bluuebunny/crossref_metadata_2025 huggingface dataset:
A goal-oriented programming framework for grid sensor networks with reconfigurable embedded nodes
Authors: Subramanian Varun , Gilberti Michael , Doboli Alex , Pescaru Dan
Published: January 2013

Cyber-physical systems (CPS) are large, distributed embedded systems integrated with various sensors and actuators. CPS are rapidly emerging as an important computing paradigm in many modern applications. Developing CPS applications is currently challenging due to the sheer complexity of the related functionality as well as the broad set of constraints and unknowns that must be tackled during operation. This article presents a novel high-level programming model and the supporting optimization and middleware routines for executing applications on physically-distributed networks of reconfigurable embedded systems. The proposed model describes the optimization goals, sensing inputs, actuation outputs, events, and constraints of an application, while leaving to the compiler and execution environment the task of optimally implementing the derived functionality. Experimental results discuss the additional performance optimizations enabled by the proposed model, and the timing and power consumption of the middleware routines, and present a temperature monitoring application implemented on a network of reconfigurable, embedded processors.
Adaptive calibration for fusion-based cyber-physical systems
Authors: Tan Rui , Xing Guoliang , Liu Xue , Yao Jianguo , Yuan Zhaohui
Published: January 2013

Many Cyber-Physical Systems (CPS) are composed of low-cost devices that are deeply integrated with physical environments. As a result, the performance of a CPS system is inevitably undermined by various
physical uncertainties
, which include stochastic noises, hardware biases, unpredictable environment changes, and dynamics of the physical process of interest. Traditional solutions to these issues (e.g., device calibration and collaborative signal processing) work in an open-loop fashion and hence often fail to adapt to the uncertainties after system deployment. In this article, we propose an
adaptive
system-level calibration approach for a class of CPS systems whose primary objective is to detect events or targets of interest. Through collaborative data fusion, our calibration approach features a feedback control loop that exploits system heterogeneity to mitigate the impact of aforementioned uncertainties on the system performance. In contrast to existing heuristic-based solutions, our control-theoretical calibration algorithm can ensure provable system stability and convergence. We also develop a routing algorithm for fusion-based multihop CPS systems that is robust to communication unreliability and delay. Our approach is evaluated by both experiments on a testbed of Tmotes as well as extensive simulations based on data traces gathered from a real vehicle detection experiment. The results demonstrate that our calibration algorithm enables a CPS system to maintain the optimal sensing performance in the presence of various system and environmental dynamics.
Overload provisioning in mixed-criticality cyber-physical systems
Authors: Lakshmanan Karthik , De Niz Dionisio , Rajkumar Ragunathan (RAJ) , Moreno Gabriel
Published: January 2013

Cyber-physical systems are an emerging class of applications that require tightly coupled interaction between the computational and physical worlds. These systems are typically realized using sensor/actuator interfaces connected with processing backbones. Safety is a primary concern in cyber-physical systems since the actuators directly influence the physical world. However, unexpected or unusual conditions in the physical world can manifest themselves as increased workload demands being offered to the computational infrastructure of a cyber-physical system. Guaranteeing system safety under overload conditions is therefore a prime concern in developing and deploying cyber-physical systems. In this work, we study this problem in the context of a
radar surveillance
system, where tasks have different levels of
criticality
or influence on
system safety
. In the face of overloads, we observe that the desirable property in such systems is that the more critical tasks continue to meet their timing requirements. We capture this
mixed-criticality
overload requirement using a formal overload-tolerance metric called
ductility
. Using this overload-tolerance metric, we first develop our solution in the context of uniprocessor systems, where we show that Zero-Slack scheduling (ZS) algorithms can be used to improve the overload behavior in mixed-criticality cyber-physical systems compared to existing fixed-priority scheduling algorithms like Rate-Monotonic Scheduling (RMS) and Criticality-As-Priority-Assignment (CAPA). Leveraging these results, we then develop a criticality-aware task allocation algorithm called
Compress-on-Overload Packing
(COP) for dealing with multiprocessor cyber-physical systems. Evaluation results show that COP achieves up to five times better ductility than traditional load balancing bin-packing algorithms like Worst-Fit Decreasing (WFD). Finally, we apply ZS and COP to the radar surveillance system to demonstrate the resulting improvement in system overload behavior. Our implementation of the Zero-Slack scheduler is available as a part of the Linux/RK project, which provides resource kernel extensions for Linux.
Conformance testing for cyber-physical systems
Authors: Woehrle Matthias , Lampka Kai , Thiele Lothar
Published: January 2013

Cyber-Physical Systems (CPS) require a high degree of reliability and robustness. Hence it is important to assert their correctness with respect to extra-functional properties, like power consumption, temperature, etc. In turn the physical quantities may be exploited for assessing system implementations. This article develops a methodology for utilizing measurements of physical quantities for testing the conformance of a running CPS with respect to a formal description of its required behavior allowing to uncover defects. We present foundations and implementations of this approach and demonstrate its usefulness by conformance testing power measurements of a wireless sensor node with a formal model of its power consumption.
Combining code reordering and cache configuration
Authors: Gordon-Ross Ann , Vahid Frank , Dutt Nikil
Published: January 2013

