bluuebunny/crossref_metadata_2025_split huggingface dataset:
The c.64_80del SMIM1 allele is segregating in the Hutterite population
Authors: Coghlan Gail , Zelinski Teresa 
Published: December 2015

BACKGROUNDThe high‐incidence red blood cell (RBC) antigen Vel is coded by SMIM1 (small‐membrane molecule 1 gene), where a homozygous 17 base pair deletion underlies the majority of Vel− phenotypes. Because anti‐Vel has been reported to cause severe hemolytic transfusion reactions and periodically hemolytic disease of the newborn and fetus, identification of individuals negative for Vel is clinically important.STUDY DESIGN AND METHODSRBCs from the members of a large three‐generation Hutterite family were serologically determined to be Vel+w. Genomic DNA from these family members was polymerase chain reaction amplified and analyzed for SMIM1 polymorphisms by either Sanger sequencing or restriction fragment length polymorphisms. SMIM1 genotyping was also conducted on DNA from an additional 104 Hutterites.RESULTSAll family members whose RBCs weakly expressed the Vel antigen were found to be heterozygous for the c.64_80del mutation in SMIM1. Of the 104 additional Hutterite samples, four were found to be heterozygous for the same SMIM1 mutation.CONCLUSIONAfter emigrating to the United States and Canada, the Hutterite population has expanded dramatically. Alleles that initially entered the population have been maintained within the population. The c.64_80del null allele of SMIM1 is one such allele, thus having implications for transfusion medicine and child or maternal health.
IL‐31‐induced pruritus in dogs: a novel experimental model to evaluate anti‐pruritic effects of canine therapeutics
Authors: Gonzales Andrea J. , Fleck Timothy J. , Humphrey William R. , Galvan Betsy A. , Aleo Michelle M. , Mahabir Sean P. , Tena Jezaniah‐Kira , Greenwood Karen G. , McCall Robert B. 
Published: December 2015

BackgroundPruritus is a characteristic clinical sign of allergic skin conditions including atopic dermatitis (AD) in the dog. IL‐31 is a cytokine found in the serum of some dogs with AD and can induce pruritic behaviours in laboratory beagle dogs.Hypothesis/ObjectivesThe objectives were to characterize an IL‐31‐induced pruritus model by evaluating the efficacy of prednisolone, dexamethasone and oclacitinib, and to compare the speed of anti‐pruritic effects of oclacitinib against those of prednisolone and dexamethasone.AnimalsPurpose‐bred beagle dogs were used in all studies.MethodsRandomized, blinded, placebo‐controlled studies were designed to evaluate and compare the anti‐pruritic properties of prednisolone, dexamethasone and oclacitinib following a single intravenous injection of recombinant canine IL‐31. Video surveillance was used to monitor and score pruritic behaviours in study animals.ResultsPrednisolone [0.5 mg/kg, per os (p.o.)] reduced IL‐31‐induced pruritus when given 10 h prior to observation. When the time interval between drug treatment and observation was shortened to 1 h, dexamethasone (0.2 mg/kg, intramuscular) but not prednisolone (0.25 or 0.5 mg/kg, p.o.) reduced IL‐31‐induced pruritus. Oclacitinib (0.4 mg/kg, p.o.) reduced pruritus when given 1, 6, 11 and 16 h prior to the observation period, and the anti‐pruritic activity of oclacitinib was greater when compared to prednisolone and dexamethasone at all time points assessed.Conclusion and clinical importanceThe efficacy of prednisolone, dexamethasone and oclacitinib in the IL‐31‐induced pruritus model gives confidence that this may be a relevant model for acute pruritus associated with allergic dermatitis including AD and can be used to evaluate novel compounds or formulations.
Evolution of Resistance to Continuously Increasing Streptomycin Concentrations in Populations of Escherichia coli
Authors: Spagnolo Fabrizio , Rinaldi Conrad , Sajorda Dannah Rae , Dykhuizen Daniel E. 
Published: December 2015

