bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of ciclosporin A, tacrolimus and sirolimus on cytokine production in neonatal immune cells
Authors: Puzik Alexander , Schultz Christian , Iblher Peter , Müller‐Steinhardt Michael , Härtel Christoph 
Published: September 2007

AbstractBackground: It was the aim of this study to evaluate the effects of the well‐known immunosuppressive drugs ciclosporin A (CsA), tacrolimus and sirolimus on the intracytoplasmic cytokine expression of neonatal immune cells.Methods: Immunosuppressive drugs were added to whole blood cultures of neonatal cord blood samples (n = 17) and peripheral blood samples of adults (n = 17) in vitro prior to stimulation of lymphocytes with phorbol 12‐myristate 13‐acetate (PMA)/ionomycin or monocytes.Results: Upon exposure to ciclosporin A (500 ng/mL) or tacrolimus (25 ng/mL) the number of cytokine expressing T cells was almost completely blocked in neonatal T cells while sirolimus (10 ng/mL) only inhibited intracytoplasmatic tumour necrosis factor alpha (TNF‐α) expression (mean% positive cells; 4.0 ± 2.1% vs. 1.09 ± 0.6%, p = 0.003), but mildly stimulated the intracellular expression of interleukin (IL)‐2 (24.4 ± 6.5% vs. 28.1 ± 7.1%, p = 0.041). In cord blood lymphocytes, the inhibitory effect of ciclosporin A and tacrolimus was dose‐dependent (e.g. IL‐2: control, 12.3 ± 5.33%, ciclosporin A 5 ng/mL, 10.1 ± 5.5%; 50 ng/mL, 7.1 ± 4.7%; 500 ng/mL, 1.2 ± 0.3%; tacrolimus 0.25 ng/mL, 9.3 ± 4.9%; 2.5 ng/mL, 6.1 ± 3.3%; 25 ng/mL, 1.0 ± 0.6%), while the function of adult lymphocytes was only impaired at high doses of both compounds. In contrast, the number of cytokine expressing monocytes was not influenced by ciclosporin A and tacrolimus except for a minor decrease of TNF‐α producing neonatal monocytes after addition of tacrolimus (17.9% vs. 13.9%, p = 0.031). Interestingly, sirolimus was shown to inhibit intracellular IL‐6 production in adults (63.1 ± 12.7% vs. 52.0 ± 16.0%, p = 0.005), but in neonatal monocytes intracellular IL‐6 expression was stimulated (53.5 ± 22.0% vs. 64.7 ± 19.1%, p = 0.041).Conclusions: The potent dose‐dependent inhibitory effect of ciclosporin A and tacrolimus in cord blood lymphocytes provides the basis for further studies on functional immaturity of the neonatal immune system and for future strategies to optimize umbilical cord blood transplantion. Sirolimus was demonstrated to have a distinct effect on neonatal immune cells as shown by increased expression of IL‐2 in lymphocytes and IL‐6 in monocytes, while only lymphocytic TNF‐α expression was inhibited.
UNITED STATES V. BOOKER AS A NATURAL EXPERIMENT: USING EMPIRICAL RESEARCH TO INFORM THE FEDERAL SENTENCING POLICY DEBATE*
Authors: HOFER PAUL J. 
Published: September 2007

Research Summary:In United States v. Booker, the U.S. Supreme Court held that the federal sentencing guidelines must be considered advisory, rather than mandatory, if they are to remain constitutional under the Sixth Amendment. Since the decision, the U.S. Sentencing Commission has provided policy makers with accurate and current data on changes and continuity in federal sentencing practices. Unlike previous changes in legal doctrine, Booker immediately increased the rates of upward and downward departures from the guideline range. Government‐sponsored downward departures remain the leading category of outside–the‐range sentences. The rate of within‐range sentences, although lower than in the period immediately preceding Booker, remains near rates observed earlier in the guidelines era. Despite the increase in departures, average sentence lengths for the overall caseload remain stable, because of offsetting increases in the seriousness of the crimes being sentenced and in the severity of penalties for those crimes. Analyses of the reasons that judges reported for downward departures suggest that treatment of criminal history and offender characteristics are the two leading areas of dissatisfaction with the guidelines.Policy Implications:Assessment of changes in sentencing practices following Booker by different observers depends partly on competing institutional perspectives and on different degrees of trust in the judgment of judges, prosecutors, the Sentencing Commission, and Congress. No agreement on whether Booker has bettered or worsened the system can be achieved until agreement exists on priorities among the purposes of sentencing and the goals of sentencing reform. Both this lack of agreement and an absence of needed data make consensus on Booker's effects on important sentencing goals, such as reduction of unwarranted disparity, unlikely in the near future. Similarly, lack of baseline data before Booker on the effectiveness of federal sentencing at crime control makes before‐after comparisons impossible. Despite these limitations, research provides a sounder framework for policy making than do anecdotes or speculation and sets valuable empirical parameters for the federal sentencing policy debate.
UNDERSTANDING SEXUAL VICTIMIZATION INSIDE PRISONS: FACTORS THAT PREDICT RISK*
Authors: WOLFF NANCY , SHI JING , BLITZ CYNTHIA L. , SIEGEL JANE 
Published: September 2007

