bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study of IRF6 and 8q24 region in non‐syndromic oral clefts in the Brazilian population
Authors: de Souza LT , Kowalski TW , Ferrari J , Monlléo IL , Ribeiro EM , de Souza J , Fett‐Conte AC , de Araujo TK , Gil‐da‐Silva‐Lopes VL , Ribeiro‐dos‐Santos ÂKC , dos Santos SEB , Félix TM 
Published: December 2015

ObjectivesWe investigated the association between non‐syndromic oral cleft and variants in IRF6 (rs2235371 and rs642961) and 8q24 region (rs987525) according to the ancestry contribution of the Brazilian population.Subjects and methodsSubjects with oral cleft (CL, CLP, or CP) and their parents were selected from different geographic regions of Brazil. Polymorphisms were genotyped using a TaqMan assay and genomic ancestry was estimated using a panel of 48 INDEL polymorphisms.ResultsA total of 259 probands were analyzed. A TDT detected overtransmission of the rs2235371 G allele (P = 0.0008) in the total sample. A significant association of this allele was also observed in CLP (P = 0.0343) and CLP + CL (P = 0.0027). IRF6 haplotype analysis showed that the G/A haplotype increased the risk for cleft in children (single dose: P = 0.0038, double dose: P = 0.0022) and in mothers (single dose: P = 0.0016). The rs987525 (8q24) also exhibited an association between the A allele and the CLP + CL group (P = 0.0462). These results were confirmed in the probands with European ancestry.ConclusionsThe 8q24 region plays a role in CL/P and the IRF6 G/A haplotype (rs2235371/rs642961) increases the risk for oral cleft in the Brazilian population.
Treatment of infantile subglottic hemangioma with oral propranolol
Authors: Wang Cai‐Fu , Wang Ying‐Shuo , Sun Yue‐Feng 
Published: December 2015

AbstractInfantile subglottic hemangioma (SH) can cause biphasic stridor, respiratory distress and even life‐threatening airway compromise. Treatment of SH in infants has traditionally been characterized as a challenging situation with multiple therapeutic options without consensus as to which one is the best and with risks of severe side‐effects. Four infants with SH were treated with propranolol. Treatment with oral propranolol resulted in resolution of symptoms within 2 days, followed by complete recovery. Propranolol appears to be an effective treatment for SH and should be used as a first‐line treatment for SH when intervention is required.
Regression of massive cardiac rhabdomyoma on everolimus therapy
Authors: Hoshal Steven G. , Samuel Bennett P. , Schneider Jeffrey R. , Mammen Leena , Vettukattil Joseph J. 
Published: December 2015

AbstractCardiac rhabdomyoma is the primary feature of the genetic disease, tuberous sclerosis complex, the most common cardiac tumor diagnosed in neonates and infants. Spontaneous regression is observed in most cases, but these tumors may cause hemodynamic instability, arrhythmias or other complications. We describe the case of a critically ill neonate, resuscitated after cardiac arrest secondary to massive locally invasive cardiac rhabdomyoma, who was successfully treated with everolimus (mammalian target of rapamycin [mTOR] inhibitor). Rapid tumor regression was observed on echocardiography, but it was unlikely that it was confounded by the natural disease course of regression. The presented case suggests that mTOR inhibitors may play a significant role in the treatment of large cardiac rhabdomyomas in critically ill neonates.
Pseudomonas aeruginosa antibiotic resistance in Australian cystic fibrosis centres
Authors: Smith Daniel J. , Ramsay Kay A. , Yerkovich Stephanie T. , Reid David W. , Wainwright Claire E. , Grimwood Keith , Bell Scott C. , Kidd Timothy J. 
Published: December 2015

