bluuebunny/crossref_metadata_2025 huggingface dataset:
When the Centre Cannot Hold: Patterns of Polarization inNigeria
Authors: Clementi F. , Dabalen A. L. , Molini V. , Schettino F.
Published: August 2015

This paper advances the hypothesis thatNigeria is going through a process of economic polarization. The notion of polarization is concerned with the disappearance or non‐consolidation of the middle class, which occurs when there is a tendency to concentrate in the tails, rather than the middle, of the income/consumption distribution. This paper uses newly available data and the relative distribution methodology (Handcock andMorris, 1998, 1999) to present new results on polarization. The findings confirm the sharp increase of polarization. Compared to 2003, the distribution of consumption has become more concentrated in upper and lower deciles in 2013, while the middle deciles have thinned. A between‐group analysis shows the emergence of a macro‐regional gap: while theSouth‐South andSouth‐West regions contribute mainly to polarization in the upper tail, households in theNorthEast andNorthWest zones—the conflict‐stricken areas—are more likely to fall in the lower national deciles.
Airway inflammation, cough and athlete quality of life in elite female cross‐country skiers: A longitudinal study
Authors: Kennedy M. D. , Davidson W. J. , Wong L. E. , Traves S. L. , Leigh R. , Eves N. D.
Published: August 2015

The aim of this study was to investigate the effect of a season of cross‐country training and racing on airway inflammation, cough symptoms, and athlete quality of life in female skiers. Eighteen elite female skiers performed sputum induction and completed the Leicester Cough Questionnaire (LCQ) and the Recovery‐Stress Questionnaire (REST‐Q) at three time points (T1 – May/Jun, T2 – Oct/Nov, T3 – Jan–Mar) during the year. No changes were observed between T1 and T2. However, an increase in sputum eosinophils and lymphocytes (P < 0.05) and a significant change in all three domains of the LCQ were observed between T1 and T3 (P < 0.05). A significant association was found between the total yearly hours of training and the change in the total cell count (r2 = 0.74; P = 0.006), and a number of other sputum cell counts between T1 and T3. No changes were observed for any domain of the REST‐Q. The results of this study demonstrate that airway inflammation and cough symptoms are significantly increased in elite female cross‐country skiers across a year of training and racing. The increase in airway inflammation is related to the total amount of training and is worse during the winter months when athletes are training and racing in cold, dry air.
CFTR genotype‐related body water and electrolyte balance during a marathon
Authors: Del Coso J. , Lara B. , Salinero J. J. , Areces F. , Ruiz‐Vicente D. , Gallo‐Salazar C. , Abián‐Vicén J. , Cacabelos R.
Published: August 2015

The aim of this investigation was to determine the influence of CFTR genotype on body water and electrolyte balance during a marathon. Fifty‐one experienced runners completed a marathon race. Before and after the race, body mass and a sample of venous blood were obtained. During the race, sweat samples were collected using sweat patches, and fluid and electrolyte intake were obtained using self‐reported questionnaires. Thirty‐eight participants (74.5% of the total) were 7T/7T homozygotes, 11 (21.6%) were 7T/9T heterozygotes, and one participant presented the rare genotype 5T/7T. Another participant with 9T/9T presented the mutation p.L206W. Participants with 7T/7T showed higher sweat sodium concentrations (42.2 ± 21.6 mmol/L) than 7T/9T (29.0 ± 24.7 mmol/L; P = 0.04). The runner with the 5T/7T genotype (10.2 mmol/L) and the participant with the p.L206W mutation (20.5 mmol/L) exhibited low‐range sweat sodium concentrations. However, post‐race serum sodium concentration was similar in 7T/7T and 7T/9T (142.1 ± 1.3 and 142.4 ± 1.6 mmol/L, respectively; P = 0.27) and did not show abnormalities in participants with the 5T/7T genotype (140.0 mmol/L) and the p.L206W mutation (143.0 mmol/L). Runners with the CFTR‐7T/7T genotype exhibited increased sweat sodium concentrations during a marathon. However, this phenotype was not related with increased likelihood of suffering body water and electrolyte imbalances during real competitions.
Cost–utility analysis of an advanced pressure ulcer management protocol followed by trained wound, ostomy, and continence nurses
Authors: Kaitani Toshiko , Nakagami Gojiro , Iizaka Shinji , Fukuda Takashi , Oe Makoto , Igarashi Ataru , Mori Taketoshi , Takemura Yukie , Mizokami Yuko , Sugama Junko , Sanada Hiromi
Published: August 2015

The high prevalence of severe pressure ulcers (PUs) is an important issue that requires to be highlighted in Japan. In a previous study, we devised an advanced PU management protocol to enable early detection of and intervention for deep tissue injury and critical colonization. This protocol was effective for preventing more severe PUs. The present study aimed to compare the cost‐effectiveness of the care provided using an advanced PU management protocol, from a medical provider's perspective, implemented by trained wound, ostomy, and continence nurses (WOCNs), with that of conventional care provided by a control group of WOCNs. A Markov model was constructed for a 1‐year time horizon to determine the incremental cost‐effectiveness ratio of advanced PU management compared with conventional care. The number of quality‐adjusted life‐years gained, and the cost in Japanese yen (¥) ($US1 = ¥120; 2015) was used as the outcome. Model inputs for clinical probabilities and related costs were based on our previous clinical trial results. Univariate sensitivity analyses were performed. Furthermore, a Bayesian multivariate probability sensitivity analysis was performed using Monte Carlo simulations with advanced PU management. Two different models were created for initial cohort distribution. For both models, the expected effectiveness for the intervention group using advanced PU management techniques was high, with a low expected cost value. The sensitivity analyses suggested that the results were robust. Intervention by WOCNs using advanced PU management techniques was more effective and cost‐effective than conventional care.
The exercise‐induced biochemical milieu enhances collagen content and tensile strength of engineered ligaments
Authors: West Daniel W. D. , Lee‐Barthel Ann , McIntyre Todd , Shamim Baubak , Lee Cassandra A. , Baar Keith
Published: August 2015

