bluuebunny/crossref_metadata_2025 huggingface dataset:
Practice Theory in Language Learning
Authors: Young Richard F. , Astarita Alice C.
Published: February 2013

Ortega (2011) has argued that second language acquisition is stronger and better after the social turn. Of the post‐cognitive approaches she reviews, several focus on the social context of language learning rather than on language as the central phenomenon. In this article, we present Practice Theory not as yet another approach to language learning, but as a philosophical and methodological frame within which the interplay between social context and language learning can be understood. We review the work of Bourdieu, de Certeau, Foucault, Giddens, and Goffman, who argue for the centrality of practice in human semiosis. Through analysis of introspective accounts by ten first‐generation/working class students of their foreign language learning experiences, we show how Practice Theory reveals a dialectic between the immediate experiences of language learners and the durable and transposable dispositions emanating from and integrating their past experiences.
Increased hair selenium concentration in hyperlipidemic patients
Authors: Fülöp Péter , Seres Ildikó , Jenei Zoltán , Juhász Imre , Paragh György
Published: February 2013

Selenium is an essential trace element with potential anti‐atherogenic and antioxidant effects. Experimental data suggest that selenium might be beneficial in the prevention of atherosclerosis and its complications, whereas human epidemiological studies have yielded conflicting results. Data on hair selenium status in hyperlipidemic patients are still lacking. Therefore, we analysed selenium concentrations by X‐ray fluorescence in the hair of 81 statin‐naïve patients with newly diagnosed Fredrickson‐type IIa and IIb hyperlipoproteinemia and compared their data with 43 healthy volunteers. We also assessed the frequency of other classical risk factors of atherosclerosis. Hair selenium levels were found to be significantly higher in hyperlipidemic patients compared with volunteers with normal lipid levels. Also, a significantly increased number of traditional atherosclerosis risk factors were observed in hyperlipidemic patients with hair selenium concentrations above the median in contrast to those with below. Our results suggest that high hair selenium status might be associated with adverse blood lipid profile together with an increased number of traditional risk factors in a selenium‐deplete population. These findings warrant further investigations to study the impact of selenium supplementation on the incidence of cardiovascular events.
Evaluation of nasal epithelium sampling as a tool in the preclinical development of siRNA‐based therapeutics for asthma
Authors: Healey Gareth D , Evans Neil , Hopkin Julian M , Davies Gwyneth , Walker William
Published: February 2013

The development of siRNA‐based asthma therapeutics is currently hampered by a paucity of relevant biomarkers and the need to ascertain tissue‐specific gene targeting in the context of active disease. Epithelial STAT6 expression is fundamental to asthma pathogenesis in which inflammatory changes are found throughout the respiratory tract. Therefore, to improve preclinical evaluation, we tested the efficacy of STAT6‐targeting siRNA within nasal epithelial cells (NEC's) obtained from asthmatic and non‐asthmatic donors. STAT6 expression was invariant in both donor groups and amenable to suppression by siRNA treatment. In addition, STAT6 mRNA was also suppressible by apically delivered siRNA treatment in comparative differentiated nasal epithelial cell‐line monolayer cultures. Analysis of donor NEC's showed consistent elevation in CCL26 (eotaxin‐3) mRNA within the asthmatic group suggesting potential as a relevant biomarker. Furthermore, targeting of STAT6 with siRNA attenuated IL‐13‐driven CCL26 expression in these cells, pointing to the utility of this approach in preclinical testing. Finally, siRNA‐mediated suppression of STAT6 was independent of donor disease phenotype or epithelial cell differentiation status, signifying therapeutic potential.
Adverse Oral Health and Cognitive Decline: The Health, Aging and Body Composition Study
Authors: Stewart Robert , Weyant Robert J. , Garcia Melissa E. , Harris Tamara , Launer Lenore J. , Satterfield Suzanne , Simonsick Eleanor M. , Yaffe Kristine , Newman Anne B.
Published: February 2013

Objectives

To investigate the relationship between periodontal disease and cognitive decline.

Design

Analysis of a prospective cohort study.

Setting

The Health, Aging and Body Composition (Health ABC) Study.

Participants

One thousand fifty‐three participants who were administered the Modified Mini‐Mental State Examination (3MS) at Year 1 (baseline) and Year 3 and had participated in a comprehensive periodontal examination at Year 2.

Measurements

The prospective association between a range of oral health parameters and cognitive function was examined. Decline in 3MS score from Year 3 to 5 was investigated in 947 (89.9%) participants. Covariates included age, sex, education, race, cardiovascular disease and risk, and depressive symptoms.

Results

Most indicators of adverse oral health at Year 2 were associated with cognitive impairment based on averaged 3MS scores less than 80 for Years 1 and 3, but education and race substantially confounded these associations. Higher gingival index, a measure of gingival inflammation, at Year 2 remained independently associated with this definition of cognitive impairment and, in fully adjusted analyses, was also an independent predictor of a more‐than‐5‐point cognitive decline from Year 3 to 5.

Conclusion

Periodontitis may be a risk factor for cognitive decline. Gingivitis is reversible, and periodontitis to some degree is preventable and controllable when manifest. Therefore, further research is needed to clarify potential underlying mechanisms and oral health interventions that might ameliorate cognitive decline.
Seeking a progressive relationship for learning: A theoretical scheme about the continuity of the student–educator relationship in clinical nursing education
Authors: Yaghoubinia Fariba , Heydari Abbas , Latifnejad Roudsari Robab
Published: February 2013

Aim

The student–educator relationship is an educational tool in nursing education and has long‐lasting influence on the professional development of nursing students. Currently, this relationship in clinical settings is different from that in the past due to a paradigm shift in nursing education and its emphasis on the centrality of the relationship.