AbstractBackground and objectiveIn cystic fibrosis (CF), chronic Pseudomonas aeruginosa infection is associated with increased morbidity, antibiotic treatments and mortality. By linking Australian CF registry data with a national microbiological data set, we examined the association between where treatment was delivered, its intensity and P. aeruginosa antibiotic resistance.MethodsSputa were collected from paediatric and adult CF patients attending 18 Australian CF centres. P. aeruginosa antibiotic susceptibilities determined by local laboratories were correlated with clinical characteristics, treatment intensity and infection with strains commonly shared among Australian CF patients. Between‐centre differences in treatment and antibiotic resistance were also compared.ResultsLarge variations in antibiotic usage, maintenance treatment practices and multi‐antibiotic resistant P. aeruginosa (MARPA) prevalence exist between Australian CF centres, although the overall proportions of MARPA isolates were similar in paediatric and adult centres (31% vs 35%, P = 0.29). Among paediatric centres, MARPA correlated with intravenous antibiotic usage and the Australian state where treatment was delivered, while azithromycin, reduced lung function and treating state predicted intravenous antibiotic usage. In adult centres, body mass index (BMI) and treating state were associated with MARPA, while intravenous antibiotic use was predicted by gender, BMI, dornase‐alpha, azithromycin, lung function and treating state. In adults, P. aeruginosa strains AUST‐01 and AUST‐02 independently predicted intravenous antibiotic usage.ConclusionIncreased treatment intensity in paediatric centres and the Australian state where treatment was received are both associated with greater risk of MARPA, but not worse clinical outcomes.
Analysis of Thermal-Hydraulic Fluctuations in Trillo NPP With CTF/PARCS v. 2.7 Coupled Code
Authors: Abarca A. , Miró R. , Verdú G. , Bermejo J. A. 
Published: December 2015

The low-frequency noises are fluctuations in the neutron flux density, in the low-frequency range up to 4 Hz, which generate noise in the neutron instrumentation and could affect the limitation and protection system of the reactor core. Some European pressurized water reactors (PWRs) experienced the effect of low-frequency noise, opening a new research line for the verification of the neutron-kinetics/thermal-hydraulic coupled codes. A CTF/PARCS v. 2.7 simulation study to verify whether periodical fluctuations in the core inlet temperature could activate the core protection system has been done, obtaining the frequency spectrum of the power oscillation amplitudes.
Designing a Pediatric Study for an Antimalarial Drug by Using Information from Adults
Authors: Petit Caroline , Jullien Vincent , Samson Adeline , Guedj Jérémie , Kiechel Jean-René , Zohar Sarah , Comets Emmanuelle 
Published: December 2015

ABSTRACT
The objectives of this study were to design a pharmacokinetic (PK) study by using information about adults and evaluate the robustness of the recommended design through a case study of mefloquine. PK data about adults and children were available from two different randomized studies of the treatment of malaria with the same artesunate-mefloquine combination regimen. A recommended design for pediatric studies of mefloquine was optimized on the basis of an extrapolated model built from adult data through the following approach. (i) An adult PK model was built, and parameters were estimated by using the stochastic approximation expectation-maximization algorithm. (ii) Pediatric PK parameters were then obtained by adding allometry and maturation to the adult model. (iii) A D-optimal design for children was obtained with PFIM by assuming the extrapolated design. Finally, the robustness of the recommended design was evaluated in terms of the relative bias and relative standard errors (RSE) of the parameters in a simulation study with four different models and was compared to the empirical design used for the pediatric study. Combining PK modeling, extrapolation, and design optimization led to a design for children with five sampling times. PK parameters were well estimated by this design with few RSE. Although the extrapolated model did not predict the observed mefloquine concentrations in children very accurately, it allowed precise and unbiased estimates across various model assumptions, contrary to the empirical design. Using information from adult studies combined with allometry and maturation can help provide robust designs for pediatric studies.
Key Roles of Human Polymorphonuclear Cells and Ciprofloxacin in Lactobacillus Species Infection Control
Authors: Mandras Narcisa , Tullio Vivian , Furneri Pio Maria , Roana Janira , Allizond Valeria , Scalas Daniela , Petronio Petronio Giulio , Fuochi Virginia , Banche Giuliana , Cuffini Anna Maria 
Published: December 2015

