bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial Implications of Using Firm Level Quotas to Employ Low Productive Workers
Authors: Edzes Arjen J.E. , Rijnks Richard , van Dijk Jouke 
Published: November 2013

AbstractMany Western countries struggle with the realisation of an inclusive labour market: a labour market in which everyone can participate and disabled or otherwise vulnerable, disadvantaged and low productive people can take part in the real labour market to the best of their abilities. Following countries like Germany and Austria, the latest Dutch policy proposal is to introduce mandatory quota for employers with more than 25 employees to create job openings for the disabled for 5 per cent of their workforce. A first calculation of possible job openings shows that from a national perspective a mandatory quota seems promising. However, due to differences in the regional economic structure the arrangement will not be sufficient to solve spatial inequalities in regional exclusion of disabled at the level of municipalities nor for larger regions at the NUTS 1 level like the North of the Netherlands. We conclude that more attention should be paid to the spatial variation in impact when the national government decides to decentralise the implementation of national policy measures to municipalities.
Baseline extracellular potassium level as an indicator of the rate of increase of the same on further storage in CPDA‐1 whole blood units: a potential approach to complement FIFO system for prioritisation of blood bags for release from blood‐banks
Authors: Baliarsingh S. , Jaiswal M. 
Published: November 2013

SUMMARYBackgroundPotassium levels in stored blood bags increases as they age. Hyperkalemia in transfused blood has undesirable cardiac effects.Materials and methodsWithin a 19‐month period, baseline and weekly samples from 15 CPDA‐1 whole blood bags were collected till 28 days of storage and analysed for potassium, sodium, uric acid, albumin and whole blood haemoglobin.ResultsOne unit increase in baseline (0 day) potassium in extracellular fluid of blood units was associated with the following increases in potassium levels on later days of storage: around two unit increase at 1 week (r2 = 0·50, P < 0·01) of storage; four units increase at 2 weeks (r2 = 0·64, P < 0·001) and 3 weeks (r2 = 0·51, P < 0·01) of storage; six units at 4 weeks (r2 = 0·53, P < 0·01) of storage. Baseline whole blood haemoglobin showed a moderate association with baseline potassium (r2 = 0·36, P < 0·05) and 2‐week potassium (r2 = 0·35, P < 0·05) values.ConclusionFor CPDA‐1 blood bags (i) low baseline potassium blood bags might be preferred for transfusion in cases demanding a low potassium load and (ii) coordinating the ‘first‐in‐first‐out’ (FIFO) policy with ‘early release of blood‐bags with high initial potassium’ might be helpful in improving the release of suitable blood units from blood‐banks.
Regulation of human platelet aggregation by genetically modified pig endothelial cells and thrombin inhibition
Authors: Iwase Hayato , Ekser Burcin , Hara Hidetaka , Phelps Carol , Ayares David , Cooper David K.C. , Ezzelarab Mohamed B. 
Published: November 2013

AbstractBackgroundCoagulation disorders remain barriers to successful pig‐to‐primate organ xenotransplantation. In vitro, we investigated the impact of pig genetic modifications on human platelet aggregation in response to pig aortic endothelial cells (pAEC).MethodsIn comparison to human (h)AEC and wild‐type (WT) pAEC, the expression of human complement‐ (CD46, CD55) or coagulation (thrombomodulin [TBM], endothelial protein C receptor [EPCR]) ‐regulatory proteins on pAEC from WT or α1,3‐galactosyltransferase gene‐knockout (GTKO) pigs was studied by flow cytometry. Using platelet‐aggregometry, human whole blood platelet aggregation was evaluated after co‐incubation with various AEC. Further, the inhibitory effect on aggregation of heparin, low molecular weight heparin, and hirudin was assessed.ResultsHeparin, low molecular weight heparin and hirudin almost completely prevented platelet aggregation induced by WT pAEC. The level of expression of human CD46, CD55, TBM and EPCR on pAEC was comparable to that on hAEC. Platelet aggregation induced by all genetically modified pAEC was significantly less (P < 0.05) than that by WT pAEC (which was 54%). GTKO/CD46/TBM pAEC induced the least platelet aggregation (27%)—a reduction of almost 50%—but this remained significantly greater (P < 0.01) than aggregation induced by hAEC (4%). There was significant positive correlation between reduction of aggregation and TBM or EPCR expression on pAEC (r = 0.89 and r = 0.86, respectively; P < 0.05). Platelet aggregation induced by GTKO/CD46/TBM pAEC in the presence of hirudin (1 IU/ml) was comparable to platelet aggregation induced by hAEC.ConclusionsGenetic modification of pAEC is associated with significant reduction of human platelet aggregation in vitro. With concomitant thrombin inhibition, platelet aggregation was comparable to that stimulated by hAEC.
Maximal heart rate does not limit cardiovascular capacity in healthy humans: insight from right atrial pacing during maximal exercise
Authors: Munch G. D. W. , Svendsen J. H. , Damsgaard R. , Secher N. H. , González‐Alonso J. , Mortensen S. P. 
Published: November 2013

