrates the effectiveness of the proposed controller. The results of this study can be feasible to various mechanical systems, such as high tower cranes, ladder cars or overhead cranes.
Optimization of Sandwich Panels to Blast Pulse Loading
Authors: Icardi U. , Ferrero L.
Published: July 2009

In this article, the optimization of the face sheet layers is carried out finding a spatially variable distribution of the stiffness properties that minimize the interlaminar stresses. The optimal orientation of the reinforcement fibers is the solution to the Euler—Lagrange equations representing the stationary conditions for the energy contributions under in-plane variation of plate stiffness coefficients. A refined multilayered plate model with a high-order, piecewise variation of displacements across the thickness is employed, that fulfill both the interfacial stress and displacement contact conditions, with the purpose to accurately and efficiently simulate the interlaminar stresses at the interfaces with the core.
Work on Impact Properties of Foam Sandwich Composites with Different Structure
Authors: Fan Xia  , Xiao Qing Wu
Published: July 2009

Foam core sandwich composites with various facings composed of glass, carbon woven, carbon/Kevlar hybrid, and Kevlar fabrics were fabricated by using RTM process, as well as the through-thickness stitched sandwich samples with glass fabrics; and impact performance was studied at three energy levels. This article proposes that the damage extent of foam core sandwich construction may be characterized by the average damage angle, penetration depth, and maximal cracking width. The results show that the foam core samples with Kevlar facing are optimal for the peak load at load—time plots and the lowest impact damage extent at the same energy level. Compared to the unstitched samples, the average damage angle of stitched samples increases by 48%, the maximal cracking width and penetration depth of stitched samples decrease by 67% and 4% at 25J impact energy level.
Traumatic hip dislocation in adults
Authors: Deakin DE , Porter K.
Published: July 2009

Traumatic hip dislocation occurs during high-energy trauma and is often associated with other life threatening injuries. Dislocation can be anterior or posterior and urgent reduction is mandatory to reduce the risk of avascular necrosis of the femoral head. Undisplaced femoral neck fractures should be excluded prior to attempted reduction. Various closed reduction techniques have been described and most dislocations can be reduced with a closed technique. Failure to achieve reduction makes open reduction mandatory. This review describes the diagnosis, investigation and management of this complex and challenging injury.
Numerical and Experimental Studies of a Substructural Identification Strategy
Authors: Tee K.F. , Koh C.G. , Quek S.T.
Published: July 2009

For structural health monitoring it is impractical to identify a large structure with complete measurement due to limited number of sensors and difficulty in field instrumentation. Furthermore, it is not desirable to identify a large number of unknown parameters in a full system because of numerical difficulty in convergence. A novel substructural strategy was presented for identification of stiffness matrices and damage assessment with incomplete measurement. The substructural approach was employed to identify large systems in a divide-and-conquer manner. In addition, the concept of model condensation was invoked to avoid the need for complete measurement, and the recovery process to obtain the full set of parameters was formulated. The efficiency of the proposed method is demonstrated numerically through multi-storey shear buildings subjected to random force. A fairly large structural system with 50 DOFs was identified with good results, taking into consideration the effects of noisy signals and the limited number of sensors. Two variations of the method were applied, depending on whether the sensor could be repositioned. The proposed strategy was further substantiated experimentally using an eight-storey steel plane frame model subjected to shaker and impulse hammer excitations. Both numerical and experimental results have shown that the proposed substructural strategy gave reasonably accurate identification in terms of locating and quantifying structural damage.
Structural prerequisites for endotoxic activity in the Limulus test as compared to cytokine production in mononuclear cells
Authors: Gutsmann T. , Howe J. , Zähringer U. , Garidel P. , Schromm A.B. , Koch M.H.J. , Fujimoto Y. , Fukase K. , Moriyon I. , Martínez-de-Tejada G. , Brandenburg K.
Published: July 2009

