bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms of burst release from pH-responsive polymeric microparticles
Authors: Rizi Khalida , Green Rebecca J , Khutoryanskaya Olga , Donaldson Michael , Williams Adrian C
Published: July 2011

Objectives

Microencapsulation of drugs into preformed polymers is commonly achieved through solvent evaporation techniques or spray drying. We compared these encapsulation methods in terms of controlled drug release properties of prepared microparticles and investigated the underlying mechanisms responsible for the ‘burst release’ effect.

Methods

Using two different pH-responsive polymers with a dissolution threshold of pH 6 (Eudragit L100 and AQOAT AS-MG), hydrocortisone, a model hydrophobic drug, was incorporated into microparticles below and above its solubility within the polymer matrix.

Key findings

Although, spray drying was an attractive approach due to rapid particle production and relatively low solvent waste, the oil-in-oil microencapsulation method was superior in terms of controlled drug release properties from the microparticles. Slow solvent evaporation during the oil-in-oil emulsification process allowed adequate time for drug and polymer redistribution in the microparticles and reduced uncontrolled drug burst release. Electron microscopy showed that this slower manufacturing procedure generated nonporous particles whereas thermal analysis and X-ray diffractometry showed that drug loading above the solubility limit of the drug in the polymer generated excess crystalline drug on the surface of the particles. Raman spectral mapping illustrated that drug was homogeneously distributed as a solid solution in the particles when loaded below saturation in the polymer with consequently minimal burst release.

Conclusions

Both the manufacturing method (which influenced particle porosity and density) and drug:polymer compatibility and loading (which affected drug form and distribution) were responsible for burst release seen from our particles
Mildronate treatment alters γ-butyrobetaine and l-carnitine concentrations in healthy volunteers
Authors: Liepinsh Edgars , Konrade Ilze , Skapare Elina , Pugovics Osvalds , Grinberga Solveiga , Kuka Janis , Kalvinsh Ivars , Dambrova Maija
Published: July 2011

Objectives

In this study, we aimed to investigate the effects of long-term administration of the cardioprotective drug mildronate on the concentrations of l-carnitine and γ-butyrobetaine in healthy volunteers.

Methods

Mildronate was administered perorally, at a dosage of 500 mg, twice daily. Plasma and urine samples were collected weekly. Daily meat consumption within an average, non-vegetarian diet was monitored. l-Carnitine, γ-butyrobetaine and mildronate concentrations were measured using the UPLC/MS/MS method.

Key findings

After 4 weeks, the average concentrations of l-carnitine in plasma significantly decreased by 18%. The plasma concentrations of γ-butyrobetaine increased about two-fold, and this effect was statistically significant in both the male and female groups. In urine samples, a significant increase in l-carnitine and γ-butyrobetaine levels was observed, which provides evidence for increased excretion of both substances during the mildronate treatment. At the end of the treatment period, the plasma concentration of mildronate was 20 µm on average. There were no significant differences between the effects observed in female and male volunteers. Meat consumption partially reduced the l-carnitine-lowering effects induced by mildronate.

Conclusions

Long-term administration of mildronate significantly lowers l-carnitine plasma concentrations in non-vegetarian, healthy volunteers.
Effects of Ginkgo biloba extract on the pharmacokinetics and pharmacodynamics of tolbutamide in protein-restricted rats
Authors: Taki Yuko , Hagiwara Eri , Hirose Chiemi , Shinozuka Kazumasa , Umegaki Keizo , Yamada Shizuo
Published: July 2011

Objectives

Effects of repeated administration of Ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide were examined in rats fed a low-protein diet.

Methods

Rats were given a low (7% casein) or control (20% casein) protein diet for 21 days and administered Ginkgo biloba extract (100 mg/kg per day) for the last 5 days. Tolbutamide was co-administered on the last day. Blood glucose and plasma tolbutamide concentrations were determined over the subsequent 12 h and the activity of hepatic cytochrome P450s were determined at 12 h after dosing.

Key findings

There were significant decreases in body weight, the ratio of liver to body weight, and plasma albumin concentrations in rats on the low-protein diet compared with controls. The hypoglycaemic effect of tolbutamide was significantly greater and the concentration of the drug in plasma was higher in the former group. The repeated administration of Ginkgo biloba extract had little influence on the hypoglycaemic effect of tolbutamide, but tended to decrease the drug concentration in plasma of control rats, while it reduced significantly the hypoglycaemic action and plasma concentration of tolbutamide in the protein-restricted rats.

Conclusions

The effects of Ginkgo biloba extract on the pharmacokinetics and pharmacodynamics of tolbutamide were significantly enhanced in rats on the low-protein diet.
Why does genetic causal information alter perceived treatment effectiveness? An analogue study
Authors: Wright Alison J. , Sutton Stephen R. , Hankins Matthew , Whitwell Sophia C.L. , Macfarlane Angela , Marteau Theresa M.
Published: July 2011

Objectives.  When a health problem is perceived as having a genetic cause, this appears to increase the perceived effectiveness of pharmacological treatments and reduce perceived effectiveness of non‐pharmacological treatments. Potential mediators of this effect include causal attributions, perceived severity, and perceived control over the health problem. This study aimed to use experimental methods to establish which beliefs mediate the effect of genetic causal information on perceived effectiveness of treatments.

Design. A 4(cause: environmental, family history, genetic test, family history & genetic test)×2(severity: higher or low) between‐subjects design using vignettes about heart disease risk, obesity or depression.

