bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimized surgical techniques and postoperative care improve survival rates and permit accurate telemetric recording in exercising mice
Authors: Schuler Beat , Rettich Andreas , Vogel Johannes , Gassmann Max , Arras Margarete
Published: August 2009

Background

The laboratory mouse is commonly used as a sophisticated model in biomedical research. However, experiments requiring major surgery frequently lead to serious postoperative complications and death, particularly if genetically modified mice with anatomical and physiological abnormalities undergo extensive interventions such as transmitter implantation. Telemetric transmitters are used to study cardiovascular physiology and diseases. Telemetry yields reliable and accurate measurement of blood pressure in the free-roaming, unanaesthetized and unstressed mouse, but data recording is hampered substantially if measurements are made in an exercising mouse. Thus, we aimed to optimize transmitter implantation to improve telemetric signal recording in exercising mice as well as to establish a postoperative care regimen that promotes convalescence and survival of mice after major surgery in general.

Results

We report an optimized telemetric transmitter implantation technique (fixation of the transmitter body on the back of the mouse with stainless steel wires) for subsequent measurement of arterial blood pressure during maximal exercise on a treadmill. This technique was used on normal (wildtype) mice and on transgenic mice with anatomical and physiological abnormalities due to constitutive overexpression of recombinant human erythropoietin. To promote convalescence of the animals after surgery, we established a regimen for postoperative intensive care: pain treatment (flunixine 5 mg/kg bodyweight, subcutaneously, twice per day) and fluid therapy (600 μl, subcutaneously, twice per day) were administrated for 7 days. In addition, warmth and free access to high energy liquid in a drinking bottle were provided for 14 days following transmitter implantation. This regimen led to a substantial decrease in overall morbidity and mortality. The refined postoperative care and surgical technique were particularly successful in genetically modified mice with severely compromised physiological capacities.

Conclusion

Recovery and survival rates of mice after major surgery were significantly improved by careful management of postoperative intensive care regimens including key supportive measures such as pain relief, administration of fluids, and warmth. Furthermore, fixation of the blood pressure transmitter provided constant reliable telemetric recordings in exercising mice.
Single cell cultures of Drosophila neuroectodermal and mesectodermal central nervous system progenitors reveal different degrees of developmental autonomy
Authors: Lüer Karin , Technau Gerhard M
Published: August 2009

Background

The Drosophila embryonic central nervous system (CNS) develops from two sets of progenitor cells, neuroblasts and ventral midline progenitors, which behave differently in many respects. Neuroblasts derive from the neurogenic region of the ectoderm and form the lateral parts of the CNS. Ventral midline precursors are formed by two rows of mesectodermal cells and build the CNS midline. There is plenty of evidence that individual identities are conferred to precursor cells by positional information in the ectoderm. It is unclear, however, how far the precursors can maintain their identities and developmental properties in the absence of normal external signals.

Results

To separate the respective contributions of autonomous properties versus extrinsic signals during their further development, we isolated individual midline precursors and neuroectodermal precursors at the pre-mitotic gastrula stage, traced their development in vitro, and analyzed the characteristics of their lineages in comparison with those described for the embryo. Although individually cultured mesectodermal cells exhibit basic characteristics of CNS midline progenitors, the clones produced by these progenitors differ from their in situ counterparts with regard to cell numbers, expression of molecular markers, and the separation of neuronal and glial fate. In contrast, clones derived from individually cultured precursors taken from specific dorsoventral zones of the neuroectoderm develop striking similarities to the lineages of neuroblasts that normally delaminate from these zones and develop in situ.

Conclusion

This in vitro analysis allows for the first time a comparison of the developmental capacities in situ and in vitro of individual neural precursors of defined spatial and temporal origin. The data reveal that cells isolated at the pre-mitotic and pre-delamination stage express characteristics of the progenitor type appropriate to their site of origin in the embryo. However, presumptive neuroblasts, once specified in the neuroectoderm, exhibit a higher degree of autonomy regarding generation of their lineages compared to mesectodermal midline progenitors.
Antigen delivery by α2-macroglobulin enhances the cytotoxic T lymphocyte response
Authors: Bowers Edith V , Horvath Jeffrey J , Bond Jennifer E , Cianciolo George J , Pizzo Salvatore V
Published: August 2009

α-2M*-mediated antigen delivery leads to cross-presentation and improved cell-mediated immunity, suggesting that α-2M* may have applications for vaccines based on weakly immunogenic subunits.

