bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ceftaroline plus Avibactam Demonstrates Bactericidal Activity against Pathogenic Anaerobic Bacteria in a One-Compartment
In Vitro
Pharmacokinetic/Pharmacodynamic Model
Authors: Werth Brian J. , Rybak Michael J. 
Published: November 2013

ABSTRACT

Anaerobic pathogens are often associated with polymicrobial infections, such as diabetic foot infections. Patients with these infections are often treated with broad-spectrum, multidrug therapies targeting resistant Gram-positive bacteria, such as methicillin-resistant
Staphylococcus aureus
, as well as Gram-negative bacteria and anaerobes. The broad-spectrum, non-beta-lactam, beta-lactamase inhibitor avibactam has been combined with ceftaroline and may provide a single-product alternative for complicated polymicrobial infections. We compared the activity of ceftaroline-avibactam (CPA) to that of ertapenem (ERT) against common anaerobic pathogens in an
in vitro
pharmacokinetic/pharmacodynamic (PK/PD) model. Simulations of doses of ceftaroline-fosamil at 600 mg every 8 h (q8h) (maximum free drug concentration [
fC
max
], 17.04 mg/liter, and half-life [
t
1/2
], 2.66 h) plus avibactam at 600 mg q8h (
fC
max
, 11.72 mg/liter, and
t
1/2
, 1.8 h) and of ertapenem at 1 g q24h (
f
C
max
, 13 mg/liter, and
t
1/2
, 4 h) were evaluated against two strains of
Bacteroides fragilis
, one strain of
Prevotella bivia
, and one strain of
Finegoldia magna
in an anaerobic one-compartment
in vitro
PK/PD model over 72 h with a starting inoculum of ∼8 log
10
CFU/ml. Bactericidal activity was defined as a reduction of ≥3 log
10
CFU/ml from the starting inoculum. Both CPA and ERT were bactericidal against all four strains. CPA demonstrated improved activity against
Bacteroides
strains compared to that of ERT but had similar activity against
Finegoldia magna
and
P. bivia
, although modest regrowth was observed with CPA against
P. bivia
. No resistance emerged from any of the models. The pharmacokinetics achieved were 92 to 105% of the targets. CPA has potent
in vitro
activity against common anaerobic pathogens at clinically relevant drug exposures and may be a suitable single product for the management of complicated polymicrobial infections.
Population Pharmacokinetic Modeling of the Unbound Levofloxacin Concentrations in Rat Plasma and Prostate Tissue Measured by Microdialysis
Authors: Hurtado Felipe K. , Weber Benjamin , Derendorf Hartmut , Hochhaus Guenther , Dalla Costa Teresa 
Published: November 2013

ABSTRACT

Levofloxacin is a broad-spectrum fluoroquinolone used in the treatment of both acute and chronic bacterial prostatitis. Currently, the treatment of bacterial prostatitis is still difficult, especially due to the poor distribution of many antimicrobials into the prostate, thus preventing the drug to reach effective interstitial concentrations at the infection site. Newer fluoroquinolones show a greater penetration into the prostate. In the present study, we compared the unbound levofloxacin prostate concentrations measured by microdialysis to those in plasma after a 7-mg/kg intravenous bolus dose to Wistar rats. Plasma and dialysate samples were analyzed using a validated high-pressure liquid chromatography-fluorescence method. Both noncompartmental analysis (NCA) and population-based compartmental modeling (NONMEM 6) were performed. Unbound prostate tissue concentrations represented 78% of unbound plasma levels over a period of 12 h by comparing the extent of exposure (unbound AUC
0–∞
) of 6.4 and 4.8 h·μg/ml in plasma and tissue, respectively. A three-compartment model with simultaneous passive diffusion and saturable distribution kinetics from the prostate to the central compartment gave the best results in terms of curve fitting, precision of parameter estimates, and model stability. The following parameter values were estimated by the population model:
V
1
(0.38 liter; where
V
1
represents the volume of the central compartment), CL (0.22 liter/h),
k
12
(2.27 h
−1
),
k
21
(1.44 h
−1
),
k
13
(0.69 h
−1
),
V
max
(7.19 μg/h),
k
M
(0.35 μg/ml),
V
3
/fu
prostate
(0.05 liter; where fu
prostate
represents the fraction unbound in the prostate), and
k
31
(3.67 h
−1
). The interindividual variability values for
V
1
, CL,
V
max
, and
k
M
were 21, 37, 42, and 76%, respectively. Our results suggest that levofloxacin is likely to be substrate for efflux transporters in the prostate.
Association of HER1 amplification with poor prognosis in well differentiated gastric carcinomas
Authors: Kandel Christine , Leclair François , Bou-Hanna Chantal , Laboisse Christian L , Mosnier Jean-François 
Published: November 2013

