bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antimicrobial drug use in Austrian pig farms: plausibility check of electronic on‐farm records and estimation of consumption
Authors: Trauffler M. , Griesbacher A. , Fuchs K. , Köfer J. 
Published: July 2014

Electronic drug application records from farmers from 75 conventional pig farms were revised and checked for their plausibility. The registered drug amounts were verified by comparing the farmers' records with veterinarians' dispensary records. The antimicrobial consumption was evaluated from 2008 to 2011 and expressed in weight of active substance(s), number of used daily doses (nUDD), number of animal daily doses (nADD) and number of product‐related daily doses (nPrDD). All results were referred to one year and animal bodyweight (kg biomass). The data plausibility proof revealed about 14 per cent of unrealistic drug amount entries in the farmers' records. The annual antimicrobial consumption was 33.9 mg/kg/year, 4.9 UDDkg /kg/year, 1.9 ADDkg /kg/year and 2.5 PrDDkg /kg/year (average). Most of the antimicrobials were applied orally (86 per cent) and at group‐level. Main therapy indications were metaphylactic/prophylactic measures (farrow‐to‐finish and fattening farms) or digestive tract diseases (breeding farms). The proportion of the ‘highest priority critically important antimicrobials’ was low (12 per cent). After determination of a threshold value, farms with a high antimicrobial use could be detected. Statistical tests showed that the veterinarian had an influence on the dosage, the therapy indication and the active substance. Orally administered antimicrobials were mostly underdosed, parenterally administered antimicrobials rather correctly or overdosed.
Correlations in Single File Diffusion: Open and Closed Systems
Authors: Tripathi Ashwani Kr. , Kumar Deepak 
Published: July 2014

We present a discussion of positional and velocity correlations of particles in single-file diffusion, based on some earlier work. We consider two physical situations: (a) An open system of N hard-core particles on an infinite line. (b) A large system with a fixed density of hard-core particles at an arbitrary temperature. In the first case (a), moments and correlations show unusual behavior. The average displacement of a particle is nonzero and grows as t1/2. Furthermore it depends on the position of the particle. Particles on the right of center are pushed right and those on the left are pushed left. The mean-square displacement also depends on the position. The diffusion constant is small for particles around the center but grows rapidly toward edges. Certain correlations in particle displacement grow with separation. For the second case (b) we give exact results for velocity-velocity auto-correlator of a tagged particle and establish that with time this correlator becomes negative and approaches zero as a power-law t-3/2 at long times. The mobility of the tagged particle is shown to decrease rapidly with density as has been observed in experiments. [Formula: see text] Special Issue Comments: This article presents mathematical results on the dynamics in expanding files, and constant density files. This article is connected to the Special Issue articles about advanced statistical properties in single file dynamics29 and files with force and advanced formulations.30
Single-File Transport of Classical Electrons on the Surface of Liquid Helium
Authors: Rees David G. , Kono Kimitoshi 
Published: July 2014

Electrons trapped on the surface of liquid helium form a model two-dimensional system. Because the electron density is low (~ 109 cm-2) and the Coulomb interaction between the electrons is essentially unscreened, the system can be regarded as a classical analogue of the degenerate Fermi gas. Electrons on helium have therefore long been used to study many-body transport phenomena in two dimensions. Here we review recent experiments investigating the transport of electrons on helium through microscopic constrictions formed in microchannel devices. Two constriction geometries are studied; short saddle-point constrictions and long constrictions in which the length greatly exceeds the width. In both cases, the constriction width can be tuned electrostatically so that the electrons move in single file. As the width of the short constriction is increased, a periodic suppression of the electron current is observed due to pinning for commensurate states of the electron lattice. A related phenomenon is observed for the long constriction whereby the quasi-one-dimensional Wigner lattice exhibits reentrant melting as the number of electron chains increases. Our results demonstrate that electrons on helium are an ideal system in which to study many-body transport in the limit of single-file motion. [Formula: see text] Special Issue Comments: This article presents experimental results on the dynamics of classical electrons moving on the surface of liquid helium in narrow channels with constrictions, with a focus on the "quantum wire", i.e. single file, regime. This article is related to the Special Issue articles about advanced statistical properties in single file dynamics34 and the mathematical results on electron dynamics in liquid helium.35
Serum Matrix Metalloproteinase-3 as a Noninvasive Biomarker of Histological Synovitis for Diagnosis of Rheumatoid Arthritis
Authors: Ma Jian-Da , Zhou Jing-Jing , Zheng Dong-Hui , Chen Le-Feng , Mo Ying-Qian , Wei Xiu-ning , Yang Li-Juan , Dai Lie 
Published: July 2014

