bluuebunny/crossref_metadata_2025 huggingface dataset:
The Formation and Sustainability of same Product Retail Store Clusters in A Modern Mega City
Authors: Mandhachitara Rujirutana , Shannon Randall
Published: March 2016

Compared with manufacturing locational analysis, relatively few scholarly researchers have demonstrated serious interest in examining the forces responsible for same store retail clustering in large cities. The centrifugal and centripetal forces influencing retail locations were once the subject of serious intellectual debate. Same product retail store (SPRS) clusters, which were once common in the retail landscape of Manhattan and other Western primary cities, are now in severe decline. However, there remain modern megacities where similar retail store cluster phenomenon is resurgent. This paper attempts to examine the formation and sustainability of the SPRS clustering phenomenon illustrated by Bangkok, Thailand. The authors find 14,468 SPRS permanent retail outlets located in 299 clusters. The data were mapped and then classified according to the North American Industrial Classification System. Locational Gini coefficients were computed to permit an analysis of the city's retail clustering within and between its fifty administrative districts.
Children post liver transplantation hospitalized with fever are at a high risk for bacterial infections
Authors: Ashkenazi‐Hoffnung L. , Mozer‐Glassberg Y. , Bilavsky E. , Yassin R. , Shamir R. , Amir J.
Published: March 2016

Background

Although infections post liver transplantation are a main cause of morbidity and mortality, data are limited on transplanted children. The objective of this study was to investigate the incidence, etiology, and predictors of infection in pediatric liver transplant recipients (LTR) in the specific practical clinical setting of hospitalization for fever in order to elucidate the appropriate management of these patients.

Methods

Clinical and laboratory data were retrospectively collected for all febrile pediatric LTR hospitalized from 2004 to 2012.

Results

We analyzed 133 hospital admissions for fever among 44 pediatric LTR. Of these, 73 bacterial (54.8%) and 46 viral infections (34.5%) were diagnosed. No cases of protozoa or fungal infections were reported. Bacterial infections were most frequent during the first year post transplantation with ascending cholangitis being the most prevalent. Twenty‐six (36%) bacterial infections were microbiologically documented and 47 (64%) were clinically documented. Of the microbiologically confirmed cases, gram‐negative bacteria, namely Enterobacteriaceae, were most common (57.7%). Seven cases of bacteremia were observed including 1 case presenting with severe sepsis. Compared with the white blood cell count and absolute neutrophil count, C‐reactive protein level was found to be a more sensitive biomarker for bacterial disease. Older age on admission was a significant risk factor for bacterial infection.

Conclusion

Febrile hospitalized pediatric LTR are immunocompromised hosts at high risk for bacterial infections, and usually warrant prompt evaluation and empirical antibiotic treatment upon admission.
MOL1 is required for cambium homeostasis in Arabidopsis
Authors: Gursanscky Nial Rau , Jouannet Virginie , Grünwald Karin , Sanchez Pablo , Laaber‐Schwarz Martina , Greb Thomas
Published: March 2016

Plants maintain pools of pluripotent stem cells which allow them to constantly produce new tissues and organs. Stem cell homeostasis in shoot and root tips depends on negative regulation by ligand–receptor pairs of the CLE peptide and leucine‐rich repeat receptor‐like kinase (LRR‐RLK) families. However, regulation of the cambium, the stem cell niche required for lateral growth of shoots and roots, is poorly characterized. Here we show that the LRR‐RLK MOL1 is necessary for cambium homeostasis in Arabidopsis thaliana. By employing promoter reporter lines, we reveal that MOL1 is active in a domain that is distinct from the domain of the positively acting CLE41/PXY signaling module. In particular, we show that MOL1 acts in an opposing manner to the CLE41/PXY module and that changing the domain or level of MOL1 expression both result in disturbed cambium organization. Underlining discrete roles of MOL1 and PXY, both LRR‐RLKs are not able to replace each other when their expression domains are interchanged. Furthermore, MOL1 but not PXY is able to rescue CLV1 deficiency in the shoot apical meristem. By identifying genes mis‐expressed in mol1 mutants, we demonstrate that MOL1 represses genes associated with stress‐related ethylene and jasmonic acid hormone signaling pathways which have known roles in coordinating lateral growth of the Arabidopsis stem. Our findings provide evidence that common regulatory mechanisms in different plant stem cell niches are adapted to specific niche anatomies and emphasize the importance of a complex spatial organization of intercellular signaling cascades for a strictly bidirectional tissue production.
Assemblage thinking and actor‐network theory: conjunctions, disjunctions, cross‐fertilisations
Authors: Müller Martin , Schurr Carolin
Published: March 2016

This paper shows that assemblage thinking and actor‐network theory (ANT) have much more to gain from each other than debate has so far conceded. Exploring the conjunctions and disjunctions between the two approaches, it proposes three cross‐fertilisations that have implications for understanding three key processes in our socio‐material world: stabilisation, change and affect. First, the conceptual vocabulary of ANT can enrich assemblage thinking with an explicitly spatial account of the ways in which assemblages are drawn together, reach across space and are stabilised. Second, each approach is better attuned to conceptualising a particular kind of change in socio‐material relations: ANT describes change without rupture, or fluidity, whereas assemblage thinking describes change with rupture, or events. Third and last, assemblage thinking could fashion ANT with a greater sensitivity for the productive role of affect in bringing socio‐material relations into being through the production of desire/wish (désir). We demonstrate the implications of these cross‐fertilisations for empirical work through a case study of the global market for assisted reproduction.
Establishment and characterization of a canine soft tissue sarcoma patient‐derived xenograft model
Authors: Frazier J. P. , Beirne E. , Ditzler S. H. , Tretyak I. , Casalini J. R. , Thirstrup D. J. , Knoblaugh S. , Ward J. G. , Tripp C. D. , Klinghoffer R. A.
Published: March 2016

