bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oritavancin Population Pharmacokinetics in Healthy Subjects and Patients with Complicated Skin and Skin Structure Infections or Bacteremia
Authors: Rubino Christopher M. , Van Wart Scott A. , Bhavnani Sujata M. , Ambrose Paul G. , McCollam Jill S. , Forrest Alan 
Published: July 2009

ABSTRACT

Oritavancin is a novel glycopeptide antimicrobial agent with potent in vitro activity against a wide variety of gram-positive bacteria, including multidrug-resistant strains of staphylococci and enterococci. A population pharmacokinetic model was developed to describe the disposition of oritavancin with data from a pooled population of phase 1 healthy subjects and phase 2 and 3 patients with complicated skin and skin structure infections or
Staphylococcus aureus
bacteremia. In addition, the potential influence of factors such as the subject's age, gender, and clinical laboratory measures on oritavancin disposition was evaluated. Oritavancin was administered as both single- and multiple-dose intravenous (i.v.) infusions in fixed doses ranging from 100 to 800 mg or weight-based doses ranging from 0.02 to 10 mg/kg of body weight, with infusion durations ranging from 0.13 to 6.5 h across all studies. The most robust fit to the data (
n
= 6,290 oritavancin plasma concentrations from 560 subjects) was obtained using a three-compartment model with zero-order i.v. infusion and first-order elimination. The model was parameterized using total clearance (CL), volume of central compartment (Vc), distributional clearances from the central to both the first and second peripheral compartments, and volumes of distribution for both the first and second peripheral compartments. Weight and study phase (phase 1 versus phase 2/3) were identified as significant predictors of the interindividual variability in CL, while body surface area and age were significant for Vc. These results suggest that dose modification may be warranted in patients weighing >110 kg. However, the mild nature of the observed relationships for Vc suggest that dosing adjustments are not necessary for elderly patients.
In Vitro 24-Hour Time-Kill Studies of Vancomycin and Linezolid in Combination versus Methicillin-Resistant
Staphylococcus aureus
Authors: Singh Shveta Rani , Bacon Alfred E. , Young David C. , Couch Kimberly A. 
Published: July 2009

ABSTRACT

Many clinicians are trying unique strategies, including vancomycin and linezolid in combination, for treatment of patients who do not respond to conventional therapy against methicillin (meticillin)-resistant
Staphylococcus aureus
. In our study, which illustrated in vitro activity only, no synergistic activity was seen when the two agents were combined. Conversely, antagonistic activity occurred in three of five strains when linezolid was added to vancomycin. Our results indicate that vancomycin and linezolid in combination should be avoided.
Evaluation of Vancomycin and Daptomycin Potency Trends (MIC Creep) against Methicillin-Resistant
Staphylococcus aureus
Isolates Collected in Nine U.S. Medical Centers from 2002 to 2006
Authors: Sader Helio S. , Fey Paul D. , Fish Douglas N. , Limaye Ajit P. , Pankey George , Rahal James , Rybak Michael J. , Snydman David R. , Steed Lisa L. , Waites Ken , Jones Ronald N. 
Published: July 2009

ABSTRACT

Vancomycin MIC creep has been reported by some institutions but not confirmed in large surveillance studies. We evaluated the possible occurrence of MIC creep when testing vancomycin and daptomycin against methicillin (oxacillin)-resistant
Staphylococcus aureus
(MRSA) by using precise incremental reference MIC methods. Nine hospitals (one in each U.S. census region) randomly selected bloodstream MRSA strains (target, 40/year) from 2002 to 2006. MICs were determined by the reference broth microdilution method using incremental dilutions (eight for each log
2
dilution step). Isolates for which vancomycin MICs were >1 μg/ml were typed by pulsed-field gel electrophoresis (PFGE). The vancomycin MIC mode was either 0.625 μg/ml (for eight hospitals) or 0.813 μg/ml (for one hospital), and vancomycin MIC results for 72.9% of strains were between 0.563 and 0.688 μg/ml. No yearly variation in the central tendency of vancomycin MICs for the wild-type population in any medical center was observed; however, when data were analyzed by the geometric mean statistic, vancomycin MIC increases (at three sites) and declines (at three sites) were observed. The daptomycin MIC mode varied from 0.156 μg/ml (2003 to 2005) to 0.219 μg/ml (2002 and 2006), and MIC results for 83.5% (80.3 to 89.2% in each of the centers) of isolates fell between these values. Among PFGE-typed strains, 43 of 55 (78%; from seven hospitals) showed a pattern consistent with that of the USA100 clone, which was represented by all strains from two hospitals and 64 to 88% of strains from five other medical centers; only one strain (2%) was USA300. In conclusion, the perception of MIC creep may vary according to the methods used to analyze the data. Geometric mean MIC data revealed a possible, very-low-level MIC creep at three of nine sites over the 5-year period, which was not evident using modal MICs or the data from all nine hospitals (+0.02 μg/ml). The occurrence of isolates for which the vancomycin MIC was >1 μg/ml was very unusual, with no increased trend, but these organisms were usually clonal (USA100).
In Vitro Antiviral Activity of V-073 against Polioviruses
Authors: Oberste M. Steven , Moore Deborah , Anderson Barbara , Pallansch Mark A. , Pevear Daniel C. , Collett Marc S. 
Published: July 2009

