bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of Sport-Specific Drills Training or High-Intensity Interval Training in Young Tennis Players
Authors: Fernandez-Fernandez Jaime , Sanz David , Sarabia Jose Manuel , Moya Manuel
Published: May 2016

Purpose:

To compare the effects of combining high-intensity training (HIT) and sport-specific drill training (MT) versus sportspecific drill training alone (DT) on fitness performance characteristics in young tennis players.

Methods:

Twenty young tennis players (14.8 ± 0.1 y) were assigned to either DT (n = 10) or MT (n = 10) for 8 wk. Tennis drills consisted of two 16- to 22-min on-court exercise sessions separated by 3 min of passive rest, while MT consisted of 1 sport-specific DT session and 1 HIT session, using 16–22 min of runs at intensities (90–95%) related to the velocity obtained in the 30–15 Intermittent Fitness Test (VIFT) separated by 3 min of passive rest. Pre- and posttests included peak oxygen uptake (VO2peak), VIFT, speed (20 m, with 5- and 10-m splits), 505 Agility Test, and countermovement jump (CMJ).

Results:

There were significant improvements after the training period in VO2peak (DT 2.4%, ES = moderate; MT 4.2%, ES = large) and VIFT (DT 2.2%, ES = small; MT 6.3%, ES = large) for both DT and MT, with no differences between training protocols. Results also showed a large increase in the 505 Agility Test after MT, while no changes were reported in the other tests (sprint and CMJ), either for MT or DT.

Conclusions:

Even though both training programs resulted in significant improvements in aerobic performance, a mixed program combining tennis drills and runs based on the VIFT led to greater gains and should be considered the preferred training method for improving aerobic power in young athletes.
No Improved Performance With Repeated-Sprint Training in Hypoxia Versus Normoxia: A Double-Blind and Crossover Study
Authors: Montero David , Lundby Carsten
Published: May 2016

Context:

Few recent studies indicate that short-term repeated-sprint (RS) training in hypoxia (RSH) improves RS performance compared with identical training under normoxic conditions (RSN) in endurance-trained subjects.

Purpose:

To determine the effects of RSH against RSN on RS performance under normoxic and moderate hypoxic conditions, using a randomized, doubleblind, crossover experimental design.

Methods:

Fifteen endurance-trained male subjects (age 25 ± 4 y) performed 4 wk of RS training (3 sessions/wk) in normobaric hypoxia (RSH, FiO2 = 13.8%) and normoxia (RSN, FiO2 = 20.9%) in a crossover manner. Before and after completion of training, RS tests were performed on a cycle ergometer with no prior exercise (RSNE), after an incremental exercise test (RSIE), and after a time-trial test (RSTT) in normoxia and hypoxia.

Results:

Peak power outputs at the incremental exercise test and time-trial performance were unaltered by RSH in normoxia and hypoxia. RS performance was generally enhanced by RSH, as well as RSN, but there were no additional effects of RSH over RSN on peak and mean sprint power output and the number of repeated sprints performed in the RSNE, RSIE, and RSTT trials under normoxic and hypoxic conditions.

Conclusions:

The present double-blind crossover study indicates that RSH does not improve RS performance compared with RSN in normoxic and hypoxic conditions in endurance-trained subjects. Therefore, caution should be exercised when proposing RSH as an advantageous method to improve exercise performance.
The Commonality Between Approaches to Determine Jump Fatigue During Basketball Activity in Junior Players: In-Game Versus Across-Game Decrements
Authors: Scanlan Aaron T. , Fox Jordan L. , Borges Nattai R. , Dalbo Vincent J.
Published: May 2016

Purpose:

Declines in high-intensity activity during game play (in-game approach) and performance tests measured pre- and postgame (across-game approach) have been used to assess player fatigue in basketball. However, a direct comparison of these approaches is not available. Consequently, this study examined the commonality between in- and across-game jump fatigue during simulated basketball game play.

Methods:

Australian, state-level, junior male basketball players (n = 10; 16.6 ± 1.1 y, 182.4 ± 4.3 cm, 68.3 ± 10.2 kg) completed 4 × 10-min standardized quarters of simulated basketball game play. In-game jump height during game play was measured using video analysis, while across-game jump height was determined pre-, mid-, and postgame play using an in-ground force platform. Jump height was determined using the flight-time method, with jump decrement calculated for each approach across the first half, second half, and entire game.

Results:

A greater jump decrement was apparent for the in-game approach than for the across-game approach in the first half (37.1% ± 11.6% vs 1.7% ± 6.2%; P = .005; d = 3.81, large), while nonsignificant, large differences were evident between approaches in the second half (d = 1.14) and entire game (d = 1.83). Nonsignificant associations were evident between in-game and across-game jump decrement, with shared variances of 3–26%.

Conclusions:

Large differences and a low commonality were observed between in- and across-game jump fatigue during basketball game play, suggesting that these approaches measure different constructs. Based on our findings, it is not recommended that basketball coaches use these approaches interchangeably to monitor player fatigue across the season.
Ecological Validity of the Session Rating of Perceived Exertion for Quantifying Internal Training Load in Fencing
Authors: Turner Anthony N. , Buttigieg Conor , Marshall Geoff , Noto Angelo , Phillips James , Kilduff Liam
Published: May 2016