Methods.  A total of 647 adults, randomly assigned to read one of the experimental vignettes, were interviewed. Key outcomes were perceived effectiveness of medication and of non‐pharmacological treatments. Potential mediators of perceived severity, perceived controllability, and causal attributions were also assessed.

Results.  For heart disease risk, genetic causes reduced perceived effectiveness of non‐pharmacological treatments (an effect mediated by causal attributions and perceived control) but did not influence perceived medication effectiveness. For obesity, neither severity nor cause influenced the perceived effectiveness of either treatment. For depression, genetic causes only increased perceived effectiveness of medication for more severe depression, an effect mediated by perceived control.

Conclusions.  The impact of genetic causal information on perceived effectiveness of treatments varies with type of health problem. When genetic causal information influences perceived treatment effectiveness, it does so by altering causal attributions and perceived controllability. However, these effects are small and unlikely to translate into clinically meaningful differences in health‐enhancing behaviours.
‘Waste the waist’: The development of an intervention to promote changes in diet and physical activity for people with high cardiovascular risk
Authors: Gillison Fiona , Greaves Colin , Stathi Afroditi , Ramsay Rosemary , Bennett Paul , Taylor Gordon , Francis Margaret , Chandler Roger
Published: July 2011

Objectives. To identify an evidence‐based intervention to promote changes in diet and physical activity and adapt it for a UK primary care setting for people with high cardiovascular risk.

Design. A three‐stage mixed‐methods design was used to facilitate a strategic approach to programme selection and adaptation.

Method. Stage 1: Criteria for scientific quality and local appropriateness were developed for the selection/adaptation of an intervention to promote lifestyle change in people of high cardiovascular risk through (1) patient interviews, (2) a literature search to extract evidence‐based criteria for behavioural interventions, and (3) stakeholder consultation. Stage 2: Potential interventions for adaptation were identified and ranked according to their performance against the criteria developed in Stage 1. Stage 3: Intervention mapping (IM) techniques were used to (1) specify the behavioural objectives that participants would need to reach in order to attain programme outcomes, and (2) adapt the selected intervention to ensure that evidence‐based strategies to target all identified behavioural objectives were included.

Results. Four of 23 potential interventions identified met the 11 essential criteria agreed by a multi‐disciplinary stakeholder committee. Of these, the Greater Green Triangle programme (Laatikainenet al., 2007) was ranked highest and selected for adaptation. The IM process identified 13 additional behaviour change strategies that were used to adapt the intervention for the local context.

Conclusions. IM provided a useful set of techniques for the systematic adaptation of an existing lifestyle intervention to a new population and context, and facilitated transparent working processes for a multi‐disciplinary team.
The transmission of attitudes towards food: Twofold specificity of similarities with parents and friends
Authors: Guidetti Margherita , Conner Mark , Prestwich Andrew , Cavazza Nicoletta
Published: July 2011

Objectives. The present study explored whether similarity of students’ food attitudes with those of their parents and friends varies as a function of both the food and type of measurement. We expected greater resemblance with parents for attitudes towards fruit and for implicit attitudes and greater resemblance with friends for attitudes towards snacks and for explicit attitudes.

Design. We compared the resemblance in implicit and explicit attitudes towards fruit and preference for sweet over savoury snacks between target‐parent and target‐friend pairings. The parental‐peer mutual influence effect was separated from cultural effect by comparing real and random dyads.

Methods. Target participants were 85 students who recruited one parent and one best friend each. All participants completed online two Implicit Association Tests and rated their liking for fruit and sweet/savoury snacks.

Results. Our target participants’ attitudes towards fruit were predicted by those of their parents rather than friends, with this relationship being detected through implicit but not explicit measures. Conversely, target participants’ preference for sweet over savoury snacks was predicted with those of their friends but not parents, with this relationship being detected through explicit but not implicit measures.

Conclusions. Young adults’ resemblance to parents and friends, in terms of food attitudes, seems specific both to the food type and to the attitude measure, suggesting that parents’ influence concerns healthy food and is exerted at an implicit attitude level; whereas friends’ influence concerns junk food and is exerted at an explicit attitude level. The theoretical and practical implications are discussed.
The impact of ignoring multiple membership data structures in multilevel models
Authors: Chung Hyewon , Beretvas S. Natasha
Published: July 2011

This study compared the use of the conventional multilevel model (MM) with that of the multiple membership multilevel model (MMMM) for handling multiple membership data structures. Multiple membership data structures are commonly encountered in longitudinal educational data sets in which, for example, mobile students are members of more than one higher‐level unit (e.g., school). While the conventional MM requires the user either to delete mobile students’ data or to ignore prior schools attended, MMMM permits inclusion of mobile students’ data and models the effect of all schools attended on student outcomes. The simulation study identified underestimation of the school‐level predictor coefficient, as well as underestimation of the level‐two variance component with corresponding overestimation of the level‐one variance when multiple membership data structures were ignored. Results are discussed along with limitations and ideas for future MMMM methodological research as well as implications for applied researchers.
Evolutionary behavioural science and crime: Aetiological and intervention implications
Authors: Ward Tony , Durrant Russil
Published: July 2011

