bluuebunny/crossref_metadata_2025_split huggingface dataset:
An anthropomorphic phantom for quantitative evaluation of breast MRI
Authors: Freed Melanie , de Zwart Jacco A. , Loud Jennifer T. , El Khouli Riham H. , Myers Kyle J. , Greene Mark H. , Duyn Jeff H. , Badano Aldo 
Published: February 2011

Purpose:In this study, the authors aim to develop a physical, tissue‐mimicking phantom for quantitative evaluation of breast MRI protocols. The objective of this phantom is to address the need for improved standardization in breast MRI and provide a platform for evaluating the influence of image protocol parameters on lesion detection and discrimination. Quantitative comparisons between patient and phantom image properties are presented.Methods:The phantom is constructed using a mixture of lard and egg whites, resulting in a random structure with separate adipose‐ and glandular‐mimicking components. and relaxation times of the lard and egg components of the phantom were estimated at 1.5 T from inversion recovery and spin‐echo scans, respectively, using maximum‐likelihood methods. The image structure was examined quantitatively by calculating and comparing spatial covariance matrices of phantom and patient images. A static, enhancing lesion was introduced by creating a hollow mold with stereolithography and filling it with a gadolinium‐doped water solution.Results:Measured phantom relaxation values fall within 2 standard errors of human values from the literature and are reasonably stable over 9 months of testing. Comparison of the covariance matrices of phantom and patient data demonstrates that the phantom and patient data have similar image structure. Their covariance matrices are the same to within error bars in the anterior‐posterior direction and to within about two error bars in the right‐left direction. The signal from the phantom's adipose‐mimicking material can be suppressed using active fat‐suppression protocols. A static, enhancing lesion can also be included with the ability to change morphology and contrast agent concentration.Conclusions:The authors have constructed a phantom and demonstrated its ability to mimic human breast images in terms of key physical properties that are relevant to breast MRI. This phantom provides a platform for the optimization and standardization of breast MRI imaging protocols for lesion detection and characterization.
Voriconazole-Induced Inhibition of the Fungicidal Activity of Amphotericin B in
Candida
Strains with Reduced Susceptibility to Voriconazole: an Effect Not Predicted by the MIC Value Alone
Authors: Lignell Anders , Löwdin Elisabeth , Cars Otto , Sanglard Dominique , Sjölin Jan 
Published: February 2011

ABSTRACT

An antagonistic effect of voriconazole on the fungicidal activity of sequential doses of amphotericin B has previously been demonstrated in
Candida albicans
strains susceptible to voriconazole. Because treatment failure and the need to switch to other antifungals are expected to occur more often in infections that are caused by resistant strains, it was of interest to study whether the antagonistic effect was still seen in
Candida
strains with reduced susceptibility to voriconazole. With the hypothesis that antagonism will not occur in voriconazole-resistant strains,
C. albicans
strains with characterized mechanisms of resistance against voriconazole, as well as
Candida glabrata
and
Candida krusei
strains with differences in their degrees of susceptibility to voriconazole were exposed to voriconazole or amphotericin B alone, to both drugs simultaneously, or to voriconazole followed by amphotericin B in an
in vitro
kinetic model. Amphotericin B administered alone or simultaneously with voriconazole resulted in fungicidal activity. When amphotericin B was administered after voriconazole, its activity was reduced (median reduction, 61%; range, 9 to 94%). Levels of voriconazole-dependent inhibition of amphotericin B activity differed significantly among the strains but were not correlated with the MIC values (correlation coefficient, −0.19;
P
= 0.65). Inhibition was found in
C. albicans
strains with increases in
CDR1
and
CDR2
expression but not in the strain with an increase in
MDR1
expression. In summary, decreased susceptibility to voriconazole does not abolish voriconazole-dependent inhibition of the fungicidal activity of amphotericin B in voriconazole-resistant
Candida
strains. The degree of interaction could not be predicted by the MIC value alone.
Contribution of N-Glucuronidation to Efavirenz Elimination
In Vivo
in the Basal and Rifampin-Induced Metabolism of Efavirenz
Authors: Cho Doo-Yeoun , Ogburn Evan T. , Jones David , Desta Zeruesenay 
Published: February 2011

