bluuebunny/crossref_metadata_2025 huggingface dataset:
Canadian Family Physicians and Complementary/Alternative Medicine: The Role of Practice Setting, Medical Training, and Province of Practice*
Authors: HIRSCHKORN KRISTINE A. , ANDERSEN ROBERT , BOURGEAULT IVY L.
Published: April 2009

Cette étude jette une certaine lumière sur la façon selon laquelle les médecins de famille canadiens offrent des services de médecine douce et complémentaire (MDC) à leurs patients, et pourquoi ils le font. Les résultats des recherches des auteurs démontrent que les environnements organisationnels découragent les médecins d'offrir des services de MDC alors que les cliniques indépendantes y sont plus favorables. Les médecins formés dans les facultés de médecine francophones sont moins susceptibles que leurs collègues formés en anglais d'offrir de tels services, et ceux de Colombie‐Britannique sont les plus portés à le faire. Les différences interprovinciales ne semblent pas liées à la présence ou à l'absence de législation de « preuve négative », qui est considérée faciliter la fourniture de ces services par les médecins.

The present study sheds some light on how and why Canadian family physicians offer complementary and alternative medicine (CAM) services to their patients. Our results suggest that organizational settings discourage physicians from offering CAM, while solo clinics are most conducive. Physicians trained in French‐language medical schools are less likely than their English‐language trained colleagues to offer CAM services, and those in British Columbia are the most likely to do so. Provincial differences do not appear to be related to the presence or absence of “negative proof” legislation that is considered to facilitate CAM provision by physicians.
In vivo role of FdhD and FdmE in formate metabolism in Pseudomonas putida: Redundancy and expression in the stationary phase
Authors: Roca Amalia , Ramos Juan L.
Published: April 2009

In Pseudomonas putida two open reading frames (ORFs) PP0257 and PP0492 were originally annotated as accessory formate dehydrogenase proteins. The ORF PP0492 (fdmD) is at the 3′ end of the ORF PP0489 through PP0491 operon that encodes one of the formate dehydrogenases of P. putida and it is transcribed with this operon preferentially at the stationary phase. The ORF PP0257 (fdhD) is unlinked to formate dehydrogenase clusters and, as to multi‐component formate dehydrogenases, PP0257 is also preferentially expressed in the stationary phase, although transcription can be mediated by either RpoD or RpoS. The transcriptional level of expression of fdhD increased in response to formaldehyde/formate or chemicals that yield these cited C1 compounds through their metabolism. In spite of these correlations, inactivation of PP0257 does not produce a significant effect on in vivo formate dehydrogenase activity, while inactivation of PP0492 leads to a 60% decrease in in vivo activity. These results suggest that redundancy in formaldehyde/formate metabolism in P. putida extends to the proteins involved in maturation/location of formate dehydrogenase complexes.
Leibniz on Natural Teleology and the Laws of Optics
Authors: MCDONOUGH JEFFREY K.
Published: April 2009

This essay examines one of the cornerstones of Leibniz’s defense of teleology within the order of nature. The first section explores Leibniz’s contributions to the study of geometrical optics, and argues that his “Most Determined Path Principle” or “MDPP” allows him to bring to the fore philosophical issues concerning the legitimacy of teleological explanations by addressing two technical objections raised by Cartesians to non‐mechanistic derivations of the laws of optics. The second section argues that, by drawing on laws such as the MDPP, Leibniz is able to introduce a thin notion of teleology that gives him the resources to respond to the most pressing charges of his day against teleological explanations within natural philosophy. Finally, the third section argues that contemporary philosophers have been overly hasty in their dismissal of Leibniz’s account of natural teleology, and indeed that their own generally thin conceptions of teleology have left them with few well‐motivated resources for resisting his elegant position.
Can ‘Intrinsic’ Be Defined Using Only Broadly Logical Notions?1
Authors: MARSHALL DAN
Published: April 2009

An intrinsic property is roughly a property things have in virtue of how they are, as opposed to how they are related to things outside of them. This paper argues that it is not possible to give a definition of ‘intrinsic’ that involves only logical, modal and mereological notions, and does not depend on any special assumptions about either properties or possible worlds.
The Effect of Fiber Diameter Distribution on the Elasticity of a Fiber Mass
Authors: Alkhagen Mårten , Toll Staffan
Published: April 2009

A random mass of loose fibers interacting by fiber-fiber contact is considered. As proposed in a previous paper, the elastic response is modeled based on the statistical mechanics of bending and torsion of fiber segments between fiber-fiber contact points. Presently we show how the statistical approach can be used to account for a distribution of fiber diameters rather than just a single diameter. The resulting expression has the same form and the same set of parameters as its single-diameter counterpart, except for two dimensionless reduction factors, which depend on the fiber diameter distribution only and reduce to unity for monodisperse fibers. Uniaxial compressibility experiments are performed on several materials with different bimodal fiber diameter distributions and are compared to model predictions. Even though no additional parameters were introduced to model the effect of mixed fiber diameters, the behavior is accurately predicted. Notably, the effect of the nonuniform fiber diameter is strong: A mixture of two fiber diameters differing by a factor of 2 can reduce the response by an order of magnitude, compared to the case of uniform diameter.
Steady-State Wave Propagation in Multilayered Viscoelastic Media Excited by a Moving Dynamic Distributed Load
Authors: Sun Lu , Gu Wenjun , Luo Feiquan
Published: April 2009

