Exploring the origins of echo-time-dependent quantitative susceptibility mapping (QSM) measurements in healthy tissue and cerebral microbleeds

Publication date: 1 April 2017
Source:NeuroImage, Volume 149
Author(s): Matthew J. Cronin, Nian Wang, Kyle S. Decker, Hongjiang Wei, Wen-Zhen Zhu, Chunlei Liu
Quantitative susceptibility mapping (QSM) is increasingly used to measure variation in tissue composition both in the brain and in other areas of the body in a range of disease pathologies. Although QSM measurements were originally believed to be independent of the echo time (TE) used in the gradient-recalled echo (GRE) acquisition from which they are derived; recent literature (Sood et al., 2016) has shown that these measurements can be highly TE-dependent in a number of brain regions.In this work we systematically investigate possible causes of this effect through analysis of apparent frequency and QSM measurements derived from data acquired at multiple TEs in vivo in healthy brain regions and in cerebral microbleeds (CMBs); QSM data acquired in a gadolinium-doped phantom; and in QSM data derived from idealized simulated phase data. Apparent frequency measurements in the optic radiations (OR) and central corpus callosum (CC) were compared to those predicted by a 3-pool white matter model, however the model failed to fully explain contrasting frequency profiles measured in the OR and CC.Our results show that TE-dependent QSM measurements can be caused by a failure of phase unwrapping algorithms in and around strong susceptibility sources such as CMBs; however, in healthy brain regions this behavior appears to result from intrinsic non-linear phase evolution in the MR signal. From these results we conclude that care must be taken when deriving frequency and QSM measurements in strong susceptibility sources due to the inherent limitations in phase unwrapping; and that while signal compartmentalization due to tissue microstructure and content is a plausible cause of TE-dependent frequency and QSM measurements in healthy brain regions, better sampling of the MR signal and more complex models of tissue are needed to fully exploit this relationship.



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Local and interregional alpha EEG dynamics dissociate between memory for search and memory for recognition

Publication date: 1 April 2017
Source:NeuroImage, Volume 149
Author(s): Joram van Driel, Eren Gunseli, Martijn Meeter, Christian N.L. Olivers
Attention during visual search is thought to be guided by an active visual working memory (VWM) representation of the search target. We tested the hypothesis that a VWM representation used for searching a target among competing information (a "search template") is distinct from VWM representations used for simple recognition tasks, without competition. We analyzed EEG from 20 human participants while they performed three different VWM-based visual detection tasks. All tasks started with identical lateralized VWM cues, but differed with respect to the presence and nature of competing distractors during the target display at test, where participants performed a simple recognition task without distractors, or visual search in pop-out (distinct) and serial (non-distinct) search displays. Performance was worst for non-distinct search, and best for simple recognition. During the one second delay period between cue and test, we observed robust suppression of EEG dynamics in the alpha (8–14Hz) band over parieto-occipital sites contralateral to the relevant VWM item, both in terms of local power as well as interregional phase synchrony within a posterior-parietal network. Importantly, these lateralization dynamics were more strongly expressed prior to search compared to simple recognition. Furthermore, before the VWM cue, alpha phase synchrony between prefrontal and mid-posterior-parietal sites was strongest for non-distinct search, reflecting enhanced anticipatory control prior to VWM encoding. Directional connectivity analyses confirmed this effect to be in an anterior-to-posterior direction. Together, these results provide evidence for frontally mediated top-down control of VWM in preparation of visual search.



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Semantic attributes are encoded in human electrocorticographic signals during visual object recognition

Publication date: 1 March 2017
Source:NeuroImage, Volume 148
Author(s): Kyle Rupp, Matthew Roos, Griffin Milsap, Carlos Caceres, Christopher Ratto, Mark Chevillet, Nathan E. Crone, Michael Wolmetz
Non-invasive neuroimaging studies have shown that semantic category and attribute information are encoded in neural population activity. Electrocorticography (ECoG) offers several advantages over non-invasive approaches, but the degree to which semantic attribute information is encoded in ECoG responses is not known. We recorded ECoG while patients named objects from 12 semantic categories and then trained high-dimensional encoding models to map semantic attributes to spectral-temporal features of the task-related neural responses. Using these semantic attribute encoding models, untrained objects were decoded with accuracies comparable to whole-brain functional Magnetic Resonance Imaging (fMRI), and we observed that high-gamma activity (70–110Hz) at basal occipitotemporal electrodes was associated with specific semantic dimensions (manmade-animate, canonically large-small, and places-tools). Individual patient results were in close agreement with reports from other imaging modalities on the time course and functional organization of semantic processing along the ventral visual pathway during object recognition. The semantic attribute encoding model approach is critical for decoding objects absent from a training set, as well as for studying complex semantic encodings without artificially restricting stimuli to a small number of semantic categories.



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EEG neural correlates of goal-directed movement intention

Publication date: 1 April 2017
Source:NeuroImage, Volume 149
Author(s): Joana Pereira, Patrick Ofner, Andreas Schwarz, Andreea Ioana Sburlea, Gernot R. Müller-Putz
Using low-frequency time-domain electroencephalographic (EEG) signals we show, for the same type of upper limb movement, that goal-directed movements have different neural correlates than movements without a particular goal. In a reach-and-touch task, we explored the differences in the movement-related cortical potentials (MRCPs) between goal-directed and non-goal-directed movements. We evaluated if the detection of movement intention was influenced by the goal-directedness of the movement. In a single-trial classification procedure we found that classification accuracies are enhanced if there is a goal-directed movement in mind. Furthermore, by using the classifier patterns and estimating the corresponding brain sources, we show the importance of motor areas and the additional involvement of the posterior parietal lobule in the discrimination between goal-directed movements and non-goal-directed movements. We discuss next the potential contribution of our results on goal-directed movements to a more reliable brain-computer interface (BCI) control that facilitates recovery in spinal-cord injured or stroke end-users.

Graphical abstract

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Increased sensitivity to age-related differences in brain functional connectivity during continuous multiple object tracking compared to resting-state

Publication date: 1 March 2017
Source:NeuroImage, Volume 148
Author(s): Erlend S. Dørum, Tobias Kaufmann, Dag Alnæs, Ole A. Andreassen, Geneviève Richard, Knut K. Kolskår, Jan Egil Nordvik, Lars T. Westlye
Age-related differences in cognitive agility vary greatly between individuals and cognitive functions. This heterogeneity is partly mirrored in individual differences in brain network connectivity as revealed using resting-state functional magnetic resonance imaging (fMRI), suggesting potential imaging biomarkers for age-related cognitive decline. However, although convenient in its simplicity, the resting state is essentially an unconstrained paradigm with minimal experimental control. Here, based on the conception that the magnitude and characteristics of age-related differences in brain connectivity is dependent on cognitive context and effort, we tested the hypothesis that experimentally increasing cognitive load boosts the sensitivity to age and changes the discriminative network configurations. To this end, we obtained fMRI data from younger (n=25, mean age 24.16±5.11) and older (n=22, mean age 65.09±7.53) healthy adults during rest and two load levels of continuous multiple object tracking (MOT). Brain network nodes and their time-series were estimated using independent component analysis (ICA) and dual regression, and the edges in the brain networks were defined as the regularized partial temporal correlations between each of the node pairs at the individual level. Using machine learning based on a cross-validated regularized linear discriminant analysis (rLDA) we attempted to classify groups and cognitive load from the full set of edge-wise functional connectivity indices.While group classification using resting-state data was highly above chance (approx. 70% accuracy), functional connectivity (FC) obtained during MOT strongly increased classification performance, with 82% accuracy for the young and 95% accuracy for the old group at the highest load level. Further, machine learning revealed stronger differentiation between rest and task in young compared to older individuals, supporting the notion of network dedifferentiation in cognitive aging. Task-modulation in edgewise FC was primarily observed between attention- and sensorimotor networks; with decreased negative correlations between attention- and default mode networks in older adults. These results demonstrate that the magnitude and configuration of age-related differences in brain functional connectivity are partly dependent on cognitive context and load, which emphasizes the importance of assessing brain connectivity differences across a range of cognitive contexts beyond the resting-state.



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Memorability: A stimulus-driven perceptual neural signature distinctive from memory

Publication date: 1 April 2017
Source:NeuroImage, Volume 149
Author(s): Wilma A. Bainbridge, Daniel D. Dilks, Aude Oliva
A long-standing question in neuroscience is how perceptual processes select stimuli for encoding and later retrieval by memory processes. Using a functional magnetic resonance imaging study with human participants, we report the discovery of a global, stimulus-driven processing stream that we call memorability. Memorability automatically tags the statistical distinctiveness of stimuli for later encoding, and shows separate neural signatures from both low-level perception (memorability shows no signal in early visual cortex) and classical subsequent memory based on individual memory. Memorability and individual subsequent memory show dissociable neural substrates: first, memorability effects consistently emerge in the medial temporal lobe (MTL), whereas individual subsequent memory effects emerge in the prefrontal cortex (PFC). Second, memorability effects remain consistent even in the absence of memory (i.e., for forgotten images). Third, the MTL shows higher correlations with memorability-based patterns, while the PFC shows higher correlations with individual memory voxels patterns. Taken together, these results support a reformulated framework of the interplay between perception and memory, with the MTL determining stimulus statistics and distinctiveness to support later memory encoding, and the PFC comparing stimuli to specific individual memories. As stimulus memorability is a confound present in many previous memory studies, these findings should stimulate a revisitation of the neural streams dedicated to perception and memory.



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In vivo detection of microstructural correlates of brain pathology in preclinical and early Alzheimer Disease with magnetic resonance imaging

Publication date: 1 March 2017
Source:NeuroImage, Volume 148
Author(s): Yue Zhao, Marcus E. Raichle, Jie Wen, Tammie L. Benzinger, Anne M. Fagan, Jason Hassenstab, Andrei G. Vlassenko, Jie Luo, Nigel J. Cairns, Jon J. Christensen, John C. Morris, Dmitriy A. Yablonskiy
BackgroundAlzheimer disease (AD) affects at least 5 million individuals in the USA alone stimulating an intense search for disease prevention and treatment therapies as well as for diagnostic techniques allowing early identification of AD during a long pre-symptomatic period that can be used for the initiation of prevention trials of disease-modifying therapies in asymptomatic individuals.MethodsOur approach to developing such techniques is based on the Gradient Echo Plural Contrast Imaging (GEPCI) technique that provides quantitative in vivo measurements of several brain-tissue-specific characteristics of the gradient echo MRI signal (GEPCI metrics) that depend on the integrity of brain tissue cellular structure.Preliminary data were obtained from 34 participants selected from the studies of aging and dementia at the Knight Alzheimer's Disease Research Center at Washington University in St. Louis. Cognitive status was operationalized with the Clinical Dementia Rating (CDR) scale. The participants, assessed as cognitively normal (CDR=0; n=23) or with mild AD dementia (CDR=0.5 or 1; n=11) underwent GEPCI MRI, a collection of cognitive performance tests and CSF amyloid (Aβ) biomarker Aβ42. A subset of 19 participants also underwent PET PiB studies to assess their brain Aβ burden. According to the Aβ status, cognitively normal participants were divided into normal (Aβ negative; n=13) and preclinical (Aβ positive; n=10) groups.ResultsGEPCI quantitative measurements demonstrated significant differences between all the groups: normal and preclinical, normal and mild AD, and preclinical and mild AD. GEPCI quantitative metrics characterizing tissue cellular integrity in the hippocampus demonstrated much stronger correlations with psychometric tests than the hippocampal atrophy. Importantly, GEPCI-determined changes in the hippocampal tissue cellular integrity were detected even in the hippocampal areas not affected by the atrophy.Our studies also uncovered strong correlations between GEPCI brain tissue metrics and beta-amyloid (Aβ) burden defined by positron emission tomography (PET) – the current in vivo gold standard for detection of cortical Aβ, thus supporting GEPCI as a potential surrogate marker for Aβ imaging – a known biomarker of early AD. Remarkably, the data show significant correlations not only in the areas of high Aβ accumulation (e.g. precuneus) but also in some areas of medial temporal lobe (e.g. parahippocampal cortex), where Aβ accumulation is relatively low.ConclusionWe have demonstrated that GEPCI provides a new approach for the in vivo evaluation of AD-related tissue pathology in the preclinical and early symptomatic stages of AD. Since MRI is a widely available technology, the GEPCI surrogate markers of AD pathology have a potential for improving the quality of AD diagnostic, and the evaluation of new disease-modifying therapies.



