bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antimicrobial Penetration and Efficacy in an
In Vitro
Oral Biofilm Model
Authors: Corbin Audrey , Pitts Betsey , Parker Albert , Stewart Philip S. 
Published: May 2011

ABSTRACT

The penetration and overall efficacy of six mouthrinse actives was evaluated by using an
in vitro
flow cell oral biofilm model. The technique involved preloading biofilm cells with a green fluorescent dye that leaked out as the cells were permeabilized by a treatment. The loss of green color, and of biomass, was observed by time-lapse microscopy during 60 min of treatment under continuous flow conditions. The six actives analyzed were ethanol, sodium lauryl sulfate, triclosan, chlorhexidine digluconate (CHX), cetylpyridinium chloride, and nisin. Each of these agents effected loss of green fluorescence throughout biofilm cell clusters, with faster action at the edge of a cell cluster and slower action in the cluster center. The time to reach half of the initial fluorescent intensity at the center of a cell cluster, which can be viewed as a combined penetration and biological action time, ranged from 0.6 to 19 min for the various agents. These times are much longer than the predicted penetration time based on diffusion alone, suggesting that anti-biofilm action was controlled more by the biological action time than by the penetration time of the active. None of the agents tested caused any removal of the biofilm. The extent of fluorescence loss after 1 h of exposure to an active ranged from 87 to 99.5%, with CHX being the most effective. The extent of fluorescence loss
in vitro
, but not penetration and action time, correlated well with the relative efficacy data from published clinical trials.
In Vitro
Susceptibility of Pythium insidiosum to Macrolides and Tetracycline Antibiotics
Authors: Loreto Érico Silva , Mario Débora Alves Nunes , Denardi Laura Bedin , Alves Sydney Hartz , Santurio Janio Morais 
Published: May 2011

ABSTRACT

We describe the
in vitro
activity of macrolides and tetracycline antibiotics against
Pythium insidiosum
. The MICs were determined according to CLSI procedures (visual MIC) and by a colorimetric method [3-(4,5-dimethyl-2-thiazyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT)]. The lowest geometric mean (GM) MIC (MICs in μg/ml) (0.39 and 0.7 by visual reading and colorimetric method, respectively) and MIC ranges (0.125 to 2.0) were obtained for minocycline, while the highest MICs were shown for erythromycin (GM of 7.58 and 12.25 by visual reading and colorimetric method, respectively, and MIC ranged from 2 to 32). This significant
in vitro
activity makes these classes of antibiotics good candidates for experimental treatment of pythiosis.
Pharmacokinetics of Lopinavir in HIV-Infected Adults Receiving Rifampin with Adjusted Doses of Lopinavir-Ritonavir Tablets
Authors: Decloedt Eric H. , McIlleron Helen , Smith Peter , Merry Concepta , Orrell Catherine , Maartens Gary 
Published: May 2011

ABSTRACTRifampin coadministration dramatically reduces plasma lopinavir (LPV) concentrations. In healthy volunteers, doubling the dose of a lopinavir-ritonavir (LPV/r) capsule formulation overcame this interaction, but a subsequent study of double doses of the tablet formulation was stopped early owing to hepatotoxicity. However, healthy-volunteer study findings may not apply to HIV-infected adults. We evaluated the steady-state pharmacokinetics of LPV in HIV-infected adults virologically suppressed on an LPV/r regimen who were given rifampin, and the dose of the LPV/r tablet formulation was gradually increased. The steady-state pharmacokinetics of LPV/r were evaluated at baseline, a week after commencing rifampin, a week after the LPV/r dose was increased 1.5 times, and a week after the LPV/r dose was doubled. Twenty-one participants were enrolled. The median [interquartile range (IQR)] predose LPV concentrations (C0) were 8.1 (6.2 to 9.8) mg/liter at baseline, 1.7 (0.3 to 3.0) mg/liter after 7 days of rifampin, 5.9 (2.1 to 9.9) mg/liter with 1.5 times the dose of LPV/r, and 10.8 (7.0 to 13.1) mg/liter with double-dose LPV/r. There were no significant differences in the LPV area under the plasma concentration-time curve from 0 to 12 h (AUC0-12),C0,C12, maximum concentration of drug in serum (Cmax), or half-life (t1/2) between the baseline and double-dose LPV/r time points. Treatment was generally well tolerated, with two participants developing asymptomatic grade 3/4 transaminitis. Doubling the dose of the tablet formulation of LPV/r overcomes induction by rifampin. Less hepatotoxicity occurred in our cohort of HIV-infected participants than was reported in healthy-volunteer studies.
Development, Evaluation, and Application of an
In Silico
Model for Antimalarial Drug Treatment and Failure
Authors: Winter Katherine , Hastings Ian M. 
Published: May 2011