Methods

The purpose of this grounded theory study was to explore the continuity of the student–educator relationship in the Iranian context of clinical nursing education. Ten bachelor nursing students and 10 clinical educators at Mashhad University of Medical Sciences, Iran, were selected through purposive and theoretical sampling. The data were collected through semi‐structured interviews and participant observation. Interviews were transcribed verbatim, and data analysis was done through open, axial, and selective coding, using MAXQDA ver. 2007 qualitative data analysis software.

Results

The core category emerging from the data analysis was “seeking a progressive relationship for learning”. Other major categories linked to and embraced within this core category were: “creating emotional connection”, “trying to continue the relationship chain”, and “adapting the behaviors”.

Conclusion

The findings indicated that in the Iranian sociocultural context, students and educators gain some action/interaction strategies for continuity of their relationship. It is obvious that the role of the nursing clinical educators and their relationship skills are critical in the relationship continuity of clinical settings.
PUBLIC AND SUBSIDIZED HOUSING AS A PLATFORM FOR BECOMING A UNITED STATES CITIZEN*
Authors: Carruthers John I. , Duncan Natasha T. , Waldorf Brigitte S.
Published: February 2013

ABSTRACT Each year, hundreds of thousands of people immigrate to the United States seeking a better way of life, and still hundreds of thousands more become citizens. Some spend time living in public and subsidized housing, sponsored by the Department of Housing and Urban Development (HUD), and, each year, thousands of these individuals attain citizenship. This paper presents an econometric analysis of the propensity of noncitizens living in HUD‐sponsored housing to naturalize. Providing housing and other forms of public assistance to noncitizens is controversial but the fact of the matter is that, under current rules, many qualify for aid so, facing that fact, an important contribution of this research is to identify the type of program that works best in the context of broader national objectives. The key finding is that the market‐based approach of the housing choice voucher program—and the spatial mobility it facilitates—significantly and substantively contribute to naturalization.
Effects of straw treatment and nitrogen supplementation on digestibility, intake and physiological responses of water intake as well as urine and faecal characteristics
Authors: Ghasemi E. , Khorvash M. , Ghorbani G. R. , Elmamouz F.
Published: February 2013

This study investigates the effects of feeding diet based on untreated (UT) or ensiled alkali‐treated (ET) barley straw with either urea or casein supplementation, on feed intake, digestibility, ruminal pH, water intake and faecal and urinary characteristics. Four sheep fitted with ruminal cannulas were used in a 4 × 4 Latin square design with a 2 × 2 factorial arrangement of treatments. Barley straw was treated by the dry (spraying) method in pH adjusted of hydrogen peroxide (pH 11.5), ensiled for 6 weeks and included at 65% of the diet dry matter (DM). The results showed that straw pH reduced from 11.58 to 8.60 after 6 weeks of ensilage. The ET diet increased average DM digestibility and intake by 19% and 43% respectively. Total water intake was similar across treatments, while the water/DM intake ratio was 23% higher with the UT diet than with the ET one. Ruminal (6.73 vs. 6.84) and faecal (8.67 vs. 9.05) pH decreased but urinary pH (6.14 vs. 8.13) increased as a result of feeding animals on the ET diet compared with the UT diet. Compared with the UT diet, the ET one decreased faecal fibre (12%), moisture (32%) and water holding capacity, while it increased faecal ash (10%) and density (20%). The volume of urine excreted by the sheep fed with the ET diet increased by 67%, but their urine specific gravity (SG) decreased. No significant effects were observed for the dietary N supplementation and interactions between straw type × N supplementation with regard to any of the measured characteristics except for DM intake, which reduced due to the casein supplementation in the ET diet. These results indicate that the alkali treatment and ensilage of barley straw increased digestibility, intake, faecal consistency and urinary pH and dilution but decreased straw alkalinity as well as ruminal and faecal pH.
The effect of very low food intake on digestive physiology and forage digestibility in horses
Authors: Clauss M. , Schiele K. , Ortmann S. , Fritz J. , Codron D. , Hummel J. , Kienzle E.
Published: February 2013

Equid digestion is often conceptualized as a high‐throughput/low‐efficiency system, in particular compared with ruminants. It is commonly assumed that ruminants have an advantage when resources are limited; the effect of low food intake on digestive physiology of horses has, however, not been explored to our knowledge. We used four adult ponies [initial body mass (BM) 288 ± 65 kg] in two subsequent trials with grass hay‐only diets [in dry matter (DM): hay1, mid‐early cut, crude protein (CP) 10.5%, neutral detergent fibre (NDF) 67.6%; hay2, late cut, CP 5.8%, NDF 69.5%], each fed subsequently at four different dry matter intake (DMI) levels: ad libitum and at 75, 55 and 30 g/kg0.75/day. We particularly expected digesta mean retention times (MRT) to increase, and hence fibre digestibility to increase, with decreasing DMI. Ponies maintained BM on the first, but lost BM and body condition on DMI55 and DMI30. MRTs were negatively correlated to DMI and ranged (for particles <2 mm) from 23/31 h (hay1/2) on the ad libitum to 38/48 h on DMI30. Digestibilities of DM, nutrients and fibre components decreased from DMI75 to DMI30; apparent digestibilities of organic matter and NDF (hay1/2) dropped from 47/43% and 42/37%, respectively, on the ad libitum DMI to 35/35% and 30/28% on DMI30. Additional differences evident between the two hays included a higher estimated ‘true’ protein digestibility for hay1 and finer faecal particles on hay2; there were no differences in faecal particle size between intake levels. The results suggest that below a certain food intake threshold, the major digestive constraint is not fermentation time but nutrient supply to gut bacteria. The threshold for such an effect probably varies between feeds and might differ between ruminants and equids.
History of the invasion of the anther smut pathogen on Silene latifolia in North America
Authors: Fontaine Michael C. , Gladieux Pierre , Hood Michael E. , Giraud Tatiana
Published: February 2013