Key points

Exercise acutely increases the concentrations of metabolites and hormones such as growth hormone (GH) and, to a lesser extent, insulin‐like growth factor 1 (IGF‐1); however, the biological function of this response is unclear.

Pharmacological administration of these hormones stimulates collagen synthesis in muscle and tendon; however, whether the post‐exercise biochemical milieu has a similar action is unknown.

Treating engineered ligaments with serum obtained from young healthy men after exercise resulted in more collagen and improved tensile strength over those treated with serum from resting men.

Further, we show that the increase in collagen induced by post‐exercise serum (i) is not reproduced by treatment with recombinant GH or IGF‐1, and (ii) is associated with the activation of PI3 kinase/mTORC1 and ERK1/2 signalling.

Exercise stimulates a dramatic change in the concentration of circulating hormones, such as growth hormone (GH), but the biological functions of this response are unclear. Pharmacological GH administration stimulates collagen synthesis; however, whether the post‐exercise systemic milieu has a similar action is unknown. We aimed to determine whether the collagen content and tensile strength of tissue‐engineered ligaments is enhanced by serum obtained post‐exercise. Primary cells from a human anterior cruciate ligament (ACL) were used to engineer ligament constructs in vitro. Blood obtained from 12 healthy young men 15 min after resistance exercise contained GH concentrations that were ∼7‐fold greater than resting serum (P < 0.001), whereas IGF‐1 was not elevated at this time point (P = 0.21 vs. rest). Ligament constructs were treated for 7 days with medium supplemented with serum obtained at rest (RestTx) or 15 min post‐exercise (ExTx), before tensile testing and collagen content analysis. Compared with RestTx, ExTx enhanced collagen content (+19%; 181 ± 33 vs. 215 ± 40 μg per construct P = 0.001) and ligament mechanical properties – maximal tensile load (+17%, P = 0.03 vs. RestTx) and ultimate tensile strength (+10%, P = 0.15 vs. RestTx). In a separate set of engineered ligaments, recombinant IGF‐1, but not GH, enhanced collagen content and mechanics. Bioassays in 2D culture revealed that acute treatment with post‐exercise serum activated mTORC1 and ERK1/2. In conclusion, the post‐exercise biochemical milieu, but not recombinant GH, enhances collagen content and tensile strength of engineered ligaments, in association with mTORC1 and ERK1/2 activation.
Identification of critical functional determinants of kainate receptor modulation by auxiliary protein Neto2
Authors: Griffith Theanne N. , Swanson Geoffrey T.
Published: August 2015

Key points

Kainate receptors (KARs) are ionotropic glutamate receptors (iGluRs) that modulate synaptic transmission and intrinsic neuronal excitability.

KARs associate with the auxiliary proteins neuropilin‐ and tolloid‐like 1 and 2 (Neto1 and Neto2), which act as allosteric modulators of receptor function impacting all biophysical properties of these receptors studied to date.

M3–S2 linkers play a critical role in KAR gating; we found that individual residues in these linkers bidirectionally influence Neto2 modulation of KAR desensitization in an agonist specific manner.

We also identify the D1 dimer interface as a novel site of Neto2 modulation and functionally correlate the actions of Neto2 modulation of desensitization with modulation of cation sensitivity.

We identify these domains as determinants of Neto2 modulation. Thus, our work contributes to the understanding of auxiliary subunit modulation of KAR function and could aid the development of KAR‐specific modulators to alter receptor function.

Kainate receptors (KARs) are important modulators of synaptic transmission and intrinsic neuronal excitability in the CNS. Their activity is shaped by the auxiliary proteins Neto1 and Neto2, which impact KAR gating in a receptor subunit‐ and Neto isoform‐specific manner. The structural basis for Neto modulation of KAR gating is unknown. Here we identify the M3–S2 gating linker as a critical determinant contributing to Neto2 modulation of KARs. M3–S2 linkers control both the valence and magnitude of Neto2 modulation of homomeric GluK2 receptors. Furthermore, a single mutation in this domain abolishes Neto2 modulation of heteromeric receptor desensitization. Additionally, we found that cation sensitivity of KAR gating is altered by Neto2 association, suggesting that stability of the D1 dimer interface in the ligand‐binding domain (LBD) is an important determinant of Neto2 actions. Moreover, modulation of cation sensitivity was eliminated by mutations in the M3–S2 linkers, thereby correlating the action of Neto2 at these structurally discrete sites on receptor subunits. These results demonstrate that the KAR M3–S2 linkers and LBD dimer interface are critical determinants for Neto2 modulation of receptor function and identify these domains as potential sites of action for the targeted development of KAR‐specific modulators that alter the function of auxiliary proteins in native receptors.
Derivations of the band-importance function: A cross-procedure comparison
Authors: Jin In-Ki , Kates James M. , Lee Kyoungwon , Arehart Kathryn H.
Published: August 2015

