bluuebunny/crossref_metadata_2025_split huggingface dataset:
Three dimensional dose distribution comparison of simple and complex acquisition trajectories in dedicated breast CT
Authors: Shah Jainil P. , Mann Steve D. , McKinley Randolph L. , Tornai Martin P. 
Published: July 2015

Purpose:A novel breast CT system capable of arbitrary 3D trajectories has been developed to address cone beam sampling insufficiency as well as to image further into the patient's chest wall. The purpose of this study was to characterize any trajectory‐related differences in 3D x‐ray dose distribution in a pendant target when imaged with different orbits.Methods:Two acquisition trajectories were evaluated: circular azimuthal (no‐tilt) and sinusoidal (saddle) orbit with ±15° tilts around a pendant breast, using Monte Carlo simulations as well as physical measurements. Simulations were performed with tungsten (W) filtration of a W‐anode source; the simulated source flux was normalized to the measured exposure of a W‐anode source. A water‐filled cylindrical phantom was divided into 1 cm3 voxels, and the cumulative energy deposited was tracked in each voxel. Energy deposited per voxel was converted to dose, yielding the 3D distributed dose volumes. Additionally, three cylindrical phantoms of different diameters (10, 12.5, and 15 cm) and an anthropomorphic breast phantom, initially filled with water (mimicking pure fibroglandular tissue) and then with a 75% methanol‐25% water mixture (mimicking 50–50 fibroglandular‐adipose tissues), were used to simulate the pendant breast geometry and scanned on the physical system. Ionization chamber calibrated radiochromic film was used to determine the dose delivered in a 2D plane through the center of the volume for a fully 3D CT scan using the different orbits.Results:Measured experimental results for the same exposure indicated that the mean dose measured throughout the central slice for different diameters ranged from 3.93 to 5.28 mGy, with the lowest average dose measured on the largest cylinder with water mimicking a homogeneously fibroglandular breast. These results align well with the cylinder phantom Monte Carlo studies which also showed a marginal difference in dose delivered by a saddle trajectory in the central slice. Regardless of phantom material or filled fluid density, dose delivered by the saddle scan was negligibly different than the simple circular, no‐tilt scans. The average dose measured in the breast phantom was marginally higher for saddle than the circular no tilt scan at 3.82 and 3.87 mGy, respectively.Conclusions:Not only does nontraditional 3D‐trajectory CT scanning yield more complete sampling of the breast volume but also has comparable dose deposition throughout the breast and anterior chest volume, as verified by Monte Carlo simulation and physical measurements.
Technical Note: Automatic real‐time ultrasound tracking of respiratory signal using selective filtering and dynamic template matching
Authors: Wu Jiaze , Li Cheng , Gogna Apoorva , Tan Bien Soo , Ooi London Lucien , Liu Jimin , Yu Haoyong 
Published: July 2015

Purpose:In respiratory motion modeling for liver interventions, the respiratory signal is usually obtained by using special tracking devices to monitor external skin. However, due to intrinsic limits and cost consideration of these tracking devices, a purely ultrasound image‐based approach to tracking the signal is a more feasible option.Methods:In this study, a novel image‐based method is proposed to obtain the respiratory signal directly from 2D ultrasound images by automatically identifying and tracking the liver boundary. The boundary identification is a multistage process, which is the key to utilize a Hessian matrix‐based 2D filter to enhance the line‐like liver boundary and weaken other liver tissues. For tracking the identified boundary, a new dynamic template matching technique is first applied to estimate 2D displacements, and a boundary‐specific selection mechanism is then introduced to extract the respiratory signal from the 2D displacements.Results:The experiments demonstrate that their method can obtain accurate breathing signals, which are in key phases comparable to the manually annotation and highly consistent to the electromagnetic‐tracked ground‐truth signals (average correlation coefficients 0.9209 and statistically significant p < 0.01). Meanwhile, the experiments also prove their method can achieve high real‐time performance of about 80–160 Hz.Conclusions:This method provides a good alternative to traditional external‐landmark‐based tracking methods and may be widely applied for respiratory compensation in ultrasound‐guided liver interventions.
Kallistatin Ameliorates Influenza Virus Pathogenesis by Inhibition of Kallikrein-Related Peptidase 1-Mediated Cleavage of Viral Hemagglutinin
Authors: Leu Chia-Hsing , Yang Mei-Lin , Chung Nai-Hui , Huang Yen-Jang , Su Yu-Chu , Chen Yi-Cheng , Lin Chia-Cheng , Shieh Gia-Shing , Chang Meng-Ya , Wang Shainn-Wei , Chang Yao , Chao Julie , Chao Lee , Wu Chao-Liang , Shiau Ai-Li 
Published: July 2015