AimsThe pattern of E-cadherin expression and the HER1/HER2 status were studied in European patients with gastric carcinomas in relation with their differentiation and prognosis.Methods82 gastric carcinomas (five papillary, 52 tubular, 19 poorly cohesive and six mixed according to WHO classification) were investigated for E-cadherin distribution (normal: restricted to the membrane; abnormal: absent or cytoplasmic expression), HER1 and HER2 expression using HercepTest and amplification using fluorescent in situ hybridisation. Statistical analysis assessed the association between the markers and their correlation with clinicopathological parameters and follow-up information.ResultsAbnormal E-cadherin distribution was found in 34 of the 82 gastric carcinomas (41%) (18/25 poorly cohesive or mixed (72%); 16/57 papillary or tubular type (28%)). HER1 overexpression (3+) and equivocal expression (2+) were found in five carcinomas (6%; four tubular and one poorly cohesive) and eight carcinomas (10%; six tubular and two poorly cohesive), respectively. HER2 overexpression (3+) and equivocal expression (2+) were found in seven carcinomas (8%; five papillary and two tubular) and three carcinomas (4%; three tubular), respectively. Amplification ofHER1orHER2was detected in 14 gastric carcinomas (five papillary and nine tubular). All of them showed a normal E-cadherin distribution. In the univariate analysis, onlyHER1amplification had a prognostic impact, whileHER2amplification and E-cadherin expression/distribution were not per se prognostically relevant.ConclusionsE-cadherin immunostaining andHER1in situ hybridisation define a group of well differentiated gastric carcinomas with poor prognosis eligible for an aggressive therapeutic approach.
Epstein–Barr virus is rarely associated with diffuse large B cell lymphoma in Taiwan and carries a trend for a shorter median survival time
Authors: Chang Sheng-Tsung , Lu Yi-Hsuan , Lu Chin-Li , Weng Shih-Feng , Lin Shu-Hui , Kuo Szu-Yin , Chuang Yu-Ting , Takeuchi Kengo , Ohshima Koichi , Chuang Shih-Sung 
Published: November 2013

AimsEpstein–Barr virus (EBV)-positive diffuse large B cell lymphoma (DLBCL) of the elderly is characterised by frequent extranodal involvement, a morphological spectrum from polymorphous to monomorphous and a poor prognosis. The frequency is higher in Japan and Korea but lower in the West, while the status in Taiwan has not been reported yet.MethodsWe conducted a retrospective study of DLBCL in a single institute in Taiwan by immunohistochemistry and in situ hybridisation for EBV.ResultsOf the 424 consecutive DLBCL cases, 332 cases were studied for EBV. 15 (4.5%) were EBV-positive and 13 (3.9%) fulfil WHO criteria of EBV-positive DLBCL of the elderly with a median age of 75. Of these 15 cases, extranodal presentation occurred in 11 (73%) patients with predominance in the gastrointestinal tract and 6 (40%) were of germinal centre B cell phenotype. There was no difference between EBV-positive and -negative patients in terms of age, gender, nodal versus extranodal presentation, and immunophenotypical profile. EBV-positive patients showed a trend for a shorter median survival time (5.0 vs 39.3 months; p=0.058). Of all DLBCL patients, multivariable analysis revealed a significantly worse overall survival for patients older than 50 (p=0.001) and for those with bcl-6-negative tumours (p=0.003) but not with other clinicopathological factors including EBV status.ConclusionsEBV-positive DLBCL of the elderly is relatively rare in Taiwan, with an incidence intermediate between Japan/Korea and the West. Further studies are warranted to clarify the association of EBV and the clinicopathological features and the prognostic significance in patients with DLBCL.
Fascin and cyclin D1 immunoreactivity in non-neoplastic vulvar squamous epithelium, vulvar intraepithelial neoplasia and invasive squamous carcinoma: correlation with Ki67 and p16 protein expression
Authors: Stewart C J R , Crook M L 
Published: November 2013

