bluuebunny/crossref_metadata_2025 huggingface dataset:
The status of Australian nurse practitioners: the second national census
Authors: Middleton Sandy , Gardner Anne , Gardner Glenn , Della Phillip R.
Published: October 2011

Objectives.
To profile Australian nurse practitioners and their practice in 2009 and compare results with a similar 2007 census.

Methods.
Self-administered questionnaire.

Results.
A total of 293 nurse practitioners responded (response rate 76.3%). The majority were female (n = 229, 81.2%); mean age was 47.3 years (s.d. = 8.1). As in 2007, emergency nurse practitioners represented the largest clinical specialty (n = 63, 30.3%). A majority practiced in a metropolitan area (n = 133, 64.3%); a decrease from 2007. Consistent with 2007, only 71.5% (n = 208) were employed as a nurse practitioner and 22.8% (n = 46) were awaiting approval for some or all of their clinical protocols. Demographic data, allocations of tasks, and patterns of practice remained consistent with 2007 results. ‘No Medicare provider number’ (n = 182, 91.0%), ‘no authority to prescribe using the Pharmaceutical Benefits Scheme’ (n = 182, 89.6%) and ‘lack of organisational support’ (n = 105, 52.2%) were reported as ‘limiting’ or ‘extremely limiting’ to practice.

Conclusions.
Our results demonstrate less than satisfactory uptake of the nurse practitioner role despite authorisation. Barriers constraining nurse practitioner practice reduced but remained unacceptably high. Adequate professional and political support is necessary to ensure the efficacy and sustainability of this clinical role.

What is known about the topic?
The nurse practitioner is a developing new model of healthcare delivery that performs an advanced clinical role and is becoming increasingly important in the overburdened Australian healthcare system. Our census conducted in 2007 indicated that nurse practitioners perceived many barriers to their practice and were underutilised in the Australian healthcare workforce, specifically because of their inability to prescribe medications.

What does this paper add?
This paper provides a second census of Australian nurse practitioners in 2009. Similar to the results in 2007, the study indicates that nurse practitioners remain underutilised, with many unable to perform roles within their defined scope of practice because of limitations, such as inability to prescribe medications, lack of a Medicare provider number and awaiting approval for clinical protocols. Lack of support from within healthcare organisations and the nursing profession also were found.

What are the implications for practitioners?
Nurse practitioners are not being utilised to their maximum clinical capacity despite increasing pressures on the health system. Many of the barriers to nurse practitioner practice that were flagged in 2007 remained issues in 2009. It is hoped the current legislative reform through the Health Legislation Amendment (Midwives and Nurse Practitioners) Act 2010 (Cth) will adequately address these issues.
Requirements for effective malaria control with homing endonuclease genes
Authors: Deredec Anne , Godfray H. Charles J. , Burt Austin
Published: October 2011

Malaria continues to impose a substantial burden on human health. We have previously proposed that biological approaches to control the mosquito vector of disease could be developed using homing endonuclease genes (HEGs), a class of selfish or parasitic gene that exists naturally in many microbes. Recent lab studies have demonstrated that HEGs can function in mosquitoes. We constructed and analyzed a model of mosquito population genetics and malaria epidemiology to determine how well HEGs need to function in order to have a significant effect on the burden of disease. Our model, combined with currently available data, indicates that populations of
Anopheles gambiae
could be eliminated by releasing 2–3 HEGs targeting female fertility genes, or a driving-Y chromosome that is transmitted to 75–96% of progeny. Combinations of fertility-targeting HEGs and Y drive may also be effective. It is possible to eliminate the disease without eliminating the vector, but the parameter space producing this outcome appears to be small. HEGs causing a quantitative reduction in adult survival can be more effective than those targeting female fertility, but the selection coefficients that need to be imposed are still large, unless many HEGs are to be released. Simulations show that HEG-based strategies can be effective over socially relevant time frames. Important limiting assumptions of the models are that there is only a single vector species, and we model a homogeneous population, not a landscape. Nevertheless, we conclude that HEG-based approaches could have a transformational effect on malaria control efforts.
A formal mathematical framework for physiological observations, experiments and analyses
Authors: Nielsen Thomas A. , Nilsson Henrik , Matheson Tom
Published: October 2011

Experiments can be complex and produce large volumes of heterogeneous data, which make their execution, analysis, independent replication and meta-analysis difficult. We propose a mathematical model for experimentation and analysis in physiology that addresses these problems. We show that experiments can be composed from time-dependent quantities, and be expressed as purely mathematical equations. Our structure for representing physiological observations can carry information of any type and therefore provides a precise ontology for a wide range of observations. Our framework is concise, allowing entire experiments to be defined unambiguously in a few equations. In order to demonstrate that our approach can be implemented, we show the equations that we have used to run and analyse two non-trivial experiments describing visually stimulated neuronal responses and dynamic clamp of vertebrate neurons. Our ideas could provide a theoretical basis for developing new standards of data acquisition, analysis and communication in neurophysiology.
Mechanisms and pathways of growth failure in primordial dwarfism
Authors: Klingseisen Anna , Jackson Andrew P.
Published: October 2011