Session rating of perceived exertion (sRPE) is known to significantly relate to heart-rate (HR) -based methods of quantifying internal training load (TL) in a variety of sports. However, to date this has not been investigated in fencing and was therefore the aim of this study. TL was calculated by multiplying the sRPE with exercise duration and through HR-based methods calculated using Banister and Edwards TRIMP. Seven male elite foil fencers (mean ± SD age 22.3 ± 1.6 y, height 181.3 ± 6.5 cm, body mass 77.7 ± 7.6 kg) were monitored over the period of 1 competitive season. The sRPE and HR of 67 training sessions and 3 competitions (87 poule bouts and 12 knockout rounds) were recorded and analyzed. Correlation analysis was used to determine any relationships between sRPE- and HR-based methods, accounting for individual variation, mode of training (footwork drills vs sparring sessions), and stage of competition (poules vs knockouts). Across 2 footwork sessions, sRPE and Banister and Edwards TRIMP were found to be reliable, with coefficient of variation values of 6.0%, 5.2%, and 4.5%, respectively. Significant correlations with sRPE for individual fencers (r = .84–.98) and across mode of exercise (r = .73–.85) and competition stages (r = .82–.92) were found with HR-based measures. sRPE is a simple and valuable tool coaches can use to quantify TL in fencing.
Papers of note in
Science
Authors: VanHook Annalisa M.
Published: May 2016

This week’s articles highlight advances in reproductive biology, immunology, research tools, neuroscience, and the microbiome.
Papers of note in
Science Translational Medicine
Authors: Ferrarelli Leslie K.
Published: May 2016

This week’s articles describe new targets for treating bacterial infection and fragile X syndrome.
Safety and Pharmacokinetics of Quick-Dissolving Polymeric Vaginal Films Delivering the Antiretroviral IQP-0528 for Preexposure Prophylaxis
Authors: Srinivasan Priya , Zhang Jining , Martin Amy , Kelley Kristin , McNicholl Janet M. , Buckheit Robert W. , Smith James M. , Ham Anthony S.
Published: May 2016

For human immunodeficiency virus (HIV) prevention, microbicides or drugs delivered as quick-dissolving films may be more acceptable to women than gels because of their compact size, minimal waste, lack of an applicator, and easier storage and transport. This has the potential to improve adherence to promising products for preexposure prophylaxis. Vaginal films containing IQP-0528, a nonnucleoside reverse transcriptase inhibitor, were evaluated for their pharmacokinetics in pigtailed macaques. Polymeric films (22 by 44 by 0.1 mm; providing 75% of a human dose) containing IQP-0528 (1.5%, wt/wt) with and without poly(lactic-
co
-glycolic acid) (PLGA) nanoparticle encapsulation were inserted vaginally into pigtailed macaques in a crossover study design (
n
= 6). With unencapsulated drug, the median (range) vaginal fluid concentrations of IQP-0528 were 160.97 (2.73 to 2,104), 181.79 (1.86 to 15,800), and 484.50 (8.26 to 4,045) μg/ml at 1, 4, and 24 h after film application, respectively. Median vaginal tissue IQP-0528 concentrations at 24 h were 3.10 (0.03 to 222.58) μg/g. The values were similar at locations proximal, medial, and distal to the cervix. The IQP-0528 nanoparticle-formulated films delivered IQP-0528 in vaginal tissue and secretions at levels similar to those obtained with the unencapsulated formulation. A single application of either formulation did not disturb the vaginal microflora or the pH (7.24 ± 0.84 [mean ± standard deviation]). The high mucosal IQP-0528 levels delivered by both vaginal film formulations were between 1 and 5 log higher than the
in vitro
90% inhibitory concentration (IC
90
) of 0.146 μg/ml. The excellent coverage and high mucosal levels of IQP-0528, well above the IC
90
, suggest that the films may be protective and warrant further evaluation in a vaginal repeated low dose simian-human immunodeficiency virus (SHIV) transmission study in macaques and clinically in women.
Previous Antibiotic Exposure Increases Risk of Infection with Extended-Spectrum-β-Lactamase- and AmpC-Producing Escherichia coli and Klebsiella pneumoniae in Pediatric Patients
Authors: Zerr Danielle M. , Miles-Jay Arianna , Kronman Matthew P. , Zhou Chuan , Adler Amanda L. , Haaland Wren , Weissman Scott J. , Elward Alexis , Newland Jason G. , Zaoutis Theoklis , Qin Xuan
Published: May 2016

The objective of this study was to determine whether antibiotic exposure is associated with extended-spectrum-beta-lactamase- or AmpC-producing
Escherichia coli
or
Klebsiella pneumoniae
infections in children. We collected extended-spectrum-beta-lactamase- or AmpC-producing
E. coli
or
K. pneumoniae
isolates and same-species susceptible controls from normally sterile sites of patients aged ≤21 years, along with associated clinical data, at four free-standing pediatric centers. After controlling for potential confounders, the relative risk of having an extended-spectrum-beta-lactamase-producing isolate rather than a susceptible isolate was 2.2 times higher (95% confidence interval [CI], 1.49 to 3.35) among those with antibiotic exposure in the 30 days prior to infection than in those with no antibiotic exposure. The results were similar when analyses were limited to exposure to third-generation cephalosporins, other broad-spectrum beta-lactams, or trimethoprim-sulfamethoxazole. Conversely, the relative risk of having an AmpC-producing versus a susceptible isolate was not significantly elevated with any antibiotic exposure in the 30 days prior to infection (adjusted relative risk ratio, 1.12; 95% CI, 0.65 to 1.91). However, when examining subgroups of antibiotics, the relative risk of having an AmpC-producing isolate was higher for patients with exposure to third-generation cephalosporins (adjusted relative risk ratio, 4.48; 95% CI, 1.75 to 11.43). Dose-response relationships between antibiotic exposure and extended-spectrum-beta-lactamase-producing or AmpC-producing isolates were not demonstrated. These results reinforce the need to study and implement pediatric antimicrobial stewardship strategies, and they indicate that epidemiological studies of third-generation cephalosporin-resistant
E. coli
and
K. pneumoniae
isolates should include resistance mechanisms when possible.
Systematic Review of Factors Associated with Antibiotic Prescribing for Respiratory Tract Infections
Authors: McKay Rachel , Mah Allison , Law Michael R. , McGrail Kimberlyn , Patrick David M.
Published: May 2016