The purpose of this study was to compare band-importance functions (BIFs) derived by two different procedures. Intelligibility data from native speakers of Korean were used. BIFs were derived using an established procedure reported by Studebaker and Sherbecoe [J. Speech Lang. Hear. Res. 34, 427–438 (1991)] and by a recently published method reported by Kates [J. Acoust. Soc. Am. 134(5), EL459–EL464 (2013)]. The BIFs produced by the two different procedures were similar. These results indicate that the BIF calculation procedure by Kates is accurate for sentences as well as for the monosyllables used in its derivation.
Categorical scaling of partial loudness in a condition of masking release
Authors: Verhey Jesko L. , Heeren Wiebke
Published: August 2015

Categorical loudness scaling was used to measure suprathreshold release from masking. The signal was a 986-Hz sinusoid that was embedded in a bandpass-filtered masking noise. This noise was either unmodulated or was amplitude modulated with a square-wave modulator. The unmodulated noise had either the same level as the modulated noise or had a level that was reduced by the difference in thresholds for the 986-Hz signal obtained with the modulated and unmodulated noise masker presented at the same level (i.e., the masking release). A comparison with loudness matching data of the same set of subjects showed that the data obtained with loudness scaling capture main aspects of the change in suprathreshold perception of the sinusoid when the masker was modulated. The scaling data for the signal masked by the unmodulated noise with the reduced masker level were similar to that for the signal embedded in the modulated noise. This similarity supports the hypothesis that the mechanism eliciting the masking release is effectively reducing the masker level.
On the Demand for Live Sport Contests: Insights From the Secondary Market for National Football League Tickets
Authors: Diehl Mark A. , Drayer Joris , Maxcy Joel G.
Published: August 2015

This study examines the determinants of regular season National Football League (NFL) ticket prices on the secondary, or resale, market. Prices in the secondary market are dynamic and thus particularly useful for evaluating the demand for live NFL contests. A rich dataset is employed that contains information about all transactions conducted by a prominent ticketing site during a full NFL season and allows for a comprehensive investigation of the components of demand in this market. Included in the analysis is a first look at the demand for different seating locations within the stadium. The revealed determinants of demand for resale tickets were largely consistent with studies of the primary market; however, there are notable differences in spectators’ preferences for contest characteristics and uncertainty of outcome across the seating categories. The evidence also suggests that while hometown fans are the primary participants, visiting teams are likely active in the resale market.
The Effects of Performance Expectations on Total Compensation of Division I–Football Bowl Subdivision Head Coaches
Authors: Soebbing Brian P. , Wicker Pamela , Watanabe Nicholas M.
Published: August 2015

The literature examining executive and upper management compensation has looked at a variety of factors. Within sport, coaches are equivalent to these positions, with one of the major factors determining total compensation being on-field performance. However, little is known on how expectations of on-field performance compared with actual performance affect compensation. The purpose of this study is to analyze the effect of performance expectations on Division I–Football Bowl Subdivision head football coaches’ total compensation. Using data from 2006 to 2013, compensation increases when on-field performance expectations are exceeded. The impact of an additional on-field win relative to performance expectations is between 5.0 and 5.5% in terms of additional compensation. However, no statistically significant effect exists when comparing coaches at automatic qualifying versus nonautomatic qualifying schools. In addition, off-field measures of performance as well as individual and university characteristics affect total compensation.
Bridging the Gap: U.S. Sport Managers on Barriers to Industry–Academia Research Collaboration
Authors: Zaharia Noni , Kaburakis Anastasios
Published: August 2015

Collaboration between industry and academia is a subject of great interest to sport management academics and sport industry leaders in the United States. However, there is a lack of research regarding barriers to sport industry–academia collaborations and bridging the gap between sport management research and practitioners. The aim of the study was to explore trends in collaboration barriers among various research involvement levels of U.S. sport firms with sport management academia. Data were gathered from 303 sport managers working for U.S. sport companies. Results indicated several barriers for research collaborations between the U.S. sport industry and academia. Such barriers include transactional barriers, sport industry subsectors, sport organizations’ location, and age and education level of respondents.
Exploring the Trajectory of Active-Sport-Event Travel Careers: A Social Worlds Perspective
Authors: Buning Richard J. , Gibson Heather J.
Published: August 2015

Utilizing a social worlds perspective, the study examined active-sport-event travel career progression in the sport of cycling. Event travel careers are considered potentially lifelong patterns of travel to participate in events that evolve through stages with distinct behaviors and motivations. Quantitative methods were used to test tenets of an inductively derived model of the active-sport-event travel career for cyclists. An international sample of cyclists were surveyed online; N = 1,452 responded. Using general linear modeling, the results depicted an escalation in motivation related to intellectual, social, mastery competence, giving back, and competition against others with career progression. However, while travel behavior related to preferred events characteristics changed with career progression, preferred characteristics related to destinations and travel style remained relatively stagnant. Implications for destination and event management are discussed.
Degrading the degrader to promote Wnt signaling
Authors: Ferrarelli Leslie K.
Published: August 2015