Objective. To explore the correlation between matrix metalloproteinase- (MMP-) 3 and histological synovitis in rheumatoid arthritis (RA).Methods. Serum MMP-3 of 62 patients with active RA was detected by ELISA. Serial synovial tissue sections from all RA patients, 13 osteoarthritis, and 10 orthopedic arthropathies patients were stained with hematoxylin and eosin and immunohistochemically for MMP-3, CD3, CD20, CD38, CD68, and CD15.Results. The percentage of lining MMP3+ cells was significantly higher in RA patients especially with high grade synovitis and it was significantly correlated with Krenn’s synovitis scorer=0.574, P<0.001and sublining inflammatory cells. Multivariate stepwise linear regression analysis revealed that the association of the percentage of lining MMP3+ cells with activation of synovial stroma, sublining CD68+ macrophages, and CD15+ neutrophils was stronger than other histological indicators. The percentage of lining MMP3+ cells was significantly correlated with serum MMP-3 in RAr=0.656, P<0.001. Serum MMP-3 was higher in RA patients with high grade synovitis than that of low grade synovitis and significantly correlated with synovitis score and activation of synovial stroma subscore (allP<0.05).Conclusion. Serum MMP-3 may be an alternative noninvasive biomarker of histological synovitis and RA diagnosis.
Epidemiologic and Molecular Prognostic Review of Glioblastoma
Authors: Thakkar Jigisha P. , Dolecek Therese A. , Horbinski Craig , Ostrom Quinn T. , Lightner Donita D. , Barnholtz-Sloan Jill S. , Villano John L. 
Published: July 2014

AbstractGlioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system malignancy with a median survival of 15 months. The average incidence rate of GBM is 3.19/100,000 population, and the median age of diagnosis is 64 years. Incidence is higher in men and individuals of white race and non-Hispanic ethnicity. Many genetic and environmental factors have been studied in GBM, but the majority are sporadic, and no risk factor accounting for a large proportion of GBMs has been identified. However, several favorable clinical prognostic factors are identified, including younger age at diagnosis, cerebellar location, high performance status, and maximal tumor resection. GBMs comprise of primary and secondary subtypes, which evolve through different genetic pathways, affect patients at different ages, and have differences in outcomes. We report the current epidemiology of GBM with new data from the Central Brain Tumor Registry of the United States 2006 to 2010 as well as demonstrate and discuss trends in incidence and survival. We also provide a concise review on molecular markers in GBM that have helped distinguish biologically similar subtypes of GBM and have prognostic and predictive value. Cancer Epidemiol Biomarkers Prev; 23(10); 1985–96. ©2014 AACR.
Selective Release of a Cyclopamine Glucuronide Prodrug toward Stem-like Cancer Cell Inhibition in Glioblastoma
Authors: Balbous Anaïs , Renoux Brigitte , Cortes Ulrich , Milin Serge , Guilloteau Karline , Legigan Thibaut , Rivet Pierre , Boissonnade Odile , Martin Sébastien , Tripiana Caroline , Wager Michel , Bensadoun René Jean , Papot Sébastien , Karayan-Tapon Lucie 
Published: July 2014

Abstract
Recent data suggest that inhibition of the Hedgehog pathway could be a therapeutic target for glioblastoma. Alkaloid cyclopamine inhibits Hedgehog signaling, depleting stem-like cancer cells derived from glioblastoma. However, this compound is toxic for somatic stem cells, preventing its use for clinical applications. In this study, we tested a derivatization product of cyclopamine in the form of cyclopamine glucuronide prodrug (CGP-2). This compound was used in vitro and in vivo toward glioblastoma-initiating cells (GIC). Results obtained in vitro indicate that CGP-2 is active only in the presence of β-glucuronidase, an enzyme detected in high levels in necrotic areas of glioblastomas. CGP-2 decreased proliferation and inhibited the self-renewal of all GIC lines tested. Hedgehog pathway blockade by 10 μmol/L of CGP-2 induced a 99% inhibition of clonogenicity on GICs, similar to cyclopamine treatment. Combination of CGP-2 with radiation decreased clonogenic survival in all GIC lines compared with CGP-2 alone. In a subcutaneous glioblastoma xenograft model, a two-week CGP-2 treatment prevented tumor growth with 75% inhibition at 8 weeks, and this inhibition was still significant after 14 weeks. Unlike cyclopamine, CGP-2 had no detectable toxic effects in intestinal crypts. Our study suggests that inhibition of the Hedgehog pathway with CGP-2 is more effective than conventional temozolomide adjuvant, with much lower concentrations, and seems to be an effective therapeutic strategy for targeting GICs. Mol Cancer Ther; 13(9); 2159–69. ©2014 AACR.
Temozolomide Induces the Production of Epidermal Growth Factor to Regulate MDR1 Expression in Glioblastoma Cells
Authors: Munoz Jessian L. , Rodriguez-Cruz Vivian , Greco Steven J. , Nagula Vipul , Scotto Kathleen W. , Rameshwar Pranela 
Published: July 2014