The instruction cache is a popular optimization target due to the cache's high impact on system performance and power and because of the cache's predictable temporal and spatial locality. This article is an in depth study on the interaction of code reordering (a long-known technique) and cache configuration (a relatively new technique). Experimental results show that code reordering coupled with cache configuration reveals additional energy savings as high as 10--15% for several benchmarks with reduced cache area as high as 48%. To exploit these additional benefits, we architect and evaluate several design exploration heuristics for combining these two methods.
Enabling dynamic binary translation in embedded systems with scratchpad memory
Authors: Baiocchi José A. , Childers Bruce R. , Davidson Jack W. , Hiser Jason D.
Published: January 2013

Important challenges for embedded systems can be addressed by dynamic binary translation. A dynamic binary translator stores translated instructions in a software-managed code cache, which is usually large to minimize overhead. This article shows how to use a small scratchpad memory for the code cache. A small code cache may require frequent code evictions and retranslation, which degrade performance. We propose techniques to reduce the number of instructions inserted by the translator and a way to form fragments that minimizes translated code size. With our techniques, a much smaller code cache can hold a program's translated code working set.
ExoBuilding
Authors: Schnädelbach Holger , Irune Ainojie , Kirk David , Glover Kevin , Brundell Patrick
Published: January 2013

Our surroundings are becoming infused with sensors measuring a variety of data streams about the environment, people and objects. Such data can be used to make the spaces that we inhabit responsive and interactive. Personal data in its different forms are one important data stream that such spaces are designed to respond to. In turn, one stream of personal data currently attracting high levels of interest in the HCI community is physiological data (e.g., heart rate, electrodermal activity), but this has seen little consideration in building architecture or the design of responsive environments. In this context, we developed a prototype mapping a single occupant’s respiration to its size and form, while it also sonifies their heartbeat. The result is a breathing building prototype, formative trials of which suggested that it triggers behavioral and physiological adaptations in inhabitants without giving them instructions and it is perceived as a relaxing experience. In this paper, we present and discuss the results of a controlled study of this prototype, comparing three conditions: the static prototype, regular movement and sonification and a biofeedback condition, where the occupant’s physiological data directly drives the prototype and presents this data back to them. The study confirmed that the biofeedback condition does indeed trigger behavioral changes and changes in participants’ physiology, resulting in lower respiration rates as well as higher respiration amplitudes, respiration to heart rate coherence and lower frequency heart rate variability. Self-reported state of relaxation is more dependent on inhabitant preferences, their knowledge of physiological data and whether they found space to ‘let go’. We conclude with a discussion of ExoBuilding as an immersive but also sharable biofeedback training interface and the wider potential of this approach to making buildings adapt to their inhabitants.
An Empirical Study of the “Prototype Walkthrough”
Authors: Hundhausen C. D. , Fairbrother D. , Petre M.
Published: January 2013

For over a century,
studio-based
instruction has served as an effective pedagogical model in architecture and fine arts education. Because of its design orientation, human-computer interaction (HCI) education is an excellent venue for studio-based instruction. In an HCI course, we have been exploring a studio-based learning activity called the
prototype walkthrough
, in which a student project team simulates its evolving user interface prototype while a student audience member acts as a test user. The audience is encouraged to ask questions and provide feedback. We have observed that prototype walkthroughs create excellent conditions for learning about user interface design. In order to better understand the educational value of the activity, we performed a content analysis of a video corpus of 16 prototype walkthroughs held in two HCI courses. We found that the prototype walkthrough discussions were dominated by relevant design issues. Moreover, mirroring the justification behavior of the expert instructor, students justified over 80 percent of their design statements and critiques, with nearly one-quarter of those justifications having a theoretical or empirical basis. Our findings suggest that PWs provide valuable opportunities for students to actively learn HCI design by participating in authentic practice, and provide insight into how such opportunities can be best promoted.
What Does Touch Tell Us about Emotions in Touchscreen-Based Gameplay?
Authors: Gao Yuan , Bianchi-Berthouze Nadia , Meng Hongying
Published: January 2013

The increasing number of people playing games on touch-screen mobile phones raises the question of whether touch behaviors reflect players’ emotional states. This prospect would not only be a valuable evaluation indicator for game designers, but also for real-time personalization of the game experience. Psychology studies on acted touch behavior show the existence of discriminative affective profiles. In this article, finger-stroke features during gameplay on an iPod were extracted and their discriminative power analyzed. Machine learning algorithms were used to build systems for automatically discriminating between four emotional states (Excited, Relaxed, Frustrated, Bored), two levels of arousal and two levels of valence. Accuracy reached between 69% and 77% for the four emotional states, and higher results (~89%) were obtained for discriminating between two levels of arousal and two levels of valence. We conclude by discussing the factors relevant to the generalization of the results to applications other than games.
Why is your web browser using so much memory?
Authors: O'Callahan Robert
Published: January 2013

Browsers are the operating systems of the Web. They support a vast universe of applications written in a modern garbage-collected programming language. Browsers expose a rich platform API mostly implemented in C++. Browsers are also consumer software with low switching costs in an intensely competitive market. Thus in addition to standard requirements such as maximizing throughput and minimizing latency, browsers have to consider issues like-when the user closes a window while watching Task Manager, they want to see memory usage go down. Browsers have to compete to minimize memory usage even for poorly written applications. In this talk I will elucidate these requirements and describe how Firefox and other browsers address them. I will pay particular attention to issues that we don't know how to solve, and that could benefit from research attention.
GPUs as an opportunity for offloading garbage collection
Authors: Maas Martin , Reames Philip , Morlan Jeffrey , Asanović Krste , Joseph Anthony D. , Kubiatowicz John
Published: January 2013

GPUs have become part of most commodity systems. Nonetheless, they are often underutilized when not executing graphics-intensive or special-purpose numerical computations, which are rare in consumer workloads. Emerging architectures, such as integrated CPU/GPU combinations, may create an opportunity to utilize these otherwise unused cycles for offloading traditional systems tasks. Garbage collection appears to be a particularly promising candidate for offloading, due to the popularity of managed languages on consumer devices.