ABSTRACT

In this study, the contribution of efavirenz N-glucuronidation to efavirenz elimination
in vivo
was assessed. In a two-period placebo-controlled crossover trial design, a single 600-mg oral dose of efavirenz was administered to healthy volunteers (
n
= 10) pretreated with placebo pills or 600 mg/day rifampin orally for 10 days. Urine and plasma concentrations of efavirenz and 8-hydroxyefavirenz were measured by the liquid chromatography-tandem mass spectrometry method after enzymatic hydrolysis with β-glucuronidase (conjugated and unconjugated) and without enzymatic hydrolysis (unconjugated). Pharmacokinetic parameters of efavirenz within the placebo- or rifampin-treated group obtained after enzymatic hydrolysis did not show any statistically significant difference compared with those obtained without enzymatic hydrolysis (
P
> 0.05; paired
t
test, two-tailed). The amount of efavirenz excreted over 12 h was significantly larger after enzymatic hydrolysis in both the placebo (
P
= 0.007) and rifampin (
P
= 0.0001) treatment groups, supporting the occurrence of direct N-glucuronidation of efavirenz, but the relevance of this finding is limited because the amount of efavirenz excreted as unchanged or conjugated in urine is less than 1% of the dose administered. In both the placebo- and rifampin-treated groups, plasma concentrations of 8-hydroxyefavirenz and the amount excreted over 12 h were significantly larger (
P
< 0.00001) after enzymatic hydrolysis than without enzymatic hydrolysis. These findings suggest that although the occurrence of direct efavirenz N-glucuronidation is supported by the urine data, the abundance of efavirenz
N
-glucuronide in plasma is negligible and that the contribution of the N-glucuronidation pathway to the overall clearance of efavirenz seems minimal.
Intracellular Nucleotide Levels during Coadministration of Tenofovir Disoproxil Fumarate and Didanosine in HIV-1-Infected Patients
Authors: Hawkins Trevor , Veikley Wenoah , Durand-Gasselin Lucie , Babusis Darius , Reddy Y. Sunila , Flaherty John F. , Ray Adrian S. 
Published: February 2011

ABSTRACTStudies were conducted to determine if there is a mechanistic basis for reports of suboptimal virologic responses and concerns regarding the safety of regimens containing the combination of tenofovir (TFV) disoproxil fumarate (TDF) and didanosine (ddI) by assessing the pharmacokinetic consequences of coadministration of these drugs on intracellular nucleotides. This was a prospective and longitudinal study in HIV-1-infected patients of adding either TDF or ddI to a stable antiretroviral regimen containing the other drug. Intracellular concentrations of the nucleotide analogs TFV diphosphate (TFV-DP) and ddATP and the endogenous purine nucleotides dATP and 2′-dGTP in peripheral blood mononuclear cells were measured. A total of 16 patients were enrolled into the two study arms and a study extension. Intracellular TFV-DP concentrations (median, 120 fmol/106cells) and ddATP concentrations (range, 1.50 to 7.54 fmol/106cells in two patients) were unaffected following addition of ddI or TDF to a stable regimen containing the other drug. While coadministration of ddI and TDF for 4 weeks did not appear to impact dATP or dGTP concentrations, cross-sectional analysis suggested that extended therapy with ddI-containing regimens, irrespective of TDF coadministration, may decrease dATP and ddATP concentrations. Addition of TDF or ddI to a stable regimen including the other drug, in the context of ddI dose reduction, did not adversely affect the concentration of dATP, dGTP, TFV-DP, or ddATP. The association between longer-term ddI therapy and reduced intracellular nucleotide concentrations and this observation's implication for the efficacy and toxicity of ddI-containing regimens deserve further study.
Pharmacokinetic Properties of Conventional and Double-Dose Sulfadoxine-Pyrimethamine Given as Intermittent Preventive Treatment in Infancy
Authors: Salman Sam , Griffin Susan , Kose Kay , Pitus Nolene , Winmai Josephine , Moore Brioni , Siba Peter , Ilett Kenneth F. , Mueller Ivo , Davis Timothy M. E. 
Published: February 2011