α2M* targets antigens to APCs for rapid internalization, processing, and presentation. When used as an antigen-delivery vehicle, α2M* amplifies MHC class II presentation, as demonstrated by increased antibody titers. Recent evidence, however, suggests that α2M* encapsulation may also enhance antigen-specific CTL immunity. In this study, we demonstrate that α2M*-delivered antigen (OVA) enhances the production of specific in vitro and in vivo CTL responses. Murine splenocytes expressing a transgenic TCR specific for CTL peptide OVA257–264 (SIINFEKL) demonstrated up to 25-fold greater IFN-γ and IL-2 secretion when treated in vitro with α2M*-OVA compared with soluble OVA. The frequency of IFN-γ-producing cells was increased ∼15-fold, as measured by ELISPOT. Expansion of the OVA-specific CD8+ T cell population, as assayed by tetramer binding and [3H]thymidine incorporation, and OVA-specific cell-mediated cytotoxicity, as determined by a flow cytometric assay, were also enhanced significantly by α2M*-OVA. Furthermore, significant CTL responses were observed at antigen doses tenfold lower than those required with OVA alone. Finally, we also observed enhanced humoral and CTL responses by naïve mice following intradermal immunization with α2M*-OVA. These α2M*-OVA-immunized mice demonstrated increased protection against a s.c.-implanted, OVA-expressing tumor, as demonstrated by delayed tumor growth and prolonged animal survival. The observation that α2M*-mediated antigen delivery elicits specific CTL responses suggests the cross-presentation of antigen onto MHC class I. These results support α2M* as an effective antigen-delivery system that may be particularly useful for vaccines based on weakly immunogenic subunits or requiring dose sparing.
Phase II Study of Sunitinib Administered in a Continuous Once-Daily Dosing Regimen in Patients With Cytokine-Refractory Metastatic Renal Cell Carcinoma
Authors: Escudier Bernard , Roigas Jan , Gillessen Silke , Harmenberg Ulrika , Srinivas Sandhya , Mulder Sasja F. , Fountzilas George , Peschel Christian , Flodgren Per , Maneval Edna Chow , Chen Isan , Vogelzang Nicholas J.
Published: August 2009

Purpose

Sunitinib has demonstrated antitumor activity in metastatic renal cell carcinoma (mRCC) when given at 50 mg/d on a 4-weeks-on 2-weeks-off regimen. Herein, we report results of an open-label, multicenter phase II mRCC study of sunitinib administered on a continuous once-daily dosing regimen.

Patients and Methods

Eligibility criteria included histologically proven mRCC with measurable disease, failure of one prior cytokine regimen, and good performance status. Patients were randomly assigned to a sunitinib starting dose of 37.5 mg/d in the morning (AM) or evening (PM). RECIST-defined objective response rate (ORR) was the primary end point. Secondary end points included progression-free survival (PFS), overall survival (OS), adverse events (AEs), and quality-of-life measures.

Results

One hundred seven patients were randomly assigned to AM (n = 54) or PM (n = 53) dosing and on study for a median 8.3 months. Eighty-three patients discontinued, 65 due to disease progression and 16 because of AEs; two patients withdrew consent. Dosing was reduced to 25 mg/d in 46 patients (43%) due to grade 3/4 AEs. The most common grade 3 treatment-related AEs were asthenia/fatigue (16%), diarrhea (11%), hypertension (11%), hand-foot syndrome (9%), and anorexia (8%). ORR was 20% with a 7.2-month median response duration. Median PFS and OS were 8.2 and 19.8 months, respectively, at median follow-up of 26.4 months. Efficacy, tolerability, and quality-of-life results were similar between patients dosed in the AM or PM.

Conclusion

Sunitinib 37.5 mg, administered on a continuous once-daily dosing regimen, has a manageable safety profile as second-line mRCC therapy, providing flexible dosing, which can be explored in combination studies.
Phase II-I-II Study of Two Different Doses and Schedules of Pralatrexate, a High-Affinity Substrate for the Reduced Folate Carrier, in Patients With Relapsed or Refractory Lymphoma Reveals Marked Activity in T-Cell Malignancies
Authors: O'Connor Owen A. , Horwitz Steven , Hamlin Paul , Portlock Carol , Moskowitz Craig H. , Sarasohn Debra , Neylon Ellen , Mastrella Jill , Hamelers Rachel , MacGregor-Cortelli Barbara , Patterson Molly , Seshan Venkatraman E. , Sirotnak Frank , Fleisher Martin , Mould Diane R. , Saunders Mike , Zelenetz Andrew D.
Published: August 2009

Purpose

To determine the maximum-tolerated dose (MTD) and efficacy of pralatrexate in patients with lymphoma.

Patients and Methods

Pralatrexate, initially given at a dose of 135 mg/m2 on an every-other-week basis, was associated with stomatitis. A redesigned, weekly phase I/II study established an MTD of 30 mg/m2 weekly for six weeks every 7 weeks. Patients were required to have relapsed/refractory disease, an absolute neutrophil greater than 1,000/μL, and a platelet count greater than 50,000/μL for the first dose of any cycle.

Results

The every-other-week, phase II experience was associated with an increased risk of stomatitis and hematologic toxicity. On a weekly schedule, the MTD was 30 mg/m2 weekly for 6 weeks every 7 weeks. This schedule modification resulted in a 50% reduction in the major hematologic toxicities and abrogation of the grades 3 to 4 stomatitis. Stomatitis was associated with elevated homocysteine and methylmalonic acid, which were reduced by folate and vitamin B12 supplementation. Of 48 assessable patients, the overall response rate was 31% (26% by intention to treat), including 17% who experienced complete remission (CR). When analyzed by lineage, the overall response rates were 10% and 54% in patients with B- and T-cell lymphomas, respectively. All eight patients who experienced CR had T-cell lymphoma, and four of the six patients with a partial remission were positron emission tomography negative. The duration of responses ranged from 3 to 26 months.