We investigate the challenges for offloading garbage collection to a GPU, by examining the performance trade-offs for the mark phase of a mark & sweep garbage collector. We present a theoretical analysis and an algorithm that demonstrates the feasibility of this approach. We also discuss a number of algorithmic design trade-offs required to leverage the strengths and capabilities of the GPU hardware. Our algorithm has been integrated into the Jikes RVM and we present promising performance results.
The Collie
Authors: Iyengar Balaji , Tene Gil , Wolf Michael , Gehringer Edward
Published: January 2013

We describe the Collie collector, a fully concurrent compacting collector that uses transactional memory techniques to achieve wait-free compaction. The collector uses compaction as the primary means of reclaiming unused memory, and performs "individual object transplantations" as transactions. We introduce new terms and requirements useful for analyzing concurrent relocating collectors, including definitions of referrer sets, object transplantation and the notion of individually transplantable objects. The Collie collector builds on these terms and on a detailed analysis of an object's legal states during compaction.

Collie uses a combination of read barriers, write barriers and transactional memory operations. Its read-barrier supports fast, direct object referencing while using a bound, constant time, wait- free triggering path. Collie thereby avoids the constant indirection cost of Brooks [9] style barriers or handle-based heaps [25]. Collie is demonstrated using speculative multi-address atomicity [11], a form of hardware transactional memory supported by the Azul Vega architecture [2].

We evaluate the Collie collector on the Azul platform, on which previous concurrent collectors such as the Pauseless Collector [12] and its generational variant [30] have been commercially available for several years. We discuss Collie's performance while running sustained workloads, and compare it to the Pauseless collector on the same platform. The Collie collector provides significant MMU [5] improvements even in the 1-msec time windows compared to the Pauseless collector. At the same time, it matches Pauseless in throughput and in the ability to scale to large heap sizes.

We believe that the Collie collector is the first garbage collector to leverage hardware-assisted transactional memory. While Collie directly leverages Vega's speculative multi-address atomicity feature (SMA) [11], its design can be easily adapted to other hardware- assisted transactional memory systems. Specifically, the upcoming Intel TSX instruction set extensions [21] include capabilities similar to SMA. We expect Collie to be easily implementable on future commodity servers based on Intel Haswell processors and following processor generations.
Efficient FIB caching using minimal non-overlapping prefixes
Authors: Liu Yaoqing , Amin Syed Obaid , Wang Lan
Published: January 2013

The size of the global Routing Information Base (RIB) has been increasing at an alarming rate. This directly leads to the rapid growth of the global Forwarding Information Base (FIB) size, which raises serious concerns for ISPs as the FIB memory in line cards is much more expensive than regular memory modules and it is very costly to increase this memory capacity frequently for all the routers in an ISP. One potential solution is to install only the most popular FIB entries into the fast memory (i.e., a FIB cache), while storing the complete FIB in slow memory. In this paper, we propose an effective FIB caching scheme that achieves a considerably higher hit ratio than previous approaches while preventing the
cache-hiding
problem. Our experimental results show that with only 20K prefixes in the cache (5.36% of the actual FIB size), the hit ratio of our scheme is higher than 99.95%. Our scheme can also handle cache misses, cache replacement and routing updates efficiently.
Divided by Division
Authors: Neville-Neil George
Published: January 2013

Do you know of any rule of thumb for how often a piece of software should need maintenance? I’m not thinking about bug fixes, since bugs are there from the moment the code is written, but about the constant refactoring that seems to go on in code. Sometimes I feel as if programmers use refactoring as a way of keeping their jobs, rather than offering any real improvement.
Cannabinoid receptor 1 gene and irritable bowel syndrome: phenotype and quantitative traits
Authors: Camilleri Michael , Kolar Gururaj J. , Vazquez-Roque Maria I. , Carlson Paula , Burton Duane D. , Zinsmeister Alan R.
Published: January 2013