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Cardiomyopathy – an approach to the autoimmune background

Publication date: Available online 2 February 2017
Source:Autoimmunity Reviews
Author(s): Niels-Peter Becker, Johannes Müller, Gerd Wallukat, Ingolf Schimke
Autoimmunity is increasingly accepted as the origin or amplifier of various diseases. In contrast to classic autoantibodies (AABs), which induce immune responses resulting in the destruction of the affected tissue, an additional class of AABs is directed against G-protein-coupled receptors (GPCRs; GPCR-AABs). GPCR-AABs functionally affect their related GPCRs for activation of receptor mediated signal cascades. Diseases which are characterized by the presence of GPCR-AABs with evidence for disease-specific pathogenic activity could be named "functional autoantibody disease".We briefly summarize here the historical view on autoimmunity in cardiomyopathy, followed by an approach to the mechanistic autoimmunity background. Furthermore, autoantibodies with outstanding importance for cardiomyopathies as a functional autoantibody disease, such as GPCR-AABs, and mainly those directed against the beta1-adrenergic and muscarinic 2 receptor autoantibodies, were introduced. Anti-cardiac myosin and anti-cardiac troponin autoantibodies, as further potential players in autoimmune cardiomyopathy, were additionally taken into account. The basic view on the autoantibodies, their related receptor interactions and pathogenic consequences were presented.Focused specifically on GPCR-AABs, "pros and cons" of assays such as indirect assays (functional changes of cells preparations were monitored after GPCR-AAB receptor binding) and direct assays based on the ELISA technologies (GPCR epitope mimics for GPCR-AAB binding) were critically discussed.Last but not least, treatment strategies for "functional autoantibody disease", such as for GPCR-AAB removal (therapeutic plasma exchange, immunoadsorption) and in vivo GPCR-AAB attack such as intravenous IgG treatment (IVIG), B-cell depletion and GPCR-AAB binding and neutralization, are critically reflected with respect to their patient benefits.



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A quality by design (QbD) study on enoxaparin sodium loaded polymeric microspheres for colon-specific delivery

Publication date: 30 March 2017
Source:European Journal of Pharmaceutical Sciences, Volume 100
Author(s): Dana Hales, Laurian Vlase, Sebastian Alin Porav, Andreea Bodoki, Lucian Barbu-Tudoran, Marcela Achim, Ioan Tomuță
The aim of this study was to apply quality by design (QbD) for pharmaceutical development of enoxaparin sodium microspheres for colon-specific delivery. The Process Parameters (CPPs) and Critical Quality Attributes (CQAs) were identified. A central composite experimental design was used in order to develop the design space of microspheres for colon-specific delivery that have the desired Quality Target Product Profile (QTPP). The CPPs studied were Eudragit® FS-30D/Eudragit® RS-PO ratio, poly(vinyl alcohol) (PVA) concentration and sodium chloride (NaCl) concentration. The encapsulation efficiency increased with NaCl concentration increase, the percentages of enoxaparin sodium reaching 94% for some formulations. Increasing the ratio Eudragit® FS-30D/Eudragit® RS-PO ensured a relatively complete release of enoxaparin sodium in the environment simulating the colonic pH. Based on these results, the optimum conditions were decided and the optimum formulation was prepared. The results obtained for the latter in terms of in vitro enoxaparin sodium release were good, the microparticles releasing only 9.42% enoxaparin sodium in acidic environment and 15.16% in the medium which simulated duodenal pH, but allowing the release of up to 89.24% in the medium which simulated colonic pH. The in vitro release profile of enoxaparin sodium was close to the ideal one, therefore the system was successfully designed using QbD approach.

Graphical abstract

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Editorial Board

Publication date: 1 March 2017
Source:European Journal of Pharmaceutical Sciences, Volume 99





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Formulation and optimization of doxorubicin loaded polymeric nanoparticles using Box-Behnken design: ex-vivo stability and in-vitro activity

Publication date: 30 March 2017
Source:European Journal of Pharmaceutical Sciences, Volume 100
Author(s): Muhammad Vaseem Shaikh, Manika Kala, Manish Nivsarkar
Biodegradable nanoparticles (NPs) have gained tremendous interest for targeting chemotherapeutic drugs to the tumor environment. Inspite of several advances sufficient encapsulation along with the controlled release and desired size range have remained as considerable challenges. Hence, the present study examines the formulation optimization of doxorubicin loaded PLGA NPs (DOX-PLGA-NPs), prepared by single emulsion method for cancer targeting.Critical process parameters (CPP) were selected by initial screening. Later, Box-Behnken design (BBD) was used for analyzing the effect of the selected CPP on critical quality attributes (CQA) and to generate a design space. The optimized formulation was stabilized by lyophilization and was used for in-vitro drug release and in-vitro activity on A549 cell line. Moreover, colloidal stability of the NPs in the biological milieu was assessed.Amount of PLGA and PVA, oil:water ratio and sonication time were the selected independent factors for BBD. The statistical data showed that a quadratic model was fitted to the data obtained. Additionally, the lack of fit values for the models was not significant. The delivery system showed sustained release behavior over a period of 120h and was governed by Fickian diffusion. The multipoint analysis at 24, 48 and 72h showed gradual reduction in IC50 value of DOX-PLGA-NPs (p<0.05, Fig. 9). DOX-PLGA-NPs were found to be stable in the biological fluids indicating their in-vivo applicability.In conclusion, optimization of the DOX-PLGA-NPs by BBD yielded in a promising drug carrier for doxorubicin that could provide a novel treatment modality for cancer.

Graphical abstract

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Application of biopartitioning micellar chromatography and QSRR modeling for prediction of gastrointestinal absorption and design of novel β-hydroxy-β-arylalkanoic acids

Publication date: 30 March 2017
Source:European Journal of Pharmaceutical Sciences, Volume 100
Author(s): Vladimir Dobričić, Jelena Savić, Katarina Nikolic, Sote Vladimirov, Zorica Vujić, Jasmina Brborić
Gastrointestinal absorption of thirteen novel β-hydroxy-β-arylalkanoic acids (HAA) with anti-inflammatory activity was predicted by use of biopartitioning micellar chromatography and compared to ibuprofen. All tested HAA have lower retention factors (k) and lower expected gastrointestinal absorption than ibuprofen, whereas derivatives with the highest values of k are 1C, 2APTF and 2C. Quantitative structure-retention relationship (QSRR) analysis was performed in order to identify molecular descriptors with the highest influence on k and ANN(k) model was selected as optimal. Descriptors which form this model (nBM, P_VSA_LogP_8 and Eta_L) indicate that replacement of phenyl ring with a saturated or partially unsaturated one, as well as presence of halogens and nitro group should positively affect k values. On the basis of these conclusions, six novel HAA were designed and selected QSRR model was used for the prediction of their k values.

Graphical abstract

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Assessment of skin pigmentation by confocal microscopy: Influence of solar exposure and protection habits on cutaneous hyperchromias

Summary

Background

Cutaneous hyperchromias are disorders of skin pigmentation involving an increase of melanin production and its irregular accumulation in skin cells. It is known that the use of sunscreens helps to prevent changes in the skin pigmentation pattern, but the structural and morphological alterations that occur in the different types of hyperpigmentations need better elucidation.

Objective

To assess the influence of solar exposure and protection habits on the pattern of skin pigmentation using reflectance confocal microscopy (RCM).

Methods

Forty volunteers aged 18-39 years with skin hyperpigmentation participated in the study. Skin characterization was performed by imaging techniques and by assessing the habits of solar exposure and protection by applying questionnaires to the volunteers. RCM was used to record sequences of confocal sections at areas of interest and to examine cell shape and brightness in the basal cell layer of the lesion and in normal perilesional skin. Furthermore, high-resolution images were obtained for analysis of the spots.

Results

Sunlight influences the number and location of spots as the face of volunteers with higher solar exposure was covered with spots, whereas volunteers with less exposure had fewer spots located in the nose and cheeks region due to greater exposure of these areas to the sun.

Conclusion

The data showed the importance of sun protection for preventing changes in the pattern of skin pigmentation, and RCM proved to be an important tool for skin characterization.

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Hair loss at injection sites of mesotherapy for alopecia

Summary

Background

The side effects of mesotherapy for treatment of various forms of alopecia are often underreported, while scientific data for its efficacy are severely lacking.

Objective

To demonstrate the late onset side effects of mesotherapy for alopecia.

Methods

Three patients with androgenetic alopecia showed hair loss after previously uneventful mesotherapy sessions up to 1 year.

Results

Clinical, dermoscopic, and histopathological findings suggested an inflammatory scaring process at sites of mesotherapy injections.

Conclusion

Mesotherapy for androgenetic alopecia may paradoxically induce hair loss and scarring. Proper regulation and monitoring of the use of mesotherapy products for treating hair loss in women, needs to be addressed.

