bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simultaneous reduction of radiation dose and scatter for CBCT by using collimators
Authors: Li Tianfang , Li Xiang , Yang Yong , Zhang Yongqian , Heron Dwight E. , Huq M. Saiful 
Published: November 2013

Purpose:On‐board cone‐beam CT (CBCT) imaging has been widely available in radiotherapy clinic for target localization. However, the extra radiation dose from CBCT is always a concern for its frequent use. Additionally, the relatively large scatter in CBCT often degrades the image quality. By using collimators, some of the X‐rays can be stopped from reaching the patient and the detectors, hence both the scatter and the patient doses are simultaneously reduced. The authors show in this work that the collimated CBCT data can be reconstructed without any noticeable artifacts for certain collimator blocking ratios and blocking patterns, and the focus of this work is to study the relationship between the image quality and these two collimator factors.Methods:A CBCT system with collimators was simulated following the typical geometry used in clinic. Different collimator designs were tested by varying the size and the number of the collimator slits, and at the same time, the ratio of transmitted beams to total beams was varied from 100% to 10%, resulting in hundreds of different simulation scenarios. Lung and pelvis phantoms created from patients CT images were used in the simulations, and an iterative reconstruction algorithm using the compressed sensing technique was adopted. The image quality was examined by root mean square errors (RMSEs) and compared with the conventional CBCT images.Results:The CBCT image quality increases as the amount of beams passing through the collimators increases, and decreases as the size of the collimator slits increases. With ultra‐high resolution collimators, the RMSEs were comparable to the conventional CBCT image quality until the beam transmission rate is reduced below 25%.Conclusions:Collimators can reduce the scatters and radiation dose, however, the collimated CBCT image quality is strongly dependent on both the collimator blocking ratio and the blocking pattern. To achieve image quality comparable to the conventional CBCT, the amount of information and data format must be adequate.
Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem
Authors: Agudelo M. , Rodriguez C. A. , Pelaez C. A. , Vesga O. 
Published: November 2013

ABSTRACT

Several studies with animal models have demonstrated that bioequivalence of generic products of antibiotics like vancomycin, as currently defined, do not guarantee therapeutic equivalence. However, the amounts and characteristics of impurities and degradation products in these formulations do not violate the requirements of the U.S. Pharmacopeia (USP). Here, we provide experimental data with three generic products of meropenem that help in understanding how these apparently insignificant chemical differences affect the
in vivo
efficacy. Meropenem generics were compared with the innovator
in vitro
by microbiological assay, susceptibility testing, and liquid chromatography/mass spectrometry (LC/MS) analysis and
in vivo
with the neutropenic guinea pig soleus infection model (
Pseudomonas aeruginosa
) and the neutropenic mouse thigh (
P. aeruginosa
), brain (
P. aeruginosa
), and lung (
Klebisella pneumoniae
) infection models, adding the dihydropeptidase I (DHP-I) inhibitor cilastatin in different proportions to the carbapenem. We found that the concentration and potency of the active pharmaceutical ingredient,
in vitro
susceptibility testing, and mouse pharmacokinetics were identical for all products; however, two generics differed significantly from the innovator in the guinea pig and mouse models, while the third generic was therapeutically equivalent under all conditions. Trisodium adducts in a bioequivalent generic made it more susceptible to DHP-I hydrolysis and less stable at room temperature, explaining its therapeutic nonequivalence. We conclude that the therapeutic nonequivalence of generic products of meropenem is due to greater susceptibility to DHP-I hydrolysis. These failing generics are compliant with USP requirements and would remain undetectable under current regulations.
Potential of Host Defense Peptide Prodrugs as Neutrophil Elastase-Dependent Anti-Infective Agents for Cystic Fibrosis
Authors: Forde Éanna , Humphreys Hilary , Greene Catherine M. , Fitzgerald-Hughes Deirdre , Devocelle Marc 
Published: November 2013