Antibiotic use is a modifiable driver of antibiotic resistance. In many circumstances, antibiotic use is overly broad or unnecessary. We systematically assessed factors associated with antibiotic prescribing for respiratory tract infections (RTI). Studies were included if they used actual (not self-reported or intended) prescribing data, assessed factors associated with antibiotic prescribing for RTIs, and performed multivariable analysis of associations. We searched Medline, Embase, and International Pharmaceutical Abstracts using keyword and MeSH (medical subject headings) search terms. Two authors reviewed each abstract and independently appraised all included texts. Data on factors affecting antibiotic prescribing were extracted. Our searches retrieved a total of 2,848 abstracts, with 97 included in full-text review and 28 meeting full inclusion criteria. Compared to other factors, diagnosis of acute bronchitis was associated with increased antibiotic prescribing (range of adjusted odds ratios [aOR], 1.56 to 15.9). Features on physical exam, such as fever, purulent sputum, abnormal respiratory exam, and tonsillar exudate, were also associated with higher odds of antibiotic prescribing. Patient desire for an antibiotic was not associated or was modestly associated with prescription (range of aORs, 0.61 to 9.87), in contrast to physician perception of patient desire for antibiotics, which showed a stronger association (range of aORs, 2.11 to 23.3). Physician's perception of patient desire for antibiotics was strongly associated with antibiotic prescribing. Antimicrobial stewardship programs should continue to expand in the outpatient setting and should emphasize clear and direct communication between patients and physicians, as well as signs and symptoms that do and do not predict bacterial etiology of upper respiratory tract infections.
Effect of Fluoroquinolones and Macrolides on Eradication and Resistance of Haemophilus influenzae in Chronic Obstructive Pulmonary Disease
Authors: Pettigrew Melinda M. , Tsuji Brian T. , Gent Janneane F. , Kong Yong , Holden Patricia N. , Sethi Sanjay , Murphy Timothy F.
Published: May 2016

Little is known about the effect of antibiotics on eradication of carriage and development of resistance in
Haemophilus influenzae
in individuals with chronic obstructive pulmonary disease (COPD). Our goals were to assess antibiotic susceptibilities, prevalence of resistance genes, and development of resistance in
H. influenzae
and to evaluate the effect of macrolide and fluoroquinolone administration on
H. influenzae
eradication. Data were from a 15-year longitudinal study of COPD. Genome sequence data were used to determine genotype and identify resistance genes. MICs of antibiotics were determined by reference broth microdilution. Generalized linear mixed models were used to evaluate associations between antibiotic use and
H. influenzae
eradication. We examined 267
H. influenzae
isolates from 77 individuals. All newly acquired
H. influenzae
isolates were susceptible to azithromycin. Five of 27 (19%) strains developed 4-fold increases in azithromycin MICs and reached or exceeded the susceptibility breakpoint (≤4 μg/ml) during exposure.
H. influenzae
isolates were uniformly susceptible to ciprofloxacin, levofloxacin, and moxifloxacin (MIC
90
s of 0.015, 0.015, and 0.06, respectively); there were no mutations in quinolone resistance-determining regions. Fluoroquinolone administration was associated with increased
H. influenzae
eradication compared to macrolides (odds ratio [OR], 16.67; 95% confidence interval [CI], 2.67 to 104.09). There was no difference in
H. influenzae
eradication when comparing macrolide administration to no antibiotic (OR, 1.89; 95% CI, 0.43 to 8.30). Fluoroquinolones are effective in eradicating
H. influenzae
in individuals with COPD. Macrolides are ineffective in eradicating
H. influenzae
, and their use in COPD patients may lead to decreased macrolide susceptibility and resistance.
Sideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates
Authors: Calvopiña Karina , Umland Klaus-Daniel , Rydzik Anna M. , Hinchliffe Philip , Brem Jürgen , Spencer James , Schofield Christopher J. , Avison Matthew B.
Published: May 2016

Acetamido derivatives of the naturally antibacterial non-β-lactam lactivicin (LTV) have improved activity against their penicillin binding protein targets and reduced hydrolysis by β-lactamases, but penetration into Gram-negative bacteria is still relatively poor. Here we report that modification of the LTV lactone with a catechol-type siderophore increases potency 1,000-fold against
Stenotrophomonas maltophilia
, a species renowned for its insusceptibility to antimicrobials. The MIC
90
of modified lactone compound 17 (LTV17) against a global collection of extensively drug-resistant clinical
S. maltophilia
isolates was 0.063 μg · ml
−1
. Sideromimic modification does not reduce the ability of LTVs to induce production of the L1 and L2 β-lactamases in
S. maltophilia
and does not reduce the rate at which LTVs are hydrolyzed by L1 or L2. We conclude, therefore, that lactivicin modification with a siderophore known to be preferentially used by
S. maltophilia
substantially increases penetration via siderophore uptake. LTV17 has the potential to be developed as a novel antimicrobial for treatment of infections by
S. maltophilia
. More generally, our work shows that sideromimic modification in a species-targeted manner might prove useful for the development of narrow-spectrum antimicrobials that have reduced collateral effects.
Potency and Stereoselectivity of Cyclopropavir Triphosphate Action on Human Cytomegalovirus DNA Polymerase
Authors: Chen Han , Li Chengwei , Zemlicka Jiri , Gentry Brian G. , Bowlin Terry L. , Coen Donald M.
Published: May 2016

Cyclopropavir (CPV) is a promising antiviral drug against human cytomegalovirus (HCMV). As with ganciclovir (GCV), the current standard for HCMV treatment, activation of CPV requires multiple steps of phosphorylation and is enantioselective. We hypothesized that the resulting CPV triphosphate (CPV-TP) would stereoselectively target HCMV DNA polymerase and terminate DNA synthesis. To test this hypothesis, we synthesized both enantiomers of CPV-TP [(+) and (−)] and investigated their action on HCMV polymerase. Both enantiomers inhibited HCMV polymerase competitively with dGTP, with (+)-CPV-TP exhibiting a more than 20-fold lower apparent