An analytical solution of steady-state dynamic response of a multilayered viscoelastic medium to a moving distributed load is obtained using a novel approach that combines transfer matrix method with Sun’s convolution representation integrated over impulse response function of the layered medium. The layered media under consideration include elastic and viscoelastic media with four different viscoelastic constitutive models, while the moving load is allowed to have a circular spatial distribution, which is more realistic for mimicking tire footprint than a commonly used point load. Efficient numerical algorithms based on fast evaluation of various integral transformations and their inversions are developed and validated through numerical example.
Computation of Thermal Stress Intensity Factors for Bimaterial Interface Cracks Using Domain Integral Method
Authors: Khandelwal Ratnesh , Kishen J. M. Chandra
Published: April 2009

The concept of domain integral used extensively for J integral has been applied in this work for the formulation of J2 integral for linear elastic bimaterial body containing a crack at the interface and subjected to thermal loading. It is shown that, in the presence of thermal stresses, the Jk domain integral over a closed path, which does not enclose singularities, is a function of temperature and body force. A method is proposed to compute the stress intensity factors for bimaterial interface crack subjected to thermal loading by combining this domain integral with the Jk integral. The proposed method is validated by solving standard problems with known solutions.
A Thin Conducting Liquid Film on a Spinning Disk in the Presence of a Magnetic Field: Dynamics and Stability
Authors: Uma B. , Usha R.
Published: April 2009

A theoretical analysis of the effects of a magnetic field on the dynamics of a thin nonuniform conducting film of an incompressible viscous fluid on a rotating disk has been considered. A nonlinear evolution equation describing the shape of the film interface has been derived as a function of space and time and has been solved numerically. The temporal evolution of the free surface of the fluid and the rate of retention of the liquid film on the spinning disk have been obtained for different values of Hartmann number M, evaporative mass flux parameter E, and Reynolds number Re. The results show that the relative volume of the fluid retained on the spinning disk is enhanced by the presence of the magnetic field. The stability characteristics of the evolution equation have been examined using linear theory. For both zero and nonzero values of the nondimensional parameter describing the magnetic field, the results show that (a) the infinitesimal disturbances decay for small wave numbers and are transiently stable for larger wave numbers when there is either no mass transfer or there is evaporation from the film surface, and although the magnitude of the disturbance amplitude is larger when the magnetic field is present, it decays to zero earlier than for the case when the magnetic field is absent, and (b) when absorption is present at the film surface, the film exhibits three different domains of stability: disturbances of small wave numbers decay, disturbances of intermediate wave numbers grow transiently, and those of large wave numbers grow exponentially. The range of stable wave numbers increases with increase in Hartmann number.
Micromechanical Interpretation of the Dissipation Associated With Mode I Propagation of Microcracks in Brittle Materials
Authors: Pichler Bernhard , Dormieux Luc
Published: April 2009

This paper deals with the dissipation associated with quasistatic microcracking of brittle materials exhibiting softening behavior. For this purpose an elastodamaging cohesive zone model is used, in which cohesive tractions decrease (during crack propagation) with increasing displacement discontinuities. Constant cohesive tractions are included in the model as a limiting special case. Considering a representative volume element containing a dilute distribution of many parallel microcracks, we quantify energy dissipation associated with mode I microcrack propagation. This is done in the framework of thermodynamics, without restricting assumptions on the size of the cohesive zones. Model predictions are compared with exact solutions, which are accessible for constant cohesive tractions. The proposed model reliably predicts both onset of crack propagation and the dissipation during microcracking. It is shown that the energy release rate is virtually equal to the area under the softening curve, if the microscopic tensile strength is at least twice as large as the macroscopic tensile strength. This result justifies approaches relying on the concept of constant energy release rate, such as those frequently used in the engineering practice.
Digital Photothermoelastic and Numerical Analysis of Transient Thermal Stresses in Cracked Bimaterial Interfaces
Authors: Neethi Simon B. , Ramesh K.
Published: April 2009

Transient thermal stresses of a bimaterial specimen with interface cracks, under uniform cooling by convection, are analyzed by photothermoelasticity and a coupled temperature-displacement, finite element scheme. The stress intensity factors of the interface crack are determined by a multiparameter overdeterministic system of equations in a least-squares sense using the experimental data and by J-integral, numerically. The study showed that a normal temperature variation can lead to significant stresses due to the mismatch of thermal expansion coefficients.
Vibration and Snap-Through of Bent Elastica Strips Subjected to End Rotations
Authors: Plaut R. H. , Virgin L. N.
Published: April 2009

A flexible strip is rotated at its ends until it forms a deep circular arc above its ends. Then the ends are kept immovable and are rotated downward until the arch suddenly snaps into an inverted configuration. The strip is analyzed as an inextensible elastica. Two-dimensional equilibrium shapes, vibration modes and frequencies, and critical rotations for snap-through are determined using a shooting method. Experiments are also conducted and results are compared with those from the analysis. The agreement is good. In addition, a microelectromechanical systems (MEMS) example is analyzed, in which an electrostatic force below a buckled strip causes the strip to snap downward, and the critical force is obtained as a function of the vertical gap.
Modeling Forced
Convection in Finned Metal Foam Heat Sinks
Authors: DeGroot Christopher
T. , Straatman Anthony
G. , Betchen Lee
J.
Published: April 2009

