bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic and pharmacodynamic analysis comparing diverse effects of detomidine, medetomidine, and dexmedetomidine in the horse: a population analysis
Authors: Grimsrud K. N. , Ait‐Oudhia S. , Durbin‐Johnson B. P. , Rocke D. M. , Mama K. R. , Rezende M. L. , Stanley S. D. , Jusko W. J. 
Published: July 2014

The present study characterizes the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of theα2‐adrenergic receptor agonists detomidine (DET), medetomidine (MED) and dexmedetomidine (DEX) in parallel groups of horses fromin vivodata after single bolus doses. Head height (HH), heart rate (HR), and blood glucose concentrations were measured over 6 h. CompartmentalPKand minimal physiologically basedPK(mPBPK) models were applied and incorporated into basic and extended indirect response models (IRM). PopulationPK/PDanalysis was conducted using theMonolix software implementing the stochastic approximation expectation maximization algorithm. Marked reductions inHHandHRwere found. The drug concentrations required to obtain inhibition at half‐maximal effect (IC50) were approximately four times larger for DET than MED and DEX for both HH and HR. These effects were not gender dependent. Medetomidine had a greater influence on the increase in glucose concentration thanDEX. The developed models demonstrate the use of mechanistic and mPBPK/PDmodels for the analysis of clinically obtainablein vivodata.
Spleen stiffness can non‐invasively assess resolution of portal hypertension after liver transplantation
Authors: Chin Jun Liong , Chan Grace , Ryan John D. , McCormick P. Aiden 
Published: July 2014

AbstractBackground & AimsSpleen stiffness can be measured by transient elastography. Recent studies have shown that spleen stiffness correlates with hepatic venous pressure gradient and can predict oesophageal varices. Elevated spleen stiffness in cirrhosis has been attributed to splenic tissue hyperplasia and fibrosis, portal hypertension and its consequent hyperdynamic circulation. The aim of this study was to investigate changes to spleen stiffness after orthotopic liver transplantation (OLT) when portal hypertension resolves.MethodsTwenty‐one patients awaiting OLT were studied prospectively, while 11 post‐transplant patients were recruited as controls. Spleen and liver stiffness were measured with Fibroscan before and at 2–8 weeks after OLT. Criteria applied for spleen stiffness measurement were similar to liver stiffness (≥10 measurements; ≥60% success rate; interquartile range, IQR <30% of median).ResultsSpleen stiffness was significantly higher before OLT compared to post‐transplant patients [75.0 (63.9–75.0) kPa vs. 28.4 (22.0–37.5) kPa; P < 0.0001]. For patients awaiting OLT, 90% (19/21) had oesophageal varices (endoscopically or radiologically). In patients who underwent liver transplantation, spleen stiffness decreased significantly from a median of 75.0 (62.0–75.0) kPa before OLT, to 41.9 (27.0–47.4) kPa at 2 weeks after transplant and 32.9 (29.1–38.0) kPa in the subsequent 4–8 weeks after OLT (P < 0.0001). As expected, liver stiffness measurements reduced from 39.3 (24.9–75.0) kPa to 8.6 (6.8–11.8) kPa in patients receiving OLT (P = 0.0004).ConclusionsSpleen stiffness can non‐invasively assess changes in portal pressure after liver transplantation and decreases significantly when portal hypertension resolves.
Identifying the core microbial community in the gut of fungus‐growing termites
Authors: Otani Saria , Mikaelyan Aram , Nobre Tânia , Hansen Lars H. , Koné N'Golo A. , Sørensen Søren J. , Aanen Duur K. , Boomsma Jacobus J. , Brune Andreas , Poulsen Michael 
Published: July 2014