Research Summary:Broad consensus exists across the country and political spectrum that sexual victimization occurs inside prisons and that it should be prevented in accordance with basic human rights, especially inside institutions that are funded and operated by government. The challenging task is to confirm the speculation by measuring reliably the extent to which sexual victimization occurs inside prison and then to understand its causal structure in an effort to prevent it. This article addresses this challenge first by summarizing what is known about the prevalence of sexual victimization in the prisons of America and then by exploring attributes of the inmate or facility that elevate the likelihood of being sexually victimized while inside prison. This descriptive evidence provides the roadmap for more contextual research that is needed to explore the causal mechanism underlying sexual victimization. The predictive part of this article uses a data set on the self‐reported victimization experiences of approximately 8,000 inmates residing in twelve male adult prisons, one sex offender treatment prison for males, and one female adult prison, all located in a single state.Policy Implications:If the goal is to reduce sexual victimization inside prisons (as suggested by the Prison Rape Elimination Act), action is required by prison officials and researchers to identify those at elevated risk, to develop effective placement strategies that minimize the proximity of inmates who have predatory tendencies to those at risk of victimization, to accurately and reliably measure the prevalence of sexual victimization, and to train officers and inmates on the meaning and practice of “zero tolerance.” Custodial power should be targeted to ensure zero tolerance because sexual victimization inside prison is not just a crime, but it is also a crime that takes place in a facility that is created, funded, and operated by the state and where the state bears the full responsibility for keeping the people under its aegis from harm that is predictable and preventable.
Pharmacokinetics-Pharmacodynamics of Gatifloxacin in a Lethal Murine
Bacillus anthracis
Inhalation Infection Model
Authors: Ambrose Paul G. , Forrest Alan , Craig William A. , Rubino Chistopher M. , Bhavnani Sujata M. , Drusano George L. , Heine Henry S. 
Published: September 2007

ABSTRACT

We determined the pharmacokinetic-pharmacodynamic (PK-PD) measure most predictive of gatifloxacin efficacy and the magnitude of this measure necessary for survival in a murine
Bacillus anthracis
inhalation infection model. We then used population pharmacokinetic models for gatifloxacin and simulation to identify dosing regimens with high probabilities of attaining exposures likely to be efficacious in adults and children. In this work, 6- to 8-week-old nonneutropenic female BALB/c mice received aerosol challenges of 50 to 75 50% lethal doses of
B. anthracis
(Ames strain, for which the gatifloxacin MIC is 0.125 mg/liter). Gatifloxacin was administered at 6- or 8-h intervals beginning 24 h postchallenge for 21 days, and dosing was designed to produce profiles mimicking fractionated concentration-time profiles for humans. Mice were evaluated daily for survival. Hill-type models were fitted to survival data. To identify potentially effective dosing regimens, adult and pediatric population pharmacokinetic models for gatifloxacin and Monte Carlo simulation were used to generate 5,000 individual patient exposure estimates. The ratio of the area under the concentration-time curve from 0 to 24 h (AUC
0-24
) to the MIC of the drug for the organism (AUC
0-24
/MIC ratio) was the PK-PD measure most predictive of survival (
R
2
= 0.96). The 50% effective dose (ED
50
) and the ED
90
and ED
99
corresponded to AUC
0-24
/MIC ratios of 11.5, 15.8, and 30, respectively, where the maximum effect was 97% survival. Simulation results indicate that a daily gatifloxacin dose of 400 mg for adults and 10 mg/kg of body weight for children gives a 100% probability of attaining the PK-PD target (ED
99
). Sensitivity analyses suggest that the probability of PK-PD target attainment in adults and children is not affected by increases in MICs for strains of
B. anthracis
to levels as high as 0.5 mg/liter.
Biochemical Characterization of SFC-1, a Class A Carbapenem-Hydrolyzing β-Lactamase
Authors: Fonseca Fátima , Sarmento Ana Cristina , Henriques Isabel , Samyn Bart , van Beeumen Jozef , Domingues Pedro , Domingues Maria Rosário , Saavedra Maria José , Correia António 
Published: September 2007