Genetic variations in metabolism of endocannabinoids and in CNR1 (gene for cannabinoid 1 receptor) are associated with symptom phenotype, colonic transit, and left colon motility in irritable bowel syndrome (IBS). Our aim was to evaluate associations between two variations in CNR1 genotype (rs806378 and [AAT]n triplets) with symptom phenotype, small bowel and colonic transit, and rectal sensations in 455 patients with IBS and 228 healthy controls. Small bowel and colonic transit were measured by scintigraphy, rectal sensation by isobaric distensions. Associations with genotype were assessed by χ2test (symptom phenotype) and ANCOVA (quantitative traits) based on a dominant genetic model. Significant association of CNR1 rs806378 (but not CNR1 [AAT]n) genotype and symptom phenotype was observed (χ2P = 0.028). There was significant association of CNR1 rs806378 ( P = 0.014; CC vs. CT/TT) with colonic transit in IBS-diarrhea (IBS-D) group; the TT group had the fastest colonic transit at 24 and 48 h. There was significant overall association of CNR1 rs806378 with sensation rating of gas ( P = 0.025), but not pain; the strongest associations for gas ratings were in IBS-D ( P = 0.002) and IBS-alternating ( P = 0.025) subgroups. For CNR1 (AAT)n, gene-by-phenotype interactions were observed for colonic transit at 24 ( P = 0.06) and 48 h ( P = 0.002) and gas ( P = 0.046, highest for IBS-D, P = 0.034), but not pain sensation; the strongest association with transit was in controls, not in IBS. These data support the hypothesis that cannabinoid receptors may play a role in control of colonic transit and sensation in humans and deserve further study as potential mediators or therapeutic targets in lower functional gastrointestinal disorders.
Bradycardia alters Ca2+dynamics enhancing dispersion of repolarization and arrhythmia risk
Authors: Kim Jong J. , Němec Jan , Papp Rita , Strongin Robert , Abramson Jonathan J. , Salama Guy
Published: January 2013

Bradycardia prolongs action potential (AP) durations (APD adaptation), enhances dispersion of repolarization (DOR), and promotes tachyarrhythmias. Yet, the mechanisms responsible for enhanced DOR and tachyarrhythmias remain largely unexplored. Ca2+transients and APs were measured optically from Langendorff rabbit hearts at high (150 × 150 μm2) or low (1.5 × 1.5 cm2) magnification while pacing at a physiological (120 beats/min) or a slow heart rate (SHR = 50 beats/min). Western blots and pharmacological interventions were used to elucidate the regional effects of bradycardia. As a result, bradycardia (SHR 50 beats/min) increased APDs gradually (time constant τf→s= 48 ± 9.2 s) and caused a secondary Ca2+release (SCR) from the sarcoplasmic reticulum during AP plateaus, occurring at the base on average of 184.4 ± 9.7 ms after the Ca2+transient upstroke. In subcellular imaging, SCRs were temporally synchronous and spatially homogeneous within myocytes. In diastole, SHR elicited variable asynchronous sarcoplasmic reticulum Ca2+release events leading to subcellular Ca2+waves, detectable only at high magnification. SCR was regionally heterogeneous, correlated with APD prolongation ( P < 0.01, n = 5), enhanced DOR ( r = 0.9277 ± 0.03, n = 7), and was gradually reversed by pacing at 120 beats/min along with APD shortening ( P < 0.05, n = 5). A stabilizer of leaky ryanodine receptors (RyR2), 3-(4-benzylcyclohexyl)-1-(7-methoxy-2,3-dihydrobenzo[ f][1,4]thiazepin-4(5 H)-yl)propan-1-one (K201; 1 μM), suppressed SCR and reduced APD at the base, thereby reducing DOR ( P < 0.02, n = 5). Ventricular ectopy induced by bradycardia ( n = 5/15) was suppressed by K201. Western blot analysis revealed spatial differences of voltage-gated L-type Ca2+channel protein (Cav1.2α), Na+-Ca2+exchange (NCX1), voltage-gated Na+channel (Nav1.5), and rabbit ether-a-go-go-related (rERG) protein [but not RyR2 or sarcoplasmic reticulum Ca2+ATPase 2a] that correlate with the SCR distribution and explain the molecular basis for SCR heterogeneities. In conclusion, acute bradycardia elicits synchronized subcellular SCRs of sufficient magnitude to overcome the source-sink mismatch and to promote afterdepolarizations.
Body fat does not affect venous bubble formation after air dives of moderate severity: theory and experiment
Authors: Schellart Nico A. M. , van Rees Vellinga Tjeerd P. , van Hulst Rob A.
Published: January 2013

For over a century, studies on body fat (BF) in decompression sickness and venous gas embolism of divers have been inconsistent. A major problem is that age, BF, and maximal oxygen consumption (V̇o2max) show high multicollinearity. Using the Bühlmann model with eight parallel compartments, preceded by a blood compartment in series, nitrogen tensions and loads were calculated with a 40 min/3.1 bar (absolute) profile. Compared with Haldanian models, the new model showed a substantial delay in N2 uptake and (especially) release. One hour after surfacing, an increase of 14–28% in BF resulted in a whole body increase of the N2 load of 51%, but in only 15% in the blood compartment. This would result in an increase in the bubble grade of only 0.01 Kisman-Masurel (KM) units at the scale near KM = I−. This outcome was tested indirectly by a dry dive simulation (air breathing) with 53 male divers with a small range in age and V̇o2max to suppress multicollinearity. BF was determined with the four-skinfold method. Precordial Doppler bubble grades determined at 40, 80, 120, and 160 min after surfacing were used to calculate the Kisman Integrated Severity Score and were also transformed to the logarithm of the number of bubbles/cm2 (logB). The highest of the four scores yielded logB = −1.78, equivalent to KM = I−. All statistical outcomes of partial correlations with BF were nonsignificant. These results support the model outcomes. Although this and our previous study suggest that BF does not influence venous gas embolism (Schellart NAM, van Rees Vellinga TP, van Dijk FH, Sterk W. Aviat Space Environ Med 83: 951–957, 2012), more studies with different profiles under various conditions are needed to establish whether BF remains (together with age and V̇o2max) a basic physical characteristic or will become less important for the medical examination and for risk assessment.
Airway smooth muscle in the pathophysiology and treatment of asthma
Authors: Doeing Diana C. , Solway Julian
Published: January 2013