AbstractGut microbes play a crucial role in decomposing lignocellulose to fuel termite societies, with protists in the lower termites and prokaryotes in the higher termites providing these services. However, a single basal subfamily of the higher termites, the Macrotermitinae, also domesticated a plant biomass‐degrading fungus (Termitomyces), and how this symbiont acquisition has affected the fungus‐growing termite gut microbiota has remained unclear. The objective of our study was to compare the intestinal bacterial communities of five genera (nine species) of fungus‐growing termites to establish whether or not an ancestral core microbiota has been maintained and characterizes extant lineages. Using 454‐pyrosequencing of the 16S rRNA gene, we show that gut communities have representatives of 26 bacterial phyla and are dominated by Firmicutes, Bacteroidetes, Spirochaetes, Proteobacteria and Synergistetes. A set of 42 genus‐level taxa was present in all termite species and accounted for 56–68% of the species‐specific reads. Gut communities of termites from the same genus were more similar than distantly related species, suggesting that phylogenetic ancestry matters, possibly in connection with specific termite genus‐level ecological niches. Finally, we show that gut communities of fungus‐growing termites are similar to cockroaches, both at the bacterial phylum level and in a comparison of the core Macrotermitinae taxa abundances with representative cockroach, lower termite and higher nonfungus‐growing termites. These results suggest that the obligate association with Termitomyces has forced the bacterial gut communities of the fungus‐growing termites towards a relatively uniform composition with higher similarity to their omnivorous relatives than to more closely related termites.
Evaluation of the kinetics and mechanism of action of anti‐integration host factor‐mediated disruption of bacterial biofilms
Authors: Brockson M. Elizabeth , Novotny Laura A. , Mokrzan Elaine M. , Malhotra Sankalp , Jurcisek Joseph A. , Akbar Rabia , Devaraj Aishwarya , Goodman Steven D. , Bakaletz Lauren O. 
Published: July 2014

SummaryThe extracellular polymeric substance produced by many human pathogens during biofilm formation often contains extracellular DNA (eDNA). Strands of bacterial eDNA within the biofilm matrix can occur in a lattice‐like network wherein a member of the DNABII family of DNA‐binding proteins is positioned at the vertex of each crossed strand. To date, treatment of all biofilms tested with antibodies directed against one DNABII protein, Integration Host Factor (IHF), results in significant disruption. Here, using non‐typeable Haemophilus influenzae as a model organism, we report that this effect was rapid, IHF‐specific and mediated by binding of transiently dissociated IHF by anti‐IHF even when physically separated from the biofilm by a nucleopore membrane. Further, biofilm disruption fostered killing of resident bacteria by previously ineffective antibiotics. We propose the mechanism of action to be the sequestration of IHF upon dissociation from the biofilm eDNA, forcing an equilibrium shift and ultimately, collapse of the biofilm. Further, antibodies against a peptide positioned at the DNA‐binding tips of IHF were as effective as antibodies directed against the native protein. As incorporating eDNA and associated DNABII proteins is a common strategy for biofilms formed by multiple human pathogens, this novel therapeutic approach is likely to have broad utility.
Identification of host genes that affect acquisition of an integrative and conjugative element in Bacillus subtilis
Authors: Johnson Christopher M. , Grossman Alan D. 
Published: July 2014

SummaryConjugation, a major type of horizontal gene transfer in bacteria, involves transfer of DNA from a donor to a recipient using donor‐encoded conjugation machinery. Using a high‐throughput screen (Tn‐seq), we identified genes in recipients that contribute to acquisition of the integrative and conjugative element ICEBs1 by Bacillus subtilis. We found that null mutations in some genes caused an increase, and others a decrease in conjugation efficiency. Some mutations affected conjugation only when present in recipients. Other mutations affected conjugation when present in donors or recipients. Most of the genes identified are known or predicted to affect the cell envelope. Several encode enzymes involved in phospholipid biosynthesis and one encodes a homologue of penicillin‐binding proteins. Two of the genes identified also affected conjugation of Tn916, indicating that their roles in conjugation may be general. We did not identify any genes in recipients that were essential for ICEBs1 conjugation, indicating that if there are such genes, then these are either essential for cell growth or redundant. Our results indicate that acquisition of ICEBs1, and perhaps other conjugative elements, is robust and not easily avoided by mutation and that several membrane‐related functions affect the efficiency of conjugation.
An Independent Scholar: Lawrence Moonan's Legacy
Authors: Kerr Fergus 
Published: July 2014

AbstractLawrence Moonan (1937–2013) pioneered the study of the medieval Scottish philosopher Lawrence of Lindores; he published a major work on the notion of divine omnipotence in early scholasticism; and he kept worrying that in these post-Deistical times many philosophers and theologians have forgotten what it is like to think of God as strictly infinite.
Visual ground pattern modulates flight speed of male Oriental fruit moth Grapholita molesta
Authors: Kuenen Lodewyk P. S. , Gilbert Cole 
Published: July 2014