A numerical study has been undertaken to explore the details of forced convection heat transfer in finned aluminum foam heat sinks. Calculations are made using a finite-volume computational fluid dynamics (CFD) code that solves for the flow and heat transfer in conjugate fluid/porous/solid domains. The results indicate that using unfinned blocks of porous aluminum results in low convective heat transfer due to the relatively low effective thermal conductivity of the porous aluminum. The addition of aluminum fins to the heat sink significantly enhances the heat transfer with only a moderate pressure drop penalty. The convective enhancement is maximized when thermal boundary layers between adjacent fins merge together and become nearly developed for much of the length of the heat sink. It is found that the heat transfer enhancement is due to increased heat entrainment into the aluminum foam by conduction. A model for the equivalent conductivity of the finned/foam heat sinks is developed using extended surface theory. This model is used to explain the heat transfer enhancement as an increase in equivalent conductivity of the device. The model is also shown to predict the heat transfer for various heat sink geometries based on a single CFD calculation to find the equivalent conductivity of the device. This model will find utility in characterizing heat sinks and in allowing for quick assessments of the effect of varying heat sink properties.
Direct De-Ionized Water-Cooled Semiconductor Laser Package for Photodynamic Therapy of Esophageal Carcinoma: Design and Analysis
Authors: Happawana Gemunu , Premasiri Amaranath , Rosen Arye
Published: April 2009

Effective delivery of the activation light for photodynamic therapy (PDT) of internal organs is a challenge. In this paper, we present a direct de-ionized water-cooling semiconductor laser package design for PDT of esophageal carcinomas. This self-sustained photonic light delivery system is designed to provide the correct amount of light dose for optimal treatment. The direct de-ionized water-cooling technique discussed in this paper not only removes heat efficiently but also results in a high optical power output. Voltage-current and power-current characteristics, and near field optical patterns for unidirectional and direct de-ionized water-cooling, are used to show the validity of the technique. Modeling of fluid flow is conducted to investigate the effect of flowing water over the laser package.
High-Accuracy Thermal Analysis Methodology for Semiconductor Junction Temperatures by Considering Line Patterns of Three-Dimensional Modules
Authors: Kumano Yutaka , Ogura Tetsuyoshi , Yamada Toru
Published: April 2009

A novel computational fluid dynamics analysis method of predicting semiconductor junction temperatures precisely without modeling printed circuit board (PCB) line patterns was developed. First, PCBs are divided into multiple regions. The effective anisotropic thermal conductivity of each region is then assigned as follows. All the regions are divided into smaller subregions whose size is below the pattern width. The thermal conductivity of each subregion is defined by the property of the material at the center of the subregion. Next, a thermal circuit network composed of all the subregions is generated, and finally the anisotropic thermal conductivities of each region are computed by solving this thermal network matrix. When boards are divided into multiple regions, there is a convergence region size under which the analytical results show no further change. In this paper, the relationship between the size of the divided regions and the accuracy of the analytical results was investigated. It was confirmed that the calculated semiconductor junction temperatures were precisely coincident with the experimental results when the size of the regions was less than 20 times the line pattern width.
Analytical Modeling for Thermodynamic Characterization of Data Center Cooling Systems
Authors: Iyengar Madhusudan , Schmidt Roger
Published: April 2009

The increasingly ubiquitous nature of computer and internet usage in our society has driven advances in semiconductor technology, server packaging, and cluster level optimizations in the IT industry. Not surprisingly this has an impact on our societal infrastructure with respect to providing the requisite energy to fuel these power hungry machines. Cooling has been found to contribute about a third of the total data center energy consumption and is the focus of this study. In this paper we develop and present physics based models to allow the prediction of the energy consumption and heat transfer phenomenon in a data center. These models allow the estimation of the microprocessor junction and server inlet air temperatures for different flows and temperature conditions at various parts of the data center cooling infrastructure. For the case study example considered, the chiller energy use was the biggest fraction of about 41% and was also the most inefficient. The room air conditioning was the second largest energy component and was also the second most inefficient. A sensitivity analysis of plant and chiller energy efficiencies with chiller set point temperature and outdoor air conditions is also presented.
Measurement and Characterization of the Moisture-Induced Properties of ACF Package
Authors: Yoon Ji-Young , Kim Ilho , Lee Soon-Bok
Published: April 2009

This study is to observe the exact behavior of anisotropic conductive adhesion (ACF) package under humid environments by obtaining the moisture-induced properties such as diffusion coefficient (the rate of moisture movement into the materials), saturated moisture content (the maximum absorbed quantity), and swelling coefficient (length change due to the chemical interaction). So the experiments were performed to get the moisture-induced properties of ACF and FR4 using newly developed method at various temperature and relative humidity conditions. Experimental results showed that the diffusion coefficient of ACF and FR4 follows Arrhenius’ equation very well, and the saturated moisture content of them follows Henry’s law, which means linear relationship between saturated moisture content and relative humidity, but the saturated moisture content of ACF is influenced by temperature as well as relative humidity. And the swelling coefficient of ACF and FR4 increases with temperature. Especially in the case of ACF, it shows the dramatic degradation due to Tg (glass transition temperature) at nearby 85°C. Finally, as using these experimental results, the behavior of the ACF package under humid environment is predicted through finite element simulation. When wetness defined by moisture content over saturated moisture content changes from 0 to 0.9, the center of the ACF package is subject to compression and the edge of the ACF package is subject to tension in the case of transient state. After all, because the edge of the ACF package is very weak due to bending moment, the failure is easy to occur under humid environment.
Single-Phase and Two-Phase Hybrid Cooling Schemes for High-Heat-Flux Thermal Management of Defense Electronics
Authors: Sung Myung Ki , Mudawar Issam
Published: April 2009

