bluuebunny/crossref_metadata_2025 huggingface dataset:
Towards a re‐definition of ‘cardiac hypertrophy’ through a rational characterization of left ventricular phenotypes: a position paper of the Working Group ‘Myocardial Function’ of the ESC
Authors: Knöll Ralph , Iaccarino Guido , Tarone Guido , Hilfiker‐Kleiner Denise , Bauersachs Johann , Leite‐Moreira Adelino F. , Sugden Peter H. , Balligand Jean‐Luc
Published: June 2011

Many primary or secondary diseases of the myocardium are accompanied with complex remodelling of the cardiac tissue that results in increased heart mass, often identified as cardiac ‘hypertrophy’. Although there have been numerous attempts at defining such ‘hypertrophy’, the present paper delineates the reasons as to why current definitions of cardiac hypertrophy remain unsatisfying. Based on a brief review of the underlying pathophysiology and tissue and cellular events driving myocardial remodelling with or without changes in heart dimensions, as well as current techniques to detect such changes, we propose to restrict the use of the currently popular term ‘hypertrophy’ to cardiac myocytes that may or may not accompany the more complex tissue rearrangements leading to changes in shape or size of the ventricles, more broadly referred to as ‘remodelling’. We also discuss the great potential of genetically modified (mouse) models as tools to define the molecular pathways leading to the different forms of left ventricle remodelling. Finally, we present an algorithm for the stepwise assessment of myocardial phenotypes applicable to animal models using well‐established imaging techniques and propose a list of parameters most suited for a critical evaluation of such pathophysiological phenomena in mouse models. We believe that this effort is the first step towards a much auspicated unification of the terminology between the experimental and the clinical cardiologists.
Intertextualité et publicité: publier selon Jean de Tournes (1542–1564)
Authors: Jourde Michel
Published: June 2011

L'article envisage la question de la ‘politique éditoriale’ au seizième siècle à partir du lexique utilisé par un imprimeur-libraire dans ses pièces liminaires. L'ensemble de ces pièces, signées du nom de l'imprimeur (‘Jean de Tournes’) ou de sa fonction (‘l'imprimeur’), vise à affirmer l'unité d'un catalogue, d'une production. Mais cette affirmation, qui concerne à la fois la relation entre les textes publiés (
intertextualité
) et la valorisation d'une identité commerciale (
publicité
), laisse apparaître des nuances importantes entre différentes formes de cohésion ou de cohérence (la ‘correction’, le ‘recueil’, l’‘analogie’, l’‘effet’) qui ne sont pas toutes assimilables à un principe de collection ou à l'affirmation d'une conception éditoriale unitaire.
Les Compilations raisonnées des Remarques et Observations sur la langue française
Authors: Ayres-Bennett Wendy , Seijido Magali
Published: June 2011

Dans cet article nous essaierons de montrer que les compilations raisonnées des Remarques et Observations sur la langue française ont profondément modifié et influencé notre perception moderne des textes originaux. Les remarques de Vaugelas et de ses principaux successeurs ont une dimension normative bien connue mais également une dimension sociolinguistique importante: elles comportent de nombreux témoignages sur l’évolution de l'usage, la variation sociale, la variation régionale ou encore des observations sur les registres et les genres. À partir de trois études de cas — la compilation des
Remarques
de Vaugelas avec des commentaires de La Mothe Le Vayer, de Scipion Dupleix et d'un auteur anonyme, publiée par Jean Macé en 1651;
L'Art de bien parler françois
(1696) de La Touche; et les
Principes généraux et particuliers de la langue françoise
(2
e
éd. 1763) de Wailly — nous proposons de montrer que les compilations, en intégrant les remarques dans un autre format, ont effacé leur dimension sociolinguistique. Les remarques ne représentent alors plus les observations de ‘simples témoins’, mais plutôt des jugements prescriptifs et autoritaires où la notion même d'auteur se trouve gommée et où le ton est résolument plus dogmatique.
Amadis de Gaule
en français: continuation romanesque, collection, compilation
Authors: de Buzon Christine
Published: June 2011

Le corpus français de l’
Amadis de Gaule
(1540–1615) procède de la traduction, de la sélection et de la collection d'une matière amadisienne qui n'est pas seulement espagnole. Caractérisé par un mouvement d'expansion, ce corpus est augmenté par la création d'un paratexte important et d'une série d'illustrations qui tendent à faire oublier son origine étrangère. Toutefois, après 1559, le succès contesté, mais aussi l'ampleur de la matière, conduisent à la restreindre. Le florilège intitulé
Thresor d'Amadis
rassemble des passages sélectionnés dans une compilation elle-même régulièrement augmentée. L'article examine ces doubles mouvements complexes d'augmentation et de resserrement et quelques-uns de leurs effets, ainsi que, d'une part, les notions de collection, de cycle et de série pour la partie romanesque, et, d'autre part, la notion de compilation pour le
Thresor d'Amadis
. La collection des illustrations et la compilation du
Thresor
sont envisagées comme deux interprétants français des romans, le
Thresor
venant à leur secours dans un contexte défavorable à ce type de fiction. Le succès de soixante-quinze ans que connurent les
Amadis
est enfin attesté par une dernière opération de sélection-compilation, celle des dictionnaires anciens.
Probability and distributions
Authors: Peacock Janet L. , Peacock Philip J.
Published: June 2011

Independence: data and variables 204

Probability: definitions 206

Probability: properties 208

Probability distributions 210

Binomial distribution: formula 212

Binomial distribution: derivation 214

Poisson distribution 216

Continuous probability distributions 220

Normal distribution 222

Normal distribution: calculating probabilities 224

Normal distribution: percentage points 226

Central limit theorem ...
Analysing multiple observations per subject
Authors: Peacock Janet L. , Peacock Philip J.
Published: June 2011

