bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lack of Effect of Typical Rapid-Weight-Loss Practices on Balance and Anaerobic Performance in Apprentice Jockeys
Authors: Cullen SarahJane , Dolan Eimear , Brien Kate O , McGoldrick Adrian , Warrington Giles 
Published: March 2015

Balance and anaerobic performance are key attributes related to horse-racing performance, but research on the impact of making weight for racing on these parameters remains unknown. The purpose of this study was to investigate the effects of rapid weight loss in preparation for racing on balance and anaerobic performance in a group of jockeys.Methods:Twelve apprentice male jockeys and 12 age- and gender-matched controls completed 2 trials separated by 48 h. In both trials, body mass, hydration status, balance, and anaerobic performance were assessed. Between the trials, the jockeys reduced body mass by 4% using weight-loss methods typically adopted in preparation for racing, while controls maintained body mass through typical daily dietary and physical activity habits.Results:Apprentice jockeys decreased mean body mass by 4.2% ± 0.3% (P < .001) with a subsequent increase in dehydration (P < .001). The controls maintained body mass and a euhydrated state. No differences in balance, on the left or right side, or in peak power, mean power, or fatigue index were reported between the trials in either group.Conclusion:Results from this study indicate that a 4% reduction in body mass in 48 h through the typical methods employed for racing, in association with an increase in dehydration, resulted in no impairments in balance or anaerobic performance. Further research is required to evaluate performance in a sport-specific setting and to investigate the specific physiological mechanisms involved.
Association between Vancomycin Day 1 Exposure Profile and Outcomes among Patients with Methicillin-Resistant Staphylococcus aureus Infective Endocarditis
Authors: Casapao Anthony M. , Lodise Thomas P. , Davis Susan L. , Claeys Kimberly C. , Kullar Ravina , Levine Donald P. , Rybak Michael J. 
Published: March 2015

ABSTRACT

Given the critical importance of early appropriate therapy, a retrospective cohort (2002 to 2013) was performed at the Detroit Medical Center to evaluate the association between the day 1 vancomycin exposure profile and outcomes among patients with MRSA infective endocarditis (IE). The day 1 vancomycin area under the concentration-time curve (AUC
0–24
) and the minimum concentration at 24 h (
C
min 24
) was estimated for each patient using the Bayesian procedure in ADAPT 5, an approach shown to accurately predict the vancomycin exposure with low bias and high precision with limited pharmacokinetic sampling. Initial MRSA isolates were collected and vancomycin MIC was determined by broth microdilution (BMD) and Etest. The primary outcome was failure, defined as persistent bacteremia (≥7 days) or 30-day attributable mortality. Classification and regression tree analysis (CART) was used to determine the vancomycin exposure variables associated with an increased probability of failure. In total, 139 patients met study criteria; 76.3% had right-sided IE, 16.5% had left-sided IE, and 7.2% had both left and right-sided IE. A total of 89/139 (64%) experienced failure by composite definition. In the CART analysis, failure was more pronounced in patients with an AUC
0–24
/MIC as determined by BMD of ≤600 relative to those with AUC
0–24
/MIC as determined by BMD of >600 (69.8% versus 54.7%, respectively,
P
= 0.073). In the logistic regression analysis, an AUC/MIC as determined by BMD of ≤600 (adjusted odds ratio, 2.3; 95% confidence interval, 1.01 to 5.37;
P
= 0.047) was independently associated with failure. Given the retrospective nature of the present study, further prospective studies are required but these data suggest that patients with an AUC
0–24
/MIC as determined by BMD of ≤600 present an increased risk of failure.
Influence of Renal Function Estimation on Pharmacokinetic Modeling of Vancomycin in Elderly Patients
Authors: Glatard Anaïs , Bourguignon Laurent , Jelliffe Roger W. , Maire Pascal , Neely Michael N. , Goutelle Sylvain 
Published: March 2015

