bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma and Tissue Pharmacokinetics of Cefazolin in Patients Undergoing Elective and Semielective Abdominal Aortic Aneurysm Open Repair Surgery
Authors: Douglas Alexandra , Udy Andrew A. , Wallis Steven C. , Jarrett Paul , Stuart Janine , Lassig-Smith Melissa , Deans Renae , Roberts Michael S. , Taraporewalla Kersi , Jenkins Jason , Medley Gregory , Lipman Jeffrey , Roberts Jason A. 
Published: August 2011

ABSTRACT

Surgical site infections are common, so effective antibiotic concentrations at the sites of infection, i.e., in the interstitial fluid (ISF), are required. The aim of this study was to evaluate contemporary perioperative prophylactic dosing of cefazolin by determining plasma and subcutaneous ISF concentrations in patients undergoing elective/semielective abdominal aortic aneurysm (AAA) open repair surgery. This was a prospective pharmacokinetic study in a tertiary referral hospital. Cefazolin (2 g) was administered as a 3-min slow bolus 30 min prior to incision in 12 enrolled patients undergoing elective/semielective AAA open repair surgery. Serial blood, urine, and ISF (via microdialysis) samples were collected and analyzed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Cardiac output was determined using pulse waveform contours with Vigileo. The recruited patients had a median (interquartile range) age of 70 (66 to 76) years and weight of 88 (81 to 95) kg. The median (interquartile range) terminal volume of distribution was 0.14 (0.11 to 0.15) liter/kg, total clearance was 0.05 (0.03 to 0.06) liter/h, and minimum observed unbound concentration was 5.7 (5.4 to 8.1) mg/liter. The penetration of unbound drug from plasma to ISF was 85% (78% to 106%). We found correlations present, albeit weak, between cefazolin clearance and cardiac output (
r
2
= 0.11) and urinary creatinine clearance (
r
2
= 0.12). In conclusion, we found that a single 2-g dose of cefazolin administered 30 min before incision provides plasma and ISF concentrations in excess of the likely MICs for susceptible pathogens in patients undergoing AAA open repair surgery.
The Iron-Responsive Fur/RyhB Regulatory Cascade Modulates the Shigella Outer Membrane Protease IcsP
Authors: Africa Lia A. A. , Murphy Erin R. , Egan Nicholas R. , Wigley Amanda F. , Wing Helen J. 
Published: August 2011

ABSTRACT

Actin-based motility is central to the pathogenicity of the intracellular bacterial pathogen
Shigella
. Two
Shigella
outer membrane proteins, IcsA and IcsP, are required for efficient actin-based motility in the host cell cytoplasm, and the genes encoding both proteins are carried on the large virulence plasmid. IcsA triggers actin polymerization on the surface of the bacterium, leading to the formation of an actin tail that allows both intra- and intercellular spread. IcsP, an outer membrane protease, modulates the amount and distribution of the IcsA protein on the bacterial surface through proteolytic cleavage of IcsA. Transcription of
icsP
is increased in the presence of VirB, a DNA-binding protein that positively regulates many genes carried on the large virulence plasmid. In
Shigella dysenteriae
, the small regulatory RNA RyhB, which is a member of the iron-responsive Fur regulon, suppresses several virulence-associated phenotypes by downregulating levels of
virB
in response to iron limitation. Here we show that the Fur/RyhB regulatory pathway downregulates IcsP levels in response to low iron concentrations in
Shigella flexneri
and that this occurs at the level of transcription through the RyhB-dependent regulation of VirB. These observations demonstrate that in
Shigella
species the Fur/RyhB regulatory pathway provides a mechanism to finely tune the expression of
icsP
in response to the low concentrations of free iron predicted to be encountered within colonic epithelial cells.
Tobacco Smoking Affects Bacterial Acquisition and Colonization in Oral Biofilms
Authors: Kumar Purnima S. , Matthews Chad R. , Joshi Vinayak , de Jager Marko , Aspiras Marcelo 
Published: August 2011