Serial (longitudinal) data 378

Summarizing serial data 380

Calculating area under the curve 382

Other summary measures for serial data 383

Summary measures approach: key points 384

Other approaches to serial data 386

Cluster samples: units of analysis 388

Cluster samples: analysis 390

In this chapter we describe the statistical issues involved in analysing studies with more than one data point or observation per subject, such as when a series of measurements are made on each individual over time or when a group of subjects are analysed together, forming a cluster. For each of these situations, the statistical analysis needs to take account of the design of the study, and for most situations there are several possible approaches which may be used. We describe the most common approaches in terms of when the methods are appropriate, how they work, and how the results are interpreted....
Analysing multiple variables per subject
Authors: Peacock Janet L. , Peacock Philip J.
Published: June 2011

Multiple variables per subject 394

Multifactorial methods: overview 396

Multifactorial methods: model selection 398

Multifactorial methods: challenges 400

Missing data 402

Generalized linear models 404

Multiple regression 406

Multiple regression: examples 408

Multiple regression and analysis of variance 412

Main effects and interactions 414

Linear and non-linear terms ...
Meta-analysis
Authors: Peacock Janet L. , Peacock Philip J.
Published: June 2011

Meta-analysis: introduction 448

Searching for studies 450

Combining estimates in meta-analyses 452

Heterogeneity 454

Overcoming heterogeneity 456

Fixed effects estimates 458

Random effects estimates 460

Presenting meta-analyses 462

Publication bias 464

Detecting publication bias 466

Adjusting for publication bias 468

Independent patient data meta-analysis 472...
Effect of wavelength-dependent attenuation on neutron diffraction stress measurements at depth in steels
Authors: Woo Wanchuck , Em Vyacheslav , Seong Baek-Seok , Shin Eunjoo , Mikula Pavol , Joo Jongdae , Kang Mi-Hyun
Published: June 2011

The wavelength dependence of the maximum feasible penetration depth was studied for neutron diffraction stress measurements in ferritic and austenitic steels. This property was examined with wavelengths from the close vicinity of the Bragg edges, where the neutron total cross section has its local minimum and for which the scattering angles are convenient for stress measurements. These wavelengths (e.g.2.39 and 2.19 Å) are longer than those commonly used in stress measurements (∼1.6 Å). By using such wavelengths, configured by a focusing bent perfect crystal Si(111) monochromator, it was observed that the available total beam path length is about 85 mm in both ferritic and austenitic steels. This study provides specific information for choosing the instrument configuration suitable for most strain-scanning experimental tasks.
Stacking fault model of ∊-martensite and itsDIFFaXimplementation
Authors: Martin Stefan , Ullrich Christiane , Šimek Daniel , Martin Ulrich , Rafaja David
Published: June 2011

Plastic deformation of highly alloyed austenitic transformation-induced plasticity (TRIP) steels with low stacking fault energy leads typically to the formation of ∊-martensite within the original austenite. The ∊-martensite is often described as a phase having a hexagonal close-packed crystal structure. In this contribution, an alternative structure model is presented that describes ∊-martensite embedded in the austenitic matrixviaclustering of stacking faults in austenite. The applicability of the model was tested on experimental X-ray diffraction data measured on a CrMnNi TRIP steel after 15% compression. The model of clustered stacking faults was implemented in theDIFFaXroutine; the faulted austenite and ∊-martensite were represented by different stacking fault arrangements. The probabilities of the respective stacking fault arrangements were obtained from fitting the simulated X-ray diffraction patterns to the experimental data. The reliability of the model was proven by scanning and transmission electron microscopy. For visualization of the clusters of stacking faults, the scanning electron microscopy employed electron channelling contrast imaging and electron backscatter diffraction.
Extracting the pair distribution function from white-beam X-ray total scattering data
Authors: Soper Alan K. , Barney Emma R.
Published: June 2011

A general method is described for reducing white-beam X-ray total scattering raw data to the differential scattering cross section and pair distribution function. The method incorporates corrections for X-ray fluorescence,Bremsstrahlungradiation, polarization, attenuation, multiple scattering and sample container scattering, and invokes the Krogh-Moe and Norman method to put the data on an absolute scale. An accurate method to convert the differential scattering cross section to the pair distribution function is also described, and a rigorous and revised Lorch function is proposed for removing the effects of Fourier truncation oscillations. The method can be equally applied to synchrotron X-ray data, where the data analysis can be simpler than at a laboratory source.
MetLigDB: a web-based database for the identification of chemical groups to design metalloprotein inhibitors
Authors: Choi Hwanho , Kang Hongsuk , Park Hwangseo
Published: June 2011

MetLigDB (http://silver.sejong.ac.kr/MetLigDB) is a publicly accessible web-based database through which the interactions between a variety of chelating groups and various central metal ions in the active site of metalloproteins can be explored in detail. Additional information can also be retrieved, including protein and inhibitor names, the amino acid residues coordinated to the central metal ion, and the binding affinity of the inhibitor for the target metalloprotein. Although many metalloproteins have been considered promising targets for drug discovery, it is difficult to discover new inhibitors because of the difficulty in designing a suitable chelating moiety to impair the catalytic activity of the central metal ion. Because both common and specific chelating groups can be identified for varying metal ions and the associated coordination environments, MetLigDB is expected to give users insight into designing new inhibitors of metalloproteins for drug discovery.
Asymptotic Capacity of Large Fading Relay Networks with Random Node Failures
Authors: Huang Chuan , Jiang Jinhua , Cui Shuguang
Published: June 2011