Understanding the routes of pathogen introduction contributes greatly to efforts to protect against future disease emergence.

Here, we investigated the history of the invasion in North America by the fungal pathogen Microbotryum lychnidis‐dioicae, which causes the anther smut disease on the white campion Silene latifolia. This system is a well‐studied model in evolutionary biology and ecology of infectious disease in natural systems.

Analyses based on microsatellite markers show that the introduced American M. lychnidis‐dioicae probably came from Scotland, from a single population, and thus suffered from a drastic bottleneck compared with genetic diversity in the native European range. The pattern in M. lychnidis‐dioicae contrasts with that found by previous studies in its host plant species S. latifolia, also introduced in North America. In the plant, several European lineages have been introduced from across Europe. The smaller number of introductions for M. lychnidis‐dioicae probably relates to its life history traits, as it is an obligate, specialized pathogen that is neither transmitted by the seeds nor persistent in the environment.

The results show that even a nonagricultural, biotrophic, and insect‐vectored pathogen suffering from a very strong bottleneck can successfully establish populations on its introduced host.
Three Dimensional Flexural–Gravity Waves
Authors: Milewski P. A. , Wang Z.
Published: February 2013

Waves propagating on the surface of a three–dimensional ideal fluid of arbitrary depth bounded above by an elastic sheet that resists flexing are considered in the small amplitude modulational asymptotic limit. A Benney–Roskes–Davey–Stewartson model is derived, and we find that fully localized wavepacket solitary waves (or lumps) may bifurcate from the trivial state at the minimum of the phase speed of the problem for a range of depths. Results using a linear and two nonlinear elastic models are compared. The stability of these solitary wave solutions and the application of the BRDS equation to unsteady wave packets is also considered. The results presented may have applications to the dynamics of continuous ice sheets and their breakup.
Foraminiferal record of marine transgression during deposition of the Middle Miocene Badenian evaporites in Central Paratethys (Borków section, Polish Carpathian Foredeep)
Authors: Peryt Danuta
Published: February 2013

Benthic and planktonic foraminifera from a marly clay intercalation sandwiched between mid‐Badenian (Middle Miocene) gypsum deposited in an environment of an evaporitic shoal (<1 m deep) at Borków (southern Poland) indicate a major marine flooding event in the previously isolated Carpathian Foredeep Basin (Central Paratethys). After this very short‐term environmental change, benthic foraminifers started to colonize a new niche which was previously defaunated, and the pattern of benthic foraminiferal colonization is similar to that related to the reflooding which terminated the Badenian evaporite deposition. The benthic foraminifer assemblages are composed of pioneer, opportunistic, r‐selected species dominated by elphidiids. The connection of the Carpathian Foredeep Basin with the marine reservoir was short‐lived. The marly clay intercalations in evaporite sequences originating in bared basins can thus register major environmental changes.
Impacts of Trade and the Environment on Clustered Multilateral Environmental Agreements
Authors: H. Egger Peter , Jessberger Christoph , Larch Mario
Published: February 2013

Many countries align their environmental policy and environmental regulation by way of multilateral environmental agreements (MEAs). Previous work in economics provided insights in the economic and political determinants ofMEAs at large. This paper distinguishesMEAs by the main issues covered and classifies them in five clusters: biodiversity; atmosphere; land; chemicals and hazardous wastes; and seas. Then the role of environmental, economic, and political factors and of dynamic and cross‐cluster effects is studied at the level ofMEAclusters. Two findings stand out from this empirical analysis. First, economic size and multilateral trade liberalisation of countries are found to be the most important drivers ofMEAparticipation across all clusters. Second, adjustment costs turn out to deter and, in particular, cross‐cluster spillovers turn out to stimulateMEAparticipation across countries and clusters.
Impacts of point spread function accuracy on patterning prediction and proximity effect correction in low-voltage electron-beam–direct-write lithography
Authors: Liu Chun-Hung , Ng Philip C. W. , Shen Yu-Tian , Chien Sheng-Wei , Tsai Kuen-Yu
Published: February 2013