The greatest difference between species is size; however, the developmental mechanisms determining organism growth remain poorly understood. Primordial dwarfism is a group of human single-gene disorders with extreme global growth failure (which includes Seckel syndrome, microcephalic osteodysplastic primordial dwarfism I [MOPD] types I and II, and Meier-Gorlin syndrome). Ten genes have now been identified for microcephalic primordial dwarfism, encoding proteins involved in fundamental cellular processes including genome replication (ORC1 [origin recognition complex 1], ORC4, ORC6, CDT1, and CDC6), DNA damage response (ATR [ataxia-telangiectasia and Rad3-related]), mRNA splicing (U4atac), and centrosome function (CEP152, PCNT, and CPAP). Here, we review the cellular and developmental mechanisms underlying the pathogenesis of these conditions and address whether further study of these genes could provide novel insight into the physiological regulation of organism growth.
Action of Natural Abscisic Acid Precursors and Catabolites on Abscisic Acid Receptor Complexes
Authors: Kepka Michal , Benson Chantel L. , Gonugunta Vijay K. , Nelson Ken M. , Christmann Alexander , Grill Erwin , Abrams Suzanne R.
Published: October 2011

The phytohormone abscisic acid (ABA) regulates stress responses and controls numerous aspects of plant growth and development. Biosynthetic precursors and catabolites of ABA have been shown to trigger ABA responses in physiological assays, but it is not clear whether these are intrinsically active or whether they are converted into ABA in planta. In this study, we analyzed the effect of ABA precursors, conjugates, and catabolites on hormone signaling in Arabidopsis (Arabidopsis thaliana). The compounds were also tested in vitro for their ability to regulate the phosphatase moiety of ABA receptor complexes consisting of the protein phosphatase 2C ABI2 and the coreceptors RCAR1/PYL9, RCAR3/PYL8, and RCAR11/PYR1. Using mutants defective in ABA biosynthesis, we show that the physiological activity associated with ABA precursors derives predominantly from their bioconversion to ABA. The ABA glucose ester conjugate, which is the most widespread storage form of ABA, showed weak ABA-like activity in germination assays and in triggering ABA signaling in protoplasts. The ABA conjugate and precursors showed negligible activity as a regulatory ligand of the ABI2/RCAR receptor complexes. The majority of ABA catabolites were inactive in our assays. To analyze the chemically unstable 8′- and 9′-hydroxylated ABA catabolites, we used stable tetralone derivatives of these compounds, which did trigger selective ABA responses. ABA synthetic analogs exhibited differential activity as regulatory ligands of different ABA receptor complexes in vitro. The data show that ABA precursors, catabolites, and conjugates have limited intrinsic bioactivity and that both natural and synthetic ABA-related compounds can be used to probe the structural requirements of ABA ligand-receptor interactions.
Differences in biomechanical features of tongue pressure production between articulation and swallow
Authors: YANO J. , KUMAKURA I. , HORI K. , TAMINE K.‐I. , ONO T.
Published: October 2011

Summary  The purpose of this study was to compare the tongue pressure against the hard palate during the articulation of a monosyllable with that during swallowing. The participants were 20 healthy adults without swallowing or articulation disorder (10 men and 10 women, mean age ± standard deviation: 22·5 ± 0·9 years). Tongue pressure during articulation of [ki] (articulatory pressure) and during dry swallowing (swallowing pressure) was recorded by a 0·1‐mm‐thick sensor sheet with five measuring points attached to the hard palate. Biomechanical parameters such as maximal magnitude, duration, integrated value and slope gradient were compared between articulatory pressure and swallowing pressure at each measuring point. Although swallowing pressure was produced at each measuring point, articulatory pressure was found only in the posterior circumferential parts of the hard palate and was smaller in magnitude (14·9–16·7% of swallowing pressure) and integrated value, which meant the amount of work by tongue pressing (7·0–7·9%), shorter in duration (26·6–31·8%) and shallower in slope gradient, which meant the speed of tongue pressing (26·9–27·4%). Maximal magnitude was closely correlated with duration (R2 = 0·386) and slope gradient (R2 = 0·843) for articulatory pressure. These results first show the biomechanical differences between articulation and swallowing in terms of tongue contact with the hard palate. The findings suggest that tongue pressure measurement might be a useful investigation for patients with tongue motor disorder.
Direct mapping of morphological distribution of syringyl and guaiacyl lignin in the xylem of maple by time‐of‐flight secondary ion mass spectrometry
Authors: Saito Kaori , Watanabe Yoko , Shirakawa Manabu , Matsushita Yasuyuki , Imai Takanori , Koike Takayoshi , Sano Yuzou , Funada Ryo , Fukazawa Kazumi , Fukushima Kazuhiko
Published: October 2011