K
i

than (−)-CPV-TP. Moreover, (+)-CPV-TP was a more potent inhibitor than GCV-TP. (+)-CPV-TP also exhibited substantially lower apparent

K
m

and somewhat higher apparent
k
cat
values than (−)-CPV-TP and GCV-TP for incorporation into DNA by the viral polymerase. As is the case for GCV-TP, both CPV-TP enantiomers behaved as nonobligate chain terminators, with the polymerase terminating DNA synthesis after incorporation of one additional nucleotide. These results elucidate how CPV-TP acts on HCMV DNA polymerase and help explain why CPV is more potent against HCMV replication than GCV.
Ecological Effect of Solithromycin on Normal Human Oropharyngeal and Intestinal Microbiota
Authors: Rashid Mamun-Ur , Rosenborg Staffan , Panagiotidis Georgios , Holm Johan , Söderberg Löfdal Karin , Weintraub Andrej , Nord Carl Erik
Published: May 2016

Solithromycin is a new fluoroketolide. The purpose of the present study was to investigate the effect of orally administered solithromycin on the human oropharyngeal and intestinal microbiota. Thirteen healthy volunteers (median age, 27.3 years) received oral solithromycin at 800 mg on day 1 followed by 400 mg daily on days 2 to 7. Fecal and saliva samples were collected at baseline and on days 2, 5, 7, 9, 14, and 21 for pharmacokinetic and microbiological analyses. Plasma samples were collected predose on days 2, 5, and 7 as proof of exposure, and solithromycin concentration ranges were 21.9 to 258 ng/ml, 18.0 to 386 ng/ml, and 16.9 to 417 ng/ml, respectively. The solithromycin concentrations in feces were 15.8 to 65.4 mg/kg, 24.5 to 82.7 mg/kg, 21.4 to 82.7 mg/kg, 12.1 to 72.4 mg/kg, 0.2 to 25.6 mg/kg, and 0 to 0.5 mg/kg on days 2, 5, 7, 9, 14, and 21, respectively. The numbers of enterobacteria and enterococci decreased and were normalized on day 14. The numbers of lactobacilli and bifidobacteria decreased from day 2 to day 14 and were normalized on day 21. The clostridia decreased on days 2, 7, and 14 and were normalized on day 21. No
Clostridium difficile
strains or toxins were detected during the study period. The number of
Bacteroides
strains was not significantly changed. The solithromycin concentrations in saliva were 0 to 1.2 mg/liter, 0 to 0.5 mg/liter, 0 to 0.5 mg/liter, and 0 to 0.1 mg/liter on days 2, 5, 7, and 9, respectively. The numbers of streptococci decreased on day 2 and were normalized on day 5. The numbers of lactobacilli, prevotellae, fusobacteria, and leptotrichiae decreased from day 2 and were normalized on day 21.
Component Analysis of Multipurpose Contact Lens Solutions To Enhance Activity against Pseudomonas aeruginosa and Staphylococcus aureus
Authors: Lin Leo , Kim Janie , Chen Hope , Kowalski Regis , Nizet Victor
Published: May 2016

More than 125 million people wear contact lenses worldwide, and contact lens use is the single greatest risk factor for developing microbial keratitis. We tested the antibacterial activity of multipurpose contact lens solutions and their individual component preservatives against the two most common pathogens causing bacterial keratitis,
Pseudomonas aeruginosa
and
Staphylococcus aureus
. The
in vitro
antibacterial activity of five multipurpose contact lens solutions (Opti-Free GP, Boston Simplus, Boston Advance, Menicare GP, and Lobob) was assayed by the standard broth dilution method. Synergy between the preservative components found in the top performing solutions was assayed using checkerboard and time-kill assays. The ISO 14729 criteria and the standard broth dilution method were used to define an optimized contact lens solution formulation against a clinical panel of drug-susceptible and drug-resistant
P. aeruginosa
and
S. aureus
strains. Preservatives with the biguanide function group, chlorhexidine and polyaminopropylbiguanide (PAPB), had the best antistaphylococcal activity, while EDTA was the best antipseudomonal preservative. The combination of chlorhexidine and EDTA had excellent synergy against
P. aeruginosa
. A solution formulation containing chlorhexidine (30 ppm), PAPB (5 ppm), and EDTA (5,000 ppm) had three to seven times more antipseudomonal activity than anything available to consumers today. A multipurpose contact lens solution containing a combination of chlorhexidine, PAPB, and EDTA could help to reduce the incidence of microbial keratitis for contact lens users worldwide.
Antimalarial Activity of Small-Molecule Benzothiazole Hydrazones
Authors: Sarkar Souvik , Siddiqui Asim A. , Saha Shubhra J. , De Rudranil , Mazumder Somnath , Banerjee Chinmoy , Iqbal Mohd S. , Nag Shiladitya , Adhikari Susanta , Bandyopadhyay Uday
Published: May 2016

We synthesized a new series of conjugated hydrazones that were found to be active against malaria parasite
in vitro
, as well as
in vivo
in a murine model. These hydrazones concentration-dependently chelated free iron and offered antimalarial activity. Upon screening of the synthesized hydrazones, compound 5f was found to be the most active iron chelator, as well as antiplasmodial. Compound 5f also interacted with free heme (