The structural prerequisites for lipopolysaccharide (LPS) and its partial structures for the activation of the Limulus clotting cascade (Limulus amebocyte lysate [LAL] test) are described and compared with the corresponding requirements for the activation of human immune cells such as mononuclear cells. A necessary, but not sufficient, structural motif for this is the presence of the 4′-phosphate-diglucosamine backbone recognition structure (‘epitope’) in lipid A. High activity is only expressed by assemblies of endotoxins, but this is largely independent of the type of supramolecular aggregate structure. A particular conformation of the epitope within the lipid A assembly must be present, which is influenced by addition of further saccharide units to the lipid A moiety, but also reacts slightly to the acylation pattern. In contrast, the cytokine production of human immune cells induced by LPS sensitively depends on the type of its aggregate structure. In the case of a hexa-acylated bisphosphorylated lipid A structure, high activity is only observed with cubic inverted aggregates. Furthermore, addition of antimicrobial agents (such as polymyxin B) leads to a nearly complete inhibition of cytokine production, whereas the reduction in the Limulus assay is much lower. These data are important since a reliable determination of endotoxin concentrations, in particular with respect to its ability to elicit severe infections, is of high interest.
High blood pressure in Latin America: a call to action
Authors: Rubinstein Adolfo , Alcocer Luis , Chagas Antonio
Published: June 2009

High blood pressure (BP) is an enormous global problem, and is especially challenging for low- and middle-income countries such as those of Latin America. Although developed countries have benefited from significant reductions in cardiovascular and cerebrovascular disease in recent decades, comparable reductions have not been achieved in Latin America. In fact, the prevalence of high BP is increasing in many Latin American countries, and the situation will worsen without definitive efforts to correct it. The growing preponderance of hypertension and chronic diseases, coupled with expected increases in population growth, present a mounting threat to Latin American economies. This report provides a comprehensive overview of the burden of high BP throughout Latin America, and presents recommendations for change. The dismal observations warrant a call to action for improved control of high BP and other cardiovascular risk factors across Latin America. Achieving these ambitious goals will require collaborative efforts by many groups, including policymakers, international organizations, healthcare providers, schools and society as a whole.
Osseointegration evaluation of plasma nitrided titanium implants
Authors: Guerra Neto C. L. B. , da Silva M. A. M. , Alves C.
Published: June 2009

There is a need for new techniques that modify metallic implant surfaces, resulting in good bone response for low density areas. Among the different techniques, plasma nitriding is being applied in biomedicine with excellent results. However, its use in titanium dental implants is very limited owing to high process temperatures (between 700 and 800°C) that result in distortions. In order to solve this problem, the authors used a new plasma method with a hollow cathode discharge configuration. Ti grade II dental implants were nitrided in a 20% N2–H2 atmosphere at a temperature of 450°C, 150 Pa (1·5 mbar), for 1 h and inserted into rabbit tibias to assess osseointegration. The results showed that plasma nitriding caused a significant change in the surface texture of the nitrided implants and greater removal torque than that of the control implants.
Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells
Authors: Calado Rodrigo T. , Yewdell William T. , Wilkerson Keisha L. , Regal Joshua A. , Kajigaya Sachiko , Stratakis Constantine A. , Young Neal S.
Published: June 2009

Androgens have been used in the treatment of bone marrow failure syndromes without a clear understanding of their mechanism of action. Blood counts of patients with dyskeratosis congenita or aplastic anemia with mutations in telomerase genes can improve with androgen therapy. Here we observed that exposure in vitro of normal peripheral blood lymphocytes and human bone marrow–derived CD34+ cells to androgens increased telomerase activity, coincident with higher TERT mRNA levels. Cells from patients who were heterozygous for telomerase mutations had low baseline telomerase activity, which was restored to normal levels by exposure to androgens. Estradiol had an effect similar to androgens on TERT gene expression and telomerase enzymatic activity. Tamoxifen abolished the effects of both estradiol and androgens on telomerase function, and letrozole, an aromatase inhibitor, blocked androgen effects on telomerase activity. Conversely, flutamide, an androgen receptor antagonist, did not affect androgen stimulation of telomerase. Down-regulation by siRNA of estrogen receptor-α (ERα), but not ERβ, inhibited estrogen-stimulated telomerase function. Our results provide a mechanism for androgen therapy in bone marrow failure: androgens appear to regulate telomerase expression and activity mainly by aromatization and through ERα. These findings have potential implications for the choice of current androgenic compounds and the development of future agents for clinical use.
BIO5192, a small molecule inhibitor of VLA-4, mobilizes hematopoietic stem and progenitor cells
Authors: Ramirez Pablo , Rettig Michael P. , Uy Geoffrey L. , Deych Elena , Holt Matthew S. , Ritchey Julie K. , DiPersio John F.
Published: July 2009