Conclusion

Pralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma.
Pre-Emptive Treatment With Rituximab of Molecular Relapse After Autologous Stem Cell Transplantation in Mantle Cell Lymphoma
Authors: Andersen Niels S. , Pedersen Lone B. , Laurell Anna , Elonen Erkki , Kolstad Arne , Boesen Anne Marie , Pedersen Lars M. , Lauritzsen Grete F. , Ekanger Roald , Nilsson-Ehle Herman , Nordström Marie , Fredén Susanne , Jerkeman Mats , Eriksson Mikael , Väärt Jaan , Malmer Beatrice , Geisler Christian H.
Published: August 2009

Purpose

Minimal residual disease (MRD) is predictive of clinical progression in mantle-cell lymphoma (MCL). According to the Nordic MCL-2 protocol we prospectively analyzed the efficacy of pre-emptive treatment using rituximab to MCL patients in molecular relapse after autologous stem cell transplantation (ASCT).

Patients and Materials

MCL patients enrolled onto the study, who had polymerase chain reaction (PCR) detectable molecular markers and underwent ASCT, were followed with serial PCR assessments of MRD in consecutive bone marrow and peripheral blood samples after ASCT. In case of molecular relapse with increasing MRD levels, patients were offered pre-emptive treatment with rituximab 375 mg/m2 weekly for 4 weeks.

Results

Of 160 MCL patients enrolled, 145 underwent ASCT, of whom 78 had a molecular marker. Of these, 74 were in complete remission (CR) and four had progressive disease after ASCT. Of the CR patients, 36 underwent a molecular relapse up to 6 years (mean, 18.5 months) after ASCT. Ten patients did not receive pre-emptive treatment mainly due to a simultaneous molecular and clinical relapse, while 26 patients underwent pre-emptive treatment leading to reinduction of molecular remission in 92%. Median molecular and clinical relapse-free survival after pre-emptive treatment were 1.5 and 3.7 years, respectively. Of the 38 patients who remain in molecular remission for now for a median of 3.3 years (range, 0.4 to 6.6 years), 33 are still in clinical CR.

Conclusion

Molecular relapse may occur many years after ASCT in MCL, and PCR based pre-emptive treatment using rituximab is feasible, reinduce molecular remission, and may prevent clinical relapse.
Follicular Lymphoma International Prognostic Index 2: A New Prognostic Index for Follicular Lymphoma Developed by the International Follicular Lymphoma Prognostic Factor Project
Authors: Federico Massimo , Bellei Monica , Marcheselli Luigi , Luminari Stefano , Lopez-Guillermo Armando , Vitolo Umberto , Pro Barbara , Pileri Stefano , Pulsoni Alessandro , Soubeyran Pierre , Cortelazzo Sergio , Martinelli Giovanni , Martelli Maurizio , Rigacci Luigi , Arcaini Luca , Di Raimondo Francesco , Merli Francesco , Sabattini Elena , McLaughlin Peter , Solal-Céligny Philippe
Published: August 2009

Purpose

The aim of the F2 study was to verify whether a prospective collection of data would enable the development of a more accurate prognostic index for follicular lymphoma (FL) by using parameters which could not be retrospectively studied before, and by choosing progression-free survival (PFS) as principal end point.

Patients and Methods

Between January 2003 and May 2005, 1,093 patients with a newly diagnosed FL were registered and 942 individuals receiving antilymphoma therapy were selected as the study population. The variables we used for score definition were selected by means of bootstrap resampling procedures on 832 patients with complete data. Procedures to select the model that would minimize errors were also performed.

Results

After a median follow-up of 38 months, 261 events for PFS evaluation were recorded. β2-microglobulin higher than the upper limit of normal, longest diameter of the largest involved node longer than 6 cm, bone marrow involvement, hemoglobin level lower than 12 g/dL, and age older than 60 years were factors independently predictive for PFS. Using these variables, a prognostic model was devised to identify three groups at different levels of risk. The 3-year PFS rate was 91%, 69%, and 51% for patients at low, intermediate, and high risk, respectively (log-rank = 64.6; P < .00001). The 3-year survival rate was 99%, 96%, and 84% for patients at low, intermediate, and high risk, respectively (P < .0001).

Conclusion

Follicular Lymphoma International Prognostic Index 2 is a simple prognostic index based on easily available clinical data and may represent a promising new tool for the identification of patients with FL at different risk in the era of immunochemotherapy.
Pomalidomide Is Active in the Treatment of Anemia Associated With Myelofibrosis
Authors: Tefferi Ayalew , Verstovsek Srdan , Barosi Giovanni , Passamonti Francesco , Roboz Gail J. , Gisslinger Heinz , Paquette Ronald L. , Cervantes Francisco , Rivera Candido E. , Deeg H. Joachim , Thiele Juergen , Kvasnicka Hans M. , Vardiman James W. , Zhang Yanming , Bekele B. Nebiyou , Mesa Ruben A. , Gale Robert P. , Kantarjian Hagop M.
Published: August 2009

Purpose

Thalidomide and lenalidomide can alleviate anemia in myelofibrosis. However, their value is undermined by their respective potential to cause peripheral neuropathy and myelosuppression. We therefore evaluated the safety and therapeutic activity of another immunomodulatory drug, pomalidomide.

Methods

In a phase II randomized, multicenter, double-blind, adaptive design study, four treatment arms were evaluated: pomalidomide (2 mg/d) plus placebo, pomalidomide (2 mg/d) plus prednisone, pomalidomide (0.5 mg/d) plus prednisone, and prednisone plus placebo. Pomalidomide was administered for up to 12 28-day treatment cycles. Prednisone (30 mg/d) was given in a tapering dose schedule during the first three cycles. Response was assessed by International Working Group criteria.