ABSTRACT

V-073, an enterovirus capsid inhibitor, was evaluated for its spectrum of antipoliovirus activity. V-073 inhibited all 45 polioviruses tested in a virus-induced cytopathic effect protection assay, with 50% effective concentration (EC
50
) values ranging from 0.003 to 0.126 μM. Ninety percent of the polioviruses tested were inhibited at EC
50
s of ≤0.076 μM (MIC
90
= 32 ng/ml). V-073 is a promising antiviral candidate for the posteradication management of poliovirus incidents.
Impact of Low-Level Resistance to Fluoroquinolones Due to
qnrA1
and
qnrS1
Genes or a
gyrA
Mutation on Ciprofloxacin Bactericidal Activity in a Murine Model of
Escherichia coli
Urinary Tract Infection
Authors: Allou Nicolas , Cambau Emmanuelle , Massias Laurent , Chau Françoise , Fantin Bruno 
Published: July 2009

ABSTRACT

We investigated the impact of low-level resistance to fluoroquinolones on the bactericidal activity of ciprofloxacin in a murine model of urinary tract infection. The susceptible
Escherichia coli
strain CFT073 (ciprofloxacin MIC [CIP MIC] of 0.008 μg/ml) was compared to its transconjugants harboring
qnrA1
or
qnrS1
and to an S83L
gyrA
mutant. The three derivatives showed similar low-level resistance to fluoroquinolones (CIP MICs, 0.25 to 0.5 μg/ml). Bactericidal activity measured in vitro after 1, 3, and 6 h of exposure to 0.5 μg/ml of ciprofloxacin was significantly lower for the derivative strains (
P
< 0.01). In the murine model of urinary tract infection (at least 45 mice inoculated per strain), mice were treated with a ciprofloxacin regimen of 2.5 mg/kg, given subcutaneously twice daily for 2 days. In mice infected with the susceptible strain, ciprofloxacin significantly decreased viable bacterial counts (log
10
CFU/g of tissue) in the bladder (4.2 ± 0.5 versus 5.5 ± 1.3;
P
= 0.001) and in the kidney (3.6 ± 0.8 versus 5.0 ± 1.1;
P
= 0.003) compared with those of untreated mice. In contrast, no significant decrease in viable bacterial counts was observed with any of the three derivative strains. The area under the concentration-time curve from 0 to 24 h/MIC and the maximum concentration of drug in serum/MIC ratios measured in plasma were indeed equal to 827 and 147, respectively, for the parental strain, and only 12.4 to 24.8 and 2.2 to 4.4, respectively, for the derivative strains. In conclusion, low-level resistance to fluoroquinolones conferred by a
qnr
gene is associated with decreased bactericidal activity of ciprofloxacin, similar to that obtained with a
gyrA
mutation.
Actin Dynamics and Rho GTPases Regulate the Size and Formation of Parasitophorous Vacuoles Containing
Coxiella burnetii
Authors: Aguilera Milton , Salinas Romina , Rosales Eliana , Carminati Sergio , Colombo Maria I. , Berón Walter 
Published: July 2009

