bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized Trial of Food Effect on Pharmacokinetic Parameters of ABX464 Administered Orally to Healthy Male Subjects
Authors: Scherrer Didier , Rouzier Regine , Cardona Marine , Barrett P. Noel , Steens Jean-Marc , Gineste Paul , Murphy Robert L. , Tazi Jamal , Ehrlich Hartmut J. 
Published: November 2016

ABSTRACT

ABX464 is an antiviral that provides a novel approach to the reduction and control of HIV infection. Investigation of food influence is important in the optimization of treatment. An open-label, food effect, randomized study which included 2 groups of 24 subjects each was carried out to assess the bioavailability and safety of single (group 1) and repeated (group 2) oral doses of ABX464 (50 mg) under fed or fasted conditions. The maximum concentration (
C
max
) and the area under the concentration-time curve from time zero to infinity (AUC
0–∞
) of ABX464 were demonstrated to increase with food after a single dose of ABX464 (219% and 188%, respectively). The apparent terminal elimination half-lives (
t
1/2
s) under fed and fasted conditions were comparable, at about 0.80 h. The median time to maximum concentration (
T
max
) was delayed from 1.5 to 2.8 h, and the ratio of the AUC
0–∞
obtained under fed conditions to the AUC
0–∞
obtained under fasted conditions (
F
rel
) was 2.69. Comparable results were obtained on day 1 and day 10 in group 2. The increases in
C
max
and AUC
0–∞
of the metabolite ABX464–N-glucuronide (ABX464-NGlc) were, however, much more limited when ABX464 was given with food. The
t
1/2
s were also comparable under the two conditions (around 100 h). Between day 1 and day 10, the
C
max
increased by 5% under the fasted condition and by 25% under the fed condition. The most common related treatment-emergent adverse events were headaches, vomiting, and nausea. It was concluded that food has a significant impact on the levels of ABX464 in plasma with a delay in absorption and increased relative bioavailability, with a lesser impact on its biotransformation into ABX464-NGlc. ABX464 was well tolerated under both fasted and fed conditions. (This study has been registered at ClinicalTrials.gov under registration no. NCT02731885.)
TLR7 Agonist GS-9620 Is a Potent Inhibitor of Acute HIV-1 Infection in Human Peripheral Blood Mononuclear Cells
Authors: Bam Rujuta A. , Hansen Derek , Irrinki Alivelu , Mulato Andrew , Jones Gregg S. , Hesselgesser Joseph , Frey Christian R. , Cihlar Tomas , Yant Stephen R. 
Published: November 2016

ABSTRACTGS-9620 is a potent and selective oral Toll-like receptor 7 (TLR7) agonist that directly activates plasmacytoid dendritic cells (pDCs). GS-9620 suppressed hepatitis B virus (HBV) in animal models of chronic infection and transiently activated HIV expressionex vivoin latently infected peripheral blood mononuclear cells (PBMCs) from virally suppressed patients. Currently, GS-9620 is under clinical evaluation for treating chronic HBV infection and for reducing latent reservoirs in virally suppressed HIV-infected patients. Here, we investigated thein vitroanti-HIV-1 activity of GS-9620. GS-9620 potently inhibited viral replication in PBMCs, particularly when it was added 24 to 48 h prior to HIV infection (50% effective concentration = 27 nM). Depletion of pDCs but not other immune cell subsets from PBMC cultures suppressed GS-9620 antiviral activity. Although GS-9620 was inactive against HIV in purified CD4+T cells and macrophages, HIV replication was potently inhibited by conditioned medium derived from GS-9620-treated pDC cultures when added to CD4+T cells prior to infection. This suggests that GS-9620-mediated stimulation of PBMCs induced the production of a soluble factor(s) inhibiting HIV replication intrans. GS-9620-treated PBMCs primarily showed increased production of interferon alpha (IFN-α), and cotreatment with IFN-α-blocking antibodies reversed the HIV-1-inhibitory effect of GS-9620. Additional studies demonstrated that GS-9620 inhibited a postentry event in HIV replication at a step coincident with or prior to reverse transcription. The simultaneous activation of HIV-1 expression and inhibition of HIV-1 replication are important considerations for the clinical evaluation of GS-9620 since these antiviral effects may help restrict potential local HIV spread uponin vivolatency reversal.
Acquisition of Carbapenem Resistance by Plasmid-Encoded-AmpC-Expressing Escherichia coli
Authors: van Boxtel Ria , Wattel Agnes A. , Arenas Jesús , Goessens Wil H. F. , Tommassen Jan 
Published: November 2016