ABSTRACT

Lactobacilli have the potential to act as reservoirs of antibiotic resistance genes similar to those found in human pathogens, with the risk of transferring these genes to many pathogenic bacteria. In this study, we investigated the role of human polymorphonuclear cells (PMNs) against
Lactobacillus
spp. both resistant and susceptible to ciprofloxacin (a fluoroquinolone) and the effect of ciprofloxacin on the interaction between PMNs and three
Lactobacillus
spp. with different patterns of susceptibility to this drug. Hence, the primary functions of PMNs, such as phagocytosis and bacterial intracellular killing, against lactobacilli were investigated. The rate of PMN phagocytosis was high for ciprofloxacin-sensitive and ciprofloxacin-resistant strains. The patterns of intracellular killing of ciprofloxacin-sensitive and ciprofloxacin-resistant strains by PMNs underline that PMNs alone were able to kill lactobacilli. The addition of ciprofloxacin to PMNs did not result in a significant increase in the bacterial uptake by phagocytes. On the contrary, ciprofloxacin had a marked effect on PMN intracellular killing, resulting in increased numbers of killed ciprofloxacin-sensitive bacteria in comparison with antibiotic-free controls. Our data show that by itself, the profile of antibiotic resistance does not constitute an intrinsic factor of greater or lesser pathogenicity toward the host. The ability of PMNs to kill a diverse array of bacterial pathogens is essential for human innate host defense, primarily in immunocompromised patients.
Efficacy and Safety of AFN-1252, the First Staphylococcus-Specific Antibacterial Agent, in the Treatment of Acute Bacterial Skin and Skin Structure Infections, Including Those in Patients with Significant Comorbidities
Authors: Hafkin B. , Kaplan N. , Murphy B. 
Published: December 2015

ABSTRACT

This open-label noncontrolled, phase II multicenter trial was designed to evaluate the safety, tolerability, and efficacy of 200 mg of AFN-1252, a selective inhibitor of
Staphylococcus aureus
enoyl-acyl carrier protein reductase (FabI), given by mouth twice daily in the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to staphylococci. Important aspects of the current study included a comparison of early response efficacy endpoints with end-of-treatment and follow-up endpoints. Many patients in the intent-to-treat population (
n
= 103) had significant comorbidities. The overall early response rate at day 3 was 97.3% (wound, 100%; abscess, 96.6%; cellulitis, 94.4%) in the microbiologically evaluable (ME) population. Within the ME population, 82.9% of patients had a ≥20% decrease in the area of erythema, and 77.9% of patients had a ≥20% decrease in the area of induration, on day 3.
S. aureus
was detected in 97.7% of patients (
n
= 37 patients with methicillin-resistant
S. aureus
[MRSA], and
n
= 39 with methicillin-sensitive
S. aureus
[MSSA]). No isolates had increased AFN-1252 MICs posttreatment. Microbiologic eradication rates for
S. aureus
were 93.2% at short-term follow-up (STFU) and 91.9% at long-term follow-up (LTFU) in the ME population. Eradication rates for MRSA and MSSA were 91.9% and 92.3%, respectively, at STFU and 91.9% and 89.7%, respectively, at LTFU. The most frequently reported drug-related adverse events, which were mostly mild or moderate, were headache (26.2%) and nausea (21.4%). These studies demonstrate that AFN-1252 is generally well tolerated and effective in the treatment of ABSSSI due to
S. aureus
, including MRSA. (This study has been registered at ClinicalTrials.gov under registration no. NCT01519492.)
Posttreatment Antifungal Resistance among Colonizing Candida Isolates in Candidemia Patients: Results from a Systematic Multicenter Study
Authors: Jensen R. H. , Johansen H. K. , Søes L. M. , Lemming L. E. , Rosenvinge F. S. , Nielsen L. , Olesen B. , Kristensen L. , Dzajic E. , Astvad K. M. T. , Arendrup M. C. 
Published: December 2015

ABSTRACT

The prevalence of intrinsic and acquired resistance among colonizing
Candida
isolates from patients after candidemia was investigated systematically in a 1-year nationwide study. Patients were treated at the discretion of the treating physician. Oral swabs were obtained after treatment. Species distributions and MIC data were investigated for blood and posttreatment oral isolates from patients exposed to either azoles or echinocandins for <7 or ≥7 days. Species identification was confirmed using matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) and internal transcribed spacer (ITS) sequencing, susceptibility was examined by EUCAST EDef 7.2 methodology, echinocandin resistance was examined by
FKS
sequencing, and genetic relatedness was examined by multilocus sequence typing (MLST). One hundred ninety-three episodes provided 205 blood and 220 oral isolates. MLST analysis demonstrated a genetic relationship for 90% of all paired blood and oral isolates. Patients exposed to azoles for ≥7 days (
n
= 93) had a significantly larger proportion of species intrinsically less susceptible to azoles (particularly
Candida glabrata
) among oral isolates than among initial blood isolates (36.6% versus 12.9%;
P
< 0.001). A similar shift toward species less susceptible to echinocandins among 85 patients exposed to echinocandins for ≥7 days was not observed (4.8% of oral isolates versus 3.2% of blood isolates;
P
> 0.5). Acquired resistance in
Candida albicans
was rare (<5%). However, acquired resistance to fluconazole (29.4%;
P
< 0.05) and anidulafungin (21.6%;
P
< 0.05) was common in
C. glabrata
isolates from patients exposed to either azoles or echinocandins. Our findings suggest that the colonizing mucosal microbiota may be an unrecognized reservoir of resistant
Candida
species, especially
C. glabrata
, following treatment for candidemia. The resistance rates were high, raising concern in general for patients exposed to antifungal drugs.
C646, a Novel p300/CREB-Binding Protein-Specific Inhibitor of Histone Acetyltransferase, Attenuates Influenza A Virus Infection
Authors: Zhao Dongming , Fukuyama Satoshi , Sakai-Tagawa Yuko , Takashita Emi , Shoemaker Jason E. , Kawaoka Yoshihiro 
Published: December 2015