To understand the network response to large-scale physical attacks, we investigate the asymptotic capacity of a half-duplex fading relay network with random node failures when the number of relays N gets infinitely large. In this paper, a simplified independent attack model is assumed where each relay node fails with a certain probability. The noncoherent relaying scheme is considered, which corresponds to the case of zero forward-link channel state information (CSI) at the relays. Accordingly, the whole relay network can be shown equivalent to a Rayleigh fading channel, where we derive the ε-outage capacity upper bound according to the multiple access (MAC) cut-set, and the ε-outage achievable rates for both the amplify-and-forward (AF) and decode-and-forward (DF) strategies. Furthermore, we show that the DF strategy is asymptotically optimal as the outage probability ε goes to zero, with the AF strategy strictly suboptimal over all signal to noise ratio (SNR) regimes. Regarding the rate loss due to random attacks, the AF strategy suffers a less portion of rate loss than the DF strategy in the high SNR regime, while the DF strategy demonstrates more robust performance in the low SNR regime.
Cell‐based therapy for patients with vascular dementia
Authors: TAGUCHI Akihiko
Published: June 2011

The homeostasis of neuronal cells is maintained by the cerebral circulation and blood–brain barrier. Circulating bone marrow‐derived immature cells, including CD34‐positive (CD34+) cells, have been implicated in homeostasis of the cerebral microvasculature. Decreased levels of circulating CD34+ cells, associated with ageing and/or cardiovascular risk factors, correlate with poor clinical outcomes in patients with cerebrovascular and cardiovascular diseases. Clinical trials with local transplantation of bone marrow‐derived immature cells for patients with limb ischaemia, including Buerger's disease and arteriosclerosis obliterans, have been shown to improve impaired microcirculation. In the present review, current findings about the correlation between circulating immature cells and microcirculation are reviewed, and the possibility of novel cell‐based therapy in patients with vascular dementia is discussed.
Low‐dose aripiprazole resolved complex hallucinations in the left visual field after right occipital infarction (Charles Bonnet syndrome)
Authors: CHEN Cheng‐Che , LIU Hsing‐Cheng
Published: June 2011

We reported a patient who suffered from complex visual hallucinations with left homonymous hemianopsia. Brain imaging showed an acute haemorrhage infarct at the right occipital lobe. Charles Bonnet syndrome (CBS) was suspected and aripiprazole was prescribed at 5 mg daily. After 3 weeks, the symptoms of hallucinations and anxiety were relieved. Although some CBS patients might be self‐limited without discomfort, low‐dose aripiprazole can be considered as a safe medication for significantly anxious patients with CBS.
Transfection of Human Platelets with Short Interfering RNA
Authors: Hong Wei , Kondkar Altaf A. , Nagalla Srikanth , Bergmeier Wolfgang , Jin Ying , Herman Jay H. , Bray Paul F.
Published: June 2011

Platelets contain mRNAs and are capable of translating mRNA into protein, and it has been previously demonstrated that platelets increase their levels of integrin β3 overtime while in blood bank storage conditions. We are unaware of prior attempts to introduce nucleic acids into platelets. Considering the potential clinical and research utility of manipulating platelet gene expression, we tested whether small interfering RNAs (siRNAs) could be transfected into normal human platelets. Multiple conditions were tested, including lipofectamine versus electroporation, different amounts of siRNA, the effect of different buffers and the presence of plasma during transfection, and the time for optimal siRNA incorporation after transfection. Using flow cytometry to assess transfection efficiency, we found that optimal transfection was obtained using lipofectamine, washed platelets, and 400 pmoles siRNA. Cell sorting of transfected platelets suggested that the incorporated siRNA was able to knockdown the level of a targeted mRNA. This is the first ever demonstration that nucleic acids can be introduced directly into platelets, and offers proof of concept for manipulating gene expression in platelets by nonviral methods. Future technical improvements may permit improving the quality and/or lifespan of stored human platelets. Clin Trans Sci 2011; Volume 4: 180–182
Pharmacologic Correction of Dominant‐Negative GH1 Deficiency Causing Mutations
Authors: Poling Justin S. , Phillips III John A. , Cogan Joy D. , Hamid Rizwan
Published: June 2011

Purpose: Dominant‐negative growth hormone gene (GH1) mutations cause familial isolated growth hormone deficiency type II (IGHD II), which is characterized by GH deficiency, occasional multiple anterior pituitary hormone deficiencies, and anterior pituitary hypoplasia. We have previously shown that 17.5‐/22‐kDa GH1 transcript ratios correlate with the severity of the IGHD II phenotype. We hypothesized that different pharmaceutical agents could affect the GH1 transcript ratio by modulating alternative splicing.

Methods: We exposed peripheral blood mononuclear cells from IGHD II patients and unaffected family members to different pharmacologic agents and then determined the 17.5‐/22‐kDa transcript ratios by real‐time PCR.

Results: Dexamethasone and digoxin significantly increased the 17.5‐/22‐kDa transcript ratio, while sodium butyrate and 5‐iodotubericidin significantly decreased the ratio.