Stabilization of one ubiquitin ligase results in the destabilization of another that targets β-catenin for degradation.
Outbreak Caused by Enterobacteriaceae Harboring NDM-1 Metallo-β-Lactamase Carried in an IncFII Plasmid in a Tertiary Care Hospital in Mexico City
Authors: Torres-González Pedro , Bobadilla-del Valle Miriam , Tovar-Calderón Estrella , Leal-Vega Francisco , Hernández-Cruz Araceli , Martínez-Gamboa Areli , Niembro-Ortega María Dolores , Sifuentes-Osornio José , Ponce-de-León Alfredo
Published: August 2015

Carbapenem-resistant
Enterobacteriaceae
carrying New Delhi metallo-β-lactamase 1 (NDM-1) have rarely been reported in Latin America. We report of an outbreak caused by a
bla
NDM-1
-harboring plasmid spread through different bacterial species, including
Escherichia coli
(ST617) and
Enterobacter cloacae
(ST182) isolates from the same patient and three
Klebsiella pneumoniae
isolates (ST22) derived from three epidemiologically related patients. IncFII plasmids were found in all strains. Measures to control the outbreak were applied successfully.
Targeting the Parasite's DNA with Methyltriazenyl Purine Analogs Is a Safe, Selective, and Efficacious Antitrypanosomal Strategy
Authors: Rodenko Boris , Wanner Martin J. , Alkhaldi Abdulsalam A. M. , Ebiloma Godwin U. , Barnes Rebecca L. , Kaiser Marcel , Brun Reto , McCulloch Richard , Koomen Gerrit-Jan , de Koning Harry P.
Published: August 2015

The human and veterinary disease complex known as African trypanosomiasis continues to inflict significant global morbidity, mortality, and economic hardship. Drug resistance and toxic side effects of old drugs call for novel and unorthodox strategies for new and safe treatment options. We designed methyltriazenyl purine prodrugs to be rapidly and selectively internalized by the parasite, after which they disintegrate into a nontoxic and naturally occurring purine nucleobase, a simple triazene-stabilizing group, and the active toxin: a methyldiazonium cation capable of damaging DNA by alkylation. We identified 2-(3-acetyl-3-methyltriazen-1-yl)-6-hydroxypurine (compound 1) as a new lead compound, which showed submicromolar potency against
Trypanosoma brucei
, with a selectivity index of >500, and it demonstrated a curative effect in animal models of acute trypanosomiasis. We investigated the mechanism of action of this lead compound and showed that this molecule has significantly higher affinity for parasites over mammalian nucleobase transporters, and it does not show cross-resistance with current first-line drugs. Once selectively accumulated inside the parasite, the prodrug releases a DNA-damaging methyldiazonium cation. We propose that ensuing futile cycles of attempted mismatch repair then lead to G
2
/M phase arrest and eventually cell death, as evidenced by the reduced efficacy of this purine analog against a mismatch repair-deficient (
MSH2
−/−
) trypanosome cell line. The observed absence of genotoxicity, hepatotoxicity, and cytotoxicity against mammalian cells revitalizes the idea of pursuing parasite-selective DNA alkylators as a safe chemotherapeutic option for the treatment of human and animal trypanosomiasis.
Phospholipase A1 Modulates the Cell Envelope Phospholipid Content of Brucella melitensis, Contributing to Polymyxin Resistance and Pathogenicity
Authors: Kerrinnes Tobias , Young Briana M. , Leon Carlos , Roux Christelle M. , Tran Lisa , Atluri Vidya L. , Winter Maria G. , Tsolis Renée M.
Published: August 2015

A subset of bacterial pathogens, including the zoonotic
Brucella
species, are highly resistant against polymyxin antibiotics. Bacterial polymyxin resistance has been attributed primarily to the modification of lipopolysaccharide; however, it is unknown what additional mechanisms mediate high-level resistance against this class of drugs. This work identified a role for the
Brucella melitensis
gene
bveA
(
BMEII0681
), encoding a predicted esterase, in the resistance of
B. melitensis
to polymyxin B. Characterization of the enzymatic activity of BveA demonstrated that it is a phospholipase A1 with specificity for phosphatidylethanolamine (PE). Further, lipidomic analysis of
B. melitensis
revealed an excess of PE lipids in the bacterial membranes isolated from the
bveA
mutant. These results suggest that by lowering the PE content of the cell envelope, BveA increases the resistance of
B. melitensis
to polymyxin B. BveA was required for survival and replication of
B. melitensis
in macrophages and for persistent infection in mice. BveA family esterases are encoded in the genomes of the alphaproteobacterial species that coexist with the polymyxin-producing bacteria in the rhizosphere, suggesting that maintenance of a low PE content in the bacterial cell envelope may be a shared persistence strategy for association with plant and mammalian hosts.
Population Pharmacokinetics of Peramivir in Healthy Volunteers and Influenza Patients
Authors: Matsuo Yumiko , Ishibashi Toru , Hollister Alan S. , Wajima Toshihiro
Published: August 2015