Key pointsDuring high intensity whole‐body exercise, systemic and contracting skeletal muscle O2delivery and uptake () are compromised, but the underlying mechanisms remain unclear.We evaluated the effect of a ∼20 beats min−1increase in heart rate (HR) by right atrial pacing during incremental cycling and knee‐extensor exercise on cardiac output () and stroke volume (SV).An increase in HR during both exercise modalities did not alterdue to a proportional decrease in SV.The lower SV during atrial pacing in the cycling trial was associated with a diminished cardiac filling pressure, but similar arterial pressure.The results demonstrate that the human heart can achieve a higher HR than observed during maximal exercise, suggesting that HRmaxand myocardial work capacity do not limit cardiac performance in trained human subjects.Instead, restrictions in ventricular filling appear to compromise cardiac preload, SV andat exercise intensities close to.AbstractIn humans, maximal aerobic power () is associated with a plateau in cardiac output (), but the mechanisms regulating the interplay between maximal heart rate (HRmax) and stroke volume (SV) are unclear. To evaluate the effect of tachycardia and elevations in HRmaxon cardiovascular function and capacity during maximal exercise in healthy humans, 12 young male cyclists performed incremental cycling and one‐legged knee‐extensor exercise (KEE) to exhaustion with and without right atrial pacing to increase HR. During control cycling,and leg blood flow increased up to 85% of maximal workload (WLmax) and remained unchanged until exhaustion. SV initially increased, plateaued and then decreased before exhaustion (P< 0.05) despite an increase in right atrial pressure (RAP) and a tendency (P= 0.056) for a reduction in left ventricular transmural filling pressure (LVFP). Atrial pacing increased HRmaxfrom 184 ± 2 to 206 ± 3 beats min−1(P< 0.05), butremained similar to the control condition at all intensities because of a lower SV and LVFP (P< 0.05). No differences in arterial pressure, peripheral haemodynamics, catecholamines orwere observed, but pacing increased the rate pressure product and RAP (P< 0.05). Atrial pacing had a similar effect on haemodynamics during KEE, except that pacing decreased RAP. In conclusion, the human heart can be paced to a higher HR than observed during maximal exercise, suggesting that HRmaxand myocardial work capacity do not limitin healthy individuals. A limited left ventricular filling and possibly altered contractility reduce SV during atrial pacing, whereas a plateau in LVFP appears to restrictclose to.
Protective Effects of Human Lactoferrin during Aggregatibacter actinomycetemcomitans-Induced Bacteremia in Lactoferrin-Deficient Mice
Authors: Velusamy S. K. , Poojary R. , Ardeshna R. , Alabdulmohsen Waad , Fine D. H. , Velliyagounder K. 
Published: November 2013

ABSTRACT

Aggregatibacter actinomycetemcomitans
, a periodontopathogen, has been associated with several systemic diseases. Herein, we report the protective effect of human lactoferrin (hLF) during
A. actinomycetemcomitans
bacteremia in lactoferrin knockout (LFKO
−/−
) mice. The prophylactic, concurrent, and therapeutic intravenous (i.v.) administrations of hLF significantly cleared the bacteria from blood and organs. Nevertheless, all modes of hLF administration significantly decreased the concentrations of serum proinflammatory cytokines, such as interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10, and IL-12p70. Additionally, hLF administration significantly decreased hepatic and splenic proinflammatory cytokine expression levels compared to those in the non-hLF-treated group. Furthermore, administration of hLF decreased the serum C-reactive protein level, inducible nitric oxide synthase (iNOS) and myeloperoxidase (MPO) gene expression levels in liver and spleen. hLF treatment has also resulted in a 6-fold decrease in spleen weight with the migration of typical inflammatory cells in infected mice as a result of decreased inflammatory response. These results reveal that hLF protects against
A. actinomycetemcomitans
bacteremia, as indicated by rapid bacterial clearance and decreased host proinflammatory mediators.
Five-Year Retrospective Italian Multicenter Study of Visceral Leishmaniasis Treatment
Authors: Di Masi Francesco , Ursini Tamara , Iannece Maria Donata , Chianura Leonardo , Baldasso Francesco , Foti Giuseppe , Di Gregorio Pietro , Casabianca Angelo , Storaci Nunzio , Nigro Luciano , Colomba Claudia , Marazzi Maria Grazia , Todaro Giovanni , Tordini Giacinta , Zanelli Giacomo , Cenderello Giovanni , Acone Nicola , Polilli Ennio , Migliore Simona , Almi Paolo , Pizzigallo Eligio , Sagnelli Evangelista , Mazzotta Francesco , Russo Rosario , Manzoli Lamberto , Parruti Giustino 
Published: November 2013

