bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Combination of Sulfamethoxazole, Trimethoprim, and Isoniazid or Rifampin Is Bactericidal and Prevents the Emergence of Drug Resistance in Mycobacterium tuberculosis
Authors: Vilchèze Catherine , Jacobs William R. 
Published: July 2012

ABSTRACT

The challenges of developing new drugs to treat tuberculosis (TB) are indicated by the relatively small number of candidates entering clinical trials in the past decade. To overcome these issues, we reexamined two FDA-approved antibacterial drugs, sulfamethoxazole (SMX) and trimethoprim (TMP), for use in TB treatment. SMX and TMP inhibit folic acid biosynthesis and are used in combination to treat infections of the respiratory, urinary, and gastrointestinal tracts. The MICs of SMX and TMP, alone and in combination, were determined for drug-susceptible, multidrug-resistant (MDR), and extensively drug-resistant
Mycobacterium tuberculosis
strains. While TMP alone was not effective against
M. tuberculosis
, the combination of TMP and SMX was bacteriostatic against
M. tuberculosis
. Surprisingly, the combination of SMX and TMP was also active against a subset of MDR
M. tuberculosis
strains. Treatment of
M. tuberculosis
with TMP-SMX and a first-line anti-TB drug, either isoniazid or rifampin, was bactericidal, demonstrating that the combination of TMP and SMX with isoniazid or rifampin was not antagonistic. Moreover, the addition of SMX-TMP in combination with either isoniazid or rifampin also prevented the emergence of drug resistance
in vitro
. In conclusion, this study further illustrates the opportunity to reevaluate the activity of TMP-SMX
in vivo
to prevent the emergence of drug-resistant
M. tuberculosis
.
Reduced Expression of the
rplU-rpmA
Ribosomal Protein Operon in
mexXY
-Expressing Pan-Aminoglycoside-Resistant Mutants of Pseudomonas aeruginosa
Authors: Lau Calvin Ho-Fung , Fraud Sebastien , Jones Marcus , Peterson Scott N. , Poole Keith 
Published: July 2012

ABSTRACT

Pan-aminoglycoside-resistant
Pseudomonas aeruginosa
mutants expressing the
mexXY
components of the aminoglycoside-accommodating MexXY-OprM multidrug efflux system but lacking mutations in the
mexZ
gene encoding a repressor of this efflux system and in the
mexXY
promoter have been reported (S. Fraud and K. Poole, Antimicrob. Agents Chemother. 55:1068–1074, 2011). Genome sequencing of one of these mutants, K2966, revealed the presence of a mutation within the predicted promoter region of the
rplU-rpmA
operon encoding ribosomal proteins L21 and L27, consistent with an observed 2-fold decrease in expression of this operon in the mutant relative to wild-type
P. aeruginosa
PAO1. Moreover, correction of the mutation restored
rplU-rpmA
expression and, significantly, reversed the elevated
mexXY
expression and pan-aminoglycoside resistance of the mutant. Reduced
rplU-rpmA
expression was also observed in a second
mexXY
-expressing pan-aminoglycoside-resistant mutant, K2968, which, however, lacked a mutation in the
rplU-rpmA
promoter region. Restoration of
rplU-rpmA
expression in the K2968 mutant following chromosomal integration of the
rplU-rpmA
operon derived from wild-type
P. aeruginosa
failed, however, to reverse the elevated
mexXY
expression and pan-aminoglycoside resistance of this mutant, although it did so for K2966, suggesting that the mutation impacting
rplU-rpmA
expression in K2968 also impacts other
mexXY
-related genes. Increased
mexXY
expression owing to reduced
rplU-rpmA
expression in K2966 and K2968 was dependent on PA5471, whose expression was also elevated in these mutants. Thus, mutational disruption of ribosome function, by limiting expression of ribosomal constituents, promotes recruitment of
mexXY
and does so via PA5471, reminiscent of
mexXY
induction by ribosome-disrupting antimicrobial agents. Interestingly, reduced
rplU-rpmA
expression was also observed in a
mexXY
-expressing pan-aminoglycoside-resistant clinical isolate, suggesting that ribosome-perturbing mutations have clinical relevance in the recruitment of the MexXY-OprM aminoglycoside resistance determinant.
Combination of Voriconazole and Anidulafungin for Treatment of Triazole-Resistant Aspergillus fumigatus in an
In Vitro
Model of Invasive Pulmonary Aspergillosis
Authors: Jeans Adam R. , Howard Susan J. , Al-Nakeeb Zaid , Goodwin Joanne , Gregson Lea , Warn Peter A. , Hope William W. 
Published: July 2012