This study examines the cooling performance of two hybrid cooling schemes that capitalize on the merits of both microchannel flow and jet impingement to achieve the high cooling fluxes and uniform temperatures demanded by advanced defense electronics. The jets supply HFE 7100 liquid coolant gradually into each microchannel. The cooling performances of two different jet configurations, a series of circular jets and a single slot jet, are examined both numerically and experimentally. The single-phase performances of both configurations are accurately predicted using 3D numerical simulation. Numerical results point to complex interactions between the jets and the microchannel flow, and superior cooling performance is achieved by optimal selection of microchannel height. The two-phase cooling performance of the circular-jet configuration is found superior to that of the slot jet, especially in terms of high-flux heat dissipation. Unprecedented cooling fluxes, as high as 1127 W/cm2, are achieved with the circular jets without incurring CHF.
In- and Out-of-Plane
Vibrations of a Rotating Plate With Frictional Contact: Investigations on Squeal
Phenomena
Authors: Spelsberg-Korspeter Gottfried , Hochlenert Daniel , Kirillov Oleg
N. , Hagedorn Peter
Published: April 2009

Rotating plates are used as a main component in various applications. Their vibrations are mainly unwanted and interfere with the functioning of the complete system. The present paper investigates the coupling of disk (in-plane) and plate (out-of-plane) vibrations of a rotating annular Kirchhoff plate in the presence of a distributed frictional loading on its surface. The boundary value problem is derived from the basics of the theory of elasticity using Kirchhoff’s assumptions. This results in precise information about the coupling between the disk and the plate vibrations under the action of frictional forces. At the same time we obtain a new model, which is efficient for analytical treatment. Approximations to the stability boundaries of the system are calculated using a perturbation approach. In the last part of the paper nonlinearities are introduced leading to limit cycles due to self-excited vibrations.
Nine-Hospital Study Comparing Broth Microdilution and Etest Method Results for Vancomycin and Daptomycin against Methicillin-Resistant
Staphylococcus aureus
Authors: Sader Helio S. , Rhomberg Paul R. , Jones Ronald N.
Published: April 2009

Vancomycin and daptomycin MIC results for 1,800 randomly selected oxacillin (methicillin [meticillin])-resistant
Staphylococcus aureus
(MRSA) bloodstream isolates from nine U.S. hospitals (collected from 2002 to 2006) were determined by a reference broth microdilution (BMD) method using frozen-form panels with precise incremental dilutions and by the Etest technique. The Etest provided vancomycin and daptomycin MIC results that were consistently higher (0.5 to 1.5 log
2
dilution steps) than those provided by the reference BMD method. The dominant MRSA population (91.2% of MRSA isolates) would be categorized as vancomycin nonsusceptible by the MIC results from the Etest method if the susceptibility breakpoint was adjusted downward to ≤1 μg/ml, as suggested by clinical outcome studies.
GS-9191 Is a Novel Topical Prodrug of the Nucleotide Analog 9-(2-Phosphonylmethoxyethyl)Guanine with Antiproliferative Activity and Possible Utility in the Treatment of Human Papillomavirus Lesions
Authors: Wolfgang Grushenka H. I. , Shibata Riri , Wang Jianying , Ray Adrian S. , Wu Sylvia , Doerrfler Edward , Reiser Hans , Lee William A. , Birkus Gabriel , Christensen Neil D. , Andrei Graciela , Snoeck Robert
Published: April 2009

GS-9191 is a novel double prodrug of the nucleotide analog 9-(2-phosphonylmethoxyethyl)guanine (PMEG) designed as a topical agent to permeate skin and be metabolized to the active nucleoside triphosphate analog in the epithelial layer. The prodrug was shown to be metabolized intracellularly to 9-(2-phosphonylmethoxyethyl)-N6-cyclopropyl-2,6,diaminopurine (cPrPMEDAP) and subsequently deaminated to PMEG. The active form, PMEG diphosphate, was shown to be a potent inhibitor of DNA polymerase α and ß while showing weaker activity against mitochondrial DNA polymerase γ (50% enzyme inhibition observed at 2.5, 1.6, and 59.4 μM, respectively). GS-9191 was markedly more potent than PMEG or cPrPMEDAP in a series of human papillomavirus (HPV)-positive cell lines, with effective concentrations to inhibit 50% cell growth (EC50) as low as 0.03, 207, and 284 nM, respectively. In contrast, GS-9191 was generally less potent in non-HPV-infected cells and primary cells (EC50s between 1 and 15 nM). DNA synthesis was inhibited by GS-9191 within 24 h of treatment; cells were observed to be arrested in S phase by 48 h and to subsequently undergo apoptosis (between 3 and 7 days). In an animal model (cottontail rabbit papillomavirus), topical GS-9191 was shown to decrease the size of papillomas in a dose-related manner. At the highest dose (0.1%), cures were evident at the end of 5 weeks, and lesions did not recur in a 30-day follow-up period. These data suggest that GS-9191 may have utility in the treatment of HPV-induced lesions.
Epidemic Clonal Groups of
Escherichia coli
as a Cause of Antimicrobial-Resistant Urinary Tract Infections in Canada, 2002 to 2004
Authors: Johnson James R. , Menard Megan , Johnston Brian , Kuskowski Michael A. , Nichol Kim , Zhanel George G.
Published: April 2009