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Benzimidazole inhibitors from the Niclosamide chemotype inhibit Wnt/β-catenin signaling with selectivity over effects on ATP homeostasis

Publication date: Available online 3 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Robert A. Mook, Xiu-Rong Ren, Jiangbo Wang, Hailan Piao, Larry S. Barak, H. Kim Lyerly, Wei Chen
The Wnt signaling pathway plays a key role in organ and tissue homeostasis, and when dysregulated, can become a major underlying mechanism of disease, particularly cancer. We reported previously that the anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. To define Niclosamide's mechanism of Wnt/β-catenin inhibition, and to improve its selectivity and pharmacokinetic properties as an anticancer treatment, we designed a novel class of benzimidazole inhibitors of Wnt/β-catenin signaling based on SAR studies of the Niclosamide salicylanilide chemotype. Niclosamide has multiple biological activities. To address selectivity in our design, we interrogated a protonophore SAR model and used the principle of conformational restriction to identify novel Wnt/β-catenin inhibitors with less effect on ATP cellular homeostasis. These studies led to the identification of 4-chloro-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) phenol (4) and related derivatives with greater selectivity for Wnt/β-catenin signaling inhibition vs. differential effects on cellular ATP homeostasis. This is the first report that the Wnt signaling inhibitory activity of Niclosamide can be translated into a new chemical class and to show that its effects on ATP homeostasis can be separated from its inhibitory effects on Wnt signaling. These compounds could be useful tools to elucidate the mechanism of Niclosamide's inhibition of Wnt signaling, and aid the discovery of inhibitors with improved pharmacologic properties to treat cancer and diseases in which Niclosamide has important biological activity.

Graphical abstract

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Positive selection of type II collagen-reactive CD80high marginal zone B cells in DBA/1 mice

Publication date: Available online 2 February 2017
Source:Clinical Immunology
Author(s): Chanho Park, In Seong Kho, Jeong In Yang, Min-Jung Kim, Sunhoo Park, Hoon-Suk Cha, Jaejoon Lee, Tae Jin Kim
To investigate whether dysregulated selection of autoreactive marginal zone (MZ) B cells is involved in autoimmune diseases, we examined MZ B cell profile in multiple strains of mice, and found that type II collagen (CII)-reactive autoreactive CD80^high MZ B cells spontaneously developed in the DBA/1, but not in C57BL/6 mice. CD80^high MZ B cells that were characteristically found in DBA/1 mice expressed higher levels of TACI, SLAM3, and SLAM6 than the usual CD80^low MZ B cells. Notably, the CD80^high MZ B cells were more sensitive to ibrutinib, a Bruton's tyrosine kinase inhibitor, than CD80^low MZ or follicular B cells and their transient depletion via intravenous injection of ibrutinib significantly delayed the induction of collagen-induced arthritis (CIA). In summary, we suggest that the positive selection of CII-reactive CD80^high MZ B cells is a critical homeostatic process predisposing the DBA/1 mice to the CIA induction.



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Whorling cellular perineurioma: A previously undescribed variant closely mimicking monophasic fibrous synovial sarcoma

Publication date: Available online 2 February 2017
Source:Annals of Diagnostic Pathology
Author(s): Michael Michal, Dmitry V. Kazakov, Abbas Agaimy, Marta Hosova, Kvetoslava Michalova, Petr Grossmann, Petr Steiner, Faruk Skenderi, Semir Vranic, Michal Michal
The authors present a distinctive perineurioma (PN) variant which morphologically strongly resembles monophasic fibrous synovial sarcoma (MSS). The patients were 3 males and 1 female. The age ranged from 15 to 61years (mean: 44years). Locations included the sole, lower jaw, palm and foot. The tumor size ranged from 1.3cm to 2.5cm in the largest dimension (mean 1.8cm). Morphologically, all tumors had an identical, monotonous appearance. The perineurial cells were closely packed and created a confluent cellular whorls and/or sheets in a scarce stroma, with only focally discernible long, slender cytoplasmic processes typical for perineurial differentiation. The nuclei were rounded or slightly elongated to tapered, without nuclear atypia. Mitoses were rare to completely absent. Atypical mitoses, hemorrhage, necrosis or calcifications were not present. The proliferative index (Ki-67) was 1–3%. All analyzed tumors were positive for EMA, Claudin-1, GLUT-1 and negative with S100 protein, CD34, OSCAR, CK7 and TLE-1. Two cases were tested by fluorescence in situ hybridization and neither showed alterations of the SYT gene. One case studied by electron microscopy showed characteristic features of perineurial differentiation. Follow-up was available for two patients both of which showed no evidence of disease at 8years and 6months, respectively. Based on their bland morphology, perineurial features and presumably benign clinical outcome we propose the term "whorling cellular perineurioma" for these tumors, which may represent an extremely cellular variant of sclerosing PN. Awareness of this PN subtype and its distinction from MSS is of utmost clinical significance.



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Melt-pool motion, temperature variation and dendritic morphology of Inconel 718 during pulsed- and continuous-wave laser additive manufacturing: A comparative study

Publication date: 5 April 2017
Source:Materials & Design, Volume 119
Author(s): Simeng Li, Hui Xiao, Keyang Liu, Wenjia Xiao, Yanqin Li, Xu Han, Jyoti Mazumder, Lijun Song
Pulsed-wave laser additive manufacturing offers a number of advantages, such as a lower heat accumulation, a higher cooling rate, finer microstructures and improved mechanical properties over continuous-wave laser additive manufacturing. However, how pulsed laser acts on the melt pool motion, thermal field and hence microstructure is not clear. In this work, a three-dimensional transport model utilizing the level set method is developed to simulate the transient melt pool motion, heat/mass transfer and fluid flow for pulsed-wave laser additive manufacturing. A boundary restriction on the fluid velocity along the liquid/gas interface is employed to confine the liquid flow within the melt pool. The simulated melt pool geometry and temperature are compared with experimental measurements. Moreover, melt pool geometry/motion, temperature variation, and their influence on the microstructure of fabricated samples using both pulsed- and continuous-wave lasers are analyzed. It is found that pulsed-wave laser additive manufacturing features a rounder shaped melt pool, a periodically heartbeat-like motion of the melt pool and a doubled cooling rate. The higher tilt angle of the solidification front results in a dendrite growth direction more tilted to the laser scanning direction and the higher cooling rate results in finer columnar dendrites.

Graphical abstract

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Semi-solid processing of the CoCrCuFeNi high entropy alloy

Publication date: 5 April 2017
Source:Materials & Design, Volume 119
Author(s): Ł. Rogal
High entropy alloys (HEAs) are a particularly challenging material for semi-solid processing because of the high temperatures involved. In the CoCrCuFeNi HEA examined here, the globular microstructure required for the thixoforming process was obtained by the recrystallization and partial remelting method. Based on Kazakov's criteria, a detailed characterization of the solidus-liquidus temperature range, was conducted. Semi-solid metal processing of the CoCrCuFeNi HEA was carried out at 1150°C and 1340°C, which corresponded to 15% and 35% of the liquid phase, respectively. The microstructure of the thixo-cast consisted of two face-centered cubic solid solutions: one in the form of globular grains, containing near equiatomic concentrations of Co, Cr, Fe and Ni, and the other, enriched in Cu, homogeneously distributed around grains. Depending on the process temperature, significant changes were observed in the microstructure. Compression test results of the CoCrCuFeNi HEA thixo-cast showed that yield strength was around 395MPa, while the compression strength at 40% of strain reached 1810MPa at an average hardness of 201HV. The obtained values were about 30% higher than those of the ingot material after direct casting. The melting behavior, microstructure and mechanical properties, as well as the possibility of obtaining a net-shape component in a one-step operation, make the CoCrCuFeNi HEA a promising material for thixoforming.

Graphical abstract

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Single and double twin nucleation, growth, and interaction in an extruded magnesium alloy

Publication date: 5 April 2017
Source:Materials & Design, Volume 119
Author(s): F. Mokdad, D.L. Chen, D.Y. Li
The objective of this study was to identify twinning characteristics and mechanisms in an extruded AZ31 magnesium alloy under favorable conditions of profuse 101¯2 extension twinning using in-situ optical microscopy, electron backscatter diffraction, and X-ray diffraction analysis. The propagation of a single twin variant led to a relatively fast saturation of twin nucleation after which the increase in strain was predominantly accommodated by the growth of existing twin lamellas. For distinct twin variants, the intersecting twins led to the confinement of the spaces constrained by the fine twin lamellas. Embryonic twin structures acknowledged theoretically or through atomistic simulations were experimentally observed, including the vanishing of primary112¯1 embryonic twin via the nucleation and growth of either single or multiple 101¯2 secondary extension twin variants during deformation. Newly identified twin-twin interaction scenarios included the ladder-like and branching-like twinning structures which occurred depending on the applied strain, incoming twin paths, and their impingement on the pre-existing twin boundaries. The formation of the branching-like structures involved three or more non-co-zone 101¯2 extension twin variants where the activation and growth of one variant among them were found to be favored by the external stresses via Schmid factor analysis.

Graphical abstract

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Additive manufacturing of cardiovascular CoCr stents by selective laser melting

Publication date: 5 April 2017
Source:Materials & Design, Volume 119
Author(s): Ali Gökhan Demir, Barbara Previtali
In this work, the selective laser melting (SLM) of CoCr alloy powder for producing cardiovascular stents is investigated. The paper aims to assess the feasibility of producing a CoCr stent precursor through SLM as an alternative method to the conventional manufacturing cycle, which is based on microtube production and consecutive laser microcutting. Design rules for manufacturability are investigated, and a simple prototype design for additive manufacturing is proposed. The SLM process is investigated with an industrial system that utilises pulsed wave emission. Different scan strategies, namely hatching and concentric scanning, were used. Strut thickness and roughness, as well as chemical composition, were analysed. Representative conditions were further analysed by microhardness measurements and X-ray micro computed tomography. Electrochemical polishing was applied to assess the feasibility of surface finishing. The results show that SLM can be considered as a substitute operation to microtube manufacturing and laser microcutting for shaping precursors in stent manufacturing. Prototype stents with acceptable geometrical accuracy were achieved and surface quality could be improved through electrochemical polishing. The chemical composition remained unvaried, with a marginal increase in the oxide content.

Graphical abstract

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Hard-sphere displacive model of extension twinning in magnesium

Publication date: 5 April 2017
Source:Materials & Design, Volume 119
Author(s): Cyril Cayron
A crystallographic displacive model is proposed for the extension twins in magnesium. The atomic displacements are established, and the homogeneous lattice distortion is analytically expressed as a continuous angular-distortive matrix that becomes a shear when the distortion is complete. The calculations prove that a volume change of 3% occurs for the intermediate states. The twinning plane, even if untilted and restored when the distortion is complete, is not fully invariant during the transient states. The crystallographic calculations also show that the (90°, a) twins observed in nano-pillars and the (86°, a) twins observed in bulk samples differ only by a slight obliquity angle (±3.4°). Continuous features in the pole figures between the low-misoriented (86°, a) twin variants are expected; they are confirmed by EBSD maps acquired on a single crystal of magnesium. As the continuous mechanism of extension twinning is not a simple shear, a "virtual work" criterion using the value of the intermediate distortion matrix at the maximum volume change is proposed in place of the usual Schmid's law. It allows predicting the formation of extension twins for crystal orientations associated with negative Schmid factors.

