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  • Wiley-Blackwell  (474,580)
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  • 1
    Publication Date: 2018-02-02
    Description: The diagnosis of Parkinson's disease (PD) still lacks objective diagnostic markers independent of clinical criteria. Cerebrospinal fluid ( CSF) samples from 36 PD and 42 age-matched control patients were subjected to inductively coupled plasma-sector field mass spectrometry and a total of 28 different elements were quantified. Different machine learning algorithms were applied to the dataset to identify a discriminating set of elements yielding a novel biomarker signature. Using 19 stably-detected elements, the extreme gradient tree boosting model showed the best performance in the discrimination of PD and control patients with high specificity and sensitivity (78.6% and 83.3%, respectively), re-classifying the training data to 100%. The 10 times 10-fold cross validation yielded a good AUROC of 0.83. Arsenic, magnesium and selenium all showed significantly higher mean CSF levels in the PD group compared to the control group (p = 0.01, p = 0.04 and p = 0.03). Reducing the number of elements to a discriminating minimum, we identified an elemental cluster (Se, Fe, As, Ni, Mg, Sr), which most importantly contributed to the sample discrimination. Selenium was identified as the element with the highest impact within this cluster directly followed by iron. After prospective validation, this elemental fingerprint in the CSF could have the potential to be used as independent biomarker for the diagnosis of PD. Next to their value as a biomarker, this data also argues for a prominent role of these highly discriminating six elements in the pathogenesis of PD. This article is protected by copyright. All rights reserved.
    Print ISSN: 0022-3042
    Electronic ISSN: 1471-4159
    Topics: Medicine
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  • 2
    Publication Date: 2018-02-02
    Description: Purpose Introduce a novel coil design using an electrically long transversely oriented slot in a conductive sheet. Theory and Methods Theoretical considerations, numerical simulations, and experimental measurements are presented for transverse slot antennas as compared with electric dipole antennas. Results Simulations show improved central and average transmit and receive efficiency, as well as larger coverage in the transverse plane, for a single slot as compared to a single dipole element. Experiments on a body phantom confirm the simulation results for a slot antenna relative to a dipole, demonstrating a large region of relatively high sensitivity and homogeneity. Images in a human subject also show a large imaging volume for a single slot and six slot antenna array. High central transmit efficiency was observed for slot arrays relative to dipole arrays. Conclusion Transverse slots can exhibit improved sensitivity and larger field of view compared with traditional conductive dipoles. Simulations and experiments indicate high potential for slot antennas in high field MRI. Magn Reson Med, 2018. © 2018 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
    Print ISSN: 0740-3194
    Electronic ISSN: 1522-2594
    Topics: Medicine
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  • 3
    Publication Date: 2018-02-02
    Description: The purpose of this work was to evaluate the feasibility and reproducibility of the spherical mean technique (SMT), a multi-compartmental diffusion model, in the spinal cord of healthy controls, and to assess its ability to improve spinal cord characterization in multiple sclerosis (MS) patients at 3 T. SMT was applied in the cervical spinal cord of eight controls and six relapsing-remitting MS patients. SMT provides an elegant framework to model the apparent axonal volume fraction v ax , intrinsic diffusivity D ax , and extra-axonal transverse diffusivity D ex_perp (which is estimated as a function of v ax and D ax ) without confounds related to complex fiber orientation distribution that reside in diffusion MRI modeling. SMT's reproducibility was assessed with two different scans within a month, and SMT-derived indices in healthy and MS cohorts were compared. The influence of acquisition scheme on SMT was also evaluated. SMT's v ax , D ax , and D ex_perp measurements all showed high reproducibility. A decrease in v ax was observed at the site of lesions and normal appearing white matter ( p 〈 0.05), and trends towards a decreased D ax and increased D ex_perp were seen. Importantly, a twofold reduction in acquisition yielded similarly high accuracy with SMT. SMT provides a fast, reproducible, and accurate method to improve characterization of the cervical spinal cord, and may have clinical potential for MS patients. The spherical mean technique, a multi-compartmental diffusion model, provides measures of axonal volume fractions ( v ax ), intrinsic diffusivity ( D ax ), and transverse extra-axonal diffusivity ( D ex_perp ). All measurements yield high reproducibility in the spinal cord of healthy controls. In the spinal cord of patients with multiple sclerosis (MS), a decreased v ax , decreased D ax , and increased D ex_perp are observed. Furthermore, SMT is robust despite significant decreases in scan time, capable of providing accurate estimation of tissue parameters in half the scan time.
    Print ISSN: 0952-3480
    Electronic ISSN: 1099-1492
    Topics: Medicine
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  • 4
    Publication Date: 2018-02-03
    Description: We examine the dynamics and morphology of graphitic films at an air-water interface in a Langmuir trough by varying interfacial surface coverage, observing in situ interfacial structure, and by characterizing interfacial structure of depositions on mica substrates. In situ interfacial structure is visualized with Brewster angle microscopy, and depositions of the interface are characterized with atomic force microscopy and field-emission scanning electron microscopy. Compression/expansion curves exhibit a monotonically decreasing surface pressure between consecutive compressions, but demonstrate a “rebound” of hysteretic behavior when the interface is allowed to relax between consecutive compressions. This dynamic results from a competition between consolidation of the interface via agglomeration of particles or the stacking of graphene sheets, and a thermally driven relaxation where nanometer-thick particles are able to overcome capillary interactions. These results are especially relevant to applications where functional films with controlled conductivity and transparency may be produced via liquid-phase deposition methods. This article is protected by copyright. All rights reserved.
    Print ISSN: 0001-1541
    Electronic ISSN: 1547-5905
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
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  • 5
    Publication Date: 2018-02-02
    Description: A novel mesoporous zirconia-polyoxometalate ZrO 2 -P 8 W 48 hybrid was prepared using a surfactant-assisted solvent evaporation technique. The acid-base reaction between the Zr-OH groups of zirconium oxides and P 8 W 48 was followed by self-assembly with an amphiphilic triblock copolymer as template to obtain a polyoxometalate-based hybrid. The ZrO 2 -P 8 W 48 hybrid was characterized by Fourier-transform infrared spectroscopy (FT-IR), thermal gravimetric assay (TGA), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), energy-dispersive X-ray spectroscopy (EDXS), X-ray diffraction (XRD), and nitrogen sorption/desorption. Owing to the multiple hydrogen-bonding interactions between the P 8 W 48 moiety and the hydroxyl groups of glycoproteins, the ZrO 2 -P 8 W 48 hybrid exhibited highly selective isolation of glycoproteins from complex matrices that included various non-glycoproteins. The retained glycoproteins could be readily recovered using a 0.01 mol L −1 CTAB solution as stripping reagent, with recovery rates of 92%, 100%, 100%, 100%, and 74% for the five target glycoproteins, Ova, ConA, IgG, γ-Glo, and HRP, respectively. The ZrO 2 -P 8 W 48 hybrid was successfully applied to the isolation of glycoproteins from egg white and human serum samples, as confirmed by SDS-PAGE and LC-MS/MS assays. This article is protected by copyright. All rights reserved
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
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  • 6
    Publication Date: 2018-02-02
    Description: Detection and typing of amyloid deposits in tissues are two crucial steps in the management of systemic amyloidoses. The presence of amyloid deposits is routinely evaluated through Congo red staining, whereas proteomics is now a mainstay for in the identification of the deposited proteins. In this issue of Proteomics, Winter and colleagues describe a novel method based on MALDI mass spectrometry imaging (MALDI-MSI) coupled to ion mobility separation and peptide filtering, to detect the presence of amyloid in histology samples and to identify its composition, while preserving the spatial distribution of proteins in tissues. This article is protected by copyright. All rights reserved
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
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  • 7
    Publication Date: 2018-02-03
    Description: BACKGROUND Studies of adolescent and young adult (AYA) oncology end-of-life care utilization are critical because cancer is the leading cause of nonaccidental AYA death and end-of-life care contributes significantly to health care expenditures. This study was designed to determine the quantity of and disparities in inpatient utilization in the last year of life of AYAs with cancer. METHODS The California Office of Statewide Health Planning and Development administrative discharge database, linked to death certificates, was used to perform a population-based analysis of cancer patients aged 15 to 39 years who died in 2000-2011. The number of hospital days and the inpatient costs were determined for each patient in the last year of his or her life, as were clinical and sociodemographic factors associated with high inpatient utilization. Admission patterns as death approached were also evaluated. RESULTS The 12,883 patients were admitted for 40 days on average in the last year of life, and this cost $151,072 per patient in inpatient costs. As death approached, the admission rates and the percentage of all admissions occurring at nonspecialty centers increased. Five percent of patients used 20% of bed days in the last year (high utilizers). Factors associated with high utilization included younger age (15-30 years), Hispanic ethnicity, non–health maintenance organization insurance, and hematologic malignancies. CONCLUSIONS AYA oncology decedents were admitted for 40 days in their last year of life. Subgroups with high utilization had distinct sociodemographic and clinical characteristics, and nonspecialty center admissions increased as death approached. This demonstrates the need for palliative care at nonspecialty centers. Future studies need to determine whether these patterns are goal-concurrent, include high utilizers, and monitor the effects of health care reform. Cancer 2018 . © 2018 American Cancer Society .
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
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  • 8
    Publication Date: 2018-02-03
    Description: Many ectotherms show a decrease in body size with increasing latitude due to changes in climate, a pattern termed converse Bergmann's rule. Urban conditions—particularly warmer temperatures and fragmented landscapes—may impose stresses on development that could disrupt these body size patterns. To test the impact of urbanization on development and latitudinal trends in body size, we launched a citizen science project to collect periodical cicadas ( Magicicada septendecim ) from across their latitudinal range during the 2013 emergence of Brood II. Periodical cicadas are long-lived insects whose distribution spans a broad latitudinal range covering both urban and rural habitats. We used a geometric morphometric approach to assess body size and developmental stress based on fluctuating asymmetry in wing shape. Body size of rural cicadas followed converse Bergmann's rule, but this pattern was disrupted in urban habitats. In the north, urban cicadas were larger than their rural counterparts, while southern populations showed little variation in body size between habitats. We detected no evidence of differences in developmental stress due to urbanization. To our knowledge, this is the first evidence that urbanization disrupts biogeographical trends in body size, and this pattern highlights how the effects of urbanization may differ over a species’ range. To test the impact of urbanization on development and latitudinal trends in body size, we launched a citizen science project to collect periodical cicadas ( Magicicada septendecim ) from across their latitudinal range during the 2013 emergence of Brood II. We used a geometric morphometric approach to assess body size and developmental stress based on fluctuating asymmetry in wing shape.Body size of rural cicadas followed converse Bergmann's rule, but this pattern was disrupted in urban habitats.