The extent to which clonal spread contributes to emerging antimicrobial resistance in
Escherichia coli
is incompletely defined. To address this question within a recent, nationally representative strain collection, three established drug-resistant
E. coli
clonal groups (i.e., clonal group A,
E. coli
O15:K52:H1, and sequence type 131 [ST131]) were sought among 199
E. coli
urine isolates recovered from across Canada from 2002 to 2004, with stratification by resistance to trimethoprim-sulfamethoxazole (TS) and fluoroquinolones (FQs). The isolates' clonal backgrounds, virulence genotypes, and macrorestriction profiles were assessed. The three clonal groups were found to account for 37.2% of isolates overall, but accounted for 0% of TS-susceptible (TS-S) and FQ-susceptible (FQ-S) isolates, 20% of TS-resistant (TS-R) and FQ-S isolates, 60% of TS-S and FQ-R isolates, and 68% of TS-R and FQ-R isolates (
P
< 0.001).
E. coli
ST131, the most prevalent clonal group, accounted for 23.1% of isolates overall and for 44% of the FQ-R isolates. Nearly all ST131 isolates were FQ-R (96%) but, notably, cephalosporin susceptible (98%). Although the distinctive virulence profiles of the FQ-R clonal group isolates were less extensive than those of the susceptible isolates, they were significantly more extensive than those of the other FQ-R isolates. These findings indicate that among the
E. coli
urine isolates studied, resistance to TS and FQs has a prominent clonal component, with the O15:K52:H1 clonal group and especially
E. coli
ST131 being the major contributors. These clonal groups appear to be more virulent than comparably resistant isolates, possibly contributing to their success as emerging multi-drug-resistant pathogens.
Integration of Pharmacokinetic and Pharmacodynamic Indices of Orbifloxacin in Beagle Dogs after a Single Intravenous and Intramuscular Administration
Authors: Gebru Elias , Lee Joong-Su , Chang Zhi-Qiang , Hwang Mi-Hyun , Cheng Henrique , Park Seung-Chun
Published: April 2009

The pharmacokinetics (PK) and pharmacodynamics (PD) of orbifloxacin were studied in beagle dogs after intravenous (i.v.) and intramuscular (i.m.) administration at a dose of 2.5 mg/kg body weight. An absolute bioavailability of 100.1% ± 4.76%, a terminal half-life of 4.23 ± 0.2 h and 3.95 ± 0.15 h after i.v. and i.m. administration, a steady-state volume of distribution of 1.61 ± 0.13 liters/kg, and clearance of 0.31 ± 0.03 liters/h/kg were observed. Orbifloxacin showed rapid, concentration-dependent killing against theEscherichia coli,Staphylococcus aureus,Staphylococcus intermedius, andProteus mirabilisclinical isolates. Computations based on PK-PD analysis indicated that the recommended dose is unlikely to be clinically effective against some strains likeS. intermedius. Therefore, a higher dose of orbifloxacin would be worthy of consideration for treatment of certain bacterial infections in dogs.
Characterization of Cefoxitin-Resistant
Escherichia coli
Isolates from Recreational Beaches and Private Drinking Water in Canada between 2004 and 2006
Authors: Mataseje L. F. , Neumann N. , Crago B. , Baudry P. , Zhanel G. G. , Louie M. , Mulvey M. R.
Published: April 2009

A total of 142 cefoxitin-resistant
Escherichia coli
isolates from water sources were collected across Canada. Multidrug resistance was observed in 65/142 (45.8%) isolates. The
bla
CMY-2
gene was identified in 110/142 (77.5%) isolates. Sequencing of the chromosomal
ampC
promoter region showed mutations from the wild type, previously shown to hyperproduce AmpC. CMY-2-producing plasmids predominantly belonged to replicon groups I1-Iγ, A/C, and K/B. The majority of the
E. coli
isolates belonged to the nonvirulent phylogenetic groups A and B1.
Effect of Tipranavir-Ritonavir on Pharmacokinetics of Raltegravir
Authors: Hanley William D. , Wenning Larissa A. , Moreau Allison , Kost James T. , Mangin Eric , Shamp Trisha , Stone Julie A. , Gottesdiener Keith M. , Wagner John A. , Iwamoto Marian
Published: April 2009

Raltegravir (RAL) is a novel and potent human immunodeficiency virus type 1 integrase inhibitor that is predominantly metabolized via glucuronidation. The protease inhibitor combination tipranavir (TPV) at 500 mg and ritonavir (RTV) at 200 mg (TPV-RTV) has inhibitory and inductive effects on metabolic enzymes, which includes the potential to induce glucuronosyltransferase. Because RAL may be coadministered with TPV-RTV, there is the potential for the induction of RAL metabolism. Consequently, we assessed the effect of TPV-RTV on the pharmacokinetics of RAL and the safety and tolerability of this combination. Eighteen healthy adults were enrolled in this open-label study. The participants received RAL at 400 mg twice daily for 4 days (period 1) and TPV-RTV twice daily for 7 days (period 2), followed immediately by 400 mg RAL with TPV-RTV twice daily for 4 days (period 3). Under steady-state conditions, the RAL concentration at 12 h (
C
12
) was decreased when RAL was administered with TPV-RTV (geometric mean ratio [GMR], 0.45; 90% confidence interval [CI] 0.31, 0.66;
P
= 0.0021); however, the area under the concentration-time curve from time zero to 12 h (GMR, 0.76; 90% CI, 0.49, 1.19;
P
= 0.2997) and the maximum concentration in serum (GMR, 0.82; 90% CI, 0.46, 1.46;
P
= 0.5506) were not substantially affected. There were no serious adverse experiences or discontinuations due to study drug-related adverse experiences, and RAL coadministered with TPV-RTV was generally well tolerated. Although the RAL
C
12
was decreased with TPV-RTV in this study, favorable efficacy data collected in phase III studies substantiate that TPV-RTV may be coadministered with RAL without dose adjustment.
In Vitro Elution of Daptomycin by a Synthetic Crystallic Semihydrate Form of Calcium Sulfate, Stimulan
Authors: Kanellakopoulou Kyriaki , Panagopoulos Periklis , Giannitsioti Efthymia , Tsaganos Thomas , Carrer Dionyssia-Pinelopi , Efstathopoulos Nicolas , Giamarellos-Bourboulis Evangelos J.
Published: April 2009

