bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liberale Romandie, radikale Deutschschweiz? Kantonale Demokratien zwischen Repräsentation und Partizipation
Authors: Bühlmann Marc , Vatter Adrian , Dlabac Oliver , Schaub Hans‐Peter 
Published: June 2013

AbstractDer vorliegende Beitrag untersucht die weit verbreitete These, dass Deutschschweizer Kantone vor allem radikaldemokratische Merkmale aufweisen, während die lateinischen Kantone stärker liberal‐repräsentative Demokratieformen besitzen. Die empirische und mehrdimensionale Messung der Demokratiequalität in den Kantonen zeigt, dass die pauschale These der direktdemokratisch‐partizipatorischen Deutschschweizer Kantone auf der einen Seite und der repräsentativdemokratischen Stände der lateinischen Schweiz auf der anderen Seite der Komplexität der kantonalen Demokratien nicht gerecht wird. Als erklärungskräftige Alternative für die Positionen der Kantone auf den Achsen liberaler und radikaler Demokratien an der Schwelle des 21. Jahrhunderts erweist sich vielmehr die Stärke der liberalen und demokratischen Verfassungsbewegungen in den Kantonen Mitte des 19. Jahrhunderts.
Assessment of immunoglobulin concentrates on thrombogenic activity by thrombin generation assay, prekallikrein activator assay, and size‐exclusion chromatography
Authors: Seifner Alexandra , Beck Gerhard , Bayer Patrick , Eichmeir Stephanie , Lackner Friedrich , Rögelsperger Olga , Weber Katharina , Wollein Gabriele 
Published: June 2013

BackgroundImmunoglobulin G (IgG) concentrates have recently been found to be contaminated with procoagulant impurities causing thromboembolic events (TEEs) in vivo. In this study the question was raised whether a thrombin generation assay (TGA) will be able to characterize IgG samples from the Austrian market with regard to their thrombogenic potential.Study Design and MethodsA total of 44 IgG concentrates have been assayed by TGA employing pooled normal plasma and Factor (F)XI‐deficient plasma (FXIdp). Furthermore, the prekallikrein activator assay including determination of blank values, size‐exclusion chromatography, and further test systems required for batch release testing of IgG concentrates according to the European Pharmacopeia (Pharm. Eur.) were carried out.ResultsAll samples complied with acceptance criteria stated in the Plarm. Eur. and/or prescribed by the marketing approval. One intravenous immunoglobulin (IVIG) involved in TEEs exceeded a threshold level of 350 nmol peak thrombin, which was not exceeded after change of manufacture and by all the other IVIGs tested. Two hyperimmune globulins revealed elevated peak thrombin levels of up to 810 nmol in FXI and up to 285 nmol in FXIdp.ConclusionThe study indicates that the TGA is able to reliably predict procoagulant activities probably associated with the presence of FXIa and potential thrombogenicity. Comparison of thrombin generation with product‐specific acceptance criteria as well as variables from other test systems as amidolytic activity and molecular size can help to monitor IgG quality and manufacturing changes with regard to thrombogenicity.
A multicenter, randomized, active‐controlled study to investigate the efficacy and safety of intravenous ferric carboxymaltose in patients with iron deficiency anemia
Authors: Onken Jane E. , Bregman David B. , Harrington Robert A. , Morris David , Acs Peter , Akright Bruce , Barish Charles , Bhaskar Birbal S. , Smith‐Nguyen Gioi N. , Butcher Angelia , Koch Todd A. , Goodnough Lawrence T. 
Published: June 2013

