bluuebunny/crossref_metadata_2025 huggingface dataset:
A Bayesian approach to inverse modelling of stratigraphy, part 1: method
Authors: Charvin Karl , Gallagher Kerry , Hampson Gary L. , Labourdette Richard
Published: August 2008

The inference of ancient environmental conditions from their preserved response in the sedimentary record still remains an outstanding issue in stratigraphy. Since the 1970s, conceptual stratigraphic models (e.g. sequence stratigraphy) based on the underlying assumption that accommodation space is the critical control on stratigraphic architecture have been widely used. Although these methods considered more recently other possible parameters such as sediment supply and transport efficiency, they still lack in taking into account the full range of possible parameters, processes, and their complex interactions that control stratigraphic architecture. In this contribution, we present a new quantitative method for the inference of key environmental parameters (specifically sediment supply and relative sea level) that control stratigraphy. The approach combines a fully non‐linear inversion scheme with a ‘process–response’ forward model of stratigraphy. We formulate the inverse problem using a Bayesian framework in order to sample the full range of possible solutions and explicitly build in prior geological knowledge. Our methodology combines Reversible Jump Markov chain Monte Carlo and Simulated Tempering algorithms which are able to deal with variable‐dimensional inverse problems and multi‐modal posterior probability distributions, respectively. The inverse scheme has been linked to a forward stratigraphic model, BARSIM (developed by Joep Storms, University of Delft), which simulates shallow‐marine wave/storm‐dominated systems over geological timescales. This link requires the construction of a likelihood function to quantify the agreement between simulated and observed data of different types (e.g. sediment age and thickness, grain size distributions). The technique has been tested and validated with synthetic data, in which all the parameters are specified to produce a ‘perfect’ simulation, although we add noise to these synthetic data for subsequent testing of the inverse modelling approach. These tests addressed convergence and computational‐overhead issues, and highlight the robustness of the inverse scheme, which is able to assess the full range of uncertainties on the inferred environmental parameters and facies distributions.
Siglec‐F antibody administration to mice selectively reduces blood and tissue eosinophils
Authors: Zimmermann N. , McBride M. L. , Yamada Y. , Hudson S. A. , Jones C. , Cromie K. D. , Crocker P. R. , Rothenberg M. E. , Bochner B. S.
Published: August 2008

Background:  Sialic acid‐binding immunoglobulin‐like lectins (Siglecs) are a family of receptors that bind sialic acid and mostly contain immunoreceptor tyrosine‐based inhibitory motifs, suggesting that these molecules possess inhibitory functions. We have recently identified Siglec‐8 as an eosinophil‐prominent Siglec, and cross‐linking of Siglec‐8 on human eosinophils induces apoptosis. In this article, we address the in vivo consequences of Siglec engagement. We and others have identified mouse Siglec‐F as the closest functional paralog of human Siglec‐8, based on shared ligand‐binding and expression pattern. We therefore hypothesized that Siglec‐F engagement would affect levels and viability of eosinophils in vivo.

Methods:  Wild type and hypereosinophilic mice were administered Siglec‐F antibody and levels of eosinophils in peripheral blood and tissue were measured. Eosinophil apoptosis (in vivo and in vitro) was determined by binding of Annexin‐V.

Results:  Studies in IL‐5 transgenic mice, displaying hypereosinophilia, show that administration of a single dose of Siglec‐F antibody results in rapid reductions in quantum of eosinophils in the blood. This decrease was accompanied by reductions in tissue eosinophils. Quantum of eosinophils in blood was decreased using two separate antibodies, as well as in other mouse models (wild type mice and in a mouse model of chronic eosinophilic leukemia). Mechanistic studies demonstrated that Siglec‐F antibody administration induced apoptosis of eosinophils in vivo and in vitro.

Conclusion:  These data demonstrate that activation of innate immune receptors, like Siglec‐F, can significantly reduce mouse eosinophil viability. As such, targeting Siglec‐8/F may be a therapeutic approach for eosinophilic disorders.
Ultrasonographic Examination of the Scrotal Content in the Rabbit
Authors: Aksoy M , Erdem H , Hatipoğlu F , Lehimcioğlu NC , Akman O , Özkan K
Published: August 2008

Contents

This study was performed to describe a practical technique for ultrasound examination of the scrotal content of the rabbit. The scrotal content of normal rabbits and those with induced lesions (i.e. needle biopsy of the testis and epididymal ligation) were viewed using a portable scanner connected to a 5 or 7.5 MHz real time, B‐mode linear array transducer. The effect of frequency (5 and 7.5 MHz), pad material placed under the testicle (rubber, plastic and carton) and the presence of a water sack between the probe and organ were examined to optimize the technique. The best image quality was obtained using a 5‐MHz probe when the testicle was fixed on a rubber pad and covered by a water sack. Testicular parenchyma was imaged as homogeneous and moderately echoic. Caput and cauda epididymis were identified as homogeneous and less echoic compared with the testis parenchyma. Variations in the testicular echotexture that occur secondarily to epididymal ligation and testis biopsy could be screened readily. In conclusion, real‐time ultrasonography, performed as described in this study, may provide a valuable tool to screen scrotal contents and to identify certain pathological conditions that affect fertility in the rabbit.
Construct of job performance: Evidence from Chinese military soldiers
Authors: Luo Zheng‐Xue , Shi Kan , Li Wen‐Dong , Miao Dan‐Min
Published: August 2008