ABSTRACT

Although AmpC β-lactamases can barely degrade carbapenems, if at all, they can sequester them and prevent them from reaching their targets. Thus, carbapenem resistance in
Escherichia coli
and other
Enterobacteriaceae
can result from AmpC production and simultaneous reduction of antibiotic influx into the periplasm by mutations in the porin genes. Here we investigated the route and genetic mechanisms of acquisition of carbapenem resistance in a clinical
E. coli
isolate carrying
bla
CMY-2
on a plasmid by selecting for mutants that are resistant to increasing concentrations of meropenem. In the first step, the expression of OmpC, the only porin produced in the strain under laboratory conditions, was lost, leading to reduced susceptibility to meropenem. In the second step, the expression of the CMY-2 β-lactamase was upregulated, leading to resistance to meropenem. The loss of OmpC was due to the insertion of an IS
1
element into the
ompC
gene or to frameshift mutations and premature stop codons in this gene. The
bla
CMY-2
gene was found to be located on an IncIγ plasmid, and overproduction of the CMY-2 enzyme resulted from an increased plasmid copy number due to a nucleotide substitution in the
inc
gene. The clinical relevance of these genetic mechanisms became evident from the analysis of previously isolated carbapenem-resistant clinical isolates, which appeared to carry similar mutations.
A Novel
erm
(44) Gene Variant from a Human Staphylococcus saprophyticus Isolate Confers Resistance to Macrolides and Lincosamides but Not Streptogramins
Authors: Strauss Christian , Hu Yanmin , Coates Anthony , Perreten Vincent 
Published: November 2016

ABSTRACT

A novel
erm
(44) gene variant,
erm
(44)
v
, has been identified by whole-genome sequencing in a
Staphylococcus saprophyticus
isolate from the skin of a healthy person. It has the particularity to confer resistance to macrolides and lincosamides but not to streptogramin B when expressed in
S. aureus
. The
erm
(44)
v
gene resides on a 19,400-bp genomic island which contains phage-associated proteins and is integrated into the chromosome of
S. saprophyticus
.
Covalent Immobilization of Enoxacin onto Titanium Implant Surfaces for Inhibiting Multiple Bacterial Species Infection and
In Vivo
Methicillin-Resistant Staphylococcus aureus Infection Prophylaxis
Authors: Nie Bin'en , Long Teng , Ao Haiyong , Zhou Jianliang , Tang Tingting , Yue Bing 
Published: November 2016