Graphical abstract

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First-principles approach to design and evaluation of graphene as methane sensors

Publication date: 5 April 2017
Source:Materials & Design, Volume 119
Author(s): Daoguo Yang, Ning Yang, Jiaming Ni, Jing Xiao, Junke Jiang, Qiuhua Liang, Tianling Ren, Xianping Chen
In this work, graphene for use as methane (CH4) sensors has been designed and evaluated via first-principles theory. Firstly, the effect of the number of layers of graphene on methane adsorption is investigated. The results show that the methane adsorption will be increased with the number of layers, the maximum energy is 0.267eV. Furthermore, the adsorption of CH4 leads to a small opening of the band structure of graphene. As for the doping (Al-doped) in graphene, we mainly focus on the concentration of Al atoms. The Al atom was found to cause a huge increment in methane adsorption energy that can be up to 3.212eV when the concentration of Al atoms is 5.555%. Meanwhile, the doping of Al atoms also enhances the conductive properties of graphene. Lastly, the effect of defects was also investigated. While slightly smaller than that of pristine graphene, the methane adsorption energy of defected graphene is also increased with the number of layers. It was found that the model with the methane on the top of the empty atom and the H atoms on the top of the center of the carbon ring results in the best methane adsorption.

Graphical abstract

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A hybrid three-dimensionally structured electrode for lithium-ion batteries via 3D printing

Publication date: 5 April 2017
Source:Materials & Design, Volume 119
Author(s): Jie Li, Ming C. Leu, Rahul Panat, Jonghyun Park
New hybrid 3D structure electrodes with a high aspect ratio are fabricated through extrusion-based additive manufacturing to achieve high mass loading. This new 3D printed battery exhibits both high areal and specific capacity, thus overcoming the trade-off between the two of the conventional laminated batteries. This excellent battery performance is achieved by introducing a hybrid 3D structure that utilizes the benefits of the existing laminated structure and three-dimensional interdigitated structure. In addition, conventional battery paste components are used optimally to fit the 3D printing process, which eliminates the need for a complicated solvent preparation process required for a typical 3D printing process for battery applications. Using the CR2032 coin cell, the general assembly problem that occurs at the 3D structured electrodes is solved, which means that the proposed hybrid 3D structure can easily be added to the existing lamination structure. This innovative design and fabrication process demonstrates the high areal energy and power density, which is a critical requirement for energy storage systems in transportation and stationary applications.

Graphical abstract

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Sulfated glycosaminoglycans and non-classically secreted proteins, basic FGF and epimorphin, coordinately regulate TGF-β-induced cell behaviors of human scar dermal fibroblasts

Publication date: Available online 3 February 2017
Source:Journal of Dermatological Science
Author(s): Tomoatsu Horigome, Shinya Takumi, Kota Shirai, Takumi Kido, Natsumi Hagiwara-Chatani, Ayumi Nakashima, Naoki Adachi, Hiroko Yano, Yohei Hirai
BackgroundUpon skin injuries, dermal fibroblasts actively produce transforming growth factor-β (TGF-β), which leads to the formation of α-smooth muscle actin (αSMA) −positive granulation tissues. The hyperplasia or incomplete regression of these tissues subsequently causes scar formation in the skin, where sulfated glycosaminoglycans (GAGs), side chains of unique proteoglycans, are supposed to play important roles.ObjectiveThe aim of this study is to clarify the effects of sulfated GAGs on dermal cell behaviors triggered by the TGF-β signaling, along with its possible regulators basic fibroblast growth factor (bFGF) and cell surface epimorphin. bFGF and epimorphin might regulate the TGF-β-induced αSMA expression, they could exert such effects only in specific cellular contexts, given that they lack conventional signal sequences for extracellular localization.MethodsHuman scar-derived dermal fibroblasts (HSFs) were treated with TGF-β alone, TGF-β plus bFGF, and TGF-β plus cell surface expression of epimorphin. The effects of GAGs on the expression of αSMA and the cellular morphology were then investigated.ResultsA highly sulfated chondroitin sulfate (CS-E) or its substitute (heparinoid) had marked inhibitory effects on TGF-β-mediated changes in HSF behaviors. We found that heparinoid can directly associate with TGF-β, bFGF and epimorphin. We also found that bFGF downregulated αSMA, which was attenuated by heparinoid, whereas epimorphin augmented αSMA expression, which was further amplified by heparinoid.ConclusionsTGF-β, bFGF and epimorphin in the extracellular microenvironment cooperatively affect HSF behaviors under the control of a highly sulfated chondroitin sulfate. These results provide important evidence towards understanding the regulation of TGF-β-induced HSF behaviors.



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Supplementary Postoperative Parenteral Nutrition for Head and Neck Cancer Patients

Condition:   Head and Neck Neoplasm
Intervention:   Other: Parenteral Nutrition
Sponsor:   University of Copenhagen
Recruiting - verified February 2017

http://ift.tt/2k9Monf

Age-related changes in neural oscillations supporting context memory retrieval

Publication date: Available online 3 February 2017
Source:Cortex
Author(s): Jonathan Strunk, Taylor James, Jason Arndt, Audrey Duarte
Recent evidence suggests that directing attention toward single item-context associations during encoding improves young and older adults' context memory performance and reduces demands on executive functions during retrieval. In everyday situations, there are many event features competing for our attention, and our ability to successfully recover those details may depend on our ability to ignore others. Failures of selective attention may contribute to older adults' context memory impairments. In the current EEG study, we assessed the effects of age on processes supporting successful context memory retrieval of selectively attended features as indexed by neural oscillations. During encoding, young and older adults were directed to attend to a picture of an object and its relationship to one of two concurrently presented contextual details: a color or scene. At retrieval, we tested their memory for the object, its attended and unattended context features, and their confidence for both the attended and unattended features. Both groups showed greater memory for attended than unattended contextual features. However, older adults showed evidence of hyper-binding between attended and unattended context features while the young adults did not. EEG results in the theta band suggest that young and older adults recollect similar amounts of information but brain-behavior correlations suggest that this information was supportive of contextual memory performance, particularly for young adults. By contrast, sustained beta desynchronization, indicative of sensory reactivation and episodic reconstruction, was correlated with contextual memory performance for older adults only. We conclude that older adults' inhibition deficits during encoding reduced the selectivity of their contextual memories, which led to reliance on executive functions like episodic reconstruction to support successful memory retrieval.



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The use of metacognitive strategies to decrease false memories in source monitoring in patients with mild cognitive impairment

Publication date: Available online 3 February 2017
Source:Cortex
Author(s): Rebecca G. Deason, Neil A. Nadkarni, Michelle J. Tat, Sean Flannery, Bruno Frustace, Brandon A. Ally, Andrew E. Budson
Patients with amnestic mild cognitive impairment (MCI) and Alzheimer's disease (AD) often demonstrate high rates of false memories, leading to stressful and frustrating situations for both patients and caregivers in everyday life. Sometimes these false memories are due to failures in monitoring the source of the information. In the current study, we examined interventions aimed to enhance the use of the metacognitive "recall-to-reject" memory strategy. Such interventions could improve source memory and decrease false memory in patients with MCI. Because the picture superiority effect (better memory for pictures compared to words) has been shown to be present in both patients with MCI and healthy older controls, we investigated whether pictures could help patients with MCI use a recall-to-reject strategy in a simulation of real-world source memory task. In this experiment, patients with MCI and healthy older adults were asked to simulate preparing for and then taking a trip to the market. Subjects first studied 30 pictures of items in their "cupboard," followed by a list of 30 words of items on their "shopping list." At test, participants saw 90 pictures (30 cupboard, 30 list, 30 new) organized as they would be if walking down the market aisles, and are provided with either standard or metacognitive instructions. With standard instructions, they were asked if they needed to buy the item. With the metacognitive instructions, they were asked a series of questions to help guide them through a recall-to-reject strategy to highlight the different sources of memories. Results showed that the metacognitive instructions did significantly reduce the false memory rates for patients with MCI. Further studies need to investigate how to best implement these practical strategies into the everyday lives of patients.



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Functional interactions between the macaque dorsal and ventral visual pathways during three-dimensional object vision

Publication date: Available online 3 February 2017
Source:Cortex
Author(s): P. Janssen, B.-E. Verhoef, E. Premereur
The division of labor between the dorsal and the ventral visual stream in the primate brain has inspired numerous studies on the visual system in humans and in nonhuman primates. However, how and under which circumstances the two visual streams interact is still poorly understood. Here we review evidence from anatomy, modelling, electrophysiology, electrical microstimulation, reversible inactivation and functional imaging in the macaque monkey aimed at clarifying at which levels in the hierarchy of visual areas the two streams interact, and what type of information might be exchanged between the two streams during three-dimensional (3D) object viewing. Neurons in both streams encode 3D structure from binocular disparity, synchronized activity between parietal and inferotemporal areas is present during 3D structure categorization, and clusters of 3D structure-selective neurons in parietal cortex are anatomically connected to ventral stream areas. In addition, caudal intraparietal cortex exerts a causal influence on 3D-structure related activations in more anterior parietal cortex and in inferotemporal cortex. Thus, both anatomical and functional evidence indicates that the dorsal and the ventral visual stream interact during 3D object viewing.



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Cognitive fatigue: A time-based resource-sharing account

Publication date: Available online 3 February 2017
Source:Cortex
Author(s): Guillermo Borragán, Hichem Slama, Mario Bartolomei, Philippe Peigneux
Cognitive Fatigue (CF) is an important confound impacting cognitive performance. How CF is triggered and what are the features that make a cognitive effort perceived as exhausting remain unclear. In the theoretical framework of the Time-based Resource-sharing (TBRS) model (Barrouillet et al. 2004), we hypothesized that CF is an outcome of increased cognitive load due to constrained time to process ongoing cognitive demands. We tested this cognitive load-related CF hypothesis across 2 experiments manipulating both task complexity and cognitive load induced by the processing time interval. To do so, we used the TloadDback paradigm, a working memory dual task in which high and low cognitive load levels can be individually adjusted. In Experiment 1, participants were administered a high cognitive load (HCL, short processing time interval) and a low cognitive load (LCL, large processing time interval) conditions while complexity of the task was kept constant (1-back dual task). In Experiment 2, two tasks featuring different levels of complexity were both administered at the individual's maximal processing speed capacity for each task (i.e. short processing time interval). Results disclosed higher CF in the HCL than in the LCL condition in Experiment 1. On the contrary, in Experiment 2 similar levels of CF were obtained for different levels of task complexity when processing time interval was individually adjusted to induce a HCL condition. Altogether, our results indicate that processing time-related cognitive load eventually leads to the subjective feeling of CF, and to a decrease in alertness. In this framework, we propose that the development of CF can be envisioned as the result of sustained cognitive demands irrespective of task complexity.



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A Heart of Stone: Cardiac Fibroblasts Turn to Bone in Calcified Hearts

Publication date: 2 February 2017
Source:Cell Stem Cell, Volume 20, Issue 2
Author(s): Kathryn N. Ivey
The identity of the cells and molecular events driving deleterious calcification of heart muscle remains elusive. In this issue of Cell Stem Cell, Pillai et al. (2017) report that cardiac fibroblasts respond to injury by adopting an osteogenic cell fate and creating damaging calcific deposits, which can be prevented by inhibiting the activated mineralization process.

Teaser

The identity of the cells and molecular events driving deleterious calcification of heart muscle remains elusive. In this issue of Cell Stem Cell, Pillai et al. (2017) report that cardiac fibroblasts respond to injury by adopting an osteogenic cell fate and creating damaging calcific deposits, which can be prevented by inhibiting the activated mineralization process.