    Electronic ISSN: 2045-7758
    Topics: Biology
    Published by Wiley-Blackwell
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  • 9
    Publication Date: 2018-02-03
    Description: Galectin-2 (Gal-2) is a lectin thought to play protective roles in the gastrointestinal tract. Oxidation of mouse Gal-2 (mGal-2) by hydrogen peroxide (H 2 O 2 ) results in the loss of sugar-binding activity, whereas S-nitrosylation of mGal-2, which does not change its sugar-binding profile, has been shown to protect the protein from H 2 O 2 -induced inactivation. One of the two cysteine residues, C57, has been identified as being responsible for controlling H 2 O 2 -induced inactivation; however, the underlying molecular mechanism has not been elucidated. We performed structural analyses of mGal-2 using NMR and found that residues near C57 experienced significant chemical shift changes following S-nitrosylation, and that S-nitrosylation slowed the H 2 O 2 -induced aggregation of mGal-2. We also revealed that S-nitrosylation improves the thermal stability of mGal-2, and that the solvent accessibility and/or local dynamics of residues near C57 and the local dynamics of the core-forming residues in mGal-2 are reduced by S-nitrosylation. Structural models of Gal-2 indicated that C57 is located in a hydrophobic pocket that can be plugged by S-nitrosylation, which was supported by the NMR experiments. Based on these results, we propose two structural mechanisms by which S-nitrosylation protects mGal-2 from H 2 O 2 -induced aggregation without changing its sugar-binding profile: (1) stabilization of the hydrophobic pocket around C57 that prevents oxidation-induced destabilization of the pocket, and (2) prevention of oxidation of C57 during the transiently unfolded state of the protein, in which the residue is exposed to H 2 O 2 . This article is protected by copyright. All rights reserved.
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 10
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    Wiley-Blackwell
    Publication Date: 2018-02-03
    Description: Despite major advances in recent years, immunosuppressive regimens for multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and graft-versus-host disease (GVHD) have still major side effects and immunomodulation rather than immune paralysis would be desirable. Statins inhibit the rate limiting enzyme of the L-mevalonate pathway, the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. It was shown that blocking the L-mevalonate pathway reduces inflammation via effects on downstream metabolites of the pathway including farnesylpyrophosphates and geranylgeranylpyrophosphates which are essential for the attachment of GTPases like RhoA, Rac and Ras to the cell membrane. Therefore L-mevalonate pathway downstream products play critical roles in different steps of an immune response including immune cell activation, migration, cytokine production, immune metabolism and survival. This review discusses the relevance of the different metabolites for the immunomodulatory effect of statins and connects preclinical results with data from clinical studies that tested statins for the treatment of different inflammatory diseases. This article is protected by copyright. All rights reserved.
    Print ISSN: 0019-2805
    Electronic ISSN: 1365-2567
    Topics: Medicine
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  • 11
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    Wiley-Blackwell
    Publication Date: 2018-02-03
    Print ISSN: 0019-2805
    Electronic ISSN: 1365-2567
    Topics: Medicine
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  • 12
    Publication Date: 2018-02-03
    Description: Click here to view the Original Article by S. B. Pedersen et al .
    Print ISSN: 0954-6820
    Electronic ISSN: 1365-2796
    Topics: Medicine
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  • 13
    Publication Date: 2018-02-03
    Description: Background Head motion during brain structural MRI scans biases brain morphometry measurements but quantitative retrospective methods estimating head motion from structural MRI have not been evaluated. Purpose To verify the hypothesis that two metrics retrospectively computed from MR images: 1) average edge strength (AES, reduced with image blurring) and 2) entropy (ENT, increased with blurring and ringing artifacts) could be sensitive to in-scanner head motion during acquisition of T 1 -weighted MR images. Study Type Retrospective. Population/Subjects/Phantom/Specimen/Animal Model In all, 83 healthy control (HC) and 120 Parkinson's disease (PD) patients. Field Strength/Sequence 3D magnetization-prepared rapid gradient-echo (MPRAGE) images at 3T. Assessment We 1) compared AES and ENT distribution between HC and PD; 2) evaluated the correlation between tremor score (TS) and AES (or ENT) in PD; and 3) investigated cortical regions showing an association between AES (or ENT) and local and network-level covariance measures of cortical thickness (CT), gray to white matter contrast (GWC) and gray matter density maps (GMx). Statistical Tests 1) Student's t -test. 2) Spearman's rank correlation. 3) General linear model and partial least square analysis. Results AES, but not ENT, differentiated HC and PD ( P  = 0.02, HC median AES = 39.8, interquartile range = 9.8, PD median AES = 37.6, interquartile range = 8.1). In PD, AES correlated negatively with TS (ρ = –0.21, P  = 0.02) and showed a significant relationship (|Z| 〉3, P  〈 0.001) with structural covariance of CT and GWC in 54 out of 68 cortical regions. Data Conclusion In clinical populations prone to head motion, AES can provide a reliable retrospective index of motion during structural scans, identifying brain areas whose morphometric measures covary with motion. Level of Evidence: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.
    Print ISSN: 1053-1807
    Electronic ISSN: 1522-2586
    Topics: Medicine
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  • 14
    Publication Date: 2018-02-03
    Description: Purpose Diffusion kurtosis imaging (DKI) is an advanced magnetic resonance imaging modality that is known to be sensitive to changes in the underlying microstructure of the brain. Image voxels in diffusion weighted images, however, are typically relatively large making them susceptible to partial volume effects, especially when part of the voxel contains cerebrospinal fluid. In this work, we introduce the “Diffusion Kurtosis Imaging with Free Water Elimination” (DKI-FWE) model that separates the signal contributions of free water and tissue, where the latter is modeled using DKI. Theory and Methods A theoretical study of the DKI-FWE model, including an optimal experiment design and an evaluation of the relative goodness of fit, is carried out. To stabilize the ill-conditioned estimation process, a Bayesian approach with a shrinkage prior (BSP) is proposed. In subsequent steps, the DKI-FWE model and the BSP estimation approach are evaluated in terms of estimation error, both in simulation and real data experiments. Results Although it is shown that the DKI-FWE model parameter estimation problem is ill-conditioned, DKI-FWE was found to describe the data significantly better compared to the standard DKI model for a large range of free water fractions. The acquisition protocol was optimized in terms of the maximally attainable precision of the DKI-FWE model parameters. The BSP estimator is shown to provide reliable DKI-FWE model parameter estimates. Conclusion The combination of the DKI-FWE model with BSP is shown to be a feasible approach to estimate DKI parameters, while simultaneously eliminating free water partial volume effects. Magn Reson Med, 2018. © 2018 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
    Print ISSN: 0740-3194
    Electronic ISSN: 1522-2594
    Topics: Medicine
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  • 15
    Publication Date: 2018-02-03
    Description: Purpose Human osteoarthritic (OA) articular cartilage was investigated with spatially resolved pulsed gradient stimulated echo (PGStE) NMR using strong gradients. In this study, the diffusivity of fluid and biopolymer was characterized as a function of depth within human OA cartilage cores. Methods One dimensional (1D) spatially resolved diffusion profiles were measured for human OA cartilage using a standard pulsed gradient stimulated echo (PGStE) sequence with the addition of a read imaging gradient. Low gradient values (0.05 to 1.5 Tm −1 ) were used to measure fluid motion and high gradients (2.50 to 17.81 Tm −1 ) enabled analysis of biopolymer motion. Structural damage to cartilage was simulated using either salt or collagenase. Results These data demonstrate that fluid diffusion is sensitive to salt treatment and collagenase digestion, while biopolymer diffusion is sensitive only to collagenase digestion. Biopolymer and fluid diffusion are donor specific for human OA cartilage samples. Conclusion These data support that fluid diffusion is sensitive to the structure of cartilage while biopolymer diffusion is sensitive to the molecular weight of the biopolymers. The results show that diffusion of fluid and biopolymers in articular cartilage are sensitive to OA and provide complimentary information. Magn Reson Med, 2018. © 2018 International Society for Magnetic Resonance in Medicine.
    Print ISSN: 0740-3194
    Electronic ISSN: 1522-2594
    Topics: Medicine
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  • 16
    Publication Date: 2018-02-03
    Description: Measurements of exercise-induced metabolic changes, such as oxygen consumption, carbon dioxide exhalation or lactate concentration, are important indicators for assessing the current performance level of athletes in training science. With exercise-limiting metabolic processes occurring in loaded muscles, 31 P-MRS represents a particularly powerful modality to identify and analyze corresponding training-induced alterations. Against this background, the current study aimed to analyze metabolic adaptations after an exhaustive exercise in two calf muscles ( m. soleus – SOL – and m. gastrocnemius medialis – GM ) of sprinters and endurance athletes by using localized dynamic 31 P-MRS. In addition, the respiratory parameters VO 2 and VCO 2 , as well as blood lactate concentrations, were monitored simultaneously to assess the effects of local metabolic adjustments in the loaded muscles on global physiological parameters. Besides noting obvious differences between the SOL and the GM muscles, we were also able to identify distinct physiological strategies in dealing with the exhaustive exercise by recruiting two athlete groups with opposing metabolic profiles. Endurance athletes tended to use the aerobic pathway in the metabolism of glucose, whereas sprinters produced a significantly higher peak concentration of lactate. These global findings go along with locally measured differences, especially in the main performer GM , with sprinters revealing a higher degree of acidification at the end of exercise (pH 6.29 ± 0.20 vs. 6.57 ± 0.21). Endurance athletes were able to partially recover their PCr stores during the exhaustive exercise and seemed to distribute their metabolic activity more consistently over both investigated muscles. In contrast, sprinters mainly stressed Type II muscle fibers, which corresponds more to their training orientation preferring the glycolytic energy supply pathway. In conclusion, we were able to analyze the relation between specific local metabolic processes in loaded muscles and typical global adaptation parameters, conventionally used to monitor the training status of athletes, in two cohorts with different sports orientations. The effects of different training strategies were resolved by simultaneous monitoring of load-induced changes of high-energy phosphates and pH values in multiple muscle groups revealing heterogeneous metabolic adaptations. In addition these results were linked to global physiological regulations, which are commonly used to monitor the training status of athletes. This allows a comprehensive evaluation of training interventions by supporting gold standard methods of sport science with the knowledge of local changes in muscles.