Results

Eighty-four patients with myelofibrosis-associated anemia were randomly assigned to the aforementioned treatment arms: 22, 19, 22, and 21, respectively. Response in anemia was documented in 20 patients, including 15 who became transfusion independent. Response rates in the four treatment arms were 23% (95% CI, 5% to 41%), 16% (95% CI, 0% to 33%), 36% (95% CI, 16% to 56%), and 19% (95% CI, 2% to 36%). The corresponding figures for patients receiving ≥ 3 cycles of treatment (n = 62) were 38%, 23%, 40%, and 25%. Response to pomalidomide with or without prednisone was durable (range, 3.2 to 16.9+ months) and significantly better in the absence of leukocytosis (37% v 8%; P = .01); JAK2V617F or cytogenetic status did not affect response. Grade ≥ 3 toxicities were infrequent and included (in each treatment arm) neutropenia (9%; 16%; 5%; 5%), thrombocytopenia (14%; 16%; 9%; 5%), and thrombosis (9%; 5%; 0%; 0%).

Conclusion

Pomalidomide therapy at 0.5 or 2 mg/d with or without an abbreviated course of prednisone is well tolerated in patients with myelofibrosis and active in the treatment of anemia.
Phase II, Multicenter, Uncontrolled Trial of Single-Agent Sorafenib in Patients With Relapsed or Refractory, Advanced Non–Small-Cell Lung Cancer
Authors: Blumenschein George R. , Gatzemeier Ulrich , Fossella Frank , Stewart David J. , Cupit Lisa , Cihon Frank , O'Leary James , Reck Martin
Published: August 2009

Purpose

Sorafenib is an oral multikinase inhibitor that targets the Ras/Raf/MEK/ERK mitogenic signaling pathway and the angiogenic receptor tyrosine kinases, vascular endothelial growth factor receptor 2 and platelet-derived growth factor receptor β. We evaluated the antitumor response and tolerability of sorafenib in patients with relapsed or refractory, advanced non–small-cell lung cancer (NSCLC), most of whom had received prior platinum-based chemotherapy.

Patients and Methods

This was a phase II, single-arm, multicenter study. Patients with relapsed or refractory advanced NSCLC received sorafenib 400 mg orally twice daily until tumor progression or an unacceptable drug-related toxicity occurred. The primary objective was to measure response rate.

Results

Of 54 patients enrolled, 52 received sorafenib. The predominant histologies were adenocarcinoma (54%) and squamous cell carcinoma (31%). No complete or partial responses were observed. Stable disease (SD) was achieved in 30 (59%) of the 51 patients who were evaluable for efficacy. Four patients with SD developed tumor cavitation. Median progression-free survival (PFS) was 2.7 months, and median overall survival was 6.7 months. Patients with SD had a median PFS of 5.5 months. Major grades 3 to 4, treatment-related toxicities included hand-foot skin reaction (10%), hypertension (4%), fatigue (2%), and diarrhea (2%). Nine patients died within a 30-day period after discontinuing sorafenib, and one patient experienced pulmonary hemorrhage that was considered drug related.

Conclusion

Continuous treatment with sorafenib 400 mg twice daily was associated with disease stabilization in patients with advanced NSCLC. The broad activity of sorafenib and its acceptable toxicity profile suggest that additional investigation of sorafenib as therapy for patients with NSCLC is warranted.
Predictive Capacity of Three Comorbidity Indices in Estimating Mortality After Surgery for Colon Cancer
Authors: Hines Robert B. , Chatla Chakrapani , Bumpers Harvey L. , Waterbor John W. , McGwin Gerald , Funkhouser Ellen , Coffey Christopher S. , Posey James , Manne Upender
Published: August 2009

Purpose

Although, for patients with cancer, comorbidity can affect the timing of cancer detection, treatment, and prognosis, there is little information relating to the question of whether the choice of comorbidity index affects the results of studies. Therefore, to compare the association of comorbidity with mortality after surgery for colon cancer, this study evaluated the Adult Comorbidity Evaluation-27 (ACE-27), the National Institute on Aging (NIA) and National Cancer Institute (NCI) Comorbidity Index, and the Charlson Comorbidity Index (CCI).

Patients and Methods

The study population consisted of colon cancer patients (N = 496) who underwent surgery at the University of Alabama at Birmingham Hospital from 1981 to 2002. Hazard ratios (HRs) with 95% CIs were obtained using the method of Cox proportional hazards for the three comorbidity indices in predicting overall and colon cancer–specific mortality. The point estimates obtained for comorbidity and other risk factors across the three models were compared.

Results

For each index, the highest comorbidity burden was significantly associated with poorer overall survival (ACE-27: HR = 1.63; 95% CI, 1.24 to 2.15; NIA/NCI: HR = 1.83; 95% CI, 1.29 to 2.61; CCI: HR = 1.46; 95% CI, 1.14 to 1.88) as well as colon cancer–specific survival. For the other risk factors, there was little variation in the point estimates across the three models.