AimsTo investigate cyclin D1 and fascin immunoreactivity in normal, reactive and neoplastic vulvar skin correlating the findings with p16 protein and Ki67 expression.Methods66 vulvar biopsy or resection specimens demonstrating normal appearances, reactive epidermal changes, usual-type vulvar intraepithelial neoplasia (uVIN), differentiated-type VIN (dVIN), p16-positive squamous cell carcinoma (SCC) and p16-negative SCC were examined immunohistochemically for cyclin D1, fascin, Ki67 and p16 protein. Where applicable, expression patterns were compared in microanatomically distinct areas, particularly at the invasive front (deep tumour margin) of SCC.ResultsNormal epidermis showed parabasal Ki67 and cyclin D1 staining while fascin labelled cells in the lower one-third of the epithelium. Reactive and dVIN specimens demonstrated mildly increased Ki67 and cyclin D1 expression that maintained parabasal polarity, whereas uVIN and p16-positive SCC were characterised by loss of cyclin D1 staining. However, in 14 of 20 p16-positive SCC small infiltrative tumour groups and single infiltrating cells at the invasive front showed a cyclin D1-positive/ Ki67-negative phenotype. In contrast, p16-negative SCC generally showed diffuse and concordant cyclin D1 and Ki67 labelling, including at the invasive margin. Fascin expression was increased in all VIN and SCC lesions.ConclusionsVariations in cyclin D1 and Ki67 expression between p16-positive and p16-negative vulvar SCCs suggest different mechanisms of invasion in these tumour subgroups. Fascin is upregulated in vulvar squamous neoplasia but immunostaining does not discriminate in situ from invasive lesions nor putative human papilloma virus (HPV)-associated and HPV-independent SCCs.
Predictors of help-seeking behaviour among women exposed to violence in Nigeria: a multilevel analysis to evaluate the impact of contextual and individual factors
Authors: Linos Natalia , Slopen Natalie , Berkman Lisa , Subramanian S V , Kawachi Ichiro 
Published: November 2013

ObjectivesTo simultaneously examine contextual and individual-level predictors of help-seeking behaviour among women exposed to physical and sexual violence in Nigeria.DesignA multi-level cross-sectional study. We fit three 3-level random intercepts models to examine contextual and individual-level characteristics associated with help seeking, simultaneously.SettingNigerian Demographic and Health Survey for 2008.Participants5553 women (15–49 years) who reported physical or sexual violence, drawn from 23 715 women in the Nigerian Demographic and Health Survey that responded to questions on violence exposure.Main outcome measuresHelp seeking to prevent future victimisation was based on self-report.ResultsIn our sample of women exposed to physical and sexual violence, 39.7% reported that they sought help to stop the perpetrator from hurting them again. Rates of help seeking were geographically patterned by state (range: 12% to 65%). State-level development, measured by the Human Development Index (z-score), was positively associated with help seeking (OR=1.30, 95% CI 1.05 to 1.61), after adjusting for individual-level characteristics. State-level prevalence of violence against women (z-score) was negatively associated with help-seeking (OR=0.68, 95% CI 0.55 to 0.84), suggesting that service providers who may target their programmes to areas with high prevalence of violence, may need to simultaneously address barriers to help seeking. Few individual-level characteristics were associated with help seeking, including wealth, marital status, employment status, ethnicity, history of witnessing domestic violence and relationship to perpetrator.ConclusionsEfforts to support female survivors of violence should consider broader social and contextual determinants that are associated with help-seeking behaviours.
Prenatal exposure to alcohol, and gender differences on child mental health at age seven years
Authors: Niclasen J , Nybo Andersen A M , Teasdale T W , Strandberg-Larsen K 
Published: November 2013