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MAP(K)ing the Path to Stem Cell Quiescence and the Elusive Enteroendocrine Cell

Publication date: 2 February 2017
Source:Cell Stem Cell, Volume 20, Issue 2
Author(s): Simon J. Leedham
The existence and interaction of proliferating and quiescent intestinal stem cells have been debated since their discovery in the 1970s. In this issue of Cell Stem Cell, using murine intestinal organoids, Basak et al. (2017) induce stem cell quiescence by selective inhibition of EGF/MAPK signaling and define culture conditions that direct differentiation to the enteroendocrine lineage.

Teaser

The existence and interaction of proliferating and quiescent intestinal stem cells have been debated since their discovery in the 1970s. In this issue of Cell Stem Cell, using murine intestinal organoids, Basak et al. (2017) induce stem cell quiescence by selective inhibition of EGF/MAPK signaling and define culture conditions that direct differentiation to the enteroendocrine lineage.


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Revealing the Hidden Powers that Fuel Adult Neurogenesis

Publication date: 2 February 2017
Source:Cell Stem Cell, Volume 20, Issue 2
Author(s): Weijun Feng, Hai-Kun Liu
A defining characteristic of diverse stem cell populations is their distinct metabolic state, although how these states change during adult hippocampal neurogenesis is unclear. Recently in Neuron, Beckervordersandforth et al. (2017) report that adult neurogenesis requires mitochondrial electron transport and oxidative phosphorylation and that disrupting these pathways induces premature aging phenotypes.

Teaser

A defining characteristic of diverse stem cell populations is their distinct metabolic state, although how these states change during adult hippocampal neurogenesis is unclear. Recently in Neuron, Beckervordersandforth et al. (2017) report that adult neurogenesis requires mitochondrial electron transport and oxidative phosphorylation and that disrupting these pathways induces premature aging phenotypes.


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Big-Data-Driven Stem Cell Science and Tissue Engineering: Vision and Unique Opportunities

Publication date: 2 February 2017
Source:Cell Stem Cell, Volume 20, Issue 2
Author(s): Antonio Del Sol, Hans J. Thiesen, Jaime Imitola, Rafael E. Carazo Salas
Achieving the promises of stem cell science to generate precise disease models and designer cell samples for personalized therapeutics will require harnessing pheno-genotypic cell-level data quantitatively and predictively in the lab and clinic. Those requirements could be met by developing a Big-Data-driven stem cell science strategy and community.

Teaser

Achieving the promises of stem cell science to generate precise disease models and designer cell samples for personalized therapeutics will require harnessing pheno-genotypic cell-level data quantitatively and predictively in the lab and clinic. Those requirements could be met by developing a Big-Data-driven stem cell science strategy and community.


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Rejuvenating Strategies for Stem Cell-Based Therapies in Aging

Publication date: 2 February 2017
Source:Cell Stem Cell, Volume 20, Issue 2
Author(s): Joana Neves, Pedro Sousa-Victor, Heinrich Jasper
Recent advances in our understanding of tissue regeneration and the development of efficient approaches to induce and differentiate pluripotent stem cells for cell replacement therapies promise exciting avenues for treating degenerative age-related diseases. However, clinical studies and insights from model organisms have identified major roadblocks that normal aging processes impose on tissue regeneration. These new insights suggest that specific targeting of environmental niche components, including growth factors, ECM, and immune cells, and intrinsic stem cell properties that are affected by aging will be critical for the development of new strategies to improve stem cell function and optimize tissue repair processes.

Teaser

Neves et al. discuss the ways that aging impairs normal tissue regeneration and propose regenerative medicine strategies for treating age-related diseases and enhancing tissue repair by targeting both environmental and stem cell-intrinsic aging mechanisms.


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Soil Primes the Seed: Epigenetic Landscape Drives Tumor Behavior

Publication date: 2 February 2017
Source:Cell Stem Cell, Volume 20, Issue 2
Author(s): Ramon J. Whitson, Anthony E. Oro
Whether invasive tumor phenotypes like EMT arise from oncogenic drivers or from priming of the pre-tumor cell of origin remains unknown. In this issue of Cell Stem Cell, Latil et al. (2017) show that the pre-tumor niche establishes a chromatin state predisposing squamous cell carcinomas to undergo EMT and metastasis, suggesting that the pre-tumor epigenome has prognostic value.

Teaser

Whether invasive tumor phenotypes like EMT arise from oncogenic drivers or from priming of the pre-tumor cell of origin remains unknown. In this issue of Cell Stem Cell, Latil et al. (2017) show that the pre-tumor niche establishes a chromatin state predisposing squamous cell carcinomas to undergo EMT and metastasis, suggesting that the pre-tumor epigenome has prognostic value.


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Anti-inflammatory effect of the Salvia sclarea L. ethanolic extract on lipopolysaccharide-induced periodontitis in rats

Publication date: 6 March 2017
Source:Journal of Ethnopharmacology, Volume 199
Author(s): Milica Kostić, Dušanka Kitić, Milica B. Petrović, Tatjana Jevtović-Stoimenov, Marko Jović, Aleksandar Petrović, Slavoljub Živanović
Ethnopharmacological relevanceSalvia sclarea L., clary, is an aromatic plant traditionally used in folk medicine for the treatment of various diseases and conditions. Although it has been primarily used as a stomachic, there are data on traditional use of S. sclarea as an agent against gingivitis, stomatitis and aphthae.Aim of the studyThe aim of the study was to examine the effect of the S. sclarea ethanolic extract on the lipopolysaccharide (LPS)-induced periodontitis in rats from the immunological and histopathological standpoint.Material and methodsPeriodontal inflammation in rats was induced by repeated injections of LPS from Escherichia coli into the interdental papilla between the first and second right maxillary molars. The extract was administered two times a day by oral gavage (200mg/kg body weight). The inflammatory status was assessed by the measurements of proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) of gingival tissues and descriptive analysis of histological sections of periodontium. Chemical characterization of the extract was determined using high performance liquid chromatography system (HPLC). Antioxidant activity of the extract was estimated with two in vitro complementary methods: 2,2-diphenyl-1-picrylhydrazyl and β-carotene/linoleic acid models.ResultsTreatment with S. sclarea extract, compared to the untreated group of the rats, significantly diminished the process of inflammation decreasing the levels of IL-1β, IL-6 and TNF-α, reducing the gingival tissue lesions and preserving bone alveolar resorption. Considerably smaller number of inflammatory cells and larger number of fibroblasts was noticed. The administration of the extract three days earlier did not have significant preventive effects. Rosmarinic acid was the predominant compound in the extract. The extract showed strong antioxidant effects in both test systems.ConclusionsS. sclarea extract manifested anti-inflammatory effect in LPS-induced periodontitis suggesting that it may have a role as a therapeutic agent in periodontal diseases. Having in mind that overproduction of reactive oxygen species is connected to periodontitis, the strong antioxidant capacity may be contributable to anti-inflammatory properties of the extract.

Graphical abstract

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A Type II Congenital Extrahepatic Portosystemic Shunt: A Rare Cause of Abdominal Pain Diagnosed by Point-of-Care Ultrasound

Publication date: Available online 3 February 2017
Source:The Journal of Emergency Medicine
Author(s): Sun Hwa Lee, Seong Jong Yun




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Single-Center Experience with a Targeted Next Generation Sequencing Assay for Assessment of Relevant Somatic Alterations in Solid Tumors

Publication date: March 2017
Source:Neoplasia, Volume 19, Issue 3
Author(s): Aino Paasinen-Sohns, Viktor H. Koelzer, Angela Frank, Julian Schafroth, Aline Gisler, Melanie Sachs, Anne Graber, Sacha I. Rothschild, Andreas Wicki, Gieri Cathomas, Kirsten D. Mertz
Companion diagnostics rely on genomic testing of molecular alterations to enable effective cancer treatment. Here we report the clinical application and validation of the Oncomine Focus Assay (OFA), an integrated, commercially available next-generation sequencing (NGS) assay for the rapid and simultaneous detection of single nucleotide variants, short insertions and deletions, copy number variations, and gene rearrangements in 52 cancer genes with therapeutic relevance. Two independent patient cohorts were investigated to define the workflow, turnaround times, feasibility, and reliability of OFA targeted sequencing in clinical application and using archival material. Cohort I consisted of 59 diagnostic clinical samples from the daily routine submitted for molecular testing over a 4-month time period. Cohort II consisted of 39 archival melanoma samples that were up to 15years old. Libraries were prepared from isolated nucleic acids and sequenced on the Ion Torrent PGM sequencer. Sequencing datasets were analyzed using the Ion Reporter software. Genomic alterations were identified and validated by orthogonal conventional assays including pyrosequencing and immunohistochemistry. Sequencing results of both cohorts, including archival formalin-fixed, paraffin-embedded material stored up to 15years, were consistent with published variant frequencies. A concordance of 100% between established assays and OFA targeted NGS was observed. The OFA workflow enabled a turnaround of 3½ days. Taken together, OFA was found to be a convenient tool for fast, reliable, broadly applicable and cost-effective targeted NGS of tumor samples in routine diagnostics. Thus, OFA has strong potential to become an important asset for precision oncology.



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Physical and Functional Interactions between ELL2 and RB in the Suppression of Prostate Cancer Cell Proliferation, Migration, and Invasion

Publication date: March 2017
Source:Neoplasia, Volume 19, Issue 3
Author(s): Xiaonan Qiu, Laura E. Pascal, Qiong Song, Yachen Zang, Junkui Ai, Katherine J. O'Malley, Joel B. Nelson, Zhou Wang
Elongation factor, RNA polymerase II, 2 (ELL2) is expressed and regulated by androgens in the prostate. ELL2 and ELL-associated factor 2 (EAF2) form a stable complex, and their orthologs in Caenorhabditis elegans appear to be functionally similar. In C. elegans, the EAF2 ortholog eaf-1 was reported to interact with the retinoblastoma (RB) pathway to control development and fertility in worms. Because RB loss is frequent in prostate cancer, ELL2 interaction with RB might be important for prostate homeostasis. The present study explored physical and functional interaction of ELL2 with RB in prostate cancer. ELL2 expression in human prostate cancer specimens was detected using quantitative polymerase chain reaction coupled with laser capture microdissection. Co-immunoprecipitation coupled with deletion mutagenesis was used to determine ELL2 association with RB. Functional interaction between ELL2 and RB was tested using siRNA knockdown, BrdU incorporation, Transwell, and/or invasion assays in LNCaP, C4-2, and 22Rv1 prostate cancer cells. ELL2 expression was downregulated in high–Gleason score prostate cancer specimens. ELL2 could be bound and stabilized by RB, and this interaction was mediated through the N-terminus of ELL2 and the C-terminus of RB. Concurrent siRNA knockdown of ELL2 and RB enhanced cell proliferation, migration, and invasion as compared to knockdown of ELL2 or RB alone in prostate cancer cells. ELL2 and RB can interact physically and functionally to suppress prostate cancer progression.