    Print ISSN: 0952-3480
    Electronic ISSN: 1099-1492
    Topics: Medicine
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  • 17
    Publication Date: 2018-02-03
    Description: The HLA-B*27 peptidome has drawn significant attention due to the genetic association between some of the HLA-B*27 alleles and the inflammatory rheumatic disease Ankylosing Spondylitis (AS), for which a comprehensive biological explanation is still lacking. This study aims to expand the known limits of the HLA-B*27 peptidome to facilitate selection and testing of new peptides, possibly involved in the disease. The HLA peptidomes of HeLa and C1R cell lines stably transfected with the AS-associated HLA-B*27:05 allele, the non-associated HLA-B*27:09 allele, or their Cysteine 67 to Serine mutants (C67S), were analyzed on a very large scale. In addition, the peptidomes of HLA-B*27:05 and HLA-B*27:05-C67S were analyzed from the spleens of rats transgenic for these alleles. The results indicate that C67S mutation increases the percentage of peptides with glutamine or lysine at their P2 position (P2-Lys), in both HLA-B*27:05 and HLA-B*27:09. Furthermore, a small fraction of HLA-B*27 peptides contains lysine at their second position (P2), in addition to the more commonly found peptides with arginine (P2-Arg), or the less common glutamine (P2-Gln) located at this anchor position. Overall these data indicate that peptides with P2-Lys should be considered as real ligands of HLA-B*27 molecules and taken into account while looking for putative peptides implicated in the AS. This article is protected by copyright. All rights reserved
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
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  • 18
    Publication Date: 2018-02-04
    Description: Chronic arsenic exposure is associated with the development of urothelial carcinoma of the bladder (UCB). To elucidate the contribution of arsenic exposure to urothelial cancer stem cell (CSC) generation, we established an in vitro stepwise malignant model transformed by chronically exposing human urothelial cells to arsenic. Using this model, we found that chronic arsenic exposure endows urothelial cells with malignant stemness properties including increased expression of stemness-related factors such as SOX2, sphere formation, self-renewal, invasion, and chemo-resistance. SOX2 was gradually and irreversibly overexpressed in line with acquired sphere-forming and self-renewal abilities. Following gene set enrichment analyses of arsenic-exposed and arsenic-unexposed cells, we found COX2 as an enriched gene for oncogenic signature. Mechanistically, arsenic-induced COX2/PGE2 increases SOX2 expression that eventually promotes malignant stem cell generation and repopulation. In urine samples from 90 subjects exposed to arsenic and 91 control subjects, we found a significant linear correlation between SOX2 and COX2 expression and the potential of SOX2 and COX2 expression as urinary markers to detect subjects exposed to arsenic. Furthermore, the combination marker yielded a high sensitivity for UCB detection in a separate cohort. Finally, our in vitro model exhibits basal-type molecular features, and dual inhibition of EGFR and COX2 attenuated stem cell enrichment more efficiently than an EGFR inhibitor alone. In conclusion, the COX2/PGE2-SOX2 axis promotes arsenic-induced malignant stem cell transformation. In addition, our findings indicate the possible use of SOX2 and COX2 expression as urinary markers for the risk stratification and detection of UCB. This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
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  • 19
    Publication Date: 2018-02-04
    Description: Background : As an adaptation to the land, the clitellate annelid had reorganized its embryogenesis to develop “directly” without the ancestral planktonic larval stage. To study the evolution of gut development in the directly developing clitellates, we characterized the expression pattern of the conserved gut gene FoxA in the embryonic development of the leech. Results : The leech has three FoxA paralogs. Hau-FoxA1 is first expressed in a subset of endoderm cells and then in the foregut and the midgut. Hau-FoxA2 is expressed in the stomodeum, which is secondarily derived from the anterior ectoderm in the clitellates rather than the tissue around the blastopore – the ancestral site of mouth formation in Phylum Annelida. Hau-FoxA3 is expressed during the morphogenesis of segmental ganglia from the ectodermal teloblast lineages, a clitellate-specific trait. Hau-FoxA1 and Hau-FoxA2 are also expressed during the morphogenesis of the leech-specific front sucker. Conclusions : The expression patterns suggested that Hau-FoxA1 carries out most of the conserved function in the endoderm and gut development, while the other two duplicates appear to have evolved unique novel functions in the directly developing clitellate embryos. Therefore, neofunctionalization and co-option of FoxA might have made a significant contribution to the evolution of direct development in Clitellata. This article is protected by copyright. All rights reserved.
    Electronic ISSN: 1097-0177
    Topics: Medicine
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  • 20
    Publication Date: 2018-02-04
    Description: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. BRCA -associated PDAC comprises a clinically relevant subtype. A portion of these patients are highly susceptible to DNA damaging therapeutics, however, responses are heterogeneous and clinical resistance evolves. We have developed unique patient-derived xenograft (PDX) models from metastatic lesions of germline BRCA -mutated patients obtained at distinct time points; before treatment and at progression. Thus, closely mimicking clinical scenarios, to further investigate treatment naïve and resistant patients. DNA was isolated from six BRCA -mutated PDXs and classified by whole-genome sequencing to stable-genome or homologous recombination deficient (HRD)-genome. The sensitivity to DNA-damaging agents was evaluated in-vivo in three BRCA -associated PDAC PDXs models: 1. HRD-genome naïve to treatments; 2. Stable-genome naïve to treatment; 3. HRD-genome resistant to treatment. Correlation between disease course at tissue acquisition and response to PARP inhibitor (PARPi)/platinum was demonstrated in PDXs in-vivo. Only the HRD-genome PDX, naïve to treatment, was sensitive to PARP inhibitor/cisplatin treatments. Our results demonstrate heterogeneous responses to DNA damaging agents/PARPi in BRCA associated PDX thus reflecting the wide clinical spectrum. An HRD-genome PDX generated from a naïve to treatment biopsy was sensitive to platinum/PARPi whereas no benefit was observed in treating an HRD-genome PDXs generated from a patient that had acquired resistance nor stable-genome PDXs. This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
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  • 21
    Publication Date: 2018-02-04
    Description: While testicular nuclear receptor 4 (TR4) may promote prostate cancer (PCa) metastasis, its roles in the clear cell renal cell carcinoma (ccRCC) remains unclear. Here we found a higher expression of TR4 in ccRCC tumors from patients with distant metastases than those from metastasis-free patients, suggesting TR4 may play positive roles in the ccRCC metastasis. Results from in vitro multiple ccRCC cell lines also confirmed TR4's positive roles in promoting ccRCC cell invasion/migration via altering the microRNA (miR-32-5p)/TR4/HGF/Met/MMP2-MMP9 signaling. Mechanism dissection revealed that miR-32-5p could suppress TR4 protein expression via direct binding to the 3'UTR of TR4 mRNA, and TR4 might then alter the HGF/Met signaling at the transcriptional regulation via direct binding to the TR4-response-elements (TR4RE) on the HGF promoter. Then the in vitro data also demonstrated the efficacy of Sunitinib, a currently used drug to treat ccRCC, could be increased after targeting this newly identified miR-32-5p/TR4/HGF/Met signaling. The preclinical study using the in vivo mouse model with xenografted ccRCC cells confirmed the in vitro cell lines data. Together, these findings suggest that TR4 is a key player to promote ccRCC metastasis and targeting this miR-32-5p/TR4/HGF/Met signaling with small molecules including TR4-shRNA or miR-32-5p may help us to develop a new therapy to better suppress the ccRCC metastasis. This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
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  • 22
    Publication Date: 2018-02-04
    Description: BACKGROUND: The p63 gene is integral to the development of many body parts including limb, palate, teeth and urogenital tract. Loss of p63 expression may alter developmental rate, which is crucial to normal morphogenesis. To validate a novel, unbiased embryo phenotyping software tool, we tested whether delayed development contributes to the pathological phenotype of a p63 mouse mutant (p63 -/- ). We quantified dysmorphology in p63 -/- embryos and tested for universal growth delay relative to wild type (WT) embryos. Fixed embryos (n=6, p63 -/- ) aged day (E) 15.5 were micro-CT scanned and quantitatively analyzed using a digital WT atlas that defined volumetric differences between p63 -/- and WT embryos. RESULTS: p63 -/- embryos showed a growth delay of about 22 hours (0.9 days). Among the E15.5 mutants, overall size was closest to WT E14.6 mice but shape was closest to WT E14.0. The atlas clearly identified in p63 -/- embryos malformations of epithelial derivatives including limbs, tail, urogenital structures, brain, face and tooth. CONCLUSIONS: The software atlas technique described the p63 -/- phenotype as a combination of developmental delay (i.e., heterochrony) and malformation (i.e., pathological shape; failed organogenesis). This study identifies for the first time global and local roles for p63 in prenatal growth and development. This article is protected by copyright. All rights reserved.
    Electronic ISSN: 1097-0177
    Topics: Medicine
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  • 23
    Publication Date: 2018-02-04
    Description: Excessive lower oesophageal sphincter relaxation increases gastro-oesophageal acid reflux, an oesophageal adenocarcinoma risk factor. Medications that relax this sphincter (benzodiazepines, calcium channel blockers, nitrates, β2 agonists and xanthines) could promote cancer. These medications were investigated in two independent datasets. In the Scottish Primary Care Clinical Informatics Unit (PCCIU) database, a nested case-control study of oesophageal cancer was performed using GP prescription records. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CIs) for medication use and oesophageal cancer. In UK Biobank, a cohort study was conducted using self-reported medication use. Cox regression was used to calculate hazard ratios (HRs) and 95% CIs for medication use and oesophageal cancer, and by tumour subtype. Overall, 1,979 oesophageal cancer patients were matched to 9,543 controls in PCCIU, and 355 of 475,768 participants developed oesophageal cancer in UK Biobank. None of the medications investigated were significantly associated with oesophageal cancer risk apart from β2 agonists, which were associated with increased oesophageal cancer risk in PCCIU (adjusted OR 1.38, 95% CI 1.12, 1.70) but not in UK Biobank (adjusted HR 1.21, 95% CI 0.70, 2.08). Medications that relax the lower oesophageal sphincter were not associated with oesophageal cancer, apart from β2 agonists. This increased cancer risk in β2 agonist users merits further investigation. This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
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  • 24
    Publication Date: 2018-02-05
    Description: In the context of expansion of invasive species, survival of invasive plants is conditioned by their ability to adapt. In France, the water primrose Ludwigia grandiflora , an aquatic invasive species, invades yet wet meadows, leading to a depreciation of their fodder value. Understanding its potential adaption is necessary to its management, strong differences between both morphotypes were expected. So morphological and metabolic responses to terrestrial environment were analyzed for aquatic and terrestrial morphotypes. All morphological and biomass variables were greater in the terrestrial morphotype than the aquatic morphotype, independent of conditions. In terrestrial condition, both morphotypes showed a high production of sugars in root tissues, especially in the terrestrial morphotype and both morphotypes produced a low level of amino acids in shoot tissues. All results demonstrate that the terrestrial condition seems a stressful situation for both morphotypes, which activates glycolysis and fermentation pathways to improve their survival under hypoxic stress. But, only the terrestrial morphotype has been able to adjust its metabolism and maintain efficient growth. In the future, a differential transcriptomic analysis will be carried out to confirm this result. In France, the recent invasion of wet meadows by the aquatic invasive plant Ludwigia grandiflora has led the appearance of a terrestrial morphotype. Significant results reveal that this morphotype has shown new morphological and metabolomic capabilities to endure stressful conditions due to terrestrial habitat and surprisingly supplanted the aquatic morphotype in aquatic conditions. All results demonstrated the appearance of a new morphotype having new adaptive capacities.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 25
    Publication Date: 2018-02-06
    Description: While recent clinical studies demonstrate the promise of cancer immunotherapy, a barrier for broadening the clinical benefit is identifying how tumors locally suppress cytotoxic immunity. As an emerging mode of intercellular communication, exosomes secreted by malignant cells can deliver a complex payload of coding and non-coding RNA to cells within the tumor microenvironment. Here, we quantified the RNA pay-load within tumor-derived exosomes and the resulting dynamic transcriptomic response to cytotoxic T cells upon exosome delivery to better understand how tumor-derived exosomes can alter immune cell function. Exosomes derived from B16F0 melanoma cells were enriched for a subset of coding and non-coding RNAs that did not reflect the abundance in the parental cell. Upon exosome delivery, RNAseq revealed the dynamic changes in the transcriptome of CTLL2 cytotoxic T cells. In analyzing transiently co-expressed gene clusters, pathway enrichment suggested that the B16F0 exosomal payload altered mitochondrial respiration, which was confirmed independently, and upregulated genes associated with the Notch signaling pathway. Interestingly, exoso-mal miRNA appeared to have no systematic effect on downregulating target mRNA levels. This article is protected by copyright. All rights reserved.