ABSTRACTProteolytic cleavage of the hemagglutinin (HA) of influenza virus by host trypsin-like proteases is required for viral infectivity. Some serine proteases are capable of cleaving influenza virus HA, whereas some serine protease inhibitors (serpins) inhibit the HA cleavage in various cell types. Kallikrein-related peptidase 1 (KLK1, also known as tissue kallikrein) is a widely distributed serine protease. Kallistatin, a serpin synthesized mainly in the liver and rapidly secreted into the circulation, forms complexes with KLK1 and inhibits its activity. Here, we investigated the roles of KLK1 and kallistatin in influenza virus infection. We show that the levels of KLK1 increased, whereas those of kallistatin decreased, in the lungs of mice during influenza virus infection. KLK1 cleaved H1, H2, and H3 HA molecules and consequently enhanced viral production. In contrast, kallistatin inhibited KLK1-mediated HA cleavage and reduced viral production. Cells transduced with the kallistatin gene secreted kallistatin extracellularly, which rendered them more resistant to influenza virus infection. Furthermore, lentivirus-mediated kallistatin gene delivery protected mice against lethal influenza virus challenge by reducing the viral load, inflammation, and injury in the lung. Taking the data together, we determined that KLK1 and kallistatin contribute to the pathogenesis of influenza virus by affecting the cleavage of the HA peptide and inflammatory responses. This study provides a proof of principle for the potential therapeutic application of kallistatin or other KLK1 inhibitors for influenza. Since proteolytic activation also enhances the infectivity of some other viruses, kallistatin and other kallikrein inhibitors may be explored as antiviral agents against these viruses.
Determination of Bedaquiline in Human Serum Using Liquid Chromatography-Tandem Mass Spectrometry
Authors: Alffenaar Jan-Willem C. , Bolhuis Mathieu , van Hateren Kai , Sturkenboom Marieke , Akkerman Onno , de Lange Wiel , Greijdanus Ben , van der Werf Tjip , Touw Daan 
Published: July 2015

ABSTRACT

Bedaquiline, a diarylquinoline for the treatment of multidrug-resistant tuberculosis (TB), relies on exposure-dependent killing. As data on drug exposure in specific populations are scarce, pharmacokinetic studies may be of interest. No simple and robust validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been reported to date. Therefore, a new method using a quadrupole mass spectrometer was developed for analysis of bedaquiline and
N
-monodesmethyl bedaquiline (M2) in human serum, using deuterated bedaquiline as the internal standard. The calibration curve was linear over a range of 0.05 (lower limit of quantification [LLOQ]) to 6.00 mg/liter for both bedaquiline and M2, with correlation coefficient values of 0.997 and 0.999, respectively. The calculated accuracy ranged from 1.9% to 13.6% for bedaquiline and 2.9% to 8.5% for M2. Within-run precision ranged from 3.0% to 7.2% for bedaquiline and 3.1% to 5.2% for M2, and between-run precision ranged from 0.0% to 4.3% for bedaquiline and 0.0% to 4.6% for M2. Evaluation of serum concentrations in a patient receiving bedaquiline showed high levels at the end of treatment, reflecting accumulation of the drug. More observational pharmacokinetic data are needed to relate altered drug concentrations to clinical outcome or adverse drug effects. A simple LC-MS/MS method to quantify bedaquiline and M2 levels in human serum using a deuterated internal standard has been validated. This method can be used in clinical studies and daily practice.
Population Approach To Analyze the Pharmacokinetics of Free and Total Lopinavir in HIV-Infected Pregnant Women and Consequences for Dose Adjustment
Authors: Fauchet Floris , Treluyer Jean-Marc , Illamola Silvia M. , Pressiat Claire , Lui Gabrielle , Valade Elodie , Mandelbrot Laurent , Lechedanec Jerome , Delmas Sandrine , Blanche Stéphane , Warszawski Josiane , Urien Saik , Tubiana Roland , Hirt Déborah 
Published: July 2015