Electron-beam–direct-write lithography at lower accelerating voltages has been considered as a candidate for next-generation lithography. Although long-range proximity effects are substantially reduced with the voltage, proximity effect correction (PEC) is still necessary since short-range proximity effects are relatively prominent. The effectiveness of model-based PEC can be limited severely if an inaccurate point spread function (PSF) characterizing electron scattering within resist is adopted. Recently, a new PSF form using a promising calibration method has been developed to more accurately characterize the electron scattering and thus significantly improve patterning fidelity at 5 keV. However, influences of adopting the conventional and new PSF forms for the usage of patterning practical circuit layouts have not been intensively studied. This work extensively investigates impacts of PSF accuracy on patterning prediction and PEC under different resist thickness conditions suitable for various lithographic half-pitch nodes, where the critical features of practical circuit layouts are used to quantitatively evaluate their performance. In addition, patterning fidelity limitation suffered from proximity effects is examined to determine whether PEC should be applied. Simulation results indicate that the new PSF form can significantly improve the fitting accuracy, patterning prediction, and PEC results over the conventional PSF forms, especially for circuit layouts with smaller feature sizes.
Development of XFCT imaging strategy for monitoring the spatial distribution of platinum‐based chemodrugs: Instrumentation and phantom validation
Authors: Kuang Yu , Pratx Guillem , Bazalova Magdalena , Qian Jianguo , Meng Bowen , Xing Lei
Published: February 2013

Purpose:

Developing an imaging method to directly monitor the spatial distribution of platinum‐based (Pt) drugs at the tumor region is of critical importance for early assessment of treatment efficacy and personalized treatment. In this study, the authors investigated the feasibility of imaging platinum (Pt)‐based drug distribution using x‐ray fluorescence (XRF, a.k.a. characteristic x ray) CT (XFCT).

Methods:

A 5‐mm‐diameter pencil beam produced by a polychromatic x‐ray source equipped with a tungsten anode was used to stimulate emission of XRF photons from Pt drug embedded within a water phantom. The phantom was translated and rotated relative to the stationary pencil beam in a first‐generation CT geometry. The x‐ray energy spectrum was collected for 18 s at each position using a cadmium telluride detector. The spectra were then used for the K‐shell XRF peak isolation and sinogram generation for Pt. The distribution and concentration of Pt were reconstructed with an iterative maximum likelihood expectation maximization algorithm. The capability of XFCT to multiplexed imaging of Pt, gadolinium (Gd), and iodine (I) within a water phantom was also investigated.

Results:

Measured XRF spectrum showed a sharp peak characteristic of Pt with a narrow full‐width at half‐maximum (FWHM) (FWHMKα1 = 1.138 keV, FWHMKα2 = 1.052 keV). The distribution of Pt drug in the water phantom was clearly identifiable on the reconstructed XRF images. Our results showed a linear relationship between the XRF intensity of Pt and its concentrations (R2 = 0.995), suggesting that XFCT is capable of quantitative imaging. A transmission CT image was also obtained to show the potential of the approach for providing attenuation correction and morphological information. Finally, the distribution of Pt, Gd, and I in the water phantom was clearly identifiable in the reconstructed images from XFCT multiplexed imaging.

Conclusions:

XFCT is a promising modality for monitoring the spatial distribution of Pt drugs. The technique may be useful in tailoring tumor treatment regimen in the future.
Gantry and isocenter displacements of a linear accelerator caused by an add‐on micromultileaf collimator
Authors: Riis Hans L. , Zimmermann Sune J. , Hjelm‐Hansen Mogens
Published: February 2013

Purpose:

The delivery of high quality stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) treatments to the patient requires knowledge of the position of the isocenter to submillimeter accuracy. To meet the requirements the deviation between the radiation and mechanical isocenters must be less than 1 mm. The use of add‐on micromultileaf collimators (μMLCs) in SRS and SRT is an additional challenge to the anticipated high‐level geometric and dosimetric accuracy of the treatment. The aim of this work was to quantify the gantry excursions during rotation with and without an add‐on μMLC attached to the gantry head. In addition, the shift in the position of the isocenter and its correlation to the kV beam center of the cone‐beam CT system was included in the study.

Methods:

The quantification of the gantry rotational performance was done using a pointer supported by an in‐house made rigid holder attached to the gantry head of the accelerator. The pointer positions were measured using a digital theodolite. To quantify the effect of an μMLC of 50 kg, the measurements were repeated with the μMLC attached to the gantry head. The displacement of the isocenter due to an add‐on μMLC of 50 kg was also investigated. In case of the pointer measurement the μMLC was simulated by weights attached to the gantry head. A method of least squares was applied to determine the position and displacement of the mechanical isocenter. Additionally, the displacement of the radiation isocenter was measured using a ball‐bearing phantom and the electronic portal image device system. These measurements were based on 8 MV photon beams irradiated onto the ball from the four cardinal angles and two opposed collimator angles. The measurements and analysis of the data were carried out automatically using software delivered by the manufacturer.

Results:

The displacement of the mechanical isocenter caused by a 50 kg heavy μMLC was found to be (−0.01 ± 0.05, −0.10 ± 0.03, −0.26 ± 0.05) mm in lateral, longitudinal, and vertical direction, respectively. Similarly, the displacement of the radiation isocenter was found to be (0.00 ± 0.03, −0.08 ± 0.06, −0.32 ± 0.02) mm. Good agreement was found between the displacement of the two isocenters. A displacement of the kV cone‐beam CT beam center due to the attached weight of 50 kg could not be detected.