BackgroundMany patients receiving oral iron for iron deficiency anemia (IDA) cannot tolerate or fail to respond to therapy, and existing intravenous (IV) iron formulations often require repeated administrations. Ferric carboxymaltose (FCM), a nondextran IV formulation, permits larger single doses.Study Design and MethodsWe evaluated FCM versus oral iron in IDA patients. After 14 days of oral iron, 507 participants responding inadequately to oral iron (hemoglobin [Hb] increase <1 g/dL; Cohort 1) were assigned to Group A (two doses of FCM, 750 mg, 1 week apart) or Group B (oral iron, 325 mg, 3 × day for 14 additional days). Also, 504 subjects not appropriate for oral iron (Cohort 2) were assigned to Group C (FCM as above) or Group D (standard‐of‐care IV iron). The primary efficacy endpoint was change to highest observed Hb from baseline to Day 35. The composite safety endpoint included all‐cause mortality, nonfatal myocardial infarction, nonfatal stroke, unstable angina, heart failure, arrhythmias, and hyper‐ or hypotensive events.ResultsMean (± standard deviation [SD]) Hb increase was significantly greater in Group A–FCM than Group B–oral iron: 1.57 (±1.19) g/dL versus 0.80 (±0.80) g/dL (p = 0.001). Post hoc comparison of Group C–FCM and Group D–IV standard of care also demonstrated significant mean (±SD) increase in Hb from baseline to highest value by Day 35 in Group C versus Group D: 2.90 (±1.64) g/dL versus 2.16 (±1.25) g/dL (p = 0.001). Safety endpoints occurred in 17 of 499 (3.4%) participants receiving FCM versus 16 of 498 (3.2%) in comparator groups.ConclusionTwo 750‐mg FCM infusions are safe and superior to oral iron in increasing Hb levels in IDA patients with inadequate oral iron response.
Physical activity is associated with retained muscle metabolism in human myotubes challenged with palmitate
Authors: Green C. J. , Bunprajun T. , Pedersen B. K. , Scheele C. 
Published: June 2013

Key points
It is known that saturated fatty acids play a role in the progression of insulin resistance in skeletal muscle while physical activity promotes insulin sensitivity.
The effect of diet and exercise on muscle satellite/stem cells is not well defined: we found that differentiated human muscle satellite cells exhibit metabolic differences. These differences were associated with physical activity level and may reflect a memory of the in vivo environment.
Differentiated muscle satellite cells from physically active individuals have a higher tolerance to saturated fatty acids reflected by a partial protection from fatty acid‐induced insulin resistance.
Physical activity and diet have significant effects on the physiological function of differentiated human muscle satellite cells. As these cells exhibit some phenotypes associated with in vivo adaptations and are involved in muscle maintenance, dysregulatory function could have profound effects on health.
Abstract  The aim of this study was to investigate whether physical activity is associated with preserved muscle metabolism in human myotubes challenged with saturated fatty acids. Human muscle satellite cells were isolated from sedentary or active individuals and differentiated into myocytes in culture. Metabolic differences were then investigated in the basal state or after chronic palmitate treatment. At basal, myocytes from sedentary individuals exhibited higher CD36 and HSP70 protein expression as well as elevated phosphorylation of c‐Jun NH2‐terminal kinase (JNK) and insulin receptor substrate 1 (IRS1) serine307 compared to myocytes from active individuals. Despite equal lipid accumulation following palmitate treatment, myocytes from sedentary individuals exhibited delayed acetyl coenzyme A carboxylase phosphorylation compared to the active group. Myocytes from sedentary individuals had significantly higher basal glucose uptake and palmitate promoted insulin resistance in sedentary myocytes. Importantly, myocytes from active individuals were partially protected from palmitate‐induced insulin resistance. Palmitate treatment enhanced IRS1 serine307 phosphorylation in myocytes from sedentary individuals and correlated positively to JNK phosphorylation. In conclusion, muscle satellite cells retain metabolic differences associated with physical activity. Physical activity partially protects myocytes from fatty acid‐induced insulin resistance and inactivity is associated with dysregulation of metabolism in satellite cells challenged with palmitate. Although the benefits of physical activity on whole body physiology have been well investigated, this paper presents novel findings that both diet and exercise impact satellite cells directly. Given the fact that satellite cells are important for muscle maintenance, a dysregulated function could have profound effects on health. Therefore the effects of lifestyle on satellite cells needs to be delineated.
SNARE proteins are essential in the potentiation of NMDA receptors by group II metabotropic glutamate receptors
Authors: Cheng Jia , Liu Wenhua , Duffney Lara J. , Yan Zhen 
Published: June 2013

