bluuebunny/crossref_metadata_2025 huggingface dataset:
Trade, globalization and uneven development
Authors: Sheppard Eric
Published: July 2011

Mainstream geographical economics propagates the free trade doctrine, presenting capitalism as entailing, but capable of overcoming, uneven geographical development. Geographers have failed to engage with the international trade theories that rationalize this, or develop alternatives. Beginning with the entanglements through which trade happens, I examine how theories rationalizing the free trade doctrine isolate trade, mobilizing a narrow sociospatial ontology. Marxisant trade theories offer important critiques, but are similarly marred by limited sociospatial ontologies. By contrast, attending to the entanglements of trade, geographical political economy can decenter the free trade doctrine, creating space for taking seriously alternative trading imaginaries and practices.
Treatment of refractory chronic cluster headache by chronic occipital nerve stimulation
Authors: Fontaine Denys , Christophe Sol Jean , Raoul Sylvie , Fabre Nelly , Geraud Gilles , Magne Christine , Sakarovitch Charlotte , Lanteri-Minet Michel
Published: July 2011

Background: Greater occipital nerve stimulation (ONS) has been recently proposed to treat severe chronic cluster headache patients (CCH) refractory to medical treatment. We report the results of a French multidisciplinary cohort study.

Methods: Thirteen CCH patients were operated and data were collected prospectively. All of them suffered from CCH according to the International Headache Society classification, lasting for more than 2 years, refractory to pharmacological prophylactic treatment with adequate trials, with at least one daily attack. Chronic ONS was delivered through a subcutaneous occipital electrode connected to an implanted generator, in order to induce paraesthesias perceived locally in the lower occipital region.

Results: After surgery (mean follow-up 14,6 months), the mean attack frequency and intensity decreased by 68% and 49%, respectively. At last follow-up, 10/13 patients were considered as responders (improvement >50%). Prophylactic treatment could be stopped or reduced in 8/13 cases. Local infection occurred in one patient, leading to hardware removal.

Conclusions: Our data confirmed the results of the 36 similar cases reported in the literature, suggesting that ONS may act as a prophylactic treatment in chronic CH. Considering their respective risks, ONS should be proposed before deep brain stimulation in severe refractory CCH patients.
The Clinical Utility and Diagnostic Performance of Magnetic Resonance Imaging for Identification of Early and Advanced Knee Osteoarthritis
Authors: Quatman Carmen E. , Hettrich Carolyn M. , Schmitt Laura C. , Spindler Kurt P.
Published: July 2011

Background: Current diagnostic strategies for detection of structural articular cartilage abnormalities, the earliest structural signs of osteoarthritis, often do not capture the condition until it is too far advanced for the most potential benefit of noninvasive interventions.

Purpose: To systematically review the literature relative to the following questions: (1) Is magnetic resonance imaging (MRI) a valid, sensitive, specific, accurate, and reliable instrument to identify knee articular cartilage abnormalities compared with arthroscopy? (2) Is MRI a sensitive tool that can be utilized to identify early cartilage degeneration?

Study Design: Systematic review.

Methods: A systematic search was performed in November 2010 using PubMed MEDLINE (from 1966), CINAHL (from 1982), SPORTDiscus (from 1985), SCOPUS (from 1996), and EMBASE (from 1974) databases.

Results: Fourteen level I and 13 level II studies were identified that met inclusion criteria and provided information related to diagnostic performance of MRI compared with arthroscopic evaluation. The diagnostic performance of MRI demonstrated a large range of sensitivities, specificities, and accuracies. The sensitivity for identifying articular cartilage abnormalities in the knee joint was reported between 26% and 96%. Specificity and accuracy were reported between 50% and 100% and between 49% and 94%, respectively. The sensitivity, specificity, and accuracy for identifying early osteoarthritis were reported between 0% and 86%, 48% and 95%, and 5% and 94%, respectively. As a result of inconsistencies between imaging techniques and methodological shortcomings of many of the studies, a meta-analysis was not performed, and it was difficult to fully synthesize the information to state firm conclusions about the diagnostic performance of MRI.

Conclusion: There is evidence in some MRI protocols that MRI is a relatively valid, sensitive, specific, accurate, and reliable clinical tool for identifying articular cartilage degeneration. Because of heterogeneity of MRI sequences, it is not possible to make definitive conclusions regarding its global clinical utility for guiding diagnosis and treatment strategies.