ABSTRACT

Voriconazole is a first-line agent for the treatment of invasive pulmonary aspergillosis. Isolates with elevated voriconazole MICs are increasingly being seen, and the optimal treatment regimen is not defined. We investigated whether the combination of voriconazole with anidulafungin may be beneficial for the treatment of
A. fumigatus
strains with elevated voriconazole MICs. We used an
in vitro
model of the human alveolus to define the exposure-response relationships for a wild-type strain (voriconazole MIC, 0.5 mg/liter) and strains with defined molecular mechanisms of triazole resistance (MICs, 4 to 16 mg/liter). All strains had anidulafungin minimum effective concentrations (MECs) of 0.0078 mg/liter. Exposure-response relationships were estimated using galactomannan as a biomarker. Concentrations of voriconazole and anidulafungin were measured using high-performance liquid chromatography (HPLC). The interaction of voriconazole and anidulafungin was described using the Greco model. Fungal growth was progressively inhibited with higher drug exposures of voriconazole. Strains with elevated voriconazole MICs required proportionally greater voriconazole exposures to achieve a comparable antifungal effect. Galactomannan concentrations were only marginally reduced by anidulafungin monotherapy. An additive effect between voriconazole and anidulafungin was apparent. In conclusion, the addition of anidulafungin does not markedly alter the exposure-response relationship of voriconazole. A rise in serum galactomannan during combination therapy with voriconazole and anidulafungin should be interpreted as treatment failure and not attributed to a paradoxical reaction related to echinocandin treatment.
The WalKR System Controls Major Staphylococcal Virulence Genes and Is Involved in Triggering the Host Inflammatory Response
Authors: Delauné Aurélia , Dubrac Sarah , Blanchet Charlène , Poupel Olivier , Mäder Ulrike , Hiron Aurélia , Leduc Aurélie , Fitting Catherine , Nicolas Pierre , Cavaillon Jean-Marc , Adib-Conquy Minou , Msadek Tarek 
Published: July 2012

ABSTRACTThe WalKR two-component system is essential for the viability ofStaphylococcus aureus, playing a central role in controlling cell wall metabolism. We produced a constitutively active form of WalR inS. aureusthrough a phosphomimetic amino acid replacement (WalRc, D55E). The strain displayed significantly increased biofilm formation and alpha-hemolytic activity. Transcriptome analysis was used to determine the full extent of the WalKR regulon, revealing positive regulation of major virulence genes involved in host matrix interactions (efb,emp,fnbA, andfnbB), cytolysis (hlgACB,hla, andhlb), and innate immune defense evasion (scn,chp, andsbi), through activation of the SaeSR two-component system. The impact on pathogenesis of varying cell envelope dynamics was studied using a murine infection model, showing that strains producing constitutively active WalRcare strongly diminished in their virulence due to early triggering of the host inflammatory response associated with higher levels of released peptidoglycan fragments. Indeed, neutrophil recruitment and proinflammatory cytokine production were significantly increased when the constitutively activewalRcallele was expressed, leading to enhanced bacterial clearance. Taken together, our results indicate that WalKR play an important role in virulence and eliciting the host inflammatory response by controlling autolytic activity.
Intracellular Trafficking of Clostridium perfringens Iota-Toxin b
Authors: Nagahama Masahiro , Umezaki Mariko , Tashiro Ryo , Oda Masataka , Kobayashi Keiko , Shibutani Masahiro , Takagishi Teruhisa , Ishidoh Kazumi , Fukuda Mitsunori , Sakurai Jun 
Published: July 2012