ABSTRACT

The carbapenem-hydrolyzing β-lactamase SFC-1 from
Serratia fonticola
UTAD54 was overexpressed in
Escherichia coli
, purified, and characterized. The enzyme exhibited an apparent molecular mass of 30.5 kDa, determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. SFC-1 hydrolyzes penicillins, cephalosporins, aztreonam, and carbapenems and is inhibited by clavulanic acid, sulbactam, and tazobactam.
Pharmacodynamics of Doxycycline in a Murine Malaria Model
Authors: Batty Kevin T. , Law Angela S. F. , Stirling Verity , Moore Brioni R. 
Published: September 2007

ABSTRACT
Doxycycline is reported to impair second-generation parasite schizogony. The effects of doxycycline alone and combined with dihydroartemisinin were investigated in a murine malaria model. Doxycycline lowered the rate of parasite growth within 2 days, with maximum effect in 6 days. Addition of dihydroartemisinin led to an additive antimalarial effect.
Antistaphylococcal Activity of CG400549, a New Experimental FabI Inhibitor, Compared with That of Other Agents
Authors: Bogdanovich Tatiana , Clark Catherine , Kosowska-Shick Klaudia , Dewasse Bonifacio , McGhee Pamela , Appelbaum Peter C. 
Published: September 2007

ABSTRACT

Among 203 strains of
Staphylococcus aureus
, the MICs of CG400549 were 0.06 to 1.0 μg/ml, with MIC
50
and MIC
90
values of 0.25 μg/ml each. All strains were susceptible to linezolid and quinupristin-dalfopristin (MICs, 0.25 to 2.0 μg/ml). The daptomycin MICs were 0.25 to 2.0 μg/ml for methicillin-susceptible and 0.25 to 4.0 μg/ml against methicillin-resistant strains (including vancomycin-intermediate strains). Single-passage selection testing showed low resistance frequencies with CG400549, but multistep analysis showed that CG400549 yielded resistant mutants after 14 to 17 days in all strains tested.
Pharmacokinetics of Telbivudine in Subjects with Various Degrees of Renal Impairment
Authors: Zhou Xiao-Jian , Swan Suzanne , Smith William B. , Marbury Thomas C. , Dubuc-Patrick Gloria , Chao George C. , Brown Nathaniel A. 
Published: September 2007

ABSTRACT

This study evaluates the effect of renal impairment on the pharmacokinetics of telbivudine. Thirty-six subjects were assigned, on the basis of creatinine clearance (CL
CR
), to 1 of 5 renal function groups with 6 to 8 subjects per group: normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease [ESRD] requiring hemodialysis. Subjects received a single oral dose of telbivudine at 600 mg (normal function and mild impairment), 400 mg (moderate impairment), or 200 mg (severe impairment and ESRD); plasma and/or urine samples were collected over a 48-h period for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. The pharmacokinetics of 600 mg of telbivudine were comparable for subjects with mild renal impairment and normal renal function. Likewise, for subjects with moderate to severe impairment, including ESRD, reduced doses from 200 to 400 mg produced plasma exposure similar to that for subjects with normal renal function. These results indicate that the pharmacokinetics of telbivudine were dependent on renal function, especially for subjects with moderate to severe renal impairment or ESRD. Apparent total plasma clearance, renal clearance (CL
R
), and urinary excretion of telbivudine decreased as renal function deteriorated. A linear relationship was established between CL
R
and CL
CR
. In ESRD subjects, a routine 3.5- to 4-h hemodialysis session removed telbivudine from plasma at an extraction ratio of ∼45%, representing a ∼23% reduction in total exposure. These results suggest that while no adjustment of the telbivudine dose appears necessary for subjects with mild renal impairment, dose adjustment is warranted for those with moderate to severe renal impairment or ESRD in order to achieve optimal plasma exposure.
In Vitro Efficacy of New Antifolates against Trimethoprim-Resistant
Bacillus anthracis
Authors: Barrow Esther W. , Dreier Jürg , Reinelt Stefan , Bourne Philip C. , Barrow William W. 
Published: September 2007

