bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sinusoidal high‐intensity exercise does not elicit ventilatory limitation in chronic obstructive pulmonary disease
Authors: Porszasz Janos , Rambod Mehdi , van der Vaart Hester , Rossiter Harry B. , Ma Shuyi , Kiledjian Rafi , Casaburi Richard 
Published: January 2013

New Findings
What is the central question of this study?Is it possible for patients with chronic obstructive pulmonary disease to avoid ventilatory limitation during high‐intensity exercise by using a fast‐fluctuating sinusoidal exercise task?
What is the main finding and its importance?Sinusoidal exercise, with a cycle time of 60 s superimposed upon a mean work rate at critical power, resulted in minimal fluctuations in the exercise ventilation. Thus, high‐intensity exercise, with excursions well above peak aerobic power, was sustained for up to 20 min in chronic obstructive pulmonary disease patients, and the end‐exercise ventilation was less than peak. This exercise protocol may prove beneficial in rehabilitative exercise training programmes where large gains in skeletal muscle adaptation are the goal.
During exercise at critical power (CP) in chronic obstructive pulmonary disease (COPD) patients, ventilation approaches its maximum. As a result of the slow ventilatory dynamics in COPD, ventilatory limitation during supramaximal exercise might be escaped using rapid sinusoidal forcing. Nine COPD patients [age, 60.2 ± 6.9 years; forced expiratory volume in the first second (FEV1), 42 ± 17% of predicted; and FEV1/FVC, 39 ± 12%] underwent an incremental cycle ergometer test and then four constant work rate cycle ergometer tests; tolerable duration (tlim) was recorded. Critical power was determined from constant work rate testing by linear regression of work rate versus 1/tlim. Patients then completed fast (FS; 60 s period) and slow (SS; 360 s period) sinusoidally fluctuating exercise tests with mean work rate at CP and peak at 120% of peak incremental test work rate, and one additional test at CP; each for a 20 min target. The value of tlim did not differ between CP (19.8 ± 0.6 min) and FS (19.0 ± 2.5 min), but was shorter in SS (13.2 ± 4.2 min; P < 0.05). The sinusoidal ventilatory amplitude was minimal (37.4 ± 34.9 ml min−1 W−1) during FS but much larger during SS (189.6 ± 120.4 ml min−1 W−1). The total ventilatory response in SS reached 110 ± 8.0% of the incremental test peak, suggesting ventilatory limitation. Slow components in ventilation during constant work rate and FS exercises were detected in most subjects and contributed appreciably to the total response asymptote. The SS exercise was associated with higher mid‐exercise lactate concentrations (5.2 ± 1.7, 7.6 ± 1.7 and 4.5 ± 1.3 mmol l−1 in FS, SS and CP). Large‐amplitude, rapid sinusoidal fluctuation in work rate yields little fluctuation in ventilation despite reaching 120% of the incremental test peak work rate. This high‐intensity exercise strategy might be suitable for programmes of rehabilitative exercise training in COPD.
Relevance of vascular peroxisome proliferator‐activated receptor γ coactivator‐1α to molecular alterations in atherosclerosis
Authors: Valero‐Muñoz M. , Martín‐Fernández B. , Ballesteros S. , Martínez‐Martínez E. , Blanco‐Rivero J. , Balfagón G. , Cachofeiro V. , Lahera V. , de las Heras N. 
Published: January 2013

New Findings
What is the central question of this study?Does PGC‐1α play a key role in vascular alterations induced by cholesterol+coconut oil diet in rabbits?
What is the main finding and its importance?Vascular expression of PGC‐1α, SIRT1 and PPARγ were reduced in atherosclerotic rabbits. Furthermore, PGC‐1α correlated with processes involved in atherosclerosis (endothelial dysfunction, oxidative stress and inflammation). Reduction of PGC‐1α seems to play an important role in the molecular alterations during the development of atherosclerosis.
Peroxisome proliferator‐activated receptor γ coactivator‐1α (PGC‐1α) is emerging as a novel factor that plays a critical role in integrating signalling pathways in the control of cellular and systemic metabolism. We investigated the role of vascular expression of PGC‐1α and related factors, such as sirtuin 1 (SIRT1), peroxisome proliferator‐activated receptor γ (PPARγ) and adiponectin, during the atherosclerotic process. Endothelial function, vascular superoxide anion production and inflammatory mediators were also evaluated. This study was carried out in male New Zealand rabbits fed a diet containing 0.5% cholesterol and 14% coconut oil for 8 weeks. Animals developed mixed dyslipidaemia and atherosclerotic lesions, which were associated with endothelial dysfunction, aortic overproduction of superoxide anions and inflammation. Expression of PGC‐1α, SIRT1, PPARγ and adiponectin was reduced (P < 0.05) in aorta from atherosclerotic rabbits. Levels of PGC‐1α were correlated negatively (P < 0.05) with total cholesterol levels, aortic superoxide anion production and tumour necrosis factor‐α expression, and positively (P < 0.05) with maximal relaxation in response to acetylcholine. The observed results suggest that PGC‐1α could be considered to be a link between the main atherosclerotic processes (endothelial dysfunction, oxidation and inflammation) and alterations of other factors involved in vascular wall integrity, such as SIRT1, PPARγ and adiponectin.
Combined Intravenous and Intraventricular Administration of Colistin Methanesulfonate in Critically Ill Patients with Central Nervous System Infection
Authors: Ziaka Mairi , Markantonis Sophia L. , Fousteri Marizoza , Zygoulis Paris , Panidis Dimitris , Karvouniaris Marios , Makris Demosthenes , Zakynthinos Epaminondas 
Published: January 2013