In this paper, we argue that evolutionary behavioural science can be fruitfully applied to the explanation of criminal behaviour and subsequent interventions with offenders based on this understanding. First, we provide a brief overview of evolutionary theory and the three main approaches applied to the social and behavioural sciences, human behavioural ecology, evolutionary psychology, and gene‐culture co‐evolution theory. Second, we examine two examples of crimes that have been approached from an evolutionary standpoint, psychopathy, and rape. Third, we discuss four implications of adopting an evolutionary behavioural perspective for therapeutic and prevention work with offenders.
Experimental Study of a Two-Phase Thermosyphon With Porous Graphite Foam Insert
Authors: Jin L. W. , Leong K. C. , Pranoto I. , Li H. Y. , Chai J. C.
Published: July 2011

This paper presents an experimental study of heat transfer in a pool boiling evaporator with porous insert. Porous graphite foams were structured into cubic block and straight fin shapes and tested with FC-72 and HFE-7000 coolants with the objective of maximizing the heat transfer in a pool boiling configuration. A two-phase thermosyphon facility was developed to investigate the system’s performance using graphite foams of block and fin structures. The effects of foam configuration, working fluid type, and coolant filling volume on pool boiling heat transfer were analyzed. The results showed that the coolant filling volume has negligible effect on cooling performance. On the other hand, the thermosyphon performance is significantly affected by the coolant properties and the configuration of the porous graphite foam. A comparison of the Bond numbers obtained for FC-72 and HFE-7000 indicates that the bubbles have to overcome higher surface tension forces before departing the foam surface in HFE-7000. Meanwhile, the effect of the foam configuration on the boiling heat transfer performance implies that a properly designed geometry of the porous graphite foam will lead to significant enhancement of the evaporation process in a thermosyphon system.
Steam Electrolysis Characteristics for Various H2 and O2 Concentrations in Supply Gases
Authors: Wang Zhenwei , Mori Masashi
Published: July 2011

The steam electrolysis performance of a Ni-based electrode-supported tubular cell with a Sc2O3-stabilized ZrO2 electrolyte was evaluated at 650°C for various concentrations of H2 and O2 in the supply gases. It was found that an increase in the concentration of electrolytic products (H2 and O2) around the relevant electrode decreased the electrode polarization, and enhanced the electrolysis performance. This result suggests that the electrolysis can be performed with no carrier gases, and the direct storage of the steam electrolysis products H2 and O2 is feasible.
Stainless Steel/Yttria Stabilized Zirconia Composite Supported Solid Oxide Fuel Cell
Authors: Molin Sebastian , Tolczyk Mateusz , Gazda Maria , Jasinski Piotr
Published: July 2011

In this paper composite supports for solid oxide fuel cells were fabricated and evaluated. Substrates were composed of stainless steel and yttria stabilized zirconia (YSZ) powders mixed in different volume ratios. Their sintering behavior (linear shrinkage, resulting porosity) and high temperature properties (oxidation resistance, electrical conductivity) were evaluated. Based on those results the best composition for composite supports was selected and fuel cells were fabricated. Thin YSZ electrolytes were deposited on one side of the support and sintered at 1350 °C in pure hydrogen, while LNF (LaNi0.6Fe0.4O3) cathodes were deposited on the top of the electrolyte and fired in situ at 800 °C. The fuel cells provided power density of about 80 mWcm-2 at 800 °C. It is worth noting that this performance was achieved without adding any catalytically active phases into composite support, while at the same time the supports exhibited relatively low porosity. This demonstrates that stainless steel can serve as an anode active material. Degradation of this fuel cell was fast (12%/h), nonetheless its performance seems interesting for further investigation.
Strategies for the Analysis of the Behavior of an Adhesive in Bonded Assemblies
Authors: Yves Cognard Jean , Créac’hcadec Romain , Sohier Laurent
Published: July 2011

Experimental and numerical analyses of the mechanical behavior of bonded joints can be made particularly difficult by the influence of edge effects. Therefore, understanding the stress distribution in an adhesive joint can lead to improvements in adhesively-bonded assemblies. Such an analysis is proposed in the case of usual single lap shear specimens. Stress singularities can contribute to the initiation and propagation of cracks in the adhesive. Thus, in order to obtain reliable experimental data to analyze the nonlinear behavior of an adhesive in an assembly, tests which strongly limit the influence of stress singularities must be proposed. The design and the abilities of such a device for shear tests are presented. Moreover, some experimental results obtained using a modified Arcan fixture, which has been designed to strongly limit edge effects, are presented in the case of monotonic and complex history loadings. Furthermore, a 2D non associated elasto-visco-plastic model is proposed to accurately describe the experimental behavior under tensile-shear monotonic loadings. An extension of this model is also proposed to represent relaxation type effects under shear loadings.
Modeling the S-N Curves of Polyamide PA66 Using a Serial Hybrid Neural Network
Authors: Klemenc Jernej , Wagner Andrej , Fajdiga Matija
Published: July 2011

The fatigue damage to polymers generally depends on the material properties as well as on the mechanical, thermal, chemical, and other environmental influences. In this article, a methodology for modeling the dependence of the PA66 S-N curves on the material parameters, the material state, and the operating conditions is presented. The core of the presented methodology is a multilayer perceptron neural network combined with an analytical model of the PA66 S-N curve. Such a hybrid approach simultaneously utilizes the good approximation capabilities of the multilayer perceptron and knowledge of the phenomenon under consideration, because the analytical model for the S-N curves was estimated on the basis of the existing experimental data from the literature. The article presents the theoretical background of the applied methodology. The applicability and uncertainty of the presented methodology were assessed for the available data from the literature. The results show that it was possible to approximate the PA66 S-N curves for different input parameters if the space of the input parameters was adequately covered by the corresponding S-N curves.
Incompressible Criterion and Pressure Drop for Gaseous Slip Flow in Circular and Noncircular Microchannels
Authors: Duan Zhipeng
Published: July 2011