AbstractInsects flying in a horizontal pheromone plume must attend to visual cues to ensure that they make upwind progress. Moreover, it is suggested that flying insects will also modulate their flight speed to maintain a constant retinal angular velocity of terrestrial contrast elements. Evidence from flies and honeybees supports such a hypothesis, although tests with male moths and beetles flying in pheromone plumes are not conclusive. These insects typically fly faster at higher elevations above a high‐contrast ground pattern, as predicted by the hypothesis, although the increase in speed is not sufficient to demonstrate quantitatively that they maintain constant visual angular velocity of the ground pattern. To test this hypothesis more rigorously, the flight speed of male oriental fruit moths (OFM) Grapholita molesta Busck (Lepidoptera: Tortricidae) flying in a sex pheromone plume in a laboratory wind tunnel is measured at various heights (5–40 cm) above patterns of different spatial wavelength (1.8–90°) in the direction of flight. The OFM modulate their flight speed three‐fold over different patterns. They fly fastest when there is no pattern in the tunnel or the contrast elements are too narrow to resolve. When the spatial wavelength of the pattern is sufficiently wide to resolve, moths fly at a speed that tends to maintain a visual contrast frequency of 3.5 ± 3.2 Hz rather than a constant angular velocity, which varies from 57 to 611° s−1. In addition, for the first time, it is also demonstrated that the width of a contrast pattern perpendicular to the flight direction modulates flight speed.
A Replicate Designed Bioequivalence Study To Compare Two Fixed-Dose Combination Products of Artesunate and Amodiaquine in Healthy Chinese Volunteers
Authors: Liu Yun , Hu Chaoying , Liu Gangyi , Jia Jingying , Yu Chen , Zhu Jianmin , Zheng Qingsi , Zhang Kanyin E. 
Published: July 2014

ABSTRACT

Artesun-Plus is a fixed-dose combination antimalarial agent containing artesunate and amodiaquine. The current study was conducted to compare the pharmacokinetic and safety profiles of Artesun-Plus and the WHO-designated comparator product Artesunate Amodiaquine Winthrop. To overcome the high intrasubject variability of artesunate, the study applied a two-sequence and four-period crossover (2 by 4), replicate study design to assess bioequivalence between the two products in 31 healthy male Chinese volunteers under fasting conditions. The results showed that the values of the geometric mean ratios of maximum concentration of drug in plasma (
C
max
) and area under the concentration-time curve from time zero to the last blood sample collection (AUC
0-last
) for the artesunate component in the test and reference products were 95.9% and 93.9%, respectively, and that the corresponding 90% confidence intervals were 84.5% to 108.7% and 87.2% to 101.1%, while the geometric mean ratios for the amodiaquine component in the test and reference products were 95.0% and 100.0%, respectively, and the corresponding 90% confidence intervals were 86.7% to 104.1% and 93.5% to 107.0%. In conclusion, bioequivalence between the two artesunate and amodiaquine fixed-dose combination products was demonstrated for both components. The study also confirmed high intrasubject variability, especially for artesunate: the coefficients of variation (CV) of
C
max
values for the test and reference products were 39.2% and 43.7%, respectively, while those for amodiaquine were 30.6% and 30.2%, respectively.
In Vivo
Activity of Cefquinome against Escherichia coli in the Thighs of Neutropenic Mice
Authors: Shan Qi , Liang Chaoping , Wang Jing , Li Jufeng , Zeng Zhenling 
Published: July 2014

ABSTRACT

Cefquinome is a cephalosporin with broad-spectrum antibacterial activity, including activity against enteric Gram-negative bacilli such as
Escherichia coli
. We utilized a neutropenic mouse model of colibacillosis to examine the pharmacodynamic (PD) characteristics of cefquinome, as measured by organism number in homogenized thigh cultures after 24 h of therapy. Serum drug levels following 4-fold-escalating single doses of cefquinome were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic (PK) properties of cefquinome were linear over a dose range of 10 to 640 mg/kg of body weight. Serum half-lives ranged from 0.29 to 0.32 h. Dose fractionation studies over a 24-h dose range of 2.5 to 320 mg/kg were conducted every 3, 6, 12, or 24 h. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. The free percentage of the dosing interval that the serum levels exceed the MIC (
fT
>MIC
) was the PK-PD index that best correlated with efficacy (
R
2
= 73% for
E. coli
, compared with 13% for the maximum concentration of the free drug in serum [
f
C
max
]/MIC and 45% for the free-drug area under the concentration-time curve from 0 to 24 h [
f
AUC
0-24
]/MIC). Subsequently, we employed a similar dosing strategy by using 4-fold-increasing total cefquinome doses administered every 4 h to treat animals infected with four additional
E. coli
isolates. A sigmoid maximum-effect (
E
max
) model was used to estimate the magnitudes of the %
fT
>MIC
associated with net bacterial stasis, a 1-log
10
CFU reduction from baseline, and a 2-log
10
CFU reduction from baseline; the corresponding values were 28.01% ± 2.27%, 37.23% ± 4.05%, and 51.69% ± 9.72%. The potent bactericidal activity makes cefquinome an attractive option for the treatment of infections caused by
E. coli
.
Sigma S-Dependent Antioxidant Defense Protects Stationary-Phase Escherichia coli against the Bactericidal Antibiotic Gentamicin
Authors: Wang Jing-Hung , Singh Rachna , Benoit Michael , Keyhan Mimi , Sylvester Matthew , Hsieh Michael , Thathireddy Anuradha , Hsieh Yi-Ju , Matin A. C. 
Published: July 2014