Key points
Activation of group II metabotropic glutamate receptors (mGluRs) enhances NMDA receptor (NMDAR)‐mediated currents in cortical pyramidal neurons.
In this study, we found that group II mGluR‐induced enhancement of NMDAR currents was associated with increased NMDAR surface expression and synaptic localization.
Inhibition of SNAP‐25 or knockdown of syntaxin 4 blocked the enhancement of NMDAR currents by group II mGluRs.
Group II mGluRs increase the activity of Rab4 small GTPase. Rab4 knockdown or dominant negative Rab4 abolished the enhancing effect of Group II mGluRs on NMDAR currents.
These results suggest that SNARE proteins and Rab4 are key molecules involved in the enhancement of NMDAR exocytosis and function by group II mGluRs. Identification of key molecules involved in NMDAR up‐regulation could provide novel drug targets for schizophrenia treatment.
Abstract  The group II metabotropic glutamate receptors (group II mGluRs) have emerged as the new drug targets for the treatment of mental disorders like schizophrenia. To understand the potential mechanisms underlying the antipsychotic effects of group II mGluRs, we examined their impact on NMDA receptors (NMDARs), since NMDAR hypofunction has been implicated in schizophrenia. The activation of group II mGluRs caused a significant enhancement of NMDAR currents in cortical pyramidal neurons, which was associated with increased NMDAR surface expression and synaptic localization. We further examined whether these effects of group II mGluRs are through the regulation of NMDAR exocytosis via SNARE proteins, a family of proteins involved in vesicle fusion. We found that the enhancing effect of APDC, a selective agonist of group II mGluRs, on NMDAR currents was abolished when botulinum toxin was delivered into the recorded neurons to disrupt the SNARE complex. Inhibiting the function of two key SNARE proteins, SNAP‐25 and syntaxin 4, also eliminated the effect of APDC on NMDAR currents. Moreover, the application of APDC increased the activity of Rab4, a small Rab GTPase mediating fast recycling from early endosomes to the plasma membrane, and enhanced the interaction between syntaxin 4 and Rab4. Knockdown of Rab4 or expression of dominant‐negative Rab4 attenuated the effect of APDC on NMDAR currents. Taken together, these results have identified key molecules involved in the group II mGluR‐induced potentiation of NMDAR exocytosis and function.
Monte Carlo modeling for dose assessment in cone beam CT for oral and maxillofacial applications
Authors: Zhang G. , Marshall N. , Bogaerts R. , Jacobs R. , Bosmans H. 
Published: June 2013

Purpose:To adjust Monte Carlo modeling for dose assessment in dedicated cone beam computed tomography (CBCT) of the oral and maxillofacial region.Methods:Two different CBCT systems with different fields of view (FOVs), beam qualities, and scan geometries were modeled using Monte Carlo simulation. Dose calculations for typical CBCT examinations were performed with the head and neck part of four computational anatomical phantoms.Results:Simulation results compared favorably to values acquired experimentally using physical phantoms (in the literature). For a given phantom scanned with 90 kV and 60 × 60 mm FOV, effective dose per mAs was on average the same for the two different systems. Exposing the four phantoms under identical settings for the same CBCT system resulted in variations in organ doses of greater than 100%, leading to differences in effective dose of 30%. For one system, the dose dependence on the operating tube potential can be described with a quadratic polynomial function. Dose distributions over the axial plane were presented as contour plots.Conclusions:Monte Carlo modeling is an efficient and accurate means of evaluating dose distributions for dedicated cone beam oral and maxillofacial CT. Results suggest large dose differences among patients undergoing the same examination on a given system, supporting approaches toward patient specific dosimetry. A dedicated and standardized computational phantom for head and neck dosimetry should be established.
A moving blocker system for cone‐beam computed tomography scatter correction
Authors: Ouyang Luo , Song Kwang , Wang Jing 
Published: June 2013

Purpose:Scatter contamination in cone‐beam computed tomography (CBCT) degrades the image quality by introducing shading artifacts. A moving‐blocker‐based approach has been proposed to simultaneously estimate scatter and reconstruct the complete volume within field of view (FOV) from a single CBCT scan. Promising results were obtained from our simulation studies. In this work, the authors demonstrated experimentally the effectiveness of the moving‐blocker‐based scatter correction approach by implementing a moving blocker system on a LINAC on‐board kV CBCT imaging system.Methods:A physical attenuator (i.e., “blocker”) consisting of equal spaced lead strips was mounted on a linear actuator. A step motor connected to the actuator drove the blocker to move back and forth along gantry rotation axis during the CBCT acquisition. Scatter signal was estimated from the blocked region of imaging panel, and interpolated into the unblocked region. A statistics‐based iterative image reconstruction algorithm was used to reconstruct CBCT images from unblocked projections after the scatter signal was subtracted. Experimental studies were performed on a Catphan phantom and an anthropomorphic pelvis phantom to evaluate performance of the moving blocker system.Results:The scatter‐induced shading artifacts were substantially reduced in the images acquired with the moving blocker system. CT number error in selected regions of interest reduced from 318 to 17 and from 239 to 10 for the Catphan phantom and pelvis phantom, respectively.Conclusions:The authors demonstrated experimentally that the moving blocker system can successfully estimate the scatter signal in projection data and obtain complete volumetric information within the FOV using a single scan.
Does the γ dose distribution comparison technique default to the distance to agreement test in clinical dose distributions?
Authors: Low Daniel A. , Morele Delphine , Chow Philip , Dou Tai H. , Ju Tao 
Published: June 2013