Lignin, one of the main structural polymer of plant cell walls, varies in amount and monomeric composition among tissue and cell types, as well as among plant species. However, few analytical methods are available that can conveniently and accurately determine the morphological distribution of lignin units at the cellular level. In this report, we used time‐of‐flight secondary ion mass spectrometry (TOF‐SIMS) to directly map guaiacyl (G) and syringyl (S) lignin units in several successive growth rings of the maple xylem. TOF‐SIMS imaging and a semiquantitative approach revealed clear difference in the annual distribution of lignins between the fiber and vessel. While the vessel walls were constantly G‐rich with varied S/G ratios through a growth ring, the fibers showed fairly regular annual distribution of lignins in which the earlywood was S‐rich with an almost constant S/G ratio and the latewood was G‐rich resulting from a decrease of the S unit. The reliability of TOF‐SIMS results was demonstrated by its high correlation with the results of thioacidolysis on radial distribution of the S/G ratio in several contiguous tree rings and also in the latewood and earlywood of each ring. These results indicate that TOF‐SIMS allows direct visualization of lignin composition in plant tissues.
Inspiratory training increases insulin sensitivity in elderly patients
Authors: Silva Mayra dos Santos , Martins Ana Claudia , Cipriano Gerson , Ramos Luiz Roberto , Lopes Guiomar Silva
Published: October 2011

Aim:  Physiological degeneration in the aging process can cause a notable decline in carbohydrate metabolism. Respiratory training has been recommended to elderly patients in an attempt to prevent or minimize the alterations to the cardiorespiratory, metabolic and cognitive systems and to improve their quality of life. The objective of this work was to investigate the influence of inspiratory muscular training, with Threshold, on insulin resistance in elderly people.

Methods:  This study included 14 insulin resistant elderly volunteers, ranging in age from 61 to 82 years old. Insulin resistance was confirmed using the homeostatic model assessment. The patients were divided into two groups: experimental and control. The program lasted 12 weeks, with 30‐min training daily using Threshold to train the inspiratory muscles.

Results:  The experimental group had improved insulin resistance, with decreased glycemia and insulin requirements, a lower homeostatic model assessment of insulin resistance, and increased respiratory force and performance.

Conclusion:  The small sample does not allow for conclusions, but we can suggest that inspiratory muscular training improves insulin sensitivity in elderly patients with insulin resistance. Geriatr Gerontol Int 2012; 12: 345–351.
Faster decline of physical performance in older adults with higher levels of baseline locomotive function
Authors: Yamada Minoru , Uemura Kazuki , Mori Shuhei , Nagai Koutatsu , Uehara Toshiaki , Arai Hidenori , Aoyama Tomoki
Published: October 2011

Aim:  The purpose of this longitudinal study was to determine whether the rate of decline in community‐dwelling older adults varies according to baseline locomotive function levels.

Methods:  This longitudinal study was conducted in community‐dwelling older adults in Kyoto, Japan. In addition to information about falls, physical performance was assessed using a series of tests, including 10‐m walking time, timed up and go (TUG) test, functional reach, one‐leg stand test, and five chair stand test. The outcomes for each patient were measured once in 2009 and then followed up 1 year later. The change in physical performance was then determined. We divided the participants into tertiles (T1, T2, and T3) according to timed up and go test results, and the differences among the three groups were compared.

Results:  Of the 252 individuals who were enrolled in the study, 231 (91.6%) completed the 12‐month follow‐up: 77 in the T1 group; 78 in the T2 group; and 76 in the T3 group. The T1 group showed a significantly larger decrease than the T2 and T3 groups in the 10‐m walking time and TUG tests (P < 0.05). However, there were no significant differences in functional reach, one‐leg standing test, or five chair stand test among the three groups. In the T1 group, the number of falls and elderly who had developed fear of falling increased during the study period.

Conclusions:  This study demonstrated that elderly with the highest baseline performances were more likely to show a greater decline in locomotive performance than the other groups. Further study is required to elucidate the mechanism of faster physical functional decline in robust elderly. Geriatr Gerontol Int 2012; 12: 238–246.
Effectiveness of Multiple Release Sites in Reintroduction of Persian Fallow Deer
Authors: BERGER‐TAL ODED , BAR‐DAVID SHIRLI , SALTZ DAVID
Published: October 2011

Abstract:  Releasing animals in more than one location may increase or decrease the probability of success of a reintroduction project, yet the question of how many release sites to use has received little attention. We used empirical data from the reintroduction program of the Persian fallow deer (Dama mesopotamica) (Galilee region in northern Israel) in an individual‐based spatially explicit simulation model to assess the effects of releasing deer from multiple sites. We examined whether multiple release sites increase reintroduction success, and if so, whether the optimal number of sites for a given scenario can be determined and whether the outcome differs if animals are released alternately (i.e., the location of the release alternates yearly between sites) or consecutively (i.e., one release site is used for several years, then another is used, and so forth). We selected 8 potential release sites in addition to the original site and simulated the release of 180 individuals at a rate of 10 individuals per year in different combinations of the original site and 1–4 additional sites. In our model, releasing animals into the wild at multiple sites produced higher population growth and greater spatial expansion than releasing animals at only one site and a consecutive‐release approach was superior to an alternate‐release approach. We suggest that through the use of simulation modeling that is based on empirical data from previous releases, managers can make better‐informed decisions regarding the use of multiple release sites and greatly improve the probability of reintroduction success.
Reduced Effect of Tasmanian Devil Facial Tumor Disease at the Disease Front
Authors: HAMEDE RODRIGO , LACHISH SHELLY , BELOV KATHERINE , WOODS GREGORY , KREISS ALEXANDRE , PEARSE ANNE‐MAREE , LAZENBY BILLIE , JONES MENNA , McCALLUM HAMISH
Published: October 2011