ABSTRACT

Q fever is a disease caused by
Coxiella burnetii
. In the host cell, this pathogen generates a large parasitophorous vacuole (PV) with lysosomal characteristics. Here we show that F-actin not only is recruited to but also is involved in the formation of the typical PV. Treatment of infected cells with F-actin-depolymerizing agents alters PV development. The small PVs formed in latrunculin B-treated cells were loaded with transferrin and Lysotracker and labeled with an antibody against cathepsin D, suggesting that latrunculin B did not affect vacuole cargo and its lysosomal characteristics. Nevertheless, the vacuoles were unable to fuse with latex bead phagosomes. It is known that actin dynamics are regulated by the Rho family GTPases. To assess the role of these GTPases in PV formation, infected cells were transfected with pEGFP expressing wild-type and mutant Rac1, Cdc42, and RhoA proteins. Rac1 did not show significant PV association. In contrast, PVs were decorated by both the wild types and constitutively active mutants of Cdc42 and RhoA. This association was inhibited by treatment of infected cells with chloramphenicol, suggesting a role for bacterial protein synthesis in the recruitment of these proteins. Interestingly, a decrease in vacuole size was observed in cells expressing dominant-negative RhoA; however, these small vacuoles accumulated transferrin, Lysotracker, and DQ-BSA. In summary, these results suggest that actin, likely modulated by the GTPases RhoA and Cdc42 and by bacterial proteins, is involved in the formation of the typical PV.
Improved method for assessing iron stores in the bone marrow
Authors: Phiri K S , Calis J C J , Kachala D , Borgstein E , Waluza J , Bates I , Brabin B , van Hensbroek M Boele 
Published: July 2009

Background:Bone marrow iron microscopy has been the “gold standard” method of assessing iron deficiency. However, the commonly used method of grading marrow iron remains highly subjective.Aim:To improve the bone marrow grading method by developing a detailed protocol that assesses iron in fragments, in macrophages around fragments and in erythroblasts.Methods:A descriptive study of marrow aspirates of 303 children (aged 6–60 months) with severe anaemia and 22 controls (children undergoing elective surgery) was conducted at hospitals in southern Malawi (2002–04).Results:Using an intensive marrow iron grading method, 22% and 39% of cases and controls had deficient iron stores, and 40% and 46% had functional iron deficiency, respectively. Further evaluation of the iron status classification by the intensive method showed that functional iron deficiency was associated with significantly increased C-reactive protein concentrations (126.7 (85.6) mg/l), and iron stores deficiency with significantly increased soluble transferrin receptor concentrations (21.7 (12.5) μg/ml).Conclusions:Iron assessment can be greatly improved by a more intense marrow examination. This provides a useful iron status classification which is of particular importance in areas where there is a high rate of inflammatory conditions.
Appropriateness of antineutrophil cytoplasmic antibody testing in a tertiary hospital
Authors: Robinson P C , Steele R H 
Published: July 2009

Aims:To determine whether indications for ordering antineutrophil cytoplasmic antibodies (ANCA) meet the 1999 guidelines proposed for ANCA testing; and to examine the test characteristics of the ANCA test.Methods:The indications for all ANCA tests over a two-year period were assessed and compared to the 1999 guidelines for the appropriate testing of ANCA.Results:1127 tests were examined. Overall 33.4% had an indication meeting the 1999 guidelines. The commonest non-guideline indications were ocular or orbital inflammation, liver disease and inflammatory bowel disease. All tests with a positive ANCA had indications for testing in line with the 1999 guidelines. In all but one case an ANCA associated small vessel vasculitis (AASVV) was present.Conclusions:ANCA is ordered for a wide range of guideline and non-guideline indications. No cases of AASVV would have been missed if ordering were restricted to tests meeting the 1999 guidelines.
MGMT methylation in diffuse large B-cell lymphoma: validation of quantitative methylation-specific PCR and comparison with MGMT protein expression
Authors: Uccella S , Cerutti R , Placidi C , Marchet S , Carnevali I , Bernasconi B , Proserpio I , Pinotti G , Tibiletti M G , Furlan D , Capella C 
Published: July 2009

Aims:(1) To validate a quantitative real time methylation specific PCR assay (MethyLight) for the detection of O6-methylguanine-DNA methyltransferase (MGMT) gene methylation status (MS) in diffuse large B-cell lymphoma (DLBCL). (2) To determine the immunohistochemical (IHC) expression of the MGMT protein and correlate it with MS. Both IHC and MethyLight results were compared with patient’s outcome.Methods:71 patients with primary nodal DLBCL were studied. MGMT immunoreactivity was detected using a specific monoclonal antibody. The MS of MGMT gene was analysed in 52/71 DLBCL using MethyLight. A selected subset of 40 DLBCL was also analysed using qualitative methylation-specific PCR (MSP). Statistical analysis of overall survival (OS), lymphoma-specific survival (LSS) and progression free survival (PFS) was performed according to IHC and MS results.Results:19/71 DLBCLs (27%) were MGMT-negative at IHC; all were analysed, together with 33/52 MGMT-positive DLBCLs. MethyLight showed a better performance than MSP. There was a good correlation between the presence of MGMT expression and the unmethylated status; the absence of IHC expression was poorly correlated with the presence of methylation. Better OS, LSS and PFS was found in DLBCLs with MGMT gene methylation. DLBCLs not expressing MGMT at IHC showed a longer PFS.Conclusions:The quantitative real-time methylation-specific PCR assay for the detection of MGMT gene hypermethylation has been validated for the first time in DLBCL. Immunohistochemistry seems to represent an useful preliminary test to identify unmethylated cases; MS analysis may be performed in non-immunoreactive cases to identify truly methylated DLBCLs, which bear a better prognosis.
Immunophenotype of neoplastic plasma cells in AL amyloidosis
Authors: Deshmukh M , Elderfield K , Rahemtulla A , Naresh K N 
Published: July 2009