ABSTRACT

Pharmacological mechanism-based modeling was refined and used to develop an
in silico
model of antimalarial drug treatment validated against clinical and field data. We used this approach to investigate key features of antimalarial drug action and effectiveness, with emphasis on the current generation of artemisinin combination therapies. We made the following conclusions. (i) The development of artemisinin tolerance and resistance will, unless checked, have an immediate, large impact on the protection afforded to its partner drug and on the likely clinical efficacy of artemisinin combination therapies. (ii) Long follow-up periods are required in clinical trials to detect all drug failures; the follow-up periods of 28 days recommended by the World Health Organization are likely to miss at least 50% of drug failures, and we confirmed recent suggestions that 63 days would be a more appropriate follow-up period. (iii) Day 7 serum drug concentrations are a significant risk factor of failure, although, paradoxically, receiver operating characteristic curve analysis revealed that their predictive power is relatively poor. (iv) The pharmacokinetic properties of the partner drugs in artemisinin-containing combination therapies are the most important determinants of treatment outcome, particularly the maximum killing rate. We discuss the assumptions made in such modeling approaches and how similar approaches may be refined in future work.
Azithromycin Inhibits Expression of the GacA-Dependent Small RNAs RsmY and RsmZ in Pseudomonas aeruginosa
Authors: Pérez-Martínez Isabel , Haas Dieter 
Published: May 2011

ABSTRACT

Azithromycin at clinically relevant doses does not inhibit planktonic growth of the opportunistic pathogen
Pseudomonas aeruginosa
but causes markedly reduced formation of biofilms and quorum-sensing-regulated extracellular virulence factors. In the Gac/Rsm signal transduction pathway, which acts upstream of the quorum-sensing machinery in
P. aeruginosa
, the GacA-dependent untranslated small RNAs RsmY and RsmZ are key regulatory elements. As azithromycin treatment and mutational inactivation of
gacA
have strikingly similar phenotypic consequences, the effect of azithromycin on
rsmY
and
rsmZ
expression was investigated. In planktonically growing cells, the antibiotic strongly inhibited the expression of both small RNA genes but did not affect the expression of the housekeeping gene
proC
. The azithromycin treatment resulted in reduced expression of
gacA
and
rsmA
, which are known positive regulators of
rsmY
and
rsmZ
, and of the PA0588-PA0584 gene cluster, which was discovered as a novel positive regulatory element involved in
rsmY
and
rsmZ
expression. Deletion of this cluster resulted in diminished ability of
P. aeruginosa
to produce pyocyanin and to swarm. The results of this study indicate that azithromycin inhibits
rsmY
and
rsmZ
transcription indirectly by lowering the expression of positive regulators of these small RNA genes.
Spermidine Synthase Is Required for Virulence of Leishmania donovani
Authors: Gilroy Caslin , Olenyik Tamara , Roberts Sigrid C. , Ullman Buddy 
Published: May 2011

ABSTRACT

Genetic lesions in the polyamine biosynthetic pathway of
Leishmania donovani
, the causal agent of visceral leishmaniasis, are conditionally lethal mutations that render the insect vector form of the parasite auxotrophic for polyamines. Recently, we have demonstrated that a Δ
odc
L. donovani
null mutant lacking ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, was profoundly compromised in its ability to infect mice, indicating that ODC is essential for the infectious mammalian stage of the parasite and further validating the enzyme as a possible drug target. To assess whether other components of the polyamine biosynthetic pathway were also essential for parasite virulence, a cell line deficient in spermidine synthase (SPDSYN), the enzyme that converts putrescine to spermidine, was created by double-targeted gene replacement within a virulent
L. donovani
background. This Δ
spdsyn
strain was auxotrophic for polyamines, required spermidine for growth in its insect vector form, and was adversely impacted in its ability to infect mice. These findings establish that SPDSYN, like ODC, is essential for maintaining a robust infection in mammals and indicate that pharmacologic inhibition of SPDSYN, and perhaps all components of the polyamine biosynthetic pathway, is a valid therapeutic strategy for the treatment of visceral and, potentially, other forms of leishmaniasis.
Porphyromonas gingivalis Induction of MicroRNA-203 Expression Controls Suppressor of Cytokine Signaling 3 in Gingival Epithelial Cells
Authors: Moffatt Catherine E. , Lamont Richard J. 
Published: May 2011

