bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developmental underpinnings of differences in rodent novelty‐seeking and emotional reactivity
Authors: Clinton Sarah M. , Stead John D. H. , Miller Sue , Watson Stanley J. , Akil Huda 
Published: August 2011

AbstractInnate differences in human temperament strongly influence how individuals cope with stress and also predispose towards specific types of psychopathology. The present study examines the developing brain in an animal model of temperamental differences to examine how altered neurodevelopment may engender differences in emotional reactivity that are stable throughout the animal’s life. We utilize selectively‐bred High Responder (bHR) and Low Responder (bLR) rats that exhibit dramatic emotional behavior differences, with bHRs exhibiting exaggerated novelty‐exploration, aggression, impulsivity and drug self‐administration, and bLRs showing marked behavioral inhibition and exaggerated anxiety‐like and depressive‐like behavior. Using Affymetrix microarrays, we assessed bLR and bHR gene expression in the developing brain on postnatal days (P)7, 14 and 21, focusing on the hippocampus and nucleus accumbens, two regions related to emotionality and known to differ in adult bLR and bHR rats. We found dramatic gene expression differences between bLR and bHR in the P7 and P14 hippocampus, with minimal differences in the nucleus accumbens. Some of the most profound differences involved genes critical for neurodevelopment and synaptogenesis. Stereological studies evaluated hippocampal structure in developing bHR and bLR pups, revealing enhanced hippocampal volume and cell proliferation in bLR animals. Finally, behavioral studies showed that the characteristic bHR and bLR behavioral phenotypes emerge very early in life, with exploratory differences apparent at P16 and anxiety differences present by P25. Together these data point to specific brain regions and critical periods when the bHR and bLR phenotypes begin to diverge, which may eventually allow us to test possible therapeutic interventions to normalize extreme phenotypes (e.g. the anxiety‐prone nature of bLRs or drug addiction proclivity of bHRs).
Potentially pathogenic free‐living amoebae (FLA) isolated in Spanish wastewater treatment plants
Authors: García A. , Goñi P. , Clavel A. , Lobez S. , Fernandez M. T. , Ormad M. P. 
Published: August 2011

SummaryThis work studies the characterization of pathogenic free‐living amoebae (FLA) from sewage effluents. Some of them, such as Acanthamoeba, Naegleria, Hartmannella, Sappinia, Balamuthia and Paravahlkampfia have been reported as a cause of diseases in humans. Therefore, the study of their habitats and their pathogenicity has become necessary. The population of potentially pathogenic FLA was analysed in five Spanish wastewater treatment plants. Five of the seven FLA isolated were identified as genus Acanthamoeba genotypes T3, T4, T7 and T9. Hartmannella and Naegleria were also isolated. Acanthamoeba demonstrated great thermotolerance and osmotolerance. It was also observed that treatment with sodium hypochlorite showed no significative reduction in the number of amoeba at concentrations of 0–100 ppm. The high resistance of FLA cysts to disinfection methods is a trojan horse for public health insofar as they colonize water systems and allow the survival of intracellular microorganisms resistant to FLA. The results of this work advance current knowledge of the FLA population.
Carbapenems: Past, Present, and Future
Authors: Papp-Wallace Krisztina M. , Endimiani Andrea , Taracila Magdalena A. , Bonomo Robert A. 
Published: August 2011

ABSTRACTIn this review, we summarize the current “state of the art” of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the β-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most β-lactamases, in some cases act as “slow substrates” or inhibitors of β-lactamases, and still target penicillin binding proteins. This “value-added feature” of inhibiting β-lactamases serves as a major rationale for expansion of this class of β-lactams. We describe the initial discovery and development of the carbapenem family of β-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.
Efficacy of NZ2114, a Novel Plectasin-Derived Cationic Antimicrobial Peptide Antibiotic, in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus
Authors: Xiong Yan Q. , Hady Wessam Abdel , Deslandes Antoine , Rey Astrid , Fraisse Laurent , Kristensen Hans-Henrik , Yeaman Michael R. , Bayer Arnold S. 
Published: August 2011