Spontaneously occurring soft tissue sarcoma (STS) is relatively common in canine cancer patients. Because of the similarities to human disease, canine STSs are a valuable and readily available resource for the study of new therapeutics. In this study, a canine patient‐derived xenograft (PDX) model, CDX‐STS2, was established. The CDX‐STS2 model was engrafted and expanded for systemic administration studies with chemotherapeutic agents commonly used to treat STS, including doxorubicin, docetaxel and gemcitabine. Immunohistochemistry for drug‐specific biomarkers and tumour growth measurement revealed tumour sensitivity to doxorubicin and docetaxel, whereas gemcitabine had no effect on tumour growth. Although many human PDX tumour models have been established, relatively few canine PDX models have been reported to date. CDX‐STS2 represents a new STS PDX research model of canine origin that will be useful in bridging preclinical research with clinical studies of STS in pet dogs.
Treatment of advanced canine anal sac adenocarcinoma with hypofractionated radiation therapy: 77 cases (1999–2013)
Authors: McQuown B. , Keyerleber M. A. , Rosen K. , McEntee M. C. , Burgess K. E.
Published: March 2016

Currently no standard of care exists for advanced, inoperable or metastatic anal sac adenocarcinoma (ASAC). The objective of this retrospective study was to assess the role of hypofractionated radiation therapy (RT) in 77 dogs with measurable ASAC. A total of 38% of dogs experienced a partial response to RT. For dogs presenting with clinical signs related to the tumour, improvement or resolution of signs was noted in 63%. For dogs presenting with hypercalcemia of malignancy, resolution was noted in 31% with RT alone and an additional 46% with radiation, prednisone, and/or bisphosphonates. Median overall survival was 329 days (range: 252–448 days). Median progression free survival was 289 days (range: 224–469). There was no difference in survival based on radiation protocol, use of chemotherapy, previous surgery or advanced stage. Radiation toxicities were mild and infrequent. Hypofractionated RT is well tolerated and is applicable in the treatment of advanced primary, locoregional or metastatic ASAC.
Microbiological characterization of a newly established pig breed, Aachen Minipigs
Authors: Plotzki Elena , Heinrichs Gerd , Kubícková Barbara , Ulrich Rainer G. , Denner Joachim
Published: March 2016

Background

To alleviate the shortage of human donor organs or tissues for the treatment of organ and tissue failure including diabetes, pigs are considered suitable donor animals. As organs from conventional pigs are usually too large, those from minipigs may be better suited. We recently characterized the Göttingen Minipigs, a breed well characterized concerning the presence of zoonotic microorganisms and found hepatitis E virus (HEV) and porcine cytomegalovirus (PCMV) in some animals. Here, we characterize another minipig, the Aachen Minipig (AaMP), a pig breed recently established close to the town Aachen in Germany.

Methods

The animals were tested for the prevalence and expression of porcine endogenous retroviruses (PERVs) and the presence of some selected microorganisms, among them HEV, PCMV, and porcine lymphotropic herpesviruses (PLHVs) using highly sensitive and specific PCR and RT‐PCR methods. In addition, we screened for antibodies against HEV and PLHV.

Results

PERV‐A, PERV‐B, and PERV‐C sequences were found in the genome of all Aachen Minipigs. HEV RNA was found by real‐time RT‐PCR in most, and DNA of PCMV, PLHV‐2, and PLHV‐3 was found by PCR in some animals. The animals were free of eight other microorganisms tested, but some were seropositive for porcine circovirus 2 (PCV2), porcine reproductive and respiratory syndrome virus (PRRSV), and porcine epidemic diarrhea virus (PEDV).

Conclusion

Based on medical examinations by veterinarians, the AaMP are in a good health status and seem to harbor only few microorganisms. To improve their status for use as donor pigs in xenotransplantation, the viruses detected might be eliminated by selection of negative animals, Cesarean section, and vaccination.
Uncertainty and variability in computational and mathematical models of cardiac physiology
Authors: Mirams Gary R. , Pathmanathan Pras , Gray Richard A. , Challenor Peter , Clayton Richard H.
Published: March 2016

Key points

Mathematical and computational models of cardiac physiology have been an integral component of cardiac electrophysiology since its inception, and are collectively known as the Cardiac Physiome.

We identify and classify the numerous sources of variability and uncertainty in model formulation, parameters and other inputs that arise from both natural variation in experimental data and lack of knowledge.

The impact of uncertainty on the outputs of Cardiac Physiome models is not well understood, and this limits their utility as clinical tools.

We argue that incorporating variability and uncertainty should be a high priority for the future of the Cardiac Physiome.

We suggest investigating the adoption of approaches developed in other areas of science and engineering while recognising unique challenges for the Cardiac Physiome; it is likely that novel methods will be necessary that require engagement with the mathematics and statistics community.