ABSTRACT

Vancomycin is a renally excreted drug, and its body clearance correlates with creatinine clearance. However, the renal function estimation equation that best predicts vancomycin clearance has not been established yet. The objective of this study was to compare the abilities of different renal function estimation equations to describe vancomycin pharmacokinetics in elderly patients. The NPAG algorithm was used to perform population pharmacokinetic analysis of vancomycin concentrations in 78 elderly patients. Six pharmacokinetic models of vancomycin clearance were built, based on the following equations: Cockcroft-Gault (CG), Jelliffe (JEL), Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) (both in milliliters per minute per 1.73 m
2
), and modified MDRD and CKD-EPI equations (both in milliliters per minute). Goodness-of-fit and predictive performances of the six PK models were compared in a learning set (58 subjects) and a validation set (20 patients). Final analysis was performed to estimate population parameters in the entire population. In the learning step, the MDRD-based model best described the data, but the CG- and JEL-based models were the least biased. The mean weighted errors of prediction were significantly different between the six models (
P
= 0.0071). In the validation group, predictive performances were not significantly different. However, the use of a renal function estimation equation different from that used in the model building could significantly alter predictive performance. The final analysis showed important differences in parameter distributions and AUC estimation across the six models. This study shows that methods used to estimate renal function should not be considered interchangeable for pharmacokinetic modeling and model-based estimation of vancomycin concentrations in elderly patients.
Population Pharmacokinetics and Monte Carlo Dosing Simulations of Meropenem during the Early Phase of Severe Sepsis and Septic Shock in Critically Ill Patients in Intensive Care Units
Authors: Jaruratanasirikul Sutep , Thengyai Suriyan , Wongpoowarak Wibul , Wattanavijitkul Thitima , Tangkitwanitjaroen Kanyawisa , Sukarnjanaset Waroonrat , Jullangkoon Monchana , Samaeng Maseetoh 
Published: March 2015

ABSTRACT

Pathophysiological changes during the early phase of severe sepsis and septic shock in critically ill patients, resulting in altered pharmacokinetic (PK) patterns for antibiotics, are important factors influencing therapeutic success. The aims of this study were (i) to reveal the population PK parameters and (ii) to assess the probability of target attainment (PTA) for meropenem. The PK studies were carried out following administration of 1 g of meropenem every 8 h during the first 24 h of severe sepsis and septic shock in nine patients, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the free plasma drug concentration remains above the MIC (
fT
>MIC
) and 80%
fT
>MIC
. The volume of distribution (
V
) and total clearance (CL) of meropenem in these patients were 23.7 liters and 7.82 liters/h, respectively. For pathogens with MICs of 4 μg/ml, the PTAs of 40%
fT
>MIC
following administration of meropenem as a 1-h infusion of 1 g every 8 h and a 4-h infusion of 0.5 g every 8 h were 92.52% and 90.29%, respectively. For pathogens with MICs of 2 μg/ml in immunocompromised hosts, the PTAs of 80%
fT
>MIC
following administration of 1-h and 4-h infusions of 2 g of meropenem every 8 h were 84.32% and 94.72%, respectively. These findings indicated that the
V
of meropenem was greater and the CL of meropenem was lower than the values obtained in a previous study with healthy subjects. The maximum recommended dose, i.e., 2 g of meropenem every 8 h, may be required for treatment of life-threatening infections in this patient population.
Bactericidal Efficiency and Modes of Action of the Novel Antimicrobial Peptide T9W against Pseudomonas aeruginosa
Authors: Zhu Xin , Shan Anshan , Ma Zhi , Xu Wei , Wang Jiajun , Chou Shuli , Cheng Baojing 
Published: March 2015