The construct of job performance has been one of the important topics in job performance research. The present study investigated the construct of job performance among Chinese military soldiers using both qualitative and quantitative methods. First, after interviewing 95 officers and soldiers, we categorized and conceptualized eight sets of typical behavioural incidents related to soldiers' job performance, and designed a questionnaire measuring job performance. Then, using a sample of 1402 Chinese soldiers, questionnaire reliability and validity were tested, and then the questionnaire was revised. The construct of job performance was further refined using confirmatory factor analyses and regression analyses using another sample of 1068 soldiers. The results showed that Chinese military soldiers' job performance consisted of two dimensions of task performance and contextual performance. Furthermore, task performance had three subfactors: military training, task accomplishment and work capability, whereas contextual performance encompassed four factors: helping others, love of learning, promoting organizational benefit and self‐discipline. Task performance and contextual performance contributed independently to overall job performance.
Incident Command System as a Response Model Within Emergency Operation Centers during Hurricane Rita
Authors: Lutz Leslie D. , Lindell Michael K.
Published: August 2008

This study examines the degree to which the use of the Incident Command System (ICS) influenced the performance of Texas emergency operations centers (EOCs) during Hurricane Rita. Staff in evacuation, transition, and host county EOCs completed a questionnaire that assessed demographic variables, EOC physical environment, ICS experience, ICS implementation, and team climate. The results indicated that the duties each ICS section performed varied substantially from one EOC to another. Moreover, ICS experience and ICS implementation lacked statistically significant correlations with team climate, even though EOCs' physical environments did. Finally, staff from emergency relevant agencies (e.g., public works and social services) seemed to have more problems with ICS than did staff from emergency mission agencies (e.g., fire and police departments). Thus, there needs to be further study of ICS application in emergencies other than structural and wildland fires, as well as the development of new ICS training materials for emergency relevant agencies to supplement the current ICS training materials for emergency mission agencies.
Human adenosine deaminase as an allosteric modulator of human A1adenosine receptor: abolishment of negative cooperativity for [3H](R)‐pia binding to the caudate nucleus
Authors: Gracia Eduard , Cortés Antoni , Meana J. Javier , García‐Sevilla Jesus , Herhsfield Michael S. , Canela Enric I. , Mallol Josefa , Lluís Carmen , Franco Rafael , Casadó Vicent
Published: August 2008

It has been shown that adenosine deaminase (ADA; EC 3.5.4.4) behaves as an ecto‐enzyme anchored to membrane proteins, among them A1adenosine receptors (A1Rs). Bovine ADA interacts with A1Rs from many species and regulates agonists binding to receptors in an activity‐independent form. However, it was not known whether human ADA exerted any effect on the agonist binding to human A1Rs, because of both technical difficulties in obtaining pure human ADA and tissues containing human A1Rs. In this study, human ADA was purified to homogeneity. Taking in consideration that A1Rs form homodimers and taking advantage of a new procedure to fit binding data to receptors dimers, which allows to calculate ligand dissociation constants and the degree of cooperativity between the two subunits in the dimer, here it is demonstrated that human ADA markedly enhances the agonist and antagonist affinity and abolishes the negative cooperativity on agonist binding to human striatal A1Rs. ADA also increases the ability of the agonist to decrease the forskolin‐induced cAMP levels. The results show that human ADA, apart from reducing the adenosine concentration and thus preventing A1R desensitization, binds to A1R behaving as an allosteric effector that markedly enhances agonist affinity and increases receptor functionality. The physiological role of the interaction is to make receptors more sensitive to adenosine. This powerful regulation has important implications for the physiology and pharmacology of neuronal A1Rs.
Lipid peroxidation up‐regulates BACE1 expression in vivo: a possible early event of amyloidogenesis in Alzheimer’s disease
Authors: Chen Liuji , Na Ren , Gu Mingjun , Richardson Arlan , Ran Qitao
Published: August 2008

Increased lipid peroxidation is shown to be an early event of Alzheimer’s disease (AD). However, it is not clear whether and how increased lipid peroxidation might lead to amyloidogenesis, a hallmark of AD. Glutathione peroxidase 4 (Gpx4) is an essential antioxidant defense enzyme that protects an organism against lipid peroxidation. Gpx4+/− mice show increased lipid peroxidation in brain, as evidenced by their elevated levels of 4‐hydroxy‐2‐nonenal. To understand the role of lipid peroxidation in amyloidogenesis, we studied secretase activities in Gpx4+/− mice as a function of age. Both young (6 months) and middle‐aged (17–20 months) Gpx4+/− mice had higher levels of β‐secretase activity than their age‐matched wildtype controls, and the increased β‐secretase activity in Gpx4+/− mice was a result of up‐regulation of β‐site amyloid precursor protein cleavage enzyme 1 (BACE1) expression at the protein level. The high level of BACE1 protein led to increased endogenous β‐amyloid (Aβ)1–40 in middle‐aged Gpx4+/− mice. We further studied amyloidogenesis in APPGpx4+/− mice. Our data indicate that APPGpx4+/− mice had significantly increased amyloid plaque burdens and increased Aβ1–40 and Aβ1–42 levels compared with APPGpx4+/+ mice. Therefore, our results indicate that increased lipid peroxidation leads to increased amyloidogenesis through up‐regulation of BACE1 expression in vivo, a mechanism that may be important in pathogenesis of AD at early stages.
Mitochondrial alterations in Parkinson’s disease: new clues
Authors: Vila Miquel , Ramonet David , Perier Celine
Published: August 2008