Conclusion

The results obtained from these three indices were strikingly similar. For patients with severe comorbidity, all three indices were statistically significant in predicting shorter survival after surgery for colon cancer.
Reference Point: Samuel Johnson and the Encyclopedias the David Fleeman Memorial Lecture, 2007
Authors: Tankard Paul
Published: August 2009

Samuel Johnson was interested in encyclopedias, and in his own lifetime, encyclopedias were interested in him. This essay examines five eighteenth-century encyclopedias: Rees's revision of Chambers' Cyclopaedia (1778-86), Kippis's revised Biographia Britannica (1777-93), and the first three editions of the Encyclopaedia Britannica (1768-71, 1777-84, 1788-97). In these five works, I have located 121 articles in which Johnson is mentioned or quoted as an authority; by giving a sense of the character of his presence, the essay traces the evolution of his reputation. The essay also draws attention to a number of curious details, including early critiques of Johnson's work, and mentions of Johnsonian publications or attributions that have been sometimes overlooked. The whole is intended to be a contribution to the understanding of Johnson's near-contemporary reception and reputation.
Preserved Remains: Embalming Practices in Eighteenth-Century England
Authors: Zigarovich Jolene
Published: August 2009

This paper looks at the cultural discourse of embalming in the eighteenth century. Not uncommon, embalming was performed, improved, and commercialized. From mummy unrollings, to churchyard reorderings, to public viewings of “curiosities,” the embalmed were often exposed to public circulation and commodification. As a mortuary practice, embalming spread beyond royal tradition, infiltrating the burial rites of the wealthy and aristocratic in an effort to preserve social distinction posthumously, demonstrating the increasing preoccupation with mortality and the corpse, and the intense anxiety about bodily dissolution after death. And at this time, the religious connotation of the uncorrupted corpse becomes translated into the endorsement of preservation as a guarantee that the body and soul will be properly rejoined in the afterlife. In medical terms, surgical innovations demanded improved embalming procedures that inevitably played a part in the rise of the task for the undertaker. This essay maintains that the curious history of preservation techniques in eighteenth-century Britain ultimately contributes to the understanding of a culture's attitudes towards death, the body, and representation.
Modelling and control of a SCARA robot using quantitative feedback theory
Authors: Amiri-M Amir-A , Gharib M R , Moavenian M , Torabiz K
Published: August 2009

In this paper, a practical method to design a robust controller for a SCARA robot using quantitative feedback theory (QFT) is proposed. The models used to describe robots contain uncertainties that are the result of insufficient knowledge on the dynamics of the robot, external disturbances, pay load changes, and friction, etc. Thus, the application of robust control methods to create the precise control of robots is of considerable interest. This paper considers a robot arm manipulator, a system whose models contain non-linear coupled transfer functions. In the first step of applying the QFT technique the non-linear plant is converted into a family of linear uncertain plants. This is achieved using a fixed-point theorem and then suitable disturbance rejection bounds are found. A robust controller is designed for the tracking problem. Non-linear simulations on the tracking problem for a three-dimension elliptical path are performed and the results highlight the success of the designed controllers and pre-filters. The presented results indicate that applying the proposed technique successfully overcomes the obstacles to robust control of non-linear SCARA robots.
Passivity-based control of linear switched reluctance motors
Authors: Yang J M , Li H P , Jin X , Liu J , Zhao S W , Zhong Q , Cheung N C
Published: August 2009

In this paper, a non-linear controller for linear switched reluctance motors (LSRMs) is developed by utilizing their properties and the energy dissipation theory. As the electrical time constant is much smaller than the mechanical time constant, the whole LSRM driving system can be treated as a two-time-scale system. It is then decomposed into an electrical subsystem and a mechanical subsystem, which are interconnected by negative feedbacks. Controllers for these two subsystems are designed to guarantee that both systems are passive. Because a system consisting of two passive subsystems connected through negative feedbacks is still passive as a whole, stability of an LSRM driving system can be achieved at system level. The proposed control strategy is characterized by a simple structure and easy implementation. Experimental results are also provided to prove the effectiveness and robustness of the proposed position control for LSRM.
Practical approach to dependence modelling using copulas
Authors: Dutfoy A , Lebrun R
Published: August 2009

Modelling the stochastic dependence between random inputs of a system is of uttermost importance for a sensible evaluation of its reliability. Most of the time, this modelling is made using some linear correlation coefficients. The current paper underlines the potential pitfalls of such an approach and gives a short introduction to the concept of copula, which appears to be the exact concept of stochastic dependence from a theoretical point of view.

From a practical point of view, the identification of the copula of a multi-dimensional random vector can be challenging. After a short presentation of the concept of measure of association, the current paper introduces the new concept of dependence information as a multi-scalar synthesis of the copula. Thanks to several numerical simulations, it proposes first practical rules to select a copula for the dependence modelling, based on specific dependence information and the expected reliability level of the system under study.
Methodological developments for probabilistic risk analyses of socio-technical systems
Authors: Léger A , Weber P , Levrat E , Duval C , Farret R , Iung B
Published: August 2009

Nowadays, the risk analysis of critical systems cannot be focused only on a technical dimension. Indeed, well-known accidents in nuclear or aerospace areas underlined initiating causes also related to technical and organizational viewpoints. This led to the development of methods for risk assessment considering three main aspects on the system resources: the technical process, the operator constraining the process, and the organization constraining human actions on the process. However, only few scientific works have tried to join these methods in a unique and global approach. Thus this paper focuses on a methodology that aims to achieve the integration of the different methods in order to assess the risks probabilistically. The integration is based on (a) system knowledge structuring and (b) its unified modelling by means of Bayesian networks also supporting quantification and simulation phases. The methodology is applied to an industrial case to show its feasibility and to draw conclusions regarding the model relevance for system risk analysis. The results of the methodology can be used by decision makers to prioritize their actions when faced with potential or real risks.
Product Line Pricing in a Supply Chain
Authors: Dong Lingxiu , Narasimhan Chakravarthi , Zhu Kaijie
Published: August 2009