ABSTRACT

Infection is one of the most important causes of titanium implant failure
in vivo
. A developing prophylactic method involves the immobilization of antibiotics, especially vancomycin, onto the surface of the titanium implant. However, these methods have a limited effect in curbing multiple bacterial infections due to antibiotic specificity. In the current study, enoxacin was covalently bound to an amine-functionalized Ti surface by use of a polyethylene glycol (PEG) spacer, and the bactericidal effectiveness was investigated
in vitro
and
in vivo
. The titanium surface was amine functionalized with 3-aminopropyltriethoxysilane (APTES), through which PEG spacer molecules were covalently immobilized onto the titanium, and then the enoxacin was covalently bound to the PEG, which was confirmed by X-ray photoelectron spectrometry (XPS). A spread plate assay, confocal laser scanning microscopy (CLSM), and scanning electron microscopy (SEM) were used to characterize the antimicrobial activity. For the
in vivo
study, Ti implants were inoculated with methicillin-resistant
Staphylococcus aureus
(MRSA) and implanted into the femoral medullary cavity of rats. The degree of infection was assessed by radiography, micro-computed tomography, and determination of the counts of adherent bacteria 3 weeks after surgery. Our data demonstrate that the enoxacin-modified PEGylated Ti surface effectively prevented bacterial colonization without compromising cell viability, adhesion, or proliferation
in vitro
. Furthermore, it prevented MRSA infection of the Ti implants
in vivo
. Taken together, our results demonstrate that the use of enoxacin-modified Ti is a potential approach to the alleviation of infections of Ti implants by multiple bacterial species.
Efavirenz Is Predicted To Accumulate in Brain Tissue: an
In Silico
,
In Vitro
, and
In Vivo
Investigation
Authors: Curley Paul , Rajoli Rajith K. R. , Moss Darren M. , Liptrott Neill J. , Letendre Scott , Owen Andrew , Siccardi Marco 
Published: November 2016

ABSTRACT

Adequate concentrations of efavirenz in the central nervous system (CNS) are necessary to suppress viral replication, but high concentrations may increase the likelihood of CNS adverse drug reactions. The aim of this investigation was to evaluate the efavirenz distribution in the cerebrospinal fluid (CSF) and the brain by using a physiologically based pharmacokinetic (PBPK) simulation for comparison with rodent and human data. The efavirenz CNS distribution was calculated using a permeability-limited model on a virtual cohort of 100 patients receiving efavirenz (600 mg once daily). Simulation data were then compared with human data from the literature and with rodent data. Wistar rats were administered efavirenz (10 mg kg of body weight
−1
) once daily over 5 weeks. Plasma and brain tissue were collected for analysis via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The median maximum concentrations of drug (
C
max
) were predicted to be 3,184 ng ml
−1
(interquartile range [IQR], 2,219 to 4,851 ng ml
−1
), 49.9 ng ml
−1
(IQR, 36.6 to 69.7 ng ml
−1
), and 50,343 ng ml
−1
(IQR, 38,351 to 65,799 ng ml
−1
) in plasma, CSF, and brain tissue, respectively, giving a tissue-to-plasma ratio of 15.8. Following 5 weeks of oral dosing of efavirenz (10 mg kg
−1
), the median plasma and brain tissue concentrations in rats were 69.7 ng ml
−1
(IQR, 44.9 to 130.6 ng ml
−1
) and 702.9 ng ml
−1
(IQR, 475.5 to 1,018.0 ng ml
−1
), respectively, and the median tissue-to-plasma ratio was 9.5 (IQR, 7.0 to 10.9). Although it is useful, measurement of CSF concentrations may give an underestimation of the penetration of antiretrovirals into the brain. The limitations associated with obtaining tissue biopsy specimens and paired plasma and CSF samples from patients make PBPK modeling an attractive tool for probing drug distribution.
Comparative
In Vivo
Efficacies of Tedizolid in Neutropenic versus Immunocompetent Murine Streptococcus pneumoniae Lung Infection Models
Authors: Abdelraouf Kamilia , Nicolau David P. 
Published: November 2016