ABSTRACT

Clostridium perfringens
iota-toxin is composed of an enzymatic component (Ia) and a binding component (Ib). Ib binds to a cell surface receptor, undergoes oligomerization in lipid rafts, and binds Ia. The resulting complex is then endocytosed. Here, we show the intracellular trafficking of iota-toxin. After the binding of the Ib monomer with cells at 4°C, oligomers of Ib formed at 37°C and later disappeared. Immunofluorescence staining of Ib revealed that the internalized Ib was transported to early endosomes. Some Ib was returned to the plasma membrane through recycling endosomes, whereas the rest was transported to late endosomes and lysosomes for degradation. Degraded Ib was delivered to the plasma membrane by an increase in the intracellular Ca
2+
concentration caused by Ib. Bafilomycin A1, an endosomal acidification inhibitor, caused the accumulation of Ib in endosomes, and both nocodazole and colchicine, microtubule-disrupting agents, restricted Ib's movement in the cytosol. These results indicated that an internalized Ia and Ib complex was delivered to early endosomes and that subsequent delivery of Ia to the cytoplasm occurs mainly in early endosomes. Ib was either sent back to the plasma membranes through recycling endosomes or transported to late endosomes and lysosomes for degradation. Degraded Ib was transported to plasma membranes.
Coagulases as Determinants of Protective Immune Responses against Staphylococcus aureus
Authors: McAdow Molly , DeDent Andrea C. , Emolo Carla , Cheng Alice G. , Kreiswirth Barry N. , Missiakas Dominique M. , Schneewind Olaf 
Published: July 2012

ABSTRACTDuring infection,Staphylococcus aureussecretes two coagulases (Coa and von Willebrand factor binding protein [vWbp]), which, following an association with host prothrombin and fibrinogen, form fibrin clots and enable the establishment of staphylococcal disease. Within the genomes of differentS. aureusisolates, coagulase gene sequences are variable, and this has been exploited for a classification of types. We show here that antibodies directed against the variable prothrombin binding portion of coagulases confer type-specific immunity through the neutralization ofS. aureusclotting activity and protection from staphylococcal disease in mice. By combining variable portions of coagulases from North American isolates into hybrid Coa and vWbp proteins, a subunit vaccine that provided protection against challenge with different coagulase-typeS. aureusstrains in mice was derived.
Increased Chain Length Promotes Pneumococcal Adherence and Colonization
Authors: Rodriguez Jesse L. , Dalia Ankur B. , Weiser Jeffrey N. 
Published: July 2012

ABSTRACTStreptococcus pneumoniaeis a mucosal pathogen that grows in chains of variable lengths. Short-chain forms are less likely to activate complement, and as a consequence they evade opsonophagocytic clearance more effectively during invasive disease. When grown in human nasal airway surface fluid, pneumococci exhibited both short- and long-chain forms. Here, we determined whether longer chains provide an advantage during colonization when the organism is attached to the epithelial surface. Chain-forming mutants and the parental strain grown under conditions to promote chain formation showed increased adherence to human epithelial cells (A549 cells)in vitro. Additionally, adherence to A549 cells selected for longer chains within the wild-type strain.In vivoin a murine model of colonization, chain-forming mutants outcompeted the parental strain. Together, our results demonstrate that morphological heterogeneity in the pneumococcus may promote colonization of the upper respiratory tract by enhancing the ability of the organism to bind to the epithelial surface.
Stressor-Induced Increase in Microbicidal Activity of Splenic Macrophages Is Dependent upon Peroxynitrite Production
Authors: Allen Rebecca G. , Lafuse William P. , Powell Nicole D. , Webster Marketon Jeanette I. , Stiner-Jones La'Tonia M. , Sheridan John F. , Bailey Michael T. 
Published: July 2012

ABSTRACTExposing mice to a social stressor called social disruption (SDR) that involves repeated social defeat during intermale aggression results in increased circulating cytokines, such as interleukin-1α (IL-1α) and IL-1β, and increased reactivity of splenic CD11b+macrophages to inflammatory stimuli. For example, upon lipopolysaccharide stimulation, macrophages from stressor-exposed mice produce higher levels of cytokines than do cells from nonstressed controls. Moreover, the SDR stressor enhances the ability of these macrophages to killEscherichia colibothin vitroandin vivo, through a Toll-like receptor 4-dependent mechanism. The present study tested the hypothesis that stressor-enhanced bacterial killing is due to increases in the production of peroxynitrite. Male mice were exposed to the SDR stressor or were left undisturbed. Upon stimulation withE. coli, splenic macrophages from SDR-exposed mice expressed significantly increased levels of inducible nitric oxide synthase mRNA and produced higher levels of peroxynitrite. Blocking the production of peroxynitrite abrogated the SDR-induced increase in microbicidal activity. Studies in IL-1 receptor type 1 knockout mice indicated that the increased microbicidal activity and peroxynitrite production was dependent upon IL-1 signaling. These data confirm and extend the importance of IL-1 signaling for stressor-induced immunopotentiation; the finding that inhibiting superoxide or nitric oxide production inhibits both peroxynitrite production and killing ofE. colidemonstrates that peroxynitrite mediates the stressor-induced increase in bacterial killing.
The Metal Ion-Dependent Adhesion Site Motif of the Enterococcus faecalis EbpA Pilin Mediates Pilus Function in Catheter-Associated Urinary Tract Infection
Authors: Nielsen Hailyn V. , Guiton Pascale S. , Kline Kimberly A. , Port Gary C. , Pinkner Jerome S. , Neiers Fabrice , Normark Staffan , Henriques-Normark Birgitta , Caparon Michael G. , Hultgren Scott J. 
Published: July 2012