Abstract
Glioblastoma multiforme (GBM) commonly resists the frontline chemotherapy treatment temozolomide. The multidrug resistance gene (MDR1) and its protein, P-glycoprotein (P-gp), are associated with chemoresistance. This study investigated the mechanisms underlying MDR1-mediated resistance by GBM to temozolomide. P-gp trafficking was studied by flow cytometry and Western blot analysis. MDR1 expression was analyzed by real-time PCR and reporter gene assays. AP-1 interaction with MDR1 was studied by chromatin immunoprecipitation assay. EGF production was analyzed by ELISA, EGFR signaling was determined by Western blot analysis, and in vivo response to erlotinib and/or temozolomide was studied in nude mice. During the early phase of temozolomide treatment, intracellular P-gp was trafficked to the cell membrane, followed by conformational change into active P-gp. At the later phase, gene transcription of MDR1 was induced by temozolomide-mediated production of EGF. EGF activated ERK1/2-JNK-AP-1 cofactors (c-jun and c-fos). An inhibitor of EGFR kinase (erlotinib) given to nude mice with GBM prevented temozolomide-induced resistance. The results identified an essential role for activated EGFR in the resistance of GBM to temozolomide. Temozolomide resistance occurred through a biphasic response; first, by a conformational change in P-gp into the active form and, second, by releasing EGF, which caused autocrine stimulation of GBM cells to induce MDR1. Pharmacologic inhibition of EGFR kinase blunted the ability of GBM cells to resist temozolomide. These findings may explain reports on the common occurrence of mutant EGFR (EGFRvIII) and EGFR expansion in the resistance of GBM cells. Mol Cancer Ther; 13(10); 2399–411. ©2014 AACR.
BET Protein Antagonist JQ1 Is Synergistically Lethal with FLT3 Tyrosine Kinase Inhibitor (TKI) and Overcomes Resistance to FLT3-TKI in AML Cells Expressing FLT-ITD
Authors: Fiskus Warren , Sharma Sunil , Qi Jun , Shah Bhavin , Devaraj Santhana G.T. , Leveque Christopher , Portier Bryce P. , Iyer Swaminathan , Bradner James E. , Bhalla Kapil N. 
Published: July 2014