ABSTRACT

New strategies to develop novel broad-spectrum antiviral drugs against influenza virus infections are needed due to the emergence of antigenic variants and drug-resistant viruses. Here, we evaluated C646, a novel p300/CREB-binding protein-specific inhibitor of histone acetyltransferase (HAT), as an anti-influenza virus agent
in vitro
and
in vivo
and explored how C646 affects the viral life cycle and host response. Our studies highlight the value of targeting HAT activity for anti-influenza drug development.
Suppression of Emergence of Resistance in Pathogenic Bacteria: Keeping Our Powder Dry, Part 1
Authors: Drusano G. L. , Louie Arnold , MacGowan Alasdair , Hope William 
Published: December 2015

ABSTRACT

We are in a crisis of bacterial resistance. For economic reasons, most pharmaceutical companies are abandoning antimicrobial discovery efforts, while, in health care itself, infection control and antibiotic stewardship programs have generally failed to prevent the spread of drug-resistant bacteria. At this point, what can be done? The first step has been taken. Governments and international bodies have declared there is a worldwide crisis in antibiotic drug resistance. As discovery efforts begin anew, what more can be done to protect newly developing agents and improve the use of new drugs to suppress resistance emergence? A neglected path has been the use of recent knowledge regarding antibiotic dosing as single agents and in combination to minimize resistance emergence, while also providing sufficient early bacterial kill. In this review, we look at the data for resistance suppression. Approaches include increasing the intensity of therapy to suppress resistant subpopulations; developing concepts of clinical breakpoints to include issues surrounding suppression of resistance; and paying attention to the duration of therapy, which is another important issue for resistance suppression. New understanding of optimizing combination therapy is of interest for difficult-to-treat pathogens like
Pseudomonas aeruginosa
,
Acinetobacter
spp., and multidrug-resistant (MDR)
Enterobacteriaceae
. These lessons need to be applied to our old drugs to preserve them as well and need to be put into national and international antibiotic resistance strategies. As importantly, from a regulatory perspective, new chemical entities should have a corresponding resistance suppression plan at the time of regulatory review. In this way, we can make the best of our current situation and improve future prospects.
Treatment with a Nucleoside Polymerase Inhibitor Reduces Shedding of Murine Norovirus in Stool to Undetectable Levels without Emergence of Drug-Resistant Variants
Authors: Rocha-Pereira Joana , Van Dycke Jana , Neyts Johan 
Published: December 2015

ABSTRACT

Prolonged norovirus shedding may occur in certain patients, such as organ transplant recipients. We established a mouse model for persistent norovirus infection (using the mouse norovirus MNV.CR6 strain). The nucleoside viral polymerase inhibitor 2′-
C
-methylcytidine (2CMC), but not favipiravir (T-705), reduced viral shedding to undetectable levels. Viral rebound was observed after stopping treatment, which was again effectively controlled by treatment with 2CMC. No drug-resistant variants emerged.
The Staphylococcus aureus Chaperone PrsA Is a New Auxiliary Factor of Oxacillin Resistance Affecting Penicillin-Binding Protein 2A
Authors: Jousselin Ambre , Manzano Caroline , Biette Alexandra , Reed Patricia , Pinho Mariana G. , Rosato Adriana E. , Kelley William L. , Renzoni Adriana 
Published: December 2015