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Loss of Pin1 Suppresses Hedgehog-Driven Medulloblastoma Tumorigenesis

Publication date: March 2017
Source:Neoplasia, Volume 19, Issue 3
Author(s): Tao Xu, Honglai Zhang, Sung-Soo Park, Sriram Venneti, Rork Kuick, Kimberly Ha, Lowell Evan Michael, Mariarita Santi, Chiyoko Uchida, Takafumi Uchida, Ashok Srinivasan, James M. Olson, Andrzej A. Dlugosz, Sandra Camelo-Piragua, Jean-François Rual
Medulloblastoma is the most common malignant brain tumor in children. Therapeutic approaches to medulloblastoma (combination of surgery, radiotherapy, and chemotherapy) have led to significant improvements, but these are achieved at a high cost to quality of life. Alternative therapeutic approaches are needed. Genetic mutations leading to the activation of the Hedgehog pathway drive tumorigenesis in ~30% of medulloblastoma. In a yeast two-hybrid proteomic screen, we discovered a novel interaction between GLI1, a key transcription factor for the mediation of Hedgehog signals, and PIN1, a peptidylprolyl cis/trans isomerase that regulates the postphosphorylation fate of its targets. The GLI1/PIN1 interaction was validated by reciprocal pulldowns using epitope-tagged proteins in HEK293T cells as well as by co-immunoprecipiations of the endogenous proteins in a medulloblastoma cell line. Our results support a molecular model in which PIN1 promotes GLI1 protein abundance, thus contributing to the positive regulation of Hedgehog signals. Most importantly, in vivo functional analyses of Pin1 in the GFAP-tTA;TRE-SmoA1 mouse model of Hedgehog-driven medulloblastoma demonstrate that the loss of Pin1 impairs tumor development and dramatically increases survival. In summary, the discovery of the GLI1/PIN1 interaction uncovers PIN1 as a novel therapeutic target in Hedgehog-driven medulloblastoma tumorigenesis.



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Primary epithelioid sarcoma of the kidney and adrenal gland: report of 2 cases with immunohistochemical and molecular cytogenetic studies

Publication date: March 2017
Source:Human Pathology, Volume 61
Author(s): Mir B. Alikhan, Garrison Pease, William Watkin, Raymon Grogan, Thomas Krausz, Tatjana Antic
Epithelioid sarcoma (ES) is a malignant mesenchymal neoplasm with some morphologic or immunophenotypic evidence of epithelial differentiation. The "classic" subtype occurs in younger patients, often in distal extremities as compared with the "proximal" type. Tumors of the proximal type primarily arising in solid organs are rare with only few case reports in the literature. We report 2 cases of primary ES in the kidney of a 27-year-old woman and the adrenal gland of a 73-year-old man. Clinical examination and imaging, including computed tomography and positron-emission tomography, did not reveal tumor elsewhere in both cases. Histologic features were those of ES, proximal type with epithelioid/rhabdoid phenotype. Immunohistochemical study in both cases showed strong, diffuse expression of epithelial markers, CD34, and CD31. Nuclear expression of SMARCB1 protein was lost, but fluorescence in situ hybridization analysis was negative for SMARCB1 deletion. We believe that these are the first reports of primary kidney and adrenal gland ES.



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Ethnic differences in male reproductive hormones and relationships with adiposity and insulin resistance in older men

Abstract

Objectives

To assess ethnic differences in male reproductive hormone levels and to determine if any differences are explained by adiposity, insulin resistance (IR), or comorbidities in older men.

Design

Multi-ethnic cross-sectional observational study.

Participants

Community dwelling middle-aged and elderly men residing in the U.K. aged 40-84 years of South Asian (SA; n=180), White European (WE; n=328) or African Caribbean (AC; n=166) origin.

Observations

Measured testosterone (T), calculated free T (cFT), SHBG, and LH in SA, WE and AC men along with an assessment of body composition, IR, life-style factors and medical conditions.

Results

Age-adjusted mean T and cFT levels were lower in SA men when compared to WE and AC men (mean (SEM) T: SA: 14.0±0.4; WE: 17.1±0.3; AC: 17.2±0.5 nmol/L, p<0.001; cFT: SA: 283±7; WE: 313±5; AC: 314±8 pmol/L, p<0.006). Compared to WE and AC men, SA men had higher levels of body fat, IR, comorbidities and diabetes. After adjusting for body fat, IR and other confounders, T levels in SA men remained lower than in WE men (p=0.04) but ethnic differences in cFT became non-significant. LH levels were higher in SA than WE men in age-adjusted and fully-adjusted models.

Conclusions

T and cFT are lower in SA men than in WE and AC men. Whether ethnic-specific reference ranges for T and cFT might be appropriate in clinical practice requires further investigation. Ethnic differences in cFT, but not T, appear to be, more readily, explained by ethnic differences in adiposity, thus providing insights into potential pathophysiological mechanisms.

This article is protected by copyright. All rights reserved.

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Utility Of I 124 PET/CT In Identifying Radioiodine Avid Lesions In Differentiated Thyroid Cancer; A Systematic Review And Meta-Analysis

Abstract

Introduction

Diagnostic I-123 scans have been shown to underestimate the disease burden in differentiated thyroid cancer (DTC) when compared to I-131 post treatment scans, especially in children and patients who have had prior Radioiodine (RAI) therapy and/or distant metastasis.I-124 PET/CT has been shown to be highly effective in imaging DTC related metastatic disease.

Methods

We performed a systematic review and meta-analysis of studies investigating the sensitivity and specificity of I-124 PET/CT in identifying lesions amenable to RAI therapy as confirmed by I-131 post-treatment scanning.

Results

There were 141 patients and 415 lesions of DTC identified altogether. There was significant heterogeneity in the individual studies. The pooled sensitivity of the 124-I PET/CT in detecting lesions of differentiated thyroid cancer amenable to I-131 therapy was 94.2% (91.3-96.4% CI, p <0.01) and the pooled specificity was 49.0% (34.8 -63.4% CI,p<0.01). The pooled positive likelihood ratio (LR) was 1.43 (1.05-1.94 CI) and the pooled negative LR was 0.28 (0.15-0.53 CI). Overall, the diagnostic odds ratio was 7.90 (3.39–18.48 CI). There were a small but increased number of lesions identified by I-124 PET/CT that was not detected on post-treatment scan.

Conclusion

I-124 PET/CT is a sensitive tool to diagnose RAI avid DTC lesions, but also detects some new lesions that are not visualized on the post-treatment I-131 scan. Further carefully designed dosimetric studies may be required to fully establish the role of I-124 PET CT for identifying potential lesions for I131 therapy. I-124 PET/CT in DTC patients may have other applications in specific clinical situations .

This article is protected by copyright. All rights reserved.

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Metabolomics analysis of serum from subjects after occupational exposure to acrylamide using UPLC-MS

Publication date: Available online 3 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Sheng-Yuan Wang, Cui-Ping Yu, Yu-Lin Pan, Xiao-Rong Zhou, Rui Xin, Yue Wang, Wei-Wei Ma, Ran Gao, Chao Wang, Yong-Hui Wu
Since occupational exposure to acrylamide (ACR) may cause nerve damage, sensitive biomarkers to evaluate the early effects of ACR on human health are needed. In the present study, we have compared a group of individuals with occupational exposure to ACR (contact group, n = 65) with a group of individuals with no exposure (non-contact group, n = 60). Serum metabolomics analysis of the contact and non-contact groups was carried out using ultra performance liquid chromatograph/time of flight mass spectrometry, combined with multivariate analysis, to identify potential metabolites. Serum biochemical indexes of the contact and non-contact groups were also determined using an automatic biochemistry analyzer. There was a clear separation between the contact group and the non-contact group; receiver operator characteristic curve analysis suggested that phytosphingosine, 4E,15Z-bilirubin IXa and tryptophan were the best metabolites to use as biomarkers. Liver function was also found to be abnormal in the contact group. Important, ACR-related, metabolic changes were seen in the contact group and new biomarkers for assessing the toxicity of ACR on the central nervous system have been proposed. This study will provide a sound basis for exploring the toxic mechanisms and metabolic pathways of ACR.



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JAK-STAT signaling in the therapeutic landscape of myeloproliferative neoplasms

Publication date: Available online 3 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Jennifer M. O'Sullivan, Claire N. Harrison
Myeloproliferative neoplasms (MPN) are a group of disorders defined by clonal proliferation of mature myeloid cells with overlapping clinical features. The driver mutations of these disorders, namely JAK2 (Janus Kinase), MPL (Myeloproliferative Leukaemia Virus) and CALR (Calreticulin) upregulate JAK-STAT signaling with increase in downstream transcription and gene expression. Epigenetic mutations are prevalent in MPNs but their interplay with aberrant JAK-STAT signaling is not known. This understanding lead to development of first targeted treatment in MPN; ruxolitinib for primary myelofibrosis. This has shown clinical benefit in overall survival and symptoms improvement but has yet to show significant disease modifying effects. This review will focus on contemporaneous understanding of altered JAK-STAT signaling in MPN and targeted treatments in clinical practice.



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Identification of miRNAs as biomarkers for acquired endocrine resistance in breast cancer

Publication date: Available online 3 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Penn Muluhngwi, Carolyn M. Klinge
Therapies targeting estrogen receptor α (ERα) including tamoxifen, a selective estrogen receptor modulator (SERM) and aromatase inhibitors (AI), e.g., letrozole, have proven successful in reducing the death rate for breast cancer patients whose initial tumors express ERα. However, about 40% of patients develop acquired resistance to these endocrine treatments. There is a critical need to develop sensitive circulating biomarkers that accurately identify signaling pathways altered in breast cancer patients resistant to endocrine therapies. Serum miRNAs have the potential to serve as biomarkers of the progression of endocrine-resistant breast cancer due to their cancer-specific expression and stability. Exosomal transfer of miRNAs has been implicated in metastasis and endocrine-resistance. This review focuses on miRNAs in breast tumors and in serum, including exosomes, from breast cancer patients that are associated with resistance to tamoxifen since it is best-studied.



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Mitochondrial T3 receptor and targets

Publication date: Available online 3 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Chantal Wrutniak-Cabello, François Casas, Gérard Cabello
The demonstration that TRα1 mRNA encodes a nuclear thyroid hormone receptor and two proteins imported into mitochondria with molecular masses of 43 and 28 KDa has brought new clues to better understand the pleiotropic influence of iodinated hormones. If p28 activity remains unknown, p43 binds to T3 responsive elements occurring in the organelle genome, and, in the T3 presence, stimulates mitochondrial transcription and the subsequent synthesis of mitochondrial encoded proteins. This influence increases mitochondrial activity and through changes in the mitochondrial/nuclear crosstalk affects important nuclear target genes regulating cell proliferation and differentiation, oncogenesis, or apoptosis. In addition, this pathway influences muscle metabolic and contractile phenotype, as well as glycaemia regulation. Interestingly, according to the process considered, p43 exerts opposite or cooperative effects with the well-known T3 pathway, thus allowing a fine tuning of the physiological influence of this hormone.