Abstract
Recently, treatment with bromodomain and extraterminal protein antagonist (BA) such as JQ1 has been shown to inhibit growth and induce apoptosis of human acute myelogenous leukemia (AML) cells, including those expressing FLT3-ITD. Here, we demonstrate that cotreatment with JQ1 and the FLT3 tyrosine kinase inhibitor (TKI) ponatinib or AC220 synergistically induce apoptosis of cultured and primary CD34+ human AML blast progenitor cells (BPC) expressing FLT3-ITD. Concomitantly, as compared with each agent alone, cotreatment with JQ1 and the FLT3-TKI caused greater attenuation of c-MYC, BCL2, and CDK4/6. Simultaneously, cotreatment with JQ1 and the FLT3-TKI increased the levels of p21, BIM, and cleaved PARP, as well as mediated marked attenuation of p-STAT5, p-AKT, and p-ERK1/2 levels in AML BPCs. Conversely, cotreatment with JQ1 and FLT3-TKI was significantly less active against CD34+ normal bone marrow progenitor cells. Knockdown of BRD4 by short hairpin RNA also sensitized AML cells to FLT3-TKI. JQ1 treatment induced apoptosis of mouse Ba/F3 cells ectopically expressing FLT3-ITD with or without FLT3-TKI–resistant mutations F691L and D835V. Compared with the parental human AML FLT3-ITD–expressing MOLM13, MOLM13-TKIR cells resistant to AC220 were markedly more sensitive to JQ1-induced apoptosis. Furthermore, cotreatment with JQ1 and the pan-histone deacetylase inhibitor (HDI) panobinostat synergistically induced apoptosis of FLT3-TKI–resistant MOLM13-TKIR and MV4-11-TKIR cells. Collectively, these findings support the rationale for determining the in vivo activity of combined therapy with BA and FLT3-TKI against human AML cells expressing FLT3-ITD or with BA and HDI against AML cells resistant to FLT3-TKI. Mol Cancer Ther; 13(10); 2315–27. ©2014 AACR.
An In Vivo Antilymphatic Screen in Zebrafish Identifies Novel Inhibitors of Mammalian Lymphangiogenesis and Lymphatic-Mediated Metastasis
Authors: Astin Jonathan W. , Jamieson Stephen M.F. , Eng Tiffany C.Y. , Flores Maria V. , Misa June P. , Chien Annie , Crosier Kathryn E. , Crosier Philip S. 
Published: July 2014

Abstract
The growth of new lymphatic vessels (lymphangiogenesis) in tumors is an integral step in the metastatic spread of tumor cells, first to the sentinel lymph nodes that surround the tumor and then elsewhere in the body. Currently, no selective agents designed to prevent lymphatic vessel growth have been approved for clinical use, and there is an important potential clinical niche for antilymphangiogenic agents. Using a zebrafish phenotype-based chemical screen, we have identified drug compounds, previously approved for human use, that have antilymphatic activity. These include kaempferol, a natural product found in plants; leflunomide, an inhibitor of pyrimidine biosynthesis; and cinnarizine and flunarizine, members of the type IV class of calcium channel antagonists. Antilymphatic activity was confirmed in a murine in vivo lymphangiogenesis Matrigel plug assay, in which kaempferol, leflunomide, and flunarizine prevented lymphatic growth. We show that kaempferol is a novel inhibitor of VEGFR2/3 kinase activity and is able to reduce the density of tumor-associated lymphatic vessels as well as the incidence of lymph node metastases in a metastatic breast cancer xenograft model. However, in this model, kaempferol administration was also associated with tumor deposits in the pancreas and diaphragm, and flunarizine was found to be tumorigenic. Although this screen revealed that zebrafish is a viable platform for the identification and development of mammalian antilymphatic compounds, it also highlights the need for focused secondary screens to ensure appropriate efficacy of hits in a tumor context. Mol Cancer Ther; 13(10); 2450–62. ©2014 AACR.
Sex Differences in Long-Term Mortality After Myocardial Infarction
Authors: Bucholz Emily M. , Butala Neel M. , Rathore Saif S. , Dreyer Rachel P. , Lansky Alexandra J. , Krumholz Harlan M. 
Published: July 2014

Background—
Studies of sex differences in long-term mortality after acute myocardial infarction have reported mixed results. A systematic review is needed to characterize what is known about sex differences in long-term outcomes and to define gaps in knowledge.

Methods and Results—
We searched the Medline database from 1966 to December 2012 to identify all studies that provided sex-based comparisons of mortality after acute myocardial infarction. Only studies with at least 5 years of follow-up were reviewed. Of the 1877 identified abstracts, 52 studies met the inclusion criteria, of which 39 were included in this review. Most studies included fewer than one-third women. There was significant heterogeneity across studies in patient populations, methodology, and risk adjustment, which produced substantial variability in risk estimates. In general, most studies reported higher unadjusted mortality for women compared with men at both 5 and 10 years after acute myocardial infarction; however, many of the differences in mortality became attenuated after adjustment for age. Multivariable models varied between studies; however, most reported a further reduction in sex differences after adjustment for covariates other than age. Few studies examined sex-by-age interactions; however, several studies reported interactions between sex and treatment whereby women have similar mortality risk as men after revascularization.