Slip flow in various noncircular microchannels has been further examined, and a simple model for a normalized Poiseuille number is proposed. As for slip flow, no solutions or graphical and tabulated data exist for most geometries; the developed simple model fills this void and can be used to predict the Poiseuille number, mass flow rate, tangential momentum accommodation coefficient, pressure distribution, and pressure drop of slip flow in noncircular microchannels by the research community for the practical engineering design of microchannels. The incompressible flow criterion for gas flow in microchannels is given. A Mach number less than 0.3 is not sufficient to ensure that the flow is incompressible. Compressibility depends on the product of two dimensionless parameters: L/L(DRe)(DRe) and Ma (Arkilic et al., 1997, “Gaseous Slip Flow in Long Microchannels,” J. Microelectromech. Syst., 6(2), pp. 167–178). Some flows where Ma < 0.3 are low speed compressible flows. A fresh general pressure drop model for isothermal low Mach number compressible flow in microchannels is proposed. If the pressure drop is less than 10% of the outlet pressure, the flow can be considered as incompressible for practical engineering applications. This paper improves and extends previous studies on slip flow in noncircular microchannels.
Analysis of Droplet Generation in Electrospray Using a Carbon Fiber Based Microfluidic Emitter
Authors: Sen A. K. , Darabi J. , Knapp D. R.
Published: July 2011

This work presents simulation of jet break up in electrospray ionization using a microfluidic emitter. The emitter comprises a pointed carbon fiber located coaxial with a fused silica capillary of 360 microns OD and 75 microns ID, with its sharp tip extending 30 microns beyond the capillary terminus. The numerical model employs leaky-dielectric formulations for solving the electrodynamics and volume-of-fluid method for tracking the liquid-air interface. The existing leaky-dielectric model is modified to account for the presence of free charges inside the bulk of the liquid as well as at the interface. A small velocity perturbation is used at the capillary inlet to emulate the natural disturbance necessary for the jet break up. First, the model is validated by comparing model predictions with experimental results for a conventional emitter reported in literature. Then, it is applied to simulate the electrospray performance of the Carbon Fiber (CF) emitter including the Taylor cone and jet break up processes. Model predictions for CF emitter are compared with experimental results in terms of jet-length and current-flow characteristics. The influence of emitter geometry, operating conditions and liquid properties on the electrospray performance are investigated. Droplet diameter is correlated with flow rate and liquid properties and the correlation results are compared with that reported in literature.
Optimizing photon sieves to approach Fresnel diffraction limit via pixel-based inverse lithography
Authors: Cheng Mosong , Zhou Chenggang
Published: July 2011

This article presents a novel, rigorous method to construct photonic sieves whose imaging resolution approaches the Fresnel diffraction limit. Photon sieves (PS), which use holes in place of Fresnel Zone Plate (FZP) as diffractive elements, offer many advantages, such as low fabrication cost, higher contrast, narrower main lobe and smaller side lobes. Particularly in EUV imaging, the minimum feature size for fabricating a FZP limits the achievable NA or, equivalently, outermost zone width. And PS allows for much higher NA than FZP, because its hole size can be much larger than the outermost zone width in a FZP without losing resolution. Thus it is of great interest to apply PS in EUV imaging or maskless lithography (ML2). When used in imaging, the Point Spread Function (PSF) on the focal plane should approximate a δ-function. To explore the optimal design of PS, we presented a technique from inverse lithography that treats the PS as a mask, uses Fresnel diffraction as the transfer function, and seeks to minimize the difference between its coherent PSF and δ-function. The performances of optimized PS, common PS and FZP are presented. Optimized PS shows slightly smaller focused spot size than common PS (50 nm vs. 53 nm FWHM with NA 0.12), indicating the simple version of PS is close to optimum in low NA. However, when comparing the imaging results of 40–60 nm half-pitch gratings using these PS as objective lens, the optimized PS shows contrast over 100% higher than common PS. This is attributed to the first sidelobe of the PSF, which has 180° phase shift from the main lobe and reduces image blurring. So the slight reduction in spot size and favorable sidelobe of the optimized PS lead to significantly better image quality when the feature size to be imaged is near the resolution limit. The optimized PS also shows better tolerance of fabrication errors. Both PS are much superior to FZP, indicating great potential of PS in EUV microscopy. In ML2 with UV light, however, PS does not offer advantages over FZP.
Development of Newborn and Infant Vaccines
Authors: Sanchez-Schmitz Guzman , Levy Ofer
Published: July 2011

Insights into immune ontogeny will inform translation of new vaccines that are safe and effective for newborns and infants.
CXCL5 Mediates UVB Irradiation–Induced Pain
Authors: Dawes John M. , Calvo Margarita , Perkins James R. , Paterson Kathryn J. , Kiesewetter Hannes , Hobbs Carl , Kaan Timothy K. Y. , Orengo Christine , Bennett David L. H. , McMahon Stephen B.
Published: July 2011