ABSTRACT

Porphyromonas gingivalis
is a pathogen in severe periodontal disease. Able to exploit an intracellular lifestyle within primary gingival epithelial cells (GECs), a reservoir of
P. gingivalis
can persist within the gingival epithelia. This process is facilitated by manipulation of the host cell signal transduction cascades which can impact cell cycle, cell death, and cytokine responses. Using microarrays, we investigated the ability of
P. gingivalis
33277 to regulate microRNA (miRNA) expression in GECs. One of several miRNAs differentially regulated by GECs in the presence of
P. gingivalis
was miRNA-203 (miR-203), which was upregulated 4-fold compared to uninfected controls. Differential regulation of miR-203 was confirmed by quantitative reverse transcription-PCR (qRT-PCR). Putative targets of miR-203, suppressor of cytokine signaling 3 (SOCS3) and SOCS6, were evaluated by qRT-PCR. SOCS3 and SOCS6 mRNA levels were reduced >5-fold and >2-fold, respectively, in
P. gingivalis
-infected GECs compared to controls. Silencing of miR-203 using a small interfering RNA construct reversed the inhibition of SOCS3 expression. A dual luciferase assay confirmed binding of miR-203 to the putative target binding site of the SOCS3 3′ untranslated region. Western blot analysis demonstrated that activation of signal transducer and activator of transcription 3 (Stat3), a downstream target of SOCS, was diminished following miR-203 silencing. This study shows that induction of miRNAs by
P. gingivalis
can modulate important host signaling responses.
Anaplasma phagocytophilum Infects Mast Cells via α1,3-Fucosylated but Not Sialylated Glycans and Inhibits IgE-Mediated Cytokine Production and Histamine Release
Authors: Ojogun Nore , Barnstein Brian , Huang Bernice , Oskeritzian Carole A. , Homeister Jonathon W. , Miller Daniel , Ryan John J. , Carlyon Jason A. 
Published: May 2011

ABSTRACT

Mast cells are sentinels for infection. Upon exposure to pathogens, they release their stores of proinflammatory cytokines, chemokines, and histamine. Mast cells are also important for the control of certain tick-borne infections.
Anaplasma phagocytophilum
is an obligate intracellular tick-transmitted bacterium that infects neutrophils to cause the emerging disease granulocytic anaplasmosis.
A. phagocytophilum
adhesion to and infection of neutrophils depend on sialylated and α1,3-fucosylated glycans. We investigated the hypotheses that
A. phagocytophilum
invades mast cells and inhibits mast cell activation. We demonstrate that
A. phagocytophilum
binds and/or infects murine bone marrow-derived mast cells (BMMCs), murine peritoneal mast cells, and human skin-derived mast cells.
A. phagocytophilum
infection of BMMCs depends on α1,3-fucosylated, but not sialylated, glycans.
A. phagocytophilum
binding to and invasion of BMMCs do not elicit proinflammatory cytokine secretion. Moreover,
A. phagocytophilum
-infected cells are inhibited in the release of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), IL-13, and histamine following stimulation with IgE or antigen. Thus,
A. phagocytophilum
mitigates mast cell activation. These findings potentially represent a novel means by which
A. phagocytophilum
usurps host defense mechanisms and shed light on the interplay between mast cells and vector-borne bacterial pathogens.
SlyA Is a Transcriptional Regulator Involved in the Virulence of Enterococcus faecalis
Authors: Michaux Charlotte , Sanguinetti Maurizio , Reffuveille Fany , Auffray Yanick , Posteraro Brunella , Gilmore Michael S. , Hartke Axel , Giard Jean-Christophe 
Published: May 2011

ABSTRACT

Phylogenetic analysis of the crystal structure of the
Enterococcus faecalis
SlyA (EF_3002) transcriptional factor places it between the SlyA and MarR regulator subfamilies. Proteins of these families are often involved in the regulation of genes important for bacterial virulence and stress response. To gather evidence for the role of this putative regulator in
E. faecalis
biology, we dissected the genetic organization of the
slyA
-EF_3001 locus and constructed a
slyA
deletion mutant as well as complemented strains. Interestingly, compared to the wild-type parent, the Δ
slyA
mutant is more virulent in an insect infection model (
Galleria mellonella
), exhibits increased persistence in mouse kidneys and liver, and survives better inside peritoneal macrophages. In order to identify a possible SlyA regulon, global microarray transcriptional analysis was performed. This study revealed that the
slyA
-EF_3001 locus appears to be autoregulated and that 117 genes were differentially regulated in the Δ
slyA
mutant. In the mutant strain, 111 were underexpressed and 6 overexpressed, indicating that SlyA functions mainly as an activator of transcription.
Enhancement of Neutrophil Function by Interleukin-18 Therapy Protects Burn-Injured Mice from Methicillin-Resistant Staphylococcus aureus
Authors: Kinoshita Manabu , Miyazaki Hiromi , Ono Satoshi , Inatsu Akihito , Nakashima Hiroyuki , Tsujimoto Hironori , Shinomiya Nariyoshi , Saitoh Daizoh , Seki Shuhji 
Published: May 2011