ABSTRACT
The aims of this study were to describe the unbound and total lopinavir (LPV) pharmacokinetics in pregnant women in order to evaluate if a dosing adjustment is necessary during pregnancy. Lopinavir placental transfer is described, and several genetic covariates were tested to explain its variability. A total of 400 maternal, 79 cord blood, and 48 amniotic fluid samples were collected from 208 women for LPV concentration determinations and pharmacokinetics analysis. Among the maternal LPV concentrations, 79 samples were also used to measure the unbound LPV concentrations. Population pharmacokinetics models were developed by using NONMEM software. Two models were developed to describe (i) unbound and total LPV pharmacokinetics and (ii) LPV placental transfer. The pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. A pregnancy effect was found on maternal clearance (39% increase), whereas the treatment group (monotherapy versus triple therapy) or the genetic polymorphisms did not explain the pharmacokinetics or placental transfer of LPV. Efficient unbound LPV concentrations in nonpregnant women were similar to those measured during the third trimester of pregnancy. Our study showed a 39% increase of maternal total LPV clearance during pregnancy, whereas unbound LPV concentrations were similar to those simulated in nonpregnant women. The genetic polymorphisms selected did not influence the LPV pharmacokinetics or placental transfer. Thus, we suggest that the LPV dosage should not be increased during pregnancy.
Leishmanicidal Activities of Novel Methylseleno-Imidocarbamates
Authors: Fernández-Rubio Celia , Campbell Daphne , Vacas Andrés , Ibañez Elena , Moreno Esther , Espuelas Socorro , Calvo Alfonso , Palop Juan Antonio , Plano Daniel , Sanmartin Carmen , Nguewa Paul A. 
Published: July 2015

ABSTRACT

The generation of new antileishmanial drugs has become a priority. Selenium and its derivatives stand out as having promising leishmanicidal activity. In fact, some parasites express selenoproteins and metabolize selenium. Recently, selenium derivatives have shown the potential to reduce parasitemia, clinical manifestations, and mortality in parasite-infected mice. In this paper, after selecting four candidates according to drug similarity parameters, we observed that two of them, called compounds 2b [methyl-
N
,
N
′-di(thien-2-ylcarbonyl)-imidoselenocarbamate] and 4b [methyl-
N
,
N
′-di(5-nitrothien-3-ylcarbonyl)-imidoselenocarbamate], exhibit low 50% inhibitory concentrations (IC
50
s) (<3 μM) and good selectivity indexes (SIs) (>5) in
Leishmania major
promastigotes and lack toxicity on macrophages. In addition, in analysis of their therapeutic potential against
L. major
in vitro
infection, both compounds display a dramatic reduction of amastigote burden (∼80%) with sublethal concentrations. Furthermore, in macrophages, these selenocompounds induce nitric oxide production, which has been described to be critical for defense against intracellular pathogens. Compounds 2b and 4b were demonstrated to cause cell cycle arrest in G
1
. Interestingly, evaluation of expression of genes related to proliferation (PCNA), treatment resistance (ABC transporter and alpha-tubulin), and virulence (quinonoid dihydropteridine reductase [QDPR]) showed several alterations in gene expression profiling. All these results prompt us to propose both compounds as candidates to treat leishmanial infections.
Characterization of HIV-1 Resistance to Tenofovir AlafenamideIn Vitro
Authors: Margot Nicolas A. , Johnson Audun , Miller Michael D. , Callebaut Christian 
Published: July 2015

ABSTRACTTenofovir alafenamide (TAF) is an investigational prodrug of the HIV-1 nucleotide reverse transcriptase (RT) inhibitor (NtRTI) tenofovir (TFV), with improved potency and drug delivery properties over the current prodrug, tenofovir disoproxil fumarate (TDF). TAF is currently in phase 3 clinical studies for the treatment of HIV-1 infection, in combination with other antiretroviral agents. Phase 1 and 2 studies have shown that TAF was associated with increased peripheral blood mononuclear cell (PBMC) drug loading and increased suppression of HIV-1 replication compared to treatment with TDF. In this study, selection ofin vitroresistance to both TAF and the parent compound, TFV, led to the emergence of HIV-1 with the K65R amino acid substitution in RT with 6.5-fold-reduced susceptibility to TAF. Although TAF is more potent than TFVin vitro, the antiviral susceptibilities to TAF and TFV of a large panel of nucleoside/nucleotide RT inhibitor (NRTI)-resistant mutants were highly correlated (R2= 0.97), indicating that the two compounds have virtually the same resistance profile when assessed as fold change from the wild type. TAF showed full antiviral activity in PBMCs against primary HIV-1 isolates with protease inhibitor, nonnucleoside RT inhibitor (NNRTI), or integrase strand transfer inhibitor resistance but reduced activity against isolates with extensive NRTI resistance amino acid substitutions. However, the increased cell loading of TFV with TAF versus TDF observedin vivosuggests that TAF may retain activity against TDF-resistant mutant viruses.
Protective Effect of Ginsenosides Rg1 and Re on Lipopolysaccharide-Induced Sepsis by Competitive Binding to Toll-Like Receptor 4
Authors: Su Fei , Xue Yin , Wang Yuemin , Zhang Lili , Chen Wangxue , Hu Songhua 
Published: July 2015