Peramivir is an intravenous anti-influenza agent that inhibits viral growth by selectively inhibiting neuraminidase in human influenza A and B viruses. To characterize its pharmacokinetics, a population pharmacokinetic analysis of peramivir was performed using 3,199 plasma concentration data samples from 332 subjects in six clinical studies in Japan and the United States, including studies with renal impairment subjects, elderly subjects, and influenza patients. A three-compartment model well described the plasma concentration data for peramivir, and creatinine clearance was found to be the most important factor influencing clearance. Age and body weight were also found to be covariates for clearance and the volume of distribution, respectively. No difference in pharmacokinetics was found between genders or between Japanese and U.S. subjects. Small differences in pharmacokinetics were observed between uninfected subjects and influenza patients (clearance was 18% higher and the volume of distribution was 6% lower in influenza patients). Monte Carlo simulations indicated that single adjusted doses of 1/3- and 1/6-fold for patients with moderate and severe renal impairment, respectively, would give areas under the curve comparable to those for patients with normal renal function. The population pharmacokinetic model developed for peramivir should be useful for understanding its pharmacokinetic characteristics and for dose adjustment on the basis of renal function.
Investigating Clinically Adequate Concentrations of Oseltamivir Carboxylate in End-Stage Renal Disease Patients Undergoing Hemodialysis Using a Population Pharmacokinetic Approach
Authors: Kamal Mohamed A. , Lien Kayla Yi Ting , Robson Richard , Subramoney Vishak , Clinch Barry , Rayner Craig R. , Gibiansky Leonid
Published: August 2015

End-stage renal disease (ESRD) patients receiving hemodialysis (HD) are at heightened risk for influenza, but the optimal oseltamivir dosage regimen for treating or preventing influenza in this high-risk population is still uncertain. Pharmacokinetic data for 24 adults with ESRD were pooled from a single-dose and a multiple-dose study to develop a population pharmacokinetic model using nonlinear mixed-effects modeling. The final model comprised five compartments, two each to describe the systemic pharmacokinetics of oseltamivir phosphate and its metabolite, oseltamivir carboxylate (OC), and a delay compartment to describe oseltamivir metabolism. Estimated OC clearance in the model was markedly faster during HD sessions (7.43 liters/min) than at other times (0.19 liter/min). Model simulations showed that 30 mg oseltamivir given after every HD session is the most suitable regimen for influenza treatment, producing trough OC concentrations above the median value achieved with the 75-mg twice-daily regimen in patients with normal renal function and peak concentrations below the highest oseltamivir exposures known to be well tolerated (median exposures after twice-daily dosing of 450 mg). Administration of the first dose following diagnosis of influenza need not wait until after the next HD session: addition of a single 30-mg dose during the 12 h before the next HD session raises OC exposures quickly without posing any safety risk. Further simulation showed that 30 mg oseltamivir given after every other HD session is the most suitable regimen for influenza prophylaxis.
Population Pharmacokinetic Analysis of Isoniazid, Acetylisoniazid, and Isonicotinic Acid in Healthy Volunteers
Authors: Seng Kok-Yong , Hee Kim-Hor , Soon Gaik-Hong , Chew Nicholas , Khoo Saye H. , Lee Lawrence Soon-U
Published: August 2015

In this study, we aimed to quantify the effects of the
N
-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolism
in vivo
and identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function. A two-compartment model with first-order absorption best described the INH pharmacokinetics. AcINH and INA data were best described by a two- and a one-compartment model, respectively, linked to the INH model. In the final model for INH, the derived metabolic phenotypes for NAT2 were identified as a significant covariate in the INH clearance, reducing its interindividual variability from 86% to 14%. The INH clearance in fast eliminators was 1.9- and 7.7-fold higher than in intermediate and slow eliminators, respectively (65 versus 35 and 8 liters/h). Creatinine clearance was confirmed as a significant covariate for AcINH clearance. Simulations suggested that the current dosing guidelines (200 mg for 30 to 45 kg and 300 mg for >45 kg) may be suboptimal (3 mg/liter ≤
C
max
≤ 6 mg/liter) irrespective of the acetylator class. The analysis established a model that adequately characterizes INH, AcINH, and INA pharmacokinetics in healthy Asians. Our results refine the NAT2 phenotype-based predictions of the pharmacokinetics for INH.
Multicenter Study of Epidemiological Cutoff Values and Detection of Resistance in Candida spp. to Anidulafungin, Caspofungin, and Micafungin Using the Sensititre YeastOne Colorimetric Method
Authors: Espinel-Ingroff A. , Alvarez-Fernandez M. , Cantón E. , Carver P. L. , Chen S. C.-A. , Eschenauer G. , Getsinger D. L. , Gonzalez G. M. , Govender N. P. , Grancini A. , Hanson K. E. , Kidd S. E. , Klinker K. , Kubin C. J. , Kus J. V. , Lockhart S. R. , Meletiadis J. , Morris A. J. , Pelaez T. , Quindós G. , Rodriguez-Iglesias M. , Sánchez-Reus F. , Shoham S. , Wengenack N. L. , Borrell Solé N. , Echeverria J. , Esperalba J. , Gómez-G. de la Pedrosa E. , García García I. , Linares M. J. , Marco F. , Merino P. , Pemán J. , Pérez del Molino L. , Roselló Mayans E. , Rubio Calvo C. , Ruiz Pérez de Pipaon M. , Yagüe G. , Garcia-Effron G. , Guinea J. , Perlin D. S. , Sanguinetti M. , Shields R. , Turnidge J.
Published: August 2015