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) infection is a grave concern in burn-injured patients. We investigated the efficacy of interleukin-18 (IL-18) treatment in postburn MRSA infection. Alternate-day injections of IL-18 into burn-injured C57BL/6 mice significantly increased their survival after MRSA infection and after methicillin-sensitiveS. aureusinfection. Although IL-18 treatment of burn-injured mice augmented natural IgM production before MRSA infection and gamma interferon (IFN-γ) production after MRSA infection, neither IgM nor IFN-γ significantly contributed to the improvement in mouse survival. IL-18 treatment increased/restored the serum tumor necrosis factor (TNF), IL-17, IL-23, granulocyte colony-stimulating factor (G-CSF), and macrophage inflammatory protein (MIP-2) levels, as well as the neutrophil count, after MRSA infection of burn-injured mice; it also improved impaired neutrophil functions, phagocytic activity, production of reactive oxygen species, and MRSA-killing activity. However, IL-18 treatment was ineffective against MRSA infection in both burn- and sham-injured neutropenic mice. Enhancement of neutrophil functions by IL-18 was also observedin vitro. Furthermore, when neutrophils from IL-18-treated burn-injured mice were adoptively transferred into nontreated burn-injured mice 2 days after MRSA challenge, survival of the recipient mice increased. NOD-SCID mice that have functionally intact neutrophils and macrophages (but not T, B, or NK cells) were substantially resistant to MRSA infection. IL-18 treatment increased the survival of NOD-SCID mice after burn injury and MRSA infection. An adoptive transfer of neutrophils using NOD-SCID mice also showed a beneficial effect of IL-18-activated neutrophils, similar to that seen in C57BL/6 mice. Thus, although neutrophil functions were impaired in burn-injured mice, IL-18 therapy markedly activated neutrophil functions, thereby increasing survival from postburn MRSA infection.
The Nasal Dendritic Cell-Targeting Flt3 Ligand as a Safe Adjuvant Elicits Effective Protection against Fatal Pneumococcal Pneumonia
Authors: Kataoka Kosuke , Fujihashi Kohtaro , Oma Keita , Fukuyama Yoshiko , Hollingshead Susan K. , Sekine Shinichi , Kawabata Shigetada , Ito Hiro-O , Briles David E. , Oishi Kazunori 
Published: May 2011

ABSTRACTWe have previously shown that a pneumococcal surface protein A (PspA)-based vaccine containing DNA plasmid encoding the Flt3 ligand (FL) gene (pFL) as a nasal adjuvant prevented nasal carriage ofStreptococcus pneumoniae. In this study, we further investigated the safety and efficacy of this nasal vaccine for the induction of PspA-specific antibody (Ab) responses against lung infection withS. pneumoniae.C57BL/6 mice were nasally immunized with recombinant PspA/Rx1 (rPspA) plus pFL three times at weekly intervals. When dynamic translocation of pFL was initially examined, nasal pFL was taken up by nasal dendritic cells (DCs) and epithelial cells (nECs) but not in the central nervous systems, including olfactory nerve and epithelium. Of importance, nasal pFL induced FL protein synthesis with minimum levels of inflammatory cytokines in the nasal washes (NWs) and bronchoalveolar lavage fluid (BALF). NWs and BALF as well as plasma of mice given nasal rPspA plus pFL contained increased levels of rPspA-specific secretory IgA and IgG Ab responses that were correlated with elevated numbers of CD8+and CD11b+DCs and interleukin 2 (IL-2)- and IL-4-producing CD4+T cells in the nasal mucosa-associated lymphoid tissues (NALT) and cervical lymph nodes (CLNs). Thein vivoprotection by rPspA-specific Abs was evident in markedly reduced numbers of CFU in the lungs, airway secretions, and blood when mice were nasally challenged withStreptococcus pneumoniaeWU2. Our findings show that nasal pFL is a safe and effective mucosal adjuvant for the enhancement of bacterial antigen (Ag) (rPspA)-specific protective immunity through DC-induced Th2-type and IL-2 cytokine responses.
Increased knee valgus alignment and moment during single-leg landing after overhead stroke as a potential risk factor of anterior cruciate ligament injury in badminton
Authors: Kimura Yuka , Ishibashi Yasuyuki , Tsuda Eiichi , Yamamoto Yuji , Hayashi Yoshimitsu , Sato Shuichi 
Published: May 2011