A vertically integrated channel would prefer to coordinate the pricing of its products. In this paper, we investigate drivers of product line pricing decisions in a bilateral monopoly where a manufacturer produces and sells two substitutable or complementary products to a retailer. In a two-stage game, each firm commits credibly in the first stage to a pricing scheme within its own organization: product line pricing (PLP) or nonproduct line pricing (NPLP). In the second stage, depending on the relative balance of power in the supply chain, the firms engage in either a Nash or a leader-follower pricing game. We study the equilibrium of the two-stage game under a general symmetric demand function. With strategic interaction between firms, a firm may choose NPLP as the equilibrium pricing strategy. In particular, when the second stage is a leader-follower game, the price leader chooses PLP, and the follower may choose NPLP only if the inefficiency of using NPLP empowers the follower by increasing the demand sensitivity to the leader's margin. When the second stage is a vertical Nash game, whether NPLP occurs in equilibrium depends on the nature of coupling between demand interdependence and vertical strategic dependence: NPLP can be an equilibrium only if products are demand substitutes (complements) and vertical strategic dependencies are complementary (substitutable). We find that prisoner's dilemma exists in the first stage for both types of second-stage pricing games. In those cases, one firm may have the incentive to commit to a pricing scheme in the first stage prior to its channel partner and steer the supply chain away from prisoner's dilemma.
A Breath of Fresh Air? Firm Type, Scale, Scope, and Selection Effects in Drug Development
Authors: Arora Ashish , Gambardella Alfonso , Magazzini Laura , Pammolli Fabio
Published: August 2009

This paper compares the innovation performance of established pharmaceutical firms and biotech companies, controlling for differences in the scale and scope of research. We develop a structural model to analyze more than 3,000 drug research and development projects advanced to preclinical and clinical trials in the United States between 1980 and 1994. Key to our approach is careful attention to the issue of selection. Firms choose which compounds to advance into clinical trials. This choice depends not only on the technical promise of the compound, but also on commercial considerations such as the expected profitability of the market or concerns about product cannibalization. After controlling for selection, we find that (a) even after controlling for scale and scope in research, established pharmaceutical firms are more innovative than newly entered biotech firms; (b) older biotech firms display selection behaviors and innovation performances similar to established pharmaceutical firms; and (c) compounds licensed during preclinical trials are as likely to succeed as internal compounds of the licensor, which is inconsistent with the “lemons” hypothesis in technology markets.
Multifunctional oxide nanostructures by metal-organic chemical vapor deposition (MOCVD)
Authors: Weiss François , Audier Marc , Bartasyte Ausrine , Bellet Daniel , Girardot Cécile , Jimenez Carmen , Kreisel Jens , Pignard Stéphane , Salaun Mathieu , Ternon Céline
Published: August 2009

The development of thin films, in the context of ongoing reduction in the size of electronic systems, poses challenging questions for the materials sciences of multifunctional nanostructures. These include the limits of size reduction, integration of heterogeneous functions, and system characterization or process control at an atomic scale. We present here different studies devoted to perovskite oxide materials (or materials with derived structure), where in specific directions of the crystal structure the atomic organization decreases down to a few nanometers, thus building nanostructures. In these materials, very original physical phenomena are observed in multilayers or superlattices, nanowires (NWs) or nanodots, mainly because strain, surfaces, and interfaces play here a predominant role and can tune the physical properties. Metal-organic chemical vapor deposition (MOCVD) routes have been used for the synthesis of oxide materials. We first introduce the basic rules governing the choice of metal-organic precursors for the MOCVD reaction. Next we discuss the principles of the pulsed injection MOCVD system. A laser-assisted MOCVD system, designed to the direct growth of 2D and 3D photonic structures, will also be described. Selected case studies will finally be presented, illustrating the powerful development of different oxide nanostructures based on dielectric, ferroelectric, or superconducting oxides, manganites, and nickelates, as well as first results related to the growth of ZnO NWs.
Toward defining materials chemistry (IUPAC Technical Report)
Authors: Day Peter , Interrante Leonard V. , West Anthony R.
Published: August 2009

This report describes the results of a Project whose goals were to "assemble, collate and disseminate information about the scope of the newly-emerging discipline of materials chemistry, leading to an authoritative definition of the subject within the family of chemical sciences" and further, as a corollary, "to recommend to IUPAC how this new discipline might best be represented within the IUPAC structure". The history and current status of the research and teaching, only recently labeled as "materials chemistry", is described. This field has become one of the major growth sectors in pure and applied chemistry and now accounts for a significant fraction of all publications in the chemical sciences, based on measures such as journal citations and submitted papers and journals that are devoted entirely or in part to this subject. Nonetheless, there is still considerable confusion about what does, and does not, fall within the scope of "materials chemistry", and there is no consensus regarding a definition for the subject. After examining existing definitions for "chemistry" and "materials science" and considering prior attempts to define the subject, the following working definition for "materials chemistry" was suggested: "Materials chemistry comprises the application of chemistry to the design, synthesis, characterization, processing, understanding and utilisation of materials, particularly those with useful, or potentially useful, physical properties." In conclusion, the report suggests that IUPAC consider elevating this field from its current Subdivision status to that of "a cross-divisional Committee that would work with all the current IUPAC Divisions to develop and co-sponsor new projects, in the area of chemical education, nomenclature, terminology, health and safety, etc., that will increase the recognition of the current and future importance of this field to the international chemistry community".
Spatiotemporal Delivery Strategies for Promoting Musculoskeletal Tissue Regeneration
Authors: Guldberg Robert E
Published: August 2009