ABSTRACT

Intermittent preventive treatment in infancy (IPTi) entails routine administration of antimalarial treatment doses at specified times in at-risk infants. Sulfadoxine-pyrimethamine (SDX/PYR) is a combination that has been used as first-line IPTi. Because of limited pharmacokinetic data and suggestions that higher milligram/kilogram pediatric doses than recommended should be considered, we assessed SDX/PYR disposition, randomized to conventional (25/1.25 mg/kg of body weight) or double (50/2.5 mg/kg) dose, in 70 Papua New Guinean children aged 2 to 13 months. Blood samples were drawn at baseline, 28 days, and three time points randomly selected for each infant at 4 to 8 h or 2, 5, 7, 14, or 21 days. Plasma SDX, PYR, and N
4
-acetylsulfadoxine (NSX, the principal metabolite of SDX) were assayed by high-performance liquid chromatography (HPLC). Using population modeling incorporating hepatic maturation and cystatin C-based renal function, two-compartment models provided best fits for PYR and SDX/NSX plasma concentration profiles. The area under the plasma concentration-time curve from 0 h to infinity (AUC
0-∞
) was greater with the double dose versus the conventional dose of PYR (4,915 versus 2,844 μg/day/liter) and SDX (2,434 versus 1,460 mg/day/liter). There was a 32% reduction in SDX relative bioavailability with the double dose but no evidence of dose-dependent metabolism. Terminal elimination half-lives (15.6 days for PYR, 9.1 days for SDX) were longer than previously reported. Both doses were well tolerated without changes in hemoglobin or hepatorenal function. Five children in the conventional and three in the double-dose group developed malaria during follow-up. These data support the potential use of double-dose SDX/PYR in infancy, but further studies should examine the influence of hepatorenal maturation in very young infants.
Role of VltAB, an ABC Transporter Complex, in Viologen Tolerance in
Streptococcus mutans
Authors: Biswas Saswati , Biswas Indranil 
Published: February 2011

ABSTRACT

Streptococcus mutans
, a Gram-positive organism, is the primary causative agent in the formation of dental caries in humans. To persist in the oral cavity,
S. mutans
must be able to tolerate rapid environmental fluctuations and exposure to various toxic chemicals. However, the mechanisms underlying the ability of this cariogenic pathogen to survive and proliferate under harsh environmental conditions remain largely unknown. Here, we wanted to understand the mechanisms by which
S. mutans
withstands exposure to methyl viologen (MV), a quaternary ammonium compound (QAC) that generates superoxide radicals in the cell. To elucidate the essential genes for MV tolerance, screening of ∼3,500 mutants generated by IS
S1
mutagenesis, revealed 15 MV-sensitive mutants. Among them, five and four independent insertions had occurred in SMU.905 and SMU.906 genes, respectively. These two genes are appeared to be organized in an operon and encode a putative ABC transporter complex; we designated the genes as
vltA
and
vltB
, for