ABSTRACT

We previously demonstrated that ginsenosides Rg1 and Re enhanced the immune response in C3H/HeB mice but not in C3H/HeJ mice carrying a mutation in the
Tlr4
gene. The results of the present study showed that both Rg1 and Re inhibited mRNA expression and production of proinflammatory mediators that included tumor necrosis factor α, interleukin-1β, interleukin-6, cyclooxygenase-2, and inducible nitric oxide synthase from lipopolysaccharide (LPS)-stimulated macrophages. Rg1 was found to be distributed both extracellularly and intracellularly but Re was located only extracellularly to compete with LPS for binding to Toll-like receptor 4. Preinjection of Rg1 and Re into rats suppressed LPS-induced increases in body temperature, white blood cell counts, and levels of serum proinflammatory mediators. Preinjection of Rg1 and Re into mice prevented the LPS-induced decreases in total white blood cell counts and neutrophil counts, inhibited excessive expression of multiple proinflammatory mediators, and successfully rescued 100% of the mice from sepsis-associated death. More significantly, when administered after lethal LPS inoculation, Rg1, but not Re, still showed a potent antisepsis effect and protected 90% of the mice from death. The better protection efficacy of Rg1 could result from its intracellular distribution, suggesting that Rg1 may be an ideal antisepsis agent.
In Silico
-Based High-Throughput Screen for Discovery of Novel Combinations for Tuberculosis Treatment
Authors: Singh Ragini , Ramachandran Vasanthi , Shandil Radha , Sharma Sreevalli , Khandelwal Swati , Karmarkar Malancha , Kumar Naveen , Solapure Suresh , Saralaya Ramanatha , Nanduri Robert , Panduga Vijender , Reddy Jitendar , Prabhakar K. R. , Rajagopalan Swaminathan , Rao Narasimha , Narayanan Shridhar , Anandkumar Anand , Balasubramanian V. , Datta Santanu 
Published: July 2015

ABSTRACT

There are currently 18 drug classes for the treatment of tuberculosis, including those in the development pipeline. An
in silico
simulation enabled combing the innumerably large search space to derive multidrug combinations. Through the use of ordinary differential equations (ODE), we constructed an
in silico
kinetic platform in which the major metabolic pathways in
Mycobacterium tuberculosis
and the mechanisms of the antituberculosis drugs were integrated into a virtual proteome. The optimized model was used to evaluate 816 triplets from the set of 18 drugs. The experimentally derived cumulative fractional inhibitory concentration (∑FIC) value was within twofold of the model prediction. Bacterial enumeration revealed that a significant number of combinations that were synergistic for growth inhibition were also synergistic for bactericidal effect. The
in silico
-based screen provided new starting points for testing in a mouse model of tuberculosis, in which two novel triplets and five novel quartets were significantly superior to the reference drug triplet of isoniazid, rifampin, and ethambutol (HRE) or the quartet of HRE plus pyrazinamide (HREZ).
Catalase Expression Is Modulated by Vancomycin and Ciprofloxacin and Influences the Formation of Free Radicals in Staphylococcus aureus Cultures
Authors: Wang Ying , Hougaard Anni B. , Paulander Wilhelm , Skibsted Leif H. , Ingmer Hanne , Andersen Mogens L. 
Published: July 2015