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 26
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    Wiley-Blackwell
    Publication Date: 2018-02-06
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 27
    Publication Date: 2018-02-06
    Print ISSN: 0270-9139
    Electronic ISSN: 1527-3350
    Topics: Medicine
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  • 28
    Publication Date: 2018-02-06
    Description: Early detection and clear delineation of microscopic lesions during surgery are critical to the prognosis and survival of patients with hepatocellular carcinoma (HCC), a devastating malignancy without effective treatments except for resection. Tools to specifically identify and differentiate micronodules from normal tissue in HCC patients can have a positive impact on survival. Here, we discovered a peptide that preferentially binds to HCC cells through phage display. Significant accumulation of the fluorescence-labeled peptide in tumor from ectopic and orthotopic HCC mice was observed within 2 h of systemic injection. Contrast between tumor and surrounding liver is up to 6.5-fold and useful contrast lasts for 30 h. Micronodules (0.03 cm in diameter) in liver and lung can clearly be distinguished from normal tissue with this fluorescence-labeled peptide in orthotopic HCC mice and HCC patients. Compared to indocyanine green (ICG), an FDA-approved imaging contrast agent, up to 8.7-fold higher differentiation ratio of tumor-to-fibrosis is achieved with this fluorescence-labeled peptide. Importantly, this peptide enables up to 10-fold differentiation between HCC-to-peritumoral tissue in human tissues and the complete removal of tumor in HCC mice with surgical navigation. No abnormalities in behavior or activity are observed after systemic treatment, indicating the absence of overt toxicity. The peptide is metabolized with a half-life of approximately 4 h in serum. Conclusions: Our findings demonstrate that micronodules can be specifically differentiated with high sensitivity from surrounding tissue with this molecule, opening clinical possibilities for early detection and precise surgery of HCC. This article is protected by copyright. All rights reserved.
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    Electronic ISSN: 1527-3350
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  • 29
    Publication Date: 2018-02-06
    Description: There is a well-known relationship between the cholinergic system and learning, memory and other common cognitive processes. The process for researching and developing new drugs has lead researchers to repurpose older ones. This study investigated the effects of ebselen on the activity of acethylcholinesterase (AChE) isoforms in vitro and in an amnesia model induced by scopolamine in Swiss mice. In vitro , ebselen at concentrations equal or higher than 10 µM inhibited the activity of cortical and hippocampal G4/AChE, but not G1/AChE isoform. Treatment of mice with ebselen (50 mg/kg, i.p.) was effective against impairment of spatial recognition memory in both Y- maze and novel object recognition tests induced by scopolamine (1 mg/kg, i.p.). Ebselen (50 mg/kg) inhibited hippocampal AChE activity in mice. The present study demonstrates that ebselen inhibited the G4/AChE isoform in vitro and elicited an anti-amnesic effect in a mouse model induced by scopolamine. These findings reveal ebselen as a potential compound in terms of opening up valid therapeutic avenues for the treatment of memory impairment diseases. This article is protected by copyright. All rights reserved
    Electronic ISSN: 0091-7419
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 30
    Publication Date: 2018-02-06
    Description: ABSTRACT Imaging mass cytometry is a novel imaging modality that enables simultaneous antibody-based detection of more than 40 epitopes and molecules in tissue sections at subcellular resolution using isotopically pure metal tags. Essential for any imaging approach where antigen detection is performed is the so-called counterstaining that reveals the overall structure of the tissue. Counterstaining is necessary since antigens of interest are often present only in a small subset of cells while the rest of tissue structures are not visible. Since most biological tissues are nearly transparent or non-fluorescent, chromogenic reagents such as haematoxylin (for immunohistochemistry) or fluorescent dyes such as DAPI (that stains nuclei for epifluorescence and confocal microscopy) are utilized. Here, we describe a metal-based counterstain for imaging mass cytometry based on simple oxidation and subsequent covalent binding of the tissue components to ruthenium tetroxide (RuO 4 ). RuO 4 counterstaining reveals general tissue structure both in areas with high cell content and in stromal areas with low cellularity and fibrous or hyaline material in a manner analogous to haematoxylin in immunohistochemical counterstaining or eosin or other anionic dyes in conventional histology. Our new counterstain approach is applicable to any metal-based imaging technique and will facilitate the adaptation of imaging mass cytometry for routine applications in clinical and research laboratories.
    Print ISSN: 0022-3417
    Electronic ISSN: 1096-9896
    Topics: Medicine
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  • 31
    Publication Date: 2018-02-06
    Description: Process operability emerged in the last decades as a powerful tool for the design and control of chemical processes. Recent efforts in operability have been focused on the calculation of the desired input set for process design and intensification of natural gas utilization applications described by nonlinear models. However, there is still a gap in terms of problem dimensionality that nonlinear operability methods can handle. To fill this gap, in this paper, the incorporation of bilevel and parallel programming approaches into classical process operability concepts is discussed. Results on the implementation of the proposed method show a reduction in computational time up to 2 orders of magnitude, when compared to the original results without parallelization. These results could be extrapolated for use in a supercomputer as presented in the computational time analysis performed. In terms of intensification, the proposed approach can produce a natural gas combined cycle plant modular design with a dramatic reduction in size, from the original 400 to 0.11 [MW], while still keeping the high net plant efficiency. This approach thus provides a computationally efficient framework for process intensification of high-dimensional nonlinear energy systems towards modularity. The proposed approach also enables the verification of a modular design and conditions that can be obtained according to economic and physical constraints associated with a specific natural gas well production. This article is protected by copyright. All rights reserved.
    Print ISSN: 0001-1541
    Electronic ISSN: 1547-5905
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
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  • 32
    Publication Date: 2018-02-06
    Description: Hydrothermal pretreatment with characteristic of green chemistry is considered as promising technology in the biorefineries. In this study, using material balance and multi-scale characterization techniques, the effects of process severity factor and pH on chemical behaviors of lignin-carbohydrate complex (LCC) were systematically studied. During pretreatment, spatial relocation of lignin with covalently linked xylan facilitated local cell wall collapse. A kinetic model was established to describe the behaviors of LCC components changing with severity factor. It was found that cleavage of LCC linkage was strongly pH-dependent. Low pH dominated cleavage of coumarate/ferulate esters which cross-linking lignin with xylan and repolymerization of aromatics either from furfural or lignin into polymers such as pseudo lignin, while high pH which allowed the existence of soluble LCC dominated the aldol condensations from xylose to aromatics and depolymerizaton of lignin to phenols. Detailed reaction pathways concerned with LCC were finally established to elucidate the underlying mechanism. This article is protected by copyright. All rights reserved.
    Print ISSN: 0001-1541
    Electronic ISSN: 1547-5905
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
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  • 33
    Publication Date: 2018-02-06
    Description: A planar cyclone is designed for visualizing bubbles in the cross-section of a degassing hydrocyclone. The pressure distribution is studied through a series of experiments and Reynolds stress model simulations. The velocity distribution of the planar cyclone mostly exhibits the quasi-forced vortex zone and boundary layer zone. The bubble dynamics are simulated using both Euler–Euler and Euler–Lagrange approaches, and the output is compared with the imaging results. The Euler–Euler simulation provides more accurate predictions of the bubble trajectory. The histograms of residence time and traveling distance given by the Euler–Lagrange approach exhibit a reasonably regular pattern. With higher values of the inlet Reynolds number, stronger forces acting on the bubbles lead to a decreased but more uniform residence time. This article is protected by copyright. All rights reserved.
    Print ISSN: 0001-1541
    Electronic ISSN: 1547-5905
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
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  • 34
    Publication Date: 2018-02-06
    Description: The first paper of this study discussed the development of the Hu-Lee-Sum (HLS) correlation and demonstrated the generality and universality of the correlation to predict structure I hydrates suppression temperature for any single salt system. However, natural gas commonly forms structure II hydrates, and mixed salts naturally occur in oil and gas production. Therefore, reliable prediction of structure II hydrates suppression temperature in presence of mixed salts over a wide range of pressure is considerably important. The contribution for each salt in salt mixtures is accounted for in the effective mole fraction to extend the HLS correlation for mixed salts systems. Moreover, a parameter ( α ) is introduced to account for the effect of hydrate structure on the hydrate suppression temperature. Herein, the HLS correlation is further shown to be universal and reliable to predict the hydrate suppression temperature for more complicated systems for mixed gases and mixed salts. This article is protected by copyright. All rights reserved.
    Print ISSN: 0001-1541
    Electronic ISSN: 1547-5905
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
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  • 35
    Publication Date: 2018-02-06
    Description: A predictive approach for calculating the binary interaction parameters ( τ ij ) of the nonrandom two liquid (NRTL) local composition model is developed, combining molecular simulations with the two-fluid theory. The binary interaction parameters are determined for the following three sets of model binary mixtures: water + methanol, methanol + methyl acrylate, and water + methyl acrylate. For each binary mixture, the interaction parameters are expressed in terms of molecular size and strength of interactions, which are in turn, calculated from molecular simulations. We show that the binary interaction parameters determined from simulations are in qualitative agreement with those estimated from regressing experimental data. The major factors that determine the binary interaction parameters are outlined based on simple thermodynamic arguments for each mixture. This article is protected by copyright. All rights reserved.
    Print ISSN: 0001-1541
    Electronic ISSN: 1547-5905
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
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  • 36
    Publication Date: 2018-02-06
    Description: We strongly agree with both teams that our review has limitations including the paucity of the information of some reported cases and the limitations inherent to the Naranjo score. Nevertheless, the Naranjo score was developed to achieve consensus in estimating the probability that a drug has caused an adverse event. It is the only tool that can be used to homogenize the reading of very heterogeneous notifications. This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
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  • 37
    Publication Date: 2018-02-06
    Description: Aim Warren et al 1 set out to assess the effect of an intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe chronic plaque psoriasis. Setting and design This is a prospective, double-blind, randomised (3:1), placebo-controlled study, conducted across 16 centres in Germany, France, the Netherlands, and the UK. Study exposure Methotrexate-naïve adults with a diagnosis of moderate to severe chronic plaque psoriasis for at least 6 months before baseline were randomly assigned to receive weekly subcutaneous injections of either methotrexate at a starting dose of 17.5 mg, or placebo for 16 weeks (first phase).Dose escalation to 22.5 mg/week was implemented after 8 weeks if patients did not achieve PASI 50. Treatment was combined with folic acid 5 mg/week. The first phase of the study was followed by an open-label period from 16-52 weeks (second phase), in which both groups received weekly methotrexate injections. At week 24, dose escalation to 22.5 mg/week was possible in patients not achieving PASI 50. Outcomes Psoriasis severity was measured using the PASI (Psoriasis Area and Severity Index). The authors also used two other psoriasis severity measures and two quality of life measures, looked at safety indices and performed a sub-study analysing paired skin biopsies at baseline and week 16 (histopathology, immunohistochemistry and expression of interleukin (IL)17A, interferon-γ and tumour necrosis factor-α). Primary outcome measures The primary outcome was the proportion of patients reaching PASI 75 at week 16. Results 120 patients were included in this trial, most of whom were middle-aged white men with longstanding psoriasis and a mean BMI of 30.1 kg/m 2 . PASI 75 was achieved in 41% of patients receiving methotrexate vs. 10% of patients receiving placebo (RR 3.93, 95% CI 1.31–11.81; p=0.0026) at week 16. Subcutaneous methotrexate was generally well tolerated, with no serious adverse events related to this treatment over the 52-week study. Conclusions Warren et al conclude that the 52-week risk-benefit profile of subcutaneous methotrexate is favourable in patients with psoriasis. This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
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  • 38
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    Publication Date: 2018-02-06
    Description: We are concerned about the content and possible misinterpretation of a research letter by Le Moigne et al. published on 19 June 2017 in the British Journal of Dermatology online.[ 1] We share the concern expressed by the authors about possible psychiatric effects of oral retinoids. However, case reports rank low in the hierarchy of evidence, as a result of their inherent limitations, including publication bias and a lack of control groups. This article is protected by copyright. All rights reserved.
