bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effects of Shock from Defibrillation Threshold Testing on Cardiac Systolic and Diastolic Function
Authors: KODANI TAKESHI , MINE TAKANAO , KISHIMA HIDEYUKI , MASUYAMA TOHRU 
Published: July 2016

BackgroundInappropriate implantable cardioverter defibrillator (ICD) shocks are associated with increased overall mortality. However, it remains unclear whether shocks from defibrillation threshold (DFT) testing directly impair cardiac function.MethodsDFT testing was performed in 34 patients who underwent ICD/cardiac resynchronization therapy with a defibrillator implantation/generator exchange. Heart rate and cardiac function, including left ventricular (LV) systolic pressure, LV end‐diastolic pressure, peak positive and negative dp/dt ( + dp/dt and –dp/dt, respectively) of LV pressure, and the tau index, were assessed with a Mikro‐Cath™ diagnostic pressure catheter (CD Leycom, Zoetermeer, the Netherlands). These parameters were measured before and 1 minute, 3 minutes, 5 minutes, 10 minutes, and 15 minutes after DFT testing.ResultsPeak positive dp/dt increased over baseline at each interval (976 ± 229 mm Hg/s vs 1,039 ± 258, 1,049 ± 245, 1,042 ± 247, 1,037 ± 259, and 1,034 ± 254 mm Hg/s, respectively; P < 0.01). Furthermore, peak negative dp/dt (–1,140 ± 397 mm Hg/s vs –1,185 ± 447, 1,193 ± 435, –1,195 ± 434, –1,189 ± 449, and –1,186 ± 459 mm Hg/s, respectively; P < 0.01) and the tau index (65.1 ± 18.5 vs 62.5 ± 16.8*, 62.4 ± 15.9**, 63.0 ± 16.8*, and 62.8 ± 18.7*, respectively; *P < 0.05, **P < 0.01) decreased compared to those at baseline at each interval.ConclusionShock after DFT testing improved LV systolic and diastolic function immediately, especially in patients with preserved LV ejection fraction.
Airway remodelling in COPD: It's not asthma!
Authors: Jones Robyn L. , Noble Peter B. , Elliot John G. , James Alan L. 
Published: July 2016

ABSTRACT
COPD is defined as airflow limitation that is not reversed by treatment. In asthma, airflow limitation is not only reversible, but also inducible. This is called ‘airway hyperresponsiveness’ (AHR) and is associated with thickening of the airway wall, predominantly the layer of airway smooth muscle, due to more cells, bigger cells and more extracellular matrix (ECM) in proportion to the increase in smooth muscle. AHR is also observed in COPD if the changes in airflow are expressed as a percent of the baseline lung function. However, the absolute change in baseline lung function that can be induced in COPD is actually less than that seen in normal subjects, suggesting that the airways in COPD are resistant not only to opening, but also to closing. This observation agrees with physiological measures showing increased airway wall stiffness in COPD. Like asthma, airway wall thickness is increased in COPD, including the layer of smooth muscle. Unlike asthma, however, fixed airflow obstruction appears to be characterized by a disproportionate increase in the ECM within the smooth muscle layer. In this review, we summarize the studies of airway matrix deposition in COPD and put forward the proposal that the airway remodelling in COPD is different from that in asthma and call for a systematic analysis of airway matrix deposition in COPD.
Arterial stiffness in obstructive sleep apnoea: Is there a difference between daytime and night‐time?
Authors: Sarinc Ulasli Sevinc , Sariaydin Muzaffer , Ozkececi Gulay , Gunay Ersin , Halici Bilal , Unlu Mehmet 
Published: July 2016

ABSTRACTBackground and objectiveObstructive sleep apnoea syndrome (OSAS) is a common chronic systemic disease in the general population, with known associated cardiovascular outcomes. We aimed to investigate arterial stiffness in OSAS patients and compare daytime and night‐time values with control subjects.MethodsA total of 104 patients undergoing investigation for OSAS with polysomnography also underwent pulse wave velocity (PWV) and augmentation index (AIx) measurements with Mobil‐O‐Graph for 24 h. Eighty‐two patients were found to have OSAS and 22 did not have OSAS and acted as controls.Results
PWV values of the 82 OSAS patients during the 24‐h period, both daytime and night‐time, were significantly higher than that of the control subjects. Moreover, night‐time levels of AIx were significantly higher in OSAS patients than control subjects (P = 0.025). PWV during night‐time was higher than daytime measurements in OSAS patients (P = 0.012). Apnoea hypopnoea index (AHI) was significantly correlated with PWV and AIx over 24 h (P = 0.0001, r = 0.412; P = 0.002, r = 0.333, respectively). Positive correlations were also found between oxygen desaturation index (ODI) with PWV and AIx during the night (P = 0.0001, r = 0.480; P = 0.002, r = 0.325, respectively). However, daytime AIx was not significantly correlated with ODI (P = 0.052, r = 0.205).Conclusion
OSAS patients, without known cardiovascular disease, have increased PWV, indicating an increased arterial stiffness, compared with control subjects and correlations between AHI and arterial stiffness indices suggest increased arterial stiffness with increased disease severity. Therefore, arterial stiffness should be considered as a possible cause for cardiovascular complications in OSAS patients.
Growth, Real Exchange Rates and Trade Protectionism since the Financial Crisis
Authors: Georgiadis Georgios , Gräb Johannes 
Published: July 2016