Mitochondrial dysfunction has long been associated with Parkinson’s disease (PD). In particular, complex I impairment and subsequent oxidative stress have been widely demonstrated in experimental models of PD and in post‐mortem PD samples. A recent wave of new studies is providing novel clues to the potential involvement of mitochondria in PD. In particular, (i) mitochondria‐dependent programmed cell death pathways have been shown to be critical to PD‐related dopaminergic neurodegeneration, (ii) many disease‐causing proteins associated with familial forms of PD have been demonstrated to interact either directly or indirectly with mitochondria, (iii) aging‐related mitochondrial changes, such as alterations in mitochondrial DNA, are increasingly being associated with PD, and (iv) anomalies in mitochondrial dynamics and intra‐neuronal distribution are emerging as critical participants in the pathogenesis of PD. These new findings are revitalizing the field and reinforcing the potential role of mitochondria in the pathogenesis of PD. Whether a primary or secondary event, or part of a multi‐factorial pathogenic process, mitochondrial dysfunction remains at the forefront of PD research and holds the promise as a potential molecular target for the development of new therapeutic strategies for this devastating, currently incurable, disease.
Unravelling the microbial role in ooid formation – results of an in situ experiment in modern freshwater Lake Geneva in Switzerland
Authors: PLEE K. , ARIZTEGUI D. , MARTINI R. , DAVAUD E.
Published: August 2008

The microbial role in the formation of the cortex of low‐Mg calcite freshwater ooids in western part of Lake Geneva in Switzerland has been suggested previously, but not demonstrated conclusively. Early work mostly concentrated in hypersaline milieus, and hence little is known about their genesis in freshwater environments. We designed an in situ experiment to mimic the natural process of low‐Mg calcite precipitation. A special device was placed in the ooid‐rich bank of the lake. It contained frosted glass (SiO2) slides, while quartz (SiO2) is the most abundant mineral composition of ooid nuclei that acted as artificial substrates to favour microbial colonization. Microscopic inspection of the slides revealed a clear seasonal pattern of carbonate precipitates, which were always closely associated with biofilms that developed on the surface of the frosted slides containing extracellular polymeric substance, coccoid and filamentous cyanobacteria, diatoms and heterotrophic bacteria. Carbonate precipitation peaks during early spring and late summer, and low‐Mg calcite crystals mostly occur in close association with filamentous and coccoid cyanobacteria (e.g. Tolypothrix, Oscillatoria and Synechococcus, Anacystis, respectively). Further scanning electron microscope inspection of the samples revealed low‐Mg calcite with crystal forms varying from anhedral to euhedral rhombohedra, depending on the seasons. Liquid cultures corroborate the in situ observations and demonstrate that under the same physicochemical conditions the absence of biofilms prevents the precipitation of low‐Mg calcite crystals.

These results illustrate that biofilms play a substantial role in low‐Mg calcite ooid cortex formation. It further demonstrates the involvement of microbes in the early stages of ooid development. Combined with ongoing microbial cultures under laboratory‐controlled conditions, the outcome of our investigation favoured the hypothesis of external microbial precipitation of low‐Mg calcite as the main mechanism involved in the early stage of ooid formation in freshwater Lake Geneva.
Effects of various concentrations of glycolic acid at the corneoxenometry and collaxenometry bioassays
Authors: Xhauflaire‐Uhoda Emmanuelle , Piérard‐Franchimont Claudine , Piérard Gérald E
Published: August 2008

Background  Glycolic acid is an α‐hydroxy acid used as a chemical peeling for more than a quarter century. The primary tissue target is the stratum corneum.

Objective  This study aims to assess the effects of various concentrations of glycolic acid on the stratum corneum and collagen fibers using two selected bioassays.

Methods  Corneoxenometry was performed to test the effects on human stratum corneum. Collaxenometry was similarly designed to quantify the effect on sheets of collagen fibers. Different glycolic acid concentrations ranging from 5% to 70% in alcohol were tested, respectively, for 3‐ and 10‐min exposure times.

Results  Both bioassays showed consistent reactivities with a dose–effect relationship when using a 3‐min exposure time. By contrast, the tests appeared unreliable or uninformative for the 10‐min exposure time.

Conclusion  Corneoxenometry and collaxenometry appear useful for in vitro testing peeling agents during short exposure times.
Facial scars after a road accident – combined treatment with pulsed dye laser and Q‐switched Nd:YAG laser
Authors: Martins Andréa , Trindade Felicidade , Leite Luiz
Published: August 2008

We report the case of a woman who presented with several facial scars following a road accident. Treatment was carried out using combined laser treatment with pulsed dye laser (PDL) and Q‐switched neodymium:yttrium‐aluminum‐garnet laser (QS Nd:YAG laser). No side effects or complications from treatment were noted or reported. The patient had very good cosmetic results with this combined technique. A variety of facial scars – erythematous, pigmented, atrophic, and hypertrophic – may occur as a result of trauma, surgery, burns, and skin disease. Surgery with other adjunctive methods including radiotherapy, intralesional steroids, and pressure therapy have shown variable results. Laser treatment has been attempted for scar revision since the 1980s. The PDL is the optimal treatment for reducing scar bulk and symptoms. It also decreases erythema and telangiectasia associated with scars, normalizes the skin surface texture, and improves the scar pliability. The QS Nd:YAG laser (1064 nm) is highly effective for traumatic tattoo removal, resulting in complete clearance in the majority of cases.
Prognostic implication and biological roles of RhoH in acute myeloid leukaemia
Authors: Iwasaki Toshihiro , Katsumi Akira , Kiyoi Hitoshi , Tanizaki Ryohei , Ishikawa Yuichi , Ozeki Kazutaka , Kobayashi Miki , Abe Akihiro , Matsushita Tadashi , Watanabe Takashi , Amano Mutsuki , Kojima Tetsuhito , Kaibuchi Kozo , Naoe Tomoki
Published: August 2008