Abstract:  Pathogen‐driven declines in animal populations are increasingly regarded as a major conservation issue. The Tasmanian devil (Sarcophilus harrisii) is threatened with extinction by devil facial tumor disease, a unique transmissible cancer. The disease is transmitted through direct transfer of tumor cells, which is possible because the genetic diversity of Tasmanian devils is low, particularly in the major histocompatibility complex genes of the immune system. The far northwest of Tasmania now holds the last remaining disease‐free wild devil populations. The recent discovery of unique major histocompatibility complex genotypes in the northwestern region of Tasmania has raised the possibility that some animals may be resilient to the disease. We examined the differences in the epidemiology and population effects of devil facial tumor disease at 3 well‐studied affected sites in eastern Tasmania and 1 in western Tasmania (West Pencil Pine). In contrast to the 3 eastern sites, there has been no rapid increase in disease prevalence or evidence of population decline at West Pencil Pine. Moreover, this is the only onsite at which the population age structure has remained unaltered 4 years after the first detection of disease. The most plausible explanations for the substantial differences in population effects and epidemiology of the disease between eastern and western sites are geographic differences in genotypes or phenotypes of devils and functional differences between tumor strains in the 2 regions. We suggest that conservation efforts focus on identifying whether either or both these explanations are correct and then, if resistance alleles exist, to attempt to spread the resistant alleles into affected populations. Such assisted selection has rarely been attempted for the management of wildlife diseases, but it may be widely applicable.
Methodology for Setting Risk‐Based Concentrations of Contaminants in Soil and Groundwater and Application to a Model Contaminated Site
Authors: Fujinaga Aiichiro , Uchiyama Iwao , Morisawa Shinsuke , Yoneda Minoru , Sasamoto Yuzuru
Published: October 2011

In Japan, environmental standards for contaminants in groundwater and in leachate from soil are set with the assumption that they are used for drinking water over a human lifetime. Where there is neither a well nor groundwater used for drinking, the standard is thus too severe. Therefore, remediation based on these standards incurs excessive effort and cost. In contrast, the environmental‐assessment procedure used in the United States and the Netherlands considers the site conditions (land use, existing wells, etc.); however, a risk assessment is required for each site. Therefore, this study proposes a new framework for judging contamination in Japan by considering the merits of the environmental standards used and a method for risk assessment. The framework involves setting risk‐based concentrations that are attainable remediation goals for contaminants in soil and groundwater. The framework was then applied to a model contaminated site for risk management, and the results are discussed regarding the effectiveness and applicability of the new methodology.
On the Publicity of Two‐Stage Spin‐Offs and Equity Carve‐Outs
Authors: Chahine Salim , Goergen Marc
Published: October 2011

We investigate the effect of pre‐offer publicity on ownership, pricing, and aftermarket performance for equity carve‐outs (ECOs) and two‐stage spin‐offs (COSOs). Contrary to ECOs, for COSOs the parent firm's shareholders end up with free shares in the subsidiary. As the value of large share blocks is likely to be negatively affected by the emergence of new blocks after the divestiture, we hypothesize that parent firms undertaking COSOs may conduct more pre‐offer publicity to attract more retail investors, keeping outside ownership diffuse and inflating aftermarket performance until the distribution of the free shares. We find empirical support for our hypotheses.
Superfluid effects on gauging core temperatures of neutron stars in low-mass X-ray binaries
Authors: Ho Wynn C. G.
Published: October 2011

Neutron stars accreting matter from low-mass binary companions are observed to undergo bursts of X-rays due to the thermonuclear explosion of material on the neutron star surface. We use recent results on superfluid and superconducting properties to show that the core temperature in these neutron stars may not be uniquely determined for a range of observed accretion rates. The degeneracy in inferred core temperatures could contribute to explaining the difference between neutron stars which have very short recurrence times between multiple bursts and those which have long recurrence times between bursts: short bursting sources have higher temperatures and normal neutrons in the stellar core, while long bursting sources have lower temperatures and superfluid neutrons. If correct, measurements of the lowest luminosity from among the short bursting sources and highest luminosity from among the long bursting sources can be used to constrain the critical temperature for the onset of neutron superfluidity.
Glycoprotein IIb‐IIIa Inhibitors
Authors: De Luca Giuseppe
Published: October 2011

Platelets play a pivotal role in the pathogenesis of coronary artery disease and myocardial infarction. Therefore, great interests have been focused in the last decades on improvement in antiplatelet therapies, that currently are regarded as main pillars in the prevention and treatment of coronary artery disease, with special attention to glycoprotein IIb‐IIIa (GP IIb‐IIIa) receptors, that mediates the final stage of platelet activation. GP IIb‐IIIa inhibitors, especially abciximab, have been shown to improve clinical outcome in patients undergoing primary angioplasty for STEMI. Upstream administration cannot routinely recommended, but may potentially be considered among high‐risk patients within the first 4 h from symptoms onset. In case of periprocedural administration of antithrombotic therapy, Bivalirudin should be considered, especially in patients at high risk for bleeding complications. Among high‐risk patients with acute coronary syndromes, an early invasive strategy with selective downstream administration of GP IIb‐IIIa inhibitors is the strategy of choice, whereas bivalirudin should be considered in patients at high risk for bleeding complications. Among patients with unstable angina GP IIb‐IIIa inhibitors should be considered only in case of evidence of intracoronary thrombus or in case of thrombotic complications (as provisional use). Further, randomized trials are certainly needed in the era of new oral antiplatelet therapies, and with strategies to prevent bleeding complications such as larger use of radial approach, mechanical closure devices, bivalirudin, or postprocedural protamine administration to promote early sheat removal.
Basic characteristics of uniaxial extension rheology: Comparing monodisperse and bidisperse polymer melts
Authors: Wang Yangyang , Cheng Shiwang , Wang Shi-Qing
Published: October 2011