ABSTRACT

The antipseudomonal efficiency and mechanism of action of a novel engineered antimicrobial peptide, T9W, were evaluated in this study. T9W displayed high activity, with a lethal concentration (LC) of 1 to 4 μM against
Pseudomonas aeruginosa
, including against ciprofloxacin-, gentamicin-, and ceftazidime-resistant strains, even in the presence of 50 to 300 mM NaCl, 1 to 5 mM Ca
2+
, or 0.5 to 2 mM Mg
2+
. The time-kill curve (TKC) analysis demonstrated concentration-dependent activity, with T9W achieving complete killing in less than 30 min at 1× LC and in less than 5 min at 4× LC. Combination TKC analyses additionally demonstrated a synergistic effect with ciprofloxacin and gentamicin. The selectivity of T9W was further supported by its ability to specifically eliminate
P. aeruginosa
in a coculture with macrophages without toxicity to the mammalian cells. The results from fluorescent measurement indicated that T9W bound to lipopolysaccharide (LPS) and induced
P. aeruginosa
membrane depolarization, and microscopic observations and flow cytometry further indicated that T9W targeted the
P. aeruginosa
cell membrane and disrupted cytoplasmic membrane integrity, thereby causing cellular content release leading to cell death. This study revealed the potential usefulness of T9W as a novel antimicrobial agent against
P. aeruginosa
.
Structural Characterization of an Alternative Mode of Tigecycline Binding to the Bacterial Ribosome
Authors: Schedlbauer Andreas , Kaminishi Tatsuya , Ochoa-Lizarralde Borja , Dhimole Neha , Zhou Shu , López-Alonso Jorge P. , Connell Sean R. , Fucini Paola 
Published: March 2015

ABSTRACT

Although both tetracycline and tigecycline inhibit protein synthesis by sterically hindering the binding of tRNA to the ribosomal A site, tigecycline shows increased efficacy in both
in vitro
and
in vivo
activity assays and escapes the most common resistance mechanisms associated with the tetracycline class of antibiotics. These differences in activities are attributed to the
tert
-butyl-glycylamido side chain found in tigecycline. Our structural analysis by X-ray crystallography shows that tigecycline binds the bacterial 30S ribosomal subunit with its tail in an extended conformation and makes extensive interactions with the 16S rRNA nucleotide C1054. These interactions restrict the mobility of C1054 and contribute to the antimicrobial activity of tigecycline, including its resistance to the ribosomal protection proteins.
Antimicrobial and Biophysical Properties of Surfactant Supplemented with an Antimicrobial Peptide for Treatment of Bacterial Pneumonia
Authors: Banaschewski Brandon J. H. , Veldhuizen Edwin J. A. , Keating Eleonora , Haagsman Henk P. , Zuo Yi Y. , Yamashita Cory M. , Veldhuizen Ruud A. W. 
Published: March 2015

ABSTRACT

Antibiotic-resistant bacterial infections represent an emerging health concern in clinical settings, and a lack of novel developments in the pharmaceutical pipeline is creating a “perfect storm” for multidrug-resistant bacterial infections. Antimicrobial peptides (AMPs) have been suggested as future therapeutics for these drug-resistant bacteria, since they have potent broad-spectrum activity, with little development of resistance. Due to the unique structure of the lung, bacterial pneumonia has the additional problem of delivering antimicrobials to the site of infection. One potential solution is coadministration of AMPs with exogenous surfactant, allowing for distribution of the peptides to distal airways and opening of collapsed lung regions. The objective of this study was to test various surfactant-AMP mixtures with regard to maintaining pulmonary surfactant biophysical properties and bactericidal functions. We compared the properties of four AMPs (CATH-1, CATH-2, CRAMP, and LL-37) suspended in bovine lipid-extract surfactant (BLES) by assessing surfactant-AMP mixture biophysical and antimicrobial functions. Antimicrobial activity was tested against methillicin-resistant
Staphylococcus aureus
and
Pseudomonas aeruginosa
. All AMP/surfactant mixtures exhibited an increase of spreading compared to a BLES control. BLES+CATH-2 mixtures had no significantly different minimum surface tension versus the BLES control. Compared to the other cathelicidins, CATH-2 retained the most bactericidal activity in the presence of BLES. The BLES+CATH-2 mixture appears to be an optimal surfactant-AMP mixture based on
in vitro
assays. Future directions involve investigating the potential of this mixture in animal models of bacterial pneumonia.
Ceftobiprole- and Ceftaroline-Resistant Methicillin-Resistant Staphylococcus aureus
Authors: Chan Liana C. , Basuino Li , Diep Binh , Hamilton Stephanie , Chatterjee Som S. , Chambers Henry F. 
Published: March 2015