ABSTRACT

Colistin pharmacokinetics were prospectively studied after intravenous administration of colistin methanesulphonate in critically ill patients without central nervous system infection (controls,
n
= 5) and in patients with external ventricular drain-associated ventriculitis after intravenous administration (EVDViv,
n
= 3) or combined intravenous/intraventricular administration (EVDVcomb,
n
= 4). Cerebrospinal fluid (CSF)/serum colistin concentration ratios were higher in EVDViv than in control patients (11% versus 7%,
P
≤ 0.05) and in EVDVcomb compared to all other patients (
P
< 0.0001). CSF colistin concentrations above the MIC of 0.5 μg/ml were achieved only in EVDVcomb patients.
Vancomycin AUC/MIC Ratio and 30-Day Mortality in Patients with Staphylococcus aureus Bacteremia
Authors: Holmes Natasha E. , Turnidge John D. , Munckhof Wendy J. , Robinson J. Owen , Korman Tony M. , O'Sullivan Matthew V. N. , Anderson Tara L. , Roberts Sally A. , Warren Sanchia J. C. , Gao Wei , Howden Benjamin P. , Johnson Paul D. R. 
Published: January 2013

ABSTRACT

A ratio of the vancomycin area under the concentration-time curve to the MIC (AUC/MIC) of ≥400 has been associated with clinical success when treating
Staphylococcus aureus
pneumonia, and this target was recommended by recently published vancomycin therapeutic monitoring consensus guidelines for treating all serious
S. aureus
infections. Here, vancomycin serum trough levels and vancomycin AUC/MIC were evaluated in a “real-world” context by following a cohort of 182 patients with
S. aureus
bacteremia (SAB) and analyzing these parameters within the critical first 96 h of vancomycin therapy. The median vancomycin trough level at this time point was 19.5 mg/liter. There was a significant difference in vancomycin AUC/MIC when using broth microdilution (BMD) compared with Etest MIC (medians of 436.1 and 271.5, respectively;
P
< 0.001). Obtaining the recommended vancomycin target AUC/MIC of ≥400 using BMD was not associated with lower 30-day all-cause or attributable mortality from SAB (
P
= 0.132 and
P
= 0.273, respectively). However, an alternative vancomycin AUC/MIC of >373, derived using classification and regression tree analysis, was associated with reduced mortality (
P
= 0.043) and remained significant in a multivariable model. This study demonstrated that we obtained vancomycin trough levels in the target therapeutic range early during the course of therapy and that obtaining a higher vancomycin AUC/MIC (in this case, >373) within 96 h was associated with reduced mortality. The MIC test method has a significant impact on vancomycin AUC/MIC estimation. Clinicians should be aware that the current target AUC/MIC of ≥400 was derived using the reference BMD method, so adjustments to this target need to be made when calculating AUC/MIC ratio using other MIC testing methods.
In Vitro
Antifungal Susceptibility of Clinically Relevant Species Belonging to Aspergillus Section
Flavi
Authors: Gonçalves Sarah S. , Stchigel Alberto M. , Cano Josep , Guarro Josep , Colombo Arnaldo L. 
Published: January 2013