Conclusions—
Sex differences in long-term mortality after acute myocardial infarction are largely explained by differences in age, comorbidities, and treatment use between women and men. Future research should aim to clarify how these differences in risk factors and presentation contribute to the sex gap in mortality.
Wolff-Parkinson-White Syndrome in the Era of Catheter Ablation
Authors: Pappone Carlo , Vicedomini Gabriele , Manguso Francesco , Saviano Massimo , Baldi Mario , Pappone Alessia , Ciaccio Cristiano , Giannelli Luigi , Ionescu Bogdan , Petretta Andrea , Vitale Raffaele , Cuko Amarild , Calovic Zarko , Fundaliotis Angelica , Moscatiello Mario , Tavazzi Luigi , Santinelli Vincenzo 
Published: July 2014

Background—
The management of Wolff-Parkinson-White is based on the distinction between asymptomatic and symptomatic presentations, but evidence is limited in the asymptomatic population.

Methods and Results—

The Wolff-Parkinson-White registry was an 8-year prospective study of either symptomatic or asymptomatic Wolff-Parkinson-White patients referred to our Arrhythmology Department for evaluation or ablation. Inclusion criteria were a baseline electrophysiological testing with or without radiofrequency catheter ablation (RFA). Primary end points were the percentage of patients who experienced ventricular fibrillation (VF) or potentially malignant arrhythmias and risk factors. Among 2169 enrolled patients, 1001 (550 asymptomatic) did not undergo RFA (no-RFA group) and 1168 (206 asymptomatic) underwent ablation (RFA group). There were no differences in clinical and electrophysiological characteristics between the 2 groups except for symptoms. In the no-RFA group, VF occurred in 1.5% of patients, virtually exclusively (13 of 15) in children (median age, 11 years), and was associated with a short accessory pathway antegrade refractory period (
P
<0.001) and atrioventricular reentrant tachycardia initiating atrial fibrillation (
P
<0.001) but not symptoms. In the RFA group, ablation was successful in 98.5%, and after RFA, no patients developed malignant arrhythmias or VF over the 8-year follow-up. Untreated patients were more likely to experience malignant arrhythmias and VF (log-rank
P
<0.001). Time-dependent receiver-operating characteristic curves for predicting VF identified an optimal anterograde effective refractory period of the accessory pathway cutoff of 240 milliseconds.

Conclusions—
The prognosis of the Wolff-Parkinson-White syndrome essentially depends on intrinsic electrophysiological properties of AP rather than on symptoms. RFA performed during the same procedure after electrophysiological testing is of benefit in improving the long-term outcomes.
Atrial Fibrillation and Cognitive Decline–The Role of Subclinical Cerebral Infarcts
Authors: Chen Lin Y. , Lopez Faye L. , Gottesman Rebecca F. , Huxley Rachel R. , Agarwal Sunil K. , Loehr Laura , Mosley Thomas , Alonso Alvaro 
Published: July 2014

Background and Purpose—
The mechanism underlying the association of atrial fibrillation (AF) with cognitive decline in stroke-free individuals is unclear. We examined the association of incident AF with cognitive decline in stroke-free individuals, stratified by subclinical cerebral infarcts (SCIs) on brain MRI scans.

Methods—
We analyzed data from 935 stroke-free participants (mean age±SD, 61.5±4.3 years; 62% women; and 51% black) from 1993 to 1995 through 2004 to 2006 in the Atherosclerosis Risk in Communities Study, a biracial community-based prospective cohort study. Cognitive testing (including the digit symbol substitution and the word fluency tests) was performed in 1993 to 1995, 1996 to 1998, and 2004 to 2006 and brain MRI scans in 1993 to 1995 and 2004 to 2006.

Results—

During follow-up, there were 48 incident AF events. Incident AF was associated with greater annual average rate of decline in digit symbol substitution (−0.77; 95% confidence interval, −1.55 to 0.01;
P
=0.054) and word fluency (−0.80; 95% confidence interval, −1.60 to −0.01;
P
=0.048). Among participants without SCIs on brain MRI scans, incident AF was not associated with cognitive decline. In contrast, incident AF was associated with greater annual average rate of decline in word fluency (−2.65; 95% confidence interval, −4.26 to −1.03;
P
=0.002) among participants with prevalent SCIs in 1993 to 1995. Among participants who developed SCIs during follow-up, incident AF was associated with a greater annual average rate of decline in digit symbol substitution (−1.51; 95% confidence interval, −3.02 to −0.01;
P
=0.049).

Conclusions—
The association of incident AF with cognitive decline in stroke-free individuals can be explained by the presence or development of SCIs, raising the possibility of anticoagulation as a strategy to prevent cognitive decline in AF.