ABSTRACT

Though the bacterial opportunist
Enterococcus faecalis
causes a myriad of hospital-acquired infections (HAIs), including catheter-associated urinary tract infections (CAUTIs), little is known about the virulence mechanisms that it employs. However, the endocarditis- and biofilm-associated pilus (Ebp), a member of the sortase-assembled pilus family, was shown to play a role in a mouse model of
E. faecalis
ascending UTI. The Ebp pilus comprises the major EbpC shaft subunit and the EbpA and EbpB minor subunits. We investigated the biogenesis and function of Ebp pili in an experimental model of CAUTI using a panel of chromosomal pilin deletion mutants. A nonpiliated pilus knockout mutant (EbpABC
−
strain) was severely attenuated compared to its isogenic parent OG1RF in experimental CAUTI. In contrast, a nonpiliated
ebpC
deletion mutant (EbpC
−
strain) behaved similarly to OG1RF
in vivo
because it expressed EbpA and EbpB. Deletion of the minor pilin gene
ebpA
or
ebpB
perturbed pilus biogenesis and led to defects in experimental CAUTI. We discovered that the function of Ebp pili
in vivo
depended on a predicted metal ion-dependent adhesion site (MIDAS) motif in EbpA’s von Willebrand factor A domain, a common protein domain among the tip subunits of sortase-assembled pili. Thus, this study identified the Ebp pilus as a virulence factor in
E. faecalis
CAUTI and also defined the molecular basis of this function, critical knowledge for the rational development of targeted therapeutics.

IMPORTANCE
Catheter-associated urinary tract infections (CAUTIs), one of the most common hospital-acquired infections (HAIs), present considerable treatment challenges for physicians. Inherently resistant to several classes of antibiotics and with a propensity to acquire vancomycin resistance, enterococci are particularly worrisome etiologic agents of CAUTI. A detailed understanding of the molecular basis of
Enterococcus faecalis
pathogenesis in CAUTI is necessary for the development of preventative and therapeutic strategies. Our results elucidated the importance of the
E. faecalis
Ebp pilus and its subunits for enterococcal virulence in a mouse model of CAUTI. We further showed that the metal ion-dependent adhesion site (MIDAS) motif in EbpA is necessary for Ebp function
in vivo
. As this motif occurs in other sortase-assembled pili, our results have implications for the molecular basis of virulence not only in
E. faecalis
CAUTI but also in additional infections caused by enterococci and other Gram-positive pathogens.
Food or medicine: ethnic variations in perceptions of advanced cancer patients and their caregivers regarding artificial hydration during the last weeks of life: Table 1
Authors: Torres-Vigil Isabel , Cohen Marlene Z , de la Rosa Allison , Cárdenas-Turanzas Marylou , Burbach Beth E , Tarleton Kenneth W , Shen Whey-May , Bruera Eduardo 
Published: July 2012