ABSTRACT

The role of
mecA
mutations in conferring resistance to ceftobiprole and ceftaroline, cephalosporins with anti-methicillin-resistant
Staphylococcus aureus
(MRSA) activity, was determined with MRSA strains COL and SF8300. The SF8300 ceftaroline-passaged mutant carried a single
mecA
mutation, E447K (E-to-K change at position 447), and expressed low-level resistance. This mutation in COL conferred high-level resistance to ceftobiprole but only low-level resistance to ceftaroline. The COL ceftaroline-passaged mutant, which expressed high-level resistance to ceftobiprole and ceftaroline, had mutations in
pbp2
,
pbp4
, and
gdpP
but not
mecA
.
Activity of Ceftazidime-Avibactam against Fluoroquinolone-Resistant Enterobacteriaceae and Pseudomonas aeruginosa
Authors: Pitart C. , Marco F. , Keating T. A. , Nichols W. W. , Vila J. 
Published: March 2015

ABSTRACT

Ceftazidime-avibactam and comparator antibiotics were tested by the broth microdilution method against 200
Enterobacteriaceae
and 25
Pseudomonas aeruginosa
strains resistant to fluoroquinolones (including strains with the extended-spectrum β-lactamase [ESBL] phenotype and ceftazidime-resistant strains) collected from our institution. The MICs and mechanisms of resistance to fluoroquinolone were also studied. Ninety-nine percent of fluoroquinolone-resistant
Enterobacteriaceae
strains were inhibited at a ceftazidime-avibactam MIC of ≤4 mg/liter (using the susceptible CLSI breakpoint for ceftazidime alone as a reference). Ceftazidime-avibactam was very active against ESBL
Escherichia coli
(MIC
90
of 0.25 mg/liter), ESBL
Klebsiella pneumoniae
(MIC
90
of 0.5 mg/liter), ceftazidime-resistant AmpC-producing species (MIC
90
of 1 mg/liter), non-ESBL
E. coli
(MIC
90
of ≤0.125 mg/liter), non-ESBL
K. pneumoniae
(MIC
90
of 0.25 mg/liter), and ceftazidime-nonresistant AmpC-producing species (MIC
90
of ≤0.5 mg/liter). Ninety-six percent of fluoroquinolone-resistant
P. aeruginosa
strains were inhibited at a ceftazidime-avibactam MIC of ≤8 mg/liter (using the susceptible CLSI breakpoint for ceftazidime alone as a reference), with a MIC
90
of 8 mg/liter. Additionally, fluoroquinolone-resistant mutants from each species tested were obtained
in vitro
from two strains, one susceptible to ceftazidime and the other a β-lactamase producer with a high MIC against ceftazidime but susceptible to ceftazidime-avibactam. Thereby, the impact of fluoroquinolone resistance on the activity of ceftazidime-avibactam could be assessed. The MIC
90
values of ceftazidime-avibactam for the fluoroquinolone-resistant mutant strains of
Enterobacteriaceae
and
P. aeruginosa
were ≤4 mg/liter and ≤8 mg/liter, respectively. We conclude that the presence of fluoroquinolone resistance does not affect
Enterobacteriaceae
and
P. aeruginosa
susceptibility to ceftazidime-avibactam; that is, there is no cross-resistance.
Impact of Antimalarial Treatment and Chemoprevention on the Drug Sensitivity of Malaria Parasites Isolated from Ugandan Children
Authors: Tumwebaze Patrick , Conrad Melissa D. , Walakira Andrew , LeClair Norbert , Byaruhanga Oswald , Nakazibwe Christine , Kozak Benjamin , Bloome Jessica , Okiring Jaffer , Kakuru Abel , Bigira Victor , Kapisi James , Legac Jennifer , Gut Jiri , Cooper Roland A. , Kamya Moses R. , Havlir Diane V. , Dorsey Grant , Greenhouse Bryan , Nsobya Samuel L. , Rosenthal Philip J. 
Published: March 2015