Neither breakpoints (BPs) nor epidemiological cutoff values (ECVs) have been established forCandidaspp. with anidulafungin, caspofungin, and micafungin when using the Sensititre YeastOne (SYO) broth dilution colorimetric method. In addition, reference caspofungin MICs have so far proven to be unreliable.Candidaspecies wild-type (WT) MIC distributions (for microorganisms in a species/drug combination with no detectable phenotypic resistance) were established for 6,007Candida albicans, 186C. dubliniensis, 3,188C. glabratacomplex, 119C. guilliermondii, 493C. krusei, 205C. lusitaniae, 3,136C. parapsilosiscomplex, and 1,016C. tropicalisisolates. SYO MIC data gathered from 38 laboratories in Australia, Canada, Europe, Mexico, New Zealand, South Africa, and the United States were pooled to statistically define SYO ECVs. ECVs for anidulafungin, caspofungin, and micafungin encompassing ≥97.5% of the statistically modeled population were, respectively, 0.12, 0.25, and 0.06 μg/ml forC. albicans, 0.12, 0.25, and 0.03 μg/ml forC. glabratacomplex, 4, 2, and 4 μg/ml forC. parapsilosiscomplex, 0.5, 0.25, and 0.06 μg/ml forC. tropicalis, 0.25, 1, and 0.25 μg/ml forC. krusei, 0.25, 1, and 0.12 μg/ml forC. lusitaniae, 4, 2, and 2 μg/ml forC. guilliermondii, and 0.25, 0.25, and 0.12 μg/ml forC. dubliniensis. Species-specific SYO ECVs for anidulafungin, caspofungin, and micafungin correctly classified 72 (88.9%), 74 (91.4%), 76 (93.8%), respectively, of 81Candidaisolates with identifiedfksmutations. SYO ECVs may aid in detecting non-WT isolates with reduced susceptibility to anidulafungin, micafungin, and especially caspofungin, since testing the susceptibilities ofCandidaspp. to caspofungin by reference methodologies is not recommended.
Case-Control Study and Case Series of Pseudohyperphosphatemia during Exposure to Liposomal Amphotericin B
Authors: Bohm Nicole M. , Hoover Katherine C. , Wahlquist Amy E. , Zhu Yusheng , Velez Juan Carlos Q.
Published: August 2015

Pseudohyperphosphatemia due to an interaction between liposomal amphotericin B and the Beckman Coulter PHOSm assay occurs sporadically and remains underrecognized in clinical practice. This retrospective case-control study compares the incidences of hyperphosphatemia in adult inpatients exposed to liposomal amphotericin B or a triazole. A case series of patients with confirmed pseudohyperphosphatemia is described. A total of 80 exposures to liposomal amphotericin B and 726 exposures to triazoles were identified. Among subjects without chronic kidney disease and no concomitant acute kidney injury, hyperphosphatemia occurred more often during liposomal amphotericin B therapy than during triazole therapy (40% [14/35 cases] versus 10% [47/475 cases] of cases;
P
< 0.01; adjusted odds ratio, 5.2 [95% confidence interval {CI}, 2.3 to 11.9]). Among individuals with chronic kidney disease and no concomitant acute kidney injury, hyperphosphatemia also occurred more often during liposomal amphotericin B exposure (59% [10/17 cases] versus 20% [34/172 cases] of cases;
P
< 0.01; adjusted odds ratio, 6.0 [95% CI, 2.0 to 18.0]). When acute kidney injury occurred during antifungal exposure, the frequencies of hyperphosphatemia were not different between treatments. Seven episodes of unexpected hyperphosphatemia during liposomal amphotericin B exposure prompted a confirmatory test using an endpoint-based assay that found lower serum phosphorus levels (median difference of 2.5 mg/dl [range, 0.6 to 3.6 mg/dl]). Liposomal amphotericin B exposure confers a higher likelihood of developing hyperphosphatemia than that with exposure to a triazole antifungal, which is likely attributable to pseudohyperphosphatemia. Elevated phosphorus levels in patients receiving liposomal amphotericin B at institutions using the Beckman Coulter PHOSm assay should be interpreted cautiously.
Emtricitabine Seminal Plasma and Blood Plasma Population Pharmacokinetics in HIV-Infected Men in the EVARIST ANRS-EP 49 Study
Authors: Valade Elodie , Tréluyer Jean-Marc , Illamola Silvia M. , Bouazza Naïm , Foissac Frantz , De Sousa Mendes Maïlys , Lui Gabrielle , Chenevier-Gobeaux Camille , Suzan-Monti Marie , Rouzioux Christine , Assoumou Lambert , Viard Jean-Paul , Hirt Déborah , Urien Saïk , Ghosn Jade
Published: August 2015

We aimed to describe blood plasma (BP) and seminal plasma (SP) pharmacokinetics of emtricitabine (FTC) in HIV-1-infected men, assess its penetration in the male genital tract, and evaluate its impact on seminal plasma HIV load (spVL) detection. Men from the EVARIST ANRS EP49 study receiving combined antiretroviral therapy with FTC and with suppressed BP viral load were included in the study. A total of 236 and 209 FTC BP and SP concentrations, respectively, were available. A population pharmacokinetic model was developed with Monolix 4.1.4. The impact of FTC seminal exposure on spVL detection was explored by receiver operating characteristic (ROC) curves and mixed-effects logistic regressions. FTC BP pharmacokinetics was described by a two-compartment model. The addition of an effect compartment with different input and output constants best described FTC SP pharmacokinetics. No covariates were found to explain the variability in SP. FTC exposures (area under the concentration-time curve from 0 to 24 h [AUC
0–24
]) were higher in SP than in BP (median AUC
0–24
, 38.04 and 12.95 mg · liter
−1
· h, respectively). The median (range) SP-to-BP AUC
0–24
ratio was 2.91 (0.84 to 10.08). Less than 1% of FTC AUC
0–24
ratios were lower than 1. The impact of FTC SP AUC
0–24
or FTC SP-to-BP AUC
0–24
ratio on spVL detection was not significant (
P
= 0.943 or 0.893, respectively). This is the first population model describing FTC pharmacokinetics simultaneously in both BP and SP. FTC distributes well in the male genital tract with higher FTC concentrations in SP than in BP. FTC seminal plasma exposures were considered efficient in the majority of men.
Ceftolozane-Tazobactam Activity against Phylogenetically Diverse Clostridium difficile Strains
Authors: Gonzalez Mark D. , Wallace Meghan A. , Hink Tiffany , Dubberke Erik R. , Burnham Carey-Ann D.
Published: August 2015