The Cardiac Physiome effort is one of the most mature and successful applications of mathematical and computational modelling for describing and advancing the understanding of physiology. After five decades of development, physiological cardiac models are poised to realise the promise of translational research via clinical applications such as drug development and patient‐specific approaches as well as ablation, cardiac resynchronisation and contractility modulation therapies. For models to be included as a vital component of the decision process in safety‐critical applications, rigorous assessment of model credibility will be required. This White Paper describes one aspect of this process by identifying and classifying sources of variability and uncertainty in models as well as their implications for the application and development of cardiac models. We stress the need to understand and quantify the sources of variability and uncertainty in model inputs, and the impact of model structure and complexity and their consequences for predictive model outputs. We propose that the future of the Cardiac Physiome should include a probabilistic approach to quantify the relationship of variability and uncertainty of model inputs and outputs.

image
Universal diffraction of atoms and molecules from a quantum reflection grating
Authors: Zhao Bum Suk , Zhang Weiqing , Schöllkopf Wieland
Published: March 2016

Researchers observed universal diffraction of He, He
2
, and D
2
quantum-reflected tens of nanometers above a ruled diffraction grating.
Why do some males choose to breed at home when most other males disperse?
Authors: Davidian Eve , Courtiol Alexandre , Wachter Bettina , Hofer Heribert , Höner Oliver P.
Published: March 2016

A long-term study on spotted hyenas shows that male philopatry and dispersal may result from a single process of habitat selection.
Cavity magnomechanics
Authors: Zhang Xufeng , Zou Chang-Ling , Jiang Liang , Tang Hong X.
Published: March 2016

Coherent magnon-phonon interaction is demonstrated in a ferrimagnetic sphere.
Assessing faculty professional development in STEM higher education: Sustainability of outcomes
Authors: Derting Terry L. , Ebert-May Diane , Henkel Timothy P. , Maher Jessica Middlemis , Arnold Bryan , Passmore Heather A.
Published: March 2016

New faculty sustained the implementation of learner-centered courses in biology following professional development.
Inverse correlation between quasiparticle mass and
T
c
in a cuprate high-
T
c
superconductor
Authors: Putzke Carsten , Malone Liam , Badoux Sven , Vignolle Baptiste , Vignolles David , Tabis Wojciech , Walmsley Philip , Bird Matthew , Hussey Nigel E. , Proust Cyril , Carrington Antony
Published: March 2016

Contrary to what is expected near a quantum critical point, pressure decreases the quasiparticle mass of a high-
T
c
superconductor.
Harnessing surface-bound enzymatic reactions to organize microcapsules in solution
Authors: Shklyaev Oleg E. , Shum Henry , Sen Ayusman , Balazs Anna C.
Published: March 2016

A model developed for convective aggregation of microcapsules predicts a mechanism for the spontaneous assembly of protocells.
Wolbachia Modulates Lipid Metabolism in Aedes albopictus Mosquito Cells
Authors: Molloy Jennifer C. , Sommer Ulf , Viant Mark R. , Sinkins Steven P.
Published: March 2016

Certain strains of the intracellular endosymbiontWolbachiacan strongly inhibit or block the transmission of viruses such as dengue virus (DENV) byAedesmosquitoes, and the mechanisms responsible are still not well understood. Direct infusion and liquid chromatography-Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry-based lipidomics analyses were conducted usingAedes albopictusAa23 cells that were infected with thewMel andwMelPop strains ofWolbachiain comparison to uninfected Aa23-T cells. Substantial shifts in the cellular lipid profile were apparent in the presence ofWolbachia. Most significantly, almost all sphingolipid classes were depleted, and some reductions in diacylglycerols and phosphatidylcholines were also observed. These lipid classes have previously been shown to be selectively enriched in DENV-infected mosquito cells, suggesting thatWolbachiamay produce a cellular lipid environment that is antagonistic to viral replication. The data improve our understanding of the intracellular interactions betweenWolbachiaand mosquitoes.

IMPORTANCEMosquitoes transmit a variety of important viruses to humans, such as dengue virus and Zika virus. Certain strains of the intracellular bacterial genus calledWolbachiafound in or introduced into mosquitoes can block the transmission of viruses, including dengue virus, but the mechanisms responsible are not well understood. We found substantial shifts in the cellular lipid profiles in the presence of these bacteria. Some lipid classes previously shown to be enriched in dengue virus-infected mosquito cells were depleted in the presence ofWolbachia, suggesting thatWolbachiamay produce a cellular lipid environment that inhibits mosquito-borne viruses.
Two Bacterial Genera, Sodalis and Rickettsia, Associated with the Seal Louse Proechinophthirus fluctus (Phthiraptera: Anoplura)
Authors: Boyd Bret M. , Allen Julie M. , Koga Ryuichi , Fukatsu Takema , Sweet Andrew D. , Johnson Kevin P. , Reed David L.
Published: March 2016

Roughly 10% to 15% of insect species host heritable symbiotic bacteria known as endosymbionts. The lice parasitizing mammals rely on endosymbionts to provide essential vitamins absent in their blood meals. Here, we describe two bacterial associates from a louse,
Proechinophthirus fluctus
, which is an obligate ectoparasite of a marine mammal. One of these is a heritable endosymbiont that is not closely related to endosymbionts of other mammalian lice. Rather, it is more closely related to endosymbionts of the genus
Sodalis
associated with spittlebugs and feather-chewing bird lice. Localization and vertical transmission of this endosymbiont are also more similar to those of bird lice than to those of other mammalian lice. The endosymbiont genome appears to be degrading in symbiosis; however, it is considerably larger than the genomes of other mammalian louse endosymbionts. These patterns suggest the possibility that this
Sodalis
endosymbiont might be recently acquired, replacing a now-extinct, ancient endosymbiont. From the same lice, we also identified an abundant bacterium belonging to the genus
Rickettsia
that is closely related to
Rickettsia ricketsii
, a human pathogen vectored by ticks. No obvious masses of the
Rickettsia
bacterium were observed in louse tissues, nor did we find any evidence of vertical transmission, so the nature of its association remains unclear.