ABSTRACT

The
in vitro
antifungal susceptibility of 77 isolates belonging to different clinically relevant species of
Aspergillus
section
Flavi
, including those of different phylogenetic clades of
A. flavus
, was tested for nine antifungal agents using a microdilution reference method (CLSI, M38-A2). Terbinafine and the echinocandins demonstrated lower MICs/MECs for all species evaluated, followed by posaconazole. Amphotericin B showed MICs ≥ 2 μg/ml for 38 (49.4%) of the 77 isolates tested.
Involvement of Efflux Pumps in the Resistance to Peptidoglycan Synthesis Inhibitors in Mycobacterium tuberculosis
Authors: Dinesh Neela , Sharma Sreevalli , Balganesh Meenakshi 
Published: January 2013

ABSTRACT

We evaluated the contributions of
Mycobacterium tuberculosis
efflux pumps towards intrinsic resistance to different classes of peptidoglycan synthesis inhibitors (PSI). Our study indicates that the efflux pump knockout strains are more susceptible to PSI than the wild type. Vancomycin and ceftriaxone exhibited up to 3 log increased kill on efflux pump mutants compared to the wild-type strain, strongly suggesting an important role for efflux pumps in the intrinsic resistance of
M. tuberculosis
to PSI.
Evaluating 5-Nitrofurans as Trypanocidal Agents
Authors: Bot Christopher , Hall Belinda S. , Álvarez Guzmán , Di Maio Rossanna , González Mercedes , Cerecetto Hugo , Wilkinson Shane R. 
Published: January 2013

ABSTRACT

The nitroheterocycle nifurtimox, as part of a nifurtimox-eflornithine combination therapy, represents one of a limited number of treatments targeting
Trypanosoma brucei
, the causative agent of human African trypanosomiasis. The mode of action of this prodrug involves an initial activation reaction catalyzed by a type I nitroreductase (NTR), an enzyme found predominantly in prokaryotes, leading to the formation of a cytotoxic unsaturated open-chain nitrile metabolite. Here, we evaluate the trypanocidal activities of a library of other 5-nitrofurans against the bloodstream form of
T. brucei
as a preliminary step in the identification of additional nitroaromatic compounds that can potentially partner with eflornithine. Biochemical screening against the purified enzyme revealed that all 5-nitrofurans were effective substrates for
T. brucei
NTR (TbNTR), with the preferred compounds having apparent
k
cat
/

K
m

values approximately 50-fold greater than those of nifurtimox. For several compounds,
in vitro
reduction by this nitroreductase yielded products characterized by mass spectrometry as either unsaturated or saturated open-chain nitriles. When tested against the bloodstream form of
T. brucei
, many of the derivatives displayed significant growth-inhibitory properties, with the most potent compounds generating 50% inhibitory concentrations (IC
50
s) around 200 nM. The antiparasitic activities of the most potent agents were demonstrated to be NTR dependent, as parasites having reduced levels of the enzyme displayed resistance to the compounds, while parasites overexpressing TbNTR showed hypersensitivity. We conclude that other members of the 5-nitrofuran class of nitroheterocycles have the potential to treat human African trypanosomiasis, perhaps as an alternative partner prodrug to nifurtimox, in the next generation of eflornithine-based combinational therapies.
Selective Serotonin Reuptake Inhibitor Fluoxetine Inhibits Replication of Human Enteroviruses B and D by Targeting Viral Protein 2C
Authors: Ulferts Rachel , van der Linden Lonneke , Thibaut Hendrik Jan , Lanke Kjerstin H. W. , Leyssen Pieter , Coutard Bruno , De Palma Armando M. , Canard Bruno , Neyts Johan , van Kuppeveld Frank J. M. 
Published: January 2013

ABSTRACT

Although the genus
Enterovirus
contains many important human pathogens, there is no licensed drug for either the treatment or the prophylaxis of enterovirus infections. We report that fluoxetine (Prozac)—a selective serotonin reuptake inhibitor—inhibits the replication of human enterovirus B (HEV-B) and HEV-D but does not affect the replication of HEV-A and HEV-C or human rhinovirus A or B. We show that fluoxetine interferes with viral RNA replication, and we identified viral protein 2C as the target of this compound.
Pharmacokinetics of Anidulafungin in Critically Ill Patients with Candidemia/Invasive Candidiasis
Authors: Liu Ping , Ruhnke Markus , Meersseman Wouter , Paiva José Artur , Kantecki Michal , Damle Bharat 
Published: January 2013