BackgroundIt remains uncertain whether exposure to lower doses of alcohol is damaging to the developing fetus. The present study aimed to investigate associations for boys and girls between prenatal exposure to binge drinking and lower doses of alcohol in pregnancy, and parent-reported behavioural and emotional development at age seven.MethodsThis study used data from the Danish National Birth Cohort. Associations between cumulated alcohol exposure and binge drinking from full pregnancy and parent scores on the Strengths and Difficulties Questionnaire (SDQ) measured at age seven were investigated. The SDQ was used as continuous externalising/internalising scores, and as above/below cut-off for the specific scales of hyperactivity/inattention, conduct, emotional and peer problems. Inclusion criteria were information on alcohol exposure from three interviews, SDQ scores at age seven and being born full term (n=37 152).ResultsControlling for relevant confounders, small positive associations were observed between binge drinking and internalising (relative change in mean: 1.04–1.06), externalising scores (relative change in mean: 1.01–1.07), and conduct scores (OR 1.12 to 1.23) for boys. No associations were observed with lower doses of alcohol.ConclusionsExposure to binge drinking is weakly associated with impaired behavioural and emotional development measured at age seven. Large differences in background characteristics were observed between the groups defined by cumulated alcohol exposure, leaving the interpretations of findings uncertain.
The Activation of the WNT Signaling Pathway Is a Hallmark in Neurofibromatosis Type 1 Tumorigenesis
Authors: Luscan Armelle , Shackleford Ghjuvan'Ghjacumu , Masliah-Planchon Julien , Laurendeau Ingrid , Ortonne Nicolas , Varin Jennifer , Lallemand François , Leroy Karen , Dumaine Valérie , Hivelin Mikael , Borderie Didier , De Raedt Thomas , Valeyrie-Allanore Laurence , Larousserie Frédérique , Terris Benoît , Lantieri Laurent , Vidaud Michel , Vidaud Dominique , Wolkenstein Pierre , Parfait Béatrice , Bièche Ivan , Massaad Charbel , Pasmant Eric 
Published: November 2013

Abstract
Purpose: The hallmark of neurofibromatosis type 1 (NF1) is the onset of dermal or plexiform neurofibromas, mainly composed of Schwann cells. Plexiform neurofibromas can transform into malignant peripheral nerve sheath tumors (MPNST) that are resistant to therapies.
Experimental Design: The aim of this study was to identify an additional pathway in the NF1 tumorigenesis. We focused our work on Wnt signaling that is highly implicated in cancer, mainly in regulating the proliferation of cancer stem cells. We quantified mRNAs of 89 Wnt pathway genes in 57 NF1-associated tumors including dermal and plexiform neurofibromas and MPNSTs. Expression of two major stem cell marker genes and five major epithelial–mesenchymal transition marker genes was also assessed. The expression of significantly deregulated Wnt genes was then studied in normal human Schwann cells, fibroblasts, endothelial cells, and mast cells and in seven MPNST cell lines.
Results: The expression of nine Wnt genes was significantly deregulated in plexiform neurofibromas in comparison with dermal neurofibromas. Twenty Wnt genes showed altered expression in MPNST biopsies and cell lines. Immunohistochemical studies confirmed the Wnt pathway activation in NF1-associated MPNSTs. We then confirmed that the knockdown of NF1 in Schwann cells but not in epithelial cells provoked the activation of Wnt pathway by functional transfection assays. Furthermore, we showed that the protein expression of active β-catenin was increased in NF1-silenced cell lines. Wnt pathway activation was strongly associated to both cancer stem cell reservoir and Schwann–mesenchymal transition.
Conclusion: We highlighted the implication of Wnt pathway in NF1-associated tumorigenesis. Clin Cancer Res; 20(2); 358–71. ©2013 AACR.
Prognostic Relevance of Circulating Tumor Cells in Blood and Disseminated Tumor Cells in Bone Marrow of Patients with Squamous Cell Carcinoma of the Oral Cavity
Authors: Gröbe Alexander , Blessmann Marco , Hanken Henning , Friedrich Reinhard E. , Schön Gerhard , Wikner Johannes , Effenberger Katharina E. , Kluwe Lan , Heiland Max , Pantel Klaus , Riethdorf Sabine 
Published: November 2013