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    Electronic ISSN: 1365-2133
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  • 39
    Publication Date: 2018-02-06
    Description: Clinician's Corner represents the opinions and views of the author and does not reflect any policy or opinion of the American Cancer Society, Cancer Cytopathology , or Wiley unless this is clearly specified. Cancer Cytopathol 2018. © 2018 American Cancer Society.
    Topics: Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
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  • 40
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    Publication Date: 2018-02-06
    Description: Cover of this issue. Expression of 15-PGDH (brown) in pancreatic cancer is reduced by co-culture of activated macrophages (Green). See also Arima et al. (pp. 462–470 of this issue).
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  • 41
    Publication Date: 2018-02-06
    Description: BACKGROUND Programmed cell death protein 1 inhibitors increasingly are being used to treat patients with advanced lung carcinomas. Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) in tumor cells (TCs) and tumor-infiltrating immune cells (ICs) is used to select patients for programmed cell death protein 1 inhibition, but few studies have evaluated PD-L1 IHC in cytology specimens. The objective of the current study was to compare PD-L1 IHC in cytology cell blocks and matched surgical specimens. METHODS A total of 56 cytology specimens obtained between 2013 and 2016 with matching surgical specimens were stained with anti-PD-L1. Membranous positivity was scored as a percentage of the TCs and ICs by 2 pathologists. Results were compared between cytology and surgical specimens, and interobserver concordance was assessed. RESULTS The average PD-L1 positivity rate was 28% in TCs and 5% in ICs in surgical specimens (standard deviations of 37% and 7%, respectively), and 21% in TCs and 8% in ICs in cytology specimens (standard deviations of 33% and 15%, respectively). Interobserver concordance was high for TCs in surgical and cytology specimens (intraclass correlation coefficients of 0.96 and 0.96, respectively), and was moderate for ICs in surgical and cytology specimens (intraclass correlation coefficients of 0.47 and 0.67, respectively). There was moderate to high correlation between PD-L1 positivity in TCs between surgical and cytology specimens (Spearman correlation coefficient [Spearman r], 0.69), particularly among fine-needle aspiration specimens (Spearman r, 0.78), but not between PD-L1 positivity in ICs in surgical and cytology specimens (Spearman r, 0.14), including among fine-needle aspiration specimens (Spearman r, 0.23). CONCLUSIONS Tumor PD-L1 IHC positivity in cytology specimens appears to correlate strongly with results obtained from matching surgical specimens. PD-L1 IHC in ICs within cytology specimens does not reflect results in matched surgical specimens and should not be used in clinical decision making. Cancer Cytopathol 2018. © 2018 American Cancer Society .
    Topics: Medicine
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  • 42
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    Publication Date: 2018-02-06
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  • 43
    Publication Date: 2018-02-06
    Description: Autophagy plays a major role in the adaptive metabolic response of cancer cells during adverse conditions such as nutrient deprivation. However, specific data that assess metabolite profiles in context with adenosine triphosphate (ATP) availability and cell death susceptibility remain limited. Human breast cancer cells, MDAMB231, and normal breast epithelial cells, MCF12A, were subjected to short-term amino acid starvation and the cellular apoptotic and autophagic responses assessed. The role of autophagy in the control of cellular amino acid, ATP, free fatty acid, and glucose levels during amino acid starvation were compared. We demonstrate that breast cancer cells have an increased metabolic demand contributing to significant amino acid and ATP depletion in a nutrient-poor environment. Upregulation of autophagy was important for the generation of amino acids and free fatty acids and maintenance of cellular ATP levels. In contrast to normal cells, breast cancer cells were unable to maintain the response after 12 hours of amino acid starvation. Regulation of autophagic activity in these environments had indirect consequences on cell death susceptibility. Overall, our data provide support for autophagy as an important survival mechanism capable of providing metabolic substrates when cancer cells are faced with nutrient-deprived environments. Significance of study The results obtained in this study helps to expand our current knowledge on how cells respond to environmental changes; the biochemical and metabolic consequences and the physiological processes activated in response. The environmental stress applied in this study is relevant to tumour physiology, and results can be translated to cancer therapeutic and clinical research areas, ultimately assisting in the specific targeting of cancer cells while avoiding harm to normal cells.
    Print ISSN: 0263-6484
    Electronic ISSN: 1099-0844
    Topics: Biology , Medicine
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  • 44
    Publication Date: 2018-02-06
    Description: Pleurotus eryngii polysaccharides have been shown to exert significant biological activities to the host. However, few studies have been conducted on its effects on gastrointestinal tract (GIT) health alteration. In the present study, small intestinal and colonic proteome alterations generated by dietary supplementation with a novel homogeneous P. eryngii polysaccharide (PEP) in C57BL/6 mice, based on the isobaric tag for relative and absolute quantification (iTRAQ) proteomics were investigated. Compared to the control group, PEP supplementation resulted in a total of 113 and 194 significant differential proteins (DPs) in the small intestine and colon, respectively. Interestingly, DPs in small intestine were mainly related to the transport and biosynthetic process, along with the digestion and absorption pathway of nutrients, whereas the colonic DPs were significantly found participating in numerous metabolic processes. Moreover, the alterations of some DPs in small intestine and colon were speculated to correlate with the colonic microbiota structure and were involved in the regulation of host immune response. Subsequently, some critical DPs of small intestine and colon were selected and validated by western blotting. The current research facilitated the generation of potential insights into the health benefit activities and functional mechanisms of polysaccharides from P. eryngii . This article is protected by copyright. All rights reserved
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
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  • 45
    Publication Date: 2018-02-06
    Description: Time-to-event data are very common in observational studies. Unlike randomized experiments, observational studies suffer from both observed and unobserved confounding biases. To adjust for observed confounding in survival analysis, the commonly used methods are the Cox proportional hazards (PH) model, the weighted logrank test, and the inverse probability of treatment weighted Cox PH model. These methods do not rely on fully parametric models, but their practical performances are highly influenced by the validity of the PH assumption. Also, there are few methods addressing the hidden bias in causal survival analysis. We propose a strategy to test for survival function differences based on the matching design and explore sensitivity of the P -values to assumptions about unmeasured confounding. Specifically, we apply the paired Prentice-Wilcoxon (PPW) test or the modified PPW test to the propensity score matched data. Simulation studies show that the PPW-type test has higher power in situations when the PH assumption fails. For potential hidden bias, we develop a sensitivity analysis based on the matched pairs to assess the robustness of our finding, following Rosenbaum's idea for nonsurvival data. For a real data illustration, we apply our method to an observational cohort of chronic liver disease patients from a Mayo Clinic study. The PPW test based on observed data initially shows evidence of a significant treatment effect. But this finding is not robust, as the sensitivity analysis reveals that the P -value becomes nonsignificant if there exists an unmeasured confounder with a small impact.
    Print ISSN: 0277-6715
    Electronic ISSN: 1097-0258
    Topics: Mathematics , Medicine
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  • 46
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    Publication Date: 2018-02-06
    Description: No abstract is available for this article.
    Print ISSN: 0277-6715
    Electronic ISSN: 1097-0258
    Topics: Mathematics , Medicine
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  • 47
    Publication Date: 2018-02-07
    Print ISSN: 0899-0042
    Electronic ISSN: 1520-636X
    Topics: Chemistry and Pharmacology
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  • 48
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    In: Cancer
    Publication Date: 2018-02-07
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
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  • 49
    Publication Date: 2018-02-07
    Description: Integrating multiple facets of biodiversity to describe spatial and temporal distribution patterns is one way of revealing the mechanisms driving community assembly. We assessed the species, functional, and phylogenetic composition and structure of passerine bird communities along an elevational gradient both in wintering and breeding seasons in the Ailao Mountains, southwest China, in order to identify the dominant ecological processes structuring the communities and how these processes change with elevation and season. Our research confirms that the highest taxonomic diversity, and distinct community composition, was found in the moist evergreen broadleaf forest at high elevation in both seasons. Environmental filtering was the dominant force at high elevations with relatively cold and wet climatic conditions, while the observed value of mean pairwise functional and phylogenetic distances of low elevation was constantly higher than expectation in two seasons, suggested interspecific competition could play the key role at low elevations, perhaps because of relative rich resource result from complex vegetation structure and human-induced disturbance. Across all elevations, there was a trend of decreasing intensity of environmental filtering whereas increasing interspecific competition from wintering season to breeding season. This was likely due to the increased resource availability but reproduction-associated competition in the summer months. In general, there is a clear justification for conservation efforts to protect entire elevational gradients in the Ailao Mountains, given the distinct taxonomic, functional, and phylogenetic compositions and also elevational migration pattern in passerine bird communities. In this study, the species, functional, and phylogenetic composition and structure of passerine bird communities along an elevational gradient both in wintering and breeding seasons in the Ailao Mountains, southwest China, were assessed, in order to identify the dominant ecological processes structuring the communities and how these processes change with elevation and season. Our findings confirmed environmental filtering was the dominant force at high elevations and highlights a tendency of interspecific competition in breeding season as the driving force in shaping community structure of the passerine bird community. In general, there is a clear justification for conservation efforts to protect entire elevational gradients in the Ailao Mountains.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 50
    Publication Date: 2018-02-07