BackgroundIn badminton, knees opposite to the racket-hand side received anterior cruciate ligament (ACL) injuries during single-leg landing after overhead stroke. Most of them occurred in the backhand-side of the rear court. Comparing lower limb biomechanics during single-leg landing after overhead stroke between the forehand-side and backhand-side court may help explain the different injury rates depending on court position.HypothesisThe knee kinematics and kinetics during single-leg landing after overhead stroke following back-stepping were different between the forehand-side and backhand-side court.Study designControlled laboratory study.MethodsHip, knee and ankle joint kinematic and knee kinetic data were collected for 17 right-handed female college badminton players using a 3-dimensional motion analysis system. Subjects performed single-left-legged landing after an overhead stroke following left and right back-stepping. The kinematic and kinetic data of the left lower extremities during landing were measured and compared between left and right back-steps.ResultsHip flexion and abduction and knee valgus at the initial contact, hip and knee flexion and knee valgus at the maximum knee flexion and the maximum knee valgus moment were significantly larger for the left back-step than the right back-step (p<0.05).ConclusionSignificant differences in joint kinematics and kinetics of the lower extremity during single-leg landing after overhead stroke were observed between different back-step directions. Increased knee valgus angle and moment following back-stepping to the backhand-side might be related to the higher incidence of ACL injury during single-leg landing after overhead stroke.
Picea rubensgrowth at high versus low elevations in the Great Smoky Mountains National Park: evaluation by systems modeling
Authors: Koo Kyung-Ah , Patten Bernard C. , Creed Irena F. 
Published: May 2011

For half a century, red spruce ( Picea rubens Sarg.), a commercially and ecologically important boreal tree species, has experienced growth decline and high mortality in eastern North America. A tree growth systems model, ARIM (annual radial increment model), was developed to evaluate responsible factors for red spruce growth in the Great Smoky Mountains National Park. The dominant cause at higher elevations (1800–2000 m) was found to be air pollution involving high-frequency acidic rain and cloud immersion. The identified causes at lower elevations (1450–1700 m) were insufficient solar absorption due to photoinhibition, drought stress resulting from reduced precipitation and high evapotranspiration due to warmer temperatures, and minor effects of air pollution. The ARIM exemplifies a complex systems concept and methodology for evaluating multivariable factors in tree growth systems. ARIM provides a general model structure that incorporates complex direct and indirect interactions for tree system studies and quantitatively integrates knowledge and data from different disciplines by developing a new set of indices, the relative basis index values. The ARIM results implicate comprehensive habitat-dependent directions for long-term conservation policies and management of red spruce with environmental changes, climate change, and air pollution in the Great Smoky Mountains National Park.
Chloroplast DNA polymorphisms in eastern hemlock: range-wide genogeographic analyses and implications for gene conservation
Authors: Lemieux Michée Joseph , Beaulieu Jean , Bousquet Jean 
Published: May 2011

The objective of this study was to determine if the genetic diversity of eastern hemlock ( Tsuga canadensis (L.) Carrière) is uniformly distributed or structured. Such information is relevant to help guide conservation efforts. Individuals were sampled in 60 range-wide populations of T. canadensis and genotyped at seven polymorphic chloroplast DNA loci. All 16 chlorotypes identified in T. canadensis were highly divergent from the unique chlorotype detected in Carolina hemlock ( Tsuga caroliniana Engelm.). Among-population differentiation in T. canadensis was low (GST = 0.020) and the distribution of chlorotypes did not show any strong geographical pattern, which is likely due to the homogenizing effect of pollen gene flow during the Holocene. Nevertheless, a spatial Bayesian approach revealed two distinct groups of populations. Furthermore, an analysis of relative genetic distances indicated that southeastern Appalachian populations harboured greater population differentiation while conserving relatively high allelic richness, which might represent the imprint of an ancient glacial refugium in the region. Thus, these distinctive genetic patterns and the risk of Tsuga decline following climate warming combined with the introduction of the insect Adelges tsugae (Annand) indicate that the southern part of the range should be considered of high priority for ex situ conservation.