Clinical Relevance: Traumatic sports injuries to the knee may be significant precursor events to early onset of posttraumatic osteoarthritis. Magnetic resonance imaging may aid in early identification of structural injuries to articular cartilage as evidenced by articular cartilage degeneration grading.
Closing the Gap Between Bench and Bedside Research for Early Arthritis Therapies (EARTH)
Authors: Chu Constance R. , Beynnon Bruce D. , Buckwalter Joseph A. , Garrett William E. , Katz Jeffrey N. , Rodeo Scott A. , Spindler Kurt P. , Stanton Robert A.
Published: July 2011

This report summarizes the 2010 AOSSM/NIH (American Orthopaedic Society for Sports Medicine/National Institutes of Health) U13 Post–Joint Injury Osteoarthritis II Conference to include the discussion concerning potential study cohorts, assessment considerations, and research priorities. There was strong consensus and enthusiasm for approaching the development of disease-modifying treatments for osteoarthritis through study of “pre-osteoarthritic” cohorts, particularly human subjects under 30 years of age following acute anterior cruciate ligament injuries. Clinical study of acute treatment strategies initiated within a few days after injury will need development of recruitment pathways and short-term proof-of-concept outcome measures that are specific to the intervention being studied. For example, measures of joint inflammation can be used in short-term prospective randomized controlled trials to determine whether an anti-inflammatory intervention was effective in decreasing early inflammation. These short-term clinical trials will need to be followed by longer-term evaluation of the clinical cohorts for joint and cartilage degeneration to determine if the acute intervention affected later development of osteoarthritis. Research priorities were identified in several disciplines, particularly regarding development and validation of quantitative imaging, biomechanics, and biomarker measures of joint structure, composition, and function that predict the accelerated development of osteoarthritis. Systematic study of posttraumatic osteoarthritis is anticipated to advance understanding and treatment of all forms of osteoarthritis.
J.S. Mill’s Views on Democracy after 1848
Authors: Grollios Vasilis
Published: July 2011

In his philosophical anthropology Mill assimilated a moderate form of capitalist values. Viewed from the perspective of class, this made it impossible for him to fully applaud socialism and democracy. Many commentators confuse these two terms and, as a result, do not understand that Mill tried to promote working class interests and its social power only to the extent that they would not assail the foundations of the capitalist mode of production. Contrary to these mainstream interpretations, in this article I emphasize that Mill’s views on democracy are strongly connected to the value-laden content that the capitalist mode of production contributes to exploitation, liberty and equality. As such, Mill was not a democrat but instead was afraid of a fully fledged democratic system because it would lead to socialism.
Multifidelity metamodel building as a route to aeroelastic optimization of flexible wings
Authors: Berci M , Gaskell P H , Hewson R W , Toropov V V
Published: July 2011

High-fidelity aeroelastic simulations of the response of flexible wings to a sudden gust can result in a huge computing effort, making the search for the best wing design prohibitively expensive. As an alternative, a cost-effective multifidelity metamodelling-based optimization strategy, where a metamodel of a high-fidelity aeroelastic simulation response is built by tuning a lower fidelity aeroelastic simulation response, is proposed. In order to address and validate such an approach, both linear and non-linear aeroelastic equations for an aerofoil employing different levels of complexity for expressing the aerodynamic load are used for the high- and low-fidelity models. An aeroelastic gust response evaluation problem is formulated for the flexible wing of a small unmanned air vehicle, whose characteristic size makes it particularly susceptible to gusts. Three different approaches to tune the low-fidelity model, both explicit and implicit, are investigated and compared. Good agreement between the high-fidelity model and the corrected low-fidelity one shows that the proposed approach is indeed suitable for optimization of the aeroelastic gust performance of flexible wings.
Nonlinear model predictive control of a dual-independent variable valve timing engine with electronic throttle control
Authors: Lee T-K , Filipi Z S
Published: July 2011

Significant excursions of engine variables occur during fast transients because of slow actuator responses and system dynamics. This creates adverse effects on dynamic performance and often causes emissions penalties. The challenge is particularly pronounced in engines with an increased number of actuators. In this paper, non-linear model predictive control (NMPC) is introduced to improve the dynamic response of a flexible engine system. NMPC combines advantages of both feed forward and feedback control while considering their constraints. The length of control horizon and prediction horizon are determined to achieve the dead-beat-like optimal control during transients and ensure smooth responses. The NMPC significantly improves the engine torque response and minimizes the excursions of in-cylinder variables under highly transient operation by adjusting each actuator control input simultaneously to achieve the control objectives.
Real-time modelling of transient operation of turbocharged diesel engines
Authors: Gambarotta A , Lucchetti G , Vaja I
Published: July 2011

In fact, nowadays the optimization of engines and powertrains towards cleaner, more fuel-efficient, and safer vehicles requires virtual tools for the simulation of the whole system well in advance of the design process. Moreover, management and diagnostic issues have key roles in the exploitation of the used technologies and solutions (e.g. double-stage turbocharging, and high- and low-pressure exhaust gas recirculation). Without forgetting the importance of experimental investigations, mathematical models are very useful tools to improve both the performance and the behaviour of engines and powertrains, with applications ranging from optimization of the system layout to definition and testing of control strategies.