ABSTRACT

Changing treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterized
ex vivo
drug sensitivity and parasite polymorphisms associated with sensitivity in 459
Plasmodium falciparum
samples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations between
ex vivo
drug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity with
pfcrt
76T, as well as increased lumefantrine sensitivity with
pfmdr1
86Y, Y184, and 1246Y. Over time,
ex vivo
sensitivity decreased for lumefantrine and piperaquine and increased for chloroquine, the prevalences of
pfcrt
K76 and
pfmdr1
N86 and D1246 increased, and the prevalences of
pfdhfr
and
pfdhps
polymorphisms associated with antifolate resistance were unchanged. In recurrent infections, recent prior treatment with artemether-lumefantrine was associated with decreased
ex vivo
lumefantrine sensitivity and increased prevalence of
pfcrt
K76 and
pfmdr1
N86, 184F, and D1246. In children assigned chemoprevention with monthly dihydroartemisinin-piperaquine with documented circulating piperaquine, breakthrough infections had increased the prevalence of
pfmdr1
86Y and 1246Y compared to untreated controls. The noted impacts of therapy and chemoprevention on parasite polymorphisms remained significant in multivariate analysis correcting for calendar time. Overall, changes in parasite sensitivity were consistent with altered selective pressures due to changing treatment practices in Uganda. These changes may threaten the antimalarial treatment and preventive efficacies of artemether-lumefantrine and dihydroartemisinin-piperaquine, respectively.
Ethanol Impairs Mucosal Immunity against Streptococcus pneumoniae Infection by Disrupting Interleukin 17 Gene Expression
Authors: Trevejo-Nunez Giraldina , Chen Kong , Dufour Jason P. , Bagby Gregory J. , Horne William T. , Nelson Steve , Kolls Jay K. 
Published: March 2015

ABSTRACTAcute ethanol intoxication suppresses the host immune responses againstStreptococcus pneumoniae. As interleukin 17 (IL-17) is a critical cytokine in host defense against extracellular pathogens, includingS. pneumoniae, we hypothesized that ethanol impairs mucosal immunity against this pathogen by disrupting IL-17 production or IL-17 receptor (IL-17R) signaling. A chronic ethanol feeding model in simian immunodeficiency virus (SIV)-infected rhesus macaques and acute ethanol intoxication in a murine model were used. Transcriptome analysis of bronchial brushes in the nonhuman primate model showed downregulation of the expression of IL-17-regulated chemokines in ethanol-fed animals, a finding also replicated in the murine model. Surprisingly, recombinant CXCL1 and CXCL5 but not IL-17 or IL-23 plus IL-1β rescued bacterial burden in the ethanol group to control levels. Taken together, the results of this study suggest that ethanol impairs IL-17-mediated chemokine production in the lung. Thus, exogenous luminal restoration of IL-17-related chemokines, CXCL1 and CXCL5, improves host defenses againstS. pneumoniae.
Interleukin-6-Driven Inflammatory Response Induces Retinal Pathology in a Model of Ocular Toxoplasmosis Reactivation
Authors: Rochet Élise , Brunet Julie , Sabou Marcela , Marcellin Luc , Bourcier Tristan , Candolfi Ermanno , Pfaff Alexander W. 
Published: March 2015