ABSTRACT

Recent evidence suggests that smoking affects the composition of the disease-associated subgingival biofilm, yet little is known about its effects during the formation of this biofilm. The present investigation was undertaken to examine the contributions of smoking to the composition and proinflammatory characteristics of the biofilm during
de novo
plaque formation. Marginal and subgingival plaque and gingival crevicular fluid samples were collected from 15 current smokers and from 15 individuals who had never smoked (nonsmokers) following 1, 2, 4, and 7 days of undisturbed plaque formation. 16S rRNA gene cloning and sequencing were used for bacterial identification, and multiplex bead-based flow cytometry was used to quantify the levels of 27 immune mediators. Smokers demonstrated a highly diverse, relatively unstable initial colonization of both marginal and subgingival biofilms, with lower niche saturation than that seen in nonsmokers. Periodontal pathogens belonging to the genera
Fusobacterium
,
Cardiobacterium
,
Synergistes
, and
Selenomonas
, as well as respiratory pathogens belonging to the genera
Haemophilus
and
Pseudomonas
, colonized the early biofilms of smokers and continued to persist over the observation period, suggesting that smoking favors early acquisition and colonization of pathogens in oral biofilms. Smokers also demonstrated an early proinflammatory response to this colonization, which persisted over 7 days. Further, a positive correlation between proinflammatory cytokine levels and commensal bacteria was observed in smokers but not in nonsmokers. Taken together, the data suggest that smoking influences both the composition of the nascent biofilm and the host response to this colonization.
Ehrlichia chaffeensis TRP120 Binds a G+C-Rich Motif in Host Cell DNA and Exhibits Eukaryotic Transcriptional Activator Function
Authors: Zhu Bing , Kuriakose Jeeba A. , Luo Tian , Ballesteros Efren , Gupta Sharu , Fofanov Yuriy , McBride Jere W. 
Published: August 2011

ABSTRACT

Ehrlichia chaffeensis
is an obligately intracellular bacterium that modulates host cell gene transcription in the mononuclear phagocyte, but the host gene targets and mechanisms involved in transcriptional modulation are not well-defined. In this study, we identified a novel tandem repeat DNA-binding domain in the
E. chaffeensis
120-kDa tandem repeat protein (TRP120) that directly binds host cell DNA. TRP120 was observed by immunofluorescent microscopy in the nucleus of
E. chaffeensis
-infected host cells and was detected in nuclear extracts by Western immunoblotting with TRP120-specific antibody. The TRP120 binding sites and associated host cell target genes were identified using high-throughput deep sequencing (Illumina) of immunoprecipitated DNA (chromatin immunoprecipitation and high-throughput DNA sequencing). Multiple em motif elicitation (MEME) analysis of the most highly enriched TRP120-bound sequences revealed a G+C-rich DNA motif, and recombinant TRP120 specifically bound synthetic oligonucleotides containing the motif. TRP120 target gene binding sites were mapped most frequently to intersecting regions (intron/exon; 49%) but were also identified in upstream regulatory regions (25%) and downstream locations (26%). Genes targeted by TRP120 were most frequently associated with transcriptional regulation, signal transduction, and apoptosis. TRP120 targeted inflammatory chemokine genes, CCL2, CCL20, and CXCL11, which were strongly upregulated during
E. chaffeensis
infection and were also upregulated by direct transfection with recombinant TRP120. This study reveals that TRP120 is a novel DNA-binding protein that is involved in a host gene transcriptional regulation strategy.
Republished review: Cataract and cognitive impairment: a review of the literature
Authors: Jefferis J M , Mosimann U P , Clarke M P 
Published: August 2011

ABSTRACT
Acquired cataract and cognitive impairment are both common age-related problems, and ophthalmologists are increasingly likely to encounter patients who have both. Patients with dementia types who display early visuoperceptual impairment may present first to ophthalmology services. When these patients have coexisting cataract, it may be difficult to distinguish visual complaints due to cataract from those due to dementia. The interaction between visual impairment due to cataract and neurodegenerative disorders affecting the central visual pathways, is not fully understood. Visual impairment due to cataract may stress impaired attentional mechanisms and cataract extraction may improve cognitive performance in some patients with early cognitive impairment; however, the benefits of cataract surgery in established dementia are less clear. In this study, the literature on this subject was reviewed and the implications for practice were considered.
OPEN CHARM ANALYSIS ON THE FIRST PP COLLISIONS AT $\sqrt{s} = 7~{\rm TeV}$ WITH ALICE
Authors:   For the ALICE collaboration, ORTONA GIACOMO 
Published: August 2011