A primary regenerative medicine strategy is to stimulate or augment endogenous repair mechanisms that promote functional restoration of damaged or degenerated tissues. There is increasing evidence that maximizing the potency of tissue regenerative therapies will require design and development of delivery approaches that provide controlled spatiotemporal release of key signaling molecules. Guidance on which factors to deliver and the timing of delivery is emerging from advances in understanding of critical pathways involved in the development of integrated musculoskeletal tissues. A broad range of biomaterials-based deployment technologies are becoming available that allow controlled spatial presentation and release kinetics of biological cues. The purpose of this perspective article is to review promising spatiotemporal delivery strategies designed to promote functional tissue regeneration with an emphasis on vascularized bone repair.
Concentration of adipogenic and proinflammatory cytokines in the bone marrow supernatant fluid of osteoporotic women
Authors: Pino Ana María , Ríos Susana , Astudillo Pablo , Fernández Mireya , Figueroa Paula , Seitz Germán , Rodríguez J Pablo
Published: August 2009

Osteoporosis is characterized by low bone mass, microarchitectural deterioration of bone tissue leading to increased bone fragility, and a resulting susceptibility to fractures. Distinctive environmental bone marrow conditions appear to support the development and maintenance of the unbalance between bone resorption and bone formation; these complex bone marrow circumstances would be reflected in the fluid surrounding bone marrow cells. The content of regulatory molecules in the extracellular fluid from the human bone marrow is practically unknown. Since the content of cytokines such as adiponectin, leptin, osteoprogeterin (OPG), soluble receptor activator of nuclear factor κB ligand (s-RANKL), tumor necrosis factor α, and interleukin 6 (IL-6) may elicit conditions promoting or sustaining osteoporosis, in this work we compared the concentrations of the above-mentioned cytokines and also the level of the soluble receptors for both IL-6 and leptin in the extracellular fluid from the bone marrow of nonosteoporotic and osteoporotic human donors. A supernatant fluid (bone marrow supernatant fluid [BMSF]) was obtained after spinning the aspirated bone marrow samples; donors were classified as nonosteoporotic or osteoporotic after dual-energy X-ray absorptiometry (DXA) measuring. Specific commercially available kits were used for all measurements. The cytokines' concentration in BMSF showed differently among nonosteoporotic and osteoporotic women; this last group was characterized by higher content of proinflammatory and adipogenic cytokines. Also, osteoporotic BMSF differentiated by decreased leptin bioavailability, suggesting that insufficient leptin action may distinguish the osteoporotic bone marrow. © 2010 American Society for Bone and Mineral Research
Contribution of Trabecular and Cortical Components to Biomechanical Behavior of Human Vertebrae: An Ex Vivo Study
Authors: Roux Jean-Paul , Wegrzyn Julien , Arlot Monique E , Guyen Olivier , Delmas Pierre D , Chapurlat Roland , Bouxsein Mary L
Published: August 2009

Whereas there is clear evidence for a strong influence of bone quantity (i.e., bone mass or bone mineral density) on vertebral mechanical behavior, there are fewer data addressing the relative influence of cortical and trabecular bone microarchitecture. The aim of this study was to determine the relative contributions of bone mass, trabecular microarchitecture, and cortical thickness and curvature to the mechanical behavior of human lumbar vertebrae. Thirty-one L3 vertebrae (16 men, 15 women, aged 75 ± 10 years and 76 ± 10 years, respectively) were obtained. Bone mineral density (BMD) of the vertebral body was assessed by lateral dual energy X-ray absorptiometry (DXA), and 3D trabecular microarchitecture and anterior cortical thickness and curvature was assessed by micro-computed tomography (µCT). Then compressive stiffness, work to failure, and failure load were measured on the whole vertebral body. BMD was correlated with compressive stiffness (r = 0.60), failure load (r = 0.70), and work to failure (r = 0.55). Except for the degree of anisotropy, all trabecular and cortical parameters were correlated with mechanical behavior (r = 0.36 to 0.58, p = .05 to .001, and r = 0.36 to 0.61, p = .05 to .0001, respectively). Stepwise and multiple regression analyses indicated that the best predictor of (1) failure load was the combination of BMD, structural model index (SMI), and trabecular thickness (Tb.Th) (R = 0.80), (2) stiffness was the combination of BMD, Tb.Th, and curvature of the anterior cortex (R = 0.82), and (3) work to failure was the combination of anterior cortical thickness and BMD (R = 0.68). Our data imply that measurements of cortical thickness and curvature may enhance prediction of vertebral fragility and that therapies that improve both vertebral cortical and trabecular bone properties may provide a greater reduction in fracture risk. © 2010 American Society for Bone and Mineral Research
Computed tomographic measurements of thigh muscle cross-sectional area and attenuation coefficient predict hip fracture: The health, aging, and body composition study
Authors: Lang Thomas , Cauley Jane A , Tylavsky Frances , Bauer Douglas , Cummings Steven , Harris Tamara B
Published: August 2009