Aim:AL amyloidosis (ALA) is a form of plasma cell (PC) dyscrasia characterised by deposition of insoluble fibrillar deposits in various organs causing organ damage. This is believed to be the first study to evaluate the expression of CD79a, CD20, CD56, cyclin D1 and epithelial membrane antigen (EMA) in neoplastic PCs of ALA.Methods and Results:The study included 36 well-documented cases of ALA. In all cases presence of amyloid deposits had been documented by Congo Red stain in the bone marrow trephine biopsy (BMTB) and/or in other tissues. BMTBs showed varying degrees of PC infiltration (median 12%). In eight of the 36 cases with associated myeloma, the mean (2×SE) percentage of PCs (PC%) was 34 (18)%, while in the remaining, PC% was 15 (4)%. Expression of CD20, CD79a, CD56, cyclin D1 and EMA was noted in 42%, 86%, 50%, 53% and 83% of cases, respectively. Aberrant antigen expression in the form of CD56 and/or cyclin D1 expression was seen in 79% of cases. Nine of 10 cases with small lymphoid-like PCs were positive for CD20 and all the 10 cases were positive for cyclin D1. On the other hand, among cases without small lymphoid-like morphology, CD20 and cyclin D1 expression was seen in only 6 of 26 and 8 of 26 cases respectively (p = 0.001 and 0.002 respectively). CD20 expression correlated with cyclin D1 expression (p = 0.045). Cytological atypia/pleomorphism was predictive of associated myeloma (p = <0.001).Conclusion:Marrow involvement by neoplastic PCs in ALA can be identified by their aberrant antigen expression apart from light chain restriction, and rituximab as a possible treatment option may be explored in CD20-positive ALA.
Cyclo-oxygenase-2 overexpression is a feature of early and well-differentiated hepatocellular carcinoma with a favourable prognosis
Authors: Schmitz K J , Wohlschlaeger J , Lang H , Sotiropoulos G C , Kaiser G M , Schmid K W , Baba H A 
Published: July 2009

Aims:To determine the prognostic relevance of cyclo-oxygenase-2 (COX-2) expression in hepatocellular carcinoma (HCC) and its relationship to important clinicopathological parameters.Methods:A series of 196 patients with HCCs treated either by surgical resection (n = 106) or liver transplantation (n = 90) was investigated. Immunohistochemically confirmed COX-2 expression was correlated with a series of clinicopathologically relevant parameters as well as proliferative activity and apoptosis.Results:Overexpression of COX-2 correlated statistically with high histological tumour differentiation (p<0.001) and early TNM stage (p = 0.003). COX-2 overexpression was associated with lower apoptotic rates (p = 0.001), whereas proliferation activity did not differ significantly. In addition, COX-2 overexpression showed a significant correlation with favourable overall survival (p<0.001). In multivariate survival analysis, COX-2 expression qualified as an independent prognostic parameter (p = 0.030).Conclusions:Overexpression of COX-2 in HCC indicates early-stage cancer with less aggressive tumour behaviour and constitutes an independent prognostic factor.
Empirical Performance of the Constant Elasticity Variance Option Pricing Model
Authors: Chen Ren-Raw , Lee Cheng-Few , Lee Han-Hsing 
Published: July 2009