The Rho family of small GTPases, including Rho, Rac and Cdc42, has been well characterised as a molecular switch that transduces signals from plasma membrane to the downstream effectors. RhoH gene, a member of the Rho family, is specifically expressed in haematopoietic cells. The known function of RhoH is antagonising Rac and mediating activation of ZAP‐70 in T lymphocytes; however, biological roles of RhoH in myeloid cells remain unknown. Here, we analysed the prognostic implication of the expression level of the RhoH gene transcript in bone marrow samples from 90 newly diagnosed acute myeloid leukaemia (AML) patients using a real‐time fluorescence detection method. Kaplan–Meier analysis demonstrated that low expression of the RhoH transcript was a predictor of worse prognosis in both overall and disease‐free survival. Multivariate analysis demonstrated that low expression of RhoH was an independent unfavourable prognostic factor for both overall and disease‐free survival of AML patients. Overexpression of RhoH leads to dephosphorylation of Bad at Serine 75 residue possibly through deactivation of Rac. It is possible that low expression of RhoH (i.e. high GTP‐Rac) contributes to chemotherapy resistance in leukaemia cells. Our result suggests that inhibition of Rac and its signalling components might provide a useful anti‐leukaemic strategy.
Location of Caspase 3‐like Protease in the Development of Sieve Element and Tracheary Element of Stem in Cucurbita moschata
Authors: Hao Xia , Qian Jie , Xu Shan , Song Xin , Zhu Jian
Published: August 2008

The casepase is considered to regulate the process of programmed cell death in the development of organisms. In this study, caspase 3‐like protease was detected by immunohistochemistry and immunoelectron microscopy during the development of sieve element and tracheary element of stem in Cucurbita moschata Duch. Antibody with brown color (under light microscopy) and gold particles (under transmission electron microscopy) for detecting caspase 3‐like protease was mainly displayed in inner phloem, external phloem and xylem in the region close to procambium. From the results it was considered that caspase 3‐like protease did exist in vascular elements and played different roles during the development of sieve and tracheary elements, and different types of programmed cell death might be carried out. The caspase 3‐like protease mainly participated in making cytoplasmic streaming cease and in degrading P‐protein bodies; however, it rarely participated in the function for signal transferring in the developmental sieve element. However, it might induce calcium accumulation for rupturing the tonoplast in the signal of PCD in the developmental tracheary element.
Covariance of Floral and Vegetative Traits in Four Species of Ranunculaceae: A Comparison between Specialized and Generalized Pollination Systems
Authors: Meng Jin‐Liu , Zhou Xian‐Hui , Zhao Zhi‐Gang , Du Guo‐Zhen
Published: August 2008

Theory predicts that tighter correlation between floral traits and weaker relationship between floral and vegetative traits more likely occur in specialized flowers than generalized flowers, favoring by precise fit with pollinators. However, traits and trait correlations frequently vary under different environments. Through detecting spatiotemporal variation in phenotypic traits (floral organ size and vegetative size) and trait correlations in four Ranunculaceae species, we examined four predictions. Overall, our results supported these predictions to a certain degree. The mean coefficient of variation (CV) of floral traits in two specialized species (Delphinium kamaonense and Aconitum gymnandrum) was marginally significantly lower than that of another two generalized species (Trollius ranunculoides and Anemone obtusiloba). The two specialized species also showed marginally significantly smaller CV in floral traits than vegetative size across the two species. The absolute mean correlation between floral and vegetative traits, or that between floral traits in species with specialized flowers was not significantly lower, or higher than that in generalized plants, weakly supporting the predictions. Furthermore, we documented a large variation in trait correlations of four species among different seasons and populations. Study of covariance of floral and vegetative traits will benefit from the contrast of results obtained from generalized and specialized pollination systems.
The Sound of Silence: Valuing Acoustics in Heritage Conservation
Authors: O’CONNOR PENNY
Published: August 2008

This paper explores the reasons behind the omission of historic acoustic values from heritage assessments in Australia. Best practice dictates that all cultural heritage values associated with significant places should be assessed in order to make informed conservation and management decisions. However, the multi‐sensory nature of aesthetics has been reframed in guidance documentation in ways that run counter to the primary frame. Conventions that have developed around the way places are assessed also work against comprehensive identification of values. As a result, the consideration of aesthetics in cultural heritage is limited to contemporary visual qualities. Furthermore, because the assessment of historic value takes a diachronic rather than synchronic approach, we have little knowledge of the places past communities valued for the sounds they experienced there. Research into landscape preference and acoustic ecology highlights the importance of identifying the inherent acoustic dimension of places and the role sound plays in developing a sense of place. Two landscape areas in Western Australia's south‐west with historic acoustic values, the Boranup Sand Patch and the Lower Reaches of the Blackwood River, illustrate how historic soundscapes can provide insightful contrasts and resonances with contemporary values, and how vulnerable such places are when the sound of place is overlooked in land management policies.
Extending the School Grounds?—Bullying Experiences in Cyberspace
Authors: Juvonen Jaana , Gross Elisheva F.
Published: August 2008

Background:  Bullying is a national public health problem affecting millions of students. With the rapid increase in electronic or online communication, bullying is no longer limited to schools. The goal of the current investigation was to examine the overlap among targets of, and the similarities between, online and in‐school bullying among Internet‐using adolescents. Additionally, a number of common assumptions regarding online or cyberbullying were tested.