K
D

[equilibrium dissociation constant] = 1.17 ± 0.8 μM), an iron-containing tetrapyrrole released after hemoglobin digestion by the parasite, and inhibited heme polymerization by parasite lysate. Structure-activity relationship studies indicated that a nitrogen- and sulfur-substituted five-membered aromatic ring present within the benzothiazole hydrazones might be responsible for their antimalarial activity. The dose-dependent antimalarial and heme polymerization inhibitory activities of the lead compound 5f were further validated by following [
3
H]hypoxanthine incorporation and hemozoin formation in parasite, respectively. It is worth mentioning that compound 5f exhibited antiplasmodial activity
in vitro
against a chloroquine/pyrimethamine-resistant strain of
Plasmodium falciparum
(K1). We also evaluated
in vivo
antimalarial activity of compound 5f in a murine model where a lethal multiple-drug-resistant strain of
Plasmodium yoelii
was used to infect Swiss albino mice. Compound 5f significantly suppressed the growth of parasite, and the infected mice experienced longer life spans upon treatment with this compound. During
in vitro
and
in vivo
toxicity assays, compound 5f showed minimal alteration in biochemical and hematological parameters compared to control. In conclusion, we identified a new class of hydrazone with therapeutic potential against malaria.
Quinolone Amides as Antitrypanosomal Lead Compounds with
In Vivo
Activity
Authors: Hiltensperger Georg , Hecht Nina , Kaiser Marcel , Rybak Jens-Christoph , Hoerst Alexander , Dannenbauer Nicole , Müller-Buschbaum Klaus , Bruhn Heike , Esch Harald , Lehmann Leane , Meinel Lorenz , Holzgrabe Ulrike
Published: May 2016

Human African trypanosomiasis (HAT) is a major tropical disease for which few drugs for treatment are available, driving the need for novel active compounds. Recently, morpholino-substituted benzyl amides of the fluoroquinolone-type antibiotics were identified to be compounds highly active against
Trypanosoma brucei brucei
. Since the lead compound GHQ168 was challenged by poor water solubility in previous trials, the aim of this study was to introduce structural variations to GHQ168 as well as to formulate GHQ168 with the ultimate goal to increase its aqueous solubility while maintaining its
in vitro
antitrypanosomal activity. The pharmacokinetic parameters of spray-dried GHQ168 and the newly synthesized compounds GHQ242 and GHQ243 in mice were characterized by elimination half-lives ranging from 1.5 to 3.5 h after intraperitoneal administration (4 mice/compound), moderate to strong human serum albumin binding for GHQ168 (80%) and GHQ243 (45%), and very high human serum albumin binding (>99%) for GHQ242. For the lead compound, GHQ168, the apparent clearance was 112 ml/h and the apparent volume of distribution was 14 liters/kg of body weight (BW). Mice infected with
T. b. rhodesiense
(STIB900) were treated in a stringent study scheme (2 daily applications between days 3 and 6 postinfection). Exposure to spray-dried GHQ168 in contrast to the control treatment resulted in mean survival durations of 17 versus 9 days, respectively, a difference that was statistically significant. Results that were statistically insignificantly different were obtained between the control and the GHQ242 and GHQ243 treatments. Therefore, GHQ168 was further profiled in an early-treatment scheme (2 daily applications at days 1 to 4 postinfection), and the results were compared with those obtained with a control treatment. The result was statistically significant mean survival times exceeding 32 days (end of the observation period) versus 7 days for the GHQ168 and control treatments, respectively. Spray-dried GHQ168 demonstrated exciting antitrypanosomal efficacy.
Geographic Differences in the Contribution of
ubiA
Mutations to High-Level Ethambutol Resistance in Mycobacterium tuberculosis
Authors: Lingaraju Subramanya , Rigouts Leen , Gupta Aditi , Lee Jongseok , Umubyeyi Alaine Nyaruhirira , Davidow Amy L. , German Susan , Cho EunJin , Lee Ji-im , Cho Sang-Nae , Kim Cheon Tae , Alland David , Safi Hassan
Published: May 2016

Ethambutol (EMB) resistance can evolve through a multistep process, and mutations in the
ubiA
(
Rv3806c
) gene appear to be responsible for high-level EMB resistance in
Mycobacterium tuberculosis
. We evaluated the prevalence of
ubiA
and
embB
(
Rv3795
) mutations in EMB-resistant strains originating from Africa and South Korea. No differences in
embB
mutation frequencies were observed between strains from both origins. However,
ubiA
mutations were present in 45.5% ± 6.5% of the African EMB-resistant isolates but in only 9.5% ± 1.5% of the South Korean EMB-resistant isolates. The
ubiA
mutations associated with EMB resistance were localized to regions encoding the transmembrane domains of the protein, whereas the
embB
mutations were localized to regions encoding the extramembrane domains. Larger studies are needed to investigate the causes of increased
ubiA
mutations as a pathway to high-level EMB resistance in African countries, such as extended EMB usage during tuberculosis treatment.
High Systemic Exposure of Pyrazinoic Acid Has Limited Antituberculosis Activity in Murine and Rabbit Models of Tuberculosis
Authors: Lanoix Jean-Philippe , Tasneen Rokeya , O'Brien Paul , Sarathy Jansy , Safi Hassan , Pinn Michael , Alland David , Dartois Véronique , Nuermberger Eric
Published: May 2016