ABSTRACT

Stationary-phase bacteria are important in disease. The σ
s
-regulated general stress response helps them become resistant to disinfectants, but the role of σ
s
in bacterial antibiotic resistance has not been elucidated. Loss of σ
s
rendered stationary-phase
Escherichia coli
more sensitive to the bactericidal antibiotic gentamicin (Gm), and proteomic analysis suggested involvement of a weakened antioxidant defense. Use of the p
sfiA
genetic reporter, 3′-(
p
-hydroxyphenyl) fluorescein (HPF) dye, and Amplex Red showed that Gm generated more reactive oxygen species (ROS) in the mutant. HPF measurements can be distorted by cell elongation, but Gm did not affect stationary-phase cell dimensions. Coadministration of the antioxidant
N
-acetyl cysteine (NAC) decreased drug lethality particularly in the mutant, as did Gm treatment under anaerobic conditions that prevent ROS formation. Greater oxidative stress, due to insufficient quenching of endogenous ROS and/or respiration-linked electron leakage, therefore contributed to the greater sensitivity of the mutant; infection by a uropathogenic strain in mice showed this to be the case also
in vivo
. Disruption of antioxidant defense by eliminating the quencher proteins, SodA/SodB and KatE/SodA, or the pentose phosphate pathway proteins, Zwf/Gnd and TalA, which provide NADPH for ROS decomposition, also generated greater oxidative stress and killing by Gm. Thus, besides its established mode of action, Gm also kills stationary-phase bacteria by generating oxidative stress, and targeting the antioxidant defense of
E. coli
can enhance its efficacy. Relevant aspects of the current controversy on the role of ROS in killing by bactericidal drugs of exponential-phase bacteria, which represent a different physiological state, are discussed.
Migration of Dendritic Cells Facilitates Systemic Dissemination of Burkholderia pseudomallei
Authors: Williams Natasha L. , Morris Jodie L. , Rush Catherine M. , Ketheesan Natkunam 
Published: July 2014

ABSTRACT

Burkholderia pseudomallei
, the etiological agent for melioidosis, is an important cause of community-acquired sepsis in northern Australia and northeast Thailand. Due to the rapid dissemination of disease in acute melioidosis, we hypothesized that dendritic cells (DC) could act as a vehicle for dissemination of
B. pseudomallei
. Therefore, this study investigated the effect of
B. pseudomallei
infection on DC migration capacity and whether migration of DC enabled transportation of
B. pseudomallei
from the site of infection.
B. pseudomallei
stimulated significantly increased migration of bone marrow-derived DC (BMDC), both
in vitro
and
in vivo
, compared to uninfected BMDC. Furthermore, migration of BMDC enabled significantly increased
in vitro
trafficking of
B. pseudomallei
and
in vivo
dissemination of
B. pseudomallei
to secondary lymphoid organs and lungs of C57BL/6 mice. DC within the footpad infection site of C57BL/6 mice also internalized
B. pseudomallei
and facilitated dissemination. Although DC have previously been shown to kill intracellular
B. pseudomallei
in vitro
, the findings of this study demonstrate that
B. pseudomallei
-infected DC facilitate the systemic spread of this pathogen.
Conserved Oligopeptide Permeases Modulate Sporulation Initiation in Clostridium difficile
Authors: Edwards Adrianne N. , Nawrocki Kathryn L. , McBride Shonna M. 
Published: July 2014