ABSTRACT

Host defense peptides (HDPs) are short antimicrobial peptides of the innate immune system. Deficiencies in HDPs contribute to enhanced susceptibility to infections, e.g., in cystic fibrosis (CF). Exogenous HDPs can compensate for these deficiencies, but their development as antimicrobials is limited by cytotoxicity. Three HDP prodrugs were designed so their net positive charge is masked by a promoiety containing a substrate for the enzyme neutrophil elastase (NE). This approach can confine activation to sites with high NE levels. Enzyme-labile peptides were synthesized, and their activation was investigated using purified NE. Susceptibilities of
Pseudomonas aeruginosa
to parent and prodrug peptides in the presence and absence of NE-rich CF human bronchoalveolar lavage (BAL) fluid and different NaCl concentrations were compared. The effect of the HDP promoiety on cytotoxicity was determined with cystic fibrosis bronchial epithelial (CFBE41o-) cells. NE in CF BAL fluids activated the HDP prodrugs, restoring bactericidal activity against reference and clinical isolates of
P. aeruginosa
. However, activation also required the addition of 300 mM NaCl. Under these conditions, the bactericidal activity levels of the HDP prodrugs differed, with pro-P18 demonstrating the greatest activity (90% to 100% of that of the parent, P18, at 6.25 μg/ml). Cytotoxic effects on CFBE41o- cells were reduced by the addition of the promoiety to HDPs. We demonstrate here for the first time the selective activation of novel HDP prodrugs by a host disease-associated enzyme at
in vivo
concentrations of the CF lung. This approach may lead to the development of novel therapeutic agents with low toxicity that are active under the challenging conditions of the CF lung.
Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To EvaluateIn VitroSusceptibility Test Interpretive Criteria for Ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae
Authors: Van Wart Scott A. , Ambrose Paul G. , Rubino Christopher M. , Khariton Tatiana , Riccobene Todd A. , Friedland H. David , Critchley Ian A. , Bhavnani Sujata M. 
Published: November 2013

ABSTRACTTo provide support forin vitrosusceptibility test interpretive criteria decisions for ceftaroline againstStaphylococcus aureusandStreptococcus pneumoniae, as well as dose adjustment recommendations for renal impairment, pharmacokinetic-pharmacodynamic (PK-PD) target attainment was evaluated for simulated patients administered intravenous (i.v.) ceftaroline fosamil at 600 mg twice daily (q12h) and simulated patients with renal impairment administered various dosing regimens. Using a previously developed population PK model, Monte Carlo simulation was used to generate ceftaroline plasma concentration profiles for simulated patients with normal renal function or mild, moderate, or severe renal impairment. Using these profiles, the percentage of time during the dosing interval that free-drug concentrations remained above the MIC (f%T>MIC) for ceftaroline at steady state was calculated. Percentages of simulated patients achievingf%T>MIC targets forS. aureusandS. pneumoniaebased on murine infection models were calculated by MIC. At MICs of 2 mg/liter forS. aureusand 1 mg/liter forS. pneumoniae, the percentages of simulated patients with normal renal function and mild renal impairment following administration of ceftaroline fosamil at 600 mg q12h, moderate renal impairment following administration of ceftaroline fosamil at 400 mg q12h, and severe renal impairment following administration of ceftaroline fosamil at 300 mg q12h achievingf%T>MIC targets (≥26 forS. aureusand ≥44 forS. pneumoniae) exceeded 90%. The results of these analyses, which suggested thatin vitrosusceptibility test interpretive criteria defining susceptible could be as high as MICs of ≤2 and ≤1 mg/liter for ceftaroline againstS. aureusandS. pneumoniae, respectively, provide support for current FDA and CLSI criteria, which define susceptible as MICs of 1 and 0.5 mg/liter, respectively. Recommendations for dose adjustments for patients with renal impairment were also supported by the results of these analyses.
Metronidazole and Hydroxymetronidazole Central Nervous System Distribution: 2. Cerebrospinal Fluid Concentration Measurements in Patients with External Ventricular Drain
Authors: Frasca Denis , Dahyot-Fizelier Claire , Adier Christophe , Mimoz Olivier , Debaene Bertrand , Couet William , Marchand Sandrine 
Published: November 2013