AbstractExisting evidence suggests that protectionist activity since the financial crisis has been muted, raising the question whether the historically well‐documented relationship between growth, real exchange rates and trade protectionism has broken down. We use a novel and comprehensive dataset that stretches beyond the traditionally considered tariff and trade defense measures to study the responsiveness of trade policies to business cycles and price competitiveness in the time period since the financial crisis. We find that the specter of protectionism has not been banished. Countries continue to pursue more trade‐restrictive policies when they experience recessions and/or when their competitiveness deteriorates. Our results suggest that the global economy continues to be exposed to the risk of a creeping return of trade protectionism.
Monitoring of adenovirus (ADV)‐specific T cells in a boy with ADV pneumonia and disseminated disease after lung transplantation
Authors: Schultze‐Florey R.E. , Tischer S. , Schwerk N. , Heim A. , Eiz‐Vesper B. , Maecker‐Kolhoff B. 
Published: July 2016

AbstractHuman adenovirus (ADV) infections are the cause of severe morbidity and mortality in transplant recipients. Cidofovir (CDV) is the current standard antiviral treatment. We report the case of a 3‐year‐old boy after lung transplantation with severe ADV sepsis, who was monitored for ADV‐specific T cells during his disease and recovery. A strong increase in ADV‐specific T cells was accompanied by resolution of ADV in blood and bronchoalveolar lavage fluid. Antiviral treatment with CDV was individually adapted according to anti‐ADV immune responses, which provides a new method for tailoring antiviral treatment in lung transplant recipients.
Laparoscopic Cholecystoduodenostomy in Dogs: Canine Cadaver Feasibility Study
Authors: Díaz‐Güemes Martín‐Portugués Idoia , Maria Matos‐Azevedo Ana , Enciso Sanz Silvia , Sánchez‐Margallo Francisco Miguel 
Published: July 2016

ObjectiveTo evaluate the feasibility of laparoscopic cholecystoduodenostomy in canine cadavers using barbed self‐locking sutures.Study DesignIn vivo experimental study.AnimalsFresh male Beagle cadavers (n=5).MethodsSurgery was performed by a single veterinary surgeon. Dogs were placed in dorsal recumbency and 15° reverse Trendelenburg position. The surgical procedure was performed with four 5 mm entry ports and a 5 mm 30° telescope. The cholecystoduodenostomy technique included dissection, incision of the gallbladder, and lavage, followed by gallbladder transposition over the duodenum, incision of the duodenum, and anastomosis. The latter was performed with a 4‐0 barbed self‐locking suture (V‐Loc® 180). Subsequently, a leak test was performed by submerging the anastomosis in saline and insufflating air into the duodenum through a catheter. Total operative time and completion times for each procedural step were recorded.ResultsThe median total operative time was 151 minutes (range, 129–159). One conversion to open surgery occurred because of vascular hemorrhage. The 3 longest intraoperative steps were posterior wall anastomosis, gallbladder dissection, and anterior wall anastomosis. Intraoperative anastomotic leakage sites were identified in 3 of 5 dogs. Leaks were managed by placement of a single reinforcing conventional intracorporeal suture, which was adequate to obtain a watertight anastomosis.ConclusionThis technique cannot be recommended in clinical practice until further studies are performed and the technique is further refined.
Two Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Studies To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza A Virus Monoclonal Antibody, MHAA4549A, in Healthy Volunteers
Authors: Lim Jeremy J. , Deng Rong , Derby Michael A. , Larouche Richard , Horn Priscilla , Anderson Malia , Maia Mauricio , Carrier Stephanie , Pelletier Isabelle , Burgess Tracy , Kulkarni Priya , Newton Elizabeth , Tavel Jorge A. 
Published: July 2016