Airway smooth muscle (ASM) plays an integral part in the pathophysiology of asthma. It is responsible for acute bronchoconstriction, which is potentiated by constrictor hyperresponsiveness, impaired relaxation and length adaptation. ASM also contributes to airway remodeling and inflammation in asthma. In light of this, ASM is an important target in the treatment of asthma.
Locomotor adaptation to a soleus EMG-controlled antagonistic exoskeleton
Authors: Gordon Keith E. , Kinnaird Catherine R. , Ferris Daniel P.
Published: January 2013

Locomotor adaptation in humans is not well understood. To provide insight into the neural reorganization that occurs following a significant disruption to one's learned neuromuscular map relating a given motor command to its resulting muscular action, we tied the mechanical action of a robotic exoskeleton to the electromyography (EMG) profile of the soleus muscle during walking. The powered exoskeleton produced an ankle dorsiflexion torque proportional to soleus muscle recruitment thus limiting the soleus' plantar flexion torque capability. We hypothesized that neurologically intact subjects would alter muscle activation patterns in response to the antagonistic exoskeleton by decreasing soleus recruitment. Subjects practiced walking with the exoskeleton for two 30-min sessions. The initial response to the perturbation was to “fight” the resistive exoskeleton by increasing soleus activation. By the end of training, subjects had significantly reduced soleus recruitment resulting in a gait pattern with almost no ankle push-off. In addition, there was a trend for subjects to reduce gastrocnemius recruitment in proportion to the soleus even though only the soleus EMG was used to control the exoskeleton. The results from this study demonstrate the ability of the nervous system to recalibrate locomotor output in response to substantial changes in the mechanical output of the soleus muscle and associated sensory feedback. This study provides further evidence that the human locomotor system of intact individuals is highly flexible and able to adapt to achieve effective locomotion in response to a broad range of neuromuscular perturbations.
Alcohol Consumption, Folate Intake, Hepatocellular Carcinoma, and Liver Disease Mortality
Authors: Persson E. Christina , Schwartz Lauren M. , Park Yikyung , Trabert Britton , Hollenbeck Albert R. , Graubard Barry I. , Freedman Neal D. , McGlynn Katherine A.
Published: January 2013

Background: Excessive alcohol consumption is a well-established risk factor for liver disease and hepatocellular carcinoma (HCC). Previous studies have found that increased alcohol consumption can lead to lower absorption of folate. Conversely, higher folate intake has been inversely associated with liver damage and HCC. In the current study, we investigate the effect of alcohol consumption and folate intake on HCC incidence and liver disease mortality in the NIH–American Association of Retired Persons Diet and Health Study.

Methods: The study population included 494,743 participants who reported at baseline their dietary intake for the previous year. Alcohol and folate were analyzed with hazards ratios (HR) and 95% confidence intervals (CI) using multivariate Cox proportional hazards regression models adjusted for age, sex, race, education, smoking, body mass index, and diabetes. HCC incidence (n = 435) was determined through 2006 via linkage with cancer registries, and liver disease mortality (n = 789) was determined through 2008 via linkage to the U.S. Social Security Administration Death Master File and the National Death Index Plus by the National Center for Health Statistics.

Results: Consumption of more than three drinks per day was positively associated with both HCC incidence (HR: 1.92; 95%CI: 1.42–2.60) and liver disease mortality (HR: 5.84; 95%CI: 4.81–7.10), whereas folate intake was associated with neither outcome. Folate, however, modified the relationship between alcohol and HCC incidence (Pinteraction = 0.03), but had no effect on the relationship between alcohol and liver disease mortality (Pinteraction = 0.54).

Conclusions: These results suggest that higher folate intake may ameliorate the effect of alcohol consumption on the development of HCC.

Impact: Folate intake may be beneficial in the prevention of alcohol-associated HCC. Cancer Epidemiol Biomarkers Prev; 22(3); 415–21. ©2013 AACR.
Hormonal and Reproductive Risk Factors for Epithelial Ovarian Cancer by Tumor Aggressiveness
Authors: Poole Elizabeth M. , Merritt Melissa A. , Jordan Susan J. , Yang Hannah P. , Hankinson Susan E. , Park Yikung , Rosner Bernard , Webb Penelope M. , Cramer Daniel W. , Wentzensen Nicolas , Terry Kathryn L. , Tworoger Shelley S.
Published: January 2013

Background: Approximately half of epithelial ovarian cancers are fatal within 3 years; however, roughly 35% of women survive for at least 10 years. In the Nurses' Health Study, New England Case-Control Study, Australian Ovarian Cancer Study, and NIH-AARP Diet and Health Study, we investigated potential differences in the associations with ovarian cancer risk factors by tumor aggressiveness, defined on the basis of time from diagnosis until death.