Conclusion: Since we have previously shown that the ratio of the 17.5‐/22‐kDa GH1 transcripts correlates with severity of the IGHD II phenotype, our findings here suggest that selected previously unconsidered agents could possibly reduce the severity of IGHD II, while other agents could possibly exacerbate the disease phenotype. Clin Trans Sci 2011; Volume 4: 175–179
State Incapacity by Design: Understanding the Bihar Story
Authors: Mathew Santhosh , Moore Mick
Published: June 2011

The Indian state of Bihar has long been a byword for bad governance. It was however governed particularly badly between 1990 and 2005, and has since experienced something of a ‘governance miracle’. How can we account for the 1990–2005 deterioration? The answer lies in the interaction of three factors. The first was the type of leadership exercised by Lalu Prasad Yadav, who was Chief Minister throughout most of this period – even when his wife formally occupied the post. The second lies in electoral politics: the need to maintain the enthusiasm and morale of an electoral coalition that Yadav had constructed from a number of poorer and historically oppressed groups. Such was the scale of poverty among this core electoral coalition that Yadav had limited prospects of maintaining its cohesion and allegiance through the normal processes of promising ‘development’ and using networks of political patronage to distribute material resources to supporters. More important, that strategy would have involved a high level of dependence on the government apparatus, that was dominated by people from a number of historically‐dominant upper castes. That is our third factor. Yadav preferred to mobilise his supporters on the basis of continual confrontation with this historically oppressive elite. He kept public sector jobs vacant rather than appoint qualified people – who were mainly from the upper cases. He tried to micro‐manage the state apparatus from the Chief Minister's office. He denuded the public service of staff. He was then unable to use it to deliver ‘development’. We show that, among other things, the Bihar state government sacrificed large potential fiscal transfers from the Government of India designed for anti‐poverty programmes because it was unable to complete the relevant bureaucratic procedures. Yadav knowingly undermined the capacity of the state apparatus. There are parallels in many other parts of the world. Low state capacity is often a political choice.
Protective conditioning of the brain: expressway or roadblock?
Authors: Mergenthaler Philipp , Dirnagl Ulrich
Published: June 2011

Abstract  The brain responds to noxious stimulation with protective signalling. Over the last decades, a number of experimental strategies have been established to study endogenous brain protection. Pre‐, per‐, post‐ and remote ‘conditioning’ are now widely used to unravel the underlying mechanisms of endogenous neuroprotection. Some of these strategies are currently being tested in clinical trials to protect the human brain against anticipated damage or to boost protective responses during or after injury. Here we summarize the principles of ‘conditioning’ research and current efforts to translate this knowledge into effective treatment of patients. Conditioning to induce protected brain states provides an experimental window into endogenous brain protection and can lead to the discovery of drugs mimicking the effects of conditioning. Mechanisms of endogenous brain tolerance can be activated through a wide variety of stimuli that signal ‘danger’ to the brain. These danger signals lead to the induction of regulator and effector mechanisms, which suppress death and induce survival pathways, decrease metabolism, as well as increase substrate delivery. We conclude that preclinical research on endogenous brain protection has greatly benefited from conditioning strategies, but that clinical applications are challenging, and that we should not prematurely rush into ill‐designed and underpowered clinical trials.
Experimental Investigation Into Unsteady Effects on Film Cooling
Authors: Fawcett Richard J. , Wheeler Andrew P. S. , He Li , Taylor Rupert
Published: June 2011

The benefits of different film cooling geometries are typically assessed in terms of their time-averaged performance. It is known that the mixing between the coolant film and the main turbine passage flow is an unsteady process. The current study investigates the forms of unsteadiness that occur in engine-representative film cooling flows and how this unsteadiness affects the mixing with the mainstream flow. Cylindrical and fan-shaped cooling holes across a range of hole blowing ratios have been studied experimentally using particle image velocimetry and high speed photography. Coherent unsteadiness is found in the shear layer between the jet and the mainstream for both cylindrical and fan-shaped cooling holes. Its occurrence and sense of rotation is found to be controlled by the velocity difference between the mainstream flow and the jet, which is largely determined by the blowing ratio.
Model Verification of Mist/Steam Cooling With Jet Impingement Onto a Concave Surface and Prediction at Elevated Operating Conditions
Authors: Wang Ting , Dhanasekaran T. S.
Published: June 2011

Internal mist/steam blade cooling technology is proposed for advanced gas turbine systems that use the closed-loop steam cooling scheme. Previous experiments on mist/steam heat transfer with a 2D slot jet impingement onto a concave surface showed cooling enhancement of up to 200% at the stagnation point by injecting approximately 0.5% of mist under low temperature and pressure laboratory conditions. Realizing the difficulty in conducting experiments at elevated pressure and temperature working conditions, computational fluid dynamics (CFD) simulation becomes an opted approach to predict the potential applicability of the mist/steam cooling technique at real GT operating conditions. In this study, the CFD model is first validated within 3% and 6% deviations from experimental results for the flows of steam-only and mist/steam flow cases, respectively. The validated CFD model is then used to simulate a row of multiple holes impinging jet onto a concave surface under elevated pressure, temperature, and Reynolds number conditions. The predicted results show an off-center cooling enhancement with a local maximum of 100% at s/d=2 and an average cooling enhancement of about 50%. The mist cooling scheme is predicted to work better on a concave surface than on the flat surface. The extent of wall jet and the size of 3D recirculation zones are identified as a major influencing parameter on the curvature effect on mist cooling performance. The mist enhancement from a slot jet is more pronounced than a row of round jets. The effects of wall heat flux and mist ratio on mist cooling performance are also investigated in this study.
Toupin-Type Decay and Saint-Venant’s Principle
Authors: Zhao Jian-Zhong
Published: June 2011

Toupin’s Theorem plays the most influential role in the history of development concerning Saint-Venant’s Principle. We now review the history and the previous works, distinguishing Saint-Venant type decay from Toupin-type decay and arguing that Toupin’s Theorem is not a formulation of Saint-Venant’s Principle; Saint-Venant’s Principle stated by Love can be disproved mathematically from Toupin’s Theorem, so Toupin’s Theorem is mathematically inconsistent with Saint-Venant’s Principle; Modified Saint-Venant’s Principle can be proved or formulated, though Saint-Venant’s Principle in its general form stated by Boussinesq and Love is not true.
Simultaneous Investigation of Entrained Liquid Fraction, Liquid Film Thickness and Pressure Drop in Vertical Annular Flow
Authors: Alamu M. B. , Azzopardi B. J.
Published: June 2011