ABSTRACT

Ocular inflammation is one of the consequences of infection with the protozoan parasite
Toxoplasma gondii
. Even if lesions are self-healing in immunocompetent persons, they pose a lifetime risk of reactivation and are a serious threat to vision. As there are virtually no immunological data on reactivating ocular toxoplasmosis, we established a model of direct intravitreal injection of parasites in previously infected mice with a homologous type II strain. Two different mouse strains with variable ability to control retinal infection were studied in order to describe protective and deleterious reaction patterns. In Swiss-Webster mice, which are already relatively resistant to primary infection, no peak of parasite load was observed upon reinfection. In contrast, the susceptible inbred strain C57BL/6 showed high parasite loads after 7 days, as well as marked deterioration of retinal architecture. Both parameters were back to normal on day 21. C57BL/6 mice also reacted with a strong local production of inflammatory and Th1-type cytokines, like interleukin-6 (IL-6), IL-17A, and gamma interferon (IFN-γ), while Swiss-Webster mice showed only moderate expression of the Th2 cytokine IL-31. Interestingly, rapid intraocular production of anti-
Toxoplasma
antibodies was observed in Swiss-Webster but not in C57BL/6 mice. We then localized the cellular source of different immune mediators within the retina by immunofluorescence. Finally, neutralization experiments of IFN-γ or IL-6 demonstrated the respective protective and deleterious roles of these cytokines for parasite control and retinal integrity during reinfection. In conclusion, we developed and immunologically characterized a promising mouse model of reactivating ocular toxoplasmosis.
Characterization of a Novel Antisense RNA in the Major Pilin Locus of Neisseria meningitidis Influencing Antigenic Variation
Authors: Tan Felicia Y. Y. , Wörmann Mirka E. , Loh Edmund , Tang Christoph M. , Exley Rachel M. 
Published: March 2015

ABSTRACT

Expression of type four pili (Tfp) is essential for virulence in
Neisseria meningitidis
. Pili mediate adhesion, bacterial aggregation, and DNA uptake. In
N. meningitidis
, the major pilin subunit is encoded by the
pilE
gene. In some strains, PilE is subject to phase and antigenic variation, which can alter Tfp properties and together offer a possible mechanism of immune escape. Pilin expression and antigenic variation can be modulated in response to environmental cues; however, the precise mechanisms of such regulation remain unclear. We identified a promoter in the
pilE
locus, 3′ of the
pilE
coding sequence, on the antisense (AS) strand which is conserved in meningococci. We show that this promoter directs transcription of an AS RNA that is expressed during specific growth phases and in response to salt stress. Furthermore, we demonstrate that the transcript encompasses sequences complementary to the entire
pilE
coding sequence and 5′ untranslated region. AS RNAs can regulate the gene on the sense strand by altering transcript stability or translation. However, by using Northern blotting, quantitative reverse transcription-PCR (RT-PCR), and Western blotting, we found no significant AS RNA-dependent changes in
pilE
transcript or protein level. Instead, our data indicate that the AS RNA influences pilin antigenic variation. This work provides further insights into the complex regulation of pilin expression and variation in pathogenic
Neisseria
.

IMPORTANCE
Pathogenic
Neisseria
spp. express type four pili (Tfp) which are important for adhesion, aggregation and transformation. Some strains of
N. meningitidis
are able to vary the sequence of the major subunit (PilE) of the Tfp. The mechanisms underlying this variation are not fully defined, but the process requires several noncoding elements that are found adjacent to the
pilE
gene. In this work, we identified a
cis-
encoded RNA antisense to
pilE
in
N. meningitidis
. By using Northern blotting and RT-PCR analysis, we found that the RNA is expressed in stationary phase or following salt stress. Our work also indicates that this RNA does not significantly affect
pilE
or pilin expression levels but instead appears to modulate pilin variation.