Starting from a brief overview of actual mathematical tools for simulation of the transient operation of diesel engines, several considerations are reported on the modelling criteria and approaches with reference to fast zero-dimensional mean-value models of engines and powertrains. An original library that the present authors and co-workers have built up in recent years for the ‘real-time’ simulation of diesel engines is described, and several applications are reported. The presented models were validated and used to simulate the transient behaviour of typical automotive diesel engines.
Effect of canard stall on projectile roll and pitch damping
Authors: Montalvo C , Costello M
Published: July 2011

A computational and mathematical approach is used to investigate the effect of canard stall on projectile roll and pitch damping. For spinning projectiles with dithering canards, large angles of attack can be achieved by these canards. These large angles of attack can lead to stall that causes abnormal loads on the projectile. Because of these abnormalities, it is important to include the effects of stall on the projectile. First, the total roll and pitch moments of two canards is derived. These equations are then analysed to show that the effects of canard stall can produce a decrease in roll damping, causing roll rate to increase, and an increase in pitch damping, causing the no roll frame pitch rate to decrease. To validate this analysis, simulation is performed using a fully non-linear six-degree-of-freedom dynamic model with canard aerodynamics. The results from the simulation agree with the equations derived; thus, for projectiles that use dithering canards for control, it is important to include these non-linear effects in the projectile dynamic model.
Towards the design of cognitive functions in self-optimizing systems exemplified by a hybrid energy storage system
Authors: Dumitrescu R , Gausemeier J , Romaus C
Published: July 2011

Within the last years, mechatronics as a discipline has shaped the development of complex technical systems. Mechatronics consists of the close interaction of mechanics, electronics, control engineering and software engineering in order to achieve a better system behaviour. Due to the advances in deployment of information and communication technologies, the functionality of mechatronic systems will go far beyond the known standards with the intention to increase their robustness, flexibility and reliability. The paradigm that expresses this development is called self-optimization. Self-optimizing systems react autonomously to changing environmental conditions and optimize their behaviour during operation. The design of such systems is an interdisciplinary task. Engineers in the different fields of mechatronics have to work closely with experts from mathematical optimization and artificial intelligence. Furthermore, self-optimizing systems adopt information processing functions, which are known as cognitive functions. Even though more theories of the modelling of cognitive behaviour in technical systems are being developed and published, an applicable support of the system engineers is missing. Already the identification of self-optimization and appropriate cognitive functions area challenge. This contribution presents an approach to design cognitive functions in self-optimizing systems and its example application to a hybrid energy storage system as a subsystem of an innovative railway vehicle.
Best Practices for the Nonpharmacological Treatment of Depression at the End of Life
Authors: Stagg Emily Kathryn , Lazenby Mark
Published: July 2011

This literature review summarizes the current research on nonpharmacological management of depressive symptoms for patients nearing the end of their lives. Research suggests that major depressive disorder may affect terminally ill adults at a disproportionately high rate. Psychotherapy has not been shown to have consistent benefits among patients in the final months of life. Semi-psychotherapeutic (life review) techniques are likely most effective in patients in the final weeks of life. Non-psychotherapeutic techniques such as hypnotherapy have not been studied sufficiently to be recommended as first-line treatments. Based on the current research, it is our recommendation that psychotherapy be used first-line in patients with approximately 6 months or more to live, and that semi-psychotherapeutic techniques be first-line in patients with 6 months or less to live.
Three-dimensional vibration analysis of functionally graded thick, annular plates with variable thickness via polynomial-Ritz method
Authors: Tajeddini Vahid , Ohadi Abdolreza
Published: July 2011

In this paper, free vibration analysis of functionally graded thick, annular plates with linear and nonlinear thickness variation along the radial direction is investigated by using the polynomial-Ritz method. The material properties of the functionally graded plates are assumed to be graded in the thickness direction according to the power-law distribution in terms of the volume fractions of the constituents. The solution procedure is based on the linear, small strain, three-dimensional elasticity theory. Potential (strain) and kinetic energies of the plates are formulated, and the polynomial-Ritz method is used to solve the eigenvalue problem. In this analysis method, a set of orthogonal polynomial series for three displacement components in a cylindrical polar coordinate are used to extract an eigenvalue equation yielding natural frequencies. Upper bound convergence of the non-dimensional frequencies to the exact values within at least four significant digits is demonstrated. Numerical results are presented and compared with the available literature. The vibration frequencies are given in several examples for various boundary conditions for the first time.
Does Gender Moderate the Relationship Between Childhood Maltreatment and Adult Depression?
Authors: Arnow Bruce A. , Blasey Christine M. , Hunkeler Enid M. , Lee Janelle , Hayward Chris
Published: July 2011