We have carried out continuous and step uniaxial extension experiments on monodisperse and bidisperse styrene-butadiene random copolymers (SBR) to demonstrate that their nonlinear rheological behavior can be understood in terms of yielding through breakdown of the chain entanglement network and rubberlike rupture via non-Gaussian chain stretching leading to chain scission, respectively. In continuous extension, the sample with bidisperse molecular weight distribution showed greater resistance, due to double-networking, against the yielding-initiated failure. An introduction of 20% high molecular weight (106 g/mol) SBR to an SBR matrix (2.4 × 105 g/mol) could postpone the onset of nonuniform extension by as much as two Hencky strain units. In step extension, the bidisperse blends were also found to be more resistant to elastic breakup than the monodisperse matrix SBR. Rupture in both monodisperse and bidisperse SBR samples occurred when the finite chain extensibility was reached at sufficiently high rates. It is important to point out here that these results along with the concept of yielding allow us to clarify the concept of strain hardening in extensional rheology of entangled polymers.
Detection of Pulsed Gamma Rays Above 100 GeV from the Crab Pulsar
Authors:   The VERITAS Collaboration, Aliu E. , Arlen T. , Aune T. , Beilicke M. , Benbow W. , Bouvier A. , Bradbury S. M. , Buckley J. H. , Bugaev V. , Byrum K. , Cannon A. , Cesarini A. , Christiansen J. L. , Ciupik L. , Collins-Hughes E. , Connolly M. P. , Cui W. , Dickherber R. , Duke C. , Errando M. , Falcone A. , Finley J. P. , Finnegan G. , Fortson L. , Furniss A. , Galante N. , Gall D. , Gibbs K. , Gillanders G. H. , Godambe S. , Griffin S. , Grube J. , Guenette R. , Gyuk G. , Hanna D. , Holder J. , Huan H. , Hughes G. , Hui C. M. , Humensky T. B. , Imran A. , Kaaret P. , Karlsson N. , Kertzman M. , Kieda D. , Krawczynski H. , Krennrich F. , Lang M. J. , Lyutikov M. , Madhavan A. S , Maier G. , Majumdar P. , McArthur S. , McCann A. , McCutcheon M. , Moriarty P. , Mukherjee R. , Nuñez P. , Ong R. A. , Orr M. , Otte A. N. , Park N. , Perkins J. S. , Pizlo F. , Pohl M. , Prokoph H. , Quinn J. , Ragan K. , Reyes L. C. , Reynolds P. T. , Roache E. , Rose H. J. , Ruppel J. , Saxon D. B. , Schroedter M. , Sembroski G. H. , Şentürk G. D. , Smith A. W. , Staszak D. , Tešić G. , Theiling M. , Thibadeau S. , Tsurusaki K. , Tyler J. , Varlotta A. , Vassiliev V. V. , Vincent S. , Vivier M. , Wakely S. P. , Ward J. E. , Weekes T. C. , Weinstein A. , Weisgarber T. , Williams D. A. , Zitzer B.
Published: October 2011

This detection constrains the mechanism and emission region of gamma-ray radiation in the pulsar’s magnetosphere.
Toward Control of Large-Scale Quantum Computing
Authors: DiVincenzo David P.
Published: October 2011

Basic quantum computing elements are combined to improve quantum simulations and to create a quantum version of a central processing unit.
The Genomic Basis of Local Climatic Adaptation
Authors: Savolainen Outi
Published: October 2011

Studies of
Arabidopsis thaliana
help to identify the genomic sites associated with adaptation to local climatic conditions.
The Guts of Dietary Habits
Authors: Gophna Uri
Published: October 2011

Can dietary intervention change an individual's gut microbiome composition?
Genomics Is Not Enough
Authors: Chakravarti Aravinda
Published: October 2011

Next week, the international congress of human genetics convenes in Montreal, where genomic science, its technologies, genetic disease, and personalized medicine will be discussed. Translating current knowledge into medical practice is an important goal for the public who support medical research, and for the scientists and clinicians who articulate the critical research needs of our time. However, despite innumerable successful gene discoveries through genomics, a major impediment is our lack of knowledge of how these genes affect the fundamental biological mechanisms that are dysregulated in disease. If genomic medicine is to prosper, we need to turn our attention to this gaping hole.
Optimized Pathogen Detection with 30- Compared to 20-Milliliter Blood Culture Draws
Authors: Patel Robin , Vetter Emily A. , Harmsen W. Scott , Schleck Cathy D. , Fadel Hind J. , Cockerill Franklin R.
Published: October 2011