Pyrazinamide (PZA) is a prodrug requiring conversion to pyrazinoic acid (POA) by an amidase encoded bypncAforin vitroactivity. Mutation ofpncAis the most common cause of PZA resistance in clinical isolates. To determine whether the systemic delivery of POA or host-mediated conversion of PZA to POA could circumvent such resistance, we evaluated the efficacy of orally administered and host-derived POAin vivo. Dose-ranging plasma and intrapulmonary POA pharmacokinetics and the efficacy of oral POA or PZA treatment against PZA-susceptible tuberculosis were determined in BALB/c and C3HeB/FeJ mice. The activity of host-derived POA was assessed in rabbits infected with apncA-null mutant and treated with PZA. Median plasma POA values for the area under the concentration-time curve from 0 h to infinity (AUC0–∞) were 139 to 222 μg·h/ml and 178 to 287 μg·h/ml after doses of PZA and POA of 150 mg/kg of body weight, respectively, in mice. Epithelial lining fluid POA concentrations in infected mice were comparable after POA and PZA administration. In chronically infected BALB/c mice, PZA at 150 mg/kg reduced lung CFU counts by >2 log10after 4 weeks. POA was effective only at 450 mg/kg, which reduced lung CFU counts by ∼0.7 log10. POA had no demonstrable bactericidal activity in C3HeB/FeJ mice, nor did PZA administered to rabbits infected with a PZA-resistant mutant. Oral POA administration and host-mediated conversion of PZA to POA producing plasma POA exposures comparable to PZA administration was significantly less effective than PZA. These results suggest that the intrabacillary delivery of POA and that producing higher POA concentrations at the site of infection will be more effective strategies for maximizing POA efficacy.
Stability of Novel Siderophore Cephalosporin S-649266 against Clinically Relevant Carbapenemases
Authors: Ito-Horiyama Tsukasa , Ishii Yoshikazu , Ito Akinobu , Sato Takafumi , Nakamura Rio , Fukuhara Norio , Tsuji Masakatsu , Yamano Yoshinori , Yamaguchi Keizo , Tateda Kazuhiro
Published: May 2016

To better understand the antibacterial activity of S-649266 against carbapenemase producers, its stability against clinically relevant carbapenemases was investigated. The catalytic efficiencies (
k
cat
/

K
m

) of IMP-1, VIM-2, and L1 for S-649266 were 0.0048, 0.0050, and 0.024 μM
−1
s
−1
, respectively, which were more than 260-fold lower than that for meropenem. Only slight hydrolysis of S-649266 against KPC-3 was observed. NDM-1 hydrolyzed meropenem 3-fold faster than S-649266 at 200 μM.
Pharmacodynamic Evaluation of the Potential Clinical Utility of Fosfomycin and Meropenem in Combination Therapy against KPC-2-Producing Klebsiella pneumoniae
Authors: Albiero James , Sy Sherwin K. B. , Mazucheli Josmar , Caparroz-Assef Silvana Martins , Costa Bruno Buranello , Alves Janio Leal Borges , Gales Ana Cristina , Tognim Maria Cristina Bronharo
Published: May 2016

KPC-producing
Klebsiella pneumoniae
causes serious infections associated with high death rates worldwide. Combination therapy consisting of fosfomycin and a carbapenem is better than monotherapy to combat multidrug-resistant microorganisms, but no dosages for the combination have been defined. The MICs of meropenem and fosfomycin were evaluated against 18 clinical isolates of KPC-2-producing
K. pneumoniae
. The activities of combination antimicrobials were also determined by the checkerboard method. The MIC
50
and MIC
90
of each agent alone and in combination were challenged against short (1.5-h) or prolonged (3-h) infusion regimens of meropenem (1 g every 8 h [q8h], 1.5 g q6h, 2 g q8h) and fosfomycin (4 g q8h, 6 g q6h, 8 g q8h) by Monte Carlo simulation to evaluate the time above the MIC of the free drug concentration as a percentage of the dosing interval (
f
T>MIC). The monotherapy MIC
50
s and MIC
90
s were 32 and 256 mg/liter for meropenem and 64 and 512 mg/liter for fosfomycin, respectively. Antimicrobial combination increased bacterial susceptibility to 1/4 the MIC
50
s and to 1/8 to 1/16 the MIC
90
s of monotherapy. The antimicrobial combination demonstrated a synergistic effect for at least two-thirds of the isolates. In combination therapy, fosfomycin regimens of 6 g q6h and 8 g q8h as a 3-h infusion against the MIC
50
and MIC
90
had better chances of achieving ≥90% probability of target attainment (PTA) of 70%
f
T>MIC. Meropenem regimens of 1.5 g q6h and 2 g q8h in prolonged infusion can achieve close to 90% PTA of 40%
f
T>MIC for MIC
50
but not MIC
90
. The significant reduction in the MIC values and the achievement of appropriate PTA demonstrated that regimens containing fosfomycin with meropenem can be effective against KPC-2-producing
K. pneumoniae
.
Transcription Regulation in Archaea
Authors: Gehring Alexandra M. , Walker Julie E. , Santangelo Thomas J.
Published: May 2016

The known diversity of metabolic strategies and physiological adaptations of archaeal species to extreme environments is extraordinary. Accurate and responsive mechanisms to ensure that gene expression patterns match the needs of the cell necessitate regulatory strategies that control the activities and output of the archaeal transcription apparatus.Archaeaare reliant on a single RNA polymerase for all transcription, and many of the known regulatory mechanisms employed for archaeal transcription mimic strategies also employed for eukaryotic and bacterial species. Novel mechanisms of transcription regulation have become apparent by increasingly sophisticatedin vivoandin vitroinvestigations of archaeal species. This review emphasizes recent progress in understanding archaeal transcription regulatory mechanisms and highlights insights gained from studies of the influence of archaeal chromatin on transcription.
The IntXO-PSL Recombination System Is a Key Component of the Second Maintenance System for Bacillus anthracis Plasmid pXO1
Authors: Pomerantsev Andrei P. , Rappole Catherine , Chang Zanetta , Chahoud Margaret , Leppla Stephen H.
Published: May 2016

We previously identified three noncontiguous regions on
Bacillus anthracis
plasmid pXO1 that comprise a system for accurate plasmid partitioning and maintenance. However, deletion of these regions did not decrease retention of certain shortened pXO1 plasmids during vegetative growth. Using two genetic tools developed for DNA manipulation in
B. anthracis
(the Cre-
loxP
and Flp-FRT systems), we found two other noncontiguous pXO1 regions that together are sufficient for plasmid stability. This second pXO1 maintenance system includes the
tubZ
and
tubR
genes, characteristic of a type III partitioning system, and the IntXO recombinase gene (GBAA_RS29165), encoding a tyrosine recombinase, along with its adjacent 37-bp perfect stem-loop (PSL) target. Insertion of either the
tubZ
and
tubR
genes or the IntXO-PSL system into an unstable mini-pXO1 plasmid did not restore plasmid stability. The need for the two components of the second pXO1 maintenance system follows from the sequential roles of IntXO-PSL in generating monomeric circular daughter pXO1 molecules (thereby presumably preventing dimer catastrophe) and of TubZ/TubR in partitioning the monomers during cell division. We show that the IntXO recombinase deletes DNA regions located between two PSL sites in a manner similar to the actions of the Cre-
loxP
and Flp-FRT systems.