    Description: Current taxonomy of western Eurasian trout leaves a number of questions open; it is not clear to what extent some species are distinct genetically and morphologically. The purpose of this paper was to explore phylogeography and species boundaries in freshwater and anadromous trout from the drainages of the Black and the Caspian Seas (Ponto-Caspian). We studied morphology and mitochondrial phylogeny, combining samples from the western Caucasus within the potential range of five nominal species of trout that are thought to inhabit this region, and using the sequences available from GenBank. Our results suggest that the genetic diversity of trout in the Ponto-Caspian region is best explained with the fragmentation of catchments. (1) All trout species from Ponto-Caspian belong to the same mitochondrial clade, separated from the other trout since the Pleistocene; (2) the southeastern Black Sea area is the most likely place of diversification of this clade, which is closely related to the clades from Anatolia; (3) The species from the Black Sea and the Caspian Sea drainages are monophyletic; (4) except for the basal lineage of the Ponto-Caspian clade, Salmo rizeensis , all the lineages produce anadromous forms; (5) genetic diversification within the Ponto-Caspian clade is related to Pleistocene glacial waves; (6) the described morphological differences between the species are not fully diagnostic, and some earlier described differences depend on body size; the differences between freshwater and marine forms exceed those between the different lineages. We suggest a conservative taxonomic approach, using the names S. rizeensis and Salmo labrax for trout from the Black Sea basin and Salmo caspius and Salmo ciscaucasicus for the fish from the Caspian basin. The paper analyses mitochondrial phylogeny/phylogeography of Salmo sp. (both river trout and marine forms, “Black Sea salmon” from the drainages of the Black and Caspian seas) and compares morphology of river and marine forms from different catchments. The results show that all trouts from Ponto-Caspian are monophyletic, and diversified at the southeastern Black Sea area. The most of subclades within the Ponto-Caspian clade independently produce anadromous forms.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 51
    Publication Date: 2018-02-07
    Description: The first few months of life is the most vulnerable period for fish and their optimal hatching time with zooplankton prey is favored by natural selection. Traditionally, however, prey abundance (i.e., zooplankton density) has been considered important, whereas prey nutritional composition has been largely neglected in natural settings. High-quality zooplankton, rich in both essential amino acids (EAAs) and fatty acids (FAs), are required as starting prey to initiate development and fast juvenile growth. Prey quality is dependent on environmental conditions, and, for example, eutrophication and browning are two major factors defining primary producer community structures that will directly determine the nutritional quality of the basal food sources (algae, bacteria, terrestrial matter) for zooplankton. We experimentally tested how eutrophication and browning affect the growth and survival of juvenile rainbow trout ( Oncorhynchus mykiss ) by changing the quality of basal resources. We fed the fish on herbivorous zooplankton ( Daphnia ) grown with foods of different nutritional quality (algae, bacteria, terrestrial matter), and used GC-MS, stable isotope labeling as well as bulk and compound-specific stable isotope analyses for detecting the effects of different diets on the nutritional status of fish. The content of EAAs and omega-3 (ω-3) polyunsaturated FAs (PUFAs) in basal foods and zooplankton decreased in both eutrophication and browning treatments. The decrease in ω-3 PUFA and especially docosahexaenoic acid (DHA) was reflected to fish juveniles, but they were able to compensate for low availability of EAAs in their food. Therefore, the reduced growth and survival of the juvenile fish was linked to the low availability of DHA. Fish showed very low ability to convert alpha-linolenic acid (ALA) to DHA. We conclude that eutrophication and browning decrease the availability of the originally phytoplankton-derived DHA for zooplankton and juvenile fish, suggesting bottom-up regulation of food web quality. Our experiment with three trophic level (seston, zooplankton, and juvenile trout) showed that changes in plankton nutritional quality for zooplankton caused by eutrophication (increase in phosphorus concentration) and browning (increasing terrestrial organic matter input) have intensifying negative effects on aquatic food webs.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 52
    Publication Date: 2018-02-07
    Description: During the night, plant water loss can occur either through the roots, as hydraulic redistribution (HR), or through the leaves via the stoma, as nocturnal transpiration ( E n ), which was methodologically difficult to separate from stem refilling ( R e ). While HR and E n have been reported across a range of species, ecosystem, and climate zone, there is little understanding on the interactions between E n and/or R e and HR. As water movement at night occurs via gradients of water potential, it is expected that during periods of high atmospheric vapor pressure deficit (VPD), water loss via E n will override water loss via HR. To test this hypothesis, sap flow in stems and roots of Populus euphratica Oliv. trees, growing in a riparian zone in a hyperarid climate, was measured once in a year. Nocturnal stem sap flow was separated into E n and R e using the “forecasted refilling” method. Substantial nocturnal sap flow (38% of 24-hr flux on average) was observed and positively correlated with VPD; however, the strength of the correlation was lower ( R 2  = .55) than diurnal sap flow ( E d ) ( R 2  = .72), suggesting that nocturnal stem sap flow was attributed to both water loss through the canopy and replenishment of water in stem tissues. Partitioning of nocturnal sap flow shows that R e constituted approximately 80%, and E n ~20%, of nocturnal sap flow. The amount of root sap flow attributed to redistribution was negatively related to E d ( R 2  = .69) and the amount of acropetally sap flow in stems, R e ( R 2  = .41) and E n ( R 2  = .14). It was suggested that the magnitude of HR is more strongly depressed by R e that was recharge to the water loss via E d than by E n . It was consistent with whole-tree water balance theory, that the nighttime upward sap flow to xylem, stem refilling and transpiration, may depress hydraulic redistribution of roots. Consistent with the whole-tree water balance theory, the nighttime upward sap flow to xylem, stem refilling, and transpiration depress hydraulic redistribution of roots in Populus euphratica trees at the hyperarid zone in NW China.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 53
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    Wiley-Blackwell
    Publication Date: 2018-02-07
    Print ISSN: 0265-9247
    Electronic ISSN: 1521-1878
    Topics: Biology , Medicine
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  • 54
    Publication Date: 2018-02-07
    Description: Basal cell carcinoma (BCC) accounts for 80% of non-melanoma skin cancer. The identification of the histological subtype is crucial for the correct management of the tumor. In vivo reflectance confocal microscopy (RCM) is a novel technique that has demonstrated high sensitivity and specificity in the in vivo diagnosis of BCC. In an effort to determine reliable criteria for preoperative diagnosis of BCC subtypes, Longo et al. and Peppelman et al., described RCM criteria present in different BCC subtypes. This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
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  • 55
    Publication Date: 2018-02-07
    Description: Background Hyaluronan is a large, linear glycosaminoglycan present throughout the narrow extracellular space of the vital epidermis. Increased hyaluronan metabolism takes place in epidermal hypertrophy, wound healing and cancer. Hyaluronan is produced by hyaluronan synthases (HAS1-3) and catabolized by hyaluronidases (HYAL1 and -2), reactive oxygen species (ROS), and the KIAA1199 protein. Objectives To investigate the changes in hyaluronan metabolism during epidermal stratification and maturation, and the impact of vitamin C. Methods Hyaluronan synthesis and expression of the hyaluronan-related genes were analyzed during epidermal maturation from a simple epithelium to a fully differentiated epidermis in organotypic cultures of rat epidermal keratinocytes (REK) using qRT-PCR, immunostainings, and western blotting, in the presence and absence of vitamin C. Results With epidermal stratification, both the production and the degradation of hyaluronan were enhanced, resulting in an increase of hyaluronan fragments of various sizes. While the mRNA levels of Has3 and KIAA1199 remained stable during the maturation, Has1, Has2 , and Hyal2 showed a transient upregulation during stratification, Hyal1 remained permanently increased, and the hyaluronan receptor Cd44 decreased. At maturation, Vitamin C downregulated Has2 , Hyal2 and Cd44 , while it increased high molecular mass hyaluronan in the epidermis, and reduced small fragments in the medium, suggesting stabilization of epidermal hyaluronan. Conclusions Epidermal stratification and maturation is associated with enhanced hyaluronan turnover, and release of large amounts of hyaluronan fragments. The high turnover is suppressed by vitamin C, which is suggested to enhance normal epidermal differentiation in part through its effect on hyaluronan. This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
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  • 56
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    Publication Date: 2018-02-07
    Print ISSN: 0007-1048
    Electronic ISSN: 1365-2141
    Topics: Medicine
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  • 57
    Publication Date: 2018-02-07
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
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  • 58
    Publication Date: 2018-02-07
    Description: Flurbiprofen (F) is a nonsteroidal anti-inflammatory drug (NSAID) used therapeutically as the racemate of ( R )-enantiomer and ( S )-enantiomer. The inversion of RF to SF and vice versa was investigated in C57Bl/6 and SJL mice and Dark Agouti and Lewis rats. The enzyme α-methylacyl-CoA racemase (AMACR) is involved in the chiral inversion pathway that converts members of the 2-arylpropionic acid NSAIDs from the R-enantiomer to the S-enantiomer. We studied C57Bl/6 mice deficient in AMACR postulating that they should show reduced inversion of RF to SF. In line with the data of others in mice, ( R )-inversion to ( S )-inversion was relatively high in both the C57Bl/6 and SJL mice (fraction inverted, F I  = 37.7% and 24.7%, respectively). In contrast, in AMACR deficient mice, there was no measurable peak for SF after administration of RF. The results in both rat strains (Dark Agouti and Lewis rats, F I  = 1.4% and 4.1%, respectively) confirm the low chiral inversion of the enantiomers of flurbiprofen in the rat, as observed by other authors in the Sprague-Dawley strain (〈5%). From the present results, we conclude that for the study of flurbiprofen enantiomers, the rat is more suitable than the mouse as a model for the human in which ( R )-inversion to ( S )-inversion is negligible.
    Print ISSN: 0899-0042
    Electronic ISSN: 1520-636X
    Topics: Chemistry and Pharmacology
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  • 59
    Publication Date: 2018-02-07
    Description: The enantioseparation of ezetimibe stereoisomers by high-performance liquid chromatography on different chiral stationary phases, ie, 3 polysaccharide-based chiral columns, was studied. It was observed that cellulose-based Chiralpak IC column exhibited the best resolving ability. After the optimization of mobile phase compositions in both normal and reversed phase modes, satisfactory separation could be obtained on Chiralpak IC column, especially in normal phase mode. The use of prohibited solvents as nonstandard mobile phase gave rise to better resolution than that of standard mobile phases (n-hexane/alcohol system). In addition, the presence of ethanol in nonstandard mobile phase has played an important role in enhancing chromatographic efficiency and resolution between ezetimibe stereoisomers. Various attempts were made to comprehensively compare the chiral recognition capabilities of immobilized versus coated polysaccharide-based chiral columns, amylose-based versus cellulose-based chiral stationary phases, reversed versus normal phase modes, and standard versus nonstandard mobile phases. Moreover, possible solute-mobile phase-stationary phase interactions were derived to explain how stationary and mobile phases affected the separation. Then the method validation with respect to selectivity, linearity, precision, accuracy, and robustness was carried out, which was demonstrated to be suitable and accurate for the quantitative determination of (RRS)-ezetimibe impurity in ezetimibe bulk drug. Enantioseparation of ezetimibe stereoisomers by high-performance liquid chromatography on different polysaccharide-based chiral columns (Chiralpak AD-H, Chiralcel OD-RH, and Chiralpak IC) was studied with suitable mobile phases compositions. Attempts were made to comprehensively compare the chiral recognition capabilities of immobilized versus coated polysaccharide-based chiral columns, amylose-based versus cellulose-based chiral stationary phases, reversed versus normal phase modes, and standard versus nonstandard mobile phases. Then, the method was validated for the quantitative determination of (RRS)-ezetimibe impurity in ezetimibe bulk drug.