Using data from 23,313 patients, we assessed whether two blood culture sets of three bottles per set would detect more pathogens than two sets of two bottles per set and achieve similar sensitivity to collecting three sets of two bottles per set. We also compared the yield of aerobic and anaerobic bottles. Thirty milliliters of blood was distributed to one anaerobic and two aerobic bottles. Among 26,855 collections of ≥60 ml within 30 min, 1,379 (5.1%) were positive for a pathogen not requiring detection in more than one set to be considered a pathogen, with 72 additional distinct pathogens detected using two 30-ml compared to two 20-ml sets of one aerobic and one anaerobic bottle (increased yield, 7.9%; 95% confidence interval [CI], 6.2 to 9.8%). For conditional pathogens requiring detection in at least two positive blood cultures for classification as pathogens (i.e., otherwise classified as contaminants), there were 162 positive detections with two 30-ml sets, of which 16 would not have been detected by two 20-ml sets (increased yield, 11.0% [95% CI, 6.4 to 17.2%]). Among 134 subjects who had three sets of 30 ml each within a 30-min interval, there was complete concordance between 60 ml of blood drawn in the first two sets of 30 ml and three 20-ml sets (
P
= 1.0). One aerobic bottle plus one anaerobic bottle yielded more pathogens than two aerobic bottles for organisms requiring a single (
P
< 0.001) and two (
P
= 0.04) positive sets to be defined as pathogens. In conclusion, we showed that collection of two aerobic and one anaerobic blood culture bottles per set results in improved yield compared to two bottles per set. We also confirmed that an anaerobic bottle should be included in blood culture sets.
Substitutions in the Glycoprotein (GP) of the Candid#1 Vaccine Strain of Junin Virus Increase Dependence on Human Transferrin Receptor 1 for Entry and Destabilize the Metastable Conformation of GP
Authors: Droniou-Bonzom Magali E. , Reignier Therese , Oldenburg Jill E. , Cox Alex U. , Exline Colin M. , Rathbun Jessica Y. , Cannon Paula M.
Published: October 2011

Candid#1 (Cd1) is an attenuated vaccine strain of Junin virus, the causative agent of Argentine hemorrhagic fever. Although several substitutions are present in Cd1, their importance for attenuation has not been established. We functionally characterized the substitutions present in the Cd1 glycoprotein (GP) and identified F427I in the transmembrane domain of the GP2 subunit as reducing infectivity in a reconstituted viral system. We further showed that this phenotype derives from the destabilization of the GP metastable conformation. Lastly, we identified an increased dependence of Cd1 GP on human transferrin receptor type 1 (hTfR-1) for entry, which may affect the tropism of the attenuated strain
in vivo
.
Cerebellar regions involved in adaptation to force field and visuomotor perturbation
Authors: Donchin Opher , Rabe Kasja , Diedrichsen Jörn , Lally Níall , Schoch Beate , Gizewski Elke Ruth , Timmann Dagmar
Published: October 2011

Studies with patients and functional magnetic resonance imaging investigations have demonstrated that the cerebellum plays an essential role in adaptation to visuomotor rotation and force field perturbation. To identify cerebellar structures involved in the two tasks, we studied 19 patients with focal lesions after cerebellar infarction. Focal lesions were manually traced on magnetic resonance images and normalized using a new spatially unbiased template of the cerebellum. In addition, we reanalyzed data from 14 patients with cerebellar degeneration using voxel-based morphometry. We found that adjacent regions with only little overlap in the anterior arm area (lobules IV to VI) are important for adaptation in both tasks. Although adaptation to the force field task lay more anteriorly (lobules IV and V), lobule VI was more important for the visuomotor task. In addition, regions in the posterolateral cerebellum (Crus I and II) contributed to both tasks. No consistent involvement of the posterior arm region (lobule VIII) was found. Independence of the two kinds of adaptation is further supported by findings that performance in one task did not correlate to performance in the other task. Our results show that the anterior arm area of the cerebellum is functionally divided into a more posterior part of lobule VI, extending into lobule V, related to visuomotor adaption, and a more anterior part including lobules IV and V, related to force field adaption. The posterolateral cerebellum may process common aspects of both tasks.
Decreased Lymphangiogenesis and Lymph Node Metastasis by mTOR Inhibition in Head and Neck Cancer
Authors: Patel Vyomesh , Marsh Christina A. , Dorsam Robert T. , Mikelis Constantinos M. , Masedunskas Andrius , Amornphimoltham Panomwat , Nathan Cherie Ann , Singh Bhuvanesh , Weigert Roberto , Molinolo Alfredo A. , Gutkind J. Silvio
Published: October 2011