IMPORTANCE
Tyrosine recombinases catalyze cutting and joining reactions between short specific DNA sequences. Three types of reactions occur: integration and excision of DNA segments, inversion of DNA segments, and separation of monomeric forms from replicating circular DNA molecules. Here we show that the newly discovered site-specific IntXO-PSL recombinase system that contributes to the maintenance of the
B. anthracis
plasmid pXO1 can be used for genome engineering in a manner similar to that of the Cre-
loxP
or Flp-FRT system.
Cytokine profile of nasal and middle ear polyps in a patient with Woakes' syndrome and eosinophilic otitis media
Authors: De Loof Marie , De Leenheer Els , Holtappels Gabriële , Bachert Claus
Published: May 2016

Woakes' syndrome is characterised by severe recurrent nasal polyps in early childhood with broadening of the nose, nasal dyscrinia, frontal sinus aplasia and bronchiectasis. Eosinophilic otitis media (EOM) is an intractable condition that can cause gradual or sudden deterioration of hearing and is associated with comorbid asthma. For these reasons, both diseases must be recognised and treated appropriately. We present a case of a 20-year-old man with Woakes' syndrome complicated by EOM, with polyps in both middle ears; this condition has so far not been described as an entity of eosinophilic disease in the literature. We have, from reviewing the literature, learned that this is the first time that results of tissue examination on nasal polyposis with respect to tissue IgE, eosinophil-cationic protein, interleukin (IL)-17 and IL-5 in a patient with Woakes' syndrome and EOM, has been reported and discussed.
Risk factors associated with dystocia in a tie stall dairy herd
Authors: López Helguera I. , Behrouzi A. , Kastelic J.P. , Colazo M.G.
Published: May 2016

The aims of the study were to: (1) investigate factors affecting calf birth weight (CBW) and gestation length (GL); and (2) determine risk factors associated with dystocia in 1019 Holstein heifers and cows in a tie stall dairy herd. Calf sex (CS), sire, and GL were related to CBW in primiparous and multiparous cows, with no significant effect of season, age of primiparous cows (AGE) or days in milk (DIM) of multiparous cows at conception. Gestation length was affected by CS in primiparous, with a shorter GL for female versus male calves (275.7 ± 0.5 vs. 278.3 ± 0.4; P < 0.001). Also, GL was shorter in multiparous cows that calved during the cold season compared to those that calved in mild or warm seasons. Primiparous cows had a higher prevalence of dystocia compared to multiparous cows (32.1 vs. 8.5%; P < 0.001), but it was highly variable depending on sire (24.4%–60.0% for primiparous and 0%–21.1% for multiparous). In conclusion, CS, sire, and GL were related to CBW, whereas GL was affected by CS in primiparous and season in multiparous. The CBW was the major factor affecting dystocia in primiparous cows, whereas sire and twin pregnancies were factors related to dystocia in both primiparous and multiparous cows.
Genetic and phenotypic associations of milk β-hydroxybutyrate with ketosis in Canadian Holsteins
Authors: Koeck Astrid , Jamrozik Janusz , Kistemaker Gerrit J. , Schenkel Flavio S. , Moore Robert K. , Lefebvre Daniel M. , Kelton David F. , Miglior Filippo
Published: May 2016

The objective of this study was to investigate if milk β-hydroxybutyrate (BHBA) can be used as an indicator of ketosis. The different measures of milk BHBA were moderately genetically correlated with ketosis. The results imply that milk BHBA could be used to indirectly select animals that are more resistant to ketosis.
BaeR protein acts as an activator of nuclear factor-kappa B and Janus kinase 2 to induce inflammation in murine cell lines
Authors: Lee Seung-Jin , Birhanu Biruk Tesfaye , Awji Elias Gebru , Kim Myung Hee , Park Ji-Yong , Suh Joo-Won , Park Seung-Chun
Published: May 2016

BaeR, a response regulator protein, takes part in multidrug efflux, bacterial virulence activity, and other biological functions. Recently, BaeR was shown to induce inflammatory responses by activating the mitogen-activated protein kinases (MAPKs). In this study, we investigated additional pathways used by BaeR to induce an inflammatory response. BaeR protein was purified from Salmonella enterica Paratyphi A and subcloned into a pPosKJ expression vector. RAW 264.7 cells were treated with BaeR, and RNA was extracted by TRIzol reagent for RT-PCR. Cytokine gene expression was analyzed by using the comparative cycle threshold method, while western blotting and ELISA were used to assess protein expression. We confirmed that BaeR activates nuclear factor-kappa B (NF-κB), thereby inducing an inflammatory response and increases the production of interleukins (IL-)1β and IL-6. During this process, the Janus kinase 2 (JAK2)–STAT1 signaling pathway was activated, resulting in an increase in the release of interferons I and II. Additionally, COX-2 was activated and its expression increased with time. In conclusion, BaeR induced an inflammatory response through activation of NF-κB in addition to the MAPKs. Furthermore, activation of the JAK2–STAT1 pathway and COX-2 facilitated the cytokine binding activity, suggesting an additional role for BaeR in the modulation of the immune system of the host and the virulence activity of the pathogen.
Deep Learning Representation from Electroencephalography of Early-Stage Creutzfeldt-Jakob Disease and Features for Differentiation from Rapidly Progressive Dementia
Authors: Morabito Francesco Carlo , Campolo Maurizio , Mammone Nadia , Versaci Mario , Franceschetti Silvana , Tagliavini Fabrizio , Sofia Vito , Fatuzzo Daniela , Gambardella Antonio , Labate Angelo , Mumoli Laura , Tripodi Giovanbattista Gaspare , Gasparini Sara , Cianci Vittoria , Sueri Chiara , Ferlazzo Edoardo , Aguglia Umberto
Published: May 2016