ABSTRACT

Given that tedizolid exhibits substantial lung penetration, we hypothesize that it could achieve good efficacy against
Streptococcus pneumoniae
lung infections. We evaluated the pharmacodynamics of tedizolid for treatment of
S. pneumoniae
lung infections and compared the efficacies of tedizolid human-simulated epithelial lining fluid (ELF) exposures in immunocompetent and neutropenic murine lung infection models. ICR mice were rendered neutropenic via intraperitoneal cyclophosphamide injections and then inoculated intranasally with
S. pneumoniae
suspensions. Immunocompetent CBA/J mice were inoculated similarly. Single daily tedizolid doses were administered 4 h postinoculation (termed 0 h). Changes in log
10
CFU at 24 h compared with 0-h controls were estimated. Ratios of area under the free-drug concentration-time curve to MIC (
f
AUC
0–24
/MIC) required to achieve various efficacy endpoints against each isolate were estimated using the Hill equation. Tedizolid doses in neutropenic and immunocompetent mice that mimic the human-simulated ELF exposure were examined. Stasis, 1-log reduction, and 2-log reduction were achieved at
f
AUC
0–24
/MIC of 8.96, 24.62, and 48.34, respectively, in immunocompetent mice and 19.21, 48.29, and 103.95, respectively, in neutropenic mice. Tedizolid at 40 mg/kg of body weight/day and 55 mg/kg/day in immunocompetent and neutropenic mice, respectively, resulted in ELF AUC
0–24
comparable to that achieved in humans following a 200-mg once-daily clinical dose. These human-simulated ELF exposures were adequate to attain >2-log reduction in bacterial burden at 24 h in 3 out of 4 isolates in both models and 1.58- and 0.74-log reductions with the fourth isolate in immunocompetent and neutropenic mice, respectively. Tedizolid showed potent
in vivo
efficacy against
S. pneumoniae
in both immunocompetent and neutropenic lung infection models, which support its consideration for
S. pneumoniae
lung infections.
Efficacy of High-Dose Meropenem (Six Grams per Day) in Treatment of Experimental Murine Pneumonia Induced by Meropenem-Resistant Pseudomonas aeruginosa
Authors: Oshima Kazuhiro , Nakamura Shigeki , Iwanaga Naoki , Takemoto Koji , Miyazaki Taiga , Yanagihara Kastunori , Miyazaki Yoshitsugu , Mukae Hiroshi , Kohno Shigeru , Izumikawa Koichi 
Published: November 2016

ABSTRACT

High-dose meropenem (MEPM; 6 g/day) has been approved as a treatment for purulent meningitis; however, little is known regarding its
in vivo
efficacy in refractory lower respiratory tract infections. The purpose of this study was to evaluate the efficacy of MEPM at 6 g/day in a murine model of severe pneumonia caused by MEPM-resistant
Pseudomonas aeruginosa
. Experimental pneumonia induced by MEPM-resistant
P. aeruginosa
was treated with normal-dose MEPM (150 mg/kg of body weight, simulating a 3-g/day regimen in humans) or high-dose MEPM (500 mg/kg, simulating a 6-g/day regimen in humans). Mice treated with high-dose MEPM showed significantly restored survival relative to that of untreated mice and tended to show a survival rate higher than that of mice treated with normal-dose MEPM. The viable bacterial counts (of two clinical isolates) in the lungs decreased significantly in mice treated with high-dose MEPM from those for untreated mice (
P
< 0.001) or mice treated with normal-dose MEPM (
P
, <0.01 and <0.05). The number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) was also significantly lower in mice treated with high-dose MEPM than in untreated mice. The free MEPM concentration in the epithelial lining fluid (ELF) exceeded 16 μg/ml for 85 min in mice treated with high-dose MEPM, but not for mice treated with normal-dose MEPM. Our results demonstrate that high-dose MEPM (6 g/day) might provide better protection against pneumonia caused by MEPM-resistant strains of
P. aeruginosa
than the dose normally administered (less than 3 g/day).
Distinct Effects of Integrins αXβ2and αMβ2on Leukocyte Subpopulations during Inflammation and Antimicrobial Responses
Authors: Jawhara Samir , Pluskota Elzbieta , Cao Wei , Plow Edward F. , Soloviev Dmitry A. 
Published: November 2016