ABSTRACT

The treatment of visceral leishmaniasis (VL) is poorly standardized in Italy in spite of the existing evidence. All consecutive patients with VL admitted at 15 Italian centers as inpatients or outpatients between January 2004 and December 2008 were retrospectively considered; outcome data at 1 year after treatment were obtained for all but 1 patient. Demographic characteristics, underlying diseases, diagnostic procedures, treatment regimens and outcomes, as well as side effects were recorded. A confirmed diagnosis of VL was reported for 166 patients: 120 (72.3%) immunocompetent, 21 (12.6%) patients with immune deficiencies other than HIV infection, and 25 (15.1%) coinfected with HIV. Liposomal amphotericin B (L-AmB) was the drug almost universally used for treatment, administered to 153 (92.2%) patients. Thirty-seven different regimens, including L-AmB were used. The mean doses were 29.4 ± 7.9 mg/kg in immunocompetent patients, 32.9 ± 8.6 mg/kg in patients with non-HIV-related immunodeficiencies, and 40.8 ± 6.7 mg/kg in HIV-infected patients (
P
< 0.001). The mean numbers of infusion days were 7.8 ± 3.1 in immunocompetent patients, 9.6 ± 3.9 in non-HIV-immunodeficient patients, and 12.0 ± 3.4 in HIV-infected patients (
P
< 0.001). Mild and reversible adverse events were observed in 12.2% of cases. Responsive patients were 154 (93.3%). Successes were 98.4% among immunocompetent patients, 90.5% among non-HIV-immunodeficient patients, and 72.0% among HIV-infected patients. Among predictors of primary response to treatment, HIV infection and age held independent associations in the final multivariate models, whereas the doses and duration of L-AmB treatment were not significantly associated. Longer treatments and higher doses of L-AmB were not able to significantly modify treatment outcomes either in the immunocompetent or in the immunocompromised population.
Investigation of the Functional Role of P-Glycoprotein in Limiting the Oral Bioavailability of Lumefantrine
Authors: Wahajuddin  , Raju Kanumuri S. R. , Singh Sheelendra P. , Taneja Isha 
Published: November 2013

ABSTRACT

In the quest to explore the reason for the low and variable bioavailability of lumefantrine, we investigated the possible role of P-glycoprotein (P-gp) in lumefantrine intestinal absorption. An
in situ
single-pass intestinal perfusion study in rats with the P-gp inhibitor verapamil or quinidine and an ATPase assay with human P-gp membranes indicated that lumefantrine is a substrate of P-gp which limits its intestinal absorption. To confirm these findings, an
in vivo
pharmacokinetic study was performed in rats. The oral administration of verapamil (10 mg/kg of body weight) along with lumefantrine caused a significant increase in its bioavailability with a concomitant decrease in clearance. The increase in bioavailability of lumefantrine could be due to inhibition of P-gp and/or cytochrome P450 3A in the intestine/liver by verapamil. However, in a rat intestinal microsomal stability study, lumefantrine was found to be resistant to oxidative metabolism. Further, an
in situ
permeation study clearly showed a significant role of P-gp in limiting the oral absorption of lumefantrine. Thus, the increase in lumefantrine bioavailability with verapamil is attributed in part to the P-gp-inhibitory ability of verapamil. In conclusion, lumefantrine is a substrate of P-gp, and active efflux by P-gp across the intestine partly contributed to the low/variable bioavailability of lumefantrine.
Application of DNA Chip Scanning Technology for Automatic Detection of Chlamydia trachomatis and Chlamydia pneumoniae Inclusions
Authors: Bogdanov Anita , Endrész Valeria , Urbán Szabolcs , Lantos Ildikó , Deák Judit , Burián Katalin , Önder Kamil , Ayaydin Ferhan , Balázs Péter , Virok Dezső P. 
Published: November 2013