ABSTRACT

The evolution of antibiotic resistance in bacteria has become one of the defining problems in modern biology. Bacterial resistance to antimicrobial therapy threatens to eliminate one of the pillars of the practice of modern medicine. Yet, in spite of the importance of this problem, only recently have the dynamics of the shift from antibiotic sensitivity to resistance in a bacterial population been studied. In this study, a novel chemostat method was used to observe the evolution of resistance to streptomycin in a sensitive population of
Escherichia coli
, which grew while the concentration of antibiotic was constantly increasing. The results indicate that resistant mutants remain at a low frequency for longer than expected and do not begin to rise to a high frequency until the antibiotic concentrations are above the measured MIC, creating a “lull period” in which there were few bacterial cells growing in the chemostats. Overall, mutants resistant to streptomycin were found in >60% of the experimental trial replicates. All of the mutants detected were found to have MICs far above the maximum levels of streptomycin to which they were exposed and reached a high frequency within 96 h.
Complete Sequence of a Novel IncR-F33:A–:B– Plasmid, pKP1034, Harboring
fosA3
,
bla
KPC-2
,
bla
CTX-M-65
,
bla
SHV-12
, and
rmtB
from an Epidemic Klebsiella pneumoniae Sequence Type 11 Strain in China
Authors: Xiang Dai-Rong , Li Jun-Jie , Sheng Zi-Ke , Yu Hai-Ying , Deng Mei , Bi Sheng , Hu Fei-Shu , Chen Wei , Xue Xiao-Wei , Zhou Zhi-Bo , Doi Yohei , Sheng Ji-Fang , Li Lan-Juan 
Published: December 2015

ABSTRACT

A high fosfomycin resistance rate was observed in
Klebsiella pneumoniae
carbapenemase (KPC)-producing
K. pneumoniae
(KPC-KP) in our previous study, but little is known about its mechanisms. In this study, we explored the prevalence of plasmid-mediated fosfomycin resistance determinants among fosfomycin-resistant KPC-KP strains from a Chinese university hospital and determined the complete sequence of a novel
fosA3
-carrying plasmid isolated from an epidemic
K. pneumoniae
sequence type (ST) 11 strain. A total of 97 KPC-KP strains were studied, of which 57 (58.8%) were resistant to fosfomycin, including 44 (45.4%) harboring
fosA3
and 1 harboring
fosA
. All
fosA3
-positive strains belonged to the dominant ST11-pulse type (PT) A clone according to multilocus sequence typing and pulsed-field gel electrophoresis, suggesting clonal dissemination. The
fosA
-positive isolate belonged to ST11-PTE. The
fosA3
-carrying plasmid pKP1034 is 136,848 bp in length and is not self-transmissible. It is a multireplicon plasmid belonging to IncR-F33:A−: B−. Besides
fosA3
, a variety of other resistance determinants, including
bla
KPC-2
,
rmtB
,
bla
CTX-M-65
, and
bla
SHV-12
, are identified in pKP1034, which would allow for coselection of
fosA3
by most β-lactams and/or aminoglycosides and facilitate its dissemination despite limited use of fosfomycin in China. Detailed comparisons with related plasmids revealed that pKP1034 is highly mosaic and might have evolved from alarming recombination of the
bla
KPC-2
-carrying plasmid pKPC-LK30 from Taiwan and the epidemic
fosA3
-carrying plasmid pHN7A8 from mainland China.
In Vitro
Activity of Retapamulin and Antimicrobial Susceptibility Patterns in a Longitudinal Collection of Methicillin-Resistant Staphylococcus aureus Isolates from a Veterans Affairs Medical Center
Authors: Harrington Amanda T. , Black Jennifer A. , Clarridge Jill E. 
Published: December 2015