Fatty infiltration of muscle, myosteatosis, increases with age and results in reduced muscle strength and function and increased fall risk. However, it is unknown if increased fatty infiltration of muscle predisposes to hip fracture. We measured the mean Hounsfield unit (HU) of the lean tissue within the midthigh muscle bundle (thigh muscle HU, an indicator of intramuscular fat), its cross-sectional area (CSA, a measure of muscle mass) by computed tomography (CT), bone mineral density (BMD) of the hip and total-body percent fat by dual X-ray absorptiometry (DXA), isokinetic leg extensor strength, and the Short Physical Performance Battery (SPPB) in 2941 white and black women and men aged 70 to 79 years. Sixty-three hip fractures were validated during 6.6 years of follow-up. Proportional hazards regression analysis was used to assess the relative risk (RR) of hip fracture across variations in thigh muscle attenuation, CSA, muscle strength, and physical function for hip fracture. In models adjusted by age, race, gender, body mass index, and percentage fat, decreased thigh muscle HU resulted in increased risk of hip fracture [RR/SD = 1.58; 95% confidence interval (CI) 1.10–1.99], an association that continued to be significant after further adjustment for BMD. In models additionally adjusted by CSA, muscle strength, and SPPB score, decreased thigh muscle HU but none of the other muscle parameters continued to be associated with an increased risk of hip fracture (RR/SD = 1.42; 95% CI 1.03–1.97). Decreased thigh muscle HU, a measure of fatty infiltration of muscle, is associated with increased risk of hip fracture and appears to account for the association between reduced muscle strength, physical performance, and muscle mass and risk of hip fracture. This characteristic captures a physical characteristic of muscle tissue that may have importance in hip fracture etiology. © 2010 American Society for Bone and Mineral Research
Effects of denosumab in patients with bone metastases with and without previous bisphosphonate exposure
Authors: Body Jean-Jacques , Lipton Allan , Gralow Julie , Steger Guenther G , Gao Guozhi , Yeh Howard , Fizazi Karim
Published: August 2009

Bone metastases place patients at increased risk of skeletal-related events (SREs), including pathologic fractures, spinal cord compression, severe pain requiring radiotherapy or surgery, and hypercalcemia, because of increased osteoclast-mediated bone resorption. Denosumab, a fully human monoclonal antibody, decreases bone resorption by inhibiting RANKL, which mediates osteoclast activity. We compared the effects of denosumab in two phase 2 studies in patients with bone metastases naive to intravenous bisphosphonate therapy (IV BP; n = 255) and those with elevated levels of the bone resorption marker urinary N-telopeptide (uNTX) despite ongoing IV BP treatment (n = 111). Patients were randomized to receive IV BP every 4 weeks or subcutaneous denosumab every 4 weeks (30/120/180 mg) or every 12 weeks (60/180 mg). Patients treated with denosumab experienced a rapid and sustained reduction in bone turnover regardless of prior IV BP exposure. After 25 weeks, the median uNTX reduction was 75% (IV BP-naive) and 80% (prior IV BP) after denosumab treatment and 71% (IV BP-naive) and 56% (prior IV BP) in the IV BP arms. Denosumab patients with prior IV BP exposure had marked suppression of the osteoclast marker TRAP-5b (median reduction: denosumab 73%, IV BP 11%). SRE incidence was low across both studies. In patients previously treated with BPs, the rate of first on-study SRE was lower in the denosumab groups (8%) than the IV BP group (17%). Denosumab appeared to be well tolerated in both studies. Denosumab suppresses bone resorption markers independently of prior BP treatment, even in patients who appear to respond poorly to BPs. © 2010 American Society for Bone and Mineral Research.
Simulated resistance training during hindlimb unloading abolishes disuse bone loss and maintains muscle strength
Authors: Swift Joshua M , Nilsson Mats I , Hogan Harry A , Sumner Lindsay R , Bloomfield Susan A
Published: August 2009

This study was designed to determine the effectiveness of simulated resistance training (SRT) without weight bearing in attenuating bone and muscle loss during 28 day hindlimb unloading (HU) in mature male rats. An ambulatory control group (CC) and four groups of HU rats were used: HU, HU + anesthesia (ANHU), HU + eccentric muscle contractions (HU + ECC), and HU + isometric and eccentric muscle contractions (HU + ISO/ECC). Animals in the two SRT groups were trained once every other day at 100% daily peak isometric torque (P0). HU resulted in significantly lower plantarflexor muscle mass (−33% versus CC) and reduced isometric strength (−10%), which reductions were partially attenuated in both training groups. Significantly reduced total and cancellous volumetric bone mineral density (vBMD) and total bone mineral content (BMC) at the proximal tibia metaphysis (PTM) also was evidenced in HU and ANHU groups compared with both SRT groups (p < .05). Training resulted in greater increases in cortical bone mass and area compared with all other groups (p < .05). Fourfold higher material properties of PTM cancellous bone were demonstrated in SRT animals versus HU or CC animals. A significant reduction in midshaft periosteal bone formation rate (BFR) in the HU group (−99% versus CC) was completely abolished in HU + ECC (+656% versus CC). These results demonstrate that high-intensity muscle contractions, independent of weight-bearing forces, can effectively mitigate losses in muscle strength and provide a potent stimulus to bone during prolonged disuse. © 2010 American Society for Bone and Mineral Research.