A Large Ion Collider Experiment (ALICE) is one of the four large experiments at the Large Hadron Collider (LHC), and the one dedicated to ultra relativistic heavy ion collisions, aiming at investigating the properties of the high-density state of QCD matter produced in such events. ALICE started to collect data in proton-proton collisions at the LHC at CERN in November 2009 (with a centre of mass energy [Formula: see text]). Since March 2010 data are being recorded at an energy of [Formula: see text] while from November 7 to December 6 LHC provided Pb-Pb collisions at an energy of [Formula: see text] per nucleon-nucleon pair. In Pb-Pb collisions heavy quarks are regarded as sensitive probes of the interaction dynamics between the parton and medium produced in the collisions, and the energies available at LHC will allow to study the production of heavy flavours with high statistics. Proton-proton data will be used to measure the heavy flavours production cross section to compare with perturbative QCD calculations in an unexplored energy domain and they will provide the reference for the study of Pb-Pb collisions. After a description of the ALICE experiment focused on its heavy flavour related performance, the status of the first analysis on charm production, measured by reconstructing the decays of D0, D+, D*+, and Ds into hadronic and semi-leptonic channels will be presented. An outlook of the same measurements for the upcoming Pb-Pb run will also be discussed.
Glioblastoma Angiogenesis and Tumor Cell Invasiveness Are Differentially Regulated by β8 Integrin
Authors: Tchaicha Jeremy H. , Reyes Steve B. , Shin Jaekyung , Hossain Mohammad G. , Lang Frederick F. , McCarty Joseph H. 
Published: August 2011

Abstract
Glioblastoma multiforme (GBM) is a highly invasive brain tumor that develops florid microvascular proliferation and hemorrhage. However, mechanisms that favor invasion versus angiogenesis in this setting remain largely uncharacterized. Here, we show that integrin β8 is an essential regulator of both GBM-induced angiogenesis and tumor cell invasiveness. Highly angiogenic and poorly invasive tumors expressed low levels of β8 integrin, whereas highly invasive tumors with limited neovascularization expressed high levels of β8 integrin. Manipulating β8 integrin protein levels altered the angiogenic and invasive growth properties of GBMs, in part, reflected by a diminished activation of latent TGFβs, which are extracellular matrix protein ligands for β8 integrin. Taken together, these results establish a role for β8 integrin in differential control of angiogenesis versus tumor cell invasion in GBM. Our findings suggest that inhibiting β8 integrin or TGFβ signaling may diminish tumor cell invasiveness during malignant progression and following antivascular therapies. Cancer Res; 71(20); 6371–81. ©2011 AACR.
A Novel Kinase Inhibitor of FADD Phosphorylation Chemosensitizes through the Inhibition of NF-κB
Authors: Schinske Katrina A. , Nyati Shyam , Khan Amjad P. , Williams Terence M. , Johnson Timothy D. , Ross Brian D. , Pérez Tomás Ricardo , Rehemtulla Alnawaz 
Published: August 2011

Abstract
Fas-associated protein with death domain (FADD) is a cytosolic adapter protein essential for mediating death receptor–induced apoptosis. It has also been implicated in a number of nonapoptotic activities including embryogenesis, cell-cycle progression, cell proliferation, and tumorigenesis. Our recent studies have shown that high levels of phosphorylated FADD (p-FADD) in tumor cells correlate with increased activation of the antiapoptotic transcription factor NF-κB and is a biomarker for aggressive disease and poor clinical outcome. These findings suggest that inhibition of FADD phosphorylation is a viable target for cancer therapy. A high-throughput screen using a cell-based assay for monitoring FADD-kinase activity identified NSC 47147 as a small molecule inhibitor of FADD phosphorylation. The compound was evaluated in live cells and mouse tumors for its efficacy as an inhibitor of FADD-kinase activity through the inhibition of casein kinase 1α. NSC 47147 was shown to decrease levels of p-FADD and NF-κB activity such that combination therapy leads to greater induction of apoptosis and enhanced tumor control than either agent alone. The studies described here show the utility of bioluminescent cell–based assays for the identification of active compounds and the validation of drug–target interaction in a living subject. In addition, the presented results provide proof-of-principle studies as to the validity of targeting FADD-kinase activity as a novel cancer therapy strategy. Mol Cancer Ther; 10(10); 1807–17. ©2011 AACR.
Digitoxin-Induced Cytotoxicity in Cancer Cells Is Mediated through Distinct Kinase and Interferon Signaling Networks
Authors: Prassas Ioannis , Karagiannis George S. , Batruch Ihor , Dimitromanolakis Apostolos , Datti Alessandro , Diamandis Eleftherios P. 
Published: August 2011