ABSTRACT

This study explored metronidazole and hydroxymetronidazole distribution in the cerebrospinal fluid (CSF) of brain-injured patients. Four brain-injured patients with external ventricular drain received 500 mg of metronidazole over 0.5 h every 8 h. CSF and blood samples were collected at steady state over 8 h, and the metronidazole and hydroxymetronidazole concentrations were assayed by high-pressure liquid chromatograph. A noncompartmental analysis was performed. Metronidazole is distributed extensively within CSF, with a mean CSF to unbound plasma AUC
0–τ
ratio of 86% ± 16%. However, the concentration profiles in CSF were mostly flat compared to the plasma profiles. Hydroxymetronidazole concentrations were much lower than those of metronidazole both in plasma and in CSF, with a corresponding CSF/unbound plasma AUC
0–τ
ratio of 79% ± 16%. We describe here for the first time in detail the pharmacokinetics of metronidazole and hydroxymetronidazole in CSF.
Function of the Loading Module in CorI and of the
O
-Methyltransferase CorH in Vinyl Carbamate Biosynthesis of the Antibiotic Corallopyronin A
Authors: Schäberle Till F. , Mir Mohseni Mahsa , Lohr Friederike , Schmitz Alexander , König Gabriele M. 
Published: November 2013

ABSTRACT

Corallopyronin A is a promising
in vivo
active antibiotic, currently undergoing preclinical evaluation. This myxobacterial compound interferes with a newly identified drug target site, i.e., the switch region of the bacterial DNA-dependent RNA-polymerase (RNAP). Since this target site differs from that of known RNAP inhibitors such as the rifamycins, corallopyronin A shows no cross-resistance with other antibacterial agents. Corallopyronin A is a polyketide synthase- and nonribosomal peptide synthetase-derived molecule whose structure and biosynthesis is distinguished by several peculiarities, such as the unusual vinyl carbamate functionality whose formation involves carbonic acid as an unprecedented C1-starter unit. Using
in vitro
experiments the nature of this starter molecule was revealed to be the methyl ester of carbonic acid. Biochemical investigations showed that methylation of carbonic acid is performed by the
O
-methyltransferase CorH. These experiments shed light on the biosynthesis of the Eastern chain of α-pyrone antibiotics such as corallopyronin A.
Nutritional Control of Antibiotic Resistance via an Interface between the Phosphotransferase System and a Two-Component Signaling System
Authors: Snyder Holly , Kellogg Stephanie L. , Skarda Laura M. , Little Jaime L. , Kristich Christopher J. 
Published: November 2013

ABSTRACT

Enterococci are ubiquitous inhabitants of the gastrointestinal (GI) tract. However, antibiotic-resistant enterococci are also major causes of hospital-acquired infections. Enterococci are intrinsically resistant to cephalosporins, enabling growth to abnormally high densities in the GI tract in patients during cephalosporin therapy, thereby promoting dissemination to other sites where they cause infection. Despite its importance, many questions about the underlying basis for cephalosporin resistance remain. A specific two-component signaling system, composed of the CroS sensor kinase and its cognate response regulator (CroR), is required for cephalosporin resistance in
Enterococcus faecalis
, but little is known about the factors that control this signaling system to modulate resistance. To explore the signaling network in which CroR participates to influence cephalosporin resistance, we employed a protein fragment complementation assay to detect protein-protein interactions in
E. faecalis
cells, revealing a previously unknown association of CroR with the HPr protein of the phosphotransferase system (PTS) responsible for carbohydrate uptake and catabolite control of gene expression. Genetic and physiological analyses indicate that association with HPr restricts the ability of CroR to promote cephalosporin resistance and gene expression in a nutrient-dependent manner. Mutational analysis suggests that the interface used by HPr to associate with CroR is distinct from the interface used to associate with other cellular partners. Our results define a physical and functional connection between a critical nutrient-responsive signaling system (the PTS) and a two-component signaling system that drives antibiotic resistance in
E. faecalis
, and they suggest a general strategy by which bacteria can integrate their nutritional status with diverse environmental stimuli.
In Vitro
Combination of Anti-Cytomegalovirus Compounds Acting through Different Targets: Role of the Slope Parameter and Insights into Mechanisms of Action
Authors: Cai Hongyi , Kapoor Arun , He Ran , Venkatadri Rajkumar , Forman Michael , Posner Gary H. , Arav-Boger Ravit 
Published: November 2013