v

io

l

ogen

t

ransporter. To verify our results,
vltA
was deleted by using an antibiotic resistance marker; the mutant was just as sensitive to MV as the IS
S1
insertion mutants. Furthermore,
vltA
and
vltB
mutants were also sensitive to other viologen compounds such as benzyl and ethyl viologens. Complementation assays were also carried out to confirm the role of VltA and VltB in viologen tolerance. Sensitivity to various drugs, including a wide range of QACs, was evaluated. It appears that a functional VltA is also required for full resistance toward acriflavin, ethidium bromide, and safranin; all are well-known QACs. These results indicate that VltA/B constitute a heterodimeric multidrug efflux pump of the ABC family. BLAST-P analysis suggests that homologs of VltA/B are widely present in streptococci, enterococci, and other important Gram-positive pathogens.
Impact of the N348I Mutation in HIV-1 Reverse Transcriptase on Nonnucleoside Reverse Transcriptase Inhibitor Resistance in Non-Subtype B HIV-1
Authors: McCormick Adele L. , Parry Chris M. , Crombe Anne , Goodall Ruth L. , Gupta Ravindra K. , Kaleebu Pontiano , Kityo Cissy , Chirara Michael , Towers Greg J. , Pillay Deenan 
Published: February 2011

ABSTRACT
We investigated the effect of N348I alone and with M184V on nonnucleoside reverse transcriptase inhibitor (NNRTI) drug susceptibility and replicative capacity in B and non-B HIV-1 isolates. N348I reduced the susceptibility to all NNRTI drugs across subtypes. The replication capacity of all viruses in a variety of cell lines was impaired by N348I. Interestingly, the N348I and M184V double mutation compensated for the reduced NNRTI drug susceptibility observed in the N348I single mutant and marginally improved viral replicative capacity.
Dose-Dependent Activity of Pyrazinamide in Animal Models of Intracellular and Extracellular Tuberculosis Infections
Authors: Ahmad Zahoor , Fraig Mostafa M. , Bisson Gregory P. , Nuermberger Eric L. , Grosset Jacques H. , Karakousis Petros C. 
Published: February 2011

ABSTRACTRecentin vitropharmacokinetic data suggest that the currently recommended dose of pyrazinamide may be suboptimal for killing intracellular bacilli in humans. We evaluated a range of pyrazinamide doses against intracellular and extracellularMycobacterium tuberculosisin chronically infected mice and guinea pigs, respectively. Antibiotics were given five times weekly for 4 weeks beginning 28 days after infection. Human-equivalent doses of isoniazid reduced lung bacterial counts 10-fold in each species. Pyrazinamide given at 1/4 and 1/2 the human-equivalent dose was minimally active, while human-equivalent doses reduced lung bacterial counts by ∼1.0 log10in each species. Doubling the human-equivalent dose of pyrazinamide reduced the lung bacillary burden by 1.7 and 3.0 log10in mice and guinea pigs, respectively. As in humans and mice, pyrazinamide showed significant synergy with rifampin in guinea pigs. Clinical studies are warranted to investigate the sterilizing activity and tolerability of higher doses of pyrazinamide in combination tuberculosis regimens.
Novel HIV-1 Protease Inhibitors (PIs) Containing a Bicyclic P2 Functional Moiety, Tetrahydropyrano-Tetrahydrofuran, That Are Potent against Multi-PI-Resistant HIV-1 Variants
Authors: Ide Kazuhiko , Aoki Manabu , Amano Masayuki , Koh Yasuhiro , Yedidi Ravikiran S. , Das Debananda , Leschenko Sofiya , Chapsal Bruno , Ghosh Arun K. , Mitsuya Hiroaki 
Published: February 2011