Ceftolozane-tazobactam (C/T) is approved for the treatment of complicated intra-abdominal and urinary tract infections and has varied activity against anaerobic bacteria. Here, we evaluate the activity of C/T against a phylogenetically diverse collection of
Clostridium difficile
isolates and report uniformly high MICs (≥256 μg/ml) to C/T.
Conservation of the Host-Interacting Proteins Tp0750 and Pallilysin among Treponemes and Restriction of Proteolytic Capacity to Treponema pallidum
Authors: Houston Simon , Taylor John S. , Denchev Yavor , Hof Rebecca , Zuerner Richard L. , Cameron Caroline E.
Published: August 2015

The spirochete
Treponema pallidum
subsp.
pallidum
is the causative agent of syphilis, a chronic, sexually transmitted infection characterized by multiple symptomatic and asymptomatic stages. Although several other species in the genus are able to cause or contribute to disease,
T. pallidum
differs in that it is able to rapidly disseminate via the bloodstream to tissue sites distant from the site of initial infection. It is also the only
Treponema
species able to cross both the blood-brain and placental barriers. Previously, the
T. pallidum
proteins, Tp0750 and Tp0751 (also called pallilysin), were shown to degrade host proteins central to blood coagulation and basement membrane integrity, suggesting a role for these proteins in
T. pallidum
dissemination and tissue invasion. In the present study, we characterized Tp0750 and Tp0751 sequence variation in a diversity of pathogenic and nonpathogenic treponemes. We also determined the proteolytic potential of the orthologs from the less invasive species
Treponema denticola
and
Treponema phagedenis
. These analyses showed high levels of sequence similarity among Tp0750 orthologs from pathogenic species. For pallilysin, lower levels of sequence conservation were observed between this protein and orthologs from other treponemes, except for the ortholog from the highly invasive rabbit venereal syphilis-causing
Treponema paraluiscuniculi
.
In vitro
host component binding and degradation assays demonstrated that pallilysin and Tp0750 orthologs from the less invasive treponemes tested were not capable of binding or degrading host proteins. The results show that pallilysin and Tp0750 host protein binding and degradative capability is positively correlated with treponemal invasiveness.
A Single Amino Acid Replacement in the Sensor Kinase LiaS Contributes to a Carrier Phenotype in Group A Streptococcus
Authors: Flores Anthony R. , Jewell Brittany E. , Yelamanchili Dedipya , Olsen Randall J. , Musser James M.
Published: August 2015

Despite the high frequency of asymptomatic carriage of bacterial pathogens, we understand little about the bacterial molecular genetic underpinnings of this phenomenon. To obtain new information about the molecular genetic mechanisms underlying carriage of group A
Streptococcus
(GAS), we performed whole-genome sequencing of GAS strains recovered from a single individual during acute pharyngitis and subsequent asymptomatic carriage. We discovered that compared to the initial infection isolate, the strain recovered during asymptomatic carriage contained three single nucleotide polymorphisms, one of which was in a highly conserved region of a gene encoding a sensor kinase,
liaS
, resulting in an arginine-to-glycine amino acid replacement at position 135 of LiaS (LiaS
R135G
). Using gene replacement, we demonstrate that introduction of the carrier allele (
liaS
R135G
) into a serotype-matched invasive strain increased mouse nasopharyngeal colonization and adherence to cultured human epithelial cells. The carrier mutation also resulted in a reduced ability to grow in human blood and reduced virulence in a mouse model of necrotizing fasciitis. Repair of the mutation in the GAS carrier strain restored virulence and decreased adherence to cultured human epithelial cells. We also provide evidence that the carrier mutation alters the GAS transcriptome, including altered transcription of GAS virulence genes, providing a potential mechanism for the pleiotropic phenotypic effects. Our data obtained using isogenic strains suggest that the
liaS
R135G
mutation in the carrier strain contributes to the transition from disease to asymptomatic carriage and provides new information about this poorly described regulatory system in GAS.
Simultaneous Host-Pathogen Transcriptome Analysis during Granulibacter bethesdensis Infection of Neutrophils from Healthy Subjects and Patients with Chronic Granulomatous Disease
Authors: Greenberg David E. , Sturdevant Daniel E. , Marshall-Batty Kimberly R. , Chu Jessica , Pettinato Anthony M. , Virtaneva Kimmo , Lane John , Geller Bruce L. , Porcella Stephen F. , Gallin John I. , Holland Steven M. , Zarember Kol A.
Published: August 2015