Although considerable evidence demonstrates that adults who report childhood maltreatment are at increased risk of depression in adulthood, little is known about whether gender moderates risk. In a sample of 5,673 adult Health Maintenance Organization (HMO) patients, the authors employed the Patient Health Questionnaire-8 (PHQ-8) to assess major depressive disorder (MDD) and the Childhood Trauma Questionnaire (CTQ) to assess five different types of childhood maltreatment: emotional, physical, and sexual abuse, as well as emotional and physical neglect. Logistic regression models tested the main and interactive effects of gender and childhood maltreatment. Consistent with previous studies, men and women with histories of each type of childhood adversity were significantly more likely to meet criteria for MDD. However, the authors found no evidence that gender moderates the risk of depression. These findings suggest that men and women reporting history of childhood maltreatment are equally likely to suffer major depression in adulthood.
Tribological properties of glass fibre-reinforced Nylon 66 and quenched ductile iron against Al2O3 counterpart under oilfield water lubrication
Authors: An J , Su Z G , Gao X X , Wen Z
Published: July 2011

The friction and wear properties of glass fibre-reinforced polyamide 66 composite, quenched QT600-3 ductile iron were investigated against ceramic Al2O3 on the pin-on-disc testing machine under oilfield water-lubricated condition. Optical microscope, scanning electron microscopy, Fourier transform infrared spectrometer, digital temperature measurement system, and X-ray photoelectron spectroscope were used to characterize the microstructure, worn surface, and binding energy of C=O and C–C bonds for the studied materials. The GF/Nylon 66 composite had lower coefficient of friction than the quenched ductile iron, but it exhibited inferior wear resistance to the quenched QT600-3 ductile iron under oilfield water-lubricated condition, which was ascribed to combination of thermal softening, degradation of Nylon matrix, micro-ploughing, and tearing caused by hard Al2O3 disc during the wear testing.
Lack of support structures in prioritization decision making concerning patients and resources. Interviews with Swedish physicians
Authors: Werntoft Elisabet , Edberg Anna-Karin
Published: July 2011

Aim: To investigate physicians’ experiences in relation to prioritization and financing in health care in order to gain a deeper understanding of the reasons behind their standpoints. Methods: Eighteen physicians, seven women and eleven men, aged 30 to 69 years were interviewed and the text was analyzed using an inductive approach, also described as conventional qualitative content analysis. Results: Experience of setting healthcare priorities and difficult decision making differed widely among the physicians and seemed to be related to the number of years in professional practice. Their view of how resources should be allocated between disciplines/patients showed that they wanted politicians to make the decisions, with support from medical professions. The overwhelming impression of their reasoning showed that they lacked support structures for their decision making and could be understood under the following categories: Prioritisation, easier in theory than in practice, and Increasing costs threaten the Swedish welfare model. Conclusions: The findings of this study highlight the importance of practical national guidelines concerning vertical prioritization, also as an important measure to make prioritization more distinct and transparent. The physicians further had a need for tools to increase patients’ awareness of their health. The findings of this study also showed that an awareness of the actual costs involved might increase the responsibility among both physicians and patients. The physicians’ lack of support structures implies an urgent need for practical national guidelines, especially concerning vertical prioritization. This will also make prioritization appear clear and transparent for citizens.
The Role of Community-Based Organizations in Adolescent Sexual Health Promotion
Authors: Fisher Christopher M. , Reece Michael , Wright Eric , Dodge Brian , Sherwood-Laughlin Catherine , Baldwin Kathleen
Published: July 2011

Many scholars and practitioners have advocated for a more ecological approach to sexual health promotion for adolescents, such as one that includes involvement from schools, parents, and community organizations. Although extensive research has been conducted with schools and parents, little is known about the roles community-based organizations (CBOs) may play in the education and promotion of sexual health to young people. This study aimed to (a) identify the types of sexual health and sexuality-related questions asked by youth and programming/services, resources, and referrals currently being provided by CBOs; (b) explore the approaches used by CBOs when developing and implementing sexual health promotion programs; and (c) compare these findings with those from a similar study on school teachers, counselors, and nurses within the same state. Data collected from 169 people working in CBOs indicate that a wide variety of topics were covered by CBOs through programming and services, resources, and/or referral protocols. Topics covered varied in frequency. Overall, participants indicated a relatively comprehensive and accessible approach to providing sexuality information to youth. The results of this study suggest that CBOs should be included in the range of sources to be used for comprehensive sexual health promotion. If such organizations are supported with information, training, and resources, they could play a valuable role in the promotion of sexual health for adolescents.
Does the Red Flag Rule Induce Risk Taking in Sprint Finishes? Moral Hazard Crashes in Cycling’s Grand Tours
Authors: Lybbert Travis J. , Lybbert Troy C. , Smith Aaron , Warren Scott
Published: July 2011

Sprint finishes in professional cycling are fast, furious, and dangerous. A “red flag rule” (RFR) seeks to moderate the chaos of these finishes, but may induce moral hazard by removing the time penalty associated with crashing. To test for moral hazard, the authors use a 2005 rule change that moved the red flag from 1 km to 3 km from the finish. Data from Europe’s Grand Tours indicate that, after the rule change, both the incidence and the size of crashes nearly doubled in the 1–3 km from the finish zone. There was no such increase in crashing rates in the 3–5 km zone.
Investigation of rain erosion on a brittle material by means of numerical simulation
Authors: Salman H Anıl , Yıldırım R Orhan
Published: July 2011