ABSTRACT
Hospitalized patients with severe influenza are at significant risk for morbidity and mortality. MHAA4549A is a human monoclonal immunoglobulin (Ig) G1 antibody that binds to a highly conserved stalk region of the influenza A virus hemagglutinin protein and neutralizes all tested seasonal human influenza A virus strains. Two phase 1 trials examined the safety, tolerability, and pharmacokinetics of MHAA4549A in healthy volunteers. Both single ascending-dose trials were randomized, double blinded, and placebo controlled. Trial 1 randomized 21 healthy adults into four cohorts receiving a single intravenous dose of 1.5, 5, 15, or 45 mg/kg MHAA4549A or placebo. Trial 2 randomized 14 healthy adults into two cohorts receiving a single intravenous fixed dose of 8,400 mg or 10,800 mg of MHAA4549A or placebo. Subjects were followed for 120 days after dosing. No subject was discontinued in either trial, and no serious adverse events were reported. The most common adverse event in both studies was mild headache (trial 1, 4/16 subjects receiving MHAA4549A and 1/5 receiving placebo; trial 2, 4/8 subjects receiving MHAA4549A and 2/6 receiving placebo). MHAA4549A produced no relevant time- or dose-related changes in laboratory values or vital signs compared to those with placebo. No subjects developed an antitherapeutic antibody response following MHAA4549A administration. MHAA4549A showed linear serum pharmacokinetics, with a mean half-life of 22.5 to 23.7 days. MHAA4549A is safe and well tolerated in healthy volunteers up to a single intravenous dose of 10,800 mg and demonstrates linear serum pharmacokinetics consistent with those of a human IgG1 antibody lacking known endogenous targets in humans. (These trials have been registered at ClinicalTrials.gov under registration no. NCT01877785 and NCT02284607).
The Heterodimeric ABC Transporter EfrCD Mediates Multidrug Efflux in Enterococcus faecalis
Authors: Hürlimann Lea M. , Corradi Valentina , Hohl Michael , Bloemberg Guido V. , Tieleman D. Peter , Seeger Markus A. 
Published: July 2016

ABSTRACT

Nosocomial infections with
Enterococcus faecalis
are an emerging health problem. However, drug efflux pumps contributing to intrinsic drug resistance are poorly studied in this Gram-positive pathogen. In this study, we functionally investigated seven heterodimeric ABC transporters of
E. faecalis
that are annotated as drug efflux pumps. Deletion of
ef0789-ef0790
on the chromosome of
E. faecalis
resulted in increased susceptibility to daunorubicin, doxorubicin, ethidium, and Hoechst 33342, and the corresponding transporter was named EfrCD. Unexpectedly, the previously described heterodimeric multidrug ABC transporter EfrAB contributes marginally to drug efflux in the endogenous context of
E. faecalis
. In contrast, heterologous expression in
Lactococcus lactis
revealed that EfrAB, EfrCD, and the product of
ef2226-ef2227
(EfrEF) mediate the efflux of fluorescent substrates and confer resistance to multiple dyes and drugs, including fluoroquinolones. Four of seven transporters failed to exhibit drug efflux activity for the set of drugs and dyes tested, even upon overexpression in
L. lactis
. Since all seven transporters were purified as heterodimers after overexpression in
L. lactis
, a lack of drug efflux activity is not attributed to poor expression or protein aggregation. Reconstitution of the purified multidrug transporters EfrAB, EfrCD, and EfrEF in proteoliposomes revealed functional coupling between ATP hydrolysis and drug binding. Our analysis creates an experimental basis for the accurate prediction of drug efflux transporters and indicates that many annotated multidrug efflux pumps might be incapable of drug transport and thus might fulfill other physiological functions in the cell.
Antiprion Activity of DB772 and Related Monothiophene- and Furan-Based Analogs in a Persistently Infected Ovine Microglia Culture System
Authors: Dinkel Kelcey D. , Stanton James B. , Boykin David W. , Stephens Chad E. , Madsen-Bouterse Sally A. , Schneider David A. 
Published: July 2016