Graphical abstract

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The peritumoural adipose tissue microenvironment and cancer. The roles of fatty acid binding protein 4 and fatty acid binding protein 5

Publication date: Available online 3 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): S. Guaita-Esteruelas, J. Gumà, L. Masana, J. Borràs
The adipose tissue microenvironment plays a key role in tumour initiation and progression because it provides fatty acids and adipokines to tumour cells. The fatty acid-binding protein (FABP) family is a group of small proteins that act as intracellular fatty acid transporters. Adipose-derived FABPs include FABP4 and FABP5. Both have an important role in lipid-related metabolic processes and overexpressed in many cancers, such as breast, prostate, colorectal and ovarian. Moreover, their expression in peritumoural adipose tissue is deregulated, and their circulating levels are upregulated in some tumours. In this review, we discuss the role of the peritumoural adipose tissue and the related adipokines FABP4 and FABP5 in cancer initiation and progression and the possible pathways implicated in these processes.



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17β-Estradiol protects against the effects of a high fat diet on cardiac glucose, lipid and nitric oxide metabolism in rats

Publication date: Available online 2 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Sonja Zafirovic, Milan Obradovic, Emina Sudar-Milovanovic, Aleksandra Jovanovic, Julijana Stanimirovic, Alan J. Stewart, Samantha J. Pitt, Esma R. Isenovic
The aim of this study was to investigate the in vivo effects of estradiol (E2) on myocardial metabolism and inducible nitric oxide synthase (iNOS) expression/activity in obese rats. Male Wistar rats were fed with a normal or a high fat (HF) diet (42% fat) for 10 weeks. Half of the HF fed rats were treated with a single dose of E2 while the other half were placebo-treated. 24 h after treatment animals were sacrificed. E2 reduced cardiac free fatty acid (FFA) (p < 0.05), L-arginine (p < 0.01), iNOS mRNA (p < 0.01), and protein (p < 0.05) levels and translocation of the FFA transporter (CD36) (p < 0.01) to the plasma membrane (PM) in HF fed rats. In contrast, Akt phosphorylation at Thr³⁰⁸ (p < 0.05) and translocation of the glucose transporter GLUT4 (p < 0.05) to the PM increased after E2 treatment in HF rats. Our results indicate that E2 acts via PI3K/Akt signaling pathway to partially protect myocardial metabolism by attenuating the detrimental effects of increased iNOS expression/activity in HF fed rats.

Graphical abstract

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Melasma Treatment: A Novel Approach Using A Topical Agent That Contains An Anti-Estrogen And A Vascular Endothelial Growth Factor Inhibitor

Publication date: Available online 3 February 2017
Source:Medical Hypotheses
Author(s): Philip R. Cohen
Melasma is an acquired disorder of pigmentation that presents with asymptomatic symmetric darkening of the face. The pathogenesis of this condition is multifactorial and influenced by several factors including female sex hormones, genetic predisposition and ultraviolet light exposure. The management of melasma is usually directed at more than one of the causative etiologic factors and often incorporates a combination of topical agents, with or without the addition of physical modalities. Estrogen and angiogenesis are significant factors in the etiology of melasma. A useful addition to the therapeutic armentarium for treating melasma would include a topical agent that could effect both of these causative factors. Specifically, a topical preparation consisting of an anti-estrogen and a vascular endothelial growth factor inhibitor would accomplish this goal. Suitable candidates that target estrogen receptors and vascular endothelial growth factor are currently used in medical oncology as systemic antineoplastic agents. The anti-estrogen could be either a selective estrogen receptor modulator (such as tamoxifen or raloxifene) or an aromatase inhibitor (such as anastrozole or letrozole or exemestane). The vascular endothelial growth factor inhibitor would be bevacizumab. In conclusion, a novel--topically administered--therapy for melasma would combine an anti-estrogen and a vascular endothelial growth factor inhibitor.



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Disrupted integration of sensory stimuli with information about the movement of the body as a mechanism explaining LSD-induced experience

Publication date: Available online 3 February 2017
Source:Medical Hypotheses
Author(s): Grzegorz R. Juszczak
LSD (lysergic acid diethylamide) is a model psychedelic drug used to study mechanism underlying the effects induced by hallucinogens. However, despite advanced knowledge about molecular mechanism responsible for the effects induced by LSD and other related substances acting at serotonergic 5-HT2a receptors, we still do not understand how these drugs trigger specific sensory experiences. LSD-induced experience is characterised by perception of movement in the environment and by presence of various bodily sensations such as floating in space, merging into surroundings and movement out of the physical body (the out-of-body experience). It means that a large part of the experience induced by the LSD can be simplified to the illusory movement that can be attributed to the self or to external objects. The phenomenology of the LSD-induced experience has been combined with the fact that serotonergic neurons provide all major parts of the brain with information about the level of tonic motor activity, occurrence of external stimuli and the execution of orienting responses. Therefore, it has been proposed that LSD-induced stimulation of 5-HT2a receptors disrupts the integration of the sensory stimuli with information about the movement of the body leading to perception of illusory movement.



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Potential Positive Feedback Loop of Pineal Cyst and Posttraumatic Stress Disorder

Publication date: Available online 2 February 2017
Source:Medical Hypotheses
Author(s): Rigoberto R.T. Ramirez, Mikaela I. Poling, Joseph F. deCourten, Robert L. Chamberlain




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Prognostic significance of lymph node metastasis in Esophageal squamous cell carcinoma

Publication date: Available online 3 February 2017
Source:Pathology - Research and Practice
Author(s): Hui Wang, Feiyan Deng, Qian Liu, Yuqing Ma
Prediction of lymph node metastasis in esophageal squamous cell carcinoma(ESCC) is very important to have prognostic significance. The objective of this study which involved a relatively large number of ESCC patients was to investigate the correlated factors for lymph node metastasis and prognosis in ESCC. We analyzed a retrospective review of 446 patients with ESCC treated by esophagectomy between January 2010 and July 2016. The relationship between lymph node metastasis and clinicopathological parameters were analyzed. The association between overall survival and clinicopathological factors were evaluated using univariate and multivariable Cox regression models. In the present study, 36.8% esophageal squamous cell carcinoma patients were histologically shown to have lymph node metastasis. Lymph node metastasis was closely correlated with tumor differentiation (p=0.016), perineural invasion (p=0.022), advanced stage tumor (p<0.001) and venous invasion (p<0.001). Kaplan-Meier survival analysis revealed that patients with tumor size, higher T stage, perineuronal invasion, lymph node metastasis, N stage and LNR higher than 0.2 had unfavorable prognosis (p<0.05). The univariate analysis revealed for overall survival that tumor size, pathological stage, perineuronal invasion, lymph metastasis, N stage, involved LNR were relevant prognostic indicators. Furthermore, tumor size, lymph metastasis, N stage and LNR could as independent prognostic factors.



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Dataset of longitudinal analysis of tear cytokine levels, CD4, CD8 counts and HIV viral load in dry eye patients with HIV infection

Publication date: Available online 3 February 2017
Source:Data in Brief
Author(s): Praveen Kumar Balne, Rupesh Agrawal, Veonice Bijin Au, Bernett Lee, Eileen Loo, Louis Tong, Arkasubhra Ghosh, Stephen C Teoh, John Connolly, Petrina Tan
The data presented in this article shows the longitudinal analysis of tear fluid cytokine profiles, blood CD4 and CD8 counts and HIV viral load in 34 dry eye patients with HIV infection during the HAART therapy. Clinical samples were collected from HIV patients with dry eye disease at the time of presentation to the clinic (visit 1), three months (visit 2) and 6 months (visit 3) after the presentation. At each time point tear samples were evaluated for 41 cytokines using Luminex bead based multiplex assay and blood samples were tested for HIV viral load and CD4 and CD8 counts.



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Multispectral 3D phase-encoded turbo spin-echo for imaging near metal: Limitations and possibilities demonstrated by simulations and phantom experiments

Publication date: June 2017
Source:Magnetic Resonance Imaging, Volume 39
Author(s): Jetse S. van Gorp, Razmara Nizak, Job G. Bouwman, Daniël B.F. Saris, Peter R. Seevinck
To see improvements in the imaging performance near biomaterial implants we assessed a multispectral fully phase-encoded turbo spin-echo (ms3D-PE-TSE) sequence for artifact reduction capabilities and scan time efficiency in simulation and phantom experiments.For this purpose, ms3D-PE-TSE and ms3D-TSE sequences were implemented to obtain multispectral images (±20kHz) of a cobalt-chromium (CoCr) knee implant embedded in agarose. In addition, a knee implant computer model and the acquired ms3D-PE-TSE images were used to investigate the possibilities for scan time acceleration using field-of-view (FOV) reduction for off-resonance frequency bins and compressed sensing reconstructions of undersampled data. Both acceleration methods were combined to acquire a +10kHz frequency bin in a second experiment.The obtained ms3D-PE-TSE images showed no susceptibility related artifacts, while ms3D-TSE images suffered from hyper-intensity artifacts. The limitations of ms3D-TSE were apparent in the far off-resonance regions (±[10–20]kHz) located close to the implant. The scan time calculations showed that ms3D-PE-TSE can be applied in a clinically relevant timeframe (~12min), when omitting the three central frequency bins. The feasibility of CS acceleration for ms3D-PE-TSE was demonstrated using retrospective reconstructions before combining CS and rFOV imaging to decrease the scan time for the +10kHz frequency bin from ~10.9min to ~3.5min, while also increasing the spatial resolution fourfold. The temporally resolved signal of ms3D-PE-TSE proved to be useful to decrease the intensity ripples after sum-of-squares reconstructions and increase the signal-to-noise ratio.The presented results suggest that the scan time limitations of ms3D-PE-TSE can be sufficiently addressed when focusing on signal acquisitions in the direct vicinity of metal implants. Because these regions cannot be measured with existing multispectral methods, the presented ms3D-PE-TSE method may enable the detection of inflammation or (pseudo-)tumors in locations close to the implant.



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GABA and GABA receptors alterations in the primary visual cortex of concave lens-induced myopic model

Publication date: Available online 2 February 2017
Source:Brain Research Bulletin
Author(s): Wen Zhao, Ai-Ling Bi, Chao-Li Xu, Xiang Ye, Mei-Qing Chen, Xin-Ting Wang, Xiao-Yan Zhang, Jun-Guo Guo, Wen-Jun Jiang, Jin Zhang, Hong-Sheng Bi
Until recently most researches on myopia mechanisms have mainly been focused on the eye ball and few investigations were explored on the upper visual pathway, such as the visual cortex. The roles of gamma-aminobutyric acid (GABA) in the retinal and in the upper visual pathway are inter-correlated. As the retinal glutamate decarboxylase (GAD), GABA, and the mRNA levels of GABA receptors increased during the concave lens induced myopia formation, however, whether GABA alterations also occurred in the visual cortex during the concave lens induction is still unknown. In the present study, using HPLC, Enzyme-Linked Immunosorbent Assay (ELISA) and Real-Time Quantitative-PCR (RT-PCR) methods, we observed the changing trends of GABA, glutamate decarboxylase (GAD), and GABA receptors in the visual cortex of concave lens-induced myopic guinea pigs. Similar to the changing patterns of retinal GABA, the concentrations of GAD, GABA and the mRNA levels of GABA receptors in the visual cortex also increased. These results indicate that the exploration on myopia mechanisms should possibly be investigated on the whole visual pathway and the detailed significance of cortical GABA alterations needs further investigation.