Purpose:To determine the validity of the assumption that the γ dose distribution comparison tool defaults to the distance to agreement test under conditions of clinically relevant steep dose gradients and γ test criteria.Methods:The assumption was tested by computing the angle θ between the dose axis and γ vector for clinical treatment plans. θ was a function of the evaluated dose distribution dose gradient and the ratio (α) of the dose difference to distance to agreement (DTA) criteria. Dose distributions from prostate, head and neck, and lung clinical treatment plans were examined: 50 treatment plans were selected for each of the prostate and head neck sites and 27 treatment plans were selected for lung. Dose‐gradient histograms were prepared for each of the treatment plans using α = 1%/mm (e.g., 3%, 3 mm dose difference and DTA criteria, respectively). To determine how frequently different values of α were used in publications, papers that referenced the original γ paper were examined to identify the dose difference and DTA criteria used in those publications. In order to compare θ calculated using α = 1%/mm to θ for other values of α, the relationship between θ and α was determined.Results:For most of the targets and critical structures, the maximum value of θ approached 90°, so the assumption that the γ tool defaulted to the DTA test in steep dose gradients was correct. Most of the published papers using the γ tool employed the 3%, 3 mm dose difference and DTA criteria, respectively. Most of the other evaluations used criteria such that α ⩾ 1%/mm, so the conclusions relating to the examined dose distributions applied. There were a few papers employing very small values of α (including one where α = 0.17%/mm), breaking the assumption that the γ dose comparison tool defaulted to the DTA tool in steep dose gradients.Conclusions:Most published cases utilized values of α ⩾ 1%/mm, and for those the implicit assumption that the γ dose comparison tool defaults to the DTA test in steep dose gradient regions was true. There were a few cases for which α was small enough to potentially invalidate this assumption. Care should be taken by investigators when selecting the γ test criteria to assure that the γ test will appropriately default to the DTA test in the steepest dose gradients being evaluated.
WHO Group 5 Drugs and Difficult Multidrug-Resistant Tuberculosis: a Systematic Review with Cohort Analysis and Meta-Analysis
Authors: Chang Kwok-Chiu , Yew Wing-Wai , Tam Cheuk-Ming , Leung Chi-Chiu 
Published: June 2013

ABSTRACTIt is often necessary to include WHO group 5 drugs in the treatment of extensively drug-resistant tuberculosis (XDR-TB) and fluoroquinolone-resistant multidrug-resistant tuberculosis (MDR-TB). As clinical evidence about the use of group 5 drugs is scarce, we conducted a systematic review using published individual patient data. We searched PubMed and OvidSP through 7 April 2013 for publications in English to assemble a cohort with fluoroquinolone-resistant MDR-TB treated with group 5 drugs. Favorable outcome was defined as sputum culture conversion, cure, or treatment completion in the absence of death, default, treatment failure, or relapse. A cohort of 194 patients was assembled from 20 articles involving 12 geographical regions. In descending order of frequency, linezolid was used in treatment of 162 (84%) patients, macrolides in 84 (43%), clofazimine in 65 (34%), amoxicillin with clavulanate in 56 (29%), thioridazine in 18 (9%), carbapenem in 16 (8%), and high-dose isoniazid in 16 (8%). Cohort analysis with robust Poisson regression models and random-effects meta-analysis similarly suggested that linezolid use significantly increased the probability (95% confidence interval) of favorable outcome by 57% (10% to 124%) and 55% (10% to 121%), respectively. Defining significant associations by risk ratios ≥ 1.2 or ≤ 0.9, neither cohort analysis nor meta-analysis demonstrated any significant add-on benefit from the use of other group 5 drugs with respect to outcome for patients treated with linezolid, although selection bias might have led to underestimation of their effects. Our findings substantiated the use of linezolid in the treatment of XDR-TB or fluoroquinolone-resistant MDR-TB and call for further studies to evaluate the roles of other group 5 drugs.
Relationship between Ceftolozane-Tazobactam Exposure and Drug Resistance Amplification in a Hollow-Fiber Infection Model
Authors: VanScoy Brian , Mendes Rodrigo E. , Castanheira Mariana , McCauley Jennifer , Bhavnani Sujata M. , Forrest Alan , Jones Ronald N. , Okusanya Olanrewaju O. , Friedrich Lawrence V. , Steenbergen Judith , Ambrose Paul G. 
Published: June 2013