The cytokine CXCL5 is a peripheral mediator of pain induced by UVB irradiation to the skin.
Optimization of Dosing for EGFR-Mutant Non–Small Cell Lung Cancer with Evolutionary Cancer Modeling
Authors: Chmielecki Juliann , Foo Jasmine , Oxnard Geoffrey R. , Hutchinson Katherine , Ohashi Kadoaki , Somwar Romel , Wang Lu , Amato Katherine R. , Arcila Maria , Sos Martin L. , Socci Nicholas D. , Viale Agnes , de Stanchina Elisa , Ginsberg Michelle S. , Thomas Roman K. , Kris Mark G. , Inoue Akira , Ladanyi Marc , Miller Vincent A. , Michor Franziska , Pao William
Published: July 2011

Predictive models of EGFR-mutant tumor behavior point to alternative drug dosing strategies to prevent and treat acquired resistance.
Deep Sequencing of the Human TCRγ and TCRβ Repertoires Suggests that TCRβ Rearranges After αβ and γδ T Cell Commitment
Authors: Sherwood Anna M. , Desmarais Cindy , Livingston Robert J. , Andriesen Jessica , Haussler Maximilian , Carlson Christopher S. , Robins Harlan
Published: July 2011

Deep sequencing provides new insights about T cell receptor rearrangement in humans.
Reengineering Translational Science: The Time Is Right
Authors: Collins Francis S.
Published: July 2011

The new National Center for Advancing Translational Sciences aims to revamp the process of biomedical research translation.
Sunshine Vitamin Sheds Light on MS
Authors: Boxer Rebecca S.
Published: July 2011

A randomized controlled trial of high-dose vitamin D in multiple sclerosis patients correlates reduced T cell reactivity with clinical benefit.
A Curious Case of Cellular Metabolism
Authors: Emadi Ashkan
Published: July 2011

Understanding how reprogramming induces a cancer cell–like metabolic signature in stem cells may yield drugs that target tumor metabolism.
Distant and New Mutations in CTX-M-1 β-Lactamase Affect Cefotaxime Hydrolysis
Authors: Pérez-Llarena Francisco José , Kerff Frédéric , Abián Olga , Mallo Susana , Fernández María Carmen , Galleni Moreno , Sancho Javier , Bou Germán
Published: July 2011

The CTX-M β-lactamases are an increasingly prevalent group of extended-spectrum β-lactamases (ESBL). Point mutations in CTX-M β-lactamases are considered critical for enhanced hydrolysis of cefotaxime. In order to clarify the structural determinants of the activity against cefotaxime in CTX-M β-lactamases, screening for random mutations was carried out to search for decreased activity against cefotaxime, with the CTX-M-1 gene as a model. Thirteen single mutants with a considerable reduction in cefotaxime MICs were selected for biochemical and stability studies. The 13 mutated genes of the CTX-M-1 β-lactamase were expressed, and the proteins were purified for kinetic studies against cephalothin and cefotaxime (as the main antibiotics). Some of the positions, such as Val103Asp, Asn104Asp, Asn106Lys, and Pro107Ser, are located in the
103
VNYN
106
loop, which had been described as important in cefotaxime hydrolysis, although this has not been experimentally confirmed. There are four mutations located close to catalytic residues—Thr71Ile, Met135Ile, Arg164His, and Asn244Asp—that may affect the positioning of these residues. We show here that some distant mutations, such as Ala219Val, are critical for cefotaxime hydrolysis and highlight the role of this loop at the top of the active site. Other distant substitutions, such as Val80Ala, Arg191, Ala247Ser, and Val260Leu, are in hydrophobic cores and may affect the dynamics and flexibility of the enzyme. We describe here, in conclusion, new residues involved in cefotaxime hydrolysis in CTX-M β-lactamases, five of which are in positions distant from the catalytic center.
In Vivo
Synergism of Ceftobiprole and Vancomycin against Experimental Endocarditis Due to Vancomycin-Intermediate Staphylococcus aureus
Authors: Entenza J. M. , Veloso T. R. , Vouillamoz J. , Giddey M. , Majcherczyk P. , Moreillon P.
Published: July 2011

The efficacy of ceftobiprole combined with vancomycin was tested against two vancomycin-intermediate
Staphylococcus aureus
(VISA) strains, PC3 and Mu50, in rats with experimental endocarditis. Animals with infected aortic vegetations were treated for 3 days with doses simulating the kinetics after intravenous administration in humans of (i) the standard dose of ceftobiprole of 500 mg every 12 h (b.i.d.) (SD-ceftobiprole), (ii) a low dose of ceftobiprole of 250 mg b.i.d. (LD-ceftobiprole), (iii) a very low dose of ceftobiprole of 125 mg b.i.d. (VLD-ceftobiprole), (iv) SD-vancomycin of 1 g b.i.d., or (v) LD- or VLD-ceftobiprole combined with SD-vancomycin. Low dosages of ceftobiprole were purposely used to highlight positive drug interactions. Treatment with SD-ceftobiprole sterilized 12 of 14 (86%) and 10 of 13 (77%) vegetations infected with PC3 and Mu50, respectively (
P
< 0.001 versus controls). In comparison, LD-ceftobiprole sterilized 10 of 11 (91%) vegetations infected with PC3 (
P
< 0.01 versus controls) but only 3 of 12 (25%) vegetations infected with Mu50 (
P
> 0.05 versus controls). VLD-ceftobiprole and SD-vancomycin alone were ineffective against both strains (≤8% sterile vegetations). In contrast, the combination of VLD-ceftobiprole and SD-vancomycin sterilized 7 of 9 (78%) and 6 of 14 (43%) vegetations infected with PC3 and Mu50, respectively, and the combination of LD-ceftobiprole and SD-vancomycin sterilized 5 of 6 (83%) vegetations infected with Mu50 (
P
< 0.05 versus controls and monotherapy). Thus, ceftobiprole monotherapy simulating standard therapeutic doses was active against VISA experimental endocarditis. Moreover, subtherapeutic LD- and VLD-ceftobiprole synergized with ineffective vancomycin to restore efficacy. Hence, combining ceftobiprole with vancomycin broadens the therapeutic margin of these two compounds against VISA infections.
First Description of an Escherichia coli Strain Producing NDM-1 Carbapenemase in Spain
Authors: Solé Mar , Pitart Cristina , Roca Ignasi , Fàbrega Anna , Salvador Pilar , Muñoz Laura , Oliveira Inés , Gascón Joaquim , Marco Francesc , Vila Jordi
Published: July 2011