ABSTRACTCationic antimicrobial peptides (CAPs) play important roles in host immune defenses. Plectasin is a defensin-like CAP isolated from the saprophytic fungusPseudoplectania nigrella. NZ2114 is a novel variant of plectasin with potent activity against Gram-positive bacteria. In this study, we investigated (i) thein vivopharmacokinetic and pharmacodynamic (PK/PD) characteristics of NZ2114 and (ii) thein vivoefficacy of NZ2114 in comparison with those of two conventional antibiotics, vancomycin or daptomycin, in an experimental rabbit infective endocarditis (IE) model due to a methicillin-resistantStaphylococcus aureus(MRSA) strain (ATCC 33591). All NZ2114 regimens (5, 10, and 20 mg/kg of body weight, intravenously [i.v.], twice daily for 3 days) significantly decreased MRSA densities in cardiac vegetations, kidneys, and spleen versus those in untreated controls, except in one scenario (5 mg/kg, splenic MRSA counts). The efficacy of NZ2114 was clearly dose dependent in all target tissues. At 20 mg/kg, NZ2114 showed a significantly greater efficacy than vancomycin (P< 0.001) and an efficacy similar to that of daptomycin. Of importance, only NZ2114 (in 10- and 20-mg/kg regimens) prevented posttherapy relapse in cardiac vegetations, kidneys, and spleen, while bacterial counts in these target tissues continued to increase in vancomycin- and daptomycin-treated animals. Thesein vivoefficacies were equivalent and significantly correlated with three PK indices investigated:fCmax/MIC (the maximum concentration of the free, unbound fraction of a drug in serum divided by the MIC),fAUC/MIC (where AUC is the area under the concentration-time curve), andf%T>MIC(%T>MICis the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions), as analyzed by a sigmoid maximum-effect (Emax) model (R2> 0.69). The superior efficacy of NZ2114 in this MRSA IE model suggests the potential for further development of this compound for treating serious MRSA infections.
Genetic Features of
bla
NDM-1
-Positive Enterobacteriaceae
Authors: Poirel Laurent , Dortet Laurent , Bernabeu Sandrine , Nordmann Patrice 
Published: August 2011

ABSTRACT

Genetic features associated with the
bla
NDM-1
gene were investigated in 6
Escherichia coli
, 7
Klebsiella pneumoniae
, 1
Citrobacter freundii
, 1
Proteus mirabilis
, and 1
Providencia stuartii
isolate of worldwide origin. Clonal diversity was observed for both
E. coli
and
K. pneumoniae
. The
bla
NDM-1
gene was carried by different plasmid types (IncA/C, IncF, IncL/M, or untypeable) and was likely chromosome borne in two isolates. The
bla
NDM-1
plasmids coharbored a variety of resistance determinants, including β-lactamase genes, quinolone resistance genes, and 16S RNA methylase genes.
Dynamics of Mutator and Antibiotic-Resistant Populations in a Pharmacokinetic/Pharmacodynamic Model of Pseudomonas aeruginosa Biofilm Treatment
Authors: Macià María D. , Pérez José L. , Molin Soeren , Oliver Antonio 
Published: August 2011

ABSTRACT

Biofilm growth, antibiotic resistance, and mutator phenotypes are key components of chronic respiratory infections by
Pseudomonas aeruginosa
in cystic fibrosis patients. We examined the dynamics of mutator and antibiotic-resistant populations in
P. aeruginosa
flow-cell biofilms, using fluorescently tagged PAO1 and PAOMS (mutator [
mutS
] derivative) strains. Two-day-old biofilms were treated with ciprofloxacin (CIP) for 4 days (t4) at 2 μg/ml, which correlated with the mutant prevention concentration (MPC) and provided an AUC/MIC ratio of 384 that should predict therapeutic success. Biofilms were monitored by confocal laser scanning microscopy (CLSM), and the numbers of viable cells and resistant mutants (4- and 16-fold MICs) were determined. Despite optimized pharmacokinetic/pharmacodynamic (PK/PD) parameters, CIP treatment did not suppress resistance development in
P. aeruginosa
biofilms. One-step resistant mutants (MexCD-OprJ or MexEF-OprN overexpression) were selected for both strains, while two-step resistant mutants (additional GyrA or GyrB mutation) were readily selected only from the mutator strain. CLSM analysis of competition experiments revealed that PAOMS, even when inoculated at a 0.01 proportion, took over the whole biofilm after only 2 days of CIP treatment outnumbering PAO1 by 3 log at t4. Our results show that mutational mechanisms play a major role in biofilm antibiotic resistance and that theoretically optimized PK/PD parameters fail to suppress resistance development, suggesting that the increased antibiotic tolerance driven by the special biofilm physiology and architecture may raise the effective MPC, favoring gradual mutational resistance development, especially in mutator strains. Moreover, the amplification of mutator populations under antibiotic treatment by coselection with resistance mutations is for the first time demonstrated
in situ
for
P. aeruginosa
biofilms.
Prior Caspofungin Exposure in Patients with Hematological Malignancies Is a Risk Factor for Subsequent Fungemia Due to Decreased Susceptibility in Candida spp.: a Case-Control Study in Paris, France
Authors: Blanchard Elodie , Lortholary Olivier , Boukris-Sitbon Karine , Desnos-Ollivier Marie , Dromer Françoise , Guillemot Didier ,   the French Mycosis Study Group
Published: August 2011