A synthetic crystallic semihydrate form of calcium sulfate, Stimulan, was evaluated as a biodegradable carrier for the daily in vitro elution of daptomycin. Daptomycin and Stimulan were admixed at a ratio of 95:5. Elution lasted for 28 days. Eluted concentrations peaked on days 1 and 11, when the mean values were 1,320.1 and 949.2 μg/ml, respectively. The lowest eluted concentration was detected on day 28. These results support the application of the system described in experimental models of osteomyelitis.
Purification of Legiobactin and Importance of This Siderophore in Lung Infection byLegionella pneumophila
Authors: Allard Kimberly A. , Dao Jenny , Sanjeevaiah Prakash , McCoy-Simandle Kessler , Chatfield Christa H. , Crumrine David S. , Castignetti Domenic , Cianciotto Nicholas P.
Published: April 2009

When cultured in a low-iron medium,Legionella pneumophilasecretes a siderophore (legiobactin) that is both reactive in the chrome azurol S (CAS) assay and capable of stimulating the growth of iron-starved legionellae. Using anion-exchange high-pressure liquid chromatography (HPLC), we purified legiobactin from culture supernatants of a virulent strain ofL. pneumophila. In the process, we detected the ferrated form of legiobactin as well as other CAS-reactive substances. Purified legiobactin had a yellow-gold color and absorbed primarily from 220 nm and below. In accordance, nuclear magnetic resonance spectroscopy revealed that legiobactin lacks aromatic carbons, and among the 13 aliphatics present, there were 3 carbonyls. When examined by HPLC, supernatants fromL. pneumophilamutants inactivated forlbtAandlbtBcompletely lacked legiobactin, indicating that the LbtA and LbtB proteins are absolutely required for siderophore activity. Independently derivedlbtAmutants, but not a complemented derivative, displayed a reduced ability to infect the lungs of A/J mice after intratracheal inoculation, indicating that legiobactin is required for optimal intrapulmonary survival byL. pneumophila. This defect, however, was not evident when thelbtAmutant and its parental strain were coinoculated into the lung, indicating that legiobactin secreted by the wild type can promote growth of the mutant intrans. Legiobactin mutants grew normally in murine lung macrophages and alveolar epithelial cells, suggesting that legiobactin promotes something other than intracellular infection of resident lung cells. Overall, these data represent the first documentation of a role for siderophore expression in the virulence ofL. pneumophila.
Borrelia burgdorferi
RevA Antigen Binds Host Fibronectin
Authors: Brissette Catherine A. , Bykowski Tomasz , Cooley Anne E. , Bowman Amy , Stevenson Brian
Published: April 2009

Borrelia burgdorferi
, the Lyme disease-causing spirochete, can persistently infect its vertebrate hosts for years.
B. burgdorferi
is often found associated with host connective tissue, where it interacts with components of the extracellular matrix, including fibronectin. Some years ago, a borrelial surface protein, named BBK32, was identified as a fibronectin-binding protein. However,
B. burgdorferi
BBK32 mutants are still able to bind fibronectin, indicating that the spirochete possesses additional mechanisms for adherence to fibronectin. We now demonstrate that RevA, an unrelated
B. burgdorferi
outer surface protein, binds mammalian fibronectin in a saturable manner. Site-directed mutagenesis studies identified the amino terminus of the RevA protein as being required for adhesion to fibronectin. RevA bound to the amino-terminal region of fibronectin. RevA binding to fibronectin was not inhibited by salt or heparin, suggesting that adhesin-ligand interactions are primarily nonionic and occur through the non-heparin-binding regions of the fibronectin amino-terminal domains.
revA
genes are widely distributed among Lyme disease spirochetes, and the present studies determined that all RevA alleles tested bound fibronectin. In addition, RevB, a paralogous protein found in a subset of
B. burgdorferi
strains, also bound fibronectin. We also confirmed that RevA is produced during mammalian infection but not during colonization of vector ticks and determined that
revA
transcription is controlled through a mechanism distinct from that of BBK32.
Nonhematopoietic Cells Control the Outcome of Infection with
Listeria monocytogenes
in a Nucleotide Oligomerization Domain 1-Dependent Manner
Authors: Mosa Ahmed , Trumstedt Christian , Eriksson Emma , Soehnlein Oliver , Heuts Frank , Janik Katrin , Klos Andreas , Dittrich-Breiholz Oliver , Kracht Michael , Hidmark Åsa , Wigzell Hans , Rottenberg Martin E.
Published: April 2009