ABSTRACT

The pharmacokinetics of intravenous anidulafungin in adult intensive care unit (ICU) patients were assessed in this study and compared with historical data from a general patient population and healthy subjects. Intensive plasma sampling was performed over a dosing interval at steady state from 21 ICU patients with candidemia/invasive candidiasis. All patients received the recommended dosing regimen (a 200-mg loading dose on day 1, followed by a daily 100-mg maintenance dose), except for a 54-year-old 240-kg female patient (who received a daily 150-mg maintenance dose instead). Plasma samples were assayed for anidulafungin using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters in ICU patients were calculated by a noncompartmental method. With the exclusion of the 240-kg patient, the median (minimum, maximum) age, weight, and body mass index (BMI) of 20 ICU patients were 57 (39, 78) years, 65 (48, 106) kg, and 23.3 (16.2, 33.8) kg/m
2
, respectively. The average anidulafungin area under the curve over the 24-hour dosing interval (AUC
0-24
), maximum concentration (
C
max
), and clearance (CL) in 20 ICU patients were 92.7 mg · h/liter, 7.7 mg/liter, and 1.3 liters/h, respectively. The exposure in the 240-kg patient at a daily 150-mg dose was within the range observed in ICU patients overall. The average AUC
0-24
and
C
max
in the general patient population and healthy subjects were 110.3 and 105.9 mg · h/liter and 7.2 and 7.0 mg/liter, respectively. The pharmacokinetics of anidulafungin in ICU patients appeared to be comparable to those in the general patient population and healthy subjects at the same dosing regimen.
Virus Susceptibility Analyses from a Phase IV Clinical Trial of Inhaled Zanamivir Treatment in Children Infected with Influenza
Authors: Yates Phillip J. , Mehta Nalini , Horton Joseph , Tisdale Margaret 
Published: January 2013

ABSTRACTA zanamivir postapproval efficacy study was conducted in children (n= 279) in Japan during three influenza seasons. Pharyngeal swab specimens (n= 714) were obtained for detailed resistance analysis. From 371 cultured viruses, 3 viruses (A/H1N1) from two subjects showed reduced susceptibility to zanamivir at day 1 (before treatment), 1 had an N74S amino acid substitution (fold shift, 46), and 2 (day 1 and day 2) had a Q136K amino acid substitution (fold shifts, 292 and 301). Q136K was detected only in cultured virus and not in the swab. From the remaining 118 cultured viruses obtained during or after treatment with zanamivir, no shifts in virus susceptibility were detected. Neuraminidase (NA) population sequencing showed that viruses from 12 subjects had emergent amino acid substitutions, but 3 with susceptibility data were not zanamivir resistant. The remainder may be natural variants. Further analysis is planned. Hemagglutinin (HA) sequencing showed that viruses from 20 subjects had 9 HA amino acid substitutions that were previously implicated in resistance to neuraminidase inhibitors inin vitroassays or that were close to the receptor binding site. Their role inin vivoresistance appears to be less important but is not well understood. NA clonal sequence analysis was undertaken to determine if minority species of resistant viruses were present. A total of 1,682 clones from 90 subjects were analyzed. Single clones from 12 subjects contained amino acid substitutions close to the NA active site. It is unclear whether these single amino acid substitutions could have been amplified after drug pressure or are just chance mutations introduced during PCR.
Reduced Drug Uptake in Phenotypically Resistant Nutrient-Starved Nonreplicating Mycobacterium tuberculosis
Authors: Sarathy Jansy , Dartois Véronique , Dick Thomas , Gengenbacher Martin 
Published: January 2013

ABSTRACT

During active tuberculosis a spectrum of physiologically different
Mycobacterium tuberculosis
bacilli reside in human tissues. Subpopulations of the pathogen survive antibiotic treatment for a prolonged time in a dormant state of phenotypic drug resistance, a phenomenon independent of genetic mutations. Here, we used an established culture model of nutrient deprivation to shift down
M. tuberculosis
from growth to nonreplicating survival, which is characterized by a drastic loss of drug susceptibility. Liquid chromatography coupled with mass spectrometry techniques were employed to quantify drug penetration in replicating and nutrient-starved nonreplicating bacilli. We found that intracellular concentrations of fluoroquinolones, rifamycins, and linezolid were lower in nonreplicating
M. tuberculosis
. Studies with pump inhibitors suggest that the observed differences were independent of efflux processes. We conclude that decreased drug permeability contributes to phenotypic drug resistance of dormant
M. tuberculosis
.
rRNA (
rrn
) Operon-Engineered Bacillus subtilis as a Feasible Test Organism for Antibiotic Discovery
Authors: Tanaka Yukinori , Nanamiya Hideaki , Yano Koichi , Kakugawa Koji , Kawamura Fujio , Ochi Kozo 
Published: January 2013