Here we show that interruption of the VCAM-1/VLA-4 axis with a small molecule inhibitor of VLA-4, BIO5192, results in a 30-fold increase in mobilization of murine hematopoietic stem and progenitors (HSPCs) over basal levels. An additive affect on HSPC mobilization (3-fold) was observed when plerixafor (AMD3100), a small molecule inhibitor of the CXCR-4/SDF-1 axis, was combined with BIO5192. Furthermore, the combination of granulocyte colony-stimulating factor (G-CSF), BIO5192, and plerixafor enhanced mobilization by 17-fold compared with G-CSF alone. HSPCs mobilized by BIO5192 or the combination of BIO5192 and plerixafor mobilized long-term repopulating cells, which successfully engraft and expand in a multilineage fashion in secondary transplantation recipients. Splenectomy resulted in a dramatic enhancement of G-CSF–induced mobilization while decreasing both plerixafor- and BIO5192-induced mobilization of HSPCs. These data provide evidence for the utility of small molecule inhibitors of VLA-4 either alone or in combination with G-CSF or AMD3100 for mobilization of hematopoietic stem and progenitor cells.
Programming tumor-reactive effector memory CD8+ T cells in vitro obviates the requirement for in vivo vaccination
Authors: Klebanoff Christopher A. , Yu Zhiya , Hwang Leroy N. , Palmer Douglas C. , Gattinoni Luca , Restifo Nicholas P.
Published: June 2009

Naive and memory CD8+ T cells can undergo programmed activation and expansion in response to a short T-cell receptor stimulus, but the extent to which in vitro programming can qualitatively substitute for an in vivo antigen stimulation remains unknown. We show that self-/tumor-reactive effector memory CD8+ T cells (TEM) programmed in vitro either with peptide-pulsed antigen-presenting cells or plate-bound anti-CD3/anti-CD28 embark on a highly stereotyped response of in vivo clonal expansion and tumor destruction nearly identical to that of vaccine-stimulated TEM cells. This programmed response was associated with an interval of antigen-independent interferon-γ (IFN-γ) release that facilitated the dynamic expression of the major histocompatibility complex class I restriction element H-2Db on responding tumor cells, leading to recognition and subsequent tumor lysis. Delaying cell transfer for more than 24 hours after stimulation or infusion of cells deficient in IFN-γ entirely abrogated the benefit of the programmed response, whereas transfer of cells unable to respond to IFN-γ had no detriment to antitumor immunity. These findings extend the phenomenon of a programmable effector response to memory CD8+ T cells and have major implications for the design of current adoptive-cell transfer trials.
Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations
Authors: Jabbour Elias , Jones Daniel , Kantarjian Hagop M. , O'Brien Susan , Tam Constantine , Koller Charles , Burger Jan A. , Borthakur Gautam , Wierda William G. , Cortes Jorge
Published: July 2009

Secondary imatinib resistance in chronic myeloid leukemia (CML) is associated in approximately 50% of cases with mutations in the BCR-ABL kinase domain, necessitating switch to one of several new tyrosine kinase inhibitors (TKIs) that act differentially on mutated BCR-ABL. We assess here whether scoring mutation based on in vitro inhibitory concentration of each TKI-mutation pair can predict long-term clinical outcome. Among 169 patients with CML after imatinib failure, mutations were detected before TKI switch in 41 (48%) treated with dasatinib and 45 (52%) treated with nilotinib. Inhibitory concentration values for each TKI-mutation pair were stratified into high (n = 42), intermediate (n = 25), low (T315I, n = 9), or unknown sensitivity (n = 10). Hematologic and cytogenetic response rates were similar for patients with or without mutations. For patients in chronic phase, hematologic and cytogenetic responses correlated with mutation score; tumors with low and intermediate scores had lower response rates than those with highly sensitive mutations, and worse event-free and overall survival. These correlations with overall survival were not seen for advanced phases. Mutation scoring can predict outcome in CML-chronic phase with imatinib failure treated with second-generation TKIs and can help in therapy selection. More complex prognostic models will be required for advanced stages of disease.
Generation and phenotypic analysis of protein S–deficient mice
Authors: Saller François , Brisset Anne C. , Tchaikovski Svetlana N. , Azevedo Monica , Chrast Roman , Fernández José A. , Schapira Marc , Hackeng Tilman M. , Griffin John H. , Angelillo-Scherrer Anne
Published: July 2009