In this work, the resistance and deformation characteristics of a brittle material against rain erosion are examined by using the non-linear, explicit software LS-DYNA. The water jet with varying speeds impinges at 90° on silica float glass plates with different thicknesses. In the simulations, the Arbitrary Lagrangian Eulerian method is used for modelling of the water. In order to analyse the deformations on the brittle material Johnson–Holmquist–Ceramics (JH-2) is used as the material model. Minimum plate thickness (for constant water jet speed) and maximum water speed (for constant plate thickness), which do not cause any damage to the target, are determined depending on the geometry, boundary conditions and assumed failure strain value for erosion. The results are compared with the water-hammer pressure.
Redesigning a large school-based clinical trial in response to changes in community practice
Authors: Gerald Lynn B , Gerald Joe K , McClure Leslie A , Harrington Kathy , Erwin Sue , Bailey William C
Published: July 2011

Background Asthma exacerbations are seasonal with the greatest risk in elementary-age students occurring shortly after returning to school following summer break. Recent research suggests that this seasonality in children is primarily related to viral respiratory tract infections. Regular hand washing is the most effective method to prevent the spread of viral respiratory infections; unfortunately, achieving hand washing recommendations in schools is difficult. Therefore, we designed a study to evaluate the effect of hand sanitizer use in elementary schools on exacerbations among children with asthma.

Purpose To describe the process of redesigning the trial in response to changes in the safety profile of the hand sanitizer as well as changes in hand hygiene practice in the schools.

Methods The original trial was a randomized, longitudinal, subject-blinded, placebo-controlled, community-based crossover trial. The primary aim was to evaluate the incremental effectiveness of hand sanitizer use in addition to usual hand hygiene practices to decrease asthma exacerbations in elementary-age children. Three events occurred that required major modifications to the original study protocol: (1) safety concerns arose regarding the hand sanitizer’s active ingredient; (2) no substitute placebo hand sanitizer was available; and (3) community preferences changed regarding hand hygiene practices in the schools.

Results The revised protocol is a randomized, longitudinal, community-based crossover trial. The primary aim is to evaluate the incremental effectiveness of a two-step hand hygiene process (hand hygiene education plus institutionally provided alcohol-based hand sanitizer) versus usual care to decrease asthma exacerbations. Enrollment was completed in May 2009 with 527 students from 30 schools. The intervention began in August 2009 and will continue through May 2011. Study results should be available at the end of 2011.

Limitations The changed design does not allow us to directly measure the effectiveness of hand sanitizer use as a supplement to traditional hand washing practices.

Conclusions The need to balance a rigorous study design with one that is acceptable to the community requires investigators to be actively involved with community collaborators and able to adapt study protocols to fit changing community practices.
Providing the results of research to participants: a mixed-method study of the benefits and challenges of a consultative approach
Authors: Dixon-Woods Mary , Tarrant Carolyn , Jackson Clare J , Jones David R , Kenyon Sara
Published: July 2011

Background How best to provide the findings of research to study participants remains poorly understood.

Purpose We aimed to develop, deliver, and evaluate a consultative approach to inform provision of feedback about research findings to participants in the Oracle Children Study (OCS). The OCS had identified adverse outcomes for some children whose mothers had been prescribed antibiotics as part of a trial in pregnancy.

Methods An iterative process, including focus groups with OCS participants and consultation with other OCS stakeholders, was used to inform the development of a feedback package, including a results leaflet, for OCS participants. A questionnaire survey of participants’ reactions to receiving the results leaflet was conducted. The Kolmogorov–Smirnov two-sample test was used to compare responses between different groups of respondents. Analysis of open-ended comments on the questionnaire was based on the constant comparative method.

Results Three focus groups with study participants provided insight into the potential emotional impact of receiving the results and into how the results might most clearly be explained. Negotiations with other stakeholders identified other priorities, including the need for scientific credibility. These multiple needs had to be balanced. The results leaflet was posted to all 4676 UK OCS participants. Survey responses were received from 1124 (25%) of participants. They indicated that the feedback was mostly well received by participants. Those whose children were affected by conditions associated with increased risk from trial participation were more likely to experience emotional distress on receiving the trial results, but there was also evidence of some other unanticipated impacts.

Limitations This study is limited by the low response rate to the survey.

Conclusions Important lessons can be learned from using a consultative approach to developing feedback about research results for study participants. Especially where the findings are unwelcome, feedback development may involve methodological, ethical, emotional, and practical challenges, be resource-intensive, and need early planning.
Beyond the 3+3 method: expanded algorithms for dose- escalation in Phase I oncology trials of two agents
Authors: Braun Thomas M , Alonzo Todd A
Published: July 2011

Background The number of published Phase I trials for determining a maximum tolerated combination of two agents is increasing, with a majority of those trials suffering from poor study design. A recent editorial proposed a 3+3+3 design, which takes the traditional 3+3 design used for one-agent dose-finding and adds an additional possible cohort of three patients.