ABSTRACT

Bacillus subtilis
contains 10 rRNA (
rrn
) operons. We found that rRNA operon-engineered
B. subtilis
strain RIK543, with only the
rrnO
operon, is specifically hypersensitive to RNA polymerase inhibitors such as rifamycin SV and rifampin (80-fold and 20-fold, respectively). In pilot screening experiments, we found actinomycete isolates successfully at an incidence of 1.9% (18/945) that produced antibacterials that were detectable only with RIK543 as the test organism. Strain RIK543 may be a feasible test organism for the discovery of novel RNA polymerase inhibitors.
wksl3, a New Biocontrol Agent for Salmonella enterica Serovars Enteritidis and Typhimurium in Foods: Characterization, Application, Sequence Analysis, and Oral Acute Toxicity Study
Authors: Kang Hyun-Wol , Kim Jae-Won , Jung Tae-Sung , Woo Gun-Jo 
Published: January 2013

ABSTRACTOf theSalmonella entericaserovars,S. Enteritidis andS. Typhimurium are responsible for most of theSalmonellaoutbreaks implicated in the consumption of contaminated foods in the Republic of Korea. Because of the widespread occurrence of antimicrobial-resistantSalmonellain foods and food processing environments, bacteriophages have recently surfaced as an alternative biocontrol tool. In this study, we isolated a virulent bacteriophage (wksl3) that could specifically infectS. Enteritidis,S. Typhimurium, and several additional serovars. Transmission electron microscopy revealed that phage wksl3 belongs to the familySiphoviridae. Complete genome sequence analysis and bioinformatic analysis revealed that the DNA of phage wksl3 is composed of 42,766 bp with 64 open reading frames. Since it does not encode any phage lysogeny factors, toxins, pathogen-related genes, or food-borne allergens, phage wksl3 may be considered a virulent phage with no side effects. Analysis of genetic similarities between phage wksl3 and four of its relatives (SS3e, vB_SenS-Ent1, SE2, and SETP3) allowed wksl3 to be categorized as a SETP3-like phage. A single-dose test of oral toxicity with BALB/c mice resulted in no abnormal clinical observations. Moreover, phage application to chicken skin at 8ï¿½C resulted in an about 2.5-log reduction in the number ofSalmonellabacteria during the test period. The strong, stable lytic activity, the significant reduction of the number ofS. Enteritidis bacteria after application to food, and the lack of clinical symptoms of this phage suggest that wksl3 may be a useful agent for the protection of foods againstS. Enteritidis andS. Typhimurium contamination.
Efficient Production of Active Polyhydroxyalkanoate Synthase in Escherichia coli by Coexpression of Molecular Chaperones
Authors: Thomson Nicholas M. , Saika Azusa , Ushimaru Kazunori , Sangiambut Smith , Tsuge Takeharu , Summers David K. , Sivaniah Easan 
Published: January 2013

ABSTRACT

The type I polyhydroxyalkanoate synthase from
Cupriavidus necator
was heterologously expressed in
Escherichia coli
with simultaneous overexpression of chaperone proteins. Compared to expression of synthase alone (14.55 mg liter
−1
), coexpression with chaperones resulted in the production of larger total quantities of enzyme, including a larger proportion in the soluble fraction. The largest increase was seen when the GroEL/GroES system was coexpressed, resulting in approximately 6-fold-greater enzyme yields (82.37 mg liter
−1
) than in the absence of coexpressed chaperones. The specific activity of the purified enzyme was unaffected by coexpression with chaperones. Therefore, the increase in yield was attributed to an enhanced soluble fraction of synthase. Chaperones were also coexpressed with a polyhydroxyalkanoate production operon, resulting in the production of polymers with generally reduced molecular weights. This suggests a potential use for chaperones to control the physical properties of the polymer.
Directed Construction and Analysis of a Sinorhizobium meliloti pSymA Deletion Mutant Library
Authors: Yurgel Svetlana N. , Mortimer Michael W. , Rice Jennifer T. , Humann Jodi L. , Kahn Michael L. 
Published: January 2013

ABSTRACT

Resources from the
Sinorhizobium meliloti
Rm1021 open reading frame (ORF) plasmid libraries were used in a medium-throughput method to construct a set of 50 overlapping deletion mutants covering all of the Rm1021 pSymA megaplasmid except the replicon region. Each resulting pSymA derivative carried a defined deletion of approximately 25 ORFs. Various phenotypes, including cytochrome
c
respiration activity, the ability of the mutants to grow on various carbon and nitrogen sources, and the symbiotic effectiveness of the mutants with alfalfa, were analyzed. This approach allowed us to systematically evaluate the potential impact of regions of Rm1021 pSymA for their free-living and symbiotic phenotypes.