The mechanism of atomization of part of the liquid film to form drops in annular two-phase flow is not entirely understood. It has been observed that drop creation only occurs when there are large disturbance waves present on the film interface. (Woodmansee and Harrantty, 1969, “Mechanisms for the Removal of Droplets From a Liquid Surface by a Parallel Air Flow,” Chem. Eng. Sci., 24, pp. 299–307) observed that ripples on these waves were precursors to drops. Though it has been reported that drops occur in bursts by (Azzopardi, Gas-Liquid Flows Begell House Inc., New York, 2006), all previous drop size or concentration measurements have always been time integrated to simplify data analysis. Dynamic time averaged drop size measurements are reported for the first time in annular flow. Experiments were carried out on a 19 mm internal diameter vertical pipe with air and water as fluids. Spraytec, a laser diffraction-based, drop size measurement instrument, was used in the drop related data acquisition. Simultaneous time-resolved measurements were carried out for drop, film thickness, and pressure drop. Film thickness has been measured using the conductance probes employing a pair of flush mounted rings as electrodes. Pressure drop was logged using differential pressure cell connected to two pressure taps located within the test section. The gas superficial velocity was varied systematically from 13 to 43 m/s at fixed liquid superficial velocities of 0.05 and 0.15 m/s, respectively. Additional tests were carried out with the gas velocity fixed at 14 m/s while the liquid superficial velocity was varied from 0.03 to 0.18 m/s. Signal acquired are presented in form of time series to permit data analysis at different levels. Based on signal analysis, interrelationships between liquid film where the drops are sourced and the contribution of the entrained liquid droplets to the overall pressure drop in the system has been elucidated. Though structures are not clearly visible in the signals acquired, the time series have been analyzed in amplitude space to yield probability density function (Pdf). Beyond gas superficial velocity of 30 m/s, Pdf of drop size distribution becomes monomodal or single-peaked marking transition to mist annular flow.
Reference air kerma and kerma‐area product as estimators of peak skin dose for fluoroscopically guided interventions
Authors: Kwon Deukwoo , Little Mark P. , Miller Donald L.
Published: June 2011

Purpose:

To determine more accurate regression formulas for estimating peak skin dose (PSD) from reference air kerma (RAK) or kerma‐area product (KAP).

Methods:

After grouping of the data from 21 procedures into 13 clinically similar groups, assessments were made of optimal clustering using the Bayesian information criterion to obtain the optimal linear regressions of (log‐transformed) PSD vs RAK, PSD vs KAP, and PSD vs RAK and KAP.

Results:

Three clusters of clinical groups were optimal in regression of PSD vs RAK, seven clusters of clinical groups were optimal in regression of PSD vs KAP, and six clusters of clinical groups were optimal in regression of PSD vs RAK and KAP. Prediction of PSD using both RAK and KAP is significantly better than prediction of PSD with either RAK or KAP alone. The regression of PSD vs RAK provided better predictions of PSD than the regression of PSD vs KAP. The partial‐pooling (clustered) method yields smaller mean squared errors compared with the complete‐pooling method.

Conclusion:

PSD distributions for interventional radiology procedures are log‐normal. Estimates of PSD derived from RAK and KAP jointly are most accurate, followed closely by estimates derived from RAK alone. Estimates of PSD derived from KAP alone are the least accurate. Using a stochastic search approach, it is possible to cluster together certain dissimilar types of procedures to minimize the total error sum of squares.
Substrates of Mitotic Kinases
Authors: Johnson Louise N.
Published: June 2011

Research provides insight into how substrate selectivity of the multiple kinases that control mitosis is achieved.
Postantibiotic Effect of Fidaxomicin and Its Major Metabolite, OP-1118, against Clostridium difficile
Authors: Babakhani Farah , Gomez Abraham , Robert Nikki , Sears Pamela
Published: June 2011

Fidaxomicin (FDX), a narrow-spectrum antibiotic recently shown to be superior to vancomycin in providing sustained clinical response to
Clostridium difficile
infection, was investigated along with its major metabolite, OP-1118, with regard to their postantibiotic effects (PAE). FDX was found to have a prolonged PAE (10 h versus ATCC strains and 5.5 h versus a clinical isolate), and OP-1118's PAE was longer than that of the standard comparator, vancomycin (3 versus 0 to 1.5 h, respectively).
Pharmacokinetics of Amodiaquine and Desethylamodiaquine in Pregnant and Postpartum Women with Plasmodium vivax Malaria
Authors: Rijken Marcus J. , McGready Rose , Jullien Vincent , Tarning Joel , Lindegardh Niklas , Phyo Aung Pyae , Win Aye Kyi , Hsi Poe , Cammas Mireille , Singhasivanon Pratap , White Nicholas J. , Nosten François
Published: June 2011

In order to study the pharmacokinetic properties of amodiaquine and desethylamodiaquine during pregnancy, 24 pregnant women in the second and third trimesters of pregnancy and with
Plasmodium vivax
malaria were treated with amodiaquine (10 mg/kg of body weight/day) for 3 days. The same women were studied again at 3 months postpartum. Plasma was analyzed for amodiaquine and desethylamodiaquine by use of a liquid chromatography-tandem mass spectrometry method. Individual concentration-time data were evaluated using noncompartmental analysis. There were no clinically relevant differences in the pharmacokinetics of amodiaquine and desethylamodiaquine between pregnant (
n
= 24) and postpartum (
n
= 18) women. The results suggest that the current amodiaquine dosing regimen is adequate for the treatment of
P. vivax
infections during pregnancy.
Quantification of Amikacin in Bronchial Epithelial Lining Fluid in Neonates
Authors: Tayman C. , El-Attug M. N. , Adams E. , Van Schepdael A. , Debeer A. , Allegaert K. , Smits A.
Published: June 2011