ABSTRACT

Mupirocin is a topical antimicrobial used to decolonize patients who carry methicillin-resistant
Staphylococcus aureus
(MRSA), and the topical agent retapamulin may be a potential alternative therapy. The goal of this study was to determine the
in vitro
activity of retapamulin as well as a panel of 15 antimicrobial agents, including mupirocin, for 403 MRSA isolates collected longitudinally from a naive population at the Veterans Affairs Puget Sound Health Care System. The MICs for retapamulin had a unimodal distribution, ranging from 0.008 to 0.5 μg/ml. One isolate had an MIC of >16 μg/ml, was also resistant to clindamycin and erythromycin, and was recovered from the nares of a patient undergoing hemodialysis. Twenty-four isolates (6%) and 11 isolates (3%) demonstrated low-level resistance (MICs of 8 to 64 μg/ml) and high-level resistance (MICs of ≥512 μg/ml), respectively, to mupirocin. Isolates were recovered from 10 patients both before and after mupirocin therapy. Of those, isolates from 2 patients demonstrated MIC changes postmupirocin therapy; in both cases, however, strain typing demonstrated that the pre- and postmupirocin strains were different. A total of 386 isolates (96%) had vancomycin MICs of ≤1.0 μg/ml; 340 isolates (84%) were resistant to levofloxacin, 18 isolates (4.5%) were resistant to trimethoprim-sulfamethoxazole, and 135 isolates (33%) had elevated MICs of 4 μg/ml for linezolid. The baseline levels of resistance were low for mupirocin (9%) and even lower for retapamulin (0.25%) Although the use of mupirocin is currently the standard therapy for decolonization practices, the activity of retapamulin warrants its consideration as an alternative therapy in MRSA decolonization regimens.
Novel Bone-Targeting Agent for Enhanced Delivery of Vancomycin to Bone
Authors: Albayati Zaineb A. F. , Sunkara Manjula , Schmidt-Malan Suzannah M. , Karau Melissa J. , Morris Andrew J. , Steckelberg James M. , Patel Robin , Breen Philip J. , Smeltzer Mark S. , Taylor K. Grant , Merten Kevyn E. , Pierce William M. , Crooks Peter A. 
Published: December 2015

ABSTRACT
We examined the pharmacokinetic properties of vancomycin conjugated to a bone-targeting agent (BT) with high affinity for hydroxyapatite after systemic intravenous administration. The results confirm enhanced persistence of BT-vancomycin in plasma and enhanced accumulation in bone relative to vancomycin. This suggests that BT-vancomycin may be a potential carrier for the systemic targeted delivery of vancomycin in the treatment of bone infections, potentially reducing the reliance on surgical debridement to achieve the desired therapeutic outcome.
Defining Clinical Exposures of Cefepime for Gram-Negative Bloodstream Infections That Are Associated with Improved Survival
Authors: Rhodes Nathaniel J. , Kuti Joseph L. , Nicolau David P. , Van Wart Scott , Nicasio Anthony M. , Liu Jiajun , Lee Benjamin J. , Neely Michael N. , Scheetz Marc H. 
Published: December 2015

ABSTRACT

The percentage of time that free drug concentrations remain above the MIC (
f
T
>MIC
) that is necessary to prevent mortality among cefepime-treated patients with Gram-negative bloodstream infections (GNBSI) is poorly defined. We conducted a retrospective study of adult patients with GNBSI. Eligible cases were frequency matched to ensure categorical representation from all MICs. Organism, MIC, infection source, gender, age, serum creatinine, weight, antibiotic history, and modified APACHE II score were collected from hospital records. Two population pharmacokinetic models (models 1 and 2) were used to impute exposures over the first 24 h in each patient from mean model parameters, covariates, and dosing history. From the imputed exposures, survival thresholds for
f
T
>MIC
were identified using classification and regression tree (CART) analysis and analyzed as nominal variables for univariate and multivariate regressions. A total of 180 patients were included in the analysis, of whom 13.9% died and 86.1% survived. Many patients (46.7% [
n
= 84/180]) received combination therapy with cefepime. Survivors had higher mean (standard deviation [SD])
f
T
>MIC
than those who died (model 1, 74.2% [29.6%] versus 52.1% [33.8%],
P
< 0.001; model 2, 85.9% [24.0%] versus 64.4% [31.4%],
P
< 0.001). CART identified
f
T
>MIC
threshold values for greater survival according to models 1 and 2 at >68% and >74%, respectively. Survival was improved for those with
f
T
>MIC
of >68% (model 1 adjusted odds ratio [aOR], 7.12; 95% confidence interval [CI], 1.90 to 26.7;
P
= 0.004) and >74% (model 2 aOR, 6.48; 95% CI, 1.90 to 22.1) after controlling for clinical covariates. Similarly, each 1% increase in cefepime
f
T
>MIC
resulted in a 2% improvement in multivariate survival probability (
P
= 0.015). Achieving a cefepime
f
T
>MIC
of 68 to 74% was associated with a higher odds of survival for patients with GNBSI. Regimens targeting this exposure should be aggressively pursued.
Clinical and Molecular Features of Decreased Chlorhexidine Susceptibility among Nosocomial Staphylococcus aureus Isolates at Texas Children's Hospital
Authors: McNeil J. Chase , Kok Eric Y. , Vallejo Jesus G. , Campbell Judith R. , Hulten Kristina G. , Mason Edward O. , Kaplan Sheldon L. 
Published: December 2015