Despite our improved understanding of cancer, the 5-year survival rate for head and neck squamous cell carcinomas (HNSCC) patients remains relatively unchanged at 50% for the past three decades. HNSCCs often metastasize to locoregional lymph nodes, and lymph node involvement represents one of the most important prognostic factors of poor clinical outcome. Among the multiple dysregulated molecular mechanism in HNSCCs, emerging basic, preclinical, and clinical findings support the importance of the mTOR signaling route in HNSCC progression. Indeed, we observed here that the activation of mTOR is a widespread event in clinical specimens of HNSCCs invading locoregional lymph nodes. We developed an orthotopic model of HNSCC consisting of the implantation of HNSCC cells into the tongues of immunocompromised mice. These orthotopic tumors spontaneously metastasize to the cervical lymph nodes, where the presence of HNSCC cells can be revealed by histologic and immunohistochemical evaluation. Both primary and metastatic experimental HNSCC lesions exhibited elevated mTOR activity. The ability to monitor and quantitate lymph node invasion in this model system enabled us to explore whether the blockade of mTOR could impact HNSCC metastasis. We found that inhibition of mTOR with rapamycin and the rapalog RAD001 diminished lymphangiogenesis in the primary tumors and prevented the dissemination of HNSCC cancer cells to the cervical lymph nodes, thereby prolonging animal survival. These findings may provide a rationale for the future clinical evaluation of mTOR inhibitors, including rapamycin and its analogues, as part of a molecular-targeted metastasis preventive strategy for the treatment of patients with HNSCC. Cancer Res; 71(22); 7103–12. ©2011 AACR.
c-MYC Functions as a Molecular Switch to Alter the Response of Human Mammary Epithelial Cells to Oncostatin M
Authors: Kan Charlene E. , Cipriano Rocky , Jackson Mark W.
Published: October 2011

Cytokines play an important role in creating an inflammatory microenvironment, which is now considered a hallmark of cancer. Although tumor cells can exploit cytokine signaling to promote growth, invasion, and metastasis, the response of normal and premalignant epithelial cells to cytokines present in a developing tumor microenvironment remains unclear. Oncostatin M (OSM), an IL-6 family cytokine responsible for STAT3 activation, has been implicated in cancer development, progression, invasion, and metastasis. Paradoxically, OSM can also suppress the growth of normal cells and certain tumor-derived cell lines. Using isogenic human mammary epithelial cells (HMEC) at different stages of neoplastic transformation, we found that OSM signaling suppressed c-MYC expression and engaged a p16- and p53-independent growth arrest that required STAT3 activity. Inhibition of STAT3 activation by expressing a dominant-negative STAT3 protein or a STAT3-shRNA prevented the OSM-mediated arrest. In addition, expression of c-MYC from a constitutive promoter also abrogated the STAT3-mediated arrest, and strikingly, cooperated with OSM to promote anchorage-independent growth (AIG), a property associated with malignant transformation. Cooperative transformation by c-MYC and OSM required PI3K and AKT signaling, showing the importance of multiple signaling pathways downstream of the OSM receptor in defining the cellular response to cytokines. These findings identify c-MYC as an important molecular switch that alters the cellular response to OSM-mediated signaling from tumor suppressive to tumor promoting. Cancer Res; 71(22); 6930–9. ©2011 AACR.
Association of Census Tract-Level Socioeconomic Status with Disparities in Prostate Cancer–Specific Survival
Authors: Freeman Vincent L. , Ricardo Ana C. , Campbell Richard T. , Barrett Richard E. , Warnecke Richard B.
Published: October 2011

Background: Social determinants of prostate cancer survival and their relation to racial/ethnic disparities thereof are poorly understood. We analyzed whether census tract-level socioeconomic status (SES) at diagnosis is a prognostic factor in men with prostate cancer and helps explain racial/ethnic disparities in survival.

Methods: We used a retrospective cohort of 833 African American and white, non-Hispanic men diagnosed with prostate cancer at four Chicago area medical centers between 1986 and 1990. Tract-level concentrated disadvantage (CD), a multidimensional area-based measure of SES, was calculated for each case, using the 1990 U.S. census data. Its association with prostate cancer–specific survival was measured by using Cox proportional hazard models adjusted for case and tumor characteristics, treatment, and health care system [private sector vs. Veterans Health Administration (VA)].

Results: Tract-level CD associated with an increased risk of death from prostate cancer (highest vs. lowest quartile, HR = 2.37, P < 0.0001). However, the association was observed in the private sector and not in the VA (per 1 SD increase, HR = 1.33, P < 0.0001 and HR = 0.93, P = 0.46, respectively). The multivariate HR for African Americans before and after accounting for tract-level CD was 1.30 (P = 0.0036) and 0.96 (P = 0.82), respectively.

Conclusions: Census tract-level SES is a social determinant of prostate-specific mortality and helps account for racial/ethnic disparities in survival. An equal-access health care system may moderate this association.

Impact: This study identifies a potential pathway for minimizing disparities in prostate cancer control. The findings need confirmation in a population-based study. Cancer Epidemiol Biomarkers Prev; 20(10); 2150–9. ©2011 AACR.
Coordinating Centers in Cancer Epidemiology Research: the Asia Cohort Consortium Coordinating Center
Authors: Rolland Betsy , Smith Briana R. , Potter John D.
Published: October 2011

Although it is tacitly recognized that a good coordinating center (CC) is essential to the success of any multisite collaborative project, very little study has been done on what makes a CC successful, why some CCs fail, or how to build a CC that meets the needs of a given project. Moreover, very little published guidance is available, as few CCs outside the clinical trial realm write about their work. The Asia Cohort Consortium (ACC) is a collaborative cancer epidemiology research project that has made strong scientific and organizational progress over the past 3 years by focusing its CC on the following activities: collaboration development; operations management; statistical and data management; and communications infrastructure and tool development. Our hope is that, by sharing our experience building the ACC CC, we can begin a conversation about what it means to run a CC for multi-institutional collaboration in cancer epidemiology, help other collaborative projects solve some of the issues associated with collaborative research, and learn from others. Cancer Epidemiol Biomarkers Prev; 20(10); 2115–9. ©2011 AACR.
Survivors at Higher Risk for Adverse Late Outcomes Due to Psychosocial and Behavioral Risk Factors
Authors: Carmack Cindy L. , Basen-Engquist Karen , Gritz Ellen R.
Published: October 2011