ABSTRACT

The anaerobic gastrointestinal pathogen
Clostridium difficile
must form a metabolically dormant spore to survive in oxygenic environments and be transmitted from host to host. The regulatory factors by which
C. difficile
initiates and controls the early stages of sporulation in
C. difficile
are not highly conserved in other
Clostridium
or
Bacillus
species. Here, we investigated the role of two conserved oligopeptide permeases, Opp and App, in the regulation of sporulation in
C. difficile
. These permeases are known to positively affect sporulation in
Bacillus
species through the import of sporulation-specific quorum-sensing peptides. In contrast to other spore-forming bacteria, we discovered that inactivating these permeases in
C. difficile
resulted in the earlier expression of early sporulation genes and increased sporulation
in vitro
. Furthermore, disruption of
opp
and
app
resulted in greater virulence and increased the amounts of spores recovered from feces in the hamster model of
C. difficile
infection. Our data suggest that Opp and App indirectly inhibit sporulation, likely through the activities of the transcriptional regulator SinR and its inhibitor, SinI. Taken together, these results indicate that the Opp and App transporters serve a different function in controlling sporulation and virulence in
C. difficile
than in
Bacillus subtilis
and suggest that nutrient availability plays a significant role in pathogenesis and sporulation
in vivo
. This study suggests a link between the nutritional status of the environment and sporulation initiation in
C. difficile
.
Tectonism and magmatism identified on asteroids
Authors: Buczkowski Debra L. , Wyrick Danielle Y. 
Published: July 2014

Abstract
Linear features generally accepted as tectonic structures have been observed on several asteroids and their presence has implications for the internal structure, strength and evolution of these various bodies. Lineaments observed on the Martian moon Phobos led to the prediction that other cratered small bodies would be similarly lineated. Observations of several small bodies, including Gaspra, Ida, Mathilde, Eros, Itokawa, Steins, Lutetia and Vesta, have identified different physical mechanisms by which linear features can be formed. Analysis shows that asteroid lineaments appear to have different origins, including impact, and that lineament orientations and magnitudes provide important constraints on the interior structure of these bodies. Being a differentiated proto-planet, Vesta is a unique body with which to study the role that internal rheologies and structures play on surface tectonic expression. Vesta presents fractures and grooves similar to the other observed asteroids, but also large-scale graben and trough structures more characteristic of terrestrial planet tectonics. Unlike many terrestrial planets, Vesta's main stressors have, however, been primarily exogenic (e.g. impacts) rather than internally driven. Nevertheless, while the search for volcanic features on Vesta has not been successful, the evaluation of the Brumalia Tholus feature suggests that the geological history of Vesta may have included magmatism.
Sun Exposure and Melanoma Survival: A GEM Study
Authors: Berwick Marianne , Reiner Anne S. , Paine Susan , Armstrong Bruce K. , Kricker Anne , Goumas Chris , Cust Anne E. , Thomas Nancy E. , Groben Pamela A. , From Lynn , Busam Klaus , Orlow Irene , Marrett Loraine D. , Gallagher Richard P. , Gruber Stephen B. , Anton-Culver Hoda , Rosso Stefano , Zanetti Roberto , Kanetsky Peter A. , Dwyer Terry , Venn Alison , Lee-Taylor Julia , Begg Colin B. ,   for the GEM Study Group
Published: July 2014

Abstract
Background: We previously reported a significant association between higher UV radiation exposure before diagnosis and greater survival with melanoma in a population-based study in Connecticut. We sought to evaluate the hypothesis that sun exposure before diagnosis was associated with greater survival in a larger, international population-based study with more detailed exposure information.
Methods: We conducted a multicenter, international population-based study in four countries—Australia, Italy, Canada, and the United States—with 3,578 cases of melanoma with an average of 7.4 years of follow-up. Measures of sun exposure included sunburn, intermittent exposure, hours of holiday sun exposure, hours of water-related outdoor activities, ambient ultraviolet B (280–320 nm) dose, histologic solar elastosis, and season of diagnosis.
Results: Results were not strongly supportive of the earlier hypothesis. Having had any sunburn in 1 year within 10 years of diagnosis was inversely associated with survival; solar elastosis—a measure of lifetime cumulative exposure—was not. In addition, none of the intermittent exposure measures—water-related activities and sunny holidays—were associated with melanoma-specific survival. Estimated ambient UVB dose was not associated with survival.
Conclusion: Although there was an apparent protective effect of sunburns within 10 years of diagnosis, there was only weak evidence in this large, international, population-based study of melanoma that sun exposure before diagnosis is associated with greater melanoma-specific survival.
Impact: This study adds to the evidence that sun exposure before melanoma diagnosis has little effect on survival with melanoma. Cancer Epidemiol Biomarkers Prev; 23(10); 2145–52. ©2014 AACR.