ABSTRACT

One of the strategies utilized to decrease infections in the hospital setting relies on topical antimicrobials and antiseptics. While their use is beneficial, concerns arise over the potential to develop resistance or tolerance to these agents. We examined nosocomial
Staphylococcus aureus
isolates from 2007 to 2013 for the presence of genes associated with tolerance to chlorhexidine. Isolates and patients were identified from an
S. aureus
surveillance study at Texas Children's Hospital. Nosocomial
S. aureus
isolates (those causing infection at ≥72 h of hospitalization) were identified and underwent PCR for the
qacA
or
qacB
(
qacA/B
) and
smr
genes associated with elevated minimum bactericidal concentrations of chlorhexidine. Molecular typing with pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and
agr
typing and a review of the medical record were performed. Two hundred forty-seven nosocomial
S. aureus
infections were identified. Overall, 111 isolates carried one or both genes (44.9%); 33.1% were positive for
smr
, 22.7% were positive for
qacA/B
, and 10.9% of the isolates possessed both genes. The
smr
-positive isolates were more often resistant to methicillin, ciprofloxacin, and/or clindamycin. The isolates positive for
qacA/B
were more often associated with indwelling central venous catheters and a vancomycin MIC of ≥2 μg/ml. Isolates carrying either
smr
or
qacA/B
were associated with a diagnosis of bacteremia. The
smr
-positive isolates more often belonged to sequence type 8 (ST8) than the isolates that were positive for
qacA/B
. Mupirocin resistance was detected in 2.8% of the isolates. Antiseptic-tolerant
S. aureus
strains are common in our children's hospital and are associated with decreased susceptibility to other systemic antimicrobials and with bloodstream infections. Further work is needed to understand the implications that these organisms have on the hospital environment and antiseptic use in the future.
In Vivo
Pharmacodynamics of Cefquinome in a Neutropenic Mouse Thigh Model of Streptococcus suis Serotype 2 at Varied Initial Inoculum Sizes
Authors: Guo Chunna , Liao Xiaoping , Wang Mingru , Wang Feng , Yan Chaoqun , Xiao Xia , Sun Jiang , Liu Yahong 
Published: December 2015