ABSTRACT

The transmissible spongiform encephalopathies are fatal neurodegenerative disorders characterized by the misfolding of the native cellular prion protein (PrP
C
) into the accumulating, disease-associated isoform (PrP
Sc
). Despite extensive research into the inhibition of prion accumulation, no effective treatment exists. Previously, we demonstrated the inhibitory activity of DB772, a monocationic phenyl-furan-benzimidazole, against PrP
Sc
accumulation in sheep microglial cells. In an effort to determine the effect of structural substitutions on the antiprion activity of DB772, we employed an
in vitro
strategy to survey a library of structurally related, monothiophene- and furan-based compounds for improved inhibitory activity. Eighty-nine compounds were screened at 1 μM for effects on cell viability and prion accumulation in a persistently infected ovine microglia culture system. Eleven compounds with activity equivalent to or higher than that of DB772 were identified as preliminary hit compounds. For the preliminary hits, cytotoxicities and antiprion activities were compared to calculate the tissue culture selectivity index. A structure-activity relationship (SAR) analysis was performed to determine molecular components contributing to antiprion activity. To investigate potential mechanisms of inhibition, effects on PrP
C
and PrP
Sc
were examined. While inhibition of total PrP
C
was not observed, the results suggest that a potential target for inhibition at biologically relevant concentrations is through PrP
C
misfolding to PrP
Sc
. Further, SAR analysis suggests that two structural elements were associated with micromolar antiprion activity. Taken together, the described data provide a foundation for deeper investigation into untested DB compounds and in the design of effective therapeutics.
Safe and Sensitive Antiviral Screening Platform Based on Recombinant Human Coronavirus OC43 Expressing the Luciferase Reporter Gene
Authors: Shen Liang , Yang Yang , Ye Fei , Liu Gaoshan , Desforges Marc , Talbot Pierre J. , Tan Wenjie 
Published: July 2016

ABSTRACT

Human coronaviruses (HCoVs) cause 15 to 30% of mild upper respiratory tract infections. However, no specific antiviral drugs are available to prevent or treat HCoV infections to date. Here, we developed four infectious recombinant HCoVs-OC43 (rHCoVs-OC43) which express the
Renilla
luciferase (Rluc) reporter gene. Among these four rHCoVs-OC43, rOC43-ns2DelRluc (generated by replacing ns2 with the Rluc gene) showed robust luciferase activity with only a slight impact on its growth characteristics. Additionally, this recombinant virus remained stable for at least 10 passages in BHK-21 cells. rOC43-ns2DelRluc was comparable to its parental wild-type virus (HCoV-OC43-WT) with respect to the quantity of the antiviral activity of chloroquine and ribavirin. We showed that chloroquine strongly inhibited HCoV-OC43 replication
in vitro
, with a 50% inhibitory concentration (IC
50
) of 0.33 μM. However, ribavirin showed inhibition of HCoV-OC43 replication only at high concentrations which may not be applicable to humans in clinical treatment, with an IC
50
of 10 μM. Furthermore, using a luciferase-based small interfering RNA (siRNA) screening assay, we identified double-stranded-RNA-activated protein kinase (PKR) and DEAD box RNA helicases (DDX3X) that exhibited antiviral activities, which were further verified by the use of HCoV-OC43-WT. Therefore, rOC43-ns2DelRluc represents a promising safe and sensitive platform for high-throughput antiviral screening and quantitative analysis of viral replication.
The DNA Polymerase Gamma R953C Mutant Is Associated with Antiretroviral Therapy-Induced Mitochondrial Toxicity
Authors: Li Min , Mislak Andrea C. , Foli Yram , Agbosu Esinam , Bose Vivek , Bhandari Shreya , Szymanski Michal R. , Shumate Christie K. , Yin Y. Whitney , Anderson Karen S. , Paintsil Elijah 
Published: July 2016

ABSTRACT
We found a heterozygous C2857T mutation (R953C) in polymerase gamma (Pol-γ) in an HIV-infected patient with mitochondrial toxicity. The R953C Pol-γ mutant binding affinity for dCTP is 8-fold less than that of the wild type. The R953C mutant shows a 4-fold decrease in discrimination of analog nucleotides relative to the wild type. R953 is located on the “O-helix” that forms the substrate deoxynucleoside triphosphate (dNTP) binding site; the interactions of R953 with E1056 and Y986 may stabilize the O-helix and affect polymerase activity.
Whole-Genome Sequencing for Detecting Antimicrobial Resistance in Nontyphoidal Salmonella
Authors: McDermott Patrick F. , Tyson Gregory H. , Kabera Claudine , Chen Yuansha , Li Cong , Folster Jason P. , Ayers Sherry L. , Lam Claudia , Tate Heather P. , Zhao Shaohua 
Published: July 2016