IMPORTANCE
Many insects are host to heritable symbiotic bacteria. These heritable bacteria have been identified from numerous species of parasitic lice. It appears that novel symbioses have formed between lice and bacteria many times, with new bacterial symbionts potentially replacing existing ones. However, little was known about the symbionts of lice parasitizing marine mammals. Here, we identified a heritable bacterial symbiont in lice parasitizing northern fur seals. This bacterial symbiont appears to have been recently acquired by the lice. The findings reported here provide insights into how new symbioses form and how this lifestyle is shaping the symbiont genome.
Vacuolar H+-ATPase Protects Saccharomyces cerevisiae Cells against Ethanol-Induced Oxidative and Cell Wall Stresses
Authors: Charoenbhakdi Sirikarn , Dokpikul Thanittra , Burphan Thanawat , Techo Todsapol , Auesukaree Choowong
Published: March 2016

During fermentation, increased ethanol concentration is a major stress for yeast cells. Vacuolar H+-ATPase (V-ATPase), which plays an important role in the maintenance of intracellular pH homeostasis through vacuolar acidification, has been shown to be required for tolerance to straight-chain alcohols, including ethanol. Since ethanol is known to increase membrane permeability to protons, which then promotes intracellular acidification, it is possible that the V-ATPase is required for recovery from alcohol-induced intracellular acidification. In this study, we show that the effects of straight-chain alcohols on membrane permeabilization and acidification of the cytosol and vacuole are strongly dependent on their lipophilicity. These findings suggest that the membrane-permeabilizing effect of straight-chain alcohols induces cytosolic and vacuolar acidification in a lipophilicity-dependent manner. Surprisingly, after ethanol challenge, the cytosolic pH in Δvma2and Δvma3mutants lacking V-ATPase activity was similar to that of the wild-type strain. It is therefore unlikely that the ethanol-sensitive phenotype ofvmamutants resulted from severe cytosolic acidification. Interestingly, thevmamutants exposed to ethanol exhibited a delay in cell wall remodeling and a significant increase in intracellular reactive oxygen species (ROS). These findings suggest a role for V-ATPase in the regulation of the cell wall stress response and the prevention of endogenous oxidative stress in response to ethanol.

IMPORTANCEThe yeastSaccharomyces cerevisiaehas been widely used in the alcoholic fermentation industry. Among the environmental stresses that yeast cells encounter during the process of alcoholic fermentation, ethanol is a major stress factor that inhibits yeast growth and viability, eventually leading to fermentation arrest. This study provides evidence for the molecular mechanisms of ethanol tolerance, which is a desirable characteristic for yeast strains used in alcoholic fermentation. The results revealed that straight-chain alcohols induced cytosolic and vacuolar acidification through their membrane-permeabilizing effects. Contrary to expectations, a role for V-ATPase in the regulation of the cell wall stress response and the prevention of endogenous oxidative stress, but not in the maintenance of intracellular pH, seems to be important for protecting yeast cells against ethanol stress. These findings will expand our understanding of the mechanisms of ethanol tolerance and provide promising clues for the development of ethanol-tolerant yeast strains.
Environmental Metabolomics of the Tomato Plant Surface Provides Insights on Salmonella enterica Colonization
Authors: Han Sanghyun , Micallef Shirley A.
Published: March 2016

Foodborne illness-causing enteric bacteria are able to colonize plant surfaces without causing infection. We lack an understanding of how epiphytic persistence of enteric bacteria occurs on plants, possibly as an adaptive transit strategy to maximize chances of reentering herbivorous hosts. We used tomato (
Solanum lycopersicum
) cultivars that have exhibited differential susceptibilities to
Salmonella enterica
colonization to investigate the influence of plant surface compounds and exudates on enteric bacterial populations. Tomato fruit, shoot, and root exudates collected at different developmental stages supported growth of
S. enterica
to various degrees in a cultivar- and plant organ-dependent manner.
S. enterica
growth in fruit exudates of various cultivars correlated with epiphytic growth data (
R
2
= 0.504;
P
= 0.006), providing evidence that plant surface compounds drive bacterial colonization success. Chemical profiling of tomato surface compounds with gas chromatography-time of flight mass spectrometry (GC-TOF-MS) provided valuable information about the metabolic environment on fruit, shoot, and root surfaces. Hierarchical cluster analysis of the data revealed quantitative differences in phytocompounds among cultivars and changes over a developmental course and by plant organ (
P
< 0.002). Sugars, sugar alcohols, and organic acids were associated with increased
S. enterica
growth, while fatty acids, including palmitic and oleic acids, were negatively correlated. We demonstrate that the plant surface metabolite landscape has a significant impact on
S. enterica
growth and colonization efficiency. This environmental metabolomics approach provides an avenue to understand interactions between human pathogens and plants that could lead to strategies to identify or breed crop cultivars for microbiologically safer produce.