A novel technique of quantitative EEG for differentiating patients with early-stage Creutzfeldt–Jakob disease (CJD) from other forms of rapidly progressive dementia (RPD) is proposed. The discrimination is based on the extraction of suitable features from the time-frequency representation of the EEG signals through continuous wavelet transform (CWT). An average measure of complexity of the EEG signal obtained by permutation entropy (PE) is also included. The dimensionality of the feature space is reduced through a multilayer processing system based on the recently emerged deep learning (DL) concept. The DL processor includes a stacked auto-encoder, trained by unsupervised learning techniques, and a classifier whose parameters are determined in a supervised way by associating the known category labels to the reduced vector of high-level features generated by the previous processing blocks. The supervised learning step is carried out by using either support vector machines (SVM) or multilayer neural networks (MLP-NN). A subset of EEG from patients suffering from Alzheimer’s Disease (AD) and healthy controls (HC) is considered for differentiating CJD patients. When fine-tuning the parameters of the global processing system by a supervised learning procedure, the proposed system is able to achieve an average accuracy of 89%, an average sensitivity of 92%, and an average specificity of 89% in differentiating CJD from RPD. Similar results are obtained for CJD versus AD and CJD versus HC.
Improving Accuracy in Face Recognition Proposal to Create a Hybrid Photo Indexing Algorithm, Consisting of Principal Component Analysis and a Triangular Algorithm (PCAaTA)
Authors: Vu L. G. , Alsadoon Abeer , Prasad P. W. C. , Rahma A. M. S.
Published: May 2016

Accurate face recognition is today vital, principally for reasons of security. Current methods employ algorithms that index (classify) important features of human faces. There are many current studies in this field but most current solutions have significant limitations. Principal Component Analysis (PCA) is one of the best facial recognition algorithms. However, there are some noises that could affect the accuracy of this algorithm. The PCA works well with the support of preprocessing steps such as illumination reduction, background removal and color conversion. Some current solutions have shown results when using a combination of PCA and preprocessing steps. This paper proposes a hybrid solution in face recognition using PCA as the main algorithm with the support of a triangular algorithm in face normalization in order to enhance indexing accuracy. To evaluate the accuracy of the proposed hybrid indexing algorithm, the PCAaTA is tested and the results are compared with current solutions.
Fréchet Similarity of Closed Polygonal Curves
Authors: Schlesinger M. I. , Vodolazskiy E. V. , Yakovenko V. M.
Published: May 2016

The article analyzes similarity of closed polygonal curves with respect to the Fréchet metric, which is stronger than the well-known Hausdorff metric and therefore is more appropriate in some applications. An algorithm is described that determines whether the Fréchet distance between two closed polygonal curves with [Formula: see text] and [Formula: see text] vertices is less than a given number [Formula: see text]. The algorithm takes [Formula: see text] time whereas the previously known algorithms take [Formula: see text] time.
Quotients of degenerate Sklyanin algebras
Authors: De Laet Kevin
Published: May 2016

In this paper, it is shown how the Heisenberg group of order 27 can be used to construct quotients of degenerate Sklyanin algebras. These quotients have properties similar to the classical Sklyanin case in the sense that they have the same Hilbert series, the same character series and a central element of degree 3. Regarding the central element of a three-dimensional Sklyanin algebra, a better way to view this using Heisenberg-invariants is shown.
THE INFORMATION BOTTLENECK METHOD FOR OPTIMAL PREDICTION OF MULTILEVEL AGENT-BASED SYSTEMS
Authors: LAMARCHE-PERRIN ROBIN , BANISCH SVEN , OLBRICH ECKEHARD
Published: May 2016

Because the dynamics of complex systems is the result of both decisive local events and reinforced global effects, the prediction of such systems could not do without a genuine multilevel approach. This paper proposes to found such an approach on information theory. Starting from a complete microscopic description of the system dynamics, we are looking for observables of the current state that allows to efficiently predict future observables. Using the framework of the information bottleneck (IB) method, we relate optimality to two aspects: the complexity and the predictive capacity of the retained measurement. Then, with a focus on agent-based models (ABMs), we analyze the solution space of the resulting optimization problem in a generic fashion. We show that, when dealing with a class of feasible measurements that are consistent with the agent structure, this solution space has interesting algebraic properties that can be exploited to efficiently solve the problem. We then present results of this general framework for the voter model (VM) with several topologies and show that, especially when predicting the state of some sub-part of the system, multilevel measurements turn out to be the optimal predictors.
Orbital stability of standing waves of a class of fractional Schrödinger equations with Hartree-type nonlinearity
Authors: Cho Yonggeun , Fall Mouhamed M. , Hajaiej Hichem , Markowich Peter A. , Trabelsi Saber
Published: May 2016

This paper is devoted to the mathematical analysis of a class of nonlinear fractional Schrödinger equations with a general Hartree-type integrand. We show the well-posedness of the associated Cauchy problem and prove the existence and stability of standing waves under suitable assumptions on the nonlinearity. Our proofs rely on a contraction argument in mixed functional spaces and the concentration-compactness method.