We analyzed the defensive role of the cytosolic innate recognition receptor nucleotide oligomerization domain 1 (NOD1) during infection with
Listeria monocytogenes
. Mice lacking NOD1 showed increased susceptibility to systemic intraperitoneal and intravenous infection with high or low doses of
L. monocytogenes
, as measured by the bacterial load and survival. NOD1 also controlled dissemination of
L. monocytogenes
into the brain. The increased susceptibility to reinfection of NOD1
−/−
mice was not associated with impaired triggering of listeria-specific T cells, and similar levels of costimulatory molecules or activation of dendritic cells was observed. Higher numbers of F480
+
Gr1
+
inflammatory monocytes and lower numbers of F480
−
Gr1
+
neutrophils were recruited into the peritoneum of infected WT mice than into the peritoneum of infected NOD1
−/−
mice. We determined that nonhematopoietic cells accounted for NOD1-mediated resistance to
L. monocytogenes
in bone marrow radiation chimeras. The levels of NOD1 mRNA in fibroblasts and bone marrow-derived macrophages (BMM) were upregulated after infection with
L. monocytogenes
or stimulation with different Toll-like receptor ligands. NOD1
−/−
BMM, astrocytes, and fibroblasts all showed enhanced intracellular growth of
L monocytogenes
compared to WT controls. Gamma interferon-mediated nitric oxide production and inhibition of
L. monocytogenes
growth were hampered in NOD1
−/−
BMM. Thus, NOD1 confers nonhematopoietic cell-mediated resistance to infection with
L. monocytogenes
and controls intracellular bacterial growth in different cell populations in vitro.
OspC-Independent Infection and Dissemination by Host-Adapted
Borrelia burgdorferi
Authors: Tilly Kit , Bestor Aaron , Dulebohn Daniel P. , Rosa Patricia A.
Published: April 2009

Borrelia burgdorferi
OspC is required for the spirochete to establish infection in a mammal by tick transmission or needle inoculation. After a brief essential period, the protein no longer is required and the gene can be shut off. Using a system in which spirochetes contain only an unstable wild-type copy of the
ospC
gene, we can obtain mice persistently infected with bacteria lacking OspC. We implanted pieces of infected mouse skin subcutaneously in naïve mice, using donors carrying wild-type or
ospC
mutant spirochetes, and found that both could infect mice by this method, with similar numbers of wild-type or
ospC
mutant spirochetes disseminated throughout the tissues of recipient mice. Recipient mouse immune responses to tissue transfer-mediated infection with wild-type or
ospC
mutant spirochetes were similar. These experiments demonstrate that mammalian host-adapted spirochetes can infect and disseminate in mice in the absence of OspC, thereby circumventing this hallmark of tick-derived or in vitro-grown spirochetes. We propose a model in which OspC is one of a succession of functionally equivalent, essential proteins that are synthesized at different stages of mammalian infection. In this model, another protein uniquely present on host-adapted spirochetes performs the same essential function initially fulfilled by OspC. The strict temporal control of
B. burgdorferi
outer surface protein gene expression may reflect immunological constraints rather than distinct functions.
Subcellular Localization of theStaphylococcus aureusHeme Iron Transport Components IsdA and IsdB
Authors: Pishchany Gleb , Dickey Susan E. , Skaar Eric P.
Published: April 2009

Staphylococcus aureusis a human pathogen that represents a tremendous threat to global public health. An important aspect ofS. aureuspathogenicity is the ability to acquire iron from its host during infection. In vertebrates, iron is sequestered predominantly within heme, the majority of which is bound by hemoglobin. To acquire iron,S. aureusbinds hemoglobin, removes heme, and transports it into the cytoplasm, where heme is degraded. This process is carried out by the iron-regulated surface determinant system (Isd); however, the mechanism by which hemoglobin recognition occurs is not completely understood. Here we report that the surface receptor components of the Isd system, IsdA and IsdB, physically interact with each other and are anchored to a discrete location within the cell wall. This organized localization pattern is dependent upon the iron status of the bacterium. Furthermore, we have found that hemoglobin colocalizes with IsdB at discrete sites within the cell wall. Virulence studies revealed that IsdB is required for the efficient colonization of the heart and that IsdB is differentially expressed within infected organs, suggesting thatS. aureusexperiences various degrees of iron starvation depending on the site of infection. These findings significantly expand our understanding of hemoglobin iron acquisition and demonstrate an orchestrated pattern of regulation and localization for theS. aureusheme iron acquisition system.
A multivariate stock–recruitment function for cohorts with sympatric subclasses: application to maternal effects in rockfish (genus Sebastes)
Authors: Lucero Yasmin
Published: April 2009

I present a multivariate stock–recruitment function (MSRF) for calculating recruitment when a cohort comprises sympatric subclasses. Sympatric subclasses emerge when there are closely interacting subgroups occupying a very similar niche, but whose ecology dictates distinct mortality rates. Examples include multispecies complexes of juvenile rockfish ( Sebastes spp.) in the California current and juvenile salmon ( Oncorhynchus spp.) in streams following different life history strategies. I derive an MSRF and apply it to the ecology of larval and juvenile rockfish with maternal effects. In several species of rockfish, older mothers produce superior larvae. This is called a maternal effect. For these species, larval and juvenile cohorts comprise several sympatric subclasses, each with a distinct mortality rate related to the age of their mothers. I apply this model to data for black rockfish ( Sebastes melanops ) in California and Oregon and find the recruitment estimates based on data from a declining population may overestimate productivity of a recovering population if maternal effects are neglected. The MSRF proves to be a flexible framework for studying recruitment in the presence of sympatric subclasses.
Elemental signatures in otoliths of hatchery rainbow trout (Oncorhynchus mykiss): distinctiveness and utility for detecting origins and movement
Authors: Gibson-Reinemer Daniel K. , Johnson Brett M. , Martinez Patrick J. , Winkelman Dana L. , Koenig Alan E. , Woodhead Jon D.
Published: April 2009