ABSTRACT

Chlamydiae are obligate intracellular bacteria that propagate in the inclusion, a specific niche inside the host cell. The standard method for counting chlamydiae is immunofluorescent staining and manual counting of chlamydial inclusions. High- or medium-throughput estimation of the reduction in chlamydial inclusions should be the basis of testing antichlamydial compounds and other drugs that positively or negatively influence chlamydial growth, yet low-throughput manual counting is the common approach. To overcome the time-consuming and subjective manual counting, we developed an automatic inclusion-counting system based on a commercially available DNA chip scanner. Fluorescently labeled inclusions are detected by the scanner, and the image is processed by ChlamyCount, a custom plug-in of the ImageJ software environment. ChlamyCount was able to measure the inclusion counts over a 1-log-unit dynamic range with a high correlation to the theoretical counts. ChlamyCount was capable of accurately determining the MICs of the novel antimicrobial compound PCC00213 and the already known antichlamydial antibiotics moxifloxacin and tetracycline. ChlamyCount was also able to measure the chlamydial growth-altering effect of drugs that influence host-bacterium interaction, such as gamma interferon, DEAE-dextran, and cycloheximide. ChlamyCount is an easily adaptable system for testing antichlamydial antimicrobials and other compounds that influence
Chlamydia
-host interactions.
A Reference Laboratory Experience of Clinically Achievable Voriconazole, Posaconazole, and Itraconazole Concentrations within the Bloodstream and Cerebral Spinal Fluid
Authors: Wiederhold Nathan P. , Pennick Gennethel J. , Dorsey Sheryl A. , Furmaga Wieslaw , Lewis James S. , Patterson Thomas F. , Sutton Deanna A. , Fothergill Annette W. 
Published: November 2013

ABSTRACT
Interest in antifungal therapeutic-drug monitoring has increased due to studies demonstrating associations between concentrations and outcomes. We reviewed the antifungal drug concentration database at our institution to gain a better understanding of achievable triazole drug levels. Antifungal concentrations were measured by high-performance liquid chromatography (HPLC), ultraperformance liquid chromatography and single-quadrupole mass spectrometry (UPLC/MS), or a bioassay. For this study, only confirmed human bloodstream (serum or plasma) and cerebral spinal fluid (CSF) concentrations of voriconazole, posaconazole, and itraconazole were analyzed. The largest numbers of bloodstream and CSF samples were found for voriconazole (14,370 and 173, respectively). Voriconazole bloodstream concentrations within the range of 1 to 5.5 μg/ml represented 50.6% of samples. Levels below the lower limit of quantification (0.2 μg/ml) were observed in 14.6% of samples, and 10.4% of samples had levels of ≥5.5 μg/ml. CSF voriconazole levels ranged from undetectable to 15.3 μg/ml and were <0.2 μg/ml in 11% of samples. Posaconazole bloodstream concentrations were ≥0.7 and ≥1.25 μg/ml in 41.6% and 18.9% of samples, respectively. Posaconazole was detected in only 4 of 22 CSF samples (undetectable to 0.56 μg/ml). Itraconazole levels, as measured by UPLC/MS, were ≥0.5 μg/ml in 43.3% and were undetectable in 33.9% of bloodstream samples. In contrast, when measured by a bioassay, itraconazole/hydroxyitraconazole bloodstream concentrations were ≥1.0 μg/ml in 72.9% of samples and were undetectable in 18% of samples. These results indicate that there is marked variability in bloodstream concentrations achieved with these three azoles. In addition, many levels within the bloodstream for each azole and for voriconazole and posaconazole in the CSF were undetectable or below thresholds associated with efficacy.
Biological Cost of Different Mechanisms of Colistin Resistance and Their Impact on Virulence in Acinetobacter baumannii
Authors: Beceiro Alejandro , Moreno Antonio , Fernández Nathalie , Vallejo Juán A. , Aranda Jesús , Adler Ben , Harper Marina , Boyce John D. , Bou Germán 
Published: November 2013