A carbapenem-resistant
Escherichia coli
strain (DVR22) was recovered from a stool specimen from a patient with traveler's diarrhea who had traveled to India. Molecular screening led to the first identification of NDM-1 in Spain. The
bla
NDM-1
gene was located in a conjugative plasmid of ca. 300 kb that also contained the
bla
CTX-M-15
,
bla
TEM-1
, Δ
bla
DHA-1
, and
armA
genes. In addition,
bla
NDM-1
was preceded by an IS
Aba125
insertion element only found in
Acinetobacter
spp.
Phylogenetic Sequence Variations in Bacterial rRNA Affect Species-Specific Susceptibility to Drugs Targeting Protein Synthesis
Authors: Akshay Subramanian , Bertea Mihai , Hobbie Sven N. , Oettinghaus Björn , Shcherbakov Dimitri , Böttger Erik C. , Akbergenov Rashid
Published: July 2011

Antibiotics targeting the bacterial ribosome typically bind to highly conserved rRNA regions with only minor phylogenetic sequence variations. It is unclear whether these sequence variations affect antibiotic susceptibility or resistance development. To address this question, we have investigated the drug binding pockets of aminoglycosides and macrolides/ketolides. The binding site of aminoglycosides is located within helix 44 of the 16S rRNA (A site); macrolides/ketolides bind to domain V of the 23S rRNA (peptidyltransferase center). We have used mutagenesis of rRNA sequences in
Mycobacterium smegmatis
ribosomes to reconstruct the different bacterial drug binding sites and to study the effects of rRNA sequence variations on drug activity. Our results provide a rationale for differences in species-specific drug susceptibility patterns and species-specific resistance phenotypes associated with mutational alterations in the drug binding pocket.
Infectious Diseases in Patients with IRAK-4, MyD88, NEMO, or IκBα Deficiency
Authors: Picard Capucine , Casanova Jean-Laurent , Puel Anne
Published: July 2011

Autosomal recessive IRAK-4 and MyD88 deficiencies predispose affected patients to recurrent invasive pyogenic bacterial infection. Both defects result in the selective impairment of cellular responses to Toll-like receptors (TLRs) other than TLR3 and of cellular responses to most interleukin-1 receptors (IL-1Rs), including IL-1R, IL-18R, and IL-33R. Hypomorphic mutations in the X-linked
NEMO
gene and hypermorphic mutations in the autosomal
IKBA
gene cause X-linked recessive and autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) syndromes. Both of these defects impair NF-κB-mediated cellular responses to multiple receptors, including TLRs, IL-1Rs, and tumor necrosis factor receptors (TNF-Rs). They therefore confer a much broader predisposition to infections than that for IRAK-4 and MyD88 deficiencies. These disorders were initially thought to be rare but have now been diagnosed in over 170 patients worldwide. We review here the infectious diseases affecting patients with inborn errors of NF-κB-dependent TLR and IL-1R immunity.
Mycoplasma genitalium: from Chrysalis to Multicolored Butterfly
Authors: Taylor-Robinson David , Jensen Jørgen Skov
Published: July 2011

The history, replication, genetics, characteristics (both biological and physical), and factors involved in the pathogenesis ofMycoplasma genitaliumare presented. The latter factors include adhesion, the influence of hormones, motility, possible toxin production, and immunological responses. The preferred site of colonization, together with current detection procedures, mainly by PCR technology, is discussed. The relationships betweenM. genitaliumand various diseases are highlighted. These diseases include acute and chronic nongonococcal urethritis, balanoposthitis, chronic prostatitis, and acute epididymitis in men and urethritis, bacterial vaginosis, vaginitis, cervicitis, pelvic inflammatory disease, and reproductive disease in women. A causative relationship, or otherwise strong association, between several of these diseases andM. genitaliumis apparent, and the extent of this, on a subjective basis, is presented; also provided is a comparison betweenM. genitaliumand two other genital tract-orientated mollicutes, namely,Mycoplasma hominis, the first mycoplasma of human origin to be discovered, andUreaplasmaspecies. Also discussed is the relationship betweenM. genitaliumand infertility and also arthritis in both men and women, as is infection in homosexual and immunodeficient patients. Decreased immunity, as in HIV infections, may enhance mycoplasmal detection and increase disease severity. Finally, aspects of the antimicrobial susceptibility and resistance ofM. genitalium, together with the treatment and possible prevention of mycoplasmal disease, are discussed.
Review and International Recommendation of Methods for Typing Neisseria gonorrhoeae Isolates and Their Implications for Improved Knowledge of Gonococcal Epidemiology, Treatment, and Biology
Authors: Unemo Magnus , Dillon Jo-Anne R.
Published: July 2011