Methods: We calculated relative risks (RR) and 95% confidence intervals (CI) for associations of known or suspected ovarian cancer risk factors with rapidly fatal (death within 3 years of diagnosis) and less aggressive tumors (all others) using Cox proportional hazards competing risks analysis (NHS and AARP) or polytomous logistic regression (NECC, AOCS). Results were combined using random effects meta-analysis.

Results: Increasing age was associated with greater risk of rapidly fatal versus less aggressive disease (RR, 5-year increase: 1.39; 95% CI, 1.29–1.49 vs. RR, 1.09; 95% CI, 1.03–1.16, respectively; Pdiff < 0.0001). Oral contraceptive use was associated with a greater decreased risk of rapidly fatal (RR, 5-year increase: 0.69; 95% CI, 0.58–0.82) versus less aggressive disease (RR, 0.81; 95% CI, 0.74–0.89; Pdiff, 0.002). Conversely, increasing parity was associated only with less aggressive disease (RR per child, 0.87; 95% CI, 0.81–0.93).

Conclusion: In this analysis of 4,342 cases, there were clear differences in risk factors for rapidly fatal versus less aggressive ovarian tumors.

Impact: Differences in risk factor associations by tumor aggressiveness suggests the developmental pathways through which the tumors develop and may be important for developing primary preventive strategies for the most aggressive cancers. Cancer Epidemiol Biomarkers Prev; 22(3); 429–36. ©2013 AACR.
Mapping of the IRF8 Gene Identifies a 3′UTR Variant Associated with Risk of Chronic Lymphocytic Leukemia but not Other Common Non-Hodgkin Lymphoma Subtypes
Authors: Slager Susan L. , Achenbach Sara J. , Asmann Yan W. , Camp Nicola J. , Rabe Kari G. , Goldin Lynn R. , Call Timothy G. , Shanafelt Tait D. , Kay Neil E. , Cunningham Julie M. , Wang Alice H. , Weinberg J. Brice , Norman Aaron D. , Link Brian K. , Leis Jose F. , Vachon Celine M. , Lanasa Mark C. , Caporaso Neil E. , Novak Anne J. , Cerhan James R.
Published: January 2013

Background: Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk.

Methods: To refine the genetic association of CLL risk, we conducted Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then conducted fine mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1,521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes.

Results: The strongest association with CLL risk was observed with a common single-nucleotide polymorphism (SNP) located within the 3′ untranslated region (UTR) of IRF8 (rs1044873, log additive OR = 0.7, P = 1.81 × 10−6). This SNP was not associated with the other NHL subtypes (all P > 0.05).

Conclusions: We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology.

Impact: These data provide support that a functional variant within the 3′UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk. Cancer Epidemiol Biomarkers Prev; 22(3); 461–6. ©2013 AACR.
Gene Expression Profile Identifies Tyrosine Kinase c-Met as a Targetable Mediator of Antiangiogenic Therapy Resistance
Authors: Jahangiri Arman , De Lay Michael , Miller Liane M. , Carbonell W. Shawn , Hu Yu-Long , Lu Kan , Tom Maxwell W. , Paquette Jesse , Tokuyasu Taku A. , Tsao Sean , Marshall Roxanne , Perry Arie , Bjorgan Kirsten M. , Chaumeil Myriam M. , Ronen Sabrina M. , Bergers Gabriele , Aghi Manish K.
Published: January 2013

Purpose: To identify mediators of glioblastoma antiangiogenic therapy resistance and target these mediators in xenografts.

Experimental Design: We conducted microarray analysis comparing bevacizumab-resistant glioblastomas (BRG) with pretreatment tumors from the same patients. We established novel xenograft models of antiangiogenic therapy resistance to target candidate resistance mediator(s).

Results: BRG microarray analysis revealed upregulation versus pretreatment of receptor tyrosine kinase c-Met, which underwent further investigation because of its prior biologic plausibility as a bevacizumab resistance mediator. BRGs exhibited increased hypoxia versus pretreatment in a manner correlating with their c-Met upregulation, increased c-Met phosphorylation, and increased phosphorylation of c-Met–activated focal adhesion kinase and STAT3. We developed 2 novel xenograft models of antiangiogenic therapy resistance. In the first model, serial bevacizumab treatment of an initially responsive xenograft generated a xenograft with acquired bevacizumab resistance, which exhibited upregulated c-Met expression versus pretreatment. In the second model, a BRG-derived xenograft maintained refractoriness to the MRI tumor vasculature alterations and survival-promoting effects of bevacizumab. Growth of this BRG-derived xenograft was inhibited by a c-Met inhibitor. Transducing these xenograft cells with c-Met short hairpin RNA inhibited their invasion and survival in hypoxia, disrupted their mesenchymal morphology, and converted them from bevacizumab-resistant to bevacizumab-responsive. Engineering bevacizumab-responsive cells to express constitutively active c-Met caused these cells to form bevacizumab-resistant xenografts.