ABSTRACT

Two mechanisms of resistance to colistin have been described in
Acinetobacter baumannii
. One involves complete loss of lipopolysaccharide (LPS), resulting from mutations in
lpxA
,
lpxC
, or
lpxD
, and the second is associated with phosphoethanolamine addition to LPS, mediated through mutations in
pmrAB
. In order to assess the clinical impacts of both resistance mechanisms,
A. baumannii
ATCC 19606 and its isogenic derivatives, AL1851 Δ
lpxA
, AL1852 Δ
lpxD
, AL1842 Δ
lpxC
, and ATCC 19606
pmrB
, were analyzed for
in vitro
growth rate,
in vitro
and
in vivo
competitive growth, infection of A549 respiratory alveolar epithelial cells, virulence in the
Caenorhabditis elegans
model, and virulence in a systemic mouse infection model. The
in vitro
growth rate of the
lpx
mutants was clearly diminished; furthermore,
in vitro
and
in vivo
competitive-growth experiments revealed a reduction in fitness for both mutant types. Infection of A549 cells with ATCC 19606 or the
pmrB
mutant resulted in greater loss of viability than with
lpx
mutants. Finally, the
lpx
mutants were highly attenuated in both the
C. elegans
and mouse infection models, while the
pmrB
mutant was attenuated only in the
C. elegans
model. In summary, while colistin resistance in
A. baumannii
confers a clear selective advantage in the presence of colistin treatment, it causes a noticeable cost in terms of overall fitness and virulence, with a more striking reduction associated with LPS loss than with phosphoethanolamine addition. Therefore, we hypothesize that colistin resistance mediated by changes in
pmrAB
will be more likely to arise in clinical settings in patients treated with colistin.
Pharmacokinetics of Colistin Methanesulfonate and Formed Colistin in End-Stage Renal Disease Patients Receiving Continuous Ambulatory Peritoneal Dialysis
Authors: Koomanachai Pornpan , Landersdorfer Cornelia B. , Chen Gong , Lee Hee Ji , Jitmuang Anupop , Wasuwattakul Somkiat , Sritippayawan Suchai , Li Jian , Nation Roger L. , Thamlikitkul Visanu 
Published: November 2013

ABSTRACT
Colistin, administered intravenously as its inactive prodrug colistin methanesulfonate (CMS), is increasingly used as last-line therapy to combat multidrug-resistant Gram-negative bacteria. CMS dosing needs to be adjusted for renal function. The impact of continuous ambulatory peritoneal dialysis (CAPD) on the pharmacokinetics of both CMS and colistin has not been studied. No CMS dosing recommendations are available for patients receiving CAPD. Eight CAPD patients received a single intravenous CMS dose (150 mg colistin base activity [CBA]) over 30 min. Serial blood and dialysate samples, and cumulative urine where applicable, were collected over 25 h. CMS and colistin concentrations were determined by high-performance liquid chromatography. Population pharmacokinetic modeling and Monte Carlo simulations were conducted. The total body clearance of CMS (excluding CAPD clearance) was 1.77 liters/h (44%) [population mean (between-subject variability)], while CAPD clearance was 0.088 liter/h (64%). The population mean terminal half-life of CMS was 8.4 h. For colistin, the total clearance/fraction of CMS metabolized to colistin (fm) (excluding CAPD clearance) was 2.74 liters/h (50%), the CAPD clearance was 0.101 liter/h (34%), and the mean terminal half-life was 13.2 h. Monte Carlo simulations suggested a loading dose of 300 mg CBA on day 1 and a maintenance dose of either 150 mg or 200 mg CBA daily to achieve a target average steady-state plasma colistin concentration of 2.5 mg/liter. Clearance by CAPD was low for both CMS and formed colistin. Therefore, CMS doses should not be increased during CAPD. Modeling and simulation enabled us to propose the first evidence-based CMS dosage regimen for CAPD patients.
Geno- and Phenotypic Characterization of Human Cytomegalovirus Mutants SelectedIn Vitroafter Letermovir (AIC246) Exposure
Authors: Goldner Thomas , Hempel Christine , Ruebsamen-Schaeff Helga , Zimmermann Holger , Lischka Peter 
Published: November 2013

ABSTRACTLetermovir is a novel antiviral compound currently in clinical development for the prevention of human cytomegalovirus (HCMV) infections. In contrast to all currently approved anti-HCMV drugs that target the viral DNA polymerase, letermovir acts via a distinct mode of action involving the viral terminase subunit pUL56. To extend our understanding of potential letermovir resistance mechanisms, we used marker transfer to characterize mutations identified in letermovir-resistant HCMV variants that were selected in cell culture.