ABSTRACT

Laboratory-based
in vitro
antimicrobial susceptibility testing is the foundation for guiding anti-infective therapy and monitoring antimicrobial resistance trends. We used whole-genome sequencing (WGS) technology to identify known antimicrobial resistance determinants among strains of nontyphoidal
Salmonella
and correlated these with susceptibility phenotypes to evaluate the utility of WGS for antimicrobial resistance surveillance. Six hundred forty
Salmonella
of 43 different serotypes were selected from among retail meat and human clinical isolates that were tested for susceptibility to 14 antimicrobials using broth microdilution. The MIC for each drug was used to categorize isolates as susceptible or resistant based on Clinical and Laboratory Standards Institute clinical breakpoints or National Antimicrobial Resistance Monitoring System (NARMS) consensus interpretive criteria. Each isolate was subjected to whole-genome shotgun sequencing, and resistance genes were identified from assembled sequences. A total of 65 unique resistance genes, plus mutations in two structural resistance loci, were identified. There were more unique resistance genes (
n =
59) in the 104 human isolates than in the 536 retail meat isolates (
n =
36). Overall, resistance genotypes and phenotypes correlated in 99.0% of cases. Correlations approached 100% for most classes of antibiotics but were lower for aminoglycosides and beta-lactams. We report the first finding of extended-spectrum β-lactamases (ESBLs) (
bla
CTX-M1
and
bla
SHV2a
) in retail meat isolates of
Salmonella
in the United States. Whole-genome sequencing is an effective tool for predicting antibiotic resistance in nontyphoidal
Salmonella
, although the use of more appropriate surveillance breakpoints and increased knowledge of new resistance alleles will further improve correlations.
Population Pharmacokinetics of Isavuconazole from Phase 1 and Phase 3 (SECURE) Trials in Adults and Target Attainment in Patients with Invasive Infections Due to Aspergillus and Other Filamentous Fungi
Authors: Desai Amit , Kovanda Laura , Kowalski Donna , Lu Qiaoyang , Townsend Robert , Bonate Peter L. 
Published: July 2016

ABSTRACT

Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent used for the treatment of invasive fungal infections. The objective of this analysis was to develop a population pharmacokinetic (PPK) model to identify covariates that affect isavuconazole pharmacokinetics and to determine the probability of target attainment (PTA) for invasive aspergillosis patients. Data from nine phase 1 studies and one phase 3 clinical trial (SECURE) were pooled to develop the PPK model (NONMEM, version 7.2). Stepwise covariate modeling was performed in Perl-speaks-NONMEM, version 3.7.6. The area under the curve (AUC) at steady state was calculated for 5,000 patients by using Monte Carlo simulations. The PTA using the estimated pharmacodynamic (PD) target value (total AUC/MIC ratio) estimated from
in vivo
PD studies of invasive aspergillosis over a range of MIC values was calculated using simulated patient AUC values. A two-compartment model with a Weibull absorption function and a first-order elimination process adequately described plasma isavuconazole concentrations. The mean estimate for isavuconazole clearance was 2.360 liters/h (percent coefficient of variation [%CV], 34%), and the mean AUC from 0 to 24 h (AUC
0–24
) was ∼100 mg·h/liter. Clearance was approximately 36% lower in Asians than in Caucasians. The PTA calculated over a range of MIC values by use of the nonneutropenic murine efficacy index corresponding to 90% survival indicated that adequate isavuconazole exposures were achieved in >90% of simulated patients to treat infections with MICs up to and including 1 mg/liter according to European Committee on Antimicrobial Susceptibility Testing methodology and in >90% of simulated patients for infections with MICs up to and including 0.5 mg/liter according to Clinical and Laboratory Standards Institute methodology. The highest MIC result for PTA was the same for Caucasian and Asian patients.
The Lantibiotic NAI-107 Efficiently Rescues Drosophila melanogaster from Infection with Methicillin-Resistant Staphylococcus aureus USA300
Authors: Thomsen Thomas T. , Mojsoska Biljana , Cruz João C. S. , Donadio Stefano , Jenssen Håvard , Løbner-Olesen Anders , Rewitz Kim 
Published: July 2016

ABSTRACT

We used the fruit fly
Drosophila melanogaster
as a cost-effective
in vivo
model to evaluate the efficacy of novel antibacterial peptides and peptoids for treatment of methicillin-resistant
Staphylococcus aureus
(MRSA) infections. A panel of peptides with known antibacterial activity
in vitro
and/or
in vivo
was tested in
Drosophila
. Although most peptides and peptoids that were effective
in vitro
failed to rescue lethal effects of
S. aureus
infections
in vivo
, we found that two lantibiotics, nisin and NAI-107, rescued adult flies from fatal infections. Furthermore, NAI-107 rescued mortality of infection with the MRSA strain USA300 with an efficacy equivalent to that of vancomycin, a widely applied antibiotic for the treatment of serious MRSA infections. These results establish
Drosophila
as a useful model for
in vivo
drug evaluation of antibacterial peptides.