Cancer survivors face significant morbidity and mortality associated with their disease and treatment regimens, some of which can be improved through modifying behavioral and psychosocial risk factors. This article examines risk factors for adverse late effects that contribute to morbidity and mortality in cancer survivors, provides a literature review on interventions to modify these risks factors, and summarizes the national recommendations and associated current practices for identifying and managing these risk factors. Finally, future directions for research and clinical practice are discussed. Cancer Epidemiol Biomarkers Prev; 20(10); 2068–77. ©2011 AACR.
Cancer Survivorship Research: A Review of the Literature and Summary of Current NCI-Designated Cancer Center Projects
Authors: Harrop J. Phil , Dean Julie A. , Paskett Electra D.
Published: October 2011

The number of cancer survivors and the amount of cancer survivorship research have grown substantially during the past three decades. This article provides a review of interventional and observational cancer survivorship research efforts as well as a summary of current cancer survivorship research projects being conducted by National Cancer Institute–designated cancer centers in an effort to identify areas that need further attention. Cancer Epidemiol Biomarkers Prev; 20(10); 2042–7. ©2011 AACR.
Mast Cells in Tumor Microenvironment Promotes the In Vivo Growth of Pancreatic Ductal Adenocarcinoma
Authors: Chang David Z. , Ma Ying , Ji Baoan , Wang Huamin , Deng Defeng , Liu Yan , Abbruzzese James L. , Liu Yong-jun , Logsdon Craig D. , Hwu Patrick
Published: October 2011

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death. No effective therapy is currently available for PDAC because of the lack of understanding of the mechanisms leading to its growth and development. Inflammatory cells, particularly mast cells, have been shown to play key roles in some cancers. We carried out this study to test the hypothesis that mast cells in the tumor microenvironment are essential for PDAC tumorigenesis.

Experimental Design: The presence of inflammatory cells at various stages of PDAC development was determined in a spontaneous mouse model of PDAC (K-rasG12V). The importance of mast cells was determined using orthotopically implanted PDAC cells in mast cell–deficient Kitw-sh/w-sh mice and further confirmed by reconstitution of wild-type bone marrow–derived mast cells. Clinical relevance was assessed by correlating the presence of mast cells with clinical outcome in patients with PDAC.

Results: In the spontaneous mouse model of PDAC (K-rasG12V), there was an early influx of mast cells to the tumor microenvironment. PDAC tumor growth was suppressed in mast cell–deficient Kitw-sh/w-sh mice, but aggressive PDAC growth was restored when PDAC cells were injected into mast cell–deficient mice reconstituted with wild-type bone marrow–derived mast cells. Mast cell infiltration into the tumor microenvironment was predictive of poor prognosis in patients with PDAC.

Conclusions: Mast cells play an important role in PDAC growth and development in mouse models and are indicative of poor prognosis in humans, which makes them a potential novel therapeutic target. Clin Cancer Res; 17(22); 7015–23. ©2011 AACR.
Novel Phosphoinositide 3-Kinase/mTOR Dual Inhibitor, NVP-BGT226, Displays Potent Growth-Inhibitory Activity against Human Head and Neck Cancer Cells In Vitro and In Vivo
Authors: Chang Kwang-Yu , Tsai Shan-Yin , Wu Ching-Ming , Yen Chia-Jui , Chuang Bin-Fay , Chang Jang-Yang
Published: October 2011

Purpose: Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway frequently accounts for the tumorigenesis in head and neck cancer. To develop a new treatment, we investigated the effect of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226), in head and neck cancer cells.

Experimental Design: The in vitro antitumor effect of BGT226 was determined in various cancer cell lines. Animal models were also applied to examine drug potency. The inhibitory ability of BGT226 on the PI3K/AKT/mTOR signaling pathway was analyzed.

Results: The growth inhibition assay revealed that BGT226 was active against all tested cancer cell lines. Cross-resistance was not observed in the cisplatin-resistant cell line. The activation of the AKT/mTOR signal cascade was suppressed by BGT226 in a concentration- and time-dependent manner. Flow cytometric analysis revealed an accumulation of cells in the G0–G1 phase with concomitant loss in the S-phase. Results of the terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) assay and the analysis of caspase 3/7 and PARP indicated that BGT226 induced cancer cell death through an apoptosis-independent pathway. BGT226 induced autophagy as indicated by the aggregation and upregulation of the microtubule-associated protein light chain 3B-II, and p62 degradation. Gene silencing of Beclin1 or cotreatment of the autophagosome inhibitor, 3-methyladenine, inhibited the BGT226-induced autophagy and led to the retrieval of colony survival. In a xenografted animal model, BGT226 significantly delayed tumor growth in a dose-dependent manner, along with suppressed cytoplasmic expression of p-p70 S6 kinase and the presence of autophagosome formation.

Conclusions: These data indicate that BGT226 is a potential drug in the treatment of head and neck cancer. Clin Cancer Res; 17(22); 7116–26. ©2011 AACR.