Amikacin efficacy is based on peak concentrations and the possibility of reaching therapeutic levels at the infection site. This study aimed to describe amikacin concentrations in the epithelial lining fluid (ELF) through bronchoalveolar lavage (BAL) in newborns. BAL fluid was collected in ventilated neonates treated with intravenous (i.v.) amikacin. Clinical characteristics, amikacin therapeutic drug monitoring serum concentrations, and the concentrations of urea in plasma were extracted from the individual patient files. Amikacin and urea BAL fluid concentrations were determined using liquid chromatography with pulsed electrochemical detection (LC-PED) and capillary electrophoresis with capacitively coupled contactless conductivity detection (CE-C4D), respectively. ELF amikacin concentrations were converted from BAL fluid concentrations through quantification of dilution (urea in plasma/urea in BAL fluid) during the BAL procedure. Twenty-two observations in 17 neonates (postmenstrual age, 31.9 [range, 25.1 to 41] weeks; postnatal age, 3.5 [range, 2 to 37] days) were collected. Median trough and peak amikacin serum concentrations were 2.1 (range, 1 to 7.1) mg/liter and 39.1 (range, 24.1 to 73.2) mg/liter; the median urea plasma concentration was 30 (8 to 90) mg/dl. The median amikacin concentration in ELF was 6.5 mg/liter, the minimum measured concentration was 1.5 mg/liter, and the maximum (peak) was 23 mg/liter. The highest measured ELF concentration was reached between 6 and 14.5 h after i.v. amikacin administration, and an estimated terminal elimination half-life was 8 to 10 h. The median and highest (peak) ELF amikacin concentrations observed in our study population were, respectively, 6.5 and 23 mg/liter. Despite the frequent use of amikacin in neonatal (pulmonary) infections, this is the first report of amikacin quantification in ELF in newborns.
Activity of Ceftaroline and Epidemiologic Trends in Staphylococcus aureus Isolates Collected from 43 Medical Centers in the United States in 2009
Authors: Richter Sandra S. , Heilmann Kristopher P. , Dohrn Cassie L. , Riahi Fathollah , Costello Andrew J. , Kroeger Jennifer S. , Biek Donald , Critchley Ian A. , Diekema Daniel J. , Doern Gary V.
Published: June 2011

A
Staphylococcus aureus
surveillance program was initiated in the United States to examine the
in vitro
activity of ceftaroline and epidemiologic trends. Susceptibility testing by Clinical and Laboratory Standards Institute broth microdilution was performed on 4,210 clinically significant isolates collected in 2009 from 43 medical centers. All isolates were screened for
mecA
by PCR and evaluated by pulsed-field gel electrophoresis. Methicillin-resistant
S. aureus
(MRSA) were analyzed for Panton-Valentine leukocidin (PVL) genes and the staphylococcal cassette chromosome
mec
(SCC
mec
) type. All isolates had ceftaroline MICs of ≤2 μg/ml with an MIC
50
of 0.5 and an MIC
90
of 1 μg/ml. The overall resistance rates, expressed as the percentages of isolates that were intermediate and resistant (or nonsusceptible), were as follows: ceftaroline, 1.0%; clindamycin, 30.2% (17.4% MIC ≥ 4 μg/ml; 12.8% inducible); daptomycin, 0.2%; erythromycin, 65.5%; levofloxacin, 39.9%; linezolid, 0.02%; oxacillin, 53.4%; tetracycline, 4.4%; tigecycline, 0%; trimethoprim-sulfamethoxazole, 1.6%; vancomycin, 0%; and high-level mupirocin, 2.2%. The
mecA
PCR was positive for 53.4% of the isolates. The ceftaroline MIC
90
s were 0.25 μg/ml for methicillin-susceptible
S. aureus
and 1 μg/ml for MRSA. Among the 2,247 MRSA isolates, 51% were USA300 (96.9% PVL positive, 99.7% SCC
mec
type IV) and 17% were USA100 (93.4% SCC
mec
type II). The resistance rates for the 1,137 USA300 MRSA isolates were as follows: erythromycin, 90.9%; levofloxacin, 49.1%; clindamycin, 7.6% (6.2% MIC ≥ 4 μg/ml; 1.4% inducible); tetracycline, 3.3%; trimethoprim-sulfamethoxazole, 0.8%; high-level mupirocin, 2.7%; daptomycin, 0.4%; and ceftaroline and linezolid, 0%. USA300 is the dominant clone causing MRSA infections in the United States. Ceftaroline demonstrated potent
in vitro
activity against recent
S. aureus
clinical isolates, including MRSA, daptomycin-nonsusceptible, and linezolid-resistant strains.
Recombinant Phenotyping of Cytomegalovirus UL54 Mutations That Emerged during Cell Passages in the Presence of either Ganciclovir or Foscarnet
Authors: Gilbert Christian , Azzi Arezki , Goyette Nathalie , Lin Sheng-Xiang , Boivin Guy
Published: June 2011