In this essay, we empirically test the Constant–Elasticity-of-Variance (CEV) option pricing model by Cox (1975, 1996 ) and Cox and Ross (1976), and compare the performances of the CEV and alternative option pricing models, mainly the stochastic volatility model, in terms of European option pricing and cost-accuracy based analysis of their numerical procedures. In European-style option pricing, we have tested the empirical pricing performance of the CEV model and compared the results with those by Bakshi et al. (1997). The CEV model, introducing only one more parameter compared with Black-Scholes formula, improves the performance notably in all of the tests of in-sample, out-of-sample and the stability of implied volatility. Furthermore, with a much simpler model, the CEV model can still perform better than the stochastic volatility model in short term and out-of-the-money categories. When applied to American option pricing, high-dimensional lattice models are prohibitively expensive. Our numerical experiments clearly show that the CEV model performs much better in terms of the speed of convergence to its closed form solution, while the implementation cost of the stochastic volatility model is too high and practically infeasible for empirical work. In summary, with a much less implementation cost and faster computational speed, the CEV option pricing model could be a better candidate than more complex option pricing models, especially when one wants to apply the CEV process for pricing more complicated path-dependent options or credit risk models.
Directable, high-resolution simulation of fire on the GPU
Authors: Horvath Christopher , Geiger Willi 
Published: July 2009

The simulation of believable, photorealistic fire is difficult because fire is highly detailed, fast-moving, and turbulent. Traditional gridbased simulation models require large grids and long simulation times to capture even the coarsest levels of detail. In this paper, we propose a novel combination of coarse particle grid simulation with very fine, view-oriented refinement simulations performed on a GPU. We also propose a simple, GPU-based volume rendering scheme. The resulting images of fire produced by the proposed techniques are extremely detailed and can be integrated seamlessly into film-resolution images.Our refinement technique takes advantage of perceptive limitations and likely viewing behavior to split the refinement stage into separable, parallel tasks. Multiple independent GPUs are employed to rapidly refine final simulations for rendering, allowing for rapid artist turnaround time and very high resolutions.Directability is achieved by allowing virtually any user-defined particle behavior as an input to the initial coarse simulation. The physical criteria enforced by the coarse stage are minimal and could be easily implemented using any of the wide variety of commercially available fluid simulation tools. The GPU techniques utilized by our refinement stage are simple and widely available on even consumer-grade GPUs, lowering the overall implementation cost of the proposed system.
SlackSim
Authors: Chen Jianwei , Annavaram Murali , Dubois Michel 
Published: July 2009

The fast simulation of chip multiprocessors (CMPs) presents a critical challenge to the architecture research community as both industry and academia shift their research focus to multicore design. Parallel simulation is a technique to accelerate microarchitecture simulation of CMPs by exploiting the inherent parallelism of CMPs. In this paper, we explore the simulation paradigm of simulating each core of a target CMP in one thread and then spreading the threads across the hardware thread contexts of a host CMP. We implement several parallel simulation schemes using POSIX Threads (Pthreads). We start with cycle-by-cycle simulation and then relax the synchronization condition in various schemes, which we call slack simulations.
In slack simulations, the Pthreads simulating different simulated cores do not synchronize after each simulated cycle, but rather they are given some slack. The slack is the difference in cycle between the simulated times of any two target cores. Small slacks, such as a few cycles, greatly improve the efficiency of parallel CMP simulations, with no or negligible simulation error. We have developed a simulation framework called SlackSim to experiment with various slack simulation schemes. Unlike previous attempts to parallelize multiprocessor simulations on distributed memory machines, SlackSim takes advantage of the efficient sharing of data in the host CMP architecture.
We demonstrate the efficiency and accuracy of some well known slack simulation schemes and of some new ones on SlackSim running on a state-of-the-art CMP platform.
Real time power estimation and thread scheduling via performance counters
Authors: Singh Karan , Bhadauria Major , McKee Sally A. 
Published: July 2009

Estimating power consumption is critical for hardware and software developers, and of the latter, particularly for OS programmers writing process schedulers. However, obtaining processor and system power consumption information can be non-trivial. Simulators are time consuming and prone to error. Power meters report whole-system consumption, but cannot give per-processor or per-thread information. More intrusive hardware instrumentation is possible, but such solutions are usually employed while designing the system, and are not meant for customer use.
Given these difficulties, plus the current availability of some form of performance counters on virtually all platforms (even though such counters were initially designed for system bring-up, and not intended for general programmer consumption), we analytically derive functions for real-time estimation of processor and system power consumption using performance counter data on real hardware. Our model uses data gathered from microbenchmarks that capture potential application behavior. The model is independent of our test benchmarks, and thus we expect it to be well suited for future applications. We target chip multiprocessors, analyzing effects of shared resources and temperature on power estimation, leveraging our model to implement a simple, power-aware thread scheduler. The NAS and SPEC-OMP benchmarks shows a median error of 5.8% and 3.9%, respectively. SPEC 2006 shows a marginally higher median error of 7.2%.