Methods:  An anonymous Web‐based survey was conducted with one thousand four hundred fifty‐four 12‐ to 17‐year‐old youth.

Results:  Within the past year, 72% of respondents reported at least 1 online incident of bullying, 85% of whom also experienced bullying in school. The most frequent forms of online and in‐school bullying involved name‐calling or insults, and the online incidents most typically took place through instant messaging. When controlling for Internet use, repeated school‐based bullying experiences increased the likelihood of repeated cyberbullying more than the use of any particular electronic communication tool. About two thirds of cyberbullying victims reported knowing their perpetrators, and half of them knew the bully from school. Both in‐school and online bullying experiences were independently associated with increased social anxiety. Ninety percent of the sample reported they do not tell an adult about cyberbullying, and only a minority of participants had used digital tools to prevent online incidents.

Conclusions:  The findings have implications for (1) school policies about cyberbullying, (2) parent education about the risks associated with online communication, and (3) youth advice regarding strategies to prevent and deal with cyberbullying incidents.
Affective Arousal as Information: How Affective Arousal Influences Judgments, Learning, and Memory
Authors: Storbeck Justin , Clore Gerald L.
Published: August 2008

The affect‐as‐information framework posits that affect is embodied information about value and importance. The valence dimension of affect provides evaluative information about stimulus objects, which plays a role in judgment and decision‐making. Affect can also provide evaluative information about one's own cognitions and response inclinations, information that guides thinking and reasoning. In particular, positive affect often promotes, and negative affect inhibits, accessible responses or dominant modes of thinking. Affect thus moderates many of the textbook phenomena in cognitive psychology. In the current review, we suggest additionally that the arousal dimension of affect amplifies reactions, leading to intensified evaluations, increased reliance on particular styles of learning, and enhanced long‐term memory for events. We conclude that whereas valenced affective cues serve as information about value, the arousal dimension provides information about urgency or importance.
The determinants of volatility on the American crude oil futures market
Authors: Lautier Delphine , Riva Fabrice
Published: August 2008

This article focuses on the volatility of crude oil futures prices on the New York Mercantile Exchange. It aims at examining whether this market creates excess volatility, which would not be observed in the absence of such a market. In order to reach this objective, price fluctuations are separated into two components: an information component that reflects a rational assessment of the information arrival, and an error component that represents the noise introduced by the trading process. We show that a significant part of the volatility recorded during exchange trading hours is caused by mispricing errors. In particular, this phenomenon affects the nearest futures contract.
Leading indicators for Arabian Gulf oil tanker rates
Authors: Tham Eric
Published: August 2008

In this paper, price drivers for the Arabian Gulf oil tanker rates were derived from the Bayesian logistic regression to form a leading indicator. A universe of price drivers was filtered based on statistical criteria and speculative backtest results. Results showed that refining margins in Asia, crude production in the Arabian Gulf, the vessel utilisation rate and Brent–Dubai spreads were the most significant price drivers of TD3. A time series of these drivers indicates that Arabian Gulf production has a declining importance relative to the Brent–Dubai spreads since 2004. A vector error correction mechanism analysis of the TD1 and TD3 benchmarks indicates that TD1 returns lag behind TD3 rates.
‘Apprehensions of Controul’: The Familial Politics of Marriage, Choice and Consent in Sir Charles Grandison*
Authors: LATIMER BONNIE
Published: August 2008

This essay explores the extent to which women's consent is requisite to marriage in Richardson's Sir Charles Grandison and is a contribution to current critical debate on Richardson's constructions of patriarchal imperatives. The essay focuses on the marriage of a minor character, Miss Mansfield, arguing that her coerced marriage is not an anomaly, but rather an example of a tendency that subtly permeates Grandison. The essay concludes, however, that we cannot read Richardson simplistically as inhibiting women's agency; rather, Miss Mansfield's marriage forms part of a background discourse that participates in contemporary debates on choice, pressure and property in marriage.
Human angiotensin‐converting enzyme I/D and α‐actinin 3 R577X genotypes and muscle functional and contractile properties
Authors: McCauley Tracey , Mastana Sarabjit S. , Hossack James , MacDonald Martin , Folland Jonathan P.
Published: August 2008