Abstract
Cardiac glycosides (e.g., digoxin, digitoxin) constitute a diverse family of plant-derived sodium pump inhibitors that have been in clinical use for the treatment of heart-related diseases (congestive heart failure, atrial arrhythmia) for many years. Recently though, accumulating in vitro and in vivo evidence highlight potential anticancer properties of these compounds. Despite the fact that members of this family have advanced to clinical trial testing in cancer therapeutics, their cytotoxic mechanism is not yet elucidated. In this study, we investigated the cytotoxic properties of cardiac glycosides against a panel of pancreatic cancer cell lines, explored their apoptotic mechanism, and characterized the kinetics of cell death induced by these drugs. Furthermore, we deployed a high-throughput kinome screening approach and identified several kinases of the Na-K-ATPase-mediated signal transduction circuitry (epidermal growth factor receptor, Src, pkC, and mitogen-activated protein kinases) as important mediators downstream of cardiac glycoside cytotoxic action. To further extend our knowledge on their mode of action, we used mass-spectrometry–based quantitative proteomics (stable isotope labeling of amino acids in cell culture) coupled with bioinformatics to capture large-scale protein perturbations induced by a physiological dose of digitoxin in BxPC-3 pancreatic cancer cells and identified members of the interferon family as key regulators of the main protein/protein interactions downstream of digitoxin action. Hence, our findings provide more in-depth information regarding the molecular mechanisms underlying cardiac glycoside-induced cytotoxicity. Mol Cancer Ther; 10(11); 2083–93. ©2011 AACR.
Altered Desmosomal Proteins in Granulomatous Myocarditis and Potential Pathogenic Links to Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Asimaki Angeliki , Tandri Harikrishna , Duffy Elizabeth R. , Winterfield Jeffrey R. , Mackey-Bojack Shannon , Picken Maria M. , Cooper Leslie T. , Wilber David J. , Marcus Frank I. , Basso Cristina , Thiene Gaetano , Tsatsopoulou Adalena , Protonotarios Nikos , Stevenson William G. , McKenna William J. , Gautam Shiva , Remick Daniel G. , Calkins Hugh , Saffitz Jeffrey E. 
Published: August 2011

Background—
Immunoreactive signal for the desmosomal protein plakoglobin (γ-catenin) is reduced at cardiac intercalated disks in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), a highly arrhythmogenic condition caused by mutations in genes encoding desmosomal proteins. Previously, we observed a false-positive case in which plakoglobin signal was reduced in a patient initially believed to have ARVC but who actually had cardiac sarcoidosis. Sarcoidosis can masquerade clinically as ARVC but has not been previously associated with altered desmosomal proteins.

Methods and Results—

We observed marked reduction in immunoreactive signal for plakoglobin at cardiac myocyte junctions in patients with sarcoidosis and giant cell myocarditis, both highly arrhythmogenic forms of myocarditis associated with granulomatous inflammation. In contrast, plakoglobin signal was not depressed in lymphocytic (nongranulomatous) myocarditis. To determine whether cytokines might promote dislocation of plakoglobin from desmosomes, we incubated cultures of neonatal rat ventricular myocytes with selected inflammatory mediators. Brief exposure to low concentrations of interleukin (IL)-17, tumor necrosis factor-α (TNF-α), and IL-6 (cytokines implicated in granulomatous myocarditis) caused translocation of plakoglobin from cell-cell junctions to intracellular sites, whereas other potent cytokines implicated in nongranulomatous myocarditis had no effect, even at much higher concentrations. We also observed myocardial expression of IL-17 and TNF-α and elevated levels of serum inflammatory mediators, including IL-6R, IL-8, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1β, in patients with ARVC (all
P
<0.0001 compared with controls).