Conclusion: These findings support the role of c-Met in survival in hypoxia and invasion, features associated with antiangiogenic therapy resistance, and growth and therapeutic resistance of xenografts resistant to antiangiogenic therapy. Therapeutically targeting c-Met could prevent or overcome antiangiogenic therapy resistance. Clin Cancer Res; 19(7); 1773–83. ©2012 AACR.
Acquired factor XIII deficiency: a therapeutic challenge
Authors: Boehlen Françoise , Casini Alessandro , Chizzolini Carlo , Mansouri Behrouz , Kohler Hans Peter , Schroeder Verena , Reber Guido , Moerloose Philippe de
Published: January 2013

Less than 60 cases of acquired factor (F)XIII deficiencies have been reported, most having distinct clinical features. To illustrate the therapeutic challenges of acquired FXIII inhibitors, we report a case of a 65-year-old patient with no previous bleeding history who suddenly developed massive haemorrhages associated to a strong and isolated FXIII inhibitor. No underlying disorder has been detected till now after three years of follow-up. Despite aggressive treatment with prednisone, rituximab, cyclophosphamide, immunoglobulin, immunoadsorption and immune tolerance his inhibitor is still present, although at low titre and with a clinical benefit since the patient has no more bleed since more than one year. Moreover the patient had a venous thromboembolic complication. After a review of the management of acquired FXIII deficiency patients and based on the management of acquired haemophilia we discuss a possible strategy for such difficult cases.
Prostaglandin D
2
-DP Signaling Promotes Endothelial Barrier Function via the cAMP/PKA/Tiam1/Rac1 Pathway
Authors: Kobayashi Koji , Tsubosaka Yoshiki , Hori Masatoshi , Narumiya Shuh , Ozaki Hiroshi , Murata Takahisa
Published: January 2013

Objective—

Prostaglandin D
2
(PGD
2
) is one of the prostanoids produced during inflammation. Although PGD
2
is known to decrease endothelial permeability through D prostanoid (DP) receptor stimulation, the detailed mechanism is unknown.

Methods and Results—

Treatment with PGD
2
(0.1–3 μmol/L) or the DP receptor agonist, BW245C (0.1–3 μmol/L), dose-dependently increased transendothelial electrical resistance and decreased the FITC-dextran permeability of human umbilical vein endothelial cells. Both indicated decreased endothelial permeability. These phenomena were accompanied by Tiam1/Rac1-dependent cytoskeletal rearrangement. BW245C (0.3 μmol/L) increased the intracellular cAMP level and subsequent protein kinase A (PKA) activity. Pretreatment with PKA inhibitory peptide, but not gene depletion of exchange protein directly activated by cAMP 1 (Epac1), attenuated BW245C-induced Rac1 activation and transendothelial electric resistance increase. In vivo, application of 2.5% croton oil or histamine (100 μg) caused vascular leakage indexed by dye extravasation. Pretreatment with BW245C (1 mg/kg) attenuated the dye extravasation. Gene deficiency of DP abolished, or inhibition of PKA significantly reduced, the DP-mediated barrier enhancement.

Conclusion—

PGD
2
-DP signaling reduces vascular permeability both in vivo and in vitro. This phenomenon is mediated by cAMP/PKA/Tiam1-dependent Epac1–independent Rac1 activation and subsequent enhancement of adherens junction in endothelial cell.
Intraventricular Fibrinolysis Does Not Increase Perihemorrhagic Edema After Intracerebral Hemorrhage
Authors: Volbers Bastian , Wagner Ingrid , Willfarth Wolfgang , Doerfler Arnd , Schwab Stefan , Staykov Dimitre
Published: January 2013

Background and Purpose—

Additional intraventricular hemorrhage leads to higher mortality and worse functional outcome after intracerebral hemorrhage (ICH). Intraventricular fibrinolysis (IVF) with recombinant tissue plasminogen activator (rtPA) is an emerging treatment strategy for such patients. However, experimental studies suggest that rtPA may exert proedematous effects and lead to increased perihemorrhagic edema (PHE) after ICH. We aimed to compare the course of PHE after ICH between patients who received IVF with rtPA and controls matched for ICH volume.

Methods—

Patients were identified retrospectively from our institutional ICH database. Sixty-four patients with ICH and intraventricular hemorrhage who were treated with IVF were compared with 64 controls, who did not receive IVF, matched for ICH volume. The course of PHE was assessed on computed tomography scans (day 1, days 2 and 3, days 4-6, 7-9, and 10-12) using a threshold-based semiautomatic volumetric algorithm. Relative PHE was calculated as a ratio of PHE volume and initial ICH volume.

Results—

The matching algorithm resulted in similar mean ICH volumes in both groups (20.01±17.5 mL, IVF vs 20.08±17.1 mL, control). Intraventricular hemorrhage volume was larger in the IVF group (26.8±19.2 mL vs 9.2±13.4 mL). The mean total rtPA dose used for IVF was 8±6 mg. PHE increased over time in both groups until day 12. At all investigated time points, there was no significant difference in relative PHE between the IVF group and controls (F=0.39;
P
=0.844).