ABSTRACT

Streptococcus suis
serotype 2 is an emerging zoonotic pathogen and causes severe disease in both pigs and human beings. Cefquinome (CEQ), a fourth-generation cephalosporin, exhibits broad-spectrum activity against Gram-positive bacteria such as
S. suis
. This study evaluated the
in vitro
and
in vivo
antimicrobial activities of CEQ against four strains of
S. suis
serotype 2 in a murine neutropenic thigh infection model. We investigated the effect of varied inoculum sizes (10
6
to 10
8
CFU/thigh) on the pharmacokinetic (PK)/pharmacodynamic (PD) indices and magnitudes of a particular PK/PD index or dose required for efficacy. Dose fractionation studies included total CEQ doses ranging from 0.625 to 640 mg/kg/24 h. Data were analyzed via a maximum effect (
E
max
) model using nonlinear regression. The PK/PD studies demonstrated that the percentage of time that serum drug levels were above the MIC of free drug (%ƒ
T
>MIC
) in a 24-h dosing interval was the primary index driving the efficacy of both inoculum sizes (
R
2
= 91% and
R
2
= 63%). CEQ doses of 2.5 and 40 mg/kg body weight produced prolonged postantibiotic effects (PAEs) of 2.45 to 8.55 h. Inoculum sizes had a significant influence on CEQ efficacy. Compared to the CEQ exposure and dosages in tests using standard inocula, a 4-fold dose (
P
= 0.006) and a 2-fold exposure time (
P
= 0.01) were required for a 1-log kill using large inocula of 10
8
CFU/thigh.
Activity of Eravacycline against Escherichia coli Clinical Isolates Collected from U.S. Veterans in 2011 in Relation to Coresistance Phenotype and Sequence Type 131 Genotype
Authors: Johnson James R. , Porter Stephen B. , Johnston Brian D. , Thuras Paul 
Published: December 2015

ABSTRACT

Eravacycline is a novel broad-spectrum fluorocycline with potent Gram-negative activity, including for multidrug-resistant strains. Among 472
Escherichia coli
clinical isolates from 24 Veterans Affairs medical centers (in 2011), divided equally as susceptible versus resistant to fluoroquinolones, broth microdilution eravacycline MICs were distributed unimodally, ranging from 0.03 to 1.0 μg/ml (MIC
50
of 0.125 μg/ml, MIC
90
of 0.25 μg/ml). Eravacycline MICs were ∼2-fold higher among fluoroquinolone-resistant, gentamicin-resistant, multidrug-resistant, and sequence type 131 (ST131) isolates (
P
< 0.01 for each comparison).
The
IL17F
and
IL17RA
Genetic Variants Increase Risk of Cerebral Malaria in Two African Populations
Authors: Marquet Sandrine , Conte Ianina , Poudiougou Belco , Argiro Laurent , Cabantous Sandrine , Dessein Hélia , Burté Florence , Oumar Aboubacar A. , Brown Biobele J. , Traore Abdoualye , Afolabi Nathaniel K. , Barry Abdoulaye , Omokhodion Samuel , Ndoumbe Ursule Ewanda , Shokunbi Wuraola A. , Sodeinde Olugbemiro , Doumbo Ogobara , Fernandez-Reyes Delmiro , Dessein Alain J. 
Published: December 2015

ABSTRACT

Cerebral malaria (CM) is a neurological complication of infection with
Plasmodium falciparum
that is partly caused by cytokine-mediated inflammation. It is not known whether interleukin-17 (IL-17) cytokines, which regulate inflammation, control the development of CM. To evaluate the involvement of IL-17 cytokines in CM, we analyzed 46 common polymorphisms in
IL17A
,
IL17F
, and
IL17RA
(which encodes the common receptor chain of the members of the IL-17 family) in two independent African populations. A case-control study involving 115 Nigerian children with CM and 160 controls from the community (CC) showed that
IL17F
reference single nucleotide polymorphism (SNP) 6913472 (rs6913472) (
P
= 0.004; odds ratio [OR] = 3.12),
IL17F
rs4715291 (
P
= 0.004; OR = 2.82),
IL17RA
rs12159217 (
P
= 0.01; OR = 2.27), and
IL17RA
rs41396547 (
P
= 0.026; OR = 3.15) were independently associated with CM. A replication study was performed in 240 nuclear Malian family trios (two parents with one CM child). We replicated the association for 3 SNPs,
IL17F
rs6913472 (
P
= 0.03; OR = 1.39),
IL17RA
rs12159217 (
P
= 0.01; OR = 1.52), and
IL17RA
rs41396547 (
P
= 0.04; OR = 3.50). We also found that one additional SNP,
IL17RA
rs41433045, in linkage disequilibrium (LD) with rs41396547, was associated with CM in both Nigeria and Mali (
P
= 0.002; OR = 4.12 in the combined sample). We excluded the possibility that SNPs outside
IL17F
and
IL17RA
, in strong LD with the associated SNPs, could account for the observed associations. Furthermore, the results of a functional study indicated that the aggravating GA genotype of
IL17F
rs6913472 was associated with lower IL-17F concentrations. Our findings show for the first time that
IL17F
and
IL17RA
polymorphisms modulate susceptibility to CM and provide evidence that IL-17F protects against CM.
Network of Surface-Displayed Glycolytic Enzymes in Mycoplasma pneumoniae and Their Interactions with Human Plasminogen
Authors: Gründel Anne , Pfeiffer Melanie , Jacobs Enno , Dumke Roger 
Published: December 2015