The angiotensin‐converting enzyme (ACE) I/D and α‐actinin 3 (ACTN3) R/X polymorphisms have been suggested to influence variations in skeletal muscle function. This study investigated the association between ACE I/D and ACTN3 R/X polymorphisms and muscle strength and contractile properties in young UK Caucasian men. Measurements of the knee extensor muscles were taken from 79 recreationally active but non‐strength‐trained males on two occasions. Isometric knee extensor strength was measured using a conventional strength‐testing chair. Maximal twitches were electrically evoked by percutaneous stimulation to assess time‐to‐peak tension, half‐relaxation time and peak rate of force development. The torque–velocity relationship was measured at four angular velocities (0, 30, 90 and 240 deg s−1) using isokinetic dynamometry, and the relative torque at high velocity was calculated (torque at 240 deg s−1 as a percentage of that at 30 deg s−1). The ACE I/D and ACTN3 R/X polymorphisms were genotyped from whole blood by polymerase chain reaction. Serum ACE activity was assayed from serum using automated spectrophotometry. Physical characteristics were independent of either genotype. Absolute and relative high‐velocity torque were not influenced by ACE or ACTN3 genotypes. Isometric strength and the time course of a maximal twitch were independent of ACE and ACTN3 genotypes. Serum ACE activity was significantly dependent on ACE genotype (P < 0.001), but was not associated with any measure of functional or contractile properties. Knee extensor functional and contractile properties, including high‐velocity strength, were not influenced by ACE and ACTN3 polymorphisms in a cohort of UK Caucasian males. Any influence of these individual polymorphisms on human skeletal muscle does not appear to be of sufficient magnitude to influence function in free‐living UK Caucasian men.
Novel Type of Staphylococcal Cassette Chromosome
mec
in a Methicillin-Resistant
Staphylococcus aureus
Strain Isolated in Sweden
Authors: Berglund Carolina , Ito Teruyo , Ikeda Megumi , Ma Xiao Xue , Söderquist Bo , Hiramatsu Keiichi
Published: August 2008

We identified a novel type of staphylococcal cassette chromosome
mec
(SCC
mec
) element carried by methicillin-resistant
Staphylococcus aureus
(MRSA) strain JCSC6082 isolated in Sweden. The SCC
mec
element was demarcated by characteristic nucleotide sequences at both ends and was integrated at the 3′ end of
orfX
. The element carried a novel combination of a type 5
ccr
gene complex and class C1
mec
gene complex. The J regions of the element were homologous to those of the SCC
mercury
element of
S. aureus
strain 85/2082, with nucleotide identity greater than 99%. However, the novel SCC
mec
element from JCSC6082 did not carry the
mer
operon nor Tn
554
, suggesting that evolution to SCC
mec
could have been from a common ancestor by acquisition of the class C1
mec
gene complex. The novel SCC
mec
element from JCSC6082 was flanked by a novel SCC-like chromosome cassette (CC6082), which was demarcated by two direct repeats and could be excised from the chromosome independently of the SCC
mec
element. Our data suggest that novel SCC
mec
elements can be generated on the staphylococcal chromosome through the recombination between extant SCC elements and
mec
gene complexes.
Low Penetration of Oseltamivir and Its Carboxylate into Cerebrospinal Fluid in Healthy Japanese and Caucasian Volunteers
Authors: Jhee S. S. , Yen M. , Ereshefsky L. , Leibowitz M. , Schulte M. , Kaeser B. , Boak L. , Patel A. , Hoffmann G. , Prinssen E. P. , Rayner C. R.
Published: August 2008

Oseltamivir is a potent, well-tolerated antiviral for the treatment and prophylaxis of influenza. Although no relationship with treatment could be demonstrated, recent reports of abnormal behavior in young individuals with influenza who were receiving oseltamivir have generated renewed interest in the central nervous system (CNS) tolerability of oseltamivir. This single-center, open-label study explored the pharmacokinetics of oseltamivir and oseltamivir carboxylate (OC) in the plasma and cerebrospinal fluid (CSF) of healthy adult volunteers over a 24-hour interval to determine the CNS penetration of both these compounds. Four Japanese and four Caucasian males were enrolled in the study. Oseltamivir and OC concentrations in CSF were low (mean of observed maximum concentrations [
C
max
], 2.4 ng/ml [oseltamivir] and 19.0 ng/ml [OC]) versus those in plasma (mean
C
max
, 115 ng/ml [oseltamivir] and 544 ng/ml [OC]), with corresponding
C
max
CSF/plasma ratios of 2.1% (oseltamivir) and 3.5% (OC). Overall exposure to oseltamivir and OC in CSF was also comparatively low versus that in plasma (mean area under the concentration-time curve CSF/plasma ratio, 2.4% [oseltamivir] and 2.9% [OC]). No gross differences in the pharmacokinetics of oseltamivir or OC were observed between the Japanese and Caucasian subjects. Oseltamivir was well tolerated. This demonstrates that the CNS penetration of oseltamivir and OC is low in Japanese and Caucasian adults. Emerging data support the idea that oseltamivir and OC have limited potential to induce or exacerbate CNS adverse events in individuals with influenza. A disease- rather than drug-related effect appears likely.
Antagonistic Effect of Rifampin on the Efficacy of High-Dose Levofloxacin in Staphylococcal Experimental Foreign-Body Infection
Authors: Murillo O. , Pachón M. E. , Euba G. , Verdaguer R. , Tubau F. , Cabellos C. , Cabo J. , Gudiol F. , Ariza J.
Published: August 2008