Conclusions—

IVF with rtPA did not lead to a relevant increase in PHE after ICH. rtPA doses used in the current study seem to be safe regarding PHE.
Extreme Rainfall in the Mediterranean: What Can We Learn from Observations?
Authors: Rebora N. , Molini L. , Casella E. , Comellas A. , Fiori E. , Pignone F. , Siccardi F. , Silvestro F. , Tanelli S. , Parodi A.
Published: January 2013

Flash floods induced by extreme rainfall events represent one of the most life-threatening phenomena in the Mediterranean. While their catastrophic ground effects are well documented by postevent surveys, the extreme rainfall events that generate them are still difficult to observe properly. Being able to collect observations of such events will help scientists to better understand and model these phenomena. The recent flash floods that hit the Liguria region (Italy) between the end of October and beginning of November 2011 give us the opportunity to use the measurements available from a large number of sensors, both ground based and spaceborne, to characterize these events. In this paper, the authors analyze the role of the key ingredients (e.g., unstable air masses, moist low-level jets, steep orography, and a slow-evolving synoptic pattern) for severe rainfall processes over complex orography. For the two Ligurian events, this role has been analyzed through the available observations (e.g., Meteosat Second Generation, Moderate Resolution Imaging Spectroradiometer, the Italian Radar Network mosaic, and the Italian rain gauge network observations). The authors then address the possible role of sea–atmosphere interactions and propose a characterization of these events in terms of their predictability.
Anatomy of Dissent
Authors: Lahsen Myanna
Published: January 2013

Based on findings from ethnographic analysis of U.S. climate scientists, this article identifies largely unrecognized sociocultural dimensions underpinning differences in scientists’ perceptions of anthropogenic climate change. It argues that culturally laden tensions among scientists have influenced some to engage with the antienvironmental movement and, as such, influence U.S. climate science politics. The tensions are rooted in broad-based and ongoing changes within U.S. science and society since the 1960s and propelled by specific scientific subgroups’ negative experiences of the rise of environmentalism and of climate modeling, in particular.   Attending to these and other experience-based cultural dynamics can help refine cultural theory and enhance understanding of the deeper battles of meaning that propel climate science politics.
Child injury prevention in the home: A national survey of safety practices and use of safety equipment in deprived families
Authors: Mulvaney CA , Watson MC , Smith S , Coupland C , Kendrick D
Published: January 2013

Objective:

To determine the prevalence of home safety practices and use of safety equipment by disadvantaged families participating in a national home safety equipment scheme in England.

Design:

Cross-sectional postal survey sent to a random sample of 1,000 families.

Setting:

England, United Kingdom.

Results:

Half the families (51%) returned a completed questionnaire. The majority of families (82.3%) reported never drinking hot drinks whilst holding a child and 90.7% reported almost always keeping medicines locked away. High numbers of families reported that they never leave their children in the bath alone (85.7%). Of families with children under one year, 82.1% would never leave the baby on a high surface but only just over half (53.3%) said they never use a baby walker. One-third of families stored cleaning products unsafely in the kitchen or bathroom. Minority ethnic families were significantly less likely to adopt a number of safety practices than white families. Ten per cent of respondents reported that their children had had one or more injuries requiring medical attention in the six months preceding completion of the questionnaire.

Conclusions:

While the prevalence of many safety practices was high in families, findings regarding the use of baby walkers, storage of cleaning products and the practices of minority ethnic families highlight issues requiring further health education intervention. National surveys such as this one provide key information necessary for planning future strategies.
Toward Organizational Environmental Virtuousness
Authors: Sadler-Smith Eugene
Published: January 2013

This article combines theories of environmental virtue ethics and organizational virtuousness in proposing the idea of “organizational environmental virtuousness.” In doing so it draws attention to the fact that previous “green management” scholarship has emphasized reduction of harm and adherence to norms and overlooked the significance of positive deviance, virtue, and virtuousness. In common with organizational virtuousness, organizational environmental virtuousness is associated with moral goodness, human impact, and unconditional social betterment. Amplifying and buffering effects of organizational environmental virtuousness support positive deviance and environmentally supportive behaviors and constrain negative deviance and environmentally antagonistic behaviors, respectively. The article concludes with a consideration of the implications of organizational virtuousness for researchers who may wish to examine its antecedents and consequences, and for practitioners who may wish to leverage environmental virtuousness in their organizations.
Policy Disputes, Political Survival, and the Onset and Severity of State Repression
Authors: Ritter Emily Hencken
Published: January 2013

Under what conditions will a state repress its citizens? The literature examining human rights violations lacks consensus over exactly how repression and dissent are interrelated. I argue that contradictions have arisen because scholars have not derived expectations consistent with modeling three common assumptions: (1) dissent and repression are causally interrelated (2) states and groups are in conflict over some policy or good and (3) authorities repress to remain in office. I develop a formal model based on these principles, and I predict that changes in the same independent variable can have divergent effects on the onset and severity of repression. Using coded event data for all states from 1990 to 2004 and a two-tiered estimator, I find that increases in executive job security decrease the likelihood that repression will occur in the first place, but increase the severity of observed violations.
Jonathan Edwards and the Future of Global Christianity
Authors: McClymond Michael J. , McDermott Gerald R.
Published: January 2013

World Christianity today is quite different from what it was a century ago. Roman Catholics, Evangelicals, and Pentecostals in Africa, Asia, and Latin America will shape the twenty-first-century theological agenda. A new agenda needs to be scripturally based, open to vibrant, Spirit-led experience, engaged with non-Christian religions, and ecumenically fruitful. Surprising as it may sound, the writings of eighteenth-century thinker Jonathan Edwards offer an excellent point of departure. He functions as a bridge figure in four ways—between Catholics and Protestants, the Christian East and West, Charismatics and non-Charismatics, and liberals and conservatives.