Selection of human cytomegalovirus variants in the presence of ganciclovir or foscarnet led to 18 DNA polymerase mutations, 14 of which had not been previously studied. Using bacterial artificial chromosome technology, each of these mutations was individually transferred into the genome of a reference strain. Following reconstitution of infectious viral stocks, each mutant was assessed for its drug susceptibility and growth kinetics in cell culture. Computer-assisted three-dimensional (3D) modeling of the polymerase was also used to position each of the mutations in one of four proposed structural domains and to predict their influence on structural stability of the protein. Among the 10 DNA polymerase mutations selected with ganciclovir, 7 (P488R, C539R, L545S, V787L, V812L, P829S, and L862F) were associated with ganciclovir resistance, whereas 2 (F595I and V946L) conferred only foscarnet resistance. Among the eight mutations selected with foscarnet, only two (T552N and S585A) conferred foscarnet resistance, whereas four (N408D, K500N, L802V, and L957F) had an impact on ganciclovir susceptibility. Surprisingly, the combination of mutations, some of which were not associated with resistance for a specific antiviral, resulted in increasing resistance effects. 3D modeling suggested that none of the mutated residues were directly involved in the polymerase catalytic site but rather had an influence on drug susceptibility by modifying the structural flexibility of the protein. Our study significantly adds to the number of DNA polymerase mutations conferringin vitrodrug resistance and emphasizes the point that evaluation of individual mutations may not accurately reflect the phenotype conferred by multiple mutations.
Determination of Tissue Penetration and Pharmacokinetics of Linezolid in Patients with Diabetic Foot Infections Using
In Vivo
Microdialysis
Authors: Wiskirchen Dora E. , Shepard Ashley , Kuti Joseph L. , Nicolau David P.
Published: June 2011

Staphylococcus aureus
and other Gram-positive organisms, including methicillin-resistant
S. aureus
, continue to be the predominant pathogens associated with diabetic foot infections. Consequently, linezolid is often used to treat these infections. The purpose of the current study was to describe the pharmacokinetic profile and determine the level of penetration of linezolid into healthy thigh tissue and infected wound tissue of the same extremity in 9 diabetic patients with chronic lower limb infections by use of
in vivo
microdialysis. Hourly plasma and dialysate samples were obtained over a 12-h dosing interval following 3 to 4 doses of linezolid (600 mg intravenously every 12 h). Plasma protein binding was also assessed at 1, 6, and 12 h postdose. The means ± standard deviations (SD) for the maximum concentration in serum (
C
max
), the volume of distribution at terminal phase (

V
z

), and the half-life (
t
1/2
) for linezolid in plasma were 11.99 ± 3.67 μg/ml, 0.71 ± 0.25 liters/kg of body weight, and 4.71 ± 1.23 h, respectively. Mean protein binding was 14.78% (range, 3.85 to 32.03%). The mean areas under the concentration-time curves from 0 to 12 h for the free, unbound fraction of linezolid (
f
AUC
0–12
values) ± SD for plasma, wound tissue, and thigh tissue were 51.24 ± 12.72, 82.76 ± 59.01, and 92.52 ± 60.44 μg · h/ml, respectively. Tissue penetration ratios (tissue
f
AUC to plasma
f
AUC) were similar for thigh (1.42; range, 1.08 to 2.23) and wound (1.27; range, 0.86 to 2.26) tissues (
P
= 0.648). With the currently approved dosing regimen, linezolid penetrated well into both healthy thigh tissue and infected wound tissue in these diabetic patients.
Knockdown of USP18 Increases Alpha 2a Interferon Signaling and Induction of Interferon-Stimulating Genes but Does Not Increase Antiviral Activity in Huh7 Cells
Authors: Murray E. J. , Burden Frances , Horscroft Nigel , Smith-Burchnell Caroline , Westby Mike
Published: June 2011

The current standard of care for hepatitis C virus (HCV) patients is cotreatment with human alpha interferon (IFN-α) and ribavirin. The host factor USP18 functions to regulate the interferon signaling pathway by acting as an off-switch. In order to understand whether the inhibition of USP18 represents a valid target for the enhancement of interferon treatment for chronic viral diseases, we have used a wide range of RNA interference (RNAi) reagents to suppress USP18 gene expression in Huh7 cell lines. We demonstrate that a USP18 knockdown results in IFN-α2a signaling (measured by increased IFN-stimulated response element [ISRE] reporter gene activity, 2′,5′-oligoadenylate synthetase [2-5 OAS] expression, and ISG15 induction) that is increased by ∼100-fold, whereas the antiviral (AV) potency in both the Huh7 HCV subgenomic replicon assay and the Huh7.5 HCV infectious virus assay increased by ∼3-fold. While the degree of the USP18 knockdown of USP18 elicited by the different RNAi reagents correlated with the enhancement of IFN-α2a signaling, it did not correlate with the enhancement of AV activity. The failure of increased IFN-α2a signaling to fully translate into increased AV potency was also observed for encephalomyocarditis virus (EMCV) assays using Huh7.5 cells. These data suggest that the IFN-mediated AV response in Huh7.5 cells has only a limited dependence on USP18 activity.
Evaluation of the Antimicrobial Activity of Lysostaphin-Coated Hernia Repair Meshes
Authors: Satishkumar Rohan , Sankar Sriram , Yurko Yuliya , Lincourt Amy , Shipp John , Heniford B. Todd , Vertegel Alexey
Published: June 2011