    Print ISSN: 0899-0042
    Electronic ISSN: 1520-636X
    Topics: Chemistry and Pharmacology
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  • 60
    Publication Date: 2018-02-07
    Description: Facultative reproductive strategies that incorporate both sexual and parthenogenetic reproduction should be optimal, yet are rarely observed in animals. Resolving this paradox requires an understanding of the economics of facultative asexuality. Recent work suggests that switching from parthenogenesis to sex can be costly and that females can resist mating to avoid switching. However, it remains unclear whether these costs and resistance behaviors are dependent on female age. We addressed these questions in the Cyclone Larry stick insect, Sipyloidea larryi , by pairing females with males (or with females as a control) in early life prior to the start of parthenogenetic reproduction, or in mid- or late life after a period of parthenogenetic oviposition. Young females were receptive to mating even though mating in early life caused reduced fecundity. Female resistance to mating increased with age, but reproductive switching in mid- or late life did not negatively affect female survival or offspring performance. Overall, mating enhanced female fitness because fertilized eggs had higher hatching success and resulted in more adult offspring than parthenogenetic eggs. However, female fecundity and offspring viability were also enhanced in females paired with other females, suggesting a socially mediated maternal effect. Our results provide little evidence that switching from parthenogenesis to sex at any age is costly for S. larryi females. However, age-dependent effects of switching on some fitness components and female resistance behaviors suggest the possibility of context-dependent effects that may only be apparent in natural populations. In facultatively parthenogenetic animals, individual females can switch from asexual to sexual reproduction by mating. The economics of switching could influence the reproductive potential of facultative parthenogenesis, but the effect of switching on fitness is unclear. Using the facultatively parthenogenetic Cyclone Larry stick insect, Sipyloidea larryi, we show that mating at any age boosts lifetime fitness, suggesting that switching to sex carries few costs in this species.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 61
    Publication Date: 2018-02-07
    Description: Information on the distribution of multiple species in a common landscape is fundamental to effective conservation and management. However, distribution data are expensive to obtain and often limited to high-profile species in a system. A recently developed technique, environmental DNA (eDNA) sampling, has been shown to be more sensitive than traditional detection methods for many aquatic species. A second and perhaps underappreciated benefit of eDNA sampling is that a sample originally collected to determine the presence of one species can be re-analyzed to detect additional taxa without additional field effort. We developed an eDNA assay for the western pearlshell mussel ( Margaritifera falcata ) and evaluated its effectiveness by analyzing previously collected eDNA samples that were annotated with information including sample location and deposited in a central repository. The eDNA samples were initially collected to determine habitat occupancy by nonbenthic fish species at sites that were in the vicinity of locations recently occupied by western pearlshell. These repurposed eDNA samples produced results congruent with historical western pearlshell surveys and permitted a more precise delineation of the extent of local populations. That a sampling protocol designed to detect fish was also successful for detecting a freshwater mussel suggests that rapidly accumulating collections of eDNA samples can be repurposed to enhance the efficiency and cost-effectiveness of aquatic biodiversity monitoring. A perhaps underappreciated benefit of eDNA sampling is that a sample originally collected to determine the presence of one species can be re-analyzed to detect additional taxa without additional field effort. We developed an eDNA assay for the freshwater mussel western pearlshell (Margaritifera falcata) and evaluated the efficacy of re-analyzing eDNA samples originally collected for the large-scale detection of nonbenthic stream fishes. Our results were largely consistent with historical western pearlshell surveys, and we further detected peripheral populations, demonstrating the validity of repurposing collections of eDNA samples to enhance the efficiency and cost-effectiveness of aquatic biodiversity monitoring.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 62
    Publication Date: 2018-02-07
    Description: Saccharomyces cerevisiae possesses a transient receptor potential (TRP) channel homolog TRPY1 in its vacuolar membrane, considered to be an ancestral TRP channel. So far, studies have focused on the channel properties of TRPY1 but its regulation and physiological role remained to be elucidated. Here we investigated TRPY1 channel function in vitro and in vivo . Patch-clamp recording of TRPY1 in yeast vacuolar membranes showed that Ca 2+ on the lumen side inhibited TRPY1-mediated channel activity, whereas luminal Zn 2+ increased the currents. TRPY1 was activated in the presence of a reducing agent, 2-mercaptoethanol. The cysteine at position 624 was identified as the target for this activating action. This activation was independent of the presence of cytosolic Ca 2+ . The amplitude of TRPY1-mediated current was reduced by addition of PI(3)P on the cytosolic side but not by PI or PI(3,5)P 2 . Measurement of the transient Ca 2+ increase in response to hyper-osmotic shock in several yeast mutants defective in different steps of the phosphatidylinositol phosphate biogenesis pathway supported this interpretation. Addition of a microtubule inhibitor strongly decreased the transient cytosolic Ca 2+ increase upon hyper-osmotic shock. Taken together, the data indicate that the vacuolar TRPY1 Ca 2+ channel mediates the perception of cytosolic signals that were induced by external changes in osmolarity, and participates in the modulation of cytosolic calcium signaling through Ca 2+ release from the vacuole to maintain intracellular Ca 2+ homeostasis in yeast. This article is protected by copyright. All rights reserved.
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 63
    Publication Date: 2018-02-07
    Description: ABSTRACT Cholangiocytes normally express primary cilia, a multisensory organelle that detects signals from the cellular environment. Cilia are significantly reduced in cholangiocarcinoma (CCA) by a mechanism involving overexpression of histone deacetylase 6 (HDAC6). Despite HDAC6 overexpression in CCA, we found no differences in its mRNA level, suggesting a post-transcriptional regulation, possibly involving miRNAs. Here we describe that at least two HDAC6-targeting miRNAs, miR-433 and miR-22, are downregulated in CCA both in vitro and in vivo . Experimental restoration of these miRNAs in CCA cells reduced HDAC6 expression, induced ciliary restoration, and decreased the malignant phenotype. Furthermore, in contrast to the mature forms, levels of precursor forms of these miRNAs were higher in CCA compared to normal cholangiocytes and accumulated in the nuclei, suggesting a defective nuclear export. We assessed the expression of Exportin-5, the protein responsible for transporting miRNA precursors out of the nucleus, and found it to be reduced by 50% in CCA compared to normal cholangiocytes. Experimental overexpression of Exportin-5 in CCA cells restored precursor and mature forms of these miRNAs to normal levels, inducing a decrease in the expression of HDAC6 and a decrease in the malignant phenotype. Conversely, shRNA depletion of Exportin-5 in normal cholangiocytes resulted in increased nuclear retention of precursor miRNAs, decreased mature miRNAs, increased cell proliferation, and shorter cilia. Conclusion: these data suggest that downregulated Exportin-5 impairs the nuclear export of miR-433 and miR-22 precursor forms, causing a decrease in levels of mature miR-433 and miR-22 forms, and leading to overexpression of HDAC6 and ciliary loss in CCA. This article is protected by copyright. All rights reserved.
    Print ISSN: 0270-9139
    Electronic ISSN: 1527-3350
    Topics: Medicine
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  • 64
    Publication Date: 2018-02-07
    Description: Pre-clinical studies suggest statins may help prevent prostate cancer (PC), but epidemiologic results are mixed. Many epidemiological studies have relatively short pre-diagnosis drug exposure data, which may miss some statin use. We completed a nested case-control study investigating the impact of statin use on PC diagnosis and clinically significant PC using data from men aged 〉=40 years in the Canadian province of Saskatchewan between 1990-2010. Drug exposure histories were derived from a population-based prescription drug database. We used conditional logistic regression to model use of statins as a class and stratified analyses for groups defined by lipophilicity. Clinically significant PC was defined as: Gleason score 8-10 OR stage C or D or III or IV at diagnosis. 12,745 cases of PC were risk-set matched on age and geographic location to 50,979 controls. Greater than 90% of subjects had pre-diagnosis drug exposure histories 〉15 years. 2064 (16.2%) cases and 7956 (15.6%) controls were dispensed one or more statin prescriptions. In multivariable models, ever prescription of statins was not associated with PC diagnosis (OR 0.97; 95% CI 0.90-1.05). Neither lipophilic statins (OR 0.96,95% CI 0.88-1.04) nor hydrophilic statins (OR 1.06, 95% CI 0.95-1.20) impacted PC diagnosis. There was no effect of the dose or duration of statin use. Diagnosis of clinically significant PC decreased with statin use (OR 0.84, 95% CI 0.73-0.97). Statin use is not associated with overall PC risk, regardless of duration or dose of statin exposure. Statin use is associated with a decreased risk of clinically significant PC. This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
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  • 65
    Publication Date: 2018-02-07
    Description: Murine radiation-induced rectocolitis is considered to be a relevant animal model of gastrointestinal inflammation. The purpose of our study was to compare quantitative MRI and histopathological features in this gastrointestinal inflammation model. Radiation rectocolitis was induced by localized single-dose radiation (27 Gy) in Sprague-Dawley rats. T 2 -weighted, T 1 -weighted and diffusion-weighted MRI was performed at 7 T in 16 rats between 2 and 4 weeks after irradiation and in 10 control rats. Rats were sacrificed and the histopathological inflammation score of the colorectal samples was assessed. The irradiated rats showed significant increase in colorectal wall thickness (2.1 ± 0.3 mm versus 0.8 ± 0.3 mm in control rats, P 〈 0.0001), normalized T 2 signal intensity (4 ± 0.8 versus 2 ± 0.4 AU, P 〈 0.0001), normalized T 1 signal intensity (1.4 ± 0.1 versus 1.1 ± 0.2 AU, P = 0.0009) and apparent and pure diffusion coefficients (ADC and D ) (2.06 × 10 −3 ± 0.34 versus 1.51 × 10 −3 ± 0.23 mm 2 /s, P = 0.0004, and 1.97 × 10 −3 ± 0.43 mm 2 /s versus 1.48 × 10 −3 ± 0.29 mm 2 /s, P = 0.008, respectively). Colorectal wall thickness ( r = 0.84, P 〈 0.0001), normalized T 2 signal intensity ( r = 0.85, P 〈 0.0001) and ADC ( r = 0.80, P 〈 0.0001) were strongly correlated with the histopathological inflammation score, whereas normalized T 1 signal intensity and D were moderately correlated ( r = 0.64, P = 0.0006, and r = 0.65, P = 0.0003, respectively). High-field MRI features of single-dose radiation-induced rectocolitis in rats differ significantly from those of control rats. Quantitative MRI characteristics, especially wall thickness, normalized T 2 signal intensity, ADC and D , are potential markers of the histopathological inflammation score. Rectocolitis is induced in rats with a single dose of 27 Gy delivered using a medical accelerator. High-field MRI features (wall thickness, normalized T 2 and T 1 signal intensities and ADC measures) of irradiated rats differ significantly from MRI features of control rats, and are correlated strongly with histopathological inflammation score.
    Print ISSN: 0952-3480
    Electronic ISSN: 1099-1492
    Topics: Medicine
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  • 66
    Publication Date: 2018-02-07
    Description: Researchers collected multiple measurements on patients with schizophrenia and their relatives, as well as control subjects and their relatives, to study vulnerability factors for schizophrenics and their near relatives. Observations across individuals from the same family are correlated, and also the multiple outcome measures on the same individuals are correlated. Traditional data analyses model outcomes separately and thus do not provide information about the interrelationships among outcomes. We propose a novel Bayesian family factor model (BFFM), which extends the classical confirmatory factor analysis model to explain the correlations among observed variables using a combination of family-member and outcome factors. Traditional methods for fitting confirmatory factor analysis models, such as full-information maximum likelihood (FIML) estimation using quasi-Newton optimization (QNO), can have convergence problems and Heywood cases (lack of convergence) caused by empirical underidentification. In contrast, modern Bayesian Markov chain Monte Carlo handles these inference problems easily. Simulations compare the BFFM to FIML-QNO in settings where the true covariance matrix is identified, close to not identified, and not identified. For these settings, FIML-QNO fails to fit the data in 13 % , 57 % , and 85 % of the cases, respectively, while MCMC provides stable estimates. When both methods successfully fit the data, estimates from the BFFM have smaller variances and comparable mean-squared errors. We illustrate the BFFM by analyzing data on data from schizophrenics and their family members.