ABSTRACT

Infections due to caspofungin-resistant
Candida
isolates in patients exposed to caspofungin therapy are increasing. We report here a nested case-control study which aimed at identifying factors associated with bloodstream infections caused by
Candida
spp. having reduced susceptibility to caspofungin (CRSC) in adults suffering from hematological malignancies. In univariate and multivariate analyses, infections with CRSC were associated with caspofungin exposure in the previous 30 days (odds ratio [OR] = 5.25; 95% confidence interval [95% CI], 1.68–16.35) and with an age of ≤65 years (OR = 3.27; 95% CI, 1.26–8.50).
Comparison of Azithromycin Pharmacokinetics following Single Oral Doses of Extended-Release and Immediate-Release Formulations in Children with Acute Otitis Media
Authors: Liu Ping , Fang Annie F. , LaBadie Robert R. , Crownover Penelope H. , Arguedas Adriano G. 
Published: August 2011

ABSTRACT

An azithromycin extended-release (ER) oral suspension was developed to improve the gastrointestinal tolerability profile without substantially compromising systemic exposure. A single dose of 30 mg/kg azithromycin immediate-release (IR) oral suspension has been used in children to treat acute otitis media (AOM). This study was conducted to compare the pharmacokinetics of a 60-mg/kg azithromycin ER single dose with a 30-mg/kg azithromycin IR single dose in children with AOM aged 6 months to 6 years (
n
= 19 per treatment). Serum samples were collected at 1, 2, 3, 4, 8, 24, 48, and 72 h after dosing. The area under the curve from time zero to 72 h postdosing (AUC
0-72
) was calculated based on a noncompartmental method. One-way analysis of variance (ANOVA) was used to compare exposure parameters (e.g., AUC
0-72
and peak concentration) as well as concentrations at each time point. The adjusted geometric mean ratio of the ER/IR AUC
0-72
was 157.98% (90% confidence interval [CI], 98.87%, 252.44%), which met the predefined criterion of the lower boundary of the 90% CI of ≥80%. As expected, due to the slower-release profile of the ER formulation, the concentrations of the ER formulation during the first 3 h were lower than those of the IR formulation. After 3 h postdosing, the lower boundaries of the 90% CI for the ER/IR concentration ratios were greater than 100%. These results indicated that a 60-mg/kg single dose of ER azithromycin provides similar or greater systemic exposure in children than the 30-mg/kg single dose of IR azithromycin.
Environmental Microbiota Represents a Natural Reservoir for Dissemination of Clinically Relevant Metallo-β-Lactamases
Authors: Scotta Claudia , Juan Carlos , Cabot Gabriel , Oliver Antonio , Lalucat Jorge , Bennasar Antonio , Albertí Sebastián 
Published: August 2011

ABSTRACT

A total of 10 metallo-β-lactamase-producing isolates of six different species, including
Brevundimonas diminuta
(
n
= 3),
Rhizobium radiobacter
(
n
= 2),
Pseudomonas monteilii
(
n
= 1),
Pseudomonas aeruginosa
(
n
= 2),
Ochrobactrum anthropi
(
n
= 1), and
Enterobacter ludwigii
(
n
= 1), were detected in the sewage water of a hospital. The presence of
bla
VIM-13
associated with a Tn
1721
-class 1 integron structure was detected in all but one of the isolates (
E. ludwigii
, which produced VIM-2), and in two of them (
R. radiobacter
), this structure was located on a plasmid, suggesting that environmental bacteria represent a reservoir for the dissemination of clinically relevant metallo-β-lactamase genes.
Identification of Inflammatory Biomarkers for Pediatric Malarial Anemia Severity Using Novel Statistical Methods
Authors: Ong'echa John M. , Davenport Gregory C. , Vulule John M. , Hittner James B. , Perkins Douglas J. 
Published: August 2011