Since levofloxacin at high doses was more active than levofloxacin at conventional doses and was the best therapy alone in a rat model of staphylococcal foreign-body infection, in this study we tested how these differences affect the activities of their respective combinations with rifampin in vitro and in vivo. In vitro studies were performed in the log and stationary phases. By using this model, rifampin at 25 mg/kg of body weight/12 h, levofloxacin at 100 mg/kg/day, levofloxacin at 100 mg/kg/day plus rifampin, levofloxacin at 50 mg/kg/day, levofloxacin at 50 mg/kg/day plus rifampin, or a control treatment was administered for 7 days; and therapy with for levofloxacin at 100 mg/kg/day alone and rifampin alone was prolonged to 14 days. We screened for the appearance of resistant strains. Killing curves in the log phase showed a clear antagonism with levofloxacin at concentrations ≥2× MIC and rifampin and tended to occur in the stationary phase. At the end of 7 days of therapy, levofloxacin at 100 mg/kg/day was the best treatment and decreased the bacterial counts from tissue cage fluid (
P
< 0.05 compared with the results for groups except those receiving rifampin alone). At the end of 14 days of therapy with levofloxacin at 100 mg/kg/day, levofloxacin at 100 mg/kg/day plus rifampin, and the control treatment, the bacterial counts on the coverslips were 2.24 (
P
< 0.05 compared with the results with the combined therapy), 3.36, and 5.4 log CFU/ml, respectively. No rifampin or levofloxacin resistance was detected in any group except that receiving rifampin alone. In conclusion, high-dose levofloxacin was the best treatment and no resistant strains appeared; the addition of rifampin showed an antagonistic effect. The efficacy of the rifampin-levofloxacin combination is not significantly improved by the dosage of levofloxacin.
Development of Caspofungin Resistance following Prolonged Therapy for Invasive Candidiasis Secondary to
Candida glabrata
Infection
Authors: Thompson George R. , Wiederhold Nathan P. , Vallor Ana C. , Villareal Nyria C. , Lewis James S. , Patterson Thomas F.
Published: August 2008

We report a case of
Candida glabrata
invasive candidiasis that developed reduced susceptibility to caspofungin during prolonged therapy. Pre- and posttreatment isolates were confirmed to be isogenic, and sequencing of hot spots known to confer echinocandin resistance revealed an F659V substitution within the
FKS2
region of the glucan synthase complex.
Macrolide Antibiotic-Mediated Downregulation of MexAB-OprM Efflux Pump Expression in
Pseudomonas aeruginosa
Authors: Sugimura Makoto , Maseda Hideaki , Hanaki Hideaki , Nakae Taiji
Published: August 2008

Macrolide antibiotics modulate the quorum-sensing system of
Pseudomonas aeruginosa
. We tested the effect of macrolide antibiotics on the cell density-dependent expression of the MexAB-OprM efflux pump and found that 1.0 μg/ml (MIC/6.25) of azithromycin suppressed the expression of MexAB-OprM by about 70%, with the result that the cells became two- to fourfold more susceptible to antibiotics such as aztreonam, tetracycline, carbenicillin, chloramphenicol, and novobiocin.
Novel Insertion Sequence- and Transposon-Mediated Genetic Rearrangements in Genomic Island SGI1 ofSalmonella entericaSerovar Kentucky
Authors: Doublet Benoît , Praud Karine , Bertrand Sophie , Collard Jean-Marc , Weill François-Xavier , Cloeckaert Axel
Published: August 2008

Salmonellagenomic island 1 (SGI1) is an integrative mobilizable element that harbors a multidrug resistance (MDR) gene cluster. Since its identification in epidemicSalmonella entericaserovar Typhimurium DT104 strains, variant SGI1 MDR gene clusters conferring different MDR phenotypes have been identified in severalS. entericaserovars and classified as SGI1-A to -O. A study was undertaken to characterize SGI1 from serovar Kentucky strains isolated from travelers returning from Africa. Several strains tested were found to contain the partially characterized variant SGI1-K, recently described in a serovar Kentucky strain isolated in Australia. This variant contained only one cassette array,aac(3)-Id-aadA7, and an adjacent mercury resistance module. Here, the uncharacterized part of SGI1-K was sequenced. Downstream of themermodule similar to that found in Tn21, a mosaic genetic structure was found, comprising (i) part of Tn1721containing the tetracycline resistance genestetRandtet(A); (ii) part of Tn5393containing the streptomycin resistance genesstrAB, IS1133, and a truncatedtnpRgene; and (iii) a Tn3-like region containing thetnpRgene and the β-lactamaseblaTEM-1gene flanked by two IS26elements in opposite orientations. The rightmost IS26element was shown to be inserted into the S044 open reading frame of the SGI1 backbone. This variant MDR region was named SGI1-K1 according to the previously described variant SGI1-K. Other SGI1-K MDR regions due to different IS26locations, inversion, and partial deletions were characterized and named SGI1-K2 to -K5. Two new SGI1 variants named SGI1-P1 and -P2 contained only the Tn3-like region comprising the β-lactamaseblaTEM-1gene flanked by the two IS26elements inserted into the SGI1 backbone. Three other new variants harbored only one IS26element inserted in place of the MDR region of SGI1 and were named SGI1-Q1 to -Q3. Thus, in serovar Kentucky, the SGI1 MDR region undergoes recombinational and insertional events of transposon and insertion sequences, resulting in a higher diversity of MDR gene clusters than previously reported and consequently a higher diversity of MDR phenotypes.
Penetration of Chlorhexidine into Human Skin
Authors: Karpanen T. J. , Worthington T. , Conway B. R. , Hilton A. C. , Elliott T. S. J. , Lambert P. A.
Published: August 2008