Conclusions—
The results suggest novel disease mechanisms involving desmosomal proteins in granulomatous myocarditis and implicate cytokines, perhaps derived in part from the myocardium, in disruption of desmosomal proteins and arrhythmogenesis in ARVC.
Marine n-3 Polyunsaturated Fatty Acids in Adipose Tissue and the Risk of Acute Coronary Syndrome
Authors: Joensen Albert Marni , Overvad Kim , Dethlefsen Claus , Johnsen Søren Paaske , Tjønneland Anne , Rasmussen Lars Hvilsted , Schmidt Erik Berg 
Published: August 2011

Background—
Marine n-3 polyunsaturated fatty acids may reduce coronary mortality. Previous data in relation to nonfatal coronary disease, however, have been inconsistent, which may be explained by the use of heterogeneous methods to assess the intake of marine n-3 polyunsaturated fatty acids. We investigated the hypothesis that the content of total and individual marine n-3 polyunsaturated fatty acids in adipose tissue is negatively associated with the incidence of acute coronary syndrome (ACS), including both fatal and nonfatal coronary disease.

Methods and Results—
In the Diet, Cancer and Health, a Danish cohort study, 57 053 subjects were enrolled and had an adipose tissue biopsy taken at inclusion. During a mean follow-up period of 7.6 years, we identified and verified all cases (n=1012) with an incident acute coronary syndrome diagnosis, and a random sample of the cohort (n=1630) had their fatty acid composition in adipose tissue determined by gas chromatography. We found negative dose-response associations between the content of total marine n-3 polyunsaturated fatty acids and individual n-3 polyunsaturated fatty acids in adipose tissue and the risk of acute coronary syndrome. Comparing men in the highest and lowest quintiles gave a hazard ratio of 0.65 (95% confidence interval, 0.45 to 0.95) for total n-3 polyunsaturated fatty acids and 0.51 (95% confidence interval, 0.36 to 0.73) for docosahexaenoic acid. Nonfatal cases constituted >86% of cases, and the association was driven primarily by a reduction in the risk of nonfatal acute coronary syndrome. No consistent associations were found among women.

Conclusion—
Intake of marine n-3 polyunsaturated fatty acids may protect against acute coronary syndrome in men.
Association of Incident Cardiovascular Disease With Periodic Limb Movements During Sleep in Older Men
Authors: Koo Brian B. , Blackwell Terri , Ancoli-Israel Sonia , Stone Katie L. , Stefanick Marcia L. , Redline Susan ,   for the Osteoporotic Fractures in Men (MrOS) Study Group
Published: August 2011

Background—
Periodic limb movements during sleep (PLMS) cause repetitive sympathetic activation and may be associated with increased cardiovascular risk. We hypothesized that PLMS frequency (periodic limb movement index [PLMI]) and PLMS arousal frequency (periodic limb movement arousal index [PLMAI]) are predictive of incident cardiovascular disease, including coronary heart disease, peripheral arterial disease, and cerebrovascular disease, in an elderly male cohort.

Methods and Results—

A total of 2911 men in the observational Outcomes of Sleep Disorders in Older Men (MrOS) Sleep Study cohort underwent in-home polysomnography with PLMS measurement and were followed up for 4 years for the outcomes coronary heart disease, cerebrovascular disease, peripheral arterial disease, and all-cause cardiovascular disease, which included coronary heart disease, cerebrovascular disease, and peripheral arterial disease. Cox proportional hazards regression assessed the association between PLMI, PLMAI, and these outcomes. Models were minimally adjusted for age, clinic, and body mass index and then fully adjusted for conventional cardiovascular risk factors. During follow-up, 500 men experienced all-cause cardiovascular disease: 345 coronary heart disease, 117 cerebrovascular disease, and 98 peripheral arterial disease events. In fully adjusted models, men with PLMAI ≥5 compared with the referent PLMA <1 group had a 1.26-fold increased relative hazard for all-cause cardiovascular disease. Similar findings were observed for PLMI and all-cause cardiovascular disease. For peripheral arterial disease, men with PLMI ≥30 compared with the referent PLMI <5 group had a 2-fold increased relative hazard (95% confidence interval, 1.14 to 3.49;
P
=0.025). Compared with the referent group, men with PLMI ≥30 had an increased risk of coronary heart disease (relative hazard, 1.31; 95% confidence interval, 1.01 to 1.70;
P
=0.045) after minimal adjustment, but this association was attenuated after further adjustments. After stratification, risk of incident all-cause cardiovascular disease among high-PLMI and high-PLMAI groups was significantly elevated only for men without prevalent hypertension (
P
for interactions <0.10).

Conclusion—
These findings provide evidence that PLMS frequency is associated with incident cardiovascular disease in community-dwelling elderly men.