ABSTRACT

Bacillus anthracis
is innately resistant to trimethoprim (TMP), a synthetic antifolate that selectively inhibits several bacterial dihydrofolate reductases (DHFRs) but not human DHFR. Previously, we were able to confirm that TMP resistance in
B. anthracis
(MIC > 2,048 μg/ml) is due to the lack of selectivity of TMP for the
B. anthracis
DHFR (E. W. Barrow, P. C. Bourne, and W. W. Barrow, Antimicrob. Agents Chemother. 48:4643-4649, 2004). In this investigation, 24 2,4-diaminopyrimidine derivatives, representing a class of compounds with dihydrophthalazine side chains, were screened for their in vitro effects on
B. anthracis
Sterne and their selectivities for the
B. anthracis
DHFR. MICs were obtained by a colorimetric (Alamar blue) broth microdilution assay. Purified human recombinant DHFR (rDHFR) and
B. anthracis
rDHFR were used in a validated enzyme assay to determine the 50% inhibitory concentrations (IC
50
s) and the selectivity ratios of the derivatives. The MICs ranged from 12.8 to 128 μg/ml for all but nine compounds, for which the MICs were ≥128 μg/ml. The IC
50
values for
B. anthracis
rDHFR ranged from 46 to 600 nM, whereas the IC
50
values for human rDHFR were >16,000 nM. This is the first report on the in vitro inhibitory actions of this class of antifolates against TMP-resistant
B. anthracis
isolates. The selective inhibition of
B. anthracis
rDHFR and the in vitro activity against
B. anthracis
demonstrate that members of this class of compounds have the potential to be developed into clinically important therapeutic choices for the treatment of infections caused by TMP-resistant bacteria, such as
B. anthracis
.
Specific Intracellular Adhesion Molecule-Grabbing Nonintegrin R1 Is Not Involved in the Murine Antibody Response to Pneumococcal Polysaccharides
Authors: Moens Leen , Jeurissen Axel , Wuyts Greet , Fallon Padraic G. , Louis Boon , Ceuppens Jan L. , Bossuyt Xavier 
Published: September 2007

ABSTRACTStreptococcus pneumoniaeis a microorganism that frequently causes serious infections in children, the elderly, and immunocompromised patients. We studied whether the specific intracellular adhesion molecule-grabbing nonintegrin R1 (Sign-R1) receptor, involved in the uptake of capsular polysaccharides (caps-PS) by antigen-presenting cells, is necessary for the antibody response to pneumococcal caps-PS and phosphorylcholine (PC). The antibody response to caps-PS and PC was evaluated after vaccination with soluble caps-PS (Pneumovax) and after vaccination with heat-killedS. pneumoniae. The role of Sign-R1 was investigated by using Sign-R1 knockout mice and anti-Sign-R1 monoclonal antibodies. The immunoglobulin M (IgM) and IgG antibody response to PC and caps-PS (serotypes 3 and 14) was not affected by anti-Sign-R1 monoclonal antibodies. The IgM antibody response in Sign-R1 knockout mice was comparable to the antibody response in wild-type mice. The IgG antibody response to serotype 3, but not to serotype 14, tended to be lower in Sign-R1 knockout mice compared to wild-type mice. In conclusion, we found that Sign-R1 is not involved in the IgM antibody production to PC and caps-PS serotype 3 or 14 and the IgG immune response to PC and caps-PS serotype 14. There is no direct relation between capture and uptake of caps-PS serotype 14 by Sign-R1 and the initiation of the anti-caps-PS antibody production in mice.
Evaluation of Two Homologous Proline-Rich Proteins of
Coccidioides posadasii
as Candidate Vaccines against Coccidioidomycosis
Authors: Herr Roger A. , Hung Chiung-Yu , Cole Garry T. 
Published: September 2007