Protein S (PS) is an important natural anticoagulant with potentially multiple biologic functions. To investigate further the role of PS in vivo, we generated Pros+/− heterozygous mice. In the null (−) allele, the Pros exons 3 to 7 have been excised through conditional gene targeting. Pros+/− mice did not present any signs of spontaneous thrombosis and had reduced PS plasma levels and activated protein C cofactor activity in plasma coagulation and thrombin generation assays. Tissue factor pathway inhibitor cofactor activity of PS could not be demonstrated. Heterozygous Pros+/− mice exhibited a notable thrombotic phenotype in vivo when challenged in a tissue factor–induced thromboembolism model. No viable Pros−/− mice were obtained through mating of Pros+/− parents. Most E17.5 Pros−/− embryos were found dead with severe intracranial hemorrhages and most likely presented consumptive coagulopathy, as demonstrated by intravascular and interstitial fibrin deposition and an increased number of megakaryocytes in the liver, suggesting peripheral thrombocytopenia. A few E17.5 Pros−/− embryos had less severe phenotype, indicating that life-threatening manifestations might occur between E17.5 and the full term. Thus, similar to human phenotypes, mild heterozygous PS deficiency in mice was associated with a thrombotic phenotype, whereas total homozygous deficiency in PS was incompatible with life.
Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens
Authors: Kumar Shaji , Giralt Sergio , Stadtmauer Edward A. , Harousseau Jean L. , Palumbo Antonio , Bensinger William , Comenzo Raymond L. , Lentzsch Suzanne , Munshi Nikhil , Niesvizky Ruben , San Miguel Jesus , Ludwig Heinz , Bergsagel Leif , Blade Joan , Lonial Sagar , Anderson Kenneth C. , Tosi Patrizia , Sonneveld Pieter , Sezer Orhan , Vesole David , Cavo Michele , Einsele Hermann , Richardson Paul G. , Durie Brian G. M. , Rajkumar S. Vincent
Published: June 2009

The past decade has witnessed a paradigm shift in the initial treatment of multiple myeloma with the introduction of novel agents such as thalidomide, lenalidomide, and bortezomib, leading to improved outcomes. High-dose therapy and autologous stem cell transplantation remains an important therapeutic option for patients with multiple myeloma eligible for the procedure. Before the advent of the novel agents, patients underwent stem cell collection prior to significant alkylating agent exposure, given its potential deleterious effect on stem cell collection. With increasing use of the novel agents in the upfront setting, several reports have emerged raising concerns about their impact on the ability to collect stem cells. An expert panel of the International Myeloma Working Group (IMWG) was convened to examine the implications of these therapies on stem collection in patients with myeloma and to develop recommendations for addressing these issues. Here we summarize the currently available data and present our perspective on the problem and potential options to overcome this problem. Specifically, we recommend early mobilization of stem cells, preferably within the first 4 cycles of initial therapy, in patients treated with novel agents and encourage participation in clinical trials evaluating novel approaches to stem cell mobilization.
Phylogeography of the Alcippe morrisonia(Aves: Timaliidae): long population history beyond late Pleistocene glaciations
Authors: Song Gang , Qu Yanhua , Yin Zuohua , Li Shouhsien , Liu Naifa , Lei Fumin
Published: June 2009

Background

The role of Pleistocene glacial oscillations in current biodiversity and distribution patterns varies with latitude, physical topology and population life history and has long been a topic of discussion. However, there had been little phylogeographical research in south China, where the geophysical complexity is associated with great biodiversity. A bird endemic in Southeast Asia, the Grey-cheeked Fulvetta,Alcippe morrisonia, has been reported to show deep genetic divergences among its seven subspecies. In the present study, we investigated the phylogeography ofA. morrisoniato explore its population structure and evolutionary history, in order to gain insight into the effect of geological events on the speciation and diversity of birds endemic in south China.

Results

Mitochondrial genes cytochrome b (Cytb) and cytochrome c oxidase I (COI) were represented by 1236 nucleotide sites from 151 individuals from 29 localities. Phylogenetic analysis showed seven monophyletic clades congruent with the geographically separated groups, which were identified as major sources of molecular variance (90.92%) by AMOVA. TCS analysis revealed four disconnected networks, and that no haplotype was shared among the geographical groups. The common ancestor of these populations was dated to 11.6 Mya and several divergence events were estimated along the population evolutionary history. Isolation by distance was inferred by NCPA to be responsible for the current intra-population genetic pattern and gene flow among geographical groups was interrupted. A late Pleistocene demographic expansion was detected in the eastern geographical groups, while the expansion time (0.2–0.4 Mya) was earlier than the Last Glacial Maximum.