ABSTRACT

Detection of free radicals in biological systems is challenging due to their short half-lives. We have applied electron spin resonance (ESR) spectroscopy combined with spin traps using the probes PBN (
N-tert
-butyl-α-phenylnitrone) and DMPO (5,5-dimethyl-1-pyrroline
N
-oxide) to assess free radical formation in the human pathogen
Staphylococcus aureus
treated with a bactericidal antibiotic, vancomycin or ciprofloxacin. While we were unable to detect ESR signals in bacterial cells, hydroxyl radicals were observed in the supernatant of bacterial cell cultures. Surprisingly, the strongest signal was detected in broth medium without bacterial cells present and it was mitigated by iron chelation or by addition of catalase, which catalyzes the decomposition of hydrogen peroxide to water and oxygen. This suggests that the signal originates from hydroxyl radicals formed by the Fenton reaction, in which iron is oxidized by hydrogen peroxide. Previously, hydroxyl radicals have been proposed to be generated within bacterial cells in response to bactericidal antibiotics. We found that when
S. aureus
was exposed to vancomycin or ciprofloxacin, hydroxyl radical formation in the broth was indeed increased compared to the level seen with untreated bacterial cells. However,
S. aureus
cells express catalase, and the antibiotic-mediated increase in hydroxyl radical formation was correlated with reduced
katA
expression and catalase activity in the presence of either antibiotic. Therefore, our results show that in
S. aureus
, bactericidal antibiotics modulate catalase expression, which in turn influences the formation of free radicals in the surrounding broth medium. If similar regulation is found in other bacterial species, it might explain why bactericidal antibiotics are perceived as inducing formation of free radicals.
Detection of Low-Level Cardinium and Wolbachia Infections in Culicoides
Authors: Mee Peter T. , Weeks Andrew R. , Walker Peter J. , Hoffmann Ary A. , Duchemin Jean-Bernard 
Published: July 2015

ABSTRACT

Bacterial endosymbionts have been identified as potentially useful biological control agents for a range of invertebrate vectors of disease. Previous studies of
Culicoides
(Diptera: Ceratopogonidae) species using conventional PCR assays have provided evidence of
Wolbachia
(1/33) and
Cardinium
(8/33) infections. Here, we screened 20 species of
Culicoides
for
Wolbachia
and
Cardinium
, utilizing a combination of conventional PCR and more sensitive quantitative PCR (qPCR) assays. Low levels of
Cardinium
DNA were detected in females of all but one of the
Culicoides
species screened, and low levels of
Wolbachia
were detected in females of 9 of the 20
Culicoides
species. Sequence analysis based on partial 16S rRNA gene and
gyrB
sequences identified “
Candidatus
Cardinium hertigii” from group C, which has previously been identified in
Culicoides
from Japan, Israel, and the United Kingdom.
Wolbachia
strains detected in this study showed 98 to 99% sequence identity to
Wolbachia
previously detected from
Culicoides
based on the 16S rRNA gene, whereas a strain with a novel
wsp
sequence was identified in
Culicoides
narrabeenensis. Cardinium
isolates grouped to geographical regions independent of the host
Culicoides
species, suggesting possible geographical barriers to
Cardinium
movement. Screening also identified
Asaia
bacteria in
Culicoides
. These findings point to a diversity of low-level endosymbiont infections in
Culicoides
, providing candidates for further characterization and highlighting the widespread occurrence of these endosymbionts in this insect group.
Host and Environmental Factors Modulate the Exposure of Free-Ranging and Farmed Red Deer (Cervus elaphus) to Coxiella burnetii
Authors: González-Barrio David , Velasco Ávila Ana Luisa , Boadella Mariana , Beltrán-Beck Beatriz , Barasona José Ángel , Santos João P. V. , Queirós João , García-Pérez Ana L. , Barral Marta , Ruiz-Fons Francisco 
Published: July 2015

ABSTRACT

The control of multihost pathogens, such as
Coxiella burnetii
, should rely on accurate information about the roles played by the main hosts. We aimed to determine the involvement of the red deer (
Cervus elaphus
) in the ecology of
C. burnetii
. We predicted that red deer populations from broad geographic areas within a European context would be exposed to
C. burnetii
, and therefore, we hypothesized that a series of factors would modulate the exposure of red deer to
C. burnetii
. To test this hypothesis, we designed a retrospective survey of 47 Iberian red deer populations from which 1,751 serum samples and 489 spleen samples were collected. Sera were analyzed by enzyme-linked immunosorbent assays (ELISA) in order to estimate exposure to
C. burnetii
, and spleen samples were analyzed by PCR in order to estimate the prevalence of systemic infections. Thereafter, we gathered 23 variables—within environmental, host, and management factors—potentially modulating the risk of exposure of deer to
C. burnetii
, and we performed multivariate statistical analyses to identify the main risk factors. Twenty-three populations were seropositive (48.9%), and
C. burnetii
DNA in the spleen was detected in 50% of the populations analyzed. The statistical analyses reflect the complexity of
C. burnetii
ecology and suggest that although red deer may maintain the circulation of
C. burnetii
without third species, the most frequent scenario probably includes other wild and domestic host species. These findings, taken together with previous evidence of
C. burnetii
shedding by naturally infected red deer, point at this wild ungulate as a true reservoir for
C. burnetii
and an important node in the life cycle of
C. burnetii
, at least in the Iberian Peninsula.