ABSTRACT

Evaluation of the protective efficacy of recombinant T-cell-reactive proteins of
Coccidioides posadasii
in a murine model of coccidioidomycosis has led to the discovery of potential vaccines against this respiratory disease. A recombinant proline-rich antigen (rAg2/Pra) has been reported to be a leading vaccine candidate. However, contradictory results exist on the protection afforded by this antigen. Subcutaneous vaccination of either C57BL/6 or BALB/c mice with rAg2/Pra plus adjuvant followed by intraperitoneal challenge with
C. posadasii
resulted in a significant reduction of the fungal burden at 12 to 14 days postchallenge compared to that in nonvaccinated animals. Use of the same vaccination protocol followed by intranasal (i.n.) challenge of C57BL/6 mice with an equal number of organisms culminated in chronic pulmonary infection or death over a 90-day period. Early studies of Ag2/Pra suggested that it is a component of an immunogenic complex. We reveal in this study that
C. posadasii
produces a homolog of the reported proline-rich antigen, designated Prp2, which shows 69% protein sequence identity and 86% similarity to Ag2/Pra. Protection against i.n. challenge of C57BL/6 mice was evaluated by vaccination with the single bacterially expressed homolog, rAg2/Pra, or rPrp2 in combination with rAg2/Pra, each in the presence of the same adjuvant. The combined vaccine provided significantly better protection than either of the single recombinant protein vaccines. Results of enzyme-linked immunospot assays of the immunized mice revealed that the two proline-rich homologs contain unique T-cell epitopes. In combination, the recombinant proteins stimulate a more heterogeneous and protective T-cell repertoire than the monovalent vaccines.
An Improved Data Flow Architecture for LogicSimulation Acceleration
Authors: Mahmood A. , Herath J. , Jayasumana J. 
Published: September 2007

The high degree of parallelism in the simulation of digital VLSI systems can be utilized by a data flow architecture
to reduce the enormous simulation times. The existing logic simulation accelerators based on the data flow principle
use a static data flow architecture along with a timing wheel mechanism to implement the event driven simulation
algorithm. The drawback in this approach is that the timing wheel becomes a bottleneck to high simulation
throughput. Other shortcomings of the existing architecture are the high communication overhead in the arbitration
and distribution networks, and reduced pipelining due to a static data flow architecture. To overcome these, three
major improvements are made to the design of a classical data flow based logic simulation accelerator. These
include:1) A novel and efficient technique for implementing a pseudo‐dynamic data flow architecture to increase
pipelining.2) Implementation of a modified distributed event driven simulation algorithm.3) Localized processors for fast evaluation of small primitives.
Resonant Tunneling in the QuantumHydrodynamic Model
Authors: Gardner Carl L. 
Published: September 2007

The phenomenon of resonant tunneling is simulated and analyzed in the quantum hydrodynamic (QHD) model
for semiconductor devices. Simulations of a parabolic well resonant tunneling diode at 77 K are presented which
show multiple regions of negative differential resistance (NDR) in the current‐voltage curve. These are the first
simulations of the QHD equations to show multiple regions of NDR.Resonant tunneling (and NDR) depend on the quantum interference of electron wavefunctions and therefore
on the phases of the wavefunctions. An analysis of the QHD equations using a moment expansion of the
Wigner‐Boltzmann equation indicates how phase information is retained in the hydrodynamic equations.
Embeddings into Hyper Petersen Networks: YetAnother Hypercube‐Like Interconnection Topology
Authors: Das Sajal K. , Öhring Sabine , Banerjee Amit K. 
Published: September 2007

A new hypercube‐like topology, called the hyper Petersen (HP) network, is proposed and analyzed, which is
constructed from the well‐known cartesian product of the binary hypercube and the Petersen graph of ten nodes.This topology is an attractive candidate for multiprocessor interconnection having such desirable properties as
regularity, high symmetry and connectivity, and logarithmic diameter. For example, an n‐dimensional hyper Petersen
network, HPn, with N=1.25 * 2n nodes is a regular graph of degree and node‐connectivity n and diameter n–1
, whereas an (n–1)‐dimensional binary hypercube, Qn−1
, with the same diameter covers only 2n−1
nodes, each
of degree (n–1). Thus the HP topology accommodates 2.5 times extra nodes than Qn−1 at the cost of increasing
the node‐degree by one. With the same degree and connectivity of n, the diameter of the HPn network is one less
than that of Qn, yet having 1.25 times larger number of nodes.Efficient routing and broadcasting schemes are presented, and node‐disjoint paths in HPn, are computed even
under faulty conditions. The versatility of the hyper Petersen networks is emphasized by embedding rings, meshes,
hypercubes and several tree‐related topologies into it. Contrary to the hypercubes, rings of odd lengths, and a
complete binary tree of height n–1 permit subgraph embeddings in HPn.
High‐Level Graphical Abstraction in Digital Design
Authors: Pearson Murray W. , Lyons Paul J. , Apperley Mark D. 
Published: September 2007

We base our approach to the design of complex logic ICs on four premises:Design of a chip′s abstract architecture—its major components, their tasks, and their
intercommunication—should precede definition of its functionality.Graphics is ideal for representing abstract architectures; text is better for functionality.The designer should not have to translate graphical information into text.Graphical and textual design capture can be integrated with synthesis.