ABSTRACT
Conventional therapy for human cytomegalovirus (CMV) relies on inhibition of the viral DNA polymerase. Ganciclovir (GCV) is the first-line therapy, but when GCV-resistant strains emerge, alternative therapies are extremely limited and are associated with significant toxicities. Combination of anti-CMV agents that act on different targets or stages of virus replication has not been well studied, mostly because of the limited number of anti-CMV agents. We report our investigation of combinations of agents that inhibit CMV by targeting the viral DNA polymerase, cellular kinases, or other cell/virus mechanisms yet to be discovered. The selected compounds differed by the slopes of their dose-response curve: compounds with a slope of 1 (GCV) representing one target or noncooperativity and compounds with high slopes indicating positive cooperativity. Analysis of anti-CMV drug combinations using the Bliss model (which accounts for the slope parameter) distinguished between combinations with synergistic, antagonistic, and additive activities. The combination of GCV and foscarnet was slightly synergistic; strong synergism was found when GCV was used with artemisinin-derived monomers or dimers or the MEK inhibitor U0126. The combination of GCV and cardiac glycosides (digoxin, digitoxin, and ouabain) was additive. The monomeric artemisinin artesunate was synergistic when combined with U0126 or the multikinase inhibitor sunitinib. However, the combination of artemisinin-derived dimers (molecular weights, 606 and 838) and U0126 or sunitinib was antagonistic. These results demonstrate that members of a specific drug class show similar patterns of combination with GCV and that the slope parameter plays an important role in the evaluation of drug combinations. Lastly, antagonism between different classes of CMV inhibitors may assist in target identification and improve the understanding of CMV inhibition by novel compounds.
Role of the
mecA
Gene in Oxacillin Resistance in a Staphylococcus aureus Clinical Strain with a
pvl
-Positive ST59 Genetic Background
Authors: Chen Feng-Jui , Wang Chen-Her , Chen Ching-Yi , Hsu Yu-Chieh , Wang Kaun-Ting 
Published: November 2013

ABSTRACT

The most prevalent community-associated methicillin-resistant
Staphylococcus aureus
(C-MRSA) strains in Taiwan, sequence type 59 (ST59) clones, carry staphylococcal cassette chromosome
mec
(SCC
mec
) type V and, to a lesser extent, type IV. These strains show wide variation in sensitivity to oxacillin, but the reasons for this variation are unknown. Here we compared the sequences of the
mecA
genes from clinical strains of different SCC
mec
types and found that they contain different
mecA
promoter mutations. Analysis of
mecA
promoter activity by reporter gene fusions showed that single base substitutions in the promoter have a strong influence on
mecA
transcription. The different
mecA
variants, including promoter sequences, were expressed in the methicillin-sensitive
Staphylococcus aureus
(MSSA) strain C195 (ST59 background). PBP 2a production among the parental strains and strains with promoter mutant
mecA
genes showed a close correlation with
mecA
transcription levels. Furthermore, the quantity of PBP 2a also closely correlated with the level of oxacillin resistance in the C195 background. Our data suggest that
mecA
promoter mutations play an important role in determining the level of oxacillin resistance. The
mecA
promoter mutation G-25A (25 bases upstream of the
mecA
translation start site) was found to be associated with a high oxacillin MIC (256 μg/ml), G-7T conferred a moderate oxacillin MIC (32 to 64 μg/ml), strains with C-33T showed a low oxacillin MIC (4 to 8 μg/ml), and A-38G reversed the effect of the C-33T mutation, restoring the oxacillin resistance level in the A-38G C-33T double mutant. These observations may explain why C-MRSA strains in Taiwan carrying SCC
mec
type IV or V have such enormous variations in oxacillin MICs.
Phosphate-Containing Polyethylene Glycol Polymers Prevent Lethal Sepsis by Multidrug-Resistant Pathogens
Authors: Zaborin Alexander , Defazio Jennifer R. , Kade Matthew , Kaiser Brooke L. Deatherage , Belogortseva Natalia , Camp David G. , Smith Richard D. , Adkins Joshua N. , Kim Sangman M. , Alverdy Alexandria , Goldfeld David , Firestone Millicent A. , Collier Joel H. , Jabri Bana , Tirrell Matthew , Zaborina Olga , Alverdy John C. 
Published: November 2013