ABSTRACTIntegrins αMβ2and αXβ2are homologous adhesive receptors that are expressed on many of the same leukocyte populations and bind many of the same ligands. Although αMβ2was extensively characterized and implicated in leukocyte inflammatory and immune functions, the roles of αXβ2remain largely obscure. Here, we tested the ability of mice deficient in integrin αMβ2or αXβ2to deal with opportunistic infections and the capacity of cells derived from these animals to execute inflammatory functions. The absence of αMβ2affected the recruitment of polymorphonuclear neutrophils (PMN) to bacterial and fungal pathogens as well as to model inflammatory stimuli, and αMβ2-deficient PMN displayed defective inflammatory functions. In contrast, deficiency of αXβ2abrogated intraperitoneal recruitment and adhesive functions of monocytes and macrophages (Mϕ) and the ability of these cells to kill/phagocytoseCandida albicansorEscherichia colicells bothex vivoandin vivo. During systemic candidiasis, the absence of αXβ2resulted in the loss of antifungal activity by tissue Mϕ and inhibited the production of tumor necrosis factor alpha (TNF-α)/interleukin-6 (IL-6) in infected kidneys. Deficiency of αMβ2suppressed Mϕ egress from the peritoneal cavity, decreased the production of anti-inflammatory IL-10, and stimulated the secretion of IL-6. The absence of αXβ2, but not of αMβ2, increased survival against a septic challenge with lipopolysaccharide (LPS) by 2-fold. Together, these results suggest that αMβ2plays a primary role in PMN inflammatory functions and regulates the anti-inflammatory functions of Mϕ, whereas αXβ2is central in the regulation of inflammatory functions of recruited and tissue-resident Mϕ.
MutS2 Promotes Homologous Recombination in Bacillus subtilis
Authors: Burby Peter E. , Simmons Lyle A. 
Published: November 2016

ABSTRACT

Bacterial MutS proteins are subdivided into two families, MutS1 and MutS2. MutS1 family members recognize DNA replication errors during their participation in the well-characterized mismatch repair (MMR) pathway. In contrast to the well-described function of MutS1, the function of MutS2 in bacteria has remained less clear. In
Helicobacter pylori
and
Thermus thermophilus
, MutS2 has been shown to suppress homologous recombination. The role of MutS2 is unknown in the Gram-positive bacterium
Bacillus subtilis
. In this work, we investigated the contribution of MutS2 to maintaining genome integrity in
B. subtilis
. We found that deletion of
mutS2
renders
B. subtilis
sensitive to the natural antibiotic mitomycin C (MMC), which requires homologous recombination for repair. We demonstrate that the C-terminal
s
mall
M
utS-
r
elated (Smr) domain is necessary but not sufficient for tolerance to MMC. Further, we developed a CRISPR/Cas9 genome editing system to test if the inducible prophage PBSX was the underlying cause of the observed MMC sensitivity. Genetic analysis revealed that MMC sensitivity was dependent on recombination and not on nucleotide excision repair or a symptom of prophage PBSX replication and cell lysis. We found that deletion of
mutS2
resulted in decreased transformation efficiency using both plasmid and chromosomal DNA. Further, deletion of
mutS2
in a strain lacking the Holliday junction endonuclease gene
recU
resulted in increased MMC sensitivity and decreased transformation efficiency, suggesting that MutS2 could function redundantly with RecU. Together, our results support a model where
B. subtilis
MutS2 helps to promote homologous recombination, demonstrating a new function for bacterial MutS2.

IMPORTANCE
Cells contain pathways that promote or inhibit recombination. MutS2 homologs are Smr-endonuclease domain-containing proteins that have been shown to function in antirecombination in some bacteria. We present evidence that
B. subtilis
MutS2 promotes recombination, providing a new function for MutS2. We found that cells lacking
mutS2
are sensitive to DNA damage that requires homologous recombination for repair and have reduced transformation efficiency. Further analysis indicates that the C-terminal Smr domain requires the N-terminal portion of MutS2 for function
in vivo
. Moreover, we show that a
mutS2
deletion is additive with a
recU
deletion, suggesting that these proteins have a redundant function in homologous recombination. Together, our study shows that MutS2 proteins have adapted different functions that impact recombination.
EFFECT OF 4 WEEKS HIGH-INTENSITY INTERMITTENT TAEKWONDO TRAINING ON BODY COMPOSITION AND PHYSICAL FITNESS IN ZULU DESCENT, SOUTH AFRICAN TAEKWONDO ATHLETES
Authors: Mathunjwa ML , Mugandani SC , Kappo AP , Ivanov S , Djarova-Daniels T 
Published: November 2016