Conclusions:

General characteristics of the gantry arm excursions and displacements caused by an add‐on μMLC have been reported. A 50 kg heavy add‐on μMLC results in a isocenter displacement downward of 0.26–0.32 mm. The authors recommend that the beam center of the kV cone‐beam CT image system should be matched to the isocenter related to the weight of the μMLC. Consequently, the imperfections in isocenter localizations are transferred to the conventional radiotherapy where the clinical consequences of uncertainties in the submillimeter regime are negligible.
Monte Carlo assessment of CT dose equilibration in PMMA and water cylinders with diameters from 6 to 55 cm
Authors: Li Xinhua , Zhang Da , Liu Bob
Published: February 2013

Purpose:

In multidetector CT, the dose integralDIL of single scan dose profile over the integration interval (−L/2, L/2) can predict the accumulated dose DL(0) at the center of the scan range (−L/2, L/2) for a helical scan of pitch = 1. Both DIL and DL(0) increase with L until the limiting levels (DI∞ and Deq) are reached. The DL(0) equilibration is related to the DIL equilibration. The aim of this study was to evaluate the DIL/DI∞ growth curve, and its variations with factors such as phantom diameter, phantom axis (center or periphery), material (PMMA or water), tube voltage, and bowtie filter (head or body).

Methods:

A Geant4‐based Monte Carlo program was used to simulate single axial scans on a clinical CT scanner, and to compute axial dose profiles in the cylinders of 90 cm in length, and 6–50 cm (PMMA) and 6–55 cm (water) in diameters.DIL/DI∞ ratios were calculated over a range of integration lengths, and were fitted to a mathematical model: f(L) = 1 − α × exp[− (L/d)n], where α, d, and n were fitting parameters. The minimum length required for DIL to approach within 2% of DI∞ was referred to as the equilibrium length Leq. It could be directly derived from data, and was also calculated from the fits.

Results:

TheLeq results of the above two approaches were consistent (deviation: 1.4% on average, and 3.6% maximum). When the other conditions (such as tube voltage, bowtie filter, and phantom material) were the same, DI∞ increased with the reduced phantom diameters. The center/periphery DI∞ ratio was greater than 1 for small phantoms, and increased with larger phantoms until their diameters were above about 16 cm. Dose to water was substantially higher than that to PMMA, especially at the centers of large phantoms. As phantom diameter increased, α, n, and Leq increased on the central axis, and initially increased and then saturated [α ≈ 0.555 (PMMA and water), n ≈ 0.81 (PMMA) and 0.80 (water), and Leq ≈ 29 cm (PMMA) and 30 cm (water)] on the peripheral axis. Bowtie filter and tube voltage affected dose, but had small effects on α, n, and Leq. Leq was almost constant on the central or peripheral phantom axis for beam widths from 0.1 to 40 mm.

Conclusions:

The mathematical model can represent theDIL/DI∞ curve from a single axial CT scan. Generally, n ≠ 1. The equilibrium dose, α, n, and Leq exhibit strong dependencies on phantom diameter and location in the phantom. On the other hand, α, n, and Leq have relatively weak dependencies on material (PMMA or water), tube voltage (80–140 kVp), and bowtie filter, and Leq is also insensitive to beam width (⩽4 cm). A weak dependency of the DIL/DI∞ curve on CT scanner using 80–140 kVp and beam width up to 4 cm is consistent with the results of this study and previous publications. The dose equilibration data provided in this paper can be useful for CT dose evaluation. A framework is presented for assessing dose at any point in infinitely long PMMA and water cylinders undergoing multidetector CT examinations.
Design and preliminary testing of a visually guided hearing aid
Authors: Kidd Gerald , Favrot Sylvain , Desloge Joseph G. , Streeter Timothy M. , Mason Christine R.
Published: February 2013

An approach to hearing aid design is described, and preliminary acoustical and perceptual measurements are reported, in which an acoustic beam-forming microphone array is coupled to an eye-glasses-mounted eye-tracker. This visually guided hearing aid (VGHA)—currently a laboratory-based prototype—senses direction of gaze using the eye tracker and an interface converts those values into control signals that steer the acoustic beam accordingly. Preliminary speech intelligibility measurements with noise and speech maskers revealed near- or better-than normal spatial release from masking with the VGHA. Although not yet a wearable prosthesis, the principle underlying the device is supported by these findings.
Antimicrobial Susceptibilities of Clinical Isolates of HACEK Organisms
Authors: Coburn Bryan , Toye Baldwin , Rawte Prasad , Jamieson Frances B. , Farrell David J. , Patel Samir N.
Published: February 2013

The “HACEK” organisms are a group of fastidious Gram-negative bacteria that cause a variety of infections, including infective endocarditis. Antimicrobial susceptibility testing is not universally available, and therapy for these infections is often empirical. We report the antimicrobial susceptibilities of 70 clinical HACEK isolates to 18 antimicrobials. All isolates were susceptible to ceftriaxone and levofloxacin, indicating that these agents remain appropriate empirical choices for the treatment of infections with this group of organisms.
Risk Factors for a Low Linezolid Trough Plasma Concentration in Acute Infections
Authors: Morata Laura , Cuesta Marta , Rojas Jhon F. , Rodriguez Sebastian , Brunet Merce , Casals Gregori , Cobos Nazareth , Hernandez Cristina , Martínez José A. , Mensa Josep , Soriano Alex
Published: February 2013