Gonorrhea, which may become untreatable due to multiple resistance to available antibiotics, remains a public health problem worldwide. Precise methods for typing
Neisseria gonorrhoeae
, together with epidemiological information, are crucial for an enhanced understanding regarding issues involving epidemiology, test of cure and contact tracing, identifying core groups and risk behaviors, and recommending effective antimicrobial treatment, control, and preventive measures. This review evaluates methods for typing
N. gonorrhoeae
isolates and recommends various methods for different situations. Phenotypic typing methods, as well as some now-outdated DNA-based methods, have limited usefulness in differentiating between strains of
N. gonorrhoeae.
Genotypic methods based on DNA sequencing are preferred, and the selection of the appropriate genotypic method should be guided by its performance characteristics and whether short-term epidemiology (microepidemiology) or long-term and/or global epidemiology (macroepidemiology) matters are being investigated. Currently, for microepidemiological questions, the best methods for fast, objective, portable, highly discriminatory, reproducible, typeable, and high-throughput characterization are
N. gonorrhoeae
multiantigen sequence typing (NG-MAST) or full- or extended-length
porB
gene sequencing. However, pulsed-field gel electrophoresis (PFGE) and Opa typing can be valuable in specific situations, i.e., extreme microepidemiology, despite their limitations. For macroepidemiological studies and phylogenetic studies, DNA sequencing of chromosomal housekeeping genes, such as multilocus sequence typing (MLST), provides a more nuanced understanding.
Onchocerciasis: the Role of Wolbachia Bacterial Endosymbionts in Parasite Biology, Disease Pathogenesis, and Treatment
Authors: Tamarozzi Francesca , Halliday Alice , Gentil Katrin , Hoerauf Achim , Pearlman Eric , Taylor Mark J.
Published: July 2011

The discovery ofWolbachiaintracellular bacteria within filarial nematodes, includingOnchocerca volvulus, the causative agent of onchocerciasis or “river blindness,” has delivered a paradigm shift in our understanding of the parasite's biology, to where we now know that the bacterial endosymbionts are essential for normal development of larvae and embryos and may support the long-term survival of adult worms. The apparent mutualistic dependency has also offered a novel approach to the treatment of onchocerciasis through the use of antibiotics to eliminateWolbachia, delivering for the first time a treatment which has significant macrofilaricidal efficacy. Studies with other filarial nematode species have also highlighted a role forWolbachiain transmission and infection of the mammalian host through a fascinating manipulation of mast cell-mediated vasodilation to enhance infectivity of vector-borne larvae.Wolbachiahas also been identified as the principal driver of innate and adaptive Th1 inflammatory immunity, which can either contribute to disease pathogenesis or, with theWolbachia-mediated recruitment of mast cells, enhance infectivity. TheWolbachiaactivation of innate inflammation also drives inflammatory adverse events in response to chemotherapy with either diethylcarbamazine (DEC) or ivermectin. In this review we summarize the experimental and field trial data which have uncovered the importance ofWolbachiasymbiosis in onchocerciasis.
Expert Systems in Clinical Microbiology
Authors: Winstanley Trevor , Courvalin Patrice
Published: July 2011

This review aims to discuss expert systems in general and how they may be used in medicine as a whole and clinical microbiology in particular (with the aid of interpretive reading). It considers rule-based systems, pattern-based systems, and data mining and introduces neural nets. A variety of noncommercial systems is described, and the central role played by the EUCAST is stressed. The need for expert rules in the environment of reset EUCAST breakpoints is also questioned. Commercial automated systems with on-board expert systems are considered, with emphasis being placed on the “big three”: Vitek 2, BD Phoenix, and MicroScan. By necessity and in places, the review becomes a general review of automated system performances for the detection of specific resistance mechanisms rather than focusing solely on expert systems. Published performance evaluations of each system are drawn together and commented on critically.
Mechanisms of Obligatory Intracellular Infection with Anaplasma phagocytophilum
Authors: Rikihisa Yasuko
Published: July 2011

Anaplasma phagocytophilumpersists in nature by cycling between mammals and ticks. Human infection by the bite of an infected tick leads to a potentially fatal emerging disease called human granulocytic anaplasmosis.A. phagocytophilumis an obligatory intracellular bacterium that replicates inside mammalian granulocytes and the salivary gland and midgut cells of ticks.A. phagocytophilumevolved the remarkable ability to hijack the regulatory system of host cells.A. phagocytophilumalters vesicular traffic to create an intracellular membrane-bound compartment that allows replication in seclusion from lysosomes. The bacterium downregulates or actively inhibits a number of innate immune responses of mammalian host cells, and it upregulates cellular cholesterol uptake to acquire cholesterol for survival. It also upregulates several genes critical for the infection of ticks, and it prolongs tick survival at freezing temperatures. Several host factors that exacerbate infection have been identified, including interleukin-8 (IL-8) and cholesterol. Host factors that overcome infection include IL-12 and gamma interferon (IFN-γ). Two bacterial type IV secretion effectors and several bacterial proteins that associate with inclusion membranes have been identified. An understanding of the molecular mechanisms underlyingA. phagocytophiluminfection will foster the development of creative ideas to prevent or treat this emerging tick-borne disease.
Inactivation of
clpB
in the Pathogen Leptospira interrogans Reduces Virulence and Resistance to Stress Conditions
Authors: Lourdault Kristel , Cerqueira Gustavo M. , Wunder Elsio A. , Picardeau Mathieu
Published: July 2011