ABSTRACT

We identified GRL-1388 and -1398, potent nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a bicyclic P2 functional moiety, tetrahydropyrano-tetrahydrofuran (Tp-THF). GRL-1388 was as potent as darunavir (DRV) against various drug-resistant HIV-1 laboratory strains with 50% effective concentration (EC
50
s) of 2.6 to 32.6 nM. GRL-1398 was significantly more potent against such variants than DRV with EC
50
s of 0.1 to 5.7 nM. GRL-1388 and -1398 were also potent against multiple-PI-resistant clinical HIV-1 variants (
CL
HIV-1
MDR
) with EC
50
s ranging from 2.7 to 21.3 nM and from 0.3 to 4.8 nM, respectively. A highly DRV-resistant HIV-1 variant selected
in vitro
remained susceptible to GRL-1398 with the EC
50
of 21.9 nM, while the EC
50
of DRV was 214.1 nM. When HIV-1
NL4-3
was selected with GRL-1398, four amino acid substitutions—leucine to phenylalanine at a position 10 (L10F), A28S, L33F, and M46I—emerged, ultimately enabling the virus to replicate in the presence of >1.0 μM the compound beyond 57 weeks of selection. When a mixture of 10 different
CL
HIV-1
MDR
strains was selected, the emergence of resistant variants was more substantially delayed with GRL-1398 than with GRL-1388 and DRV. Modeling analyses revealed that GRL-1398 had greater overall hydrogen bonding and hydrophobic interactions than GRL-1388 and DRV and that GRL-1388 and -1398 had hydrogen bonding interactions with the main chain of the active-site amino acids (Asp29 and Asp30) of protease. The present findings warrant that GRL-1398 be further developed as a potential drug for treating individuals with HIV-1 infection.
Genomic Analysis of
Acinetobacter baumannii
A118 by Comparison of Optical Maps: Identification of Structures Related to Its Susceptibility Phenotype
Authors: Ramirez Maria Soledad , Adams Mark D. , Bonomo Robert A. , Centrón Daniela , Tolmasky Marcelo E. 
Published: February 2011

ABSTRACT

Acinetobacter baumannii
A118, a naturally competent clinical isolate, is unusually susceptible to several antibiotics. Comparison of the optical map of strain A118 with
in silico
-generated restriction maps of sequenced genomes and sequence analyses showed that the AbaR region, commonly found inserted within the
comM
gene in other isolates, is missing in strain A118, which could in part explain the susceptible phenotype exhibited by this isolate. These comparative studies also showed differences in regions where genes coding for functions that may be involved in drug resistance or susceptibility are located. Further sequencing demonstrated that
cat
and
bla
ADC
, named
bla
ADC-55
, are present but that a
tet
(A) gene usually found in other strains is not. In addition,
carO
and
pbp2
, which may play a role in susceptibility to carbapenems, are present in strain A118. These findings support the idea that
A. baumannii
strains possess multiple mechanisms that contribute to antibiotic resistance, and the presence of some of them is not sufficient for a resistant phenotype. The results shown here indicate that optical mapping is a useful tool for preliminary comparative genomic analysis.
Antibodies Contribute to Effective Vaccination against Respiratory Infection by Type A
Francisella tularensis
Strains
Authors: Mara-Koosham Gopi , Hutt Julie A. , Lyons C. Rick , Wu Terry H. 
Published: February 2011

ABSTRACT

Pneumonic tularemia is a life-threatening disease caused by inhalation of the highly infectious intracellular bacterium
Francisella tularensis
. The most serious form of the disease associated with the type A strains can be prevented in experimental animals through vaccination with the attenuated live vaccine strain (LVS). The protection is largely cell mediated, but the contribution of antibodies remains controversial. We addressed this issue in a series of passive immunization studies in Fischer 344 (F344) rats. Subcutaneous LVS vaccination induced a robust serum antibody response dominated by IgM, IgG2a, and IgG2b antibodies. Prophylactic administration of LVS immune serum or purified immune IgG reduced the severity and duration of disease in naïve rats challenged intratracheally with a lethal dose of the virulent type A strain SCHU S4. The level of resistance increased with the volume of immune serum given, but the maximum survivable SCHU S4 challenge dose was at least 100-fold lower than that shown for LVS-vaccinated rats. Protection correlated with reduced systemic bacterial growth, less severe histopathology in the liver and spleen during the early phase of infection, and bacterial clearance by a T cell-dependent mechanism. Our results suggest that treatment with immune serum limited the sequelae associated with infection, thereby enabling a sterilizing T cell response to develop and resolve the infection. Thus, antibodies induced by LVS vaccination may contribute to the defense of F344 rats against respiratory infection by type A strains of
F. tularensis
.
Identification of
Vibrio cholerae
Type III Secretion System Effector Proteins
Authors: Alam Ashfaqul , Miller Kelly A. , Chaand Mudit , Butler J. Scott , Dziejman Michelle 
Published: February 2011