Linezolid is an antibiotic with time-dependent activity, and both the percentage of time that plasma concentrations exceed the MIC and the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC
24
/MIC ratio) are associated with clinical response. The aim of this study was to analyze the linezolid trough plasma concentration (
C
min
) and to determine factors associated with a
C
min
< 2 mg/liter and other clinically relevant thresholds. Characteristics of 78 patients receiving 600 mg/12 h of linezolid with a
C
min
determination at the steady state and within the first 10 days of treatment were retrospectively reviewed. Concentrations were measured using high-pressure liquid chromatography. Univariate and multivariate analysis were performed to identify risk factors of low
C
min
. A total of 29.5% of patients had a
C
min
< 2 mg/liter. The percentage was significantly higher in patients with an estimated glomerular filtration (eGF) > 80 ml/min, in intensive care unit (ICU) patients, and in patients with an infection due to
Staphylococcus aureus
. The independent predictors of
C
min
< 2 mg/liter were an eGF > 80 ml/min (odds ratio [OR], 10; 95% confidence interval [CI], 2.732 to 37.037;
P
= 0.001) and infection due to
S. aureus
(OR, 5.906; 95% CI, 1.651 to 21.126;
P
= 0.006). A linezolid
C
min
of <2 mg/liter was found in 29.5% of cases, and the risk was significantly higher among those with an eGF > 80 ml/min and in infections due to
S. aureus
. In patients with severe sepsis, a loading dose or continuous infusion and drug monitoring could improve the pharmacodynamic parameters associated with linezolid efficacy.
Single-Dose Safety, Tolerability, and Pharmacokinetics of the Antibiotic GSK1322322, a Novel Peptide Deformylase Inhibitor
Authors: Naderer Odin J. , Dumont Etienne , Zhu John , Kurtinecz Milena , Jones Lori S.
Published: February 2013

GSK1322322 is a potent inhibitor of peptide deformylase, an essential bacterial enzyme required for protein maturation. GSK1322322 is active against community-acquired skin and respiratory tract pathogens, including methicillin-resistant
Staphylococcus aureus
, multidrug-resistant
Streptococcus pneumoniae
, and atypical pathogens. This phase I, randomized, double-blind, placebo-controlled, 2-part, single-dose, dose escalation study (first time in humans) evaluated the safety, tolerability, and pharmacokinetics of GSK1322322 (powder-in-bottle formulation) in healthy volunteers. In part A, dose escalation included GSK1322322 doses of 100, 200, 400, 800, and 1,500 mg under fasting conditions and 800 mg administered with a high-fat meal. In part B, higher doses of GSK1322322 (2,000, 3,000, and 4,000 mg) were evaluated under fasting conditions. Of the 39 volunteers enrolled in the study, 29 and 10 volunteers were treated with GSK1322322 and placebo, respectively. Upon single-dose administration, GSK1322322 was absorbed rapidly, with median times to maximum plasma concentration (
T
max
) ranging from 0.5 to 1.0 h. The maximum observed plasma concentration (
C
max
) and exposure (area under the concentration-time curve [AUC]) of GSK1322322 were greater than dose proportional between 100 and 1,500 mg and less than dose proportional between 1,500 and 4,000 mg. Administration of the drug with a high-fat meal reduced the rate of absorption (reduced
C
max
and delayed
T
max
) without affecting the extent of absorption (no effect on AUC). GSK1322322 was generally well tolerated, with all adverse events being mild to moderate in intensity during both parts of the study. The most frequently reported adverse event was headache. Data from this study support further evaluation of GSK1322322.
Monte Carlo Simulations Based on Phase 1 Studies Predict Target Attainment of Ceftobiprole in Nosocomial Pneumonia Patients: a Validation Study
Authors: Muller Anouk E. , Schmitt-Hoffmann Anne H. , Punt Nieko , Mouton Johan W.
Published: February 2013

Monte Carlo simulation (MCS) of antimicrobial dosage regimens during drug development to derive predicted target attainment values is frequently used to choose the optimal dose for the treatment of patients in phase 2 and 3 studies. A criticism is that pharmacokinetic (PK) parameter estimates and variability in healthy volunteers are smaller than those in patients. In this study, the initial estimates of exposure from MCS were compared with actual exposure data in patients treated with ceftobiprole in a phase 3 nosocomial-pneumonia (NP) study (NTC00210964). Results of MCS using population PK data from ceftobiprole derived from 12 healthy volunteers were used (J. W. Mouton, A. Schmitt-Hoffmann, S. Shapiro, N. Nashed, N. C. Punt, Antimicrob. Agents Chemother. 48:1713–1718, 2004). Actual individual exposures in patients were derived after building a population pharmacokinetic model and were used to calculate the individual exposure to ceftobiprole (the percentage of time the unbound concentration exceeds the MIC [percent
fT
> MIC]) for a range of MIC values. For the ranges of percent
fT
> MIC used to determine the dosage schedule in the phase 3 NP study, the MCS using data from a single phase 1 study in healthy volunteers accurately predicted the actual clinical exposure to ceftobiprole. The difference at 50%
fT
> MIC at an MIC of 4 mg/liter was 3.5% for PK-sampled patients. For higher values of percent
fT
> MIC and MICs, the MCS slightly underestimated the target attainment, probably due to extreme values in the PK profile distribution used in the simulations. The probability of target attainment based on MCS in healthy volunteers adequately predicted the actual exposures in a patient population, including severely ill patients.
Host Defense Proteins Derived from Human Saliva Bind to Staphylococcus aureus
Authors: Heo Seok-Mo , Choi Kyoung-Soo , Kazim Latif A. , Reddy Molakala S. , Haase Elaine M. , Scannapieco Frank A. , Ruhl Stefan
Published: February 2013