The aim of the present study was to determine the effect of 4 weeks high intensity intermittent Taekwondo (TKD) training program on body composition, physical fitness and performance of South African TKD athletes of Zulu ancestry. Thirty four (n=34) active TKD athletes aged 20–26 years volunteered for this study. The athletes were divided into control and experimental groups. The control participants (10 males and 7 females) were holders of green and lower belts with provincial exposure. The experimental group (10 males and 7 females) had blue or senior belts who qualified to represent the provincial club and to compete in International championships. Both groups were subjected to a 4 week of TKD and strength training. The experimental group performing high intensity intermittent (85–95%VO2max) training and control group performing interval TKD training of lower intensity (70–75% VO2max). All subject were pre and post-tested on body composition [body mass, BMI, body fat percentage (%BF), sum of 6 skinfolds (SS)], flexibility (sit & reach), leg power (standing broad jump), muscle strength and endurance (sit-ups and push-ups), and agility (T-test) and VO2max(20 m bleep test). Resting heart rate (RHR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. Data was analyzed using pairedt-test for independent samples and Z-score individual radar plots statistics. After 4 weeks of training, athletes in the experimental group showed a reduction in body weight (p<0.05), BMI (p<0.001), SBP (p<0.05), RHR (p<0.05), SS (p<0.05), and fat % (p<0.001) and improvement (p<0.001) in flexibility, muscle strength, power, agility and VO2max. In male controls, fat % was decreased (p<0.05), flexibility and VO2maxwere increased (p<0.05). In female controls, only flexibility was improved (p<0.05). The findings of this study support the effectiveness of 4 weeks high intensity intermittent training in Taekwondo athletes of Zulu ancestry improves body composition, cardiorespiratory response and physical performance that could contribute to health and enhanced combat skills.
INTER-INDIVIDUAL DIFFERENCES IN THE RESPONSES OF VO2MAX TO PHYSICAL ACTIVITY COUNSELLING
Authors: Williamson P , Atkinson G , Batterham A 
Published: November 2016

Low cardiorespiratory fitness (VO2max) is an important risk factor for diabetes, cardiovascular disease and some cancers, making lifestyle interventions especially relevant. There is purported to be substantial inter-individual differences in how VO2maxresponds to lifestyle/exercise interventions. Recently, we described the appropriate approach for quantifying these inter-individual differences. Therefore, we aimed to apply this approach to quantify inter-individual differences in the responses of VO2max. We re-analysed data from the influential ‘Activity Counselling Trial’ (ACT), which was designed to determine the effects of general lifestyle assistance as well as formal counselling on physical activity and VO2maxin 479 men and 395 women. Importantly, an appropriate comparator group was also present in order to quantify ‘true’ inter-individual differences in VO2maxresponse. For women, the ‘true’ inter-individual responses in VO2max(expressed as a SD) were found to be±129 (95% Confidence interval: −40 to 187) ml/min in the general lifestyle assistance group and±93 (−91 to 160) ml/min in the formal lifestyle counselling group. For men, true individual differences in response were±116 (95%CI: −130 to 210) ml/min and±148 (−105 to 234) ml/min in the assistance and counselling groups, respectively.Although the mean increase in VO2maxwas greater in women, this increase corresponded to a trivial effect size. This application of the appropriate analyses to the ACT dataset indicate that, on average, the effects of activity counselling on VO2maxwere small, although there were moderate ‘true’ inter-individual differences in the VO2maxresponse in women (0.34 SD) and small ‘true’ inter-individual differences in men (0.27 SD). Further genotype investigation may therefore be warranted in order to determine the mediators of this observed heterogeneity in response.