    Print ISSN: 0277-6715
    Electronic ISSN: 1097-0258
    Topics: Mathematics , Medicine
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  • 67
    Publication Date: 2018-02-08
    Description: Introduction of O 2 to Earth's early biosphere stimulated remarkable evolutionary adaptations, and a wide range of electron acceptors allowed diverse, energy-yielding metabolic pathways. Enzymatic reduction of O 2 yielded a several-fold increase in energy production, enabling evolution of multi-cellular animal life. However, utilization of O 2 also presented major challenges as O 2 and many of its derived reactive oxygen species (ROS) are highly toxic, possibly impeding multicellular evolution after the Great Oxidation Event. Remarkably, ROS, and especially hydrogen peroxide, seem to play a major part in early diversification and further development of cellular respiration and other oxygenic pathways, thus becoming an intricate part of evolution of complex life. Hence, although harnessing of chemical and thermo-dynamic properties of O 2 for aerobic metabolism is generally considered to be an evolutionary milestone, the ability to use ROS for cell signaling and regulation may have been the first true breakthrough in development of complex life. The importance of Earth's oxygen cycle and reactive oxygen species produced on the evolution of complex life. The ability to detoxify oxygen species is not a trait that emerged as a response to increased O 2 levels but rather crucial adaptation to the early Earth's weakly oxic microenvironments.
    Print ISSN: 0265-9247
    Electronic ISSN: 1521-1878
    Topics: Biology , Medicine
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  • 68
    Publication Date: 2018-02-08
    Print ISSN: 0007-1048
    Electronic ISSN: 1365-2141
    Topics: Medicine
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  • 69
  • 70
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    Wiley-Blackwell
    In: Cancer
    Publication Date: 2018-02-08
    Description: Accumulating data suggest that factors in the social environment may be associated with cancer-related outcomes. Ethnic density, defined as the proportion of racial/ethnic minority individuals residing in a given geographic area, is 1 of the most frequently studied social environment factors, but studies on ethnic density and cancer have yielded inconsistent findings. Thus, the objective of the current review was to summarize the extant data on ethnic density and cancer-related outcomes (cancer risk, stage at diagnosis, and mortality) with the aim of identifying pathways by which ethnic density may contribute to outcomes across populations. In general, the findings indicated an association between ethnic density and increased risk for cancers of infectious origin (eg, liver, cervical) but lower risk for breast and colorectal cancers, particularly among Hispanic and Asian Americans. Hispanic ethnic density was associated with greater odds of late-stage cancer diagnosis, whereas black ethnic density was associated with greater mortality. In addition, this review highlights several methodological and conceptual issues surrounding the measurement of ethnic neighborhoods and their available resources. Clarifying the role of neighborhood ethnic density is critical to developing a greater understanding of the health risks and benefits accompanying these environments and how they may affect racial and ethnic disparities in cancer-related outcomes. Cancer 2018 . © 2018 American Cancer Society .
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
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  • 71
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    Publication Date: 2018-02-08
    Description: BACKGROUND Cancer screening rates are lowest in those without insurance or a regular provider. Since 2008, the Colorectal Cancer Prevention Network (CCPN) has provided open access colonoscopy to uninsured residents of South Carolina through established, statewide partnerships and patient navigation. Herein, we describe the structure, implementation, and clinical outcomes of this program. METHODS The CCPN provides access to colonoscopy screening at no cost to uninsured, asymptomatic patients aged 50-64 years (African Americans age 45-64 years are eligible) who live at or below 150% of the poverty line and seek medical care in free medical clinics, federally qualified health centers, or hospital-based indigent practices in South Carolina. Screening is performed by board-certified gastroenterologists. Descriptive statistics and regression analysis are used to describe the population screened, and to assess compliance rates and colonoscopy quality metrics. RESULTS Out of 〉4000 patients referred to the program, 1854 were deemed eligible, 1144 attended an in-person navigation visit, and 1030 completed a colonoscopy; 909 were included in the final sample. Nearly 90% of participants exhibited good-to-excellent bowel preparation. An overall cecal intubation rate of 99% was measured. The polyp detection rate and adenoma detection rate were 63% and 36%, respectively, with male sex and urban residence positively associated with adenoma detection. Over 13% of participants had an advanced polyp, and 1% had a cancer diagnosis or surgical intervention. CONCLUSION The CCPN program is characterized by strong collaboration with clinicians statewide, low no-show rates, and high colonoscopy quality. Future work will assess the effectiveness of the navigation approach and will explore the mechanisms driving higher adenoma detection in urban participants. Cancer 2018 . © 2018 American Cancer Society .
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
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  • 73
    Publication Date: 2018-02-08
    Description: BACKGROUND Pembrolizumab monotherapy is a standard-of-care treatment for the first- and second-line treatment of advanced non–small cell lung cancer with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) values ≥ 50% and ≥ 1%, respectively. PD-L1 testing with the PD-L1 immunohistochemistry (IHC) 22C3 pharmDx companion assay has been validated on tumor tissue with the Dako Autostainer Link 48 (ASL48). 22C3 anti–PD-L1 antibody–based laboratory-developed tests (LDTs) compatible with other autostainers and cytology samples are essential to support pembrolizumab treatment decisions across institutions globally. METHODS ASL48 and BenchMark Ultra LDTs were optimized for the evaluation of cytology samples through comparisons with cell lines with known PD-L1 expression levels (strong, moderate, and negative). The PD-L1 TPS was then evaluated for 70 paired biopsy and cytology samples (bronchial washes, n = 40; pleural effusions, n = 30) with these LDTs. Biopsy and cytology LDT TPS values were also compared with a subset of biopsy samples (n = 37) evaluated with the PD-L1 IHC 22C3 pharmDx assay on the ASL48. RESULTS Intraclass correlation coefficients of 0.884 to 0.898 were observed for biopsy samples versus cytology samples with the ASL48 and BenchMark Ultra LDTs. Concordance was high, regardless of the TPS cut point (〈1% vs ≥ 1% and 〈50% vs ≥ 50%), sample type (pleural effusion vs bronchial wash), or tumor histology (adenocarcinoma vs squamous cell carcinoma). Concordance was high for each LDT versus the PD-L1 IHC 22C3 pharmDx assay. CONCLUSIONS ALS48 and BenchMark Ultra 22C3 antibody concentrate–based LDTs have been validated for PD-L1 testing in cytology samples, and they will support reliable, high-quality PD-L1 testing across regions globally. Cancer Cytopathol 2018. © 2018 American Cancer Society.
    Topics: Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
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    Publication Date: 2018-02-08
    Description: Aims Acral lentiginous melanoma (ALM) is the most common type of melanoma in people with darker skin phototypes. There is some evidences that the etiology, pathogenesis, risk factors, and natural history of ALM differ from those of superficial spreading melanoma (SSM). ALM behaves more aggressively than SSM, but the biological explanation for these differences remains unknown. The presence of one subtype of macrophages, termed M2-macrophage (M2-M), has been found to be related to local progression, metastasis, and poor prognosis in several neoplasms. The aim of this study was to compare the density of M2-Ms in ALMs versus SSMs, and to examine whether the density of M2-Ms is associated with histopathological features predictive of adverse prognosis in cutaneous melanoma (CM), as well as development of metastasis. Methods and results Sixty-seven ALMs and 67 SSMs cases were analyzed. The tumors were classified according to thickness, ulceration, mitosis and metastasis. M2-M quantity was evaluated using immunohistochemistry with anti-CD163 and anti-CD206 antibodies. M2-Ms were increased in ALM compared with SSM, and were related to the histopathological features predictive of adverse prognosis in CM, such as thickness 〉1.0 mm, ulceration, and mitotic activity, and the development of metastasis. Conclusions Our study is the first to demonstrate increased presence of M2-Ms in ALM compared with SSM. Our findings suggest that the increased M2-Ms in ALM is associated with the main histopathological features predictive of adverse prognosis in CM, as well as the presence of metastasis and that these cells can be related with the aggressive behavior seen in ALMs. This article is protected by copyright. All rights reserved.
    Print ISSN: 0309-0167
    Electronic ISSN: 1365-2559
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 75
    Publication Date: 2018-02-08
    Description: Background CCL23 role in the inflammatory response after acute brain injuries remains elusive. Here, we evaluated whether CCL23 blood levels associate with acquired cerebral lesions and determined CCL23 predictive capacity for assessing stroke prognosis. We used pre-clinical models to study the CCL23 homologous chemokines in rodents, CCL9 and CCL6. Methods Baseline CCL23 blood levels were determined on 245 individuals, including ischemic strokes (IS), stroke-mimics and controls. Temporal profile of circulating CCL23 was explored from baseline to 24h in 20 of the IS. In an independent cohort of 120 IS with a three-month follow-up, CCL23 blood levels were included in logistic regression models to predict IS outcome. CCL9/CCL6 cerebral expression was evaluated in rodent models of brain damage. Both chemokines were also profiled in circulation and histologically located on brain following ischemia. Results Baseline CCL23 blood levels did not discriminate IS, but permitted an accurate discrimination of patients presenting acute brain lesions (p=0.003). IS exhibited a continuous increase from baseline to 24h in circulating CCL23 (p〈0.001). Baseline CCL23 blood levels resulted an independent predictor of IS outcome at hospital discharge (ORadj:19.702[1.815-213.918],p=0.014) and mortality after 3 months (ORadj:21.47[3.434-134.221],p=0.001). In preclinics, expression of rodent chemokines in neurons following cerebral lesions was elevated. CCL9 circulating levels decreased early after ischemia (p〈0.001), whereas CCL6 did not alter within the first 24h after ischemia. Conclusions Despite pre-clinical models do not seem suitable to characterize CCL23, it might be a novel promising biomarker for the early diagnosis of cerebral lesions and might facilitate the prediction of stroke patient outcome. This article is protected by copyright. All rights reserved.
    Print ISSN: 0954-6820
    Electronic ISSN: 1365-2796
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 76
    Publication Date: 2018-02-08
    Description: Purpose The bias and variance of high angular resolution diffusion imaging methods have not been thoroughly explored in the literature and may benefit from the simulation extrapolation (SIMEX) and bootstrap techniques to estimate bias and variance of high angular resolution diffusion imaging metrics. Methods The SIMEX approach is well established in the statistics literature and uses simulation of increasingly noisy data to extrapolate back to a hypothetical case with no noise. The bias of calculated metrics can then be computed by subtracting the SIMEX estimate from the original pointwise measurement. The SIMEX technique has been studied in the context of diffusion imaging to accurately capture the bias in fractional anisotropy measurements in DTI. Herein, we extend the application of SIMEX and bootstrap approaches to characterize bias and variance in metrics obtained from a Q-ball imaging reconstruction of high angular resolution diffusion imaging data. Results The results demonstrate that SIMEX and bootstrap approaches provide consistent estimates of the bias and variance of generalized fractional anisotropy, respectively. The RMSE for the generalized fractional anisotropy estimates shows a 7% decrease in white matter and an 8% decrease in gray matter when compared with the observed generalized fractional anisotropy estimates. On average, the bootstrap technique results in SD estimates that are approximately 97% of the true variation in white matter, and 86% in gray matter. Conclusion Both SIMEX and bootstrap methods are flexible, estimate population characteristics based on single scans, and may be extended for bias and variance estimation on a variety of high angular resolution diffusion imaging metrics.
    Print ISSN: 0740-3194
    Electronic ISSN: 1522-2594
    Topics: Medicine
    Published by Wiley-Blackwell
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