Purpose To investigate the utility and performance of the 3+3+3, and more generally, A+B+C algorithmic designs, in Phase I trials of two-agent combinations and to discuss the issues related to such designs.

Methods Operating characteristics for an A+B+C design can be computed exactly in the statistical software package R using publicly available functions created by the authors. Using those functions, six different A+B+C designs are compared in six different settings with respect to the dose-limiting toxicity rate of combinations that each design selects as the maximum tolerated combination, as well as the average total number of patients required by each design and the average number of patients assigned to each combination.

Results Allowing for simultaneous escalation of doses of both agents does not increase patients' exposure to overly toxic combinations, yet increases the probability of identifying the maximum tolerated combination when it occurs at higher doses of either agent, than a design that forbids simultaneous escalation. Designs in which A ≤ 3 tend to target combinations with dose-limiting toxicity rates higher than designs in which A ≥ 4.

Limitations The implicitly targeted dose-limiting toxicity rate of any given algorithmic design is not transparent, requiring computation of results under a variety of settings to help understand the operating characteristics of that design. Thus, the appropriate A+B+C design will vary from trial to trial. A+B+C designs also have ‘short memory’, as escalation decisions are based primarily on the most recent cohort of patients.

Conclusions Algorithmic A+B+C designs are potentially useful in the design of Phase I trials of combinations of two agents. However, a head-to-head comparison to model-based designs is needed to warrant their general use.
The 6-MP versus placebo clinical trial in acute leukemia
Authors: Gehan Edmund A , Freireich Emil J
Published: July 2011

Background This article gives the status of clinical cancer research in the 1950's–1960's and tells the story of the development and conduct of the 6-mercaptopurine (6-MP) versus placebo clinical trial in acute leukemia through the initiation, design, conduct and analysis stages, with emphasis on the ethical aspects of randomizing patients to 6-MP or placebo when in remission.

Purpose The specific objective was to compare the lengths of remission for patients receiving 6-MP or placebo after achieving complete or partial remission from steroid treatment.

Methods A randomized, double-blind, placebo controlled sequential study was conducted in which patients were paired by remission status at each of the eleven institutions participating in the study, and randomized to 6-MP or placebo within each pair of patients. A preference for 6-MP or placebo was recorded depending on which patient in the pair had the longer remission. The preferences were plotted according to a restricted sequential procedure devised by Peter Armitage and, depending on which boundary of the design was crossed, a statistically significant difference could be declared favoring 6-MP, placebo or no preference.

Conclusions The trial established the efficacy of 6-MP for maintaining longer remissions in acute leukemia and led to the concept of 'adjuvant chemotherapy', namely that patients with minimal disease have a substantially better response to chemotherapy than patients with advanced disease, a concept that has been followed in many other forms of cancer. Statistically, the fact that many patients were still in remission when the study was stopped (i.e. the length of remission data for these patients was 'right censored') led to the development of a generalized Wilcoxon test and was an important influence on Cox's development of the proportional hazards model. The trial had an innovative design in the early 1960's and has been an important influence on subsequent clinical research in cancer and statistical research in survival analysis.
Macrophage development from HSCs requires PU.1-coordinated microRNA expression
Authors: Ghani Saeed , Riemke Pia , Schönheit Jörg , Lenze Dido , Stumm Jürgen , Hoogenkamp Maarten , Lagendijk Anne , Heinz Sven , Bonifer Constanze , Bakkers Jeroen , Abdelilah-Seyfried Salim , Hummel Michael , Rosenbauer Frank
Published: July 2011

The differentiation of HSCs into myeloid lineages requires the transcription factor PU.1. Whereas PU.1-dependent induction of myeloid-specific target genes has been intensively studied, negative regulation of stem cell or alternate lineage programs remains incompletely characterized. To test for such negative regulatory events, we searched for PU.1-controlled microRNAs (miRs) by expression profiling using a PU.1-inducible myeloid progenitor cell line model. We provide evidence that PU.1 directly controls expression of at least 4 of these miRs (miR-146a, miR-342, miR-338, and miR-155) through temporally dynamic occupation of binding sites within regulatory chromatin regions adjacent to their genomic coding loci. Ectopic expression of the most robustly induced PU.1 target miR, miR-146a, directed the selective differentiation of HSCs into functional peritoneal macrophages in mouse transplantation assays. In agreement with this observation, disruption of Dicer expression or specific antagonization of miR-146a function inhibited the formation of macrophages during early zebrafish (Danio rerio) development. In the present study, we describe a PU.1-orchestrated miR program that mediates key functions of PU.1 during myeloid differentiation.
Genome-wide SNP discovery in tetraploid alfalfa using 454 sequencing and high resolution melting analysis
Authors: Han Yuanhong , Kang Yun , Torres-Jerez Ivone , Cheung Foo , Town Christopher D , Zhao Patrick X , Udvardi Michael K , Monteros Maria J
Published: July 2011

Background

Single nucleotide polymorphisms (SNPs) are the most common type of sequence variation among plants and are often functionally important. We describe the use of 454 technology and high resolution melting analysis (HRM) for high throughput SNP discovery in tetraploid alfalfa (Medicago sativa L.), a species with high economic value but limited genomic resources.