ABSTRACT

Antibiotic resistance among highly pathogenic strains of bacteria and fungi is a growing concern in the face of the ability to sustain life during critical illness with advancing medical interventions. The longer patients remain critically ill, the more likely they are to become colonized by multidrug-resistant (MDR) pathogens. The human gastrointestinal tract is the primary site of colonization of many MDR pathogens and is a major source of life-threatening infections due to these microorganisms. Eradication measures to sterilize the gut are difficult if not impossible and carry the risk of further antibiotic resistance. Here, we present a strategy to contain rather than eliminate MDR pathogens by using an agent that interferes with the ability of colonizing pathogens to express virulence in response to host-derived and local environmental factors. The antivirulence agent is a phosphorylated triblock high-molecular-weight polymer (here termed Pi-PEG 15–20) that exploits the known properties of phosphate (P
i
) and polyethylene glycol 15-20 (PEG 15-20) to suppress microbial virulence and protect the integrity of the intestinal epithelium. The compound is nonmicrobiocidal and appears to be highly effective when tested both
in vitro
and
in vivo
. Structure functional analyses suggest that the hydrophobic bis-aromatic moiety at the polymer center is of particular importance to the biological function of Pi-PEG 15-20, beyond its phosphate content. Animal studies demonstrate that Pi-PEG prevents mortality in mice inoculated with multiple highly virulent pathogenic organisms from hospitalized patients in association with preservation of the core microbiome.
Novel Method To Identify the Optimal Antimicrobial Peptide in a Combination Matrix, Using Anoplin as an Example
Authors: Munk J. K. , Ritz C. , Fliedner F. P. , Frimodt-Møller N. , Hansen P. R. 
Published: November 2013

ABSTRACT

Microbial resistance is an increasing health concern and a true danger to human well-being. A worldwide search for new compounds is ongoing, and antimicrobial peptides are promising lead candidates for tomorrow's antibiotics. The decapeptide anoplin (GLLKRIKTLL-NH
2
) is an especially interesting candidate because of its small size as well as its antimicrobial and nonhemolytic properties. Optimization of the properties of an antimicrobial peptide such as anoplin requires multidimensional searching in a complex chemical space. Typically, such optimization is performed by labor-intensive and costly trial-and-error methods. In this study, we show the benefit of fractional factorial design for identification of the optimal antimicrobial peptide in a combination matrix. We synthesized and analyzed a training set of 12 anoplin analogs, representative of 64 analogs in total. Using MIC, hemolysis, and high-performance liquid chromatography retention time data, we constructed analysis-of-variance models that describe the relationship between these properties and the structural characteristics of the analogs. We show that the mathematical models derived from the training set data can be used to predict the properties of other analogs in the chemical space. Hence, this method provides an efficient means of identification of the optimal peptide in the searched chemical space.
A Toxoplasma Patatin-Like Protein Changes Localization and Alters the Cytokine Response during Toxoplasmic Encephalitis
Authors: Tobin Magle Crystal , Pittman Kelly J. , Moser Lindsey A. , Boldon Kyle M. , Knoll Laura J. 
Published: November 2013

ABSTRACTToxoplasma gondiiis an obligate intracellular parasite that forms a lifelong infection within the central nervous system of its host. TheT. gondiigenome encodes six members of the patatin-like phospholipase family; related proteins are associated with host-microbe interactions in bacteria.T. gondiipatatin-like protein 1 (TgPL1) was previously determined to be necessary for parasites to suppress nitric oxide and prevent degradation in activated macrophages. Here, we show that in the rapidly replicating tachyzoite stage, TgPL1 is localized within vesicles inside the parasite that are distinct from the dense granules; however, in the encysted bradyzoite stage, TgPL1 localizes to the parasitophorous vacuole (PV) and cyst wall. While we had not previously seen a defect of the TgPL1 deletion mutant (ΔTgPL1) during acute and early chronic infection, the localization change of TgPL1 in bradyzoites caused us to reevaluate the ΔTgPL1 mutant during late chronic infection and in a toxoplasmic encephalitis (TE) mouse model. Mice infected with ΔTgPL1 are more resistant to TE and have fewer inflammatory lesions than mice infected with the wild type and ΔTgPL1 genetically complemented withTgPL1. This increased resistance to TE could result from several contributing factors. First, we found that ΔTgPL1 bradyzoites did not convert back to tachyzoites readily in tissue culture. Second, a subset of cytokine levels were higher in ΔTgPL1-infected mice, including gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and monocyte chemotactic protein 1 (MCP-1). These studies suggest that TgPL1 plays a role in the maintenance of chronicT. gondiiinfection.