ABSTRACT

AM-19226 is a pathogenic O39 serogroup
Vibrio cholerae
strain that lacks the typical virulence factors for colonization (toxin-coregulated pilus [TCP]) and toxin production (cholera toxin [CT]) and instead encodes a type III secretion system (T3SS). The mechanism of pathogenesis is unknown, and few effector proteins have been identified. We therefore undertook a survey of the open reading frames (ORFs) within the ∼49.7-kb T3SS genomic island to identify potential effector proteins. We identified 15 ORFs for their ability to inhibit growth when expressed in yeast and then used a β-lactamase (TEM1) fusion reporter system to demonstrate that 11 proteins were
bona fide
effectors translocated into HeLa cells
in vitro
in a T3SS-dependent manner. One effector, which we named VopX (A33_1663), is conserved only in
V. cholerae
and
Vibrio parahaemolyticus
T3SS-positive strains and has not been previously studied. A
vopX
deletion reduces the ability of strain AM-19226 to colonize
in vivo
, and the bile-induced expression of a
vopX-lacZ
transcriptional fusion
in vitro
is regulated by the T3SS-encoded transcriptional regulators VttR
A
and VttR
B
. An
RLM1
yeast deletion strain rescued the growth inhibition induced by VopX expression, suggesting that VopX interacts with components of the cell wall integrity mitogen-activated protein kinase (MAPK) pathway. The collective results show that the
V. cholerae
T3SS encodes multiple effector proteins, one of which likely has novel activities that contribute to disease via interference with eukaryotic signaling pathways.
Natural Antibodies against Several Pneumococcal Virulence Proteins in Children during the Pre-Pneumococcal-Vaccine Era: the Generation R Study
Authors: Lebon Ankie , Verkaik Nelianne J. , Labout Joost A. M. , de Vogel Corné P. , Hooijkaas Herbert , Verbrugh Henri A. , van Wamel Willem J. B. , Jaddoe Vincent W. V. , Hofman Albert , Hermans Peter W. M. , Ma Jiangtao , Mitchell Tim J. , Moll Henriette A. , van Belkum Alex 
Published: February 2011

ABSTRACT

The currently available pneumococcal vaccines do not protect against all serotypes of
Streptococcus pneumoniae
. A shift toward nonvaccine serotypes causing colonization and invasive disease has occurred, and studies on protein-based vaccines have been undertaken. We assessed the association between specific antibodies against pneumococcal virulence proteins and colonization and respiratory tract infections (RTIs). Additionally, we assessed the extent to which colonization induces a humoral immune response. Nasopharyngeal swabs collected from children at 1.5, 6, 14, and 24 months of age were cultured for pneumococcus. Serum samples were obtained at birth and at 6, 14, and 24 months (
n
= 57 children providing 177 serum samples). Data were collected prior to the pneumococcal vaccine era. IgG, IgA, and IgM levels against 17 pneumococcal protein vaccine candidates were measured using a bead-based flow cytometry technique (xMAP; Luminex Corporation). Information regarding RTIs was questionnaire derived. Levels of IgG against all proteins were high in cord blood, decreased in the first 6 months and increased again thereafter, in contrast to the course of IgA and IgM levels. Specific antibodies were induced upon colonization. Increased levels of IgG against BVH-3, NanA, and SP1003 at 6 months, NanA, PpmA, PsaA, SlrA, SP0189, and SP1003 at 14 months, and SlrA at 24 months were associated with a decreased number of RTIs in the third year of life but not with colonization. Maternal antipneumococcal antibodies did not protect against pneumococcal colonization and infection. Certain antibodies against pneumococcal virulence proteins, some of which are induced by colonization, are associated with a decreased number of RTIs in children. This should be taken into account in future pneumococcal vaccine studies.