IMPORTANCE
In recent years, fresh produce has emerged as a leading food vehicle for enteric pathogens.
Salmonella
-contaminated tomatoes represent a recurrent human pathogen-plant commodity pair. We demonstrate that
Salmonella
can utilize tomato surface compounds and exudates for growth. Surface metabolite profiling revealed that the types and amounts of compounds released to the plant surface differ by cultivar, plant developmental stage, and plant organ. Differences in exudate profiles explain some of the variability in
Salmonella
colonization susceptibility seen among tomato cultivars. Certain medium- and long-chain fatty acids were associated with restricted
Salmonella
growth, while sugars, sugar alcohols, and organic acids correlated with larger
Salmonella
populations. These findings uncover the possibility of selecting crop varieties based on characteristics that impair foodborne pathogen growth for enhanced safety of fresh produce.
Recording and treatment of premenstrual syndrome in UK general practice: a retrospective cohort study
Authors: Sammon Cormac J , Nazareth Irwin , Petersen Irene
Published: March 2016

Objectives

To investigate the rate of recording of premenstrual syndrome diagnoses in UK primary care and describe pharmacological treatments initiated following a premenstrual syndrome (PMS) diagnosis.

Design

Retrospective cohort study.

Setting

UK primary care.

Participants

Women registered with a practice contributing to The Health Improvement Network primary care database between 1995 and 2013.

Primary and secondary outcome measures

The primary outcome was the rate of first premenstrual syndrome records per 1000 person years, stratified by calendar year and age. The secondary outcome was the proportions of women with a premenstrual syndrome record prescribed a selective serotonin reuptake inhibitor, progestogen, oestrogen, combined oral contraceptive, progestin only contraceptive, gonadotrophin-releasing hormone, danazol and vitamin B6.

Results

The rate of recording of premenstrual syndrome diagnoses decreased over calendar time from 8.43 in 1995 to 1.72 in 2013. Of the 38 614 women without treatment in the 6 months prior to diagnosis, 54% received a potentially premenstrual syndrome-related prescription on the day of their first PMS record while 77% received a prescription in the 24 months after. Between 1995 and 1999, the majority of women were prescribed progestogens (23%) or vitamin B6(20%) on the day of their first PMS record; after 1999, these figures fell to 3% for progestogen and vitamin B6with the majority of women instead being prescribed a selective serotonin reuptake inhibitor (28%) or combined oral contraceptive (17%).

Conclusions

Recording of premenstrual syndrome diagnoses in UK primary care has declined substantially over time and preferred prescription treatment has changed from progestogen to selective serotonin reuptake inhibitor and combined oral contraceptives.
A cross-sectional observational study of high override rates of drug allergy alerts in inpatient and outpatient settings, and opportunities for improvement
Authors: Slight Sarah Patricia , Beeler Patrick E , Seger Diane L , Amato Mary G , Her Qoua L , Swerdloff Michael , Dalleur Olivia , Nanji Karen C , Cho InSook , Maniam Nivethietha , Eguale Tewodros , Fiskio Julie M , Dykes Patricia C , Bates David W
Published: March 2016

Objectives

To evaluate how often and why providers overrode drug allergy alerts in both the inpatient and outpatient settings.

Design

A cross-sectional observational study of drug allergy alerts generated over a 3-year period between 1 January 2009 and 31 December 2011.

Setting

A 793-bed tertiary care teaching affiliate of Harvard Medical School and 36 primary care practices.

Participants

Drug allergy alerts were displayed for a total of 29 420 patients across both settings.

Main outcome measures

Proportion of drug allergy alerts displayed and overridden, proportion of appropriate overrides, proportion of overrides in each medication class, different reasons for overriding and types of reactions overridden.

Results

A total of 158 023 drug allergy alerts were displayed, 131 615 (83%) in the inpatient setting and 26 408 (17%) in the outpatient setting; 128 157 (81%) of which were overridden. A random sample of inpatient (n=200, 0.19%) and outpatient (n=50, 0.25%) alert overrides were screened for appropriateness, with >96% considered appropriate. Alerts for some drug classes, such as ‘non-antibiotic sulfonamides’, were overridden for >81% of prescriptions in both settings. The most common override reason waspatient has taken previously without allergic reaction. In the inpatient setting alone, 70.9% of alerts that warned against the risk ofanaphylaxiswere overridden.

Conclusions

The information contained in patients’ drug allergy lists needs to be regularly updated. Most of the drug allergy alerts were overridden, with the majority of alert overrides in the subsample considered appropriate. Some of the rules for these alerts should be carefully reviewed and modified, or removed. Further research is needed to understand providers’ overriding of alerts that warned against the risk of ‘anaphylaxis’, which are more concerning with respect to patient safety.
Factors associated with perpetration of intimate partner violence among college students in China
Authors: Kamimura A , Nourian M M , Assasnik N , Franchek-Roa K
Published: March 2016

Objectives

Intimate partner violence (IPV) is a significant public health threat that contributes to a wide range of physical and mental health issues for victims. However, critical information on IPV in China is still lacking. The purpose of this study was to examine factors affecting IPV perpetration as well as victimisation in mainland China.

Methods

The data were from the International Dating Violence Study 2001–2006 (N=731). The lifetime prevalence of victimisation and perpetration of IPV (ie, physical, psychological and/or sexual) was used for analysis. The following individual characteristics and exposures were included in the analysis based on previous studies which showed an association between these characteristics and IPV: childhood sexual abuse history, substance abuse, violence socialisation, dominance, anger management and communication problems.

Results

Perpetrators of physical IPV have a higher prevalence of being victims of IPV than non-perpetrators. Female perpetrators have a higher prevalence of anger management issues than male perpetrators. Levels of anger management and violence socialisation are predictors of physical IPV perpetration only for female perpetrators.