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Study on the daytime OH radical and implication for its relationship with fine particles over megacity of Shanghai, China

Publication date: April 2017
Source:Atmospheric Environment, Volume 154
Author(s): Jialiang Nan, Shanshan Wang, Yanlin Guo, Yajing Xiang, Bin Zhou
To investigate on the daytime OH and its implication to fine particle, the long-path differential optical absorption spectroscopy (LP-DOAS) system was employed to observe the main OH precursors of O3, HCHO and HONO, as well as NO2 and NO3 radical from April to August 2013 over Shanghai, China. The main OH production paths from HONO, HCHO and O3 were estimated to be occupied around 57.6%, 30.5% and 11.9% during daytime. The daytime OH radical concentration under steady-state was averaged at 1.02 × 10⁷ molec cm⁻³, which was significantly impacted by the photolytic processes. The relationship between photolysis frequency j(O¹D) and OH radical suggests that heavy fine particle loads can make the photolytic reactions less efficiently and decrease the OH production and concentration. Utilizing CO as the indicator, the part of PM2.5 mass related to primary emitted sources was found less impacted by the OH levels. The contribution of secondary organic aerosol with metrics of O3 was enhanced with the increases of the OH levels, while secondary inorganic part of PM2.5 was favor of the condition that smaller OH concentrations that 5 × 10⁵–5 × 10⁶ molec cm⁻³. Meantime, a simplified multivariate model was employed to evaluate the influences of OH levels on different parts of fine particles related to different emission and sources. Normalized by solar radiation, this part of OH unrelated to radiation was found to be inversely related to the PM2.5, which indicates the self-cleansing capability of the atmosphere.



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Characteristics of elementary school children's daily exposure to black carbon (BC) in Korea

Publication date: April 2017
Source:Atmospheric Environment, Volume 154
Author(s): Hyeran Jeong, Donguk Park
A daily black carbon (BC) exposure assessment of forty 10-12 years-old children was conducted in the Seoul Metropolitan Area from August 2015 to January 2016. Each participant carried a micro-aethalometer to measure BC concentrations for 24 h while their whereabouts and microenvironments (MEs) were recorded via a time-activity diary (TAD) and follow-up interviews. Analysis of variance (ANOVA) was employed to compare average BC levels by potential risk factors including demographic, temporal, residential, and indoor/outdoor/transportation activity variables. The children's average daily exposure was 1.93 μg/m³, with a range of 0.2–85.43 μg/m³ (mean daily individual exposure ranges from 0.54 to 4.80 μg/m³). Even children attending the same elementary school reported BC exposures which differed by approximately 40%, primarily because of individually distinct time-activity patterns and the MEs with which each child interacted. On weekends (Saturdays and Sundays) (1.86 ± 2.50 μg/m³) and holidays (Saturdays, Sundays, and vacation) (1.71 ± 2.48 μg/m³), children were subject to reduced exposures to BC, likely due to decreased surrounding traffic volumes and different time-activity patterns on weekend days compared to on weekdays (from Mondays to Fridays) (1.95 ± 2.44 μg/m³) or school days (weekdays during the school semesters) (2.05 ± 2.43 μg/m³). Commuting in diesel vehicles (often to private academies) or in the subway, cooking, and environmental tobacco smoke were all found to elevate BC exposure. Likewise, proximity to traffic sources and parental indoor smoking contributed to the enhancement of residential BC concentrations. Our findings suggested a need to emplace proactive measures including diesel fleet regulation and smoking cessation campaigns to protect children from high levels of BC exposure.

Graphical abstract

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Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate

Publication date: Available online 2 February 2017
Source:Cell Metabolism
Author(s): Yi Fan, Jun-ichi Hanai, Phuong T. Le, Ruiye Bi, David Maridas, Victoria DeMambro, Carolina A. Figueroa, Serkan Kir, Xuedong Zhou, Michael Mannstadt, Roland Baron, Roderick T. Bronson, Mark C. Horowitz, Joy Y. Wu, John P. Bilezikian, David W. Dempster, Clifford J. Rosen, Beate Lanske
Intermittent PTH administration builds bone mass and prevents fractures, but its mechanism of action is unclear. We genetically deleted the PTH/PTHrP receptor (PTH1R) in mesenchymal stem cells using Prx1Cre and found low bone formation, increased bone resorption, and high bone marrow adipose tissue (BMAT). Bone marrow adipocytes traced to Prx1 and expressed classic adipogenic markers and high receptor activator of nuclear factor kappa B ligand (Rankl) expression. RANKL levels were also elevated in bone marrow supernatant and serum, but undetectable in other adipose depots. By cell sorting, Pref1⁺RANKL⁺ marrow progenitors were twice as great in mutant versus control marrow. Intermittent PTH administration to control mice reduced BMAT significantly. A similar finding was noted in male osteoporotic patients. Thus, marrow adipocytes exhibit osteogenic and adipogenic characteristics, are uniquely responsive to PTH, and secrete RANKL. These studies reveal an important mechanism for PTH's therapeutic action through its ability to direct mesenchymal cell fate.

Graphical abstract

Teaser

Fan et al. show that PTH regulates mesenchymal stem cell fate between bone and adipocyte in the marrow. Bone marrow adipocytes have distinct origins and properties from other adipocytes and are responsive to PTH, underlying the reduction in marrow adiposity in mouse models and idiopathic osteoporosis patients treated with PTH.


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Biophysical Characterization of Functionalized Titania Nanoparticles and Their Application in Dental Adhesives

Publication date: Available online 2 February 2017
Source:Acta Biomaterialia
Author(s): Jirun Sun, Elijah J. Petersen, Stephanie S. Watson, Christopher M. Sims, Alexander Kassman, Stanislav Frukhtbeyn, Drago Skrtic, Meryem T. Ok, Debbie L. Jacobs, Vytas Reipa, Qiang Ye, Bryant C. Nelson
It is demonstrated that carboxylic acid-functionalized titanium dioxide (TiO2) NPs produce significantly higher levels of reactive oxygen species (ROS) after visible light irradiation (400 nm to 800 nm, 1600 mW/cm²) in comparison to nonfunctionalized TiO2 NPs. The level of ROS produced under these irradiation conditions was not capable of generating oxidatively induced DNA damage in a cell-free system for TiO2 concentrations of 0.5 mg/L or 5 mg/L. In addition, specific incorporation of the acrylic acid-functionalized TiO2 NPs into dental composites allowed us to utilize the generated ROS to enhance photopolymerization (curing and degree of vinyl conversion (DC)) of resin adhesives and create mechanically superior and biocompatible materials for dental applications. Incorporation of the TiO2 NPs into selected dental composites increased the mean DC values by ≈ 7%. The modified TiO2 materials and dental composite materials were extensively characterized using thermogravimetric analysis, electron microscopy, Fourier transform infrared spectroscopy, and electron paramagnetic resonance. Notably, dental adhesives incorporated with acrylic acid-functionalized TiO2 NPs produced stronger bonds to human teeth following visible light curing in comparison to traditional dental adhesives not containing NPs with an increase in the shear bond strength of ≈ 29%. In addition, no leaching of the incorporated NPs was detectable from the dental adhesives after 2500 thermal cycles using inductively coupled plasma-optical emission spectroscopy, indicating that biocompatibility of the adhesives was not compromised after extensive aging. These findings suggest that NP-induced ROS may be useful to produce enhanced nanocomposite materials for selected applications in the medical device field.Statement of SignificanceTitanium dioxide nanoparticles (TiO2 NPs) have unique photocatalytic, antibacterial and UV-absorbing properties that make them beneficial additives in adhesives and composites. However, there is concern that the reactive oxygen species (ROS) produced by photoactivated TiO2 NPs might pose toxicological risks. We demonstrate that it is possible to incorporate acid-functionalized TiO2 NPs into dental resins which can be applied as dental adhesives to human teeth. The ROS generated by these NPs through visible-light irradiation may be utilized to increase the degree of vinyl conversion of resins, leading to adhesives that have an enhanced shear-bond strength to human teeth. Investigation into the potential genotoxicity of the NPs and their potential for release from dental composites indicated a low risk of genotoxic effects.

Graphical abstract

http://ift.tt/2l3FX2u

Extraordinary High Strength Ti-Zr-Ta Alloys Through Nanoscaled, Dual-Cubic Spinodal Reinforcement

Publication date: Available online 2 February 2017
Source:Acta Biomaterialia
Author(s): Arne Biesiekierski, Dehai Ping, Yuncang Li, Jixing Lin, Khurram S. Munir, Yoko Yamabe-Mitarai, Cuie Wen
While titanium alloys represent the current state-of-the-art for orthopedic biomaterials, concerns still remain over their modulus. Circumventing this via increased porosity requires high elastic admissible strains, yet also limits traditional thermomechanical strengthening techniques. To this end, a novel β-type Ti-Zr-Ta alloy system, comprised of Ti-45Zr-10Ta, Ti-40Zr-14Ta, Ti-35Zr-18Ta and Ti-30Zr-22Ta, was designed and characterized mechanically and microstructurally. As-cast, this system displayed extremely high yield strengths and elastic admissible strains, up to 1.4 GPa and potentially 1.48%, respectively. This strength was attributed to a nanoscaled, cuboidal structure of semi-coherent, dual body-centered cubic (BCC) phases, arising from the thermodynamics of interaction between Ta and Zr; this morphology occurring with dual BCC-phases is heretofore unreported in Ti-based alloys. Further, cell proliferation investigated by MTS assay suggests this was achieved without sacrificing biocompatibility, with no significant difference to either empty-well or commercially-pure Ti controls noted.Statement of SignificanceThe current research details microstructural, mechanical, and biological investigations into four novel biomedical alloys in a hitherto uninvestigated region of the Ti-Zr-Ta alloy system; Ti-45Zr-10Ta, Ti-40Zr-14Ta, Ti-35Zr-18Ta and Ti-30Zr-22Ta. We find that the investigated alloys display 0.2% yield strengths of up to 1.40 GPa and elastic admissible strains of up to 1.48%, along with biological properties comparable to that seen in the conventional metallic biomaterial ASTM Grade-2 CP-Ti, achieved in the complete absence of traditional thermomechanical processing techniques. This is attributed to the presence of a dual-BCC cuboidal nanostructure, achieved via spinodal decomposition; while similar structures have been reported in e.g. Ni-based superalloys, we believe this is the first such structure investigated in a Ti-based material. As such, this work is felt to be of great interest in aiding the design and manufacture of highly-biocompatible, porous, metallic biomaterials for orthopaedic application.

Graphical abstract

http://ift.tt/2l27K48