Bacterial infections by antibiotic-resistantStaphylococcus aureusstrains are among the most common postoperative complications in surgical hernia repair with synthetic mesh. Surface coating of medical devices/implants using antibacterial peptides and enzymes has recently emerged as a potentially effective method for preventing infections. The objective of this study was to evaluate thein vitroantimicrobial activity of hernia repair meshes coated by the antimicrobial enzyme lysostaphin at different initial concentrations. Lysostaphin was adsorbed on pieces of polypropylene (Ultrapro) mesh with binding yields of ∼10 to 40% at different coating concentrations of between 10 and 500 μg/ml. Leaching of enzyme from the surface of all the samples was studied in 2% (wt/vol) bovine serum albumin in phosphate-buffered saline buffer at 37°C, and it was found that less than 3% of adsorbed enzyme desorbed from the surface after 24 h of incubation. Studies of antibacterial activity against a cell suspension ofS. aureuswere performed using turbidity assay and demonstrated that the small amount of enzyme leaching from the mesh surface contributes to the lytic activity of the lysostaphin-coated samples. Colony counting data from the broth count (model for bacteria in wound fluid) and wash count (model for colonized bacteria) for the enzyme-coated samples showed significantly decreased numbers of CFU compared to uncoated samples (P< 0.05). A pilotin vivostudy showed a dose-dependent efficacy of lysostaphin-coated meshes in a rat model ofS. aureusinfection. The antimicrobial activity of the lysostaphin-coated meshes suggests that such enzyme-leaching surfaces could be efficient at actively resisting initial bacterial adhesion and preventing subsequent colonization of hernia repair meshes.
Genetic Organization and Mode of Action of a Novel Bacteriocin, Bacteriocin 51: Determinant of VanA-Type Vancomycin-Resistant Enterococcus faecium
Authors: Yamashita Hitoshi , Tomita Haruyoshi , Inoue Takako , Ike Yasuyoshi
Published: June 2011

Bacteriocin 51 (Bac 51) is encoded on the mobile plasmid pHY (6,037 bp), which was isolated from vancomycin-resistant
Enterococcus faecium
VRE38. Bacteriocin 51 is active against
E. faecium
,
E. hirae
, and
E. durans
. Sequence analysis of pHY showed that it encodes nine open reading frames (ORFs) from ORF1 to ORF9 (in that order). Genetic analysis suggested that ORF1 and ORF2, which were designated
bacA
and
bacB
, respectively, are the bacteriocin and immunity genes.
bacA
encodes a 144-amino-acid protein. The deduced BacA protein has a typical signal sequence at its amino terminus, and a potential signal peptidase-processing site corresponding to the V-E-A sequence is located between the 37th and 39th amino acids. The predicted mature BacA protein consists of 105 amino acids. A potential promoter sequence was identified upstream of the start codon.
bacB
encodes a 55-amino-acid protein. No obvious promoter or terminator sequence was identified between
bacA
and
bacB
. Northern blot analysis of
bacA
and
bacB
with a
bacA
RNA probe produced a transcript of approximately 700 nucleotides, which corresponded to the combined nucleotide sizes of
bacA
and
bacB
, indicating that transcription was initiated from the promoter upstream of
bacA
, continued through
bacB
, and was terminated at the terminator downstream of
bacB
. The transcription start site was determined to be the T nucleotide located 6 nucleotides downstream from the −10 promoter sequence. These results indicate that
bacA
and
bacB
constitute an operon and that
bacA
is the bacteriocin structural gene while
bacB
is the immunity gene. The purified C-terminally His tagged BacA protein of Bac 51 showed bacteriostatic activity against the indicator strain. The purified C-terminally His tagged BacA protein of Bac 32 (whose mature BacA protein has 54 amino acids) and the culture filtrates of the Bac 31- and Bac 43-producing
E. faecalis
strain FA2-2 showed bactericidal activity. Bac 31 and Bac 43 are pore-forming bacteriocins, unlike the newly characterized bacteriocin Bac 51.
Pharmacokinetics of Once-Daily Darunavir-Ritonavir and Atazanavir-Ritonavir over 72 Hours following Drug Cessation
Authors: Boffito Marta , Jackson Akil , Amara Alieu , Back David , Khoo Saye , Higgs Chris , Seymour Natalia , Gazzard Brian , Moyle Graeme
Published: June 2011

The object of this study was to investigate the pharmacokinetics of darunavir-ritonavir and atazanavir-ritonavir once-daily dosing over 72 h (h) following drug intake cessation. Volunteers received darunavir-ritonavir at 800 and 100 mg, respectively, once daily for 10 days, followed by a 7-day washout period, and atazanavir-ritonavir at 300 and 100 mg, respectively, once daily for 10 days. Full pharmacokinetic profiles were assessed for each phase for the 72 h following day 10. Pharmacokinetic parameters were determined over 24 h and to the last measurable concentration by noncompartmental methods. Seventeen subjects completed the study. The geometric mean (GM) terminal elimination half-life to 72 h of darunavir was 6.48 h, which was lower than the 0- to 24-h half-life (10.70 h). The terminal elimination half-life of atazanavir was 6.74 h, which was lower than the 0- to 24-h half-life (13.72 h). All subjects but one had darunavir concentrations higher than the target of 550 ng/ml for protease-resistant HIV isolates (equivalent to 10 times the protein-binding-corrected 50% inhibitory concentration [IC50] for wild-type virus) at 24 h postdose, and 14 out of 17 had concentrations higher than the target at 30 h postdose (GM of 1,088 and 851 ng/ml). All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/ml (equivalent to 10 times the protein-binding-corrected IC50for wild-type virus) at 24 and 30 h postdose (GM of 693 and 392 ng/ml). Two of 17 and 5 of 17 subjects were above target at 48 h postdose while on darunavir-ritonavir and atazanavir-ritonavir. Ritonavir half-life to 72 h was 6.84 h with darunavir and 6.07 with atazanavir. This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Although the rates of decline of darunavir and atazanavir slightly increased as ritonavir concentrations declined, most individuals had concentrations 6 h after the end of the ideal dosing interval of 24 h which were above the cutoff used to define therapeutic concentrations.