Polymorphonuclear leukocytes (PMN) from patients with chronic granulomatous disease (CGD) fail to produce microbicidal concentrations of reactive oxygen species (ROS) due to mutations in NOX2. Patients with CGD suffer from severe, life-threatening infections and inflammatory complications.
Granulibacter bethesdensis
is an emerging Gram-negative pathogen in CGD that resists killing by PMN of CGD patients (CGD PMN) and inhibits PMN apoptosis through unknown mechanisms. Microarray analysis was used to study mRNA expression in PMN from healthy subjects (normal PMN) and CGD PMN during incubation with
G. bethesdensis
and, simultaneously, in
G. bethesdensis
with normal and CGD PMN. We detected upregulation of antiapoptotic genes (e.g., XIAP and GADD45B) and downregulation of proapoptotic genes (e.g., CASP8 and APAF1) in infected PMN. Transcript and protein levels of inflammation- and immunity-related genes were also altered. Upon interaction with PMN,
G. bethesdensis
altered the expression of ROS resistance genes in the presence of normal but not CGD PMN. Levels of bacterial stress response genes, including the ClpB gene, increased during phagocytosis by both normal and CGD PMN demonstrating responses to oxygen-independent PMN antimicrobial systems. Antisense knockdown demonstrated that ClpB is dispensable for extracellular growth but is essential for bacterial resistance to both normal and CGD PMN. Metabolic adaptation of
Granulibacter
growth in PMN included the upregulation of pyruvate dehydrogenase. Pharmacological inhibition of pyruvate dehydrogenase by triphenylbismuthdichloride was lethal to
Granulibacter
. This study expands knowledge of microbial pathogenesis of
Granulibacter
in cells from permissive (CGD) and nonpermissive (normal) hosts and identifies potentially druggable microbial factors, such as pyruvate dehydrogenase and ClpB, to help combat this antibiotic-resistant pathogen.
The Mga Regulon but Not Deoxyribonuclease Sda1 of Invasive M1T1 Group A Streptococcus Contributes to
In Vivo
Selection of CovRS Mutations and Resistance to Innate Immune Killing Mechanisms
Authors: Liu Guanghui , Feng Wenchao , Li Dengfeng , Liu Mengyao , Nelson Daniel C. , Lei Benfang
Published: August 2015

Invasive M1T1 group A
Streptococcus
(GAS) can have a mutation in the regulatory system CovRS, and this mutation can render strains hypervirulent. Interestingly, via mechanisms that are not well understood, the host innate immune system's neutrophils select spontaneous M1T1 GAS CovRS hypervirulent mutants, thereby enhancing the pathogen's ability to evade immune killing. It has been reported that the DNase Sda1 is critical for the resistance of M1T1 strain 5448 to killing in human blood and provides pressure for
in vivo
selection of CovRS mutations. We reexamined the role of Sda1 in the selection of CovRS mutations and in GAS innate immune evasion. Deletion of
sda1
or all DNase genes in M1T1 strain MGAS2221 did not alter emergence of CovRS mutants during murine infection. Deletion of
sda1
in strain 5448 resulted in Δ
sda1
mutants with (5448 Δ
sda1
M+
strain) and without (5448 Δ
sda1
M−
strain) M protein production. The 5448 Δ
sda1
M+
strain accumulated CovRS mutations
in vivo
and resisted killing in the bloodstream, whereas the 5448 Δ
sda1
M−
strain lost
in vivo
selection of CovRS mutations and was sensitive to killing. The deletion of
emm
and a spontaneous Mga mutation in MGAS2221 reduced and prevented
in vivo
selection for CovRS mutants, respectively. Thus, in contrast to previous reports, Sda1 is not critical for
in vivo
selection of invasive M1T1 CovRS mutants and GAS resistance to innate immune killing mechanisms. In contrast, M protein and other Mga-regulated proteins contribute to the
in vivo
selection of M1T1 GAS CovRS mutants. These findings advance the understanding of the progression of invasive M1T1 GAS infections.
Regulation of DNA Replication Initiation by Chromosome Structure
Authors: Magnan David , Bates David
Published: August 2015

Recent advancements in fluorescence imaging have shown that the bacterial nucleoid is surprisingly dynamic in terms of both behavior (movement and organization) and structure (density and supercoiling). Links between chromosome structure and replication initiation have been made in a number of species, and it is universally accepted that favorable chromosome structure is required for initiation in all cells. However, almost nothing is known about whether cells use changes in chromosome structure as a regulatory mechanism for initiation. Such changes could occur during natural cell cycle or growth phase transitions, or they could be manufactured through genetic switches of topoisomerase and nucleoid structure genes. In this review, we explore the relationship between chromosome structure and replication initiation and highlight recent work implicating structure as a regulatory mechanism. A three-component origin activation model is proposed in which thermal and topological structural elements are balanced with
trans
-acting control elements (DnaA) to allow efficient initiation control under a variety of nutritional and environmental conditions. Selective imbalances in these components allow cells to block replication in response to cell cycle impasse, override once-per-cell-cycle programming during growth phase transitions, and promote reinitiation when replication forks fail to complete.
Bilateral papilloedema in Camurati-Engelmann disease
Authors: Popiela Magdalena , Austin Michael
Published: August 2015

A 23-year-old woman presented with bilateral papilloedema in a setting of Camurati-Engelmann disease (CED). She was investigated with neuroimaging showing no optic nerve canal stenosis or jugular vein canal compromise. Her MRI venogram was normal. Her opening pressure at lumbar puncture and serum alkaline phosphatase were raised. Her papilloedema resolved with long-term use of acetazolamide. We believe that our patient suffered from raised intracranial pressure directly as a result of decreasing intracranial volume secondary to CED.