ABSTRACT

Expression of the methicillin-resistant
S. aureus
(MRSA) phenotype results from the expression of the extra penicillin-binding protein 2A (PBP2A), which is encoded by
mecA
and acquired horizontally on part of the SCC
mec
cassette. PBP2A can catalyze
dd
-transpeptidation of peptidoglycan (PG) because of its low affinity for β-lactam antibiotics and can functionally cooperate with the PBP2 transglycosylase in the biosynthesis of PG. Here, we focus upon the role of the membrane-bound PrsA foldase protein as a regulator of β-lactam resistance expression. Deletion of
prsA
altered oxacillin resistance in three different SCC
mec
backgrounds and, more importantly, caused a decrease in PBP2A membrane amounts without affecting
mecA
mRNA levels. The N- and C-terminal domains of PrsA were found to be critical features for PBP2A protein membrane levels and oxacillin resistance. We propose that PrsA has a role in posttranscriptional maturation of PBP2A, possibly in the export and/or folding of newly synthesized PBP2A. This additional level of control in the expression of the
mecA
-dependent MRSA phenotype constitutes an opportunity to expand the strategies to design anti-infective agents.
Impairment of Pseudomonas aeruginosa Biofilm Resistance to Antibiotics by Combining the Drugs with a New Quorum-Sensing Inhibitor
Authors: Furiga Aurelie , Lajoie Barbora , El Hage Salome , Baziard Genevieve , Roques Christine 
Published: December 2015

ABSTRACT

Pseudomonas aeruginosa
plays an important role in chronic lung infections among patients with cystic fibrosis (CF) through its ability to form antibiotic-resistant biofilms. In
P. aeruginosa
, biofilm development and the production of several virulence factors are mainly regulated by the
rhl
and
las
quorum-sensing (QS) systems, which are controlled by two
N
-acyl-homoserine lactone signal molecules. In a previous study, we discovered an original QS inhibitor,
N
-(2-pyrimidyl)butanamide, called C11, based on the structure of C
4
-homoserine lactone, and found that it is able to significantly inhibit
P. aeruginosa
biofilm formation. However, recent data indicate that
P. aeruginosa
grows under anaerobic conditions and forms biofilms in the lungs of CF patients that are denser and more robust than those formed under aerobic conditions. Our confocal microscopy observations of
P. aeruginosa
biofilms developed under aerobic and anaerobic conditions confirmed that the biofilms formed under these two conditions have radically different architectures. C11 showed significant dose-dependent antibiofilm activity on biofilms grown under both aerobic and anaerobic conditions, with a greater inhibitory effect being seen under conditions of anaerobiosis. Gene expression analyses performed by quantitative reverse transcriptase PCR showed that C11 led to the significant downregulation of
rhl
QS regulatory genes but also to the downregulation of both
las
QS regulatory genes and QS system-regulated virulence genes,
rhlA
and
lasB
. Furthermore, the activity of C11 in combination with antibiotics against
P. aeruginosa
biofilms was tested, and synergistic antibiofilm activity between C11 and ciprofloxacin, tobramycin, and colistin was obtained under both aerobic and anaerobic conditions. This study demonstrates that C11 may increase the efficacy of treatments for
P. aeruginosa
infections by increasing the susceptibility of biofilms to antibiotics and by attenuating the pathogenicity of the bacterium.
Discovery of Structurally Diverse Small-Molecule Compounds with Broad Antiviral Activity against Enteroviruses
Authors: Zuo Jun , Kye Steve , Quinn Kevin K. , Cooper Paige , Damoiseaux Robert , Krogstad Paul 
Published: December 2015

ABSTRACT
Antiviral drugs do not currently exist for the treatment of enterovirus infections, which are often severe and potentially life-threatening. We conducted high-throughput molecular screening and identified a structurally diverse set of compounds that inhibit the replication of coxsackievirus B3, a commonly encountered enterovirus. These compounds did not interfere with the function of the viral internal ribosome entry site or with the activity of the viral proteases, but they did drastically reduce the synthesis of viral RNA and viral proteins in infected cells. Sequence analysis of compound-resistant mutants suggests that the viral 2C protein is targeted by most of these compounds. These compounds demonstrated antiviral activity against a panel of the most commonly encountered enteroviruses and thus represent potential leads for the development of broad-spectrum anti-enteroviral drugs.