Otolith chemistry in freshwater has considerable potential to reveal patterns of origin and movement, which would benefit traditional fisheries management and provide a valuable tool to curb the spread of invasive and illicitly stocked species. We evaluated the relationship between otolith and water chemistry for five markers (Ba/Ca, Mn/Ca, Sr/Ca, Zn/Ca, and 87Sr/86Sr) in rainbow trout ( Oncorhynchus mykiss ) using the existing hatchery system in Colorado and Wyoming, USA, to provide controlled, seminatural conditions. Otolith Ba/Ca, Sr/Ca, and 87Sr/86Sr reflected ambient levels, whereas Mn/Ca and Zn/Ca did not. Using only the markers correlated with water chemistry, we classified fish to their hatchery of origin with up to 96% accuracy when element and isotope data were used together. Large changes in 87Sr/86Sr were evident in otolith transects, although subtler changes in Sr/Ca were also detectable. Our results suggest the relatively few otolith markers that reflect ambient chemistry can discriminate among locations and track movements well enough to provide valuable insight in a variety of applied contexts.
Development of a new field-based approach for estimating consumption rates of fishes and comparison with a bioenergetics model for lingcod (Ophiodon elongatus)
Authors: Beaudreau Anne H. , Essington Timothy E.
Published: April 2009

Development of quantitative tools to characterize the nature of predator–prey interactions is an essential component of the science supporting ecosystem-based management and conservation. A common constraint is our capacity to estimate the feeding rates of fishes at the temporal and spatial scales at which predation occurs. This study developed a new field-based modeling approach for estimating consumption rates of large predatory fishes that requires fewer assumptions and may be more flexible than other field-based methods. We compared the field-based model results with consumption estimates from a bioenergetics model for lingcod ( Ophiodon elongatus ), a top predator in nearshore rocky habitats along the west coast of North America. The models were used to determine population-level consumption of rockfishes ( Sebastes spp.) by lingcod in marine reserves and nonreserve areas in the San Juan Channel, Washington, USA. Based on these models, rockfish consumption by lingcod may have been 5–10 times greater in marine reserves than in nonreserves during fall and summer, 2005–2007. Understanding whether lingcod predation may limit the efficacy of marine reserves for rockfish recovery requires site-specific information on the abundance and size structure of lingcod and rockfishes.
Diffusion of American lobster (Homarus americanus) in Northumberland Strait, Canada
Authors: den Heyer Cornelia Elizabeth , Chadwick E. Michael P. , Hutchings Jeffrey A.
Published: April 2009

We tested the hypothesis that American lobster ( Homarus americanus ) movement can be described as diffusion. In 2001 and 2002, 3689 lobsters, captured by experimental trap and trawl surveys, were tagged and released in Northumberland Strait, Canada. Recaptures (n = 413) were reported by roughly 200 commercial fishermen, up to 3 years after release. Only six lobsters, all females, were recaptured more than once. Recapture rates were marginally higher for males (male 12%, female 10%) and varied with area of release (range: 5%–12%) and the fishing gear used for tagging (trap 12%, trawl 11%). Maximum and mean displacements between release and recapture were 58.3 and 12.3 km, respectively. The positive linear correlation between mean square displacement (MSD) and time between release and recapture provides evidence for diffusion. We calculate a diffusion coefficient (D) of 13 km2·week–1; there was no difference in D between sexes. A power analysis showed that MSD is underestimated at small sample sizes. There were insufficient data to test for differences in D associated with sexual maturity or shell hardness at time of release. During the summer in Northumberland Strait, the lobster population spreads about 20 km. The demographic consequences of seasonal diffusion of lobster warrant study.
Detecting declines in the abundance of a bull trout (Salvelinus confluentus) population: understanding the accuracy, precision, and costs of our efforts
Authors: Al-Chokhachy Robert , Budy Phaedra , Conner Mary
Published: April 2009

Using empirical field data for bull trout ( Salvelinus confluentus ), we evaluated the trade-off between power and sampling effort–cost using Monte Carlo simulations of commonly collected mark–recapture–resight and count data, and we estimated the power to detect changes in abundance across different time intervals. We also evaluated the effects of monitoring different components of a population and stratification methods on the precision of each method. Our results illustrate substantial variability in the relative precision, cost, and information gained from each approach. While grouping estimates by age or stage class substantially increased the precision of estimates, spatial stratification of sampling units resulted in limited increases in precision. Although mark–resight methods allowed for estimates of abundance versus indices of abundance, our results suggest snorkel surveys may be a more affordable monitoring approach across large spatial scales. Detecting a 25% decline in abundance after 5 years was not possible, regardless of technique (power = 0.80), without high sampling effort (48% of study site). Detecting a 25% decline was possible after 15 years, but still required high sampling efforts. Our results suggest detecting moderate changes in abundance of freshwater salmonids requires considerable resource and temporal commitments and highlight the difficulties of using abundance measures for monitoring bull trout populations.