Conclusion

It is proposed that the complicated topology preserves high genetic diversity and ancient lineages for geographical groups ofA. morrisoniain China mainland and its two major islands, and restricts gene exchange during climate oscillations. Isolation by distance seems to be an important factor of genetic structure formation within geographical populations. Although glacial influence to population fluctuation was observed in late Pleistocene, it seems that populations in eastern China were more susceptible to climate change, and all geographical groups were growing stably through the Last Glacial Maximum. Coalescence analysis suggested that the ancestor ofA. morrisoniamight be traced back to the late Miocene, and the current phylogeographical structure ofA. morrisoniais more likely to be attributable to a series geological events than to Pleistocene glacial cycles.
Integration of Bayesian molecular clock methods and fossil-based soft bounds reveals early Cenozoic origin of African lacertid lizards
Authors: Hipsley Christy A , Himmelmann Lin , Metzler Dirk , Müller Johannes
Published: July 2009

Background

Although current molecular clock methods offer greater flexibility in modelling evolutionary events, calibration of the clock with dates from the fossil record is still problematic for many groups. Here we implement several new approaches in molecular dating to estimate the evolutionary ages of Lacertidae, an Old World family of lizards with a poor fossil record and uncertain phylogeny. Four different models of rate variation are tested in a new program for Bayesian phylogenetic analysis called TreeTime, based on a combination of mitochondrial and nuclear gene sequences. We incorporate paleontological uncertainty into divergence estimates by expressing multiple calibration dates as a range of probabilistic distributions. We also test the reliability of our proposed calibrations by exploring effects of individual priors on posterior estimates.

Results

According to the most reliable model, as indicated by Bayes factor comparison, modern lacertids arose shortly after the K/T transition and entered Africa about 45 million years ago, with the majority of their African radiation occurring in the Eocene and Oligocene. Our findings indicate much earlier origins for these clades than previously reported, and we discuss our results in light of paleogeographic trends during the Cenozoic.

Conclusion

This study represents the first attempt to estimate evolutionary ages of a specific group of reptiles exhibiting uncertain phylogenetic relationships, molecular rate variation and a poor fossil record. Our results emphasize the sensitivity of molecular divergence dates to fossil calibrations, and support the use of combined molecular data sets and multiple, well-spaced dates from the fossil record as minimum node constraints. The bioinformatics program used here, TreeTime, is publicly available, and we recommend its use for molecular dating of taxa faced with similar challenges.
Discovery of novel inhibitors of Streptococcus pneumoniae based on the virtual screening with the homology-modeled structure of histidine kinase (VicK)
Authors: Li Nan , Wang Fei , Niu Siqiang , Cao Ju , Wu Kaifeng , Li Youqiang , Yin Nanlin , Zhang Xuemei , Zhu Weiliang , Yin Yibing
Published: June 2009

Background

Due to the widespread abusage of antibiotics, antibiotic-resistance in Streptococcus pneumoniae (S. pneumoniae) has been increasing quickly in recent years, and it is obviously urgent to develop new types of antibiotics. Two-component systems (TCSs) are the major signal transduction pathways in bacteria and have emerged as potential targets for antibacterial drugs. Among the 13 pairs of TCSs proteins presenting in S. pneumoniae, VicR/K is the unique one essential for bacterium growth, and block agents to which, if can be found, may be developed as effective antibiotics against S. pneumoniae infection.

Results

Using a structure-based virtual screening (SBVS) method, 105 compounds were computationally identified as potential inhibitors of the histidine kinase (HK) VicK protein from the compound library SPECS. Six of them were then validated in vitro to be active in inhibiting the growth of S. pneumoniae without obvious cytotoxicity to Vero cell. In mouse sepsis models, these compounds are still able to decrease the mortality of the mice infected by S. pneumoniae and one compound even has significant therapeutic effect.

Conclusion

To our knowledge, these compounds are the first reported inhibitors of HK with antibacterial activity in vitro and in vivo, and are novel lead structures for developing new drugs to combat pneumococcal infection.