Leptospira interrogans
is the causative agent of leptospirosis, which is an emerging zoonotic disease. Resistance to stress conditions is largely uncharacterized for this bacterium. We therefore decided to analyze a
clpB
mutant that we obtained by random transposon mutagenesis. The mutant did not produce any of the two isoforms of ClpB. The
clpB
mutant exhibited growth defects at 30° and 37°C and in poor nutrient medium and showed increased susceptibility to oxidative stress, whereas the genetically complemented strain was restored in ClpB expression and
in vitro
wild-type growth. We also showed that the
clpB
mutant was attenuated in virulence in an animal model of acute leptospirosis. Our findings demonstrate that ClpB is involved in the general stress response. The chaperone is also necessary, either directly or indirectly, for the virulence of the pathogen
L. interrogans
.
Cholesterol Depletion Reduces Entry of Campylobacter jejuni Cytolethal Distending Toxin and Attenuates Intoxication of Host Cells
Authors: Lin Chia-Der , Lai Cheng-Kuo , Lin Yu-Hsin , Hsieh Jer-Tsong , Sing Yu-Ting , Chang Yun-Chieh , Chen Kai-Chuan , Wang Wen-Ching , Su Hong-Lin , Lai Chih-Ho
Published: July 2011

Campylobacter jejuni
is a common cause of pediatric diarrhea worldwide. Cytolethal distending toxin, produced by
Campylobacter jejuni
, is a putative virulence factor that induces cell cycle arrest and apoptosis in eukaryotic cells. Cellular cholesterol, a major component of lipid rafts, has a pivotal role in regulating signaling transduction and protein trafficking as well as pathogen internalization. In this study, we demonstrated that cell intoxication by
Campylobacter jejuni
cytolethal distending toxin is through the association of cytolethal distending toxin subunits and membrane cholesterol-rich microdomains. Cytolethal distending toxin subunits cofractionated with detergent-resistant membranes, while the distribution reduced upon the depletion of cholesterol, suggesting that cytolethal distending toxin subunits are associated with lipid rafts. The disruption of cholesterol using methyl-β-cyclodextrin not only reduced the binding activity of cytolethal distending toxin subunits on the cell membrane but also impaired their delivery and attenuated toxin-induced cell cycle arrest. Accordingly, cell intoxication by cytolethal distending toxin was restored by cholesterol replenishment. These findings suggest that membrane cholesterol plays a critical role in the
Campylobacter jejuni
cytolethal distending toxin-induced pathogenesis of host cells.
Indoleamine 2,3-Dioxygenase, Tryptophan Catabolism, and Mycobacterium avium subsp. paratuberculosis: a Model for Chronic Mycobacterial Infections
Authors: Plain Karren M. , de Silva Kumudika , Earl John , Begg Douglas J. , Purdie Auriol C. , Whittington Richard J.
Published: July 2011

Virulent mycobacterial infections progress slowly, with a latent period that leads to clinical disease in a proportion of cases.Mycobacterium aviumsubsp.paratuberculosisis an intracellular pathogen that causes paratuberculosis or Johne's disease (JD), a chronic intestinal disease of ruminants. Indoleamine 2,3-dioxygenase (IDO), an enzyme that regulates tryptophan metabolism, was originally reported to have a role in intracellular pathogen killing and has since been shown to have an important immunoregulatory role in chronic immune diseases. Here we demonstrate an association between increased IDO levels and progression to clinical mycobacterial disease in a natural host, characterizing gene expression, protein localization, and functional effects. IDO mRNA levels were significantly increased inM. aviumsubsp.paratuberculosis-infected monocytic cells. Levels of both IDO gene and protein expression were significantly upregulated within the affected tissues of sheep with JD, particularly at the site of primary infection, the ileum, of animals with severe multibacillary disease. Lesion severity was correlated with the level of IDO gene expression. IDO gene expression was also increased in the peripheral blood cells ofM. aviumsubsp.paratuberculosis-exposed sheep and cattle. IDO breaks down tryptophan, and systemic increases were functional, as shown by decreased plasma tryptophan levels, which correlated with the onset of clinical signs, a stage well known to be associated with Th1 immunosuppression. IDO may be involved in downregulating immune responses toM. aviumsubsp.paratuberculosisand other virulent mycobacteria, which may be an example of the pathogen harnessing host immunoregulatory pathways to aid survival. These findings raise new questions about the host-mycobacterium interactions in the progression from latent to clinical disease.
Twitter=quitter? An analysis of Twitter quit smoking social networks
Authors: Prochaska Judith J , Pechmann Cornelia , Kim Romina , Leonhardt James M
Published: July 2011

Objective

Widely popular, Twitter, a free social networking and micro-blogging service, offers potential for health promotion. This study examined the activity of Twitter quit smoking social network accounts.

Design

A cross‐sectional analysis identified 153 activated Twitter quit smoking accounts dating back to 2007 and examined recent account activity for the month of August 2010.

Results

The accounts had a median of 155 followers and 82 total tweets per account; 49% of accounts had >100 tweets. Posted content was largely inconsistent with clinical guidelines; 48% linked to commercial sites for quitting smoking and 43% had tweets on e‐cigarettes. In August 2010, 81 of the accounts (53%) were still active.

Conclusions

Though popular for building quit smoking social networks, many of the Twitter accounts were no longer active, and tweet content was largely inconsistent with clinical guidelines. Future research is needed to examine the effectiveness of Twitter for supporting smoking cessation.