PurposeTo identify whether advanced cancer patients receiving home hospice care and their primary caregivers view artificial hydration (AH) as food or medicine, and the demographic and clinical factors influencing these perceptions.MethodsParticipants were enrolled in a randomised, double-blind controlled trial examining the efficacy of AH in cancer hospice patients. In-depth interviews at days 1 and 4 of study enrolment explored the meanings attributed to AH at the end of life. Responses to the question, ‘Are these fluids more like food or more like medicine?’ were categorised as ‘food’, ‘medicine’, ‘both’ or ‘other’. χ2analyses were conducted with data from 122 interviews (54 patients and 68 caregivers) to identify differences between patients and caregivers, and by gender, age, ethnicity and caregiver relationship. Predictors of perceptions were identified using logistic regression analysis.ResultsOverall, 47 participants (38%) understood the fluids to be more like food, 41 (34%) as medicine, 17 (14%) as both, and 17 (14%) as ‘other’. Ethnic minority participants (n=34, 66%) were significantly more likely than non-Hispanic European Americans (n=30, 42%) to view AH as food, or both as food and medicine (p=0.034). Ethnic differences persisted in the final regression model (OR 2.7; 95% CI 1.3 to 5.7, p=0.010). No significant differences were detected between patients and caregivers, or across gender, age, caregivers' relationship to the patients, group assignment, disease severity or cancer type.ConclusionsAH was perceived as food/nutrition by many cancer patients and caregivers in the study, particularly among ethnic minorities. This perception may lead to greater distress if fluids are discontinued or withheld. Asking patients/caregivers about their AH perceptions may enhance patient/provider communication and culturally appropriate end-of-life care.
Forced suction thrombectomy after carotid stenting in patients with massive thrombus and acute extracranial internal carotid artery occlusion
Authors: Hwang Seoung Bae , Kwak Hyo Sung , Chung Gyung-Ho 
Published: July 2012

PurposeTo evaluate the safety and efficacy of emergency carotid stenting and recanalization using the modified Penumbra System (PS) technique for cases of acute extracranial internal carotid artery (ICA) occlusion and massive thrombus with acute ischemic stroke symptoms.MethodsThe clinical outcomes of patients with tandem occlusion of the ICA and middle cerebral artery (MCA) who underwent recanalization by a modified PS technique after carotid artery stenting during the period December 2009 to June 2011 were reviewed.ResultsFive patients with tandem occlusion of the ICA and MCA were enrolled. The mean National Institute of Health Stroke Scale (NIHSS) score on admission was 13 (range 9–18). The median time from symptom onset to arrival at hospital was 260 min. The median time lag between arrival at hospital and intra-arterial administration was 70 min. Recanalization by stenting of carotid artery occlusion was successfully performed in all patients. The mean number of recanalizations using the modified PS technique for distally migrated thrombus was 3. Complete recanalization of the MCA was observed in all patients. Symptomatic hemorrhage transformation did not occur during the hospital stay in any of the subjects. At discharge, the mean NIHSS score was 2.2 (range 1–6). At the 3-month follow-up the modified Rankin Scale was excellent in three of the five patients, good in one patient and poor in one patient.ConclusionsThe modified PS technique after carotid artery stenting is a safe and effective treatment for patients with a massive thrombus extending into the distal portion of the ICA and a tandem occlusion of the ICA and MCA.
Determination of small-strain stiffness of Shanghai clay on prismatic soil specimen
Authors: Li Q. , Ng C.W.W. , Liu G.B. 
Published: July 2012

Although a large number of tunnels and deep excavations have been constructed in Shanghai, small-strain stiffness properties of natural Shanghai clay have rarely been reported in the literature. In this study, the degree of inherent stiffness anisotropy of natural Shanghai clay was investigated in a triaxial apparatus equipped with local strain transducers and a shear-wave velocity measurement system. Three sets of side-mounted bender elements, consisting of one transmitter and two receivers each, were installed on a prismatic specimen. Two series of triaxial tests on prismatic specimens of intact Shanghai clay were carried out under an isotropic stress state. Shear-wave velocities and hence elastic shear moduli in different planes were determined from bender element measurements. The cross-correlation method using two received signals gives rise to the most objective and repeatable results on shear-wave velocities in comparison with other commonly used methods. Intact Shanghai clay clearly exhibits inherent stiffness anisotropy in terms of its elastic shear modulus ratio (G0(hh)/G0(hv)) of about 1.2 for a mean effective stress varying from 50 to 400 kPa. The measured higher stiffness in the horizontal plane may be attributed to the stronger layering structure in the horizontal bedding plane. A unique relationship is found that relates the normalized shear moduli to the stress state in each plane by incorporating a void ratio function in the form of F(e) = e–2.6.
Hierarchically acting sterile neutrinos
Authors: Chen Chian-Shu , Takahashi Ryo 
Published: July 2012

AbstractWe propose that a hierarchical spectrum of sterile neutrinos (eV, keV, 1013–15 GeV) is considered as the explanation for MiniBooNE and LSND oscillation anomalies, dark matter, and baryon asymmetry of the universe (BAU), respectively. The scenario can also realize the smallness of active neutrino masses by the seesaw mechanism.