Results

The alfalfa genotypes selected from M. sativa subsp. sativa var. 'Chilean' and M. sativa subsp. falcata var. 'Wisfal', which differ in water stress sensitivity, were used to prepare cDNA from tissue of clonally-propagated plants grown under either well-watered or water-stressed conditions, and then pooled for 454 sequencing. Based on 125.2 Mb of raw sequence, a total of 54,216 unique sequences were obtained including 24,144 tentative consensus (TCs) sequences and 30,072 singletons, ranging from 100 bp to 6,662 bp in length, with an average length of 541 bp. We identified 40,661 candidate SNPs distributed throughout the genome. A sample of candidate SNPs were evaluated and validated using high resolution melting (HRM) analysis. A total of 3,491 TCs harboring 20,270 candidate SNPs were located on the M. truncatula (MT 3.5.1) chromosomes. Gene Ontology assignments indicate that sequences obtained cover a broad range of GO categories.

Conclusions

We describe an efficient method to identify thousands of SNPs distributed throughout the alfalfa genome covering a broad range of GO categories. Validated SNPs represent valuable molecular marker resources that can be used to enhance marker density in linkage maps, identify potential factors involved in heterosis and genetic variation, and as tools for association mapping and genomic selection in alfalfa.
Identification of two linear B-cell epitopes from West Nile virus NS1 by screening a phage-displayed random peptide library
Authors: Sun En-Cheng , Ma Jian-Nan , Liu Ni-Hong , Yang Tao , Zhao Jing , Geng Hong-Wei , Wang Ling-Feng , Qin Yong-Li , Bu Zhi-Gao , Yang Yin-Hui , Lunt Ross A , Wang Lin-Fa , Wu Dong-Lai
Published: July 2011

Background

The West Nile virus (WNV) nonstructural protein 1 (NS1) is an important antigenic protein that elicits protective antibody responses in animals and can be used for the serological diagnosis of WNV infection. Although previous work has demonstrated the vital role of WNV NS1-specific antibody responses, the specific epitopes in the NS1 have not been identified.

Results

The present study describes the identification of two linear B-cell epitopes in WNV NS1 through screening a phage-displayed random 12-mer peptide library with two monoclonal antibodies (mAbs) 3C7 and 4D1 that directed against the NS1. The mAbs 3C7 and 4D1 recognized phages displaying peptides with the consensus motifs LTATTEK and VVDGPETKEC, respectively. Exact sequences of both motifs were found in the NS1 (895LTATTEK901 and 925VVDGPETKEC934). Further identification of the displayed B cell epitopes were conducted using a set of truncated peptides expressed as MBP fusion proteins. The data indicated that 896TATTEK901 and925VVDGPETKEC934 are minimal determinants of the linear B cell epitopes recognized by the mAbs 3C7 and 4D1, respectively. Antibodies present in the serum of WNV-positive horses recognized the minimal linear epitopes in Western blot analysis, indicating that the two peptides are antigenic in horses during infection. Furthermore, we found that the epitope recognized by 3C7 is conserved only among WNV strains, whereas the epitope recognized by 4D1 is a common motif shared among WNV and other members of Japanese encephalitis virus (JEV) serocomplex.

Conclusions

We identified TATTEK and VVDGPETKEC as NS1-specific linear B-cell epitopes recognized by the mAbs 3C7 and 4D1, respectively. The knowledge and reagents generated in this study may have potential applications in differential diagnosis and the development of epitope-based marker vaccines against WNV and other viruses of JEV serocomplex.
Parent satisfaction with a pediatric practice in Germany: A questionnaire-based study
Authors: Weissenstein Anne , Straeter Alexandra , Villalon Gloria , Luchter Elisabeth , Bittmann Stefan
Published: July 2011

Background

Parental satisfaction with a pediatric day center is essential for the medical treatment of children, since it is closely related to compliance. In order to ascertain factors which predict parental satisfaction as well as to discover possible weak points, we developed a questionnaire.

Methods

127 parents visiting the pediatric day center from October to November 2010 were asked to respond to a questionnaire. The survey was given to them directly by the doctor after their visit and it provided the opportunity to determine subjective and soft factors in quality management, which is essential for a pediatric practice. The questionnaire consisted of 27 items divided into three scales. The scales were as follows: satisfaction concerning the infrastructure and organization, satisfaction concerning the communicative and empathic competence of the doctor as well as the other staff, and finally the results and the overall impression. Moreover, the survey asked the respondents for their comments on the pediatric day center and sociodemographic data were queried.