This study evaluated a model of skin permeation to determine the depth of delivery of chlorhexidine into full-thickness excised human skin following topical application of 2% (wt/vol) aqueous chlorhexidine digluconate. Skin permeation studies were performed on full-thickness human skin using Franz diffusion cells with exposure to chlorhexidine for 2 min, 30 min, and 24 h. The concentration of chlorhexidine extracted from skin sections was determined to a depth of 1,500 μm following serial sectioning of the skin using a microtome and analysis by high-performance liquid chromatography. Poor penetration of chlorhexidine into skin following 2-min and 30-min exposures to chlorhexidine was observed (0.157 ± 0.047 and 0.077 ± 0.015 μg/mg tissue within the top 100 μm), and levels of chlorhexidine were minimal at deeper skin depths (less than 0.002 μg/mg tissue below 300 μm). After 24 h of exposure, there was more chlorhexidine within the upper 100-μm sections (7.88 ± 1.37 μg/mg tissue); however, the levels remained low (less than 1 μg/mg tissue) at depths below 300 μm. There was no detectable penetration through the full-thickness skin. The model presented in this study can be used to assess the permeation of antiseptic agents through various layers of skin in vitro. Aqueous chlorhexidine demonstrated poor permeation into the deeper layers of the skin, which may restrict the efficacy of skin antisepsis with this agent. This study lays the foundation for further research in adopting alternative strategies for enhanced skin antisepsis in clinical practice.
Antiviral Effects of Lamivudine, Emtricitabine, Adefovir Dipivoxil, and Tenofovir Disoproxil Fumarate Administered Orally Alone and in Combination to Woodchucks with Chronic Woodchuck Hepatitis Virus Infection
Authors: Menne Stephan , Butler Scott D. , George Andrea L. , Tochkov Ilia A. , Zhu Yuao , Xiong Shelly , Gerin John L. , Cote Paul J. , Tennant Bud C.
Published: August 2008

Adefovir dipivoxil (ADV) and tenofovir disoproxil fumarate (TDF) are nucleotide analogs that inhibit the replication of wild-type hepatitis B virus (HBV) and lamivudine (3TC)-resistant virus in HBV-infected patients, including those who are coinfected with human immunodeficiency virus. The combination of ADV or TDF with other nucleoside analogs is a proposed strategy for managing antiviral drug resistance during the treatment of chronic HBV infection. The antiviral effect of oral ADV or TDF, alone or in combination with 3TC or emtricitabine (FTC), against chronic woodchuck hepatitis virus (WHV) infection was evaluated in a placebo-controlled study in the woodchuck, an established and predictive model for antiviral therapy. Once-daily treatment for 48 weeks with ADV plus 3TC or TDF plus FTC significantly reduced serum WHV viremia levels from the pretreatment level by 6.2 log10and 6.1 log10genome equivalents/ml serum, respectively, followed by TDF plus 3TC (5.6 log10genome equivalents/ml), ADV alone (4.8 log10genome equivalents/ml), ADV plus FTC (one survivor) (4.4 log10genome equivalents/ml), TDF alone (2.9 log10genome equivalents/ml), 3TC alone (2.7 log10genome equivalents/ml), and FTC alone (2.0 log10genome equivalents/ml). Individual woodchucks across all treatment groups also demonstrated pronounced declines in serum WHV surface antigen, characteristically accompanied by declines in hepatic WHV replication and the hepatic expression of WHV antigens. Most woodchucks had prompt recrudescence of WHV replication after drug withdrawal, but individual woodchucks across treatment groups had sustained effects. No signs of toxicity were observed for any of the drugs or drug combinations administered. In conclusion, the oral administration of 3TC, FTC, ADV, and TDF alone and in combination was safe and effective in the woodchuck model of HBV infection.
In Vivo Pharmacodynamics of Ceftobiprole against Multiple Bacterial Pathogens in Murine Thigh and Lung Infection Models
Authors: Craig W. A. , Andes D. R.
Published: August 2008

Ceftobiprole medocaril is the parenteral prodrug of ceftobiprole, a novel pyrrolidinone broad-spectrum cephalosporin with in vitro and in vivo bactericidal activities against methicillin-resistantStaphylococcus aureus(MRSA) and penicillin-resistantStreptococcus pneumoniae(PRSP). We have used murine thigh and lung infection models in neutropenic and normal mice to characterize the in vivo pharmacokinetic (PK)-pharmacodynamic (PD) activities of ceftobiprole against multiple strains ofS. aureus(including MRSA),S. pneumoniae(including PRSP), and gram-negative bacilli. Serum levels of ceftobiprole following the administration of multiple doses were determined by a microbiological assay. In vivo bactericidal activities and postantibiotic effects (PAEs) of ceftobiprole against MRSA and PRSP strains were determined from serial CFU/thigh values following single doses of ceftobiprole (40 and 160 mg/kg of body weight). Dose fractionation studies were used to determine which PK-PD index correlated best with activity. Magnitudes of the PK-PD indices were calculated from MICs and PK parameters. A sigmoid dose-response model was used to estimate the dose (mg/kg/24 h) required to achieve a static and 2-log10kill effects over 24 h. PK results showed area under the concentration-time curve/dose values of 1.8 to 2.8 and half-lives of 0.29 to 0.51 h. MICs ranged from 0.015 to 2 μg/ml. Ceftobiprole demonstrated time-dependent killing; its in vivo PAEs varied from 3.8 h to 4.8 h for MRSA and from 0 to 0.8 h for PRSP. The time above MIC (T> MIC) correlated best with efficacy for both MRSA and PRSP. TheT> MIC values required for the static doses were significantly longer (P< 0.001) forEnterobacteriaceae(36 to 45%) than forS. aureus(14 to 28%) andS. pneumoniae(15 to 22%). The drug showed activities in the lung model similar to those in the thigh model. The presence of neutrophils significantly enhanced the activity of ceftobiprole againstS. pneumoniaebut only slightly againstKlebsiella pneumoniae. Based on its PD profile, ceftobiprole is a promising new β-lactam agent with activity against gram-negative and gram-positive organisms including MRSA and PRSP.