Proteins in human saliva are thought to modulate bacterial colonization of the oral cavity. Yet, information is sparse on how salivary proteins interact with systemic pathogens that transiently or permanently colonize the oral environment.Staphylococcus aureusis a pathogen that frequently colonizes the oral cavity and can cause respiratory disease in hospitalized patients at risk. Here, we investigated salivary protein binding to this organism upon exposure to saliva as a first step toward understanding the mechanism by which the organism can colonize the oral cavity of vulnerable patients. By using fluorescently labeled saliva and proteomic techniques, we demonstrated selective binding of major salivary components byS. aureusto include DMBT1gp-340, mucin-7, secretory component, immunoglobulin A, immunoglobulin G, S100-A9, and lysozyme C. Biofilm-grownS. aureusstrains bound fewer salivary components than in the planctonic state, particularly less salivary immunoglobulins. A corresponding adhesive component on theS. aureussurface responsible for binding salivary immunoglobulins was identified as staphylococcal protein A (SpA). However, SpA did not mediate binding of nonimmunoglobulin components, including mucin-7, indicating the involvement of additional bacterial surface adhesive components. These findings demonstrate that a limited number of salivary proteins, many of which are associated with various aspects of host defense, selectively bind toS. aureusand lead us to propose a possible role of saliva in colonization of the human mouth by this pathogen.
Phase Variation of PorA, a Major Outer Membrane Protein, Mediates Escape of Bactericidal Antibodies by Neisseria meningitidis
Authors: Tauseef Isfahan , Ali Youssif M. , Bayliss Christopher D.
Published: February 2013

Several outer membrane proteins of
Neisseria meningitidis
are subject to phase variation due to alterations in simple sequence repeat tracts. The PorA protein is a major outer membrane protein and a target for protective host immune responses. Phase variation of PorA is mediated by a poly-G repeat tract present within the promoter, leading to alterations in protein expression levels.
N. meningitidis
strain 8047 was subjected to serial passage in the presence of P1.2, a PorA-specific bactericidal monoclonal antibody. Rapid development of resistance to bactericidal activity was associated with a switch in the PorA repeat tract from 11G to 10G. Phase variants with a 10G repeat tract exhibited a 2-fold reduction in surface expression of PorA protein. A
mutS
mutant of strain 8047, with an elevated phase variation rate, exhibited a higher rate of escape and an association of escape with 10G and 9G variants, the latter having a 13-fold reduction in surface expression of PorA. We conclude that graduated reductions in the surface expression of outer membrane proteins mediated by phase variation enable meningococci to escape killing
in vitro
by bactericidal antibodies. These findings indicate how phase variation could have a major impact on immune escape and host persistence of meningococci.
RpoS Contributes to Phagocyte Oxidase-Mediated Stress Resistance during Urinary Tract Infection by Escherichia coli CFT073
Authors: Hryckowian Andrew J. , Welch Rodney A.
Published: February 2013

Uropathogenic
Escherichia coli
(UPEC) is the most common causative agent of community-acquired urinary tract infection (UTI). In order to cause UTI, UPEC must endure stresses ranging from nutrient limitation to host immune components. RpoS (σ
S
), the general stress response sigma factor, directs gene expression under a variety of inhibitory conditions. Our study of
rpoS
in UPEC strain CFT073 began after we discovered an
rpoS-
frameshift mutation in one of our laboratory stocks of “wild-type” CFT073. We demonstrate that an
rpoS
-deletion mutation in CFT073 leads to a colonization defect during UTI of CBA/J mice at 48 hours postinfection (hpi). There is no difference between the growth rates of CFT073 and CFT073
rpoS
in urine. This indicates that
rpoS
is needed for replication and survival in the host rather than being needed to address limitations imposed by urine nutrients. Consistent with previous observations in
E. coli
K-12, CFT073
rpoS
is more sensitive to oxidative stress than the wild type. We demonstrate that peroxide levels are elevated in voided urine from CFT073-infected mice compared to urine from mock-infected mice, which supports the notion that oxidative stress is generated by the host in response to UPEC. In mice that lack phagocyte oxidase, the enzyme complex expressed by phagocytes that produces superoxide, the competitive defect of CFT073
rpoS
in bladder colonization is lost. These results demonstrate that σ
S
is important for UPEC survival under conditions of phagocyte oxidase-generated stress during UTI. Though σ
S
affects the pathogenesis of other bacterial species, this is the first work that directly implicates σ
S
as important for UPEC pathogenesis.