ABSTRACT

Areas where
Plasmodium falciparum
transmission is holoendemic are characterized by high rates of pediatric severe malarial anemia (SMA) and associated mortality. Although the etiology of SMA is complex and multifactorial, perturbations in inflammatory mediator production play an important role in the pathogenic process. As such, the current study focused on identification of inflammatory biomarkers in children with malarial anemia. Febrile children (3 to 30 months of age) presenting at Siaya District Hospital in western Kenya underwent a complete clinical and hematological evaluation. Children with falciparum malaria and no additional identifiable anemia-promoting coinfections were stratified into three groups: uncomplicated malaria (hemoglobin [Hb] levels of ≥11.0 g/dl;
n
= 31), non-SMA (Hb levels of 6.0 to 10.9 g/dl;
n
= 37), and SMA (Hb levels of <6.0 g/dl;
n
= 80). A Luminex hu25-plex array was used to determine potential biomarkers (i.e., interleukin 1β [IL-1β], IL-1 receptor antagonist [IL-1Ra], IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-15, IL-17, tumor necrosis factor alpha [TNF-α], alpha interferon [IFN-α], IFN-γ, granulocyte-macrophage colony-stimulating factor [GM-CSF], macrophage inflammatory protein 1 alpha [MIP-1α], MIP-1β, IFN-inducible protein of 10 kDa [IP-10], monokine induced by IFN-γ [MIG], eotaxin, RANTES, and monocyte chemoattractant protein 1 [MCP-1]) in samples obtained prior to any treatment interventions. To determine the strongest biomarkers of anemia, a parsimonious set of predictor variables for Hb was generated by least-angle regression (LAR) analysis, controlling for the confounding effects of age, gender, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and sickle cell trait, followed by multiple linear regression analyses. IL-12p70 and IFN-γ emerged as positive predictors of Hb, while IL-2R, IL-13, and eotaxin were negatively associated with Hb. The results presented here demonstrate that the IL-12p70/IFN-γ pathway represents a set of biomarkers that predicts elevated Hb levels in children with falciparum malaria, while activation of the IL-13/eotaxin pathway favors more profound anemia.
Resistance to Yersinia pestis Infection Decreases with Age in B10.T(6R) Mice
Authors: Lambert Nathaniel D. , Langfitt Deanna M. , Nilles Matthew L. , Bradley David S. 
Published: August 2011

ABSTRACTWe demonstrate that 2-month-old female B10.T(6R) mice are highly resistant to systemic infection with the KIM5 strain ofYersinia pestisand that B10.T(6R) mice become susceptible toY. pestisinfection by the age of 5 months. In this study, young (2-month-old) and middle-aged (5- to 12-month-old) B10.T(6R) mice were infected with equal CFU counts ofY. pestis. The 50% lethal dose (LD50) for young B10.T(6R) mice was ∼1.4 × 104CFU, while middle-aged B10.T(6R) mice exhibited an LD50of ∼60 CFU. Elevated bacterial burdens were found in the spleens of middle-aged mice at 24 and 60 h and in the livers at 60 h postinfection. Immune cell infiltration was greater in the livers of resistant young mice than in those of middle-aged mice and mice of the susceptible C57BL/6N strain. Unlike susceptible mice, young B10.T(6R) mice did not develop necrotic lesions throughout the liver. Instead, livers from young B10.T(6R) mice contained granuloma-like structures. Immunohistochemical staining of liver sections from these mice at 60 h postinfection revealed that the majority of immune cells present in these structures were neutrophils. These findings suggest that resistance to plague in B10.T(6R) mice correlates with early formation of neutrophilic lesions in the liver.
SadA, a Trimeric Autotransporter from Salmonella enterica Serovar Typhimurium, Can Promote Biofilm Formation and Provides Limited Protection against Infection
Authors: Raghunathan Dhaarini , Wells Timothy J. , Morris Faye C. , Shaw Robert K. , Bobat Saeeda , Peters Sarah E. , Paterson Gavin K. , Jensen Karina Tveen , Leyton Denisse L. , Blair Jessica M. A. , Browning Douglas F. , Pravin John , Flores-Langarica Adriana , Hitchcock Jessica R. , Moraes Claudia T. P. , Piazza Roxane M. F. , Maskell Duncan J. , Webber Mark A. , May Robin C. , MacLennan Calman A. , Piddock Laura J. , Cunningham Adam F. , Henderson Ian R. 
Published: August 2011