ABSTRACT

In an era of rapidly emerging antimicrobial-resistant bacteria, it is critical to understand the importance of the relationships among drug exposure, duration of therapy, and selection of drug resistance. Herein we describe the results of studies designed to determine the ceftolozane-tazobactam exposure necessary to prevent the amplification of drug-resistant bacterial subpopulations in a hollow-fiber infection model. The challenge isolate was a CTX-M-15-producing
Escherichia coli
isolate genetically engineered to transcribe a moderate level of
bla
CTX-M-15
. This organism's
bla
CTX-M-15
transcription level was confirmed by relative quantitative reverse transcription-PCR (qRT-PCR), β-lactamase hydrolytic assays, and a ceftolozane MIC value of 16 mg/liter. In these studies, the experimental duration (10 days), ceftolozane-tazobactam dose ratio (2:1), and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The ceftolozane-tazobactam doses studied ranged from 125-62.5 to 1,500-750 mg. Negative- and positive-control arms included no treatment and piperacillin-tazobactam at 4.5 g every 6 h, respectively. An inverted-U-shaped function best described the relationship between bacterial drug resistance amplification and drug exposure. The least- and most-intensive ceftolozane-tazobactam dosing regimens, i.e., 125-62.5, 750-375, 1,000-500, and 1,500-750 mg, did not amplify drug resistance, while drug resistance amplification was observed with intermediate-intensity dosing regimens (250-125 and 500-250 mg). For the intermediate-intensity ceftolozane-tazobactam dosing regimens, the drug-resistant subpopulation became the dominant population by days 4 to 6. The more-intensive ceftolozane-tazobactam dosing regimens (750-375, 1,000-500, and 1,500-750 mg) not only prevented drug resistance amplification but also virtually sterilized the model system. These data support the selection of ceftolozane-tazobactam dosing regimens that minimize the potential for on-therapy drug resistance amplification.
Sublethal Ciprofloxacin Treatment Leads to Rapid Development of High-Level Ciprofloxacin Resistance during Long-Term Experimental Evolution of Pseudomonas aeruginosa
Authors: Jørgensen Karin Meinike , Wassermann Tina , Jensen Peter Østrup , Hengzuang Wang , Molin Søren , Høiby Niels , Ciofu Oana 
Published: June 2013

ABSTRACT

The dynamics of occurrence and the genetic basis of ciprofloxacin resistance were studied in a long-term evolution experiment (940 generations) in wild-type, reference strain (PAO1) and hypermutable (PAOΔmutS and PAOMY-Mgm)
P. aeruginosa
populations continuously exposed to sub-MICs (1/4) of ciprofloxacin. A rapid occurrence of ciprofloxacin-resistant mutants (MIC of ≥12 μg/ml, representing 100 times the MIC of the original population) were observed in all ciprofloxacin-exposed lineages of PAOΔmutS and PAOMY-Mgm populations after 100 and 170 generations, respectively, and in one of the PAO1 lineages after 240 generations. The genetic basis of resistance was mutations in
gyrA
(C248T and G259T) and
gyrB
(C1397A). Cross-resistance to beta-lactam antibiotics was observed in the bacterial populations that evolved during exposure to sublethal concentrations of ciprofloxacin. Our study shows that mutants with high-level ciprofloxacin resistance are selected in
P. aeruginosa
bacterial populations exposed to sub-MICs of ciprofloxacin. This can have implications for the long-term persistence of resistant bacteria and spread of antibiotic resistance by exposure of commensal bacterial flora to low antibiotic concentrations.