ABSTRACT

In different bacteria, primarily cytosolic and metabolic proteins are characterized as surface localized and interacting with different host factors. These moonlighting proteins include glycolytic enzymes, and it has been hypothesized that they influence the virulence of pathogenic species. The presence of surface-displayed glycolytic enzymes and their interaction with human plasminogen as an important host factor were investigated in the genome-reduced and cell wall-less microorganism
Mycoplasma pneumoniae
, a common agent of respiratory tract infections of humans. After successful expression of 19 glycolytic enzymes and production of polyclonal antisera, the localization of proteins in the mycoplasma cell was characterized using fractionation of total proteins, colony blot, mild proteolysis and immunofluorescence of
M. pneumoniae
cells. Eight glycolytic enzymes, pyruvate dehydrogenases A to C (PdhA-C), glyceraldehyde-3-phosphate dehydrogenase (GapA), lactate dehydrogenase (Ldh), phosphoglycerate mutase (Pgm), pyruvate kinase (Pyk), and transketolase (Tkt), were confirmed as surface expressed and all are able to interact with plasminogen. Plasminogen bound to recombinant proteins PdhB, GapA, and Pyk was converted to plasmin in the presence of urokinase plasminogen activator and plasmin-specific substrate
d
-valyl-leucyl-lysine-
p
-nitroanilide dihydrochloride. Furthermore, human fibrinogen was degraded by the complex of plasminogen and recombinant protein PdhB or Pgm. In addition, surface-displayed proteins (except PdhC) bind to human lung epithelial cells, and the interaction was reduced significantly by preincubation of cells with antiplasminogen. Our results suggest that plasminogen binding and activation by different surface-localized glycolytic enzymes of
M. pneumoniae
may play a role in successful and long-term colonization of the human respiratory tract.
The Effector Protein BPE005 from Brucella abortus Induces Collagen Deposition and Matrix Metalloproteinase 9 Downmodulation via Transforming Growth Factor β1 in Hepatic Stellate Cells
Authors: Arriola Benitez Paula Constanza , Rey Serantes Diego , Herrmann Claudia Karina , Pesce Viglietti Ayelén Ivana , Vanzulli Silvia , Giambartolomei Guillermo Hernán , Comerci Diego José , Delpino María Victoria 
Published: December 2015

ABSTRACTThe liver is frequently affected in patients with active brucellosis. In the present study, we identified a virulence factor involved in the modulation of hepatic stellate cell function and consequent fibrosis duringBrucella abortusinfection. This study assessed the role of BPE005 protein fromB. abortusin the fibrotic phenotype induced on hepatic stellate cells duringB. abortusinfectionin vitroandin vivo. We demonstrated that the fibrotic phenotype induced byB. abortuson hepatic stellate (LX-2) cells was dependent on BPE005, a protein associated with the type IV secretion system (T4SS) VirB fromB. abortus. Our results indicated thatB. abortusinhibits matrix metalloproteinase 9 (MMP-9) secretion through the activity of the BPE005-secreted protein and induces concomitant collagen deposition by LX-2 cells. BPE005 is a small protein containing a cyclic nucleotide monophosphate binding domain (cNMP) that modulates the LX-2 cell phenotype through a mechanism that is dependent on the cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway. Altogether, these results indicate thatB. abortustilts LX-2 cells to a profibrogenic phenotype employing a functional T4SS and the secreted BPE005 protein through a mechanism that involves the cAMP and PKA signaling pathway.