AbstractPurpose: Current staging methods for squamous cell carcinomas (SCC) of the oral cavity (OSCC) need to be improved to predict the risk of individual patients. Because hematogenous tumor cell dissemination is a key event in tumor progression, we assessed the prognostic significance of disseminated tumor cells (DTC) in bone marrow and circulating tumor cells (CTC) in peripheral blood from patients with OSCC.Experimental Design: From 110 patients with OSCC, tumors were surgically resected (R0) without neoadjuvant therapy. The CellSearch system was used to enumerate CTCs. Bone marrow was aspirated from the iliac crest, and mononuclear cells (MNC) were enriched by Ficoll density gradient centrifugation. To detect DTCs, MNCs were immunostained with the pan-keratin antibody A45-B/B3. Results were correlated with clinicopathologic parameters and clinical outcome such as recurrence and death during follow-up time (mean 916 days).Results: Ten of 80 patients (12.5%) harbored CTCs in peripheral blood, whereas in 18 of 90 patients (20.0%) DTCs in bone marrow could be detected. Surprisingly, in only 2 patients (1.8%) CTCs and DTCs were detected simultaneously. Significant correlations could be found for CTCs and tumor size (P = 0.04), nodal status and DTCs (P = 0.02), and distant metastasis with CTCs (P = 0.004) and DTCs (P = 0.005). Univariate and multivariate analyses revealed that CTCs and DTCs were significant and independent predictors of recurrence-free survival (P &lt; 0.001).Conclusions: Both DTCs and CTCs are independent prognostic markers in patients with OSCC, predicting relapse with higher sensitivity at various disease stages than routine staging procedures. Bone marrow might be an interesting target organ for future therapeutic interventions. Clin Cancer Res; 20(2); 425–33. ©2013 AACR.
Echo-Guided Mitral Repair
Authors: Drake Daniel H. , Zimmerman Karen G. , Hepner Anne M. , Nichols Cynthia D. 
Published: November 2013

Background—
Echocardiography is available in the most basic healthcare environments. Mitral repair is potentially curative and, when possible, recommended over replacement. The efficacy of echo-guided repair has not been established.

Methods and Results—

We developed a succinct set of precisely defined images observed to be highly concordant with intraoperative findings. These images guided intervention on 237 consecutive patients. None were lost to follow-up, and serial echocardiography was obtained on all repairs. This analysis includes 2037 echocardiograms. The intent to repair or replace was documented preoperatively in 98.7%. Concordance was associated with successful repair (97.8% versus 57.1%;
P
=0.001). Three-dimensional concordance was higher than 2-dimensional (100% versus 94.4%;
P
=0.05). Echocardiography guided a graduated surgical approach for degenerative and myopathic repairs by quantifying segmental prolapse, anterior leaflet closing angles, and tenting for integration of secondary chord lysis (
P
<0.001) and commissural width (
P
<0.01). Repair rates increased from 46.5% to 77.6% (
P
<0.001). Concomitant Society of Thoracic Surgeons rates were 46.6% (versus unguided 46.5%;
P
=0.99) and 54.9% (versus echo guided 77.6%;
P
<0.001). Repair was successful in 91.5% of isolated echo-guided mitral operations (versus concomitant Society of Thoracic Surgeons 70.0%;
P
<0.001). Echo-guided repair rates for degenerative, myopathic, and inflammatory diseases were 99.0%, 97.1%, and 84.2% with linearized annual recurrent regurgitation of 0.63%, 2.19%, and 4.37%, respectively.

Conclusions—
Echocardiography can reliably identify repairable mitral disease and guide intervention. Echo-guided repair is associated with a higher rate of initial success than unguided historical and concomitant national controls. Three-dimensional echo improves concordance. Secondary chord lysis is associated with durable repair and may prevent ventricular remodeling.
Cluster Analysis: A New Approach Applied to Lidar Measurements for Atmospheric Boundary Layer Height Estimation
Authors: Toledo Daniel , Córdoba-Jabonero Carmen , Gil-Ojeda Manuel 
Published: November 2013

AbstractSeveral procedures are widely applied to estimate the atmospheric boundary layer (ABL) top height by using aerosols as tracers from lidar measurements. These methods represent different mathematical approaches, relying on either the abrupt step of the aerosol concentration between the ABL and the free troposphere (FT) or the statistical analysis of vertical variations of the aerosol concentration. An alternative method—the cluster analysis (CA)—has been applied to lidar measurements for the first time, emerging as a useful and robust approach for calculating the ABL height, taking the advantage of both previous variables: the vertical aerosol distribution as obtained from the lidar range-corrected signal (RCS) and the statistical analysis of the RCS profiles in terms of its variance to determine a region of high aerosol loading variability. CA limitations under real situations are also tested, and the effects in ABL height determination of both noise and cloud contamination in RCS are examined. In particular, CA results are weakly sensitive to the signal noise due to the basic features of this statistical method. In addition, differences in the ABL top height, as estimated under cloudy and clear skies, have been found to be lower than 1.8% for a high RCS signal, while no effect is observed for low RCS cloud conditions. Moreover, the CA performance on the ABL top height determination for real cases is also presented, showing the reliable CA skills in reproducing the ABL evolution.