ABSTRACT

Salmonella enterica
is a major cause of morbidity worldwide and mortality in children and immunocompromised individuals in sub-Saharan Africa. Outer membrane proteins of
Salmonella
are of significance because they are at the interface between the pathogen and the host, they can contribute to adherence, colonization, and virulence, and they are frequently targets of antibody-mediated immunity. In this study, the properties of SadA, a purported trimeric autotransporter adhesin of
Salmonella enterica
serovar Typhimurium, were examined. We demonstrated that SadA is exposed on the
Salmonella
cell surface
in vitro
and
in vivo
during infection of mice. Expression of SadA resulted in cell aggregation, biofilm formation, and increased adhesion to human intestinal Caco-2 epithelial cells. Immunization of mice with folded, full-length, purified SadA elicited an IgG response which provided limited protection against bacterial challenge. When anti-SadA IgG titers were enhanced by administering alum-precipitated protein, a modest additional protection was afforded. Therefore, despite SadA having pleiotropic functions, it is not a dominant, protective antigen for antibody-mediated protection against
Salmonella
.
Vaccine Immunity to Coccidioidomycosis Occurs by Early Activation of Three Signal Pathways of T Helper Cell Response (Th1, Th2, and Th17)
Authors: Hung Chiung-Yu , Gonzalez Angel , Wüthrich Marcel , Klein Bruce S. , Cole Garry T. 
Published: August 2011

ABSTRACT

We have previously reported that C57BL/6 mice vaccinated with a live, attenuated mutant of
Coccidioides posadasii
, referred to as the ΔT vaccine, are fully protected against pulmonary coccidioidomycosis. This model was used here to explore the nature of vaccine immunity during the initial 2-week period after intranasal challenge. Elevated neutrophil and eosinophil infiltration into the lungs of nonvaccinated mice contrasted with markedly reduced recruitment of these cells in vaccinated animals. The numbers of lung-infiltrated macrophages and dendritic cells showed a progressive increase in vaccinated mice and corresponded with reduction of the lung infection. Concentrations of selected inflammatory cytokines and chemokines were initially higher in lung homogenates of vaccinated mice but then generally decreased at 14 days postchallenge in correlation with containment of the organism and apparent dampening of the inflammation of host tissue. Profiles of cytokines detected in lung homogenates of ΔT-vaccinated mice were indicative of a mixed T helper 1 (Th1)-, Th2-, and Th17-type immune response, a conclusion which was supported by detection of lung infiltration of activated T cells with the respective CD4
+
gamma interferon (IFN-γ)
+
, CD4
+
interleukin-5 (IL-5)
+
, and CD4
+
IL-17A
+
phenotypes. While Th1 and Th2 immunity was separately dispensed of by genetic manipulation without loss of ΔT vaccine-mediated protection, loss of functional Th17 cells resulted in increased susceptibility to infection in immunized mice. Characterization of the early events of protective immunity to
Coccidioides
infection in vaccinated mice contributes to the identification of surrogates of immune defense and provides potential insights into the design of immunotherapeutic protocols for treatment of coccidioidomycosis.
Regulator of G Protein Signaling 6 Mediates Doxorubicin-Induced ATM and p53 Activation by a Reactive Oxygen Species–Dependent Mechanism
Authors: Huang Jie , Yang Jianqi , Maity Biswanath , Mayuzumi Daisuke , Fisher Rory A. 
Published: August 2011

Abstract
Doxorubicin (DXR), among the most widely used cancer chemotherapy agents, promotes cancer cell death via activation of ataxia telangiectasia mutated (ATM) and the resultant upregulation of tumor suppressor p53. The exact mechanism by which DXR activates ATM is not fully understood. Here, we discovered a novel role for regulator of G protein signaling 6 (RGS6) in mediating activation of ATM and p53 by DXR. RGS6 was robustly induced by DXR, and genetic loss of RGS6 dramatically impaired DXR-induced activation of ATM and p53, as well as its in vivo apoptotic actions in heart. The ability of RGS6 to promote p53 activation in response to DXR was independent of RGS6 interaction with G proteins but required ATM. RGS6 mediated activation of ATM and p53 by DXR via a reactive oxygen species (ROS)-dependent and DNA damage–independent mechanism. This mechanism represents the primary means by which DXR promotes activation of the ATM–p53 apoptosis pathway that underlies its cytotoxic activity. Our findings contradict the canonical theories that DXR activates ATM primarily by promoting DNA damage either directly or indirectly (via ROS) and that RGS6 function is mediated by its interactions with G proteins. These findings reveal a new mechanism for the chemotherapeutic actions of DXR and identify RGS6 as a novel target for cancer chemotherapy. Cancer Res; 71(20); 6310–9. ©2011 AACR.