Conclusions

IPV interventions for victims should include interventions for perpetration given that many Chinese victims of IPV also perpetrate IPV. Practice and research on professional education and services for treating individuals who have IPV experience need to be developed in China.
Inequality in disability-free life expectancies among older men and women in six countries with developing economies
Authors: Santosa Ailiana , Schröders Julia , Vaezghasemi Masoud , Ng Nawi
Published: March 2016

Background

It is unclear whether the increase in life expectancy (LE) globally is coupled with a postponement of morbidity and disability. Evidence on trends and determinants of disability-free life expectancies (DFLEs) are available in high-income countries but less in low and middle-income countries (LMICs). This study examines the levels of and inequalities in LE, disability and DFLE between men and women across different age groups aged 50 years and over in six countries with developing economies.

Methods

This study utilised the cross-sectional data (n=32 724) from the WHO Study on global AGEing and adult health (SAGE) in China, Ghana, India, Mexico, the Russian Federation and South Africa in 2007–2010. Disability was measured with the activity of daily living (ADL) instrument. The DFLE was estimated using the Sullivan method based on the standard period life table and ADL-disability proportions.

Results

The disability prevalence ranged from 13% in China to 54% in India. The prevalence of disability was highest and occurred at younger age in both sexes in India. Women were more disadvantaged with higher prevalence of disability across all age groups, and the situation was worst among older women in Mexico and the Russian Federation. Though women had higher LE, their proportion of remaining LE free from disability was lower than men.

Conclusions

There are inequalities in the levels of disability and DFLE among men and women in different age groups among people aged over 50 years in these six countries. Countermeasures to decrease intercountry and gender gaps in DFLE, including improvements in health promotion and healthcare distribution, with a gender equity focus, are needed.
Interleukin-6 and associated cytokine responses to an acute bout of high-intensity interval exercise: the effect of exercise intensity and volume
Authors: Cullen Tom , Thomas Andrew W. , Webb Richard , Hughes Michael G.
Published: March 2016

Acute increases in interleukin (IL)-6 following prolonged exercise are associated with the induction of a transient anti-inflammatory state (e.g., increases in IL-10) that is partly responsible for the health benefits of regular exercise. The purposes of this study were to investigate the IL-6–related inflammatory response to high-intensity interval exercise (HIIE) and to determine the impact of exercise intensity and volume on this response. Ten participants (5 males and 5 females) completed 3 exercise bouts of contrasting intensity and volume (LOW, MOD, and HIGH). The HIGH protocol was based upon standard HIIE protocols, while the MOD and LOW protocols were designed to enable a comparison of exercise intensity and volume with a fixed duration. Inflammatory cytokine concentrations were measured in plasma (IL-6, IL-10) and also determined the level of gene expression (IL-6, IL-10, and IL-4R) in peripheral blood. The plasma IL-6 response to exercise (reported as fold changes) was significantly greater in HIGH (2.70 ± 1.51) than LOW (1.40 ± 0.32) (P = 0.04) and was also positively correlated to the mean exercise oxygen uptake (r = 0.54, P < 0.01). However, there was no change in anti-inflammatory IL-10 or IL-4R responses in plasma or at the level of gene expression. HIIE caused a significant increase in IL-6 and was greater than that seen in low-intensity exercise of the same duration. The increases in IL-6 were relatively small in magnitude, and appear to have been insufficient to induce the acute systemic anti-inflammatory effects, which are evident following longer duration exercise.
When the endothelium scores an own goal: endothelial cells actively augment metastatic extravasation through endothelial-mesenchymal transition
Authors: Gasparics Ákos , Rosivall László , Krizbai István A. , Sebe Attila
Published: March 2016

Endothelial-mesenchymal transition (EndMT) is an important mechanism during organ development and in certain pathological conditions. For example, EndMT contributes to myofibroblast formation during organ fibrosis, and it has been identified as an important source of cancer-associated fibroblasts, facilitating tumor progression. Recently, EndMT was proposed to modulate endothelial function during intravasation and extravasation of metastatic tumor cells. Evidence suggests that endothelial cells are not passive actors during transendothelial migration (TEM) of cancer cells, as there are profound changes in endothelial junctional protein expression, signaling, permeability, and contractility. This review describes these alterations in endothelial characteristics during TEM of metastatic tumor cells and discusses them in the context of EndMT. EndMT could play an important role during metastatic intravasation and extravasation, a novel hypothesis that may lead to new therapeutic approaches to tackle metastatic disease.
Tissue inhibitor of metalloproteinases 3-dependent microvascular endothelial cell barrier function is disrupted under septic conditions
Authors: Arpino Valerie , Mehta Sanjay , Wang Lefeng , Bird Ryan , Rohan Marta , Pape Cynthia , Gill Sean E.
Published: March 2016

Sepsis is associated with dysfunction of microvascular endothelial cells (MVEC) leading to tissue edema and multiple organ dysfunction. Metalloproteinases can regulate MVEC function through processing of cell surface proteins, and tissue inhibitor of metalloproteinases 3 (TIMP3) regulates metalloproteinase activity in the lung following injury. We hypothesize that TIMP3 promotes normal pulmonary MVEC barrier function through inhibition of metalloproteinase activity. Naive Timp3−/−mice had significantly higher basal pulmonary microvascular Evans blue (EB) dye-labeled albumin leak vs. wild-type (WT) mice. Additionally, cecal-ligation/perforation (CLP)-induced sepsis significantly increased pulmonary microvascular EB-labeled albumin leak in WT but not Timp3−/−mice. Similarly, PBS-treated isolated MVEC monolayers from Timp3−/−mice displayed permeability barrier dysfunction vs. WT MVEC, evidenced by lower transendothelial electrical resistance and greater trans-MVEC flux of fluorescein-dextran and EB-albumin. Cytomix (equimolar interferon γ, tumor necrosis factor α, and interleukin 1β) treatment of WT MVEC induced significant barrier dysfunction (by all three methods), and was associated with a time-dependent decrease in TIMP3 mRNA and protein levels. Additionally, basal Timp3−/−MVEC barrier dysfunction was associated with disrupted MVEC surface VE-cadherin localization, and both barrier dysfunction and VE-cadherin localization were rescued by treatment with GM6001, a synthetic metalloproteinase inhibitor. TIMP3 promotes normal MVEC barrier function, at least partially, through inhibition of metalloproteinase-dependent disruption of adherens junctions, and septic downregulation of TIMP3 may contribute to septic MVEC barrier dysfunction.
Inhibition of late Na+ current, a novel target to improve diastolic function and electrical abnormalities in Dahl salt-sensitive rats
Authors: Chi Liguo , Belardinelli Luiz , Zeng Aliya , Hirakawa Ryoko , Rajamani Sridharan , Ling Haiyun , Dhalla Arvinder K.
Published: March 2016

Late Na+ current ( INaL) is enhanced in myocytes of animals with chronic heart failure and patients with hypertrophic cardiomyopathy. To define the role of INaL in diastolic heart failure, the effects of GS-458967 (GS-967), a potent INaL inhibitor on mechanical and electrical abnormalities, were determined in an animal model of diastolic dysfunction. Dahl salt-sensitive (DSS) rats fed a high-salt (HS) diet for 8 wk, compared with a normal salt (NS) diet, had increased left ventricular (LV) mass (1,257 ± 96 vs. 891 ± 34 mg) and diastolic dysfunction [isovolumic relaxation time (IVRT): 26.8 ± 0.5 vs. 18.9 ± 0.2 ms; early transmitral flow velocity/early mitral annulus velocity (E/E') ratio: 25.5 ± 1.9 vs. 14.9 ± 0.9]. INaL in LV myocytes from HS rats was significantly increased to 0.41 ± 0.02 from 0.14 ± 0.02 pA/pF in NS rats. The action potential duration (APD) was prolonged to 136 ± 12 from 68 ± 9 ms in NS rats. QTc intervals were longer in HS vs. NS rats (267 ± 8 vs. 212 ± 2 ms). Acute and chronic treatment with GS-967 decreased the enhanced INaL to 0.24 ± 0.01 and 0.17 ± 0.02 pA/pF, respectively, vs. 0.41 ± 0.02 pA/pF in the HS group. Chronic treatment with GS-967 dose-dependently reduced LV mass, the increases in E/E' ratio, and the prolongation of IVRT by 27, 27, and 20%, respectively, at the 1.0 mg·kg−1·day−1 dose without affecting blood pressure or LV systolic function. The prolonged APDs in myocytes and QTc of HS rats were significantly reduced with GS-967 treatment. These results indicate that INaL is a significant contributor to the LV diastolic dysfunction, hypertrophy, and repolarization abnormalities and thus, inhibition of this current is a promising therapeutic target for diastolic heart failure.
Chronic high-magnitude cyclic stretch stimulates EC inflammatory response via VEGF receptor 2-dependent mechanism
Authors: Gawlak Grzegorz , Son Sophia , Tian Yufeng , O'Donnell James J. , Birukov Konstantin G. , Birukova Anna A.
Published: March 2016

Ventilator-induced lung injury (VILI) is associated with activated inflammatory signaling, such as cytokine production by endothelial and epithelial cells and macrophages, although the precise mechanisms of inflammatory activation induced by VILI-relevant cyclic stretch (CS) amplitude remain poorly understood. We show that exposure of human pulmonary endothelial cells (EC) to chronic CS at 18% linear distension (18% CS), but not at physiologically relevant 5% CS, induces “EC-activated phenotype,” which is characterized by time-dependent increase in ICAM1 and VCAM1 expression. A preconditioning of 18% CS also increased in a time-dependent fashion the release of soluble ICAM1 (sICAM1) and IL-8. Investigation of potential signaling mechanisms of CS-induced EC inflammatory activation showed that 18% CS, but not 5% CS, induced time-dependent upregulation of VEGF receptor 2 (VEGFR2), as monitored by increased protein expression and VEGFR2 tyrosine phosphorylation. Both CS-induced VEGFR2 expression and tyrosine phosphorylation were abrogated by cotreatment with reactive oxygen species inhibitor, N-acetyl cysteine. Molecular inhibition of VEGFR2 expression by gene-specific siRNA or treatment with VEGFR2 pharmacological inhibitor SU-1498 attenuated CS-induced activation of ICAM1 and VCAM1 expression and sICAM1 release. Chronic EC preconditioning at 18% CS augmented EC inflammation and barrier-disruptive response induced by proinflammatory cytokine TNF-α. This effect of chronic 18% CS preconditioning was attenuated by siRNA-induced VEGFR2 knockdown. This study demonstrates for the first time a VEGFR2-dependent mechanism of EC inflammatory activation induced by pathological CS. We conclude that, despite the recognized role of VEGF as a prosurvival and angiogenic factor, excessive activation of VEGFR2 signaling by high-tidal-volume lung mechanical ventilation may contribute to ventilator-induced (biotrauma) lung inflammation and barrier dysfunction by augmenting cell response to VILI-associated inflammatory mediators.
Elevated expression of NEU1 sialidase in idiopathic pulmonary fibrosis provokes pulmonary collagen deposition, lymphocytosis, and fibrosis
Authors: Luzina Irina G. , Lockatell Virginia , Hyun Sang W. , Kopach Pavel , Kang Phillip H. , Noor Zahid , Liu Anguo , Lillehoj Erik P. , Lee Chunsik , Miranda-Ribera Alba , Todd Nevins W. , Goldblum Simeon E. , Atamas Sergei P.
Published: March 2016

Idiopathic pulmonary fibrosis (IPF) poses challenges to understanding its underlying cellular and molecular mechanisms and the development of better therapies. Previous studies suggest a pathophysiological role for neuraminidase 1 (NEU1), an enzyme that removes terminal sialic acid from glycoproteins. We observed increased NEU1 expression in epithelial and endothelial cells, as well as fibroblasts, in the lungs of patients with IPF compared with healthy control lungs. Recombinant adenovirus-mediated gene delivery of NEU1 to cultured primary human cells elicited profound changes in cellular phenotypes. Small airway epithelial cell migration was impaired in wounding assays, whereas, in pulmonary microvascular endothelial cells, NEU1 overexpression strongly impacted global gene expression, increased T cell adhesion to endothelial monolayers, and disrupted endothelial capillary-like tube formation. NEU1 overexpression in fibroblasts provoked increased levels of collagen types I and III, substantial changes in global gene expression, and accelerated degradation of matrix metalloproteinase-14. Intratracheal instillation of NEU1 encoding, but not control adenovirus, induced lymphocyte accumulation in bronchoalveolar lavage samples and lung tissues and elevations of pulmonary transforming growth factor-β and collagen. The lymphocytes were predominantly T cells, with CD8+cells exceeding CD4+cells by nearly twofold. These combined data indicate that elevated NEU1 expression alters functional activities of distinct lung cell types in vitro and recapitulates lymphocytic infiltration and collagen accumulation in vivo, consistent with mechanisms implicated in lung fibrosis.
Functional phosphorylation sites in cardiac myofilament proteins are evolutionarily conserved in skeletal myofilament proteins
Authors: Gross Sean M. , Lehman Steven L.
Published: March 2016

Protein phosphorylation plays an important role in regulating cardiac contractile function, but phosphorylation is not thought to play a regulatory role in skeletal muscle. To examine how myofilament phosphorylation arose in the human heart, we analyzed the amino acid sequences of 25 cardiac phosphorylation sites in animals ranging from fruit flies to humans. These analyses indicated that of the 25 human phosphorylation sites examined, 11 have been conserved across vertebrates and four have been sporadically present in vertebrates. Furthermore, all 11 of the cardiac sites found across vertebrates were present in skeletal muscle isoforms, along with three sites that were sporadically present. Based on the conservation of amino acid sequences between cardiac and skeletal contractile proteins, we tested for phosphorylation in mammalian skeletal muscle using several biochemical techniques and found evidence that multiple myofilament proteins were phosphorylated. Several of these phosphorylation sites were validated using mass spectrometry, including one site that is present in slow- and fast-twitch troponin I (TnI), but was lost in cardiac TnI. Thus, several myofilament phosphorylation sites present in the human heart likely arose in invertebrate muscle, have been evolutionarily conserved in skeletal muscle, and potentially have functional effects in both skeletal and cardiac muscle.
Immunotherapy with a HER2-Targeting Listeria Induces HER2-Specific Immunity and Demonstrates Potential Therapeutic Effects in a Phase I Trial in Canine Osteosarcoma
Authors: Mason Nicola J. , Gnanandarajah Josephine S. , Engiles Julie B. , Gray Falon , Laughlin Danielle , Gaurnier-Hausser Anita , Wallecha Anu , Huebner Margie , Paterson Yvonne
Published: March 2016

Purpose: Recombinant Listeria vaccines induce tumor-specific T-cell responses that eliminate established tumors and prevent metastatic disease in murine cancer models. We used dogs with HER2/neu+ appendicular osteosarcoma, a well-recognized spontaneous model for pediatric osteosarcoma, to determine whether a highly attenuated, recombinant Listeria monocytogenes expressing a chimeric human HER2/neu fusion protein (ADXS31-164) could safely induce HER2/neu-specific immunity and prevent metastatic disease.

Experimental Design: Eighteen dogs that underwent limb amputation or salvage surgery and adjuvant chemotherapy were enrolled in a phase I dose escalation clinical trial and received either 2 × 108, 5 × 108, 1 × 109, or 3.3 × 109 CFU of ADXS31-164 intravenously every 3 weeks for 3 administrations.

Results: Only low-grade, transient toxicities were observed. ADXS31-164 broke peripheral tolerance and induced antigen-specific IFNγ responses against the intracellular domain of HER2/neu in 15 of 18 dogs within 6 months of treatment. Furthermore, ADXS31-164 reduced the incidence of metastatic disease and significantly increased duration of survival time and 1-, 2-, and 3-year survival rates when compared with a historical control group with HER2/neu+ appendicular osteosarcoma treated with amputation and chemotherapy alone.

Conclusions: These findings demonstrate that ADXS31-164 administered in the setting of minimal residual disease can induce HER2/neu-specific immunity and may reduce the incidence of metastatic disease and prolong overall survival in a clinically relevant, spontaneous, large animal model of cancer. These findings, therefore, have important translational relevance for children with osteosarcoma and adults with other HER2/neu+ cancers. Clin Cancer Res; 22(17); 4380–90. ©2016 AACR.