IMPORTANCE
UPEC must cope with a variety of stressful conditions in the urinary tract during infection. RpoS (σ
S
), the general stress response sigma factor, is known to direct the expression of many genes under a variety of stressful conditions in laboratory-adapted
E. coli
K-12. Here, we show that σ
S
is needed by the model UPEC strain CFT073 to cope with oxidative stress provided by phagocytes during infection. These findings represent the first report that implicates σ
S
in the fitness of UPEC during infection and support the idea of the need for a better understanding of the effects of this global regulator of gene expression during UTI.
A Genetic Resource for Rapid and Comprehensive Phenotype Screening of Nonessential Staphylococcus aureus Genes
Authors: Fey Paul D. , Endres Jennifer L. , Yajjala Vijaya Kumar , Widhelm Todd J. , Boissy Robert J. , Bose Jeffrey L. , Bayles Kenneth W.
Published: February 2013

To enhance the research capabilities of investigators interested in
Staphylococcus aureus
, the Nebraska Center for Staphylococcal Research (CSR) has generated a sequence-defined transposon mutant library consisting of 1,952 strains, each containing a single mutation within a nonessential gene of the epidemic community-associated methicillin-resistant
S. aureus
(CA-MRSA) isolate USA300. To demonstrate the utility of this library for large-scale screening of phenotypic alterations, we spotted the library on indicator plates to assess hemolytic potential, protease production, pigmentation, and mannitol utilization. As expected, we identified many genes known to function in these processes, thus validating the utility of this approach. Importantly, we also identified genes not previously associated with these phenotypes. In total, 71 mutants displayed differential hemolysis activities, the majority of which were not previously known to influence hemolysin production. Furthermore, 62 mutants were defective in protease activity, with only 14 previously demonstrated to be involved in the production of extracellular proteases. In addition, 38 mutations affected pigment formation, while only 7 influenced mannitol fermentation, underscoring the sensitivity of this approach to identify rare phenotypes. Finally, 579 open reading frames were not interrupted by a transposon, thus providing potentially new essential gene targets for subsequent antibacterial discovery. Overall, the Nebraska Transposon Mutant Library represents a valuable new resource for the research community that should greatly enhance investigations of this important human pathogen.

IMPORTANCE
Infections caused by
Staphylococcus aureus
cause significant morbidity and mortality in both community and hospital environments. Specific-allelic-replacement mutants are required to study the biology of this organism; however, this process is costly and time-consuming. We describe the construction and validation of a sequence-defined transposon mutant library available for use by the scientific community through the Network on Antimicrobial Resistance in
Staphylococcus aureus
(NARSA) strain repository. In addition, complementary resources, including a website (
http://app1.unmc.edu/fgx/
) and genetic tools that expedite the allelic replacement of the transposon in the mutants with useful selectable markers and fluorescent reporter fusions, have been generated. Overall, this library and associated tools will have a significant impact on studies investigating
S. aureus
pathogenesis and biology and serve as a useful paradigm for the study of other bacterial systems.
Steps to a better Belfast: physical activity assessment and promotion in primary care
Authors: Heron Neil , Tully Mark A , McKinley Michelle C , Cupples Margaret E
Published: February 2013

Background

Low physical activity (PA) levels which increase the risk of chronic disease are reported by two-thirds of the general UK population. Promotion of PA by primary healthcare professionals is advocated but more evidence is needed regarding effective ways of integrating this within everyday practice. This study aims to explore the feasibility of a randomised trial of a pedometer-based intervention, using step-count goals, recruiting patients from primary care.

Method

Patients, aged 35–75, attending four practices in socioeconomically deprived areas, were invited to complete a General Practice PA Questionnaire during routine consultations. Health professionals invited ‘inactive’ individuals to a pedometer-based intervention and were randomly allocated to group 1 (prescribed a self-determined goal) or group 2 (prescribed a specific goal of 2500 steps/day above baseline). Both groups kept step-count diaries and received telephone follow-up at 1, 2, 6 and 11 weeks. Step counts were reassessed after 12 weeks.

Results

Of the 2154 patients attending, 192 questionnaires were completed (8.9%). Of these, 83 were classified as ‘inactive’; 41(10 men; 31 women) completed baseline assessments, with the mean age of participants being 51 years. Mean baseline step counts were similar in group 1 (5685, SD 2945) and group 2 (6513, SD 3350). The mean increase in steps/day was greater in groups 1 than 2 ((2602, SD 1957) vs (748, SD 1997) p=0.005).

Conclusions

A trial of a pedometer-based intervention using self-determined step counts appears feasible in primary care. Pedometers appear acceptable to women, particularly at a perimenopausal age, when it is important to engage in impact loading activities such as walking to maintain bone mineral density. An increase of 2500 steps/day is achievable for inactive patients, but the effectiveness of different approaches to realistic goal-setting warrants further study.
Measures of exposure to road traffic injury risk
Authors: Santamariña-Rubio Elena , Pérez Katherine , Olabarria Marta , Novoa Ana M
Published: February 2013

Objective

To compare the risk of road traffic injury calculated using an exposure measure based on people’s mobility, person-hours travelled (person-hours), with the risk obtained using population census, vehicle fleet and vehicle-kilometres travelled.

Methods

The rate of road traffic injury on a working day in Catalonia in 2006 was calculated using the number of people injured from the Register of Accidents and Victims of the National Traffic Authority and as denominator: person-hours travelled, from the 2006 Daily Mobility Survey of Catalonia; population census and vehicle fleet, from the National Statistics Institute; and vehicle-kilometres, from the Ministry of Public Works.

Results

Compared with person-hours travelled: population census may underestimate the risk in groups with low mobility; vehicle-kilometres may underestimate the risk in regions with high level of non-motorised mobility and high use of public transport; vehicle fleet may underestimate the risk for collective forms of transport such as buses and for motorcyclists who make many trips but of short duration.

Conclusions

Measures of exposure involving people's mobility should be used in the estimation of road traffic injury risk, instead of vehicle's mobility, population census or vehicle fleet.