Results

A total of 67 parents (52,7%) responded to the survey. The mean parental satisfaction concerning infrastructure and organization achieved 3,61 (scale 1-very unsatisfied-through 4-very satisfied). The mean satisfaction with the expertise of the doctor and the staff was 3,56 and the overall satisfaction was 3,65. Ninety-one percent of the parents would visit the pediatric practice again and 84,2% would definitely recommend the practice to others.

Conclusion

Surveys on parental satisfaction are essential for the success of a pediatric day center. Apart from the doctors abilities to interact with the parents, other factors, such as a short waiting period, a friendly and helpful staff, as well as appealing premises are essential for a high overall level of satisfaction.
Antenatal depression and offspring psychopathology: the
influence of childhood maltreatment
Authors: Pawlby Susan , Hay Dale , Sharp Deborah , Waters Cerith S. , Pariante Carmine M.
Published: July 2011

Background

Antenatal depression and childhood maltreatment have each been associated
with offspring psychopathology, but have never been examined in the same
sample.

Aims

To determine whether childhood maltreatment influences the association
between antenatal depression and offspring psychopathology.

Method

Prospectively collected data on antenatal depression, offspring
maltreatment (age 11) and offspring psychopathology (age 11 and 16) were
analysed in 120 mother–offspring dyads from the community-based South
London Child Development Study.

Results

Antenatal depression increased the risk of maltreatment in the offspring
by almost four times. Children exposed only to antenatal depression or
only to childhood maltreatment were no more at risk of developing
psychopathology; however, children exposed to both antenatal depression
and childhood maltreatment were at almost 12 times greater risk of
developing psychopathology than offspring not so exposed.

Conclusions

Research investigating exposure to adverse events in
utero and offspring psychopathology should take account of
postnatal adverse events such as maltreatment.
Cognitive interpersonal maintenance model of eating disorders: intervention for carers
Authors: Goddard Elizabeth , Macdonald Pamela , Sepulveda Ana Rosa , Naumann Ulrike , Landau Sabine , Schmidt Ulrike , Treasure Janet
Published: July 2011

Background

Carers of people with eating disorders report high levels of distress. In addition, carers' responses to the illness may perpetuate eating disorder symptoms. A cognitive interpersonal maintenance model of eating disorders is proposed and interventions for carers may improve well-being in both carers and patients.

Aims

To examine an interpersonal maintenance model of eating disorders, using a self-help intervention for carers.

Method

A pre-test–post-test design was used with carers randomised into self-help or guided self-help, which included the Expert Carers Helping Others (ECHO) intervention. Carers' distress, well-being, proposed maintenance factors, and carer reports on the status of the patient were measured.

Results

Carers' distress reduced and secondary outcomes improved. Improvement in carers' status and perceived improvements in patients were associated with reductions in expressed emotion and in accommodating and enabling behaviours. Self-help and guided self-help versions were comparable.

Conclusions

Changes in maintenance factors from the theoretical model were associated with a reduction in carers' distress and improvement in perceived patient functioning. Interventions which specifically target maintaining factors may be of benefit.
Androgen Suppression-Induced Stimulation of Spermatogonial Differentiation in Juvenile Spermatogonial Depletion Mice Acts by Elevating the Testicular Temperature
Authors: Shetty Gunapala , Porter Karen L. , Zhou Wei , Shao Shan H. , Weng Connie C. Y. , Meistrich Marvin L.
Published: July 2011

Why both testosterone (T) suppression and cryptorchidism reverse the block in spermatogonial differentiation in adult mice homozygous for the juvenile spermatogonial depletion (jsd) mutation has been a conundrum. To resolve this conundrum, we analyzed interrelations between T suppression, testicular temperature, and spermatogonial differentiation and used in vitro techniques to separate the effects of the two treatments on the spermatogonial differentiation block in jsd mice. Temporal analysis revealed that surgical cryptorchidism rapidly stimulated spermatogonial differentiation whereas androgen ablation treatment produced a delayed and gradual differentiation. The androgen suppression caused scrotal shrinkage, significantly increasing the intrascrotal temperature. When serum T or intratesticular T (ITT) levels were modulated separately in GnRH antagonist-treated mice by exogenous delivery of T or LH, respectively, the inhibition of spermatogonial differentiation correlated with the serum T and not with ITT levels. Thus, the block must be caused by peripheral androgen action. When testicular explants from jsd mice were cultured in vitro at 32.5 C, spermatogonial differentiation was not observed, but at 37 C significant differentiation was evident. In contrast, addition of T to the culture medium did not block the stimulation of spermatogonial differentiation at 37 C, and androgen ablation with aminoglutethimide and hydroxyflutamide did not stimulate differentiation at 32.5 C, suggesting that T had no direct effect on spermatogonial differentiation in jsd mice. These data show that elevation of temperature directly overcomes the spermatogonial differentiation block in adult jsd mice and that T suppression